DIABETES
·
2025
·Vol. 74
·期 12
·2405-2417
·
IF 7.5
Guo Lei,Wu Peili,Li Qing,Feng Qijian,Lin Xiaochun,Luo Yuling,Wang Yuan,Wu Minghai,Cai Feifei,Zhang Jin,Hu Yuxuan,Wang Huiyun,Wang Yu,Luo Sirui,Tian Linlin,Fan Xinzhao,Wang Ling,Xue Yaoming,Guan Meiping
Diabetic kidney disease (DKD) progression involves intricate interactions among senescence, oxidative stress, inflammation, and fibrosis. This study systematically investigates the regulatory role and molecular mechanisms of NUAK1 in DKD pathogenesis. Bioinformatics analysis of Gene Expression Omnibus data sets identified NUAK1 as a differentially expressed gene, validated in human kidney proximal tubule epithelial (HK-2) cells, high-fat diet and streptozotocin-induced DKD mice, d -galactose–induced senescent mice, and human peripheral blood mononuclear cells. Functional studies demonstrated that NUAK1 inhibition via siRNA knockdown, pharmacological inhibitors, or kidney tubule-targeted adeno-associated virus serotype carrying shRNA against NUAK1 delivery attenuated reactive oxygen species–tumor protein 53 (ROS/P53) axis-mediated renal tubular senescence, oxidative stress, inflammation, and fibrosis in vitro and in vivo. Mechanistically, chromatin immunoprecipitation quantitative PCR revealed that transcription factor ETS1 directly binds to the NUAK1 promoter, driving its transcriptional activation in DKD. Furthermore, molecular docking and dynamics simulations identified Asiatic acid (AA) as a potent NUAK1 inhibitor, with a stable binding affinity. AA suppressed NUAK1 expression and downstream pathological processes, ameliorating renal injury in DKD models. These findings elucidate the role and regulatory mechanisms of NUAK1 in modulating ROS/P53 axis-driven tubular senescence and oxidative stress, providing a theoretical basis for structure optimization in drug development targeting NUAK1. Article Highlights Mechanisms linking renal tubular senescence to diabetic kidney disease (DKD) progression remain poorly understood. Systematic elucidation of the regulatory role of NUAK1 in the pathogenesis of DKD and its regulatory mechanisms is provided. NUAK1 is upregulated in DKD, promoting senescence via reactive oxygen species–tumor protein 53 under transcriptional activation by E26 transformation–specific 1, while Asiatic acid (AA) directly binds NUAK1 to suppress these pathological processes. NUAK1 emerges as a therapeutic target for DKD, and AA provides a natural scaffold for NUAK1 inhibitor development, offering a strategy to combat diabetes-related renal decline.
研究领域:
肾脏病学
·
分子生物学
·
糖尿病研究
·
药理学
·
衰老研究
✓ 已验证
DOI
PubMed
高影响因子
Translational Cancer Research
·
2026
·Vol. 15
·期 7
·555
·
IF 2.1
Junjie Wu,Congxing Liu,Yaya Sun,Guangqing Jiang,Yupeng Zhao,Yihong Zhang,Yiping Yin,Xin Shi
Background Colon cancer (CC) is a heterogeneous disease with increasing morbidity and mortality. Ferroptosis, a recently identified form of regulated cell death (RCD) characterized by the massive accumulation of iron-dependent lipid peroxidation (LPO), has been proven to be closely associated with various biological behaviors of CC. Moreover, accumulating evidence reveals that ALOX12 is essential for p53-mediated ferroptosis through distinct pathways. Therefore, our study aims to explore the specific mechanisms by which ALOX12 regulates tumorigenesis in CC through ferroptosis pathway. Methods We explored the characteristics of ALOX12 expression and its correlation with prognosis in CC patients and cell lines, followed by a series of functional assays in vitro and in vivo to investigate the mechanisms underlying the functions of ALOX12 in p53-driven ferroptosis. Results We discovered that ALOX12 was downregulated in CC tissues and cell lines, which was correlated with poor prognosis. Furthermore, overexpression of ALOX12 suppressed cell proliferation and tumorigenesis by upregulating reactive oxygen species (ROS)-induced stress. We continuously found that increased ALOX12 levels enhanced the sensitivity of CC cells to a distinct ferroptosis, which required both p53 activation and additional ROS, and differed from that induced by erastin. Conclusions Our study demonstrates the oncosuppressive behavior of ALOX12 in CC. Mechanistically, we discover that p53 can indirectly activate ALOX12 function by suppressing its transcriptional target SLC7A11, resulting in an ALOX12-dependent ferroptotic pathway. Targeting ALOX12 may provide a novel biomarker or new therapeutic strategies for improving the prognosis of CC.
