ONCOLOGY REPORTS
·
2018
·Vol. 40
·期 2
·867-876
·
IF 2.976
Zhibo Dai,Ligang Wang,Xiaoxiong Wang,Boxian Zhao,Wenyang Zhao,Shashank Singh Bhardwaj,Junyi Ye,Zhiqin Yin,Jun Zhang,Shiguang Zhao
Oxymatrine (OM), a natural quinolizidine alkaloid extracted from the traditional Chinese herb Sophora flavescens, has been revealed to produce antitumor activities in various cancer cell lines, including glioblastoma lines, in vitro. However, the mechanisms by which OM exerts its antitumor effect against glioma are poorly understood. The aim of this study was to investigate the role of OM in the proliferation, apoptosis and invasion of glioma cells and to reveal the underlying mechanisms. The effects of OM on U251MG cells in vitro were determined using a Cell Counting Kit‑8 (CCK‑8) assay, flow cytometric analysis, Annexin V‑FITC/PI staining, DAPI staining, a terminal deoxynucleotidyl transferase‑mediated dUTP nick end‑labeling (TUNEL) assay, a Transwell assay and western blotting. Our data indicated that OM inhibited proliferation, arrested the cell cycle at the G0/G1 phase, decreased the expression levels of G1 cell cycle regulatory proteins (cyclin D1, CDK4 and CDK6), inhibited invasion and induced apoptosis in glioma cells. Additional investigations revealed that the expression levels of p‑STAT3 and key proteins in the EGFR/PI3K/Akt/mTOR signaling pathway, such as p‑EGFR, p‑Akt and p‑mTOR, were markedly decreased after OM treatment, while the total STAT3, EGFR, Akt and mTOR levels were not affected. These findings indicated that the EGFR/PI3K/Akt/mTOR signaling pathway and STAT3 suppression may be a potential mechanism of the OM‑mediated antitumor effect in glioblastoma cells and that EGFR may be a target of OM. Hence, OM may be a promising drug and may offer a novel therapeutic strategy for malignant gliomas in the future.
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
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
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Translational Cancer Research
·
2026
·Vol. 15
·期 5
·378
·
IF 2.1
Zhongshun He,Aiping Huang,Jing Lv,Jing Zhou,Wenrong Lou,Biao Xu,Xuesong Wu
Background Malignant melanoma is among the most aggressive and life-threatening forms of skin cancer, and effective therapeutic treatment options remain limited. Thus, there is an urgent need to develop efficient and broadly applicable anti-melanoma drugs. Growing evidence suggests that baicalin (BAI) possesses anti-cancer potential; however, its anti-tumor mechanisms in melanoma cells remain to be fully elucidated. Therefore, this study aimed to investigate whether BAI exerts anti-melanoma effects. Methods A375 melanoma cells were treated with varying concentrations of BAI to assess its effects on cell proliferation, migration, invasion, and apoptosis. Network pharmacology analysis was then employed to predict potential molecular targets of BAI in melanoma treatment. Molecular docking was used to evaluate the binding interactions between BAI and the predicted targets. Finally, in vitro experiments were performed to investigate the regulatory effects of the potential targets on A375 cell functions. Results BAI significantly inhibited A375 cell proliferation, invasion, and migration, as well as inducing apoptosis of A375 cells in a dose-dependent manner (all P<0.05). Subsequent network pharmacology analysis identified three potential therapeutic targets of BAI, among which epidermal growth factor receptor (EGFR) exhibited strong binding affinity with BAI. Further in vitro experiments demonstrated that BAI suppressed EGFR-mediated PI3K/AKT pathway activation in a dose-dependent manner. Consistent with previous findings, EGFR overexpression exerted oncogenic effects in melanoma cells by inhibiting apoptosis. Mechanistically, BAI induced apoptosis in melanoma cells by targeting the EGFR-mediated PI3K/AKT signaling pathway. Conclusions This study demonstrates that BAI exerted cytotoxic effects on melanoma cells by targeting EGFR and inhibiting the PI3K/AKT pathway, thereby inducing apoptosis. These findings suggest that BAI may serve as a promising therapeutic candidate for the treatment of malignant melanoma.
