ACS Applied Materials & Interfaces
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2024
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IF 8.3
Xiaowei Niu,Jing Zhang,Jingjing Zhang,Lu Bai,Shuwen Hu,Zheng Zhang,Ming Bai
Myocardial ischemia/reperfusion (MI/R) injury, a major contributor to poor prognosis in patients with acute myocardial infarction, currently lacks effective therapeutic strategies in clinical practice. The long noncoding RNA (lncRNA) Oip5-as1 can regulate various cellular processes, such as cell proliferation, differentiation, and survival. Oip5-as1 may have potential as a therapeutic target for MI/R injury as its upregulated expression has been associated with reduced infarct size and improved cardiac function in animal models, although how to effectively and safely overexpress Oip5-as1 in vivo remains unclear. Lipid nanoparticles (LNPs) are a versatile technology for targeted drug delivery in numerous therapeutic applications. Herein, we aimed to assess the therapeutic efficacy and safety of LNPs coloaded with Oip5-as1 and a cardiomyocyte-specific binding peptide (LNP@Oip5-as1@CMP) in a murine model of MI/R injury. To achieve this, LNP@Oip5-as1@CMP was synthesized via ethanol injection method. The structural components of LNP@Oip5-as1@CMP were physicochemically analyzed. A hypoxia/reoxygenation (H/R) model in HL-1 cells and coronary artery ligation in mice were used to simulate MI/R injury. Our results demonstrated that LNPs designed for cardiomyocyte targeting and efficient Oip5-as1 delivery were successfully synthesized. In HL-1 cells, LNP@Oip5-as1@CMP treatment significantly reduced mitochondrial apoptosis caused by H/R injury. In the murine MI/R model, the intravenous administration of LNP@Oip5-as1@CMP significantly decreased myocardial infarct size and improved cardiac function. Mechanistic investigations revealed that Oip5-as1 delivery inhibited the p53 signaling pathway. However, the cardioprotective effects of Oip5-as1 were abrogated by administrating Nutlin-3a, a p53 activator. Furthermore, no signs of major organ damage were detected after LNP@Oip5-as1@CMP injection. Our study reveals the therapeutic potential of LNPs for targeted Oip5-as1 delivery in mitigating MI/R injury. These findings pave the way for advanced targeted treatments in cardiovascular diseases, emphasizing the promise of lncRNA-based therapies.
研究领域:
心血管疾病
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纳米技术
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分子生物学
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治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2023
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IF 19
Zhuo Yao,Qida Hu,Piaopiao Jin,Bowen Li,Yong Huang,Fu Zhang,Meng Wang,Junming Huang,Jing Huang,Shiyi Shao,Xinyu Zhao,Yuan Ping,Tingbo Liang
Gemcitabine (GEM), as a first-line chemotherapeutics for pancreatic ductal adenocarcinoma (PDAC) treatment, still faces several clinical challenges, restricted by instability in blood circulations, low tumor selectivity, and acquired nature characteristics of chemo-resistance. To solve these challenges, the rational design of combination therapy with GEM and other therapy modalities is imperative. Herein, a small molecular self-assembly nano-prodrug is developed, which can achieve the co-delivery of GEM, Ferrocene and nutlin-3a on the achievement of GEM-induced apoptosis with ferroptosis. In this nano-prodrug, the disulfide linkage not only acts as a GSH-responsive trigger but also plays an important role in self-assembly behavior of nanoparticle that can load nutlin-3a. Interestingly, nutlin-3a plays an important role in both ferroptosis and apoptosis, one is effectively sensitized cells to ferroptosis by inhibiting cystine uptake, and the other is promoted apoptosis by elevating p53 expression. To further enhance the drug tumor accumulation and maintain stability in systemic circulations, this nano-prodrug is then encapsulated into plectin1 receptor-targeting phospholipid micelles (DSPE-PEG-PTP), which displays high selective tumor inhibition and good biosafety on different mice models, especially in orthotopic and patient-derived xenograft (PDX) models. The findings provide new insights into the combination therapy of GEM with ferroptosis for reduced chemo-resistance on PDAC treatment.
研究领域:
肿瘤学
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药学
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纳米技术
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癌症治疗
✓ 已验证
产品关联
DOI
高影响因子
EUROPEAN JOURNAL OF MEDICAL RESEARCH
·
2025
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IF 3.4
Yun Chen,Yang Wang,Shuai Shen,Libin Zhang,Jun Liu,Xiangyun Yan,Hao Peng,Zheyuan Xu
RHDBB1 could arrest cell cycle in the TP53 mutant NCI-H596 cells; RHDBB1 promotes NSCLS by reducing DNA-PKcs dependent cells apoptosis; Targeting both TP53 and RHDBB1 may have beneficial effects on NSCLC.
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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癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2025
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IF 5.6
Jiajian Wang,Lanqing Zhang,Runfang Li,Rui Yang,Fan Yang,Fei Yu,Jihong Zhang
TP53, the most frequently mutated gene in human cancers, undergoes a functional transformation from a tumor suppressor to an oncoprotein, thereby enhancing tumor aggressiveness, metastatic potential, and resistance to therapy. Given the prevalence of p53 mutations in cancer, the reactivation of wild-type p53 function presents a compelling therapeutic strategy for these malignancies. In this study, we identified gambogic acid (GA), a natural compound, as a potent reactivator of mutant p53 transcriptional activity. Immunofluorescence and co-immunoprecipitation assays revealed that GA treatment upregulates wild-type p53 expression while depleting mutant p53 in cancer cells. The time-dependent restoration of p53′s DNA-binding capacity and transcriptional regulatory activity by GA was further demonstrated through EMSA and ChIP. Consequently, GA robustly induced the expression levels of canonical p53 downstream target genes, confirming functional restoration of p53 signaling. In addition, GA synergizes with RSL3, a GPX4 inhibitor, to promote ferroptosis in mutant p53 cancer cells in both cellular and animal studies. In summary, our findings identify GA as a promising compound that reactivates mutant p53 through thiol modification, restoring its wild-type function and inducing ferroptosis in p53-mutant cancer cells. The findings of this study establish a foundational rationale and new perspectives for a mutant p53-directed therapeutic paradigm in oncology.
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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癌症生物学
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药物发现
✓ 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）