✓ 已验证
DOI
PubMed
高影响因子
BIOMEDICAL CHROMATOGRAPHY
·
2026
·Vol. 40
·期 6
·e70452
·
IF 1.7
Xiaoqing Liu,Wenyong Liao,Xiangnan Xu,Meijing Wu,Jiwen Zhang,Yinghao Wu,Shaohong Chen,Haiyan Liu,Shujing Zhang,Linlin Xiu,Gansheng Zhong
Haizao Yuhu Decoction (HYD), a classic Traditional Chinese Medicine (TCM) formula, is used to treat Yingbing, which corresponds to goiter in modern medicine. Although HYD has been extensively studied for goiter, its specific active components and the underlying mechanisms of action remain to be fully elucidated. This study investigated the effects and mechanisms of HYD in goiter using untargeted LC–MS metabolomics (comparing HYD decoction and HYD-containing serum), network pharmacology for target prediction, and in vitro validation with a TSHR human monoclonal antibody M22 (TSHR hMAb M22)-induced thyroid cell proliferation model, followed by Western blotting to verify key pathway proteins. The comparison of metabolomic profiles between HYD decoction and HYD-containing serum revealed that 2091 metabolites (90.05%) were downregulated, while 231 were upregulated in medicated serum. Network pharmacology predicted targets including AKT1, PIK3CA, ESR2, ESR1, and TP53. HYD-containing serum exhibited pro-apoptotic effects on the cell proliferation model. The underlying mechanism may primarily involve the upregulation of the p53/PUMA/p21 pathway, which subsequently affects caspase-3 activity. Furthermore, the action of HYD may involve non-p53 multiple signaling pathways. HYD may exert its effects by modulating multiple signaling pathways, including p53/PUMA/p21, leading to apoptosis in thyroid cells.
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2025
·
IF 5.4
Maohui Liu,Jiawei Chen,Zubing Zhou,Jiexin Wang,Guangsen Li,Jinghui Xie,Lingmiao Wen,Huan Wang,Rong Gan,Peihai Zhang,Yanju Gong,Weijun Ding
Ethnopharmacological Relevance Er-Chen Decoction (ECD), a classic traditional Chinese medicine (TCM) formula, is clinically indicated for dispelling dampness and resolving phlegm. It has been widely used in the management of phlegm‒dampness syndrome, including obesity, with a long-standing clinical application history in improving obesity-related male infertility. Although its therapeutic efficacy has been validated through long-term clinical practice, the underlying molecular mechanisms remain incompletely understood. Aim This study aimed to investigate the molecular mechanisms by which ECD ameliorates obesity-related spermatogenic dysfunction (SD) through the SIRT1/p53 signaling axis. Materials and Methods A mouse model of diet-induced obesity was established by feeding a high-fat diet (HFD) for 8 weeks. Subsequently, obese mice were randomly assigned to receive interventions with ECD (low-, medium-, or high-dose) or L-carnitine (positive control) for 3 weeks. Sperm functional parameters were evaluated to assess obesity-related SD. A combination of network pharmacology analysis, molecular docking, biochemical assays, hematoxylin‒eosin (HE) staining, Oil Red O staining, transmission electron microscopy (TEM), quantitative real-time polymerase chain reaction (RT‒qPCR), immunofluorescence (IF) staining, immunohistochemical (IHC) staining, Western blotting (WB), and transcriptomic analysis was employed to dissect the molecular mechanisms underlying the protective effects of the ECD against obesity-related SD. Additionally, the bioactive components of ECD were characterized using extensive targeted mass spectrometry. Results Medium-dose ECD (ECD-M) significantly reduced body weight and lipid accumulation in HFD-induced obese mice. Notably, compared with the HFD group, the ECD-M group presented a 50% reduction in the abnormal sperm