ANALYTICAL CHEMISTRY
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2023
·
IF 7.4
Jiajia Li,Shuang Yue,Ziyuan Gao,Wenhua Hu,Zhaoliang Liu,Guoqiang Xu,Zhen Wu,Xumin Zhang,Guolin Zhang,Fuliang Qian,Junhong Jiang,Shuang Yang
Ribonuclease (RNA) modifications can alter cellular function and lead to differential immune responses by acting as discriminators between RNAs from different phyla. RNA glycosylation has recently been observed at the cell surface, and its dysregulation in disease may change RNA functions. However, determining which RNA substrates can be glycosylated remains to be explored. Here, we develop a solid-phase chemoenzymatic method (SPCgRNA) for targeting glycosylated RNAs, by which glycosylated RNA substrates can be specifically recognized. We found the differential N-glycosylation of small RNAs in hTERT-HPNE and MIA PaCa-2 cancer cells using SPCgRNA. RNA-Seq showed that the changes in glyco-miRNAs prepared from SPCgRNA were consistent with those of traditional methods. The KEGG signaling pathway analysis revealed that differential miRNA glycosylation can affect tumor cell proliferation and survival. Further studies found that NGI-1 significantly inhibited the proliferation, migration, and circulation of MIA PaCa-2 and promoted cell apoptosis. In addition, β-1,4-galactosyltransferase 1 (B4GALT1) not only affected the expression level of glycosylated miRNAs hsa-miR-21-5p but also promoted cell apoptosis and inhibited the cell cycle possibly through the p53 signaling pathway, while B4GALT1 and p53 were also affected following the hsa-miR-21-5p increase. These results suggest that B4GALT1 may catalyze miRNAs glycosylation, which further promotes cancer cell progression.
研究领域:
分子生物学
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生物化学
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肿瘤学
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PubMed
高影响因子
EXPERIMENTAL NEUROLOGY
·
2021
·
IF 5.33
Mengmeng Wang,Ying Bai,Haitao Chi,Ping Lin,Yu Wu,Jiahui Cui,Yi Wang,Jing Sun,Ming-Fei Lang
Ischemic stroke still remains a therapeutic challenge due to its complex pathogenesis and implications. By screening biomarkers in the peripheral blood of ischemic stroke patients , miR-451 was identified as a differentially expressed miRNA along the disease course of ischemic stroke. To investigate the role of miR-451, middle cerebral artery occlusion (MCAO) was performed as an ischemic stroke model in mice. Intracerebroventricular administration of miR-451 mimic in the MCAO mice significantly decreased infarct size, while miR-451 inhibitor significantly increased infarct size. To understand the molecular mechanism of the protective effect of miR-451, Phd3 (also Egln3) was validated as a new miR-451 target. Either fewer or more Phd3-positive cells were observed in brain sections from mice receiving miR-451 mimic or inhibitor, respectively. In addition, the levels of p53 (a known Phd3 target) were significantly downregulated when the levels of Phd3 were reduced, suggesting its participation in reducing apoptosis after the miR-451 administration. Indeed, reduced apoptosis upon miR-451 mimic administration was detected by TUNEL staining . In conclusion, this study demonstrated a new protective role of miR-451 in cerebral ischemia and identified Phd3 as a novel miR-451 target, linking the mechanism to the involvement of p53 in the regulation of apoptosis during the pathogenesis of ischemic stroke.
研究领域:
神经科学
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分子生物学
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医学遗传学
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高影响因子
Bioactive Materials
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2021
·
IF 14.593
Rui Zan,Hao Wang,Weijie Cai,Jiahua Ni,Bérengère J.C. Luthringer-Feyerabend,Wenhui Wang,Hongzhou Peng,Weiping Ji,Jun Yan,Jiazeng Xia,Yang Song,Xiaonong Zhang
Hydrogen has been used to suppress tumor growth with considerable efficacy. Inhalation of hydrogen gas and oral ingestion of hydrogen-rich saline are two common systemic routes of hydrogen administration. We have developed a topical delivery method of hydrogen at targeted sites through the degradation of magnesium-based biomaterials. However, the underlying mechanism of hydrogen's role in cancer treatment remains ambiguous. Here, we investigate the mechanism of tumor cell apoptosis triggered by the hydrogen released from magnesium-based biomaterials. We find that the localized release of hydrogen increases the expression level of P53 tumor suppressor proteins, as demonstrated by the in vitro RNA sequencing and protein expression analysis. Then, the P53 proteins disrupt the membrane potential of mitochondria, activate autophagy, suppress the reactive oxygen species in cancer cells, and finally result in tumor suppression. The anti-tumor efficacy of magnesium-based biomaterials is further validated in vivo by inserting magnesium wire into the subcutaneous tumor in a mouse. We also discovered that the minimal hydrogen concentration from magnesium wires to trigger substantial tumor apoptosis is 91.2 μL/mm 3 per day, which is much lower than that required for hydrogen inhalation. Taken together, these findings reveal the release of H 2 from magnesium-based biomaterial exerts its anti-tumoral activity by activating the P53-mediated lysosome-mitochondria apoptosis signaling pathway, which strengthens the therapeutic potential of this biomaterial as localized anti-tumor treatment.
