Nano Today
·
2024
·
IF 13.2
Jiaying Jin,Yijia Li,Feiyang Deng,Long Yang,Yuxing Lin,Canyu Yang,Wenbing Dai,Hua Zhang,Bing He,Qiang Zhang,Xueqing Wang
KRAS gene is mutated in 40 % of colorectal cancers (CRC), which induces malignant proliferation by regulating cellular nutrient metabolism and biosynthesis. It has been found that malignant proliferation of KRAS-mutant colorectal cancer relies on the upregulation of SLC25A22 protein expression, suggesting that inhibition the expression of both KRAS and SLC25A22 is a potential CRC therapeutics. Stably knocking down the oncogenic KRAS-G12V gene can achieve long-term gene therapy effects, while transient downregulation of SLC25A22, a normal functional gene most of the time, is preferred to kill tumor cells and minimize the side impact on normal cells. Here, two lipid nanoparticles (LNP) were designed to encapsulate KRAS-G12V CRISPR/Cas9 gene editing plasmids (pKRAS-LNPs) and SLC25A22 siRNA (siSLC-LNPs), respectively. Therapeutic effects of both nanoparticles alone and in combination on KRAS-G12V mutant colorectal cancer cells in vitro were first examined. The result showed that delivery of pKRAS-LNPs or siSLC-LNPs alone could effectively achieve KRAS-G12V gene editing or SLC25A22 gene silencing and inhibit tumor cell proliferation, while co-delivery of both LNPs could achieve stronger inhibition of tumor cell proliferation by inducing stronger apoptosis. Furthermore, we found that co-delivery of pKRAS-LNPs and siSLC-LNPs induced stronger apoptosis and cell proliferation inhibition compared to pKRAS&siSLC-LNPs that were constructed by pre-mixing pKRAS and siSLC and then encapsulating them. Finally, we validated that co-delivery of pKRAS-LNPs and siSLC-LNPs can achieve KRAS-G12V colorectal cancer treatment in vivo with a tumor inhibition rate of 61.15 %. In summary, the delivery vectors constructed for nucleic acids targeting KRAS and SLC25A22 achieved therapeutic targeting of KRAS-G12V colorectal cancer in vitro and in vivo .
研究领域:
肿瘤学
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分子生物学
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基因治疗
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癌症研究
✓ 已验证
DOI
高影响因子
Journal of Materials Chemistry B
·
2024
·Vol. 12
·期 26
·6442-6451
·
IF 6.1
Jia-Hao Bai,Qing-Tao Yu,Yi-Wu Wang,Chun-Fa Chen,Lian-Ju Ma,Yue Yuan,Yong-Jun Gan,Jia-Qi Yang,Shu Zhu,Yu-Hang Ran,Li-Lei Zhang,Hang Qian,Zheng-Huan Zhao,Qian Liu
Self-assembled DNA nanostructures hold great promise in biosensing, drug delivery and nanomedicine. Nevertheless, challenges like instability and inefficiency in cellular uptake of DNA nanostructures under physiological conditions limit their practical use. To tackle these obstacles, this study proposes a novel approach that integrates the cationic polymer polyethyleneimine (PEI) with DNA self-assembly. The hypothesis is that the positively charged linear PEI can facilitate the self-assembly of DNA nanostructures, safeguard them against harsh conditions and impart them with the cellular penetration characteristic of PEI. As a demonstration, a DNA nanotube (PNT) was successfully synthesized through PEI mediation, and it exhibited significantly enhanced stability and cellular uptake efficiency compared to conventional Mg2+-assembled DNA nanotubes. The internalization mechanism was further found to be both clathrin-mediated and caveolin-mediated endocytosis, influenced by both PEI and DNA. To showcase the applicability of this hybrid nanostructure for biomedical settings, the KRAS siRNA-loaded PNT was efficiently delivered into lung adenocarcinoma cells, leading to excellent anticancer effects in vitro. These findings suggest that the PEI-mediated DNA assembly could become a valuable tool for future biomedical applications.
研究领域:
纳米医学
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癌症治疗
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分子生物学
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DOI
PubMed
高影响因子
BIOORGANIC & MEDICINAL CHEMISTRY
·
2023
·
IF 3.5
Lu Liu,Zhendong Song,Guangjin Fan,Linlin Lou,Yuanxiang Wang,Xiaolei Zhang,Xiao-Feng Xiong
KRAS serves as a vital regulator for cellular signaling and drives tumor pathogenesis after mutation. Despite extensive research efforts spanning several decades, targeting KRAS is still challenging due to the multiple KRAS mutations and the emergence of drug resistance. Interfering the interactions between KRAS and SOS1 is one of the promising approaches for modulating KRAS functions. Herein, we discovered small-molecule SOS1 agonists with novel indazole scaffold. Through structure-based optimization, compound 11 was identified with high SOS1 activation potency (p-ERK EC 50 = 1.53 μM). In HeLa cells, compound 11 enhances cellular RAS-GTP levels and exhibits biphasic modulation of ERK1/2 phosphorylation through an on-target mechanism and presents the therapeutic potential to modulate RAS signaling by activating SOS1.