percentage (p < 0.01), along with a 60% increase in sperm concentration (p < 0.01), and showed an upward trend in both sperm progressive motility and sperm motility. Furthermore, ECD-M significantly upregulated the expression of the tight junction (TJ) proteins Occludin (p < 0.001) and β-catenin (p < 0.05), thereby restoring the integrity of the blood‒testis barrier (BTB). Mechanistically, ECD not only reversed lipid-induced inhibition of SIRT1 but also suppressed p53 acetylation, leading to a significant decrease in the ratios of cleaved caspase-3/caspase-3 (p < 0.05) and Bax/Bcl-2 (p < 0.0001) in testicular tissues. These effects collectively alleviated mitochondria-mediated apoptosis in the testes of obese mice. Conclusion ECD alleviates mitochondria-mediated apoptosis in testicular tissues by regulating the SIRT1/p53 axis, thereby mitigating obesity-related SD. These findings highlight ECD as a potential therapeutic agent for the management of obesity-related male infertility.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CELLULAR AND MOLECULAR LIFE SCIENCES
·
2026
·Vol. 83
·期 1
·211
·
IF 6.5
Feng Yuqing,Li Zhou,Lu Jinfang,Peng Xujun,He Zijin,Jia Ao,Bao Yaohui,Zheng Qiang,Xu Xuan,Ma Yuxuan,Zou Chun,Li Huiling,Zhang Dongshan
Ischemia-reperfusion (I/R) injury represents a prevalent etiology of permanent vision loss across multiple ocular pathologies. Apoptotic death and inflammation of retinal ganglion cells (RGCs) induced by I/R injury constitutes a major contributor to visual dysfunction. Nevertheless, the molecular mechanisms that initiate the apoptotic and inflammation cascade in RGCs remain largely uncharacterized. Recent investigations have demonstrated that PRD1-BF1-RIZ1 homeodomain protein 16 (PRDM16) attenuates renal cell death in acute kidney injury. However, its specific function and regulatory mechanisms in I/R-induced RGCs apoptosis and inflammation remain poorly understood. Here, we demonstrate that PRDM16 expression is markedly upregulated in RGCs and mouse retinas following I/R injury. Functionally, PRDM16 overexpression markedly attenuates I/R-induced RGCs apoptosis and inflammation, while its RGC-specific deletion exacerbates retinal structural damage and functional deficits. Mechanistically, PRDM16 binds to the Ribosomal Protein L5 (RPL5) promoter and enhances its transcription. Additionally, co-immunoprecipitation assays revealed a physical association between PRDM16 and RPL5. This PRDM16-mediated enrichment of RPL5 subsequently suppresses p53 signaling, leading to the upregulation of FCGR2B. Increased FCGR2B, in turn, inhibits the overactivation of MAPK (p38 and JNK) signaling and the assembly of the NLRP3/IL-1β inflammasome axis. In conclusion, these findings identify PRDM16 as a critical endogenous protective regulator that alleviates retinal I/R-induced damage through modulation of the RPL5/p53/FCGR2B/MAPK axis. Targeting PRDM16 regulatory networks may therefore represent a promising therapeutic strategy for retinal ischemic diseases. Graphical abstract Ischemia–reperfusion injury induces apoptosis and inflammation in RGCs. PRDM16 is upregulated in response to ischemic stress and exerts a protective effect by transcriptionally activating RPL5. Increased RPL5 suppresses p53 expression, leading to upregulation of FCGR2B and subsequent inhibition of p38 MAPK and JNK signaling. Additionally, co-immunoprecipitation assays reveal a physical association between PRDM16 and RPL5. This regulatory cascade attenuates caspase-3 activation and inflammatory mediator (NLRP3 and IL-1β) expression, ultimately protecting RGCs from ischemia-induced injury. The alternative text for this image may have been generated using AI.
