INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2025
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IF 5.2
Xiaoyu Hu,Jun Liu,Qingrong Wang,Qiongkun Hu,Hao Sun,Shi Wang,Yu Zhao,Liwei Gu,Jianying Shen,Qinghe Zhao,Feng Sui,Hai Ma
Gemcitabine, a chemotherapeutic agent widely approved for treating various cancers, faces significant clinical challenges, including drug resistance and poor tumor selectivity. To address the limitation of inadequate tumor targeting, a peptide chain was developed to specifically bind to colon cancer cells and conjugated to gemcitabine via aldehyde–amine condensation. This study aimed to exploit the oncogenic activity of the multifunctional protein α-Enolase (ENO1). The therapeutic efficacy of gemcitabine conjugated with the ENO1-targeting peptide (GCB-P) was evaluated through in vitro and in vivo experiments. Cytotoxicity assays and protein blotting analyses were performed on cell lines, including NCM-460, HCT116 and SW620. GCB-P exhibited significantly enhanced selectivity and potency against colon cancer cells compared to gemcitabine alone, with minimal cytotoxicity to normal colorectal cells. In addition, GCB-P demonstrated superior tumor-selective accumulation and release at the tumor site, as evidenced by in vivo metabolic analyses. These findings underscore the potential of GCB-P as an effective colon cancer treatment with reduced off-target toxicity. Furthermore, GCB-P displayed acid-responsive properties, facilitating precise delivery to tumor sites with the aid of homing peptides. These results highlight the promise of ENO1-targeted peptide modification for gemcitabine in developing targeted drug delivery systems for colon cancer.
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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产品关联
DOI
PubMed
高影响因子
Cancers
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2020
·Vol. 12
·期 2
·311
·
IF 6.126
Weiyi Zhang,Jie Gao,Chuanjing Cheng,Man Zhang,Wenjuan Liu,Xiaoyao Ma,Wei Lei,Erwei Hao,Xiaotao Hou,Yuanyuan Hou,Gang Bai
At present, melanoma is a common malignant tumor with the highest mortality rate of all types of skin cancer. Although the first option for treating melanoma is with chemicals, the effects are unsatisfactory and include poor medication response and high resistance. Therefore, developing new medicines or a novel combination approach would be a significant breakthrough. Here, we present cinnamaldehyde (CA) as a potential candidate, which exerted an antitumor effect in melanoma cell lines. Chemical biology methods of target fishing, molecular imaging, and live cell tracing by an alkynyl–CA probe revealed that the α-enolase (ENO1) protein was the target of CA. The covalent binding of CA with ENO1 changed the stability of the ENO1 protein and affected the glycolytic activity. Furthermore, our results demonstrated that dacarbazine (DTIC) showed a high promoting effect with CA for antimelanoma both in vivo and in vitro. The combination improved the DTIC cell cycle arrest in the S phase and markedly impacted melanoma growth. As a covalent inhibitor of ENO1, CA combined with DTIC may be beneficial in patients with drug resistance in antimelanoma therapy.Keywords:cinnamaldehyde;α-enolase (ENO1);covalent inhibitor;dacarbazine;antimelanoma
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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DOI
PubMed
高影响因子
LIFE SCIENCES
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2020
·
IF 3.647
Weiyi Zhang,Jie Gao,Fukui Shen,Xiaoyao Ma,Zhihua Wang,Xiaotao Hou,Erwei Hao,Yuanyuan Hou,Gang Bai
Aims Hepatic glucose metabolism involves a variety of catabolic and anabolic pathways, and the dynamic balance of glucose metabolism is regulated in response to environmental and nutritional changes. The molecular mechanism of glucose metabolism in liver is complex and has not been fully elucidated so far. In this study, we hope to elucidate the target and mechanism of cinnamaldehyde (CA) in regulating glucose metabolism. Materials and methods Molecular image tracing and magnetic capture in combination with an alkynyl-CA probe (Al-CA) was used to show CA covalently binds to α-enolase (ENO1) in both mouse liver and HepG2 cells. Accurate metabolic flow assays subsequently demonstrated that the utilization of glycogenic amino acids and the biosynthesis of tricarboxylic acid (TCA) cycle intermediates were strengthened, which was detected using nontargeted and targeted metabolomics analyses. Key findings Our study shows that CA covalently bonds with ENO1, which affects the stability and activity of ENO1 and changes the dynamic balance of glucose metabolism. The interruption of gluconeogenic reflux by ENO1 enhanced TCA cycle, and eventually led to a decrease in blood glucose and the improvement of mitochondrial efficiency. Significance These results provide a detailed description of how CA maintains the dynamic balance of glucose utilization and improves energy metabolism.
