MOLECULAR MEDICINE
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2024
·Vol. 30
·期 1
·1-16
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IF 6
Xie Bin,Chen Qiong,Dai Ziyu,Jiang Chen,Chen Xi
Background Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease associated with high morbidity and mortality worldwide. Oxidative injury and mitochondrial dysfunction in the airway epithelium are major events in COPD progression.Methods and resultsThe therapeutic effects of Progesterone (P4) were investigated in vivo and in vitro in this study. In vivo, in a cigarette smoke (CS) exposure-induced COPD mouse model, P4 treatment significantly ameliorated CS exposure-induced physiological and pathological characteristics, including inflammatory cell infiltration and oxidative injury, in a dose-dependent manner. The c-MYC/SIRT1/PGC-1α pathway is involved in the protective function of P4 against CS-induced COPD. In vitro, P4 co-treatment significantly ameliorated H2O2-induced oxidative injury and mitochondrial dysfunctions by promoting cell proliferation, increasing mitochondrial membrane potential, decreasing ROS levels and apoptosis, and increasing ATP content. Moreover, P4 co-treatment partially attenuated H2O2-caused inhibition in Nrf1, Tfam, Mfn1, PGR-B, c-MYC, SIRT1, and PGC-1α levels. In BEAS-2B and ASM cells, the c-MYC/SIRT1 axis regulated P4’s protective effects against H2O2-induced oxidative injury and mitochondrial dysfunctions.Conclusion P4 activates the c-MYC/SIRT1 axis, ameliorating CS-induced COPD and protecting both airway epithelial cells and smooth muscle cells against H2O2-induced oxidative damage. PGC-1α and downstream mitochondrial signaling pathways might be involved.
研究领域:
呼吸病学
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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
DRUG RESISTANCE UPDATES
·
2024
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IF 15.8
Dajun Gao,Yanting Shen,Lingfan Xu,Yi Sun,Hailiang Hu,Bin Xu,Zhong Wang,Huan Xu
Aims Tumor fatty acid (FA) metabolic plasticity plays a pivotal role in resistance to therapy and poses limitations to anticancer strategies. In this study, our aim is to uncover the role of acetate metabolism in neurodifferentiation (NED)-mediated castration-resistant prostate cancer (CRPC). Methods We conducted analyses using LC-MS/MS on clinical prostate cancer tissue before and after hormone therapy. We established tumor xenograft mouse models, primary tumor cells, and human-derived organoids to detect the novel mechanism of NED and to identify potential therapies. Results The hormone therapy-induced upregulation of acetate metabolism was mediated by acyl-CoA synthetase short-chain family member 2 (ACSS2), which increased c-MYC expression for NED induction. Notably, combined treatment with an ACSS2 inhibitor and enzalutamide significantly reduced the xenograft tumor volume. Conclusion Our findings uncovered the critical role of acetate metabolism in NED-mediated CRPC and suggest that ACSS2 inhibitors may represent a novel, low-toxicity strategy when combined with hormone therapy for treating patients with NED-mediated CRPC.
研究领域:
肿瘤学
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分子生物学
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癌症代谢
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前列腺癌
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激素治疗
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DOI
PubMed
高影响因子
Cell Death Discovery
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2024
·Vol. 10
·期 1
·1-16
·
IF 6.1
Liu Zhaohong,Xiang Peng,Zeng Shengmei,Weng Ping,Wen Yilin,Zhang Wanping,Hu Hui,Zhao Dezhang,Ma Limei,Yu Chao
Vascular endothelial injury initiates atherosclerosis (AS) progression. N -Acetylneuraminic acid (Neu5Ac) metabolic disorder was found to intensify endothelial mitochondrial damage. And GLS2-associated glutaminolysis disorder contributed to mitochondrial dysfunction. However, mechanisms underlying Neu5Ac-associated mitochondrial dysfunction as well as its association with GLS2 remains unclear. In this study, we constructed GLS2 −/− ApoE −/− mice by using HBLV-GLS2 shRNA injection. And methods like immunofluorescence, western blotting, transmission electron microscopy were applied to detect profiles of endothelial injury and AS progression both in vivo and in vitro. We demonstrated that Neu5Ac accumulation increased GLS2 expression and promoted glutaminolysis disorder, which further induced endothelial mitochondrial dysfunction via a pyroptosis-dependent pathway in vivo and in vitro. Mechanically, Neu5Ac interacted with SIRT3 and led to FOXO3a deacetylation and phosphorylation, further facilitated c-Myc antagonism and ultimately increased GLS2 levels. Inhibition of GLS2 could improve mitochondrial function and mitigate pyroptosis process. In addition, blocking Neu5Ac production using neuraminidases (NEUs) inhibitor could rescue endothelial damage and alleviate AS development in ApoE −/− mice. These findings proposed that Neu5Ac induced GLS2-mediated glutaminolysis disorder and then promoted mitochondrial dysfunction in a pyroptosis-dependent pathway. Targeting GLS2 or inhibiting Neu5Ac production could prevent AS progression.