✓ 已验证
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2020
·Vol. 8
·期 35
·7931-7940
·
IF 5.344
Man Zhang,Xuequan Zhang,Shengsheng Cai,Heng Mei,Yanmei He,Dennis Huang,Wenqiang Shi,Sai Li,Jun Cao,Bin He
Molecular targeted-photodynamic combinational therapy is a promising strategy to enhance antitumor effects; meanwhile, current nanocarriers face challenges of limited selective delivery and release of therapeutic agents to specific tumor sites, which significantly compromises their therapeutic efficacy. Herein, we report active-targeting, enzyme- and ROS-dual responsive nanoparticles (HPGBCA) consisting of CD44-targeting hyaluronic acid (HA) shells and afatinib (AFT)-loaded, ROS-sensitive poly(L-lysine)-conjugated chlorin e6 (Ce6) derivative nanoparticle cores (PGBCA). HPGBCA can actively carry AFT and Ce6 specifically to tumor cells due to the negatively charged HA and CD44-mediated active targeting. Subsequently, hyaluronidase in the endosome will further spur the degradation of the HA shell to prompt exposure of the positively charged PGBCA core for rapid endosomal escape and intracellular delivery of AFT and Ce6. Furthermore, the generation of ROS produced by Ce6 under NIR irradiation can trigger the rapid oxidation of the thioether linker to facilitate the release of AFT into the cytoplasm. In vitro and in vivo studies demonstrated that the released AFT and excessive ROS at the local site can synergistically induce cell apoptosis to enhance the therapeutic efficacy without side effects. Our developed intelligent nanoparticle provides new avenues to achieve on-demand, specific intracellular drug release for improved molecular targeted-photodynamic combination therapeutic efficacy.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Heliyon
·
2024
·
IF 3.4
Min Cai,Yangchen Mao,Wenjing Gao,Zhenzhen Wang,Jianwei Mao,Ruyi Sha
Inflammatory bowel disease (IBD) is a growing global health problem. IBD is commonly prevalent in Europe and America and the incidence rate in Asia is on the rise due to altered dietary structure. Diosgenin is a natural steroidal saponin derived from Dioscorea plants. Diosgenin is the main active ingredient of some Chinese medicines which are mainly used to treat coronary heart disease, angina and hyperlipidemia. Recently, growing evidence has exhibited a crucial role of diosgenin and dioscin in alleviating IBD in multiple ways. However, the precise mechanism of diosgenin against IBD needs further exploration. In this study, network pharmacological and systematic bioinformatic analyses were performed to investigate the diosgenin's targets against IBD. 71 targets such as SRC, TNF and STAT3 were identified as overlapped genes between diosgenin and IBD. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis exhibited their involvement in the tyrosine kinase signaling pathway and its membrane receptors. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance and its downstream Ras-MAPK pathway and PI3K-Akt pathway might become the mechanism of diosgenin against IBD. In addition, molecular docking analysis showed that diosgenin has the massive potential of direct binding to tyrosine kinase and its receptors such as SRC, EGFR, FGFR1 and VEGFR. The results above collectively provided evidence that diosgenin is a promising nutraceutical food against IBD.
