FREE RADICAL BIOLOGY AND MEDICINE
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2025
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IF 8.2
Ru Li,Yimei Ma,Anqi He,Yamin Pu,Xuanting Wan,Hongbao Sun,Ningyu Wang,Min Luo,Guan Wang,Yong Xia
The multi-kinase inhibitor sorafenib has shown potential to inhibit tumor cell growth and intra-tumoral angiogenesis by targeting several kinases, including VEGFR2 and RAF. Abnormal activation of the Ras/Raf/MAPK/ERK kinase cascade and the VEGF pathway is a common feature in breast cancer. However, the efficacy of sorafenib in breast cancer treatment remains limited. Recently, fasting has emerged as a promising non-pharmacological approach to modulate cancer metabolism and enhance the effectiveness of cancer therapies. In this study, we found that fasting significantly enhances the anti-cancer effects of sorafenib monotherapy and its combination with immunotherapy in breast cancer models without causing obvious side effects. This combined treatment effectively inhibits tumor cell proliferation and intra-tumoral angiogenesis. The fasting-induced reduction in peripheral blood glucose levels strongly correlated with enhanced sensitivity to sorafenib. Mechanistically, the combined treatment induced mitophagy, characterized by mitochondrial dysfunction and activation of the PINK1-Parkin pathway. Consequently, increased mitochondrial ROS levels promoted p53 expression, amplifying cell cycle arrest and apoptosis in breast cancer cells. Furthermore, fasting reduced lactate levels within the tumor, and the consequent glucose limitation synergized with sorafenib to activate AMPK, which in turn elevated PD-L1 expression in tumor cells, potentially enhancing their sensitivity to immunotherapy. In summary, our findings demonstrate that fasting and sorafenib, as a rational combination therapy, induce mitophagy, thereby enhancing sorafenib's efficacy in treating breast cancer through the ROS-driven p53 pathway. This study underscores the potential of fasting in breast cancer therapy and provides a foundation for optimizing the clinical application of sorafenib.
研究领域:
肿瘤学
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分子生物学
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代谢研究
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DOI
PubMed
高影响因子
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
·
2025
·Vol. 66
·期 3
·44-44
·
IF 4.7
Boda Li,Junpeng Liu,Di Zhang,Yiran Chu,Zeying Chen,Jiaruei Tsao,Taige Chen,Jiaxuan Jiang,Kai Hu
Purpose:This study aims to explore the therapeutic efficacy of evodiamine (EVO) in the treatment of dry eye disease (DED).Methods:Mouse models of DED was developed using benzalkonium chloride eye drops and subcutaneous atropine injections. Corneal epithelial defects were assessed by fluorescein sodium staining, and tear secretion was measured with the phenol red thread test. For the in vitro model, human corneal epithelial cells were cultured in a sodium chloride–enriched medium. Phenotypic and mechanistic analyses were conducted using real-time quantitative PCR, Western blotting, flow cytometry, and immunofluorescence staining.Results:The administration of EVO eye drops significantly enhanced tear secretion in mice, ameliorated ocular surface damage, decreased the expression of corneal inflammatory factors, and increased the density of conjunctival goblet cells. Furthermore, EVO reduced oxidative stress by promoting autophagy. Mechanistically, EVO-induced autophagy was mediated via the p53/mammalian target of rapamycin pathway.Conclusions:These findings suggest that EVO is a potential therapeutic agent for the treatment of DED, with its beneficial effects attributed to the activation of autophagy through the p53/mammalian target of rapamycin pathway.