研究领域:
心血管疾病
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分子生物学
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细胞生物学
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病理学
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DOI
PubMed
高影响因子
EXPERIMENTAL CELL RESEARCH
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2024
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IF 3.3
Zhen Xu,Yilin Guo,Lu Wang,Jinquan Cui
HECW1 belongs to ubiquitin ligase (E3) HECT family, and is found to be involved in tumorigenesis and tumor progression. However, the function of HECW1 in cervical cancer (CC) remains unknown. Clinical analysis showed that HECW1 is significantly decreased in CC tumor tissues. Ectopic expression of HECW1 suppressed cell growth, promoting cell cycle arrest and apoptosis in CC cells, while downregulation of HECW1 reversed these trends, impeded proliferation and accelerated cell cycle progression of CC cells. Overexpressing of HECW1 reduced mitochondrial membrane potential and the protein expression of voltage-dependent anion channel 1 (VDAC1). In addition, upregulation of HECW1 inhibited nuclear β-catenin accumulation, downregulated β-catenin/TCF/LEF-mediated transcriptional activity and the expression of downstream gene c-Myc, whereas inhibition of HECW1 received opposite results. Further results confirmed HECW1 affects the protein expression of dishevelled-1 (DVL1), a potent activator of Wnt/β‐catenin, and inhibition of HECW1 inhibited the ubiquitination of DVL1, upregulating its expression. Inhibition of DVL1 restrained the promotion effect of HECW1 suppression on cell proliferation. In vivo experiments also verified that HECW1 suppression promoted the tumor formation of CC cells. Summary, we demonstrated that HECW1 inhibits CC cell proliferation and tumor formation by downregulating DVL1 induced Wnt/β‐catenin signaling pathway activation.
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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DOI
PubMed
高影响因子
DALTON TRANSACTIONS
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2014
·Vol. 43
·期 24
·9216-9225
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IF 4.097
Qiong Wu,Tianfeng Chen,Zhao Zhang,Siyan Liao,Xiaohui Wu,Jian Wu,Wenjie Mei,Yanhua Chen,Weili Wu,Lingli Zeng,Wenjie Zheng
Two arene Ru(II) complexes coordinated by 2-(3-methoxyphenyl)imidazole[4,5-f][1,10]phenanthroline, [(η6-RC6H5)Ru(m-MOPIP)Cl]Cl (R = H, 1; R = CH3, 2), have been prepared under microwave irradiation; the crystal structure of 2 exhibits a typical “piano stool” conformation, with bond angles for N1–Ru1–Cl1 86.02 (14)° and N2–Ru1–Cl1 84.51 (14)°. The Ru–C distance for the Ru atom bound to the benzene ring is about 0.2178(8) nm, and the average Ru–N distance for Ru atom to the two chelating N atoms is about 0.2092(4) nm. The evaluation of in vitro anticancer activities revealed that these synthetic Ru(II) complexes selectively inhibited the growth of HepG2 hepatocellular carcinoma cells, with low cytotoxicity toward LO2 human normal liver cells. The results demonstrated that the complexes exhibited great selectivity between human cancer and normal cells by comparing with the ligand m-MOPIP. Furthermore, complexes 1 and 2 could bind to c-myc G4 DNA in groove binding mode in promising affinity, and the insertion of the methyl groups in the arene ligand contributed to strengthen the binding affinity. This was also confirmed by molecular docking calculation and 1H NMR analysis which showed that both 1 and 2 can bind in the loop constructed by A6–G9 and G21–A25 base pairs in c-myc G4 DNA to block the replication of c-myc oligomer. Taken together, these results suggest that arene Ru(II) complexes display application potential as small molecule inhibitors of c-myc G4 DNA.