研究领域:
药理学
·
分子生物学
·
生物信息学
·
功能性食品
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Redox Biology
·
2017
·
IF 6.337
Dan-Qian Chen,Gang Cao,Hua Chen,Dan Liu,Wei Su,Xiao-Yong Yu,Nosratola D. Vaziri,Xiu-Hua Liu,Xu Bai,Li Zhang,Ying-Yong Zhao
Changes in plasma concentration of small organic metabolites could be due to their altered production or urinary excretion and changes in their urine concentration may be due to the changes in their filtered load, tubular reabsorption, and/or altered urine volume. Therefore, these factors should be considered in interpretation of the changes observed in plasma or urine of the target metabolite(s). Fasting plasma and urine samples from 180 CKD patients and 120 age-matched healthy controls were determined by UPLC-HDMS-metabolomics and quantitative real-time RT-PCR techniques. Compared with healthy controls, patients with CKD showed activation of NF-κB and up-regulation of pro-inflammatory and pro-oxidant mRNA and protein expression as well as down-regulation of Nrf2-associated anti-oxidant gene mRNA and protein expression, accompanied by activated canonical Wnt/β-catenin signaling. 124 plasma and 128 urine metabolites were identified and 40 metabolites were significantly altered in both plasma and urine. Plasma concentration and urine excretion of 25 metabolites were distinctly different between CKD and controls. They were related to amino acid, methylamine, purine and lipid metabolisms. Logistic regression identified four plasma and five urine metabolites. Parts of them were good correlated with eGFR or serum creatinine. 5-Methoxytryptophan and homocystine and citrulline were good correlated with both eGFR and creatinine. Clinical factors were incorporated to establish predictive models. The enhanced metabolite model showed 5-methoxytryptophan, homocystine and citrulline have satisfactory accuracy, sensitivity and specificity for predictive CKD. The dysregulation of CKD was related to amino acid, methylamine, purine and lipid metabolisms. 5-methoxytryptophan, homocystine and citrulline could be considered as additional GFR-associated biomarker candidates and for indicating advanced renal injury. CKD caused dysregulation of the plasma and urine metabolome, activation of inflammatory/oxidative pathway and Wnt/β-catenin signaling and suppression of antioxidant pathway.
研究领域:
肾病学
·
代谢组学
·
分子生物学
·
临床化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ANALYTICAL BIOCHEMISTRY
·
2015
·
IF 2.219
Javier Batista Perez,Deependra Tyagi,Mo Yang,Loany Calvo,Rolando Perez,Ernesto Moreno,Jinsong Zhu
Self-assembled monolayers designed to immobilize capture antibodies are usually prepared using a mixture of functional and inactive linkers. Here, using low molar ratios (1:1 to 1:100) of the two linkers resulted in loss of binding capability of the anti-EGFR (epidermal growth factor receptor) antibody nimotuzumab, as assessed by surface plasmon resonance imaging. We then developed a simple theoretical model to predict the optimal surface density of the functional linker, taking into account the antibody size and linker diameter. A high (1:1000) dilution of the functional linker yielded the best results. As an advantage, this approach does not require chemical modification of the protein.
研究领域:
生物化学
·
分子生物学
·
生物物理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2019
·Vol. 8
·期 23
·1900965
·
IF 6.27
Yao Yang,Zhengwei Huang,Jinyuan Li,Ziran Mo,Ying Huang,Cheng Ma,Wenhao Wang,Xin Pan,Chuanbin Wu
Combination therapy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR TKIs) with other chemotherapeutic agents is a feasible strategy to overcome resistance that often occurs after 9–13 months of EGFR TKIs administration in nonsmall cell lung cancer (NSCLC). In this study, a pulmonary microspheres system that codelivers afatinib and paclitaxel (PTX) is developed for treatment of EGFR TKIs resistant NSCLC. In this system, afatinib is loaded in stearic acid-based solid lipid nanoparticles, then these nanoparticles and PTX are loaded in poly-lactide- co -glycolide-based porous microspheres. These inhaled microspheres systems are characterized including geometric particle size, drug encapsulation efficiency, morphology by scanning electron microscopy, specific surface area, in vitro drug release, and aerodynamic particle size. Cell experiments indicate that afatinib and PTX have a synergistic effect and the codelivery system shows a superior treatment effect in drug-resistant NSCLC cells. The biocompatibility, pharmacokinetic, and tissue distribution experiments in Sprague–Dawley rats show that afatinib and PTX in the system can maintain 96 h of high lung concentration but low concentration in other tissues, with acceptable safety. These results demonstrate that this system may be a prospective delivery strategy for drug combination treatment in cancers developing resistance, especially drug-resistant lung cancer.