研究领域:
肿瘤学
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生物材料科学
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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
Scientific Reports
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2017
·Vol. 7
·期 1
·1-13
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IF 4.259
Chang Hong,Li Chun,Wang Qiyan,Lu Linghui,Zhang Qian,Zhang Yi,Zhang Na,Wang Yong,Wang Wei
The ancient traditional Chinese medicine Qishenkeli (QSKL) is widely used in the treatment of heart failure (HF) in China. Previous studies have shown that QSKL has definite effects on HF. The purpose of this study is to identify the regulation of QSKL on apoptosis and clarify the underlying mechanism. An apoptosis model of H9C2 cells was induced by oxygen-glucose deprivation/recovery (OGD/R). An animal model of HF was induced by ligation of left anterior descending (LAD) coronary artery in rat. We found that QSKL reduced intracellular ROS generation, increased mitochondrial membrane potential and protected H9C2 cells against OGD/R-induced apoptosis. In vivo results showed that QSKL administration could improve cardiac functions, decrease fibrotic area, infarct size and apoptotic rate in HF model. QSKL regulated the expressions of key apoptotic molecules, including increasing Bcl-2/Bax ratio, reducing the expressions of P53, Bax and Cleaved-caspase-3. Interestingly, QSKL also regulated the phosphorylated expressions of PI3K and Akt without significantly affecting PTEN. Taken together, the protective and anti-apoptotic effects of QSKL could be mediated partly through modulating the PI3K/Akt-P53 apoptotic pathway.
研究领域:
心脏病学
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药理学
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分子生物学
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传统中药
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DOI
PubMed
高影响因子
Biomaterials Research
·
2026
·
IF 9.6
Bo Liu,Yaqin Tu,Xiangrui Li,Wenting Yu,Wenqing Zou,Wei Tang,Shimin Zong,Songwei Tan,Hongjun Xiao
Cisplatin (CDDP) is a widely used chemotherapeutic agent, but its clinical applications are constrained by ototoxic side effects. Currently, few effective strategies exist to prevent or mitigate CDDP-induced ototoxicity. Rutin is known for its cell-protective effects by reducing oxidative stress and inhibiting apoptosis. However, its limited water solubility and inefficient delivery to the inner ear pose substantial challenges. To address this, rutin is encapsulated in liposomes (Lip-Rutin) for nanoscale drug delivery, leveraging its antioxidant properties. Lip-Rutin markedly attenuates CDDP-induced oxidative stress damage and apoptosis, demonstrating a protective effect on OC-1 cells. The efficacy of Lip-Rutin in safeguarding against CDDP-induced ototoxicity is further validated through in vivo studies. Consequently, Lip-Rutin emerges as a promising novel therapeutic agent for combating CDDP-induced ototoxicity.