✓ 已验证
DOI
高影响因子
ENVIRONMENTAL SCIENCE & TECHNOLOGY
·
2025
·
IF 11.3
Jinxiu Lou,Feilong Dong,Huijie Lu,Shuangxi Fang,Xiangliang Pan
Disinfection byproducts (DBPs), such as haloacetamides (HAMs), have been associated with adverse health outcomes, including bladder cancer. The potential for DBPs to exacerbate cellular senescence, thereby linking exposure to health impacts, remains underexplored. In this study, MRC-5 cells were exposed to HAMs at concentrations of 2, 5, and 8 μg/L for 30 days to simulate long-term exposure to levels found in drinking water. All six tested HAMs significantly increased the cellular senescence degree and enriched the cellular senescence pathway at the proteomic-wide level. Specifically, HAMs upregulated microRNA-24 expression, which increased p16 mRNA levels and decreased p16 protein levels, thereby activating oncogene-induced senescence pathways. Additionally, HAMs were found to covalently bind to TNRC6A, activating the p53/p21 pathway. Principal component analysis highlighted the critical role of functional groups in activating senescence, and the interaction between HAMs and TNRC6A could extend to at least 27 other amide-containing DBPs. Prolonged exposure to HAMs at environmentally relevant levels notably exacerbates cellular senescence, shedding light on a commonly overlooked phenomenon. Given the widespread presence of DBPs in drinking water and their continuous exposure in humans, their role in cellular senescence represents an ongoing public health concern.
研究领域:
环境科学
·
毒理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
iScience
·
2024
·
IF 4.6
Yuanhong Chen,Feng Gao,Yan He,Meijun Liu,Yuan Quan,Peijing Zhang
Summary Although melanoma-associated antigen A3 and A6 (MAGEA3/6)-specific tumor vaccines have shown antitumor effects in melanoma and non-small cell lung cancer (NSCLC), many cancers do not respond because MAGEA3 can promote cancer without triggering an immune response. Here, we identified DUB3 as the MAGEA3 deubiquitinase. DUB3 interacts with, deubiquitinates and stabilizes MAGEA3. Depletion of DUB3 in hepatocellular carcinoma (HCC) cells results in MAGEA3 degradation and P53-dependent growth inhibition. Moreover, DUB3 knockout attenuates HCC tumorigenesis in vivo , which can be rescued by restoration of MAGEA3. Intriguingly, pharmacological inhibition of DUB3 by palbociclib promotes degradation of MAGEA3 and inhibits tumor growth in preclinical models implanted with parental HCC cells but not with DUB3 knockout HCC cells. In patients with HCC, DUB3 is highly expressed, and its levels positively correlate with MAGEA3 levels. Taken together, DUB3 is a MAGEA3 deubiquitinase, and abrogating DUB3 enzymatic activity by palbociclib is a promising therapeutic strategy for HCC.
研究领域:
肿瘤学
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL RESEARCH IN TOXICOLOGY
·
2016
·
IF 3.025
Xiufang Song,Qiong Shi,Zixuan Liu,Yawen Wang,Yuxin Wang,Erqun Song,Yang Song
We previously demonstrated that halogenated quinone induces DNA double strand breaks (DSBs) in a ROS-dependent manner, which coordinates with downstream repair cascade including nonhomologous end joining, base excision repair, and nucleotide excision repair. However, these error-prone processes may cause the potential risk of genome instability, and current has no information on how faithful repair route, such as homologous recombination (HR), was affected. RAD51 is a key protein in the HR pathway of DSBs repair. Here, we found that tetrachlorobenzoquinone (TCBQ) causes a time-dependent reverse U-shape biphasic trend of RAD51 expression. An increase in the early stage and a following decrease of RAD51 expression were found in both 12.5 and 25 μM TCBQ groups, wherein higher concentration faced a faster response. The upregulated RAD51 in the early phase suggested the attempting to repair TCBQ-induced DNA damage; however, the downregulation of RAD51 in the late phase implicated that the rescue probably be abandoned with severe DNA damage. This phenomenon is a general toxic manner of TCBQ regardless of cell type. Surprisingly, TCBQ showed minimum effect on RAD51 mRNA (or protein) synthesis as well as RAD51 degradation. Specific inhibition of RAD51 by siRNA amplified TCBQ-induced DNA damage and cytotoxicity, while cells with enhanced RAD51 expression resisted TCBQ-induced toxicity. The modulation of RAD51 is correlated with p53 level, which suggests p53 has a role in TCBQ-induced RAD51 clearance. Together, our data suggested that TCBQ increases genome instability and cell death through a unique mechanism of inducing DNA damage and inhibiting DNA repair.