研究领域:
药理学
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代谢
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2018
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IF 3.974
Xianyun Zheng,Ye Gao,Wanghong Li,Shu Wang
Propsilocerus akamusi (Tokunaga) is a common species of midge in Siberia , Japan, and China and an important prey species for fish and aquatic birds. Furthermore, this species has been shown to have an extraordinary capacity to resist cadmium (Cd) toxicity. In this study, isobaric tags for relative and absolute quantitation (iTRAQ) coupled liquid chromatography tandem mass spectrometry (LC-MS/MS) was used to analyze relative changes in the P. akamusi hemolymph proteome following exposure to a sublethal concentration of Cd 2+ . The results showed that Cd 2+ stress affects energy metabolism in P. akamusi . After examining the differentially expressed proteins (DEPs), only one up-regulated protein associated with metabolism, α-enolase (Eno1) was identified and further isolated and characterized. Sequence alignments showed that the deduced P. akamusi Eno1 amino acid sequence is highly conserved, with similarities of 77–95% noted when compared to other Dipteran Eno1 sequences. Furthermore, prolonged Cd 2+ exposure impacted Eno1 transcription, protein expression and enzyme activity levels. These results suggest that Eno1 may play a role in the response to Cd 2+ stress in P. akamusi .
研究领域:
环境毒理学
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蛋白质组学
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昆虫生理学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2024
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IF 5.3
Jun Liu,Xiaoyu Hu,Guanghao Yu,Qingrong Wang,Liwei Gu,Jianying Shen,Qinghe Zhao,Hao Sun,Shi Wang,Zhongyuan Guo,Yu Zhao,Hai Ma
Alpha-enolase (ENO1), a multifunctional protein with carcinogenic properties, has emerged as a promising cancer biomarker because of its differential expression in cancer and normal cells. On the basis of this characteristic, we designed a cell-targeting peptide that specifically targets ENO1 and connected it with the drug doxorubicin (DOX) by aldehyde–amine condensation. A surface plasmon resonance (SPR) assay showed that the affinity for ENO1 was stronger (KD = 2.5 µM) for the resulting cell-targeting drug, DOX-P, than for DOX. Moreover, DOX-P exhibited acid-responsive capabilities, enabling precise release at the tumor site under the guidance of the homing peptide and alleviating DOX-induced cardiotoxicity. An efficacy experiment confirmed that, the targeting ability of DOX-P toward ENO1 demonstrated superior antitumor activity against colorectal cancer than that of DOX, while reducing its toxicity to cardiomyocytes. Furthermore, in vivo metabolic distribution results indicated low accumulation of DOX-P in nontumor sites, further validating its targeting ability. These results showed that the ENO1-targeted DOX-P peptide has great potential for application in targeted drug-delivery systems for colorectal cancer therapy.