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Cell Communication and Signaling
·
2026
·Vol. 24
·期 1
·191
·
IF 11.6
Zhao Zhao,Wei Xue-Feng,Zhao Liang,Xia Jun-Yao,Li Yu-Ya,Jia Yi-Jun,Zhu Bin
Background As the earliest vertebrates with innate and adaptive immunity, teleosts offer insights into the mammalian immune system. The intestine is the largest mucosal surface in the vertebrates and is a key immunological barrier contact with the external environment such as food, pathogens, and vaccine antigens. However, intestinal early immune responses post-vaccination remains unclear. This study aimed to explore intestinal vaccine uptake and early immune response mechanisms triggered by immunization. Methods In this study, we utilized zebrafish as a model for immersion immunization. We employed zebrafish as a model for immersion immunization. We immunized zebrafish by soaking them in a vaccine for 6 h, then transferred them to normal water for continued cultivation. We observed the uptake and absorption of the vaccine by the intestines after immunization through in vivo imaging and immunofluorescence. Additionally, transcriptomic analysis was conducted to identify the key signaling pathways and gene expression changes associated with the intestinal immune response. Results With the increase in immunization time, a significantly enhanced fluorescent signal can be observed in the intestine. The expression level of IgZ in the intestine was nearly 4 times that of the control group at 3 days post-vaccination (dpv), and the survival rate after challenge could reach 27.91%, which was significantly higher than that of the control group. Transcriptomic analysis revealed substantial upregulation of pathways involved in the p53 signaling pathway, antigen presentation, and T cell immune regulation post-vaccination. There is a marked reduction in the proportions of CD4 + and CD8α + T lymphocytes within the intestine of p53 mutant zebrafish. Conclusion Our research disclosed that p53 is involved in the early immune response by regulating antigen presentation and induces T-cell immune responses. This investigation provides novel insights and establishes a foundational understanding of early intestinal immune responses.
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高影响因子
ACS Nano
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2026
·
IF 17.3
Yilin Huang,Huan Ru,Chanlin Fang,Shanshan Di,You Weng,Mingrong Qian,Yuanxiang Jin
Abstract 6PPD, as an antioxidant in tire rubber, constitutes an emerging pollutant together with nanoplastics (NPs) widely present in the environment. This study explored the potential combined toxicity risk of 6PPD and 50 nm polystyrene nanoplastics (PS-NPs) to aquatic ecosystems. The study found that the presence of PS-NPs altered the physicochemical behavior of 6PPD and was associated with reduced cardiac accumulation of 6PPD and its oxidation product 6PPD-Q. The experiment showed that 6PPD activated the p53 signaling pathway by upregulating the expression of GRK5, thereby inhibiting the expression of SLC7A11 and GPX4, leading to increased ROS, iron overload, lipid peroxidation, and mitochondrial damage in zebrafish heart and rat cardiomyocytes (H9C2), thereby triggering ferroptosis. After coexposure of PS-NPs and 6PPD, physicochemical interactions between PS-NPs and 6PPD altered the colloidal state and environmental behavior of the mixture, while the cardiac levels of both 6PPD and 6PPD-Q were reduced, accompanied by weakened ferroptosis-related responses. This study revealed the cardiotoxic mechanism of 6PPD and the mitigation effect of PS-NPs after coexposure, providing a basis for environmental pollution risk assessment.
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高影响因子
Frontiers in Oncology
·
2025
·
IF 3.3
Xiao Liu,Honglin Qu,Jingmin Li,Xuhong Sun,Zhenlin Wang,Dong Wang,Xianyong Bai,Xiaoyan Li
Background Cuproptosis, a novel cell death pathway mediated by ferredoxin 1 (FDX1) and protein lipoylation, has emerged as a valuable target in cancer therapy. Although the findings of previous research have indicated a potential correlation between p53 and cuproptosis, the precise role and underlying mechanisms of p53 in cuproptosis, particularly within the context of hepatocellular carcinoma (HCC), remain unclear. Methods To evaluate cuproptosis, three HCC cell lines (HepG2, PLC/PRF/5, and Hep3B2.1-7) with distinct p53 statuses were treated with elesclomol-Cu. p53 overexpression/knockdown, siRNA-mediated ferredoxin reductase (FDXR)/FDX1 knockdown, and the p53 activators CP-31398 and nutlin-3 were employed to elucidate the associated molecular mechanisms. Cell viability, protein expression [FDX1, dihydrolipoyl transacetylase (DLAT), FDXR], and DLAT oligomerization were assessed via Cell Counting Kit-8 (CCK-8), western blotting, and immunofluorescence analyses. A PLC/PRF/5 xenograft mouse model was used to assess combined the therapeutic efficacy of elesclomol-Cu and CP-31398. Results Elesclomol-Cu triggered cuproptosis in HCC cells, as evidenced by a dose-dependent suppression of proliferation, FDX1 upregulation, DLAT oligomerization, and rescue by the copper chelator tetrathiomolybdate (TTM). p53 activation enhanced FDXR expression, promoting FDX1 upregulation and subsequent DLAT oligomerization, thereby sensitizing HCC cells to elesclomol-Cu, whereas FDXR knockdown reversed these effects, demonstrating its role in p53-mediated potentiation of cuproptosis sensitivity. In mutant p53-R249S cells, CP-31398 functioned synergistically with elesclomol-Cu to suppress proliferation. In vivo , elesclomol-Cu and CP-31398 combination therapy significantly reduced tumor growth and Ki67 expression whilst upregulating FDXR levels. Conclusions These findings revealed that p53 enhances elesclomol-Cu-induced cuproptosis in HCC via FDXR-mediated FDX1 upregulation. This study provides mechanistic insights into p53’s role in cuproptosis and may serve as a basis for targeting copper metabolism in therapeutic strategies for HCC.