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2020
·
IF 8.758
Bing-Chen Zhang,Bang-Yue Luo,Jun-Jie Zou,Peng-Yu Wu,Jia-Li Jiang,Jing-Qing Le,Rui-Rui Zhao,Lu Chen,Jing-Wei Shao
The rapid development of CRISPR/Cas9 systems has opened up tantalizing prospects to sensitize cancers to chemotherapy using efficient targeted genome editing, but safety concerns and possible off-target effects of viral vectors remain a major obstacle for clinical application. Thus, the construction of novel nonviral tumor-targeting nanodelivery systems has great potential for the safe application of CRISPR/Cas9 systems for gene–chemo-combination therapy. Here, we report a polyamidoamine-aptamer-coated hollow mesoporous silica nanoparticle for the co-delivery of sorafenib and CRISPR/Cas9. The core–shell nanoparticles had good stability, enabled ultrahigh drug loading, targeted delivery, and controlled-release of the gene–drug combination. The nanocomplex showed >60% EGFR-editing efficiency without off-target effects in all nine similar sites, regulating the EGFR-PI3K-Akt pathway to inhibit angiogenesis, and exhibited a synergistic effect on cell proliferation. Importantly, the co-delivery nanosystem achieved efficient EGFR gene therapy and caused 85% tumor inhibition in a mouse model. Furthermore, the nanocomplex showed high accumulation at the tumor site in vivo and exhibited good safety with no damage to major organs. Due to these properties, the nanocomplex provides a versatile delivery approach for efficient co-loading of gene–drug combinations, allowing for precise gene editing and synergistic inhibition of tumor growth without apparent side effects on normal tissues.
研究领域:
癌症治疗
·
分子生物学
·
纳米技术
·
基因组编辑
✓ 已验证
DOI
PubMed
高影响因子
Metabolites
·
2024
·Vol. 14
·期 4
·224
·
IF 3.4
Jianing Ren,Jing Dai,Yue Chen,Zhenzhen Wang,Ruyi Sha,Jianwei Mao,Yangchen Mao
Rice (Oryza sativaL.) is one of the primary sources of energy and nutrients needed by the body, and rice resistant starch (RRS) has been found to have hypoglycemic effects. However, its biological activity and specific mechanisms still need to be further elucidated. In the present study, 52 RRS differential metabolites were obtained from mouse liver, rat serum, canine feces, and human urine, and 246 potential targets were identified through a literature review and database analysis. A total of 151 common targets were identified by intersecting them with the targets of type 2 diabetes mellitus (T2DM). After network pharmacology analysis, 11 core metabolites were identified, including linolenic acid, chenodeoxycholic acid, ursodeoxycholic acid, deoxycholic acid, lithocholic acid, lithocholylglycine, glycoursodeoxycholic acid, phenylalanine, norepinephrine, cholic acid, and L-glutamic acid, and 16 core targets were identified, including MAPK3, MAPK1, EGFR, ESR1, PRKCA, FYN, LCK, DLG4, ITGB1, IL6, PTPN11, RARA, NR3C1, PTPN6, PPARA, and ITGAV. The core pathways included the neuroactive ligand–receptor interaction, cancer, and arachidonic acid metabolism pathways. The molecular docking results showed that bile acids such as glycoursodeoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, lithocholic acid, deoxycholic acid, and cholic acid exhibited strong docking effects with EGFR, ITGAV, ITGB1, MAPK3, NR3C1, α-glucosidase, and α-amylase. In vitro hypoglycemic experiments further suggested that bile acids showed significant inhibitory effects on α-glucosidase and α-amylase, with CDCA and UDCA having the most prominent inhibitory effect. In summary, this study reveals a possible hypoglycemic pathway of RRS metabolites and provides new research perspectives to further explore the therapeutic mechanism of bile acids in T2DM.