研究领域:
药理学
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肿瘤学
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药物递送系统
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癌症生物学
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产品关联
DOI
PubMed
高影响因子
AGING CELL
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2024
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IF 8
Xueling He,Chen Wang,Qianyu Zhang,Tong Yang,Qiuyan Guo,Yaxu Wang,Jiayue Guo,Pengjie Wang,Junzhe Zhang,Huan Tang,Yinhua Zhu,Jigang Wang
Cellular senescence plays a critical role in repeated ultraviolet (UV) exposure-induced skin photoaging. Currently, from the perspective of regulating senescent cells, potent compounds or reliable protein targets that could effectively prevent skin photoaging have not yet been reported. Herein, we demonstrated that chlorogenic acid (CGA) significantly inhibited UVA-induced senescence of human dermis skin fibroblasts (HDF) cells by screening the natural product library. The activity-based protein profiling (ABPP) result revealed that Enolase 1 (ENO1) is one of the direct targets of CGA in HDF cells. Further mechanism research indicated that CGA covalently binds to ENO1, and prevented UVA-induced cellular senescence by suppressing the activity of ENO1 protein to block the glycolytic pathway. Importantly, we found that CGA dose-dependently reduced the skin wrinkle score, alleviated skin pathological features and inhibited senescent characteristics in a photoaging mouse model. The proteomic analysis revealed that CGA treatment effectively inhibited senescence-associated secretory phenotype (SASP) secretion and glycolysis in skin samples of mice. Collectively, our study not only demonstrated that inhibiting cell senescence is an effective anti-skin photoaging strategy, but also revealed that ENO1 is a promising protein target to prevent photoaging.
研究领域:
药理学
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皮肤病学
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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
Microbiology Spectrum
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2022
·Vol. 10
·期 4
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IF 9.043
Liping Li,Hui Lu,Xuan Zhang,Malcolm Whiteway,Hao Wu,Shanlun Tan,Jianye Zang,Shujuan Tian,Cheng Zhen,Xianlei Meng,Wanqian Li,Dazhi Zhang,Min Zhang,Yuanying Jiang
Baicalein (BE) is a promising antifungal small-molecule compound with an extended antifungal spectrum, good synergy with fluconazole, and low toxicity, but its target protein and antifungal mechanism remain elusive. In this study, we found that BE can function against Candida albicans by disrupting glycolysis through targeting Eno1 and inhibiting its function. Eno1 acts as a key therapeutic target of the drug, as BE had no antifungal activity against the eno1 null mutant in a Galleria mellonella model of C. albicans infection. To investigate the mechanism of action, we solved the crystal structure of C. albicans Eno1(CaEno1) and then compared the difference between this structure and that of Eno1 from humans. The predicted primary binding site of BE on CaEno1 is between amino acids D261 and W274, with D263, S269, and K273 playing critical roles in the interaction with BE. Both positions S269 and K273 have different residues in the human Eno1 (hEno1). This finding suggests that BE may bind selectively to CaEno1, which would limit the potential for side effects in humans. Our findings demonstrate that Eno1 is a target protein of BE and thus may serve as a novel target for the development of antifungal therapeutics acting through the inhibition of glycolysis.IMPORTANCE Baicalein (BE) is a promising antifungal agent which has been well characterized, but its target protein is still undiscovered. The protein Eno1 plays a crucial role in the survival of Candida albicans. However, there are few antifungal agents which inhibit the functions of Eno1. Here, we found that BE can function against Candida albicans by disrupting glycolysis through targeting Eno1 and inhibiting its function. We further solved the crystal structure of C. albicans Eno1(CaEno1) and predicted that the primary binding site of BE on CaEno1 is between amino acids D261 and W274, with D263, S269, and K273 playing critical roles in the interaction with BE. Our findings will be helpful to get specific small-molecule inhibitors of CaEno1 and open the way for the development of new antifungal therapeutics targeted at inhibiting glycolysis.
