JOURNAL OF MEDICINAL CHEMISTRY
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2024
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IF 6.8
Jianchao Zhang,Xiao Chen,Congli Chen,Fengming Li,Xiaoxiao Song,Chaowei Liu,Kefan Liao,Ming-Yuan Su,Chris Soon Heng Tan,Lijing Fang,Hai Rao
Proteolysis-targeting chimeras (PROTACs) selectively eliminate detrimental proteins by exploiting the ubiquitin-proteasome system (UPS), representing a promising therapeutic strategy against various diseases. Effective adaptations of degradation signal sequences and E3 ligases for PROTACs remain limited. Here, we employed three amino acids─Gly, Pro, and Lys─as the ligand to recruit the corresponding E3 ligases: CRL2ZYG11B/ZER1, GID4, and UBRs, to degrade EML4-ALK and mutant EGFR, two oncogenic drivers in NSCLC. We found that the extent of EML4-ALK and EGFR reduction can be easily fine-tuned by using different degradation signals. These amino acid-based PROTACs, termed AATacs, hindered proliferation and induced cell cycle arrest and apoptosis of NSCLC cells in vitro. Compared to other PROTACs, AATacs are small, interchangeable but with different degradation efficiency. Our study further expands the repertoire of E3 ligases and their ligands for PROTAC application, improving the versatility and utility of targeted protein degradation for therapeutic purposes.
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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产品关联
DOI
PubMed
高影响因子
CELL BIOLOGY AND TOXICOLOGY
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2024
·Vol. 40
·期 1
·1-25
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IF 5.3
Wu Wentong,Li Jinjin,Yin Yiming,Zhou Yourong,Huang Xiangliang,Cao Yashi,Chen Xueqin,Zhou Yunfang,Du Jiangxia,Xu Zhifei,Yang Bo,He Qiaojun,Yang Xiaochun,Hu Yuhuai,Yan Hao,Luo Peihua
Ensartinib, an approved ALK inhibitor, is used as a first-line therapy for advanced ALK-positive non-small cell lung cancer in China. However, the hepatotoxicity of ensartinib seriously limits its clinical application and the regulatory mechanism is still elusive. Here, through transcriptome analysis we found that transcriptional activation of TXNIP was the main cause of ensartinib-induced liver dysfunction. A high TXNIP level and abnormal TXNIP translocation severely impaired hepatic function via mitochondrial dysfunction and hepatocyte apoptosis, and TXNIP deficiency attenuated hepatocyte apoptosis under ensartinib treatment. The increase in TXNIP induced by ensartinib is related to AKT inhibition and is mediated by MondoA. Through screening potential TXNIP inhibitors, we found that the natural polyphenolic flavonoid rutin, unlike most reported TXNIP inhibitors can inhibit TXNIP by binding to TXNIP and partially promoting its proteasomal degradation. Further studies showed rutin can attenuate the hepatotoxicity of ensartinib without antagonizing its antitumor effects. Accordingly, we suggest that TXNIP is the key cause of ensartinib-induced hepatotoxicity and rutin is a potential clinically safe and feasible therapeutic strategy for TXNIP intervention. Graphical Abstract
研究领域:
肿瘤学
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药理学
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分子生物学
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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 FUNCTIONAL MATERIALS
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2025
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IF 19
Jin Duan,Zhe Liu,Gege Hang,Yanan Wang,Xiuchen Wang
Harvesting energy from the ubiquitous environmental water vapor cycle is a promising pathway for sustainable power generation. Human skin releases ≈40–340 W of thermal energy per hour through perspiration, and even converting 1% could power most low-energy wearable devices. However, achieving stable vapor capture, directional transport, and efficient charge separation in the skin microenvironment remains a key challenge for hygrothermal energy conversion. Inspired by plant transpiration, a bioinspired moisture-guiding heterogeneous interface is constructed to fabricate a Janus Alk-MXene PVA@Alk-PVA-PVDF fibrous membrane with hydrophilic adsorption, ion conduction, and evaporation-driven traction, enabling directional vapor transport and efficient charge separation. With a thickness of 0.084 mm, the membrane combines flexibility, breathability, and excellent integration compatibility for wearable applications. A 1 cm 2 Janus MEG delivers a rapid response of 1.07 s, 1.18 V output, ≈935.2 µA cm −2 short-circuit current density, and ≈1103.5 µW cm −2 power density, retaining ≈0.87 V after one month and demonstrating excellent moisture sensitivity with stable voltage output. Furthermore, a modular three-unit series–parallel configuration achieves ≈2.32 V and ≈46.4 mA under high humidity, providing a sustainable strategy for self-powered wearable electronics in medical monitoring and next-generation human–machine interaction.
研究领域:
能量收集
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材料科学
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纳米技术
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柔性电子学
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环境科学
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生物物理学
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产品关联
DOI
高影响因子
Theranostics
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2020
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IF 8.579
Yuwei Li,Shuzhen Yue,Jingyu Cao,Chengzhan Zhu,Yixiu Wang,Xin Hai,Weiling Song,Sai Bi
Chemo-gene therapy is an emerging synergetic modality for the treatment of cancers. Herein, we developed pH-responsive multifunctional DNA nanomicelles (DNMs) as delivery vehicles for controllable release of doxorubicin (Dox) and anaplastic lymphoma kinase (ALK)-specific siRNA for the chemo-gene synergetic therapy of anaplastic large cell lymphoma (ALCL). Methods: DNMs were synthesized by performing in situ rolling circle amplification (RCA) on the amphiphilic primer-polylactide (PLA) micelles, followed by functionalization of pH-responsive triplex DNA via complementary base pairing. The anticancer drug Dox and ALK-specific siRNA were co-loaded to construct Dox/siRNA/DNMs for chemo-gene synergetic cancer therapy. When exposed to the acidic microenvironment (pH below 5.0), C-G·C + triplex structures were formed, leading to the release of Dox and siRNA for gene silencing to enhance the chemosensitivity in ALCL K299 cells. The chemo-gene synergetic anticancer effect of Dox/siRNA/DNMs on ALCL was evaluated in vitro and in vivo . Results: The pH-responsive DNMs exhibited good monodispersity at different pH values, good biocompatibility, high drug loading capacity, and excellent stability even in the human serum. With the simultaneous release of anticancer drug Dox and ALK-specific siRNA in response to pH in the tumor microenvironment, the Dox/siRNA/DNMs demonstrated significantly higher treatment efficacy for ALCL compared with chemotherapy alone, because the silencing of ALK gene expression mediated by siRNA increased the chemosensitivity of ALCL cells. From the pathological analysis of tumor tissue, the Dox/siRNA/DNMs exhibited the superiority in inhibiting tumor growth, low toxic side effects and good biosafety. Conclusion: DNMs co-loaded with Dox and ALK-specific siRNA exhibited significantly enhanced apoptosis of ALCL K299 cells in vitro and effectively inhibited tumor growth in vivo without obvious toxicity, providing a potential strategy in the development of nanomedicines for synergetic cancer therapy.
研究领域:
纳米技术
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癌症治疗
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分子生物学
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药学
✓ 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）