研究领域:
毒理学
·
分子生物学
·
遗传学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2022
·
IF 6.51
Zhou Fang,Min Zhang,Rui Kang,Mingxiao Cui,Mengdi Song,Kehai Liu
Gene therapy is a superior therapeutic means in cancer therapy. However, the instability of nucleic acid and the lack of suitable delivery carrier greatly restricts its further development and application. Herein, we coupled low molecular weight polyethyleneimine (LMW PEI) through disulfide bonds , then modified it with manganese dioxide (MnO 2 ) nanosheets and nuclear localization signal peptide (NLS), as a p53 gene carrier, and finally coated it with B16F10 cell membrane to construct a novel gene-carrier system [email protected] 2 -PEI-NLS-ss/p53 ( [email protected] /p53). Tumor cell membrane coating endows nanoparticles with homotypic targeting and immune escape capabilities, disulfide-crosslinked LMW-PEI has high transfection efficiency and low toxicity, and NLS peptides enhance nuclear delivery and improve p53 gene delivery efficiency; meanwhile, MnO 2 nanosheets oxidize high intracellular concentration of glutathione (GSH), sensitizing p53 gene-mediated antitumor therapy. The results showed that the novel biofilm-camouflaged [email protected] /p53 nanoparticles had a highly specific targeting effect on homologous cancer cells and could effectively inhibit tumor growth in vitro and in vivo . Besides, MnO 2 loading improved p53-mediated tumor regression . This novel gene delivery platform is of great significance in improving gene delivery efficiency and enhancing anti-tumor therapy.
研究领域:
生物医学工程
·
癌症研究
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
LIFE SCIENCES
·
2022
·
IF 6.78
Tianfeng Yang,Cheng Cheng,Rui Xu,Jian Huo,Xiujuan Peng,Yanbin Chen,Yonghong Liang,Zhiheng Su,Yanmin Zhang
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most common cause of cancer-related deaths. The WW-domain containing oxidoreductase (WWOX) protein suppresses carcinogenesis and its absence is closely related to aggressive HCC phenotypes. In this study, by using SPR analysis, cell viability assay and xenograft mice models, we found that albendazole (ABZ), a safe and effective anthelmintic drug, exhibited the binding affinity with WWOX protein and potential inhibition effect on HCC cells in vitro and in vivo . Overexpression and knockdown of WWOX confirmed that the suppression of HCC by ABZ. Flow cytometric analysis, western blotting analysis and Co-IP were conducted to study the mechanism of ABZ. Our data showed that ABZ regulated the interaction between WWOX and its binding proteins including p53 and C-MYC. Furthermore, ABZ triggered p53-induced intrinsic apoptosis and suppressed EMT-mediated migration by C-MYC/Fibronectin axis. In addition, ∆NP73 expression was significantly inhibited by ABZ, which further sensitized p53-induced intrinsic apoptosis and cell cycle arrest. In summary, ABZ could suppress the proliferation and migration of HCC cells by regulating WWOX-dependent signaling pathway.