研究领域:
眼科
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药理学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
LIFE SCIENCES
·
2019
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IF 3.448
Jian Liu,Zhenjing Zhu,Yueyao Liu,Linlin Wei,Bai Li,Fengxia Mao,Ju Zhang,Yingchao Wang,Yufeng Liu
Aims Berberine (BBR) is reported to induce apoptosis and inhibit migration of leukemic cells, but the underlying pharmacological mechanisms have not been fully revealed. This study aims to investigate the possible mechanisms from the perspective of autophagy. Main methods P-53-null leukemic cell lines Jurkat and U937 were used for the in vitro study. MDC staining was used for observation of autophagy in leukemic cells, and Western blot analysis was for determination of the expression levels of autophagy-associated proteins. Apoptosis of the leukemic cells was detected by flow cytometry. Cellular location of MDM2 was observed with immunofluorescence staining. Ubiquitination of MDM2 was assessed by immunoprecipitation. Male 6–8-week-old NOD/SCID mice were used for evaluating the effect of BBR on chemotherapy sensitivity in vivo . Key findings BBR induced autophagy in p53-null leukemic cells, which was inhibited by autophagy inhibitors 3-methyladenine. 3-methyladenine also inhibited BBR-induced apoptosis in leukemic cells. In addition, BBR not only decreased MDM2 mRNA expression, but also enhanced MDM2 self-ubiquitination in leukemic cells. Forced overexpression of MDM2 reversed the effect of BBR on autophagy and apoptosis. Furthermore, BBR promoted doxorubicin-induced autophagy and cell death in the leukemic cells and overexpression of MDM2 suppressed these effects. In vivo , BBR combined with doxorubicin achieved better therapeutic effect than doxorubicin alone. Significance MDM2 inhibits autophagy and apoptosis in leukemic cells in a p53-independent manner. BBR induces autophagy in p53-null leukemic cells through downregulating MDM2 expression at both transcriptional and post-transcriptional levels, which may contribute to the anti-cancer effect of BBR in leukemia.
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
Cell Death & Disease
·
2024
·Vol. 15
·期 1
·1-15
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IF 8.1
Li Jingzhi,Guo Ming,Chen Lin,Chen Zhuchu,Fu Ying,Chen Yongheng
Nasopharyngeal carcinoma (NPC) is a malignant tumor that is highly prevalent in Southeast Asia, especially in South China. The pathogenesis of NPC is complex, and genetic alterations of tumor suppressors and proto-oncogenes play important roles in NPC carcinogenesis. p53 is unexpectedly highly expressed in NPC and possesses an uncommon mutation of R280T, which is different from a high frequency of hotspot mutations or low expression in other tumors. However, the mechanism of p53 loss of function and its correlation with R280T in NPC are still unclear. In this study, p53 amyloid aggregates were found to be widespread in NPC and can be mainly induced by the R280T mutation. Aggregated p53-R280T impeded its entry into the nucleus and was unable to initiate the transcription of downstream target genes, resulting in decreased NPC cell cycle arrest and apoptosis. In addition, NPC cells with p53-R280T amyloid aggregates also contributed aggressively to tumor growth in vivo. Transcriptome analysis suggested that p53 amyloid aggregation dysregulated major signaling pathways associated with the cell cycle, proliferation, apoptosis, and unfolded protein response (UPR). Further studies revealed that Hsp90, as a key molecular chaperone in p53 folding, was upregulated in NPC cells with p53-R280T aggregation, and the upregulated Hsp90 facilitated p53 aggregation in turn, forming positive feedback. Therefore, Hsp90 inhibitors could dissociate p53-R280T aggregation and restore the suppressor function of p53 in vitro and in vivo. In conclusion, our study demonstrated that p53-R280T may misfold to form aggregates with the help of Hsp90, resulting in the inability of sequestered p53 to initiate the transcription of downstream target genes. These results revealed a new mechanism for the loss of p53 function in NPC and provided novel mechanistic insight into NPC pathogenesis.