研究领域:
药理学
·
生物化学
·
分子生物学
·
糖尿病研究
·
营养学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
·
2024
·
IF 3.1
Tang Yu,Xian Zhengping,Wu Fengjiao,Cao Hongyu,Wang Lihao,Tang Qian,Du Yanan,Zheng Xuefang
In the course of clinical treatment for anti-tumor, the combination of traditional Chinese medicine (TCM) and other treatment schemes can reduce toxicity and increase efficiency. The purpose of this paper is to find out the key TCM and effective components for the treatment of non-small cell lung cancer (NSCLC) and analyze its therapeutic mechanism by analyzing the prescription of TCM combined with chemotherapy for NSCLC. Firstly, the prescriptions of TCM in the randomized controlled trials combined with chemotherapy for NSCLC were collected, and the core TCM was screened by frequency statistics, association rule analysis, and cluster analysis. Then, the intersection targets of the potential effects of NSCLC and core Chinese medicine were collected, and PPI analysis and enrichment analysis were performed on the intersection targets to screen the core targets, components, and pathways. The core components were verified by molecular docking and cell experiments. In this study, 269 prescriptions were collected, among which the frequency of medication for Astragalus membranaceus (HQ, in Chinese), Wolfiporia cocos (FL, in Chinese), and Atractylodes macrocephala (BZ, in Chinese) was over 100. Association rule analysis showed that they were highly correlated and clustered into the same category in cluster analysis. Their core components were quercetin, kaempferol, and isorhamnetin. The molecular docking results of the core components with the core targets AKT1 and EGFR obtained by PPI network analysis showed that they could bind stably. KEGG analysis screened 110 pathways including PI3K-Akt; the results of CCK-8 showed that quercetin, kaempferol, and isorhamnetin could effectively inhibit the proliferation of A549 cells, and isorhamnetin had the best inhibitory effect. Isorhamnetin can inhibit the migration and invasion of A549 cells, induce apoptosis and G1 phase arrest, and decrease the expression of P-PI3K and P-AKT in A549 cells. In a word, the key TCM for the treatment of NSCLC includes HQ, FL, and BZ. and its key components quercetin, kaempferol, and isorhamnetin have potential therapeutic effects on NSCLC according to the research results. Graphical Abstract
研究领域:
肿瘤学
·
药理学
·
中医
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2025
·
IF 4.7
Menglong Zhao,Danqing Wu,Weiqian Qiu,Hongchen Zhang,Min Chen,Haixia Zhou,Xiaoxia Ye,Zhong Han,Xiangchao Shi
4-anilinoquinazoline scaffold, a key structure in the development of EGFR-TKI anticancer drugs such as Gefitinib and Erlotinib, continues to drive advancements in non-small cell lung cancer (NSCLC) therapy. In this study, we synthesized a series of novel derivatives ( B3–B11 ). Structure-activity relationship (SAR) analysis revealed that electron-donating groups para-substituted at the 4-anilino position significantly enhanced antiproliferative activity. Notably, B10 incorporating an acrylamide group at the 4-anilino position demonstrated the most potent activity against NSCLC, with an IC 50 of 1.28 μM in A549 cells, nearly six times more effective than Gefitinib (7.81 μM). Acute toxicity studies confirmed that B10 is safe at doses below 50 mg/kg. In vivo studies using an A549 xenograft model showed a 46 % tumor growth inhibition (TGI) with B10 (25 mg/kg), surpassing the 21 % inhibition of Gefitinib at the same dose. Mechanistic studies revealed that B10 inhibited the AKT/GSK-3β/β-catenin signaling pathway, downregulating Wnt target genes (c-Myc, c-Jun), and reduced COX2 expression and IL-8 levels, showcasing its dual anti-inflammatory and antitumor effects. These results position B10 as a promising NSCLC therapeutic candidate, combining potent efficacy with a favorable safety profile, and enhance our understanding of the SAR and mechanism of action of 4-anilinoquinazoline derivatives.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
药物化学
✓ 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）