研究领域:
微生物学
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药理学
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分子生物学
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结构生物学
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DOI
高影响因子
American Journal of Cancer Research
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2021
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IF 6.166
Yuanfeng Gou,Fei Li,Xiaqin Huo,Chunyan Hao,Xiaojuan Yang,Yaping Pei,Na Li,Huiling Liu,Bingdong Zhu
α-enolase (ENO1), highly expressing in cell membranes, cytoplasm and nuclei of cervical cancer and other tumors, acts as a plasminogen receptor and a glycolytic enzyme. ENO1 is found to be associated with tumorigenesis, invasion and migration, and proves to be an ideal target of tumor therapy. In this study, ENO1 monoclonal antibodies (ENO1mAb) was prepared to blockade ENO1 and the therapeutic role was observed in cervical cancer cells. First, ENO1mAb was prepared and screened by evaluating the inhibitory effect on migration and invasion of cervical cancer cells, which is supposed to block ENO1 expressed on cell membrane. Second, folic acid (FA) conjugated PLGA nanoparticles (FA-SS-PLGA) targeting tumor cells were prepared to mediate ENO1mAb entry into cells and its anti-tumor effects were investigated in vitro . We found that PLGA/FA-SS-PLGA nanoparticles-mediated ENO1mAb could antagonize the activity of ENO1 enzyme, significantly decreased the contents of lactic acid and pyruvate, and inhibited the proliferation, migration and clone formation of cervical cancer cells compared with the sham control ( P < 0.05). In summary, ENO1mAb could specifically block ENO1 expressed on cell membrane and inhibit ENO1 glycolysis enzyme activity inside tumor cells, and plays a therapeutic role against cervical cancer cells. It suggests that ENO1mAb has promising anti-tumor effects.
研究领域:
肿瘤学
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药学
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分子生物学
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DOI
PubMed
高影响因子
MOLECULAR NUTRITION & FOOD RESEARCH
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2022
·Vol. 66
·期 11
·2100963
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IF 6.575
Xiaoyao Ma,Kaixin Liu,Yiman Han,Yongping Bai,Fukui Shen,Mukuo Wang,Wei Wei,Jianfeng Qin,Erwei Hao,Xiaotao Hou,Yuanyuan Hou,Gang Bai
Scope Glutamate (Glu) and γ-aminobutyric acid (GABA) are the major excitatory and inhibitory neurotransmitters that control information flow in the brain. GABA dysfunction is a general vulnerability factor for mental illness. Cinnamaldehyde (CA) is found to have sedation in a mental illness model. However, the specific targets and molecular mechanisms related to the sedative effects of CA have not been elucidated. Methods and Results Metabolomics analysis and target fishing showed CA could increase the expression of GABA in vivo, and α-enolase (ENO1) is the primary target protein of CA associated with sedation. CA mainly binds with ENO1 in the cerebellar granular layer of brain, which influences the first transformations of the input signals arriving in the cerebellar cortex. The α,β-unsaturated aldehyde group of CA blocks the hydroxy group of Ser40, which induces a loss in ENO1 activation. CA also disturbs the glycolysis pathway and influences the tricarboxylic acid cycle and oxidative phosphorylation, which activate gluconeogenesis to provide energy to the brain. This mechanism is verified in zebrafish with ENO1 or glutamic acid decarboxylase (GAD) deficiency. Conclusions CA demonstrates sedation and alleviates GABA dysfunction via covalent binding ENO1, which shows the potential to improve the therapy of mental illness.
研究领域:
神经科学
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药理学
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分子生物学
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生物化学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
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2024
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IF 2.7
Hongmei Chang,Siqi Zhao,Yuzhu Lei,Yunhua Hu,Yizhong Yan,Guanling Song
Titanium dioxide nanoparticles (nano-TiO 2 ) can cause a reduction in sperm counts, and lactate production in Sertoli cells plays a key role in spermatogenesis. The aim of this study was to evaluate the effect of nano-TiO 2 on lactate production in mouse Sertoli cell line (TM4 cells) and to investigate whether the effect is mediated through the PI3K/AKT/HIF-1α pathway. After TM4 cells were treated with different concentrations of nano-TiO 2 for 48 h, cell viability, contents of glucose and lactate, and the expression levels of GLUT3 and key enzymes (HK1, HK2, PFKM, ENO1, LDH) during lactate production were detected. PI3K/AKT/HIF-1α pathway proteins were measured. In addition, PI3K agonist (IGF-1) was added to explore whether nano-TiO 2 regulates HIF-1α through PI3K/AKT pathway, thereby affecting the production of lactate in TM4 cells. The results showed that nano-TiO 2 significantly inhibited TM4 cell viability, increased glucose content, decreased lactate content, and downregulated the expression levels of GLUT3 and key enzymes during lactate production. Meanwhile, nano-TiO 2 decreased the expression of PI3K/AKT pathway phosphorylated proteins and HIF-1α, and IGF attenuated this effect of nano-TiO 2 . Collectively, nano-TiO 2 downregulated the expression level of proteins and enzymes related to lactate production in TM4 cells by inhibiting PI3K/AKT/HIF-1α pathway, resulting in the decrease of lactate production in TM4 cells.