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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遗传学
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PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
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2017
·Vol. 174
·期 23
·4345-4361
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IF 5.491
Pan Chen,Dongshun Li,Yixin Chen,Jiahong Sun,Kaili Fu,Lihuan Guan,Huizhen Zhang,Yiming Jiang,Xi Li,Xuezhen Zeng,Xiao Chen,Min Huang,Huichang Bi
Background and Purpose The tumour suppressor p53 is traditionally recognized as a surveillance molecule to preserve genome integrity. Recent studies have demonstrated that it contributes to metabolic diseases. Here, we investigated the role of p53 in the regulation of bile acid disposition and cholestasis. Experimental Approach The bile acid disposition-related gene expression profile affected by p53 activation was assessed in mouse primary hepatocytes with p53 depletion and in Trp53 -null mice. Dual luciferase reporter assay was used to detect the transcriptional activities of target genes. Anticholestatic effects of p53 activator doxorubicin were investigated in a 0.5% cholic acid-fed mouse model of cholestasis. Changes in bile acids were evaluated using metabolomics analysis. Key Results Doxorubicin-mediated p53 activation induced Cyp2b10 , Sult2a1 and Abcc2/3/4 expression in mice in vitro and in vivo . ABCC3 and CYP2B6 (human orthologue of Cyp2b10 ) were identified as direct p53 target genes. Doxorubicin attenuated cholic acid-induced cholestasis in mice, as demonstrated by shrunken gall bladder, decreased serum total bile acid and total bilirubin levels and alkaline phosphatase activity. Targeted metabolomics analysis revealed that doxorubicin enhanced the excretion of bile acid metabolites from serum and liver to intestine and faeces. Up-regulation of Cyp2b10 , Sult2a1 and Abcc2/3/4 expression was further confirmed in cholestatic mice. Cholic acid-induced cholestatic injury was aggravated in p53-deficient mice and levels of bile acid in intestine and faeces were decreased. Conclusions and Implications Our findings suggest a novel role of p53 in promoting bile acid disposition and alleviating cholestatic syndrome, which provides a potential therapeutic target for cholestasis.
研究领域:
分子生物学
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肝病学
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药理学
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DOI
PubMed
高影响因子
EXPERIMENTAL CELL RESEARCH
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2023
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IF 3.7
Hanqing Zhu,Hongliang Zhang,Jiahui Guo,Chao Zhang,Quanwu Zhang,Fenghou Gao
Mdm2 promotes the ubiquitination and degradation of p53, while Mdm2-p60 can bind to p53 and reduce the Mdm2-induced p53 ubiquitination to improve its stability. USP2a can deubiquitinate and stabilize Mdm2, whether USP2a can regulate Mdm2-p60 needs to be further confirmed and elucidated. We found that oxidative stress can up-regulate USP2a at the post-transcriptional level and induce USP2a to be oxidized by forming inter-subunit disulfide bonds . The oxidized USP2a is closely related with cell apoptosis. In apoptotic cells, oxidized USP2a has enhanced protein stability and further stabilizes Mdm2-p60 through deubiquitination , and the USP2a-Mdm2-p60-p53 axis plays a role in cell apoptosis. Altogether USP2a is oxygen sensitive, oxidized USP2a exerts apoptotic effects through the Mdm2-p60-p53 axis, which provides an experimental basis for regulating p53 apoptotic signaling by targeting USP2a.
研究领域:
细胞生物学
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分子生物学
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癌症研究
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DOI
PubMed
高影响因子
MOLECULAR BIOTECHNOLOGY
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2024
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IF 2.4
Chen Ya,Zhu Congcong,Tai Zongguang,Lian Tianyan,Zhu Quangang,Chen Zhongjian
Apoptosis is a natural physiological process of programmed cell death. It is essential for maintaining the homeostasis of the body and the immune system. The dysfunction of apoptosis can lead to the development of autoimmune diseases. In psoriasis, the dysfunction of keratinocyte proliferation manifests as an impairment of apoptosis. Cordycepin is the major active component in cordyceps militaris and has pharmacological effects, including regulation of apoptosis. The pharmacological mechanism of Cordycepin in psoriasis remains unclear. In this study, bioinformatics analysis revealed that the mechanism may be associated with the p53 apoptotic pathway. Further, we confirmed in the experiments that cordycepin inhibited the interleukin (IL)-17A-induced proliferation of HaCaT cells and down-regulated the expression of proliferating cell nuclear antigen (PCNA) and Ki-67. Regulating the expression of apoptotic proteins BAX, Bcl-2, and p53 promote apoptosis. Further investigation of the upstream pathway of apoptosis revealed that cordycepin could normalize the abnormal p53-mouse double minute 2 (MDM2) feedback loop. In vivo results showed that the cordycepin gel could effectively improve imiquimod (IMQ)-induced psoriasis-like skin lesions in mice, and the p53-MDM2 pathway was verified at the protein level. In conclusion, the anti-psoriasis effect of Cordycepin and its potential mechanism have not been discussed in detail. However, our work supports the idea that Cordycepin can be further developed as an Active Pharmaceutical Ingredient (API) for the treatment of psoriasis.