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PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2024
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IF 6.8
Wen Shuai,Huan Xiao,Panpan Yang,Yiwen Zhang,Faqian Bu,Yongya Wu,Qiu Sun,Guan Wang,Liang Ouyang
The RAS-RAF-MEK-ERK signaling cascade is abnormally activated in various tumors, playing a crucial role in mediating tumor progression. As the key component at the terminal stage of this cascade, ERK1/2 emerges as a potential antitumor target and offers a promising therapeutic strategy for tumors harboring BRAF or RAS mutations. Here, we identified 36c with a (thiophen-3-yl)aminopyrimidine scaffold as a potent ERK1/2 inhibitor through structure-guided optimization for hit 18. In preclinical studies, 36c showed powerful ERK1/2 inhibitory activities (ERK1/2 IC50 = 0.11/0.08 nM) and potent antitumor efficacy both in vitro and in vivo against triple-negative breast cancer and colorectal cancer models harboring BRAF and RAS mutations. 36c could directly inhibit ERK1/2, significantly block the phosphorylation expression of their downstream substrates p90RSK and c-Myc, and induce cell apoptosis and incomplete autophagy-related cell death. Taken together, this work provides a promising ERK1/2 lead compound for multiple tumor-treatment drug discovery.
研究领域:
肿瘤学
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药理学
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药物发现
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DOI
PubMed
高影响因子
MOLECULES
·
2025
·Vol. 30
·期 17
·3551
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IF 4.6
Senhao Hu,Wenjing Wang,Yu Zou,Chunmei Li,Hongyan Zou,Chengzhi Huang,Lei Zhan
The development of low-background, facile, and robust fluorescent nanoprobes for imaging and monitoring of intracellular mRNA changes remains a great challenge. Taking advantage of the high fluorescence quenching efficiency of core-shell gold@polydopamine (Au@PDA) nanocomposites and Ca 2+ -promoting DNA adsorption stability, a simple and universal bioconjugate strategy was designed to a construct fluorescent nanoprobe for highly efficient tumor-related mRNA imaging. The fluorescence of Cy5-labeled DNA was quenched up to 92.38% by the AuNP and PDA via nanometal surface energy transfer (NSET) and photoinduced electron transfer (PET), respectively. TK1 mRNA, a biomarker of tumor growth, initiates hybridization and results in fluorescence recovery, which built the foundation for identifying the expression level changes in living cells. More importantly, three kinds of tumor-related mRNA (TK1 mRNA, GalNAc-T mRNA, and C-myc mRNA) can be detected simultaneously with different fluorophore-modified recognition sequences, which can avoid false positive signals and improve the reliability of cancer diagnostic, holding great promise for cancer diagnosis, prognosis, and therapy.
研究领域:
纳米生物技术
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分子成像
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癌症诊断
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生物分析化学
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基因表达监测
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DOI
PubMed
高影响因子
ACS Applied Nano Materials
·
2024
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IF 5.3
Liangrui Lv,Wei Yuan,Juanjuan Hu,Xuyuan Chen,Tingting Zhang,Jie Cheng,Xiaoying Wang
Protein tumor marker (PTM) analysis is of great significance for the early diagnosis and process monitoring of tumors. However, the clinical reference value of a single PTM is restricted, and existing tests for multiple PTMs majorly suffer from complex processes and poor sensitivity. Herein, a cancerous inhibitor of protein phosphatase 2A (CIP2A) and protein c-Myc (AGc-Myc) with a positive feedback path in oral squamous cell carcinoma (OSCC) was chosen as a dual PTM, and a magnetic electrochemical immunosensor (MEI) for their simultaneous detection was successfully established. Fe3O4 coated with a gold nanoparticle (MAu)-functionalized magnetic electrode (f-MGE) was of benefit to immobilize two capture antibodies (CAb) through internal forces and external magnetic fields. By a mechanical alloying (MA) method, two photoelectric materials osmosed bimetallic-matrix nanospheres (Bi-MPE), including luminol and Ru(bpy)32+ osmosed AuNPs–AgNPs nanoalloy (Lu@AuAg and Ru@AuAg), were prepared as innovative signal probes. Lu@AuAg and Ru@AuAg not only exhibit superior electrochemical properties than photoelectric material osmosed monometallic-matrix nanospheres but can directly label detection antibodies (DAb) without complex reaction conditions and additional functionalization. After immunological reactions, the distinguishable differential voltammetry pulse signals were obtained at +0.48 and +1.13 V, corresponding to AGc-Myc and CIP2A, respectively. The proposed assay showed a good linear response range from 5 pg L–1 to 5 ng L–1 for AGc-Myc and 50 pg L–1 to 50 ng L–1 for CIP2A, and a low limit of detection of 2.5 pg L–1 and 25 pg mL–1, respectively. The MEI also exhibited satisfactory selectivity, stability, and reproducibility. Moreover, when the proposed method and the ELISA kit were simultaneously applied to saliva samples of OSCC patients, the obtained results were completely consistent, reflecting the clinical practicability of this work.
研究领域:
生物化学
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生物技术
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分析化学
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医学诊断
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纳米技术
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电化学
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癌症研究
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产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）