研究领域:
肿瘤学
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
·
2026
·Vol. 1872
·期 5
·168202
·
IF 5
Xiaotong Ma,Yuchen Wang,Ruxue Diao,Mengjiao Yin,Qiuling Shen,Wuyang Lv,Mingyu Xu,Yingyu Jin
Sepsis-associated acute kidney injury (SA-AKI), defined as AKI occurring within 7 days after the onset of sepsis, is more common in critically ill patients and is strongly associated with poor prognosis. To investigate the relationship between cell death and SA-AKI, we used mRNAseq assays in SA-AKI rat kidneys. Sequencing results showed significant up-regulation of baculovirus-containing IAP repeat sequence 3 (BIRC3) and multiple forms of programmed cell death, including necroptosis, which were also verified. Meanwhile, Birinapant, an inhibitor of BIRC3, attenuated necroptosis and inflammatory responses. Furthermore, using laser confocal microscopy and coupled immunoprecipitation coupled mass spectrometry (Co-IP/MS), we identified the intercalating protein of BIRC3, NOC2 like Nucleolar Associated Transcriptional Repressor (NOC2L), for the first time. Apoptosis was quantified by flow cytometry, Annexin V-FITC, and mitochondrial membrane potentials, and cellular damage was examined by projected electron microscopy. Because NOC2L can inhibit P53 acetylation, we further investigated how P53 acetylation regulates necroptosis in SA-AKI and preliminarily discovered that BIRC3 promotes acetylation at the P53-K382 site. Concurrently, BIRC3's promotion of p53 acetylation outweighs NOC2L's inhibition of this process, and both molecules jointly regulate p53-K382 acetylation to drive downstream necroptosis. This study confirms that BIRC3 induces necroptosis in renal cells and accelerates kidney disease progression. Preliminary evidence confirms that BIRC3 promotes p53 acetylation at the K382 site. Furthermore, BIRC3 and its interacting protein NOC2L synergistically regulate p53 acetylation, thereby promoting downstream necroptosis. BIRC3 and NOC2L may serve as potential therapeutic targets for SA-AKI, offering novel therapeutic strategies.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Theranostics
·
2026
·Vol. 16
·期 7
·3408
·
IF 13.3
Binbin Ji,Hui Guo,Rong Xing,Miaomiao Sun,Yu Cheng,Chen Yao,Hanyong Zhu,Xuerong Wang,Ruihan Jiang,Xin Chen,Zimeng Liu,Suyan Wang,Fei Xu,Fangyu Zhang,Fuxing Dong,Xiucheng Pan,Jing Yang,Yuchen Pan
Rationale: Macrophage phagocytosis is essential for pathogen clearance during sepsis. We previously demonstrated that the glycolytic enzyme 6-phosphofructokinase, muscle type (PFKM), modulates macrophage functions and its deficiency alleviates sepsis in mice. However, the function of PFKM in regulating macrophage phagocytosis remains unclear. Methods: CD14 + monocytes were sorted by flow cytometry from healthy volunteers and septic patients, and the subcellular localization of PFKM was assessed by immunofluorescence. Nuclear translocation mechanisms and PFKM-p53 interaction were identified by Co-immunoprecipitation coupled with mass spectrometry (Co-IP/MS) and validated by Co-IP. Transcriptomic sequencing was used to identify the downstream target of the PFKM-p53 complex. Inflammatory cytokine levels were detected by ELISA and real-time RT-PCR, and the phagocytosis of macrophages was assessed by flow cytometry. Dual-luciferase reporter assays and ChIP were employed to investigate whether PFKM acts as a co-regulator of p53 in mediating Pdcd1 transcription. Nanobodies targeting PFKM-p53 were screened and subsequently synthesized according to the sequences. The effect of nuclear PFKM and the therapeutic effect of nanobodies were evaluated on the well-established sepsis mouse models induced by Escherichia coli or cecal ligation and puncture. Results: PFKM translocated to the macrophage nucleus during sepsis. Nuclear accumulation of PFKM impaired phagocytosis through a non-glycolytic “moonlighting” function and exacerbated sepsis. Mechanistically, PFKM interacts with p53, which facilitates its nuclear translocation. Subsequently, PFKM promotes p53 acetylation at K120, enhancing p53 binding to the Pdcd1 promoter and driving its transcription, thereby suppressing macrophage phagocytosis. Blocking the PFKM-p53 interaction with a nanobody, Nb07, restored phagocytosis of macrophages and alleviated sepsis in mice. Conclusion: Our data reveal the PFKM-p53-PD-1 axis that suppresses macrophage phagocytosis in sepsis and highlight the therapeutic potential of targeting this pathway with nanobody-based strategies.
✓ 已验证
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）