研究领域:
药理学
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皮肤科
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分子生物学
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免疫学
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DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
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2025
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IF 3.5
Min Li,Shuaijun Peng,Jingjing Bu,Siqi Quan,Liming Liu,Zhouli Yue,Linlin Wang,Yucheng Li
Gefitinib, a first-line tyrosine kinase inhibitor (TKI) target to non-small cell lung cancer (NSCLC) treatment, is known to cause hepatotoxicity, which seriously limiting its therapeutic application. This study investigated the underlying mechanisms of gefitinib-induced liver injury and the protective effects of glycyrrhizic acid (GL) in mice and AML12 cells. Sixty mice were randomly divided into six groups: control, gefitinib, glutathione (200 mg/kg), and three doses of GL (50, 100, and 200 mg/kg). Liver injury was induced in mice through daily oral administration of gefitinib (400 mg/kg) for 16 days, with hepatotoxicity was assessed through serum alanine transaminase (ALT) and aspartate transaminase (AST) levels, and hepatic histopathology. Hepatic mRNA profiles were analyzed using RNA sequencing, with differentially expressed genes (DEGs) confirmed by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot. Finally, the effect of GL on the anticancer efficacy of gefitinib was assessed in A549 and Lewis lung carcinoma (LLC) lung cancer cells, as well as in a urethane-induced lung cancer mouse model. GL treatment significantly reduced liver index and serum ALT and AST levels, while also improving hepatic histopathology. Transcriptomic analysis identified 114 DEGs linked to the p53 pathway and cell cycle regulation. Further study indicated that GL inhibited the expression of p53 and p21, thereby upregulated Cyclin D1 expression, thereby alleviating gefitinib-induced cell cycle arrest without impairing its anticancer activity in vivo and in vitro . These findings highlight the potential of GL as a safe adjunct therapy, effectively mitigating gefitinib-induced hepatotoxicity while preserving its anticancer efficacy.
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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PubMed
高影响因子
SENSORS AND ACTUATORS B-CHEMICAL
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2021
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IF 7.46
Jiaying Zhao,Danqun Huo,Xintong Geng,Jing Bao,Jingzhou Hou,Zhengfan Shui,Huisi Yang,Yanli Qi,Yian Hu,Mei Yang,Changjun Hou
p53 gene is one of the most important anticancer genes and has been recognized as a typical biomarker for the early diagnosis, classification, and prognosis evaluation of cancers. In this work, a novel biosensing strategy integrating MoS 2 -AuNPs modified carbon paper (CP) conductive substrate and enzyme signal amplification technique was developed for p53 gene detection. We constructed an immobilized DNA S1 probe and a biotinylated DNA S3 probe, which could induce the formation of an S1-p53-S3 DNA sandwich complex in the presence of target sequence p53. After conjugating avidin-HRP via biotin-avidin reaction, 3,3’,5,5’-tetramethylbenzidine would be catalyzed for signal amplification in the presence of H 2 O 2 so that the induced electrochemical response would change with proportional to the abundance of p53 gene. The proposed biosensor exhibited two linearities in the range of 1.0 × 10 −15 ∼ 1.0 × 10 -12 M and 1.0 × 10 -12 ∼ 1.0 × 10 -6 M, and the limit of detection (LOD) was 68 fM. No significant interferences were observed during detecting real serum samples. Moreover, it is worth pointing out that the biosensor together with its disposable, low-cost, and stable features can discriminate well between the mutated and wild type p53 gene extracted from tumor cells (wtTP53 in MCF-7 and mutated in SK-BR-3), demonstrating a promising applicability for clinical test.