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International Journal of Biological Sciences
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2026
·Vol. 22
·期 10
·5301
·
IF 11.7
Xue Li,Min-Yue Yin,Yan-Fei Wei,Jie Xing,Qian Zhang,Ye Zong,Shu-Tian Zhang,Si-An Xie
Dysregulated cholesterol metabolism is a recognized metabolic hallmark of cancer. While the transcription factor SREBP2 is a master regulator of this pathway, how its activation converts metabolic stress into the development of carcinogenic signals in colorectal cancer (CRC) remains unclear. Through clinical and preclinical analyses, we first confirmed that hypercholesterolemia and elevated tumoral SREBP2 are hallmarks of CRC. Using multi-omics integration, we identified CNPY3 as a direct transcriptional target of SREBP2. Functionally, CNPY3 drives CRC cell proliferation, invasion, and tumor growth via a cholesterol synthesis-independent oncogenic program. Clinically, high CNPY3 expression robustly correlated with advanced disease and poor patient survival. Mechanistically, we discovered that CNPY3 undergoes liquid-liquid phase separation (LLPS), a property dependent on its intrinsically disordered C-terminal region. This LLPS capacity is essential for its oncogenic function, as it enables CNPY3 to enhance MDM2 phosphorylation at the activating Ser166 site and promote its nuclear translocation. Consequently, CNPY3 potentiates MDM2-mediated ubiquitination and degradation of the tumor suppressor p53. Genetic ablation of p53 completely abolished the pro-tumorigenic effects of CNPY3, confirming p53 as the critical downstream effector. Crucially, this axis specifically targets wild-type p53, having no effect on common p53 mutants. Pharmacological disruption of the MDM2-p53 interaction with Nutlin-3 effectively reversed CNPY3-driven malignancy both in vitro and in vivo . Our work unveils a SREBP2-CNPY3-MDM2-p53 signaling axis that links cholesterol metabolic dysregulation to p53 pathway inactivation in CRC. We further established that the oncogenic activity of CNPY3 is mediated through its biophysical property of LLPS. These findings nominate CNPY3 as a novel prognostic biomarker and a compelling therapeutic target for p53-wild-type CRC.
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高影响因子
NEW JOURNAL OF CHEMISTRY
·
2024
·Vol. 48
·期 36
·15782-15789
·
IF 2.7
Hongling Tao,Yanyue Chen,Jiawen Liu,Jiali Liu,Yunhui Yang,Rong Hu
p53 gene is one of the most important anticancer genes and has been recognized as a typical biomarker for the early diagnosis of cancers. In this paper, a portable point-of-care testing (POCT) platform was developed for the colorimetric and photothermal dual-modal analysis of the p53 gene. Long concatemer G4 structures with high catalytic activity were formed by a target-driven hybridization chain reaction, and their catalytic properties can further be enhanced with the help of iodide ions. This dual-modal method realized the sensitive multicolor visual point-of-care detection of the p53 gene, where color variations from colourless to blue were easily distinguished by the naked eye. The temperature output was achieved by effective photothermal conversion and regulation guided by the accumulated concatemer G4 complexes in the TMB–H2O2 system, avoiding the need for complex instruments. The proposed dual-modal assay for p53 gene detection is cost-effective, simple, highly sensitive (3.34 pM), stable, and remarkably selective. It was also applied to determine the concentration of the p53 gene in spiked serum samples.