研究领域:
生殖生物学
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细胞生物学
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纳米技术
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分子生物学
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DOI
PubMed
高影响因子
Molecular Biomedicine
·
2026
·Vol. 7
·期 1
·129
·
IF 13
Wang Zhengshi,Jia Chengyou,Liu Yongqiang,Rixiati Youlutuziayi,Zhang Wentao,Mao Shiyu,Chen Haotian,Zou Libin,Ye Chen,Shen Bing,Yao Xudong
Prostate cancer (PCa) is one of the most common cancers in males, and its treatment remains challenging due to the tumor microenvironment (TME) with immunosuppressive properties and limited response to anti-PD-1 therapy. Gut microbiota-derived metabolites have recently emerged as modulators of cancer immunometabolism, however, their role in PCa progression and immunotherapy is poorly understood. Here we found that indole-3-lactic acid (ILA), a metabolite produced by Lactobacillus plantarum , exerted dual anti-tumor effects on PCa cells and the TME. Mechanistically, ILA activates the aryl hydrocarbon receptor (AHR), and the resulting AHR/ARNT heterodimer translocates into the nucleus and binds to the promoter of ASF1B. This heterodimer then recruits the HDAC1/2-NuRD complex to reduce H3K27ac levels and suppress ASF1B expression. ASF1B binds to specific residues of ENO1 via its N-terminal core domain and enhances ENO1 enzymatic activity. ILA-induced downregulation of ASF1B impairs this interaction, reduces ENO1 activity, and suppresses the PI3K/Akt pathway, thereby inhibiting the malignant phenotypes of PCa cells. Concurrently, ILA decreased CXCL8 secretion by inhibiting the PI3K/Akt/NF-κB pathway, enhancing CD8 + T cell infiltration and M1 macrophage polarization, thereby remodeling the TME. Additionally, ILA synergized with anti-PD-1 therapy to more effectively suppress tumor growth. These findings reveal a novel mechanism by which gut microbiota-derived metabolites regulate PCa progression and immunometabolism, positioning ILA as a potential therapeutic agent to improve PCa treatment.
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DOI
高影响因子
PROTEOMICS
·
2022
·Vol. 23
·期 2
·2200362
·
IF 5.393
Huichun Shi,Siyuan Liu,Zhimi Tan,Lin Yin,Liyan Zeng,Tiefu Liu,Shuye Zhang,Lijun Zhang
Enterovirus A71 (EV71) infection can cause hand, foot, and mouth disease (HFMD) and severe neurological complications in children. However, the biological processes regulated by EV71 remain poorly understood. Herein, proteomics and metabonomics studies were conducted to uncover the mechanism of EV71 infection in rhabdomyosarcoma (RD) cells and identify potential drug targets. Differential expressed proteins from enriched membrane were analyzed by isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomics technology. Twenty-six differential proteins with 1.5-fold ( p < 0.05) change were detected, including 14 upregulated proteins and 12 downregulated proteins. The upregulated proteins are mainly involved in metabolic process, especially in the glycolysis pathway. Alpha-enolase (ENO1) protein was found to increase with temporal dependence following EV71 infection. The targeted metabolomics analysis revealed that glucose absorption and glycolysis metabolites were increased after EV71 infection. The glycolysis pathway was inhibited by knocking down ENO1 or the use of a glycolysis inhibitor (dichloroacetic acid [DCA]); and we found that EV71 infection was inhibited by depleting ENO1 or using DCA. Our study indicates that EV71 may reprogram glucose metabolism by activating glycolysis, and EV71 infection can be inhibited by interrupting the glycolysis pathway. ENO1 may be a potential target against EV71, and DCA could act as an inhibitor of EV71.
研究领域:
病毒学
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蛋白质组学
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代谢组学
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分子生物学
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细胞生物学
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传染病学
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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）