研究领域:
生物传感器
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癌症诊断
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纳米技术
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电化学
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分子生物学
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DOI
高影响因子
NEW JOURNAL OF CHEMISTRY
·
2018
·Vol. 42
·期 16
·13375-13381
·
IF 3.201
Haobo Han,Wenqi Chen,Jiebing Yang,Jiayuan Zhang,Quanshun Li,Yan Yang
The modification of 2-amino-6-chloropurine on polyamidoamine was performed to synthesize a derivative, AP-PAMAM, which was then employed as a carrier for p53 gene delivery to achieve anti-tumor efficacy. Using a human prostate tumor cell line PC-3 as a model, enhanced expression level of p53 gene could be detected by RT-PCR, qPCR and western blotting. Based on the successful p53 gene transfection, an obvious anti-proliferative effect could be obtained, which was identified to be associated with the simultaneous induction of cell apoptosis and cell cycle arrest at the G1 phase. The cell apoptosis was elucidated to be triggered by the activation of the mitochondria-dependent apoptotic signaling pathway. In addition, AP-PAMAM/p53 transfection could restrain the migration of tumor cells as demonstrated by wound healing and Transwell migration assays. Notably, AP-PAMAM-mediated p53 delivery exhibited a stronger inhibitory effect on both cell proliferation and migration than the PAMAM/p53 group. In summary, AP-PAMAM/p53 transfection provided a promising route to achieve the p53-based gene therapy.
研究领域:
分子生物学
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肿瘤学
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药剂学
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DOI
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2024
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IF 7.1
Dongjing Cai,Xia Xu,Weiqian Zeng,Zheng Wang,Cheng Chen,Yunan Mo,Piyanat Meekrathok,Dandan Wang,Pengwei Peng,Zhigang Peng,Jian Qiu
Cellular senescence is a natural barrier of the transition from premalignant cells to invasive cancer. Pharmacological induction of senescence has been proposed as a possible anticancer strategy. In this study, we found that deoxyarbutin inhibited the growth of glioblastoma (GBM) cells by inducing cellular senescence, independent of tyrosinase expression. Instead, deoxyarbutin induced mitochondrial oxidative stress and damage. These aberrant mitochondria were key to the p53-dependent senescence of GBM cells. Facilitating autophagy or mitigating mitochondrial oxidative stress both suppressed p53 expression and alleviated cellular senescence induced by deoxyarbutin. Thus, our study reveals that deoxyarbutin induces mitochondrial oxidative stress to trigger the p53-dependent senescence of GBM cells. Importantly, deoxyarbutin treatment resulted in accumulation of p53, induction of cellular senescence, and inhibition of tumor growth in a subcutaneous tumor model of mouse. In conclusion, our study reveals that deoxyarbutin has therapeutic potential for GBM by inducing mitochondrial oxidative stress for p53-dependent senescence of GBM cells.
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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产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
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2025
·
IF 9.6
Xiaoyu Cui,Bin Chen,Ying Chen,Mi Zhou,Lijun Cao,Bing Hu,Jianrong Wu,Xinxin Ma,Tao Ying
Emerging evidence indicates that modulating glutathione peroxidase 4 (GPX4) to induce ferroptosis is a promising strategy for tumor treatment. However, most of the GPX4 small molecule inhibitors face limitations due to their poor delivery efficacy and low specificity of ferroptosis activation. Herein, a ferroptosis-inducing nanomedicine is developed that integrates nutlin-3 with iridium oxide nanoclusters (NUT-IrO x NCs) for enhanced ferroptosis-driven multimodal therapeutic efficacy in colorectal cancer (CRC). This NUT-IrO x NCs can induce glutathione (GSH) depletion via enhanced Ir (VI)-Ir (III) transition, while nutlin-3, a well-established inhibitor of the p53-MDM2 interaction, suppresses GSH production by modulation of the p53/SLC7A11/xCT signaling pathway. The reduction of intracellular GSH results in pronounced reductions of GPX4 enzymatic activity, consequently leading to lipid peroxidation accumulation and further enhancing ferroptosis-induced CRC therapy. This dual-pronged approach demonstrates robust anticancer therapeutic effects with favorable biocompatibility in both in vitro and in vivo CRC models. This study provides an effective strategy that highlights the benefits of inhibiting of GSH/GPX4 by activating multiple ferroptosis regulatory pathways, providing an alternative therapeutic avenue for CRC treatment.
研究领域:
肿瘤学
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纳米技术
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分子生物学
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癌症治疗
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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）