研究领域:
分子生物学
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癌症诊断
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生物化学
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高影响因子
Frontiers in Immunology
·
2025
·
IF 5.9
Weiming You,Jun Feng,Litao Guo,Jin Yan,Siqi Yan
Background Colorectal cancer (CRC) remains a major global health challenge, with limited immunotherapy efficacy in microsatellite stable (MSS) tumors that comprise ~85% of cases. The p53 tumor suppressor pathway, frequently inactivated through the mouse double minute 2 homolog (MDM2) overexpression in wild-type tumor protein 53(TP53) tumors, represents a promising therapeutic target for both direct antitumor effects and immune modulation. Methods We developed selenium nanoparticles loaded with the MDM2-targeting peptide inhibitor MI (Se@MI) using a one-pot synthesis approach. The nanoparticles were characterized by transmission electron microscopy, dynamic light scattering, and UV-Vis spectroscopy. In vitro assays included MTT cytotoxicity evaluation, cellular uptake by flow cytometry, RNA-seq, and Western blotting of p53-pathway/apoptosis markers. Antitumor efficacy was evaluated in CT26 murine colorectal cancer models, with mechanistic studies including transcriptomic analysis, immunohistochemistry, and flow cytometry. Safety profiles were assessed through body weight monitoring, hematological analysis, histopathological examination of major organs, and serum biomarker evaluation. Results Se@MI nanoparticles demonstrated uniform spherical morphology (45-50nm diameter) and displayed a positive zeta potential (+24.69 mV), indicative of favorable colloidal dispersibility. Enhanced cellular uptake (74.3% positive cells) and potent cytotoxicity (IC 50 = 1.00 μM) were observed in CT26 cells. Transcriptomic analysis revealed significant activation of p53 signaling pathways (NES = 1.504, P = 0.029) and protein analyses confirmed induction of p21, PUMA, Bax, and cleaved caspase-3. In vivo , Se@MI treatment achieved 72.23% tumor growth inhibition, significantly outperforming controls. Mechanistically, Se@MI restored p53 function by disrupting MDM2-p53 interactions, inducing apoptosis and cell cycle arrest. Importantly, Se@MI reprogrammed the tumor immune milieu through increased infiltration of CD8+ T cell and cytotoxic function while suppressing regulatory T cells. Comprehensive safety evaluation revealed excellent biocompatibility with no adverse effects on body weight, hematological parameters, organ histology, inflammatory cytokines, or hepatic/renal function markers. Conclusions Se@MI represents a novel nanomedicine strategy that combines direct p53 pathway reactivation with immune microenvironment modulation. This dual mechanism of action offers a potential strategy to boost immunotherapeutic outcomes in colorectal carcinoma and may help overcome resistance mechanisms to immune checkpoint blockade.
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CELL DEATH AND DIFFERENTIATION
·
2022
·Vol. 29
·期 11
·2177-2189
·
IF 12.067
Yang Yang,Yuan Hongyu,Zhao Lianmei,Guo Shichao,Hu Sijun,Tian Miaomiao,Nie Yongzhan,Yu Jiarui,Zhou Chaoxi,Niu Jian,Wang Guiying,Song Yongmei
P53 mutation is an important cause of chemoresistance in colorectal cancer (CRC). The investigation and identification of the downstream targets and underlying molecular mechanism of chemoresistance induced by P53 abnormalities are therefore of great clinical significance. In this study, we demonstrated and reported for the first time that leucine-rich pentatricopeptide repeat-containing protein (LRPPRC) is a key functional downstream factor and therapeutic target for P53 mutation-induced chemoresistance. Due to its RNA binding function, LRPPRC specifically bound to the mRNA of multidrug resistance 1 (MDR1), increasing MDR1 mRNA stability and protein expression. In normal cells, P53 induced by chemotherapy inhibited the expression of LRPPRC via miR-34a and in turn reduced the expression of MDR1. However, chemotherapy-induced P53/miR-34a/LRPPRC/MDR1 signalling pathway activation was lost when P53 was mutated. Additionally, the accumulated LRPPRC and MDR1 promoted drug resistance. Most importantly, gossypol-acetic acid (GAA) was recently reported by our team as the first specific inhibitor of LRPPRC. In CRC cells with P53 mutation, GAA effectively induced degradation of the LRPPRC protein and reduced chemoresistance. Both in vivo and in vitro experiments revealed that combination chemotherapy with GAA and 5-fluorouracil (5FU) yielded improved treatment outcomes. In this study, we reported a novel mechanism and target related to P53-induced drug resistance and provided corresponding interventional strategies for the precision treatment of CRC.
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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DOI
PubMed
高影响因子
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