研究领域:
肿瘤学
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分子生物学
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药物化学
✓ 已验证
DOI
PubMed
高影响因子
Pharmaceutics
·
2021
·Vol. 13
·期 9
·1428
·
IF 6.321
Dandan Luo,Xiaochun Xu,M. Zubair Iqbal,Qingwei Zhao,Ruibo Zhao,Jabeen Farheen,Quan Zhang,Peiliang Zhang,Xiangdong Kong
Pancreatic carcinoma (PC) is greatly induced by theKRASgene mutation, but effective targeted delivery for gene therapy has not existed. Small interfering ribonucleic acid (siRNA) serves as an advanced therapeutic modality and holds great promise for cancer treatment. However, the development of a non-toxic and high-efficiency carrier system to accurately deliver siRNA into cells for siRNA-targeted gene silencing is still a prodigious challenge. Herein, polyethylenimine (PEI)-modified hydroxyapatite (HAp) nanoparticles (HAp-PEI) were fabricated. The siRNA of theKRASgene (siKras) was loaded onto the surface of HAp-PEI via electrostatic interaction between siRNA and PEI to design the functionalized HAp-PEI nanoparticle (HAp-PEI/siKras). The HAp-PEI/siKras was internalized into the human PC cells PANC-1 to achieve the maximum transfection efficiency for active tumor targeting. HAp-PEI/siKras effectively knocked down the expression of theKRASgene and downregulated the expression of the Kras protein in vitro. Furthermore, the treatment with HAp-PEI/siKras resulted in greater anti-PC cells’ (PANC-1, BXPC-3, and CFPAC-1) efficacy in vitro. Additionally, the HAp-PEI exhibited no obvious in vitro cytotoxicity in normal pancreatic HPDE6-C7 cells. These findings provided a promising alternative for the therapeutic route of siRNA-targeted gene engineering for anti-pancreatic cancer therapy.Keywords:hydroxyapatite;siRNA delivery;pancreatic cancer cells;KRASgene;gene silence;anticancer
研究领域:
纳米技术
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癌症生物学
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基因治疗
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药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Bioengineering and Biotechnology
·
2023
·
IF 5.7
Yu Xiongtao,Bai Silan,Wang Lishi
In this work, gold nanoparticles@Ti3C2 MXenes nanocomposites with excellent properties were combined with toehold-mediated DNA strand displacement reaction to construct an electrochemical circulating tumor DNA biosensor. The gold nanoparticles were synthesized in situ on the surface of Ti3C2 MXenes as a reducing and stabilizing agent. The good electrical conductivity of the gold nanoparticles@Ti3C2 MXenes composite and the nucleic acid amplification strategy of enzyme-free toehold-mediated DNA strand displacement reaction can be used to efficiently and specifically detect the non-small cell cancer biomarker circulating tumor DNA KRAS gene. The biosensor has a linear detection range of 10 fM −10 nM and a detection limit of 0.38 fM, and also efficiently distinguishes single base mismatched DNA sequences. The biosensor has been successfully used for the sensitive detection of KRAS gene G12D, which has excellent potential for clinical analysis and provides a new idea for the preparation of novel MXenes-based two-dimensional composites and their application in electrochemical DNA biosensors.
研究领域:
生物医学工程
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分子诊断学
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纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULES
·
2022
·Vol. 27
·期 10
·3046
·
IF 4.927
Jiayi Qian,Ruotong Liu,Ningzhi Liu,Chanling Yuan,Qiong Wu,Yanhua Chen,Weijun Tan,Wenjie Mei
A series of arene Ru(II) complexes, [(η6-MeC6H5)Ru(L)Cl]Cl, (L=o-ClPIP,1;m-ClPIP,2andp-ClPIP,3) (o-ClPIP=2-(2-chlorophenyl)imidazo[4,5-f][1,10]phenanthroline;m-ClPIP=2-(3-chlorophenyl)imidazo[4,5-f][1,10]phenanthroline;p-ClPIP=2-(4-chlorophenyl)imidazo[4,5-f][1,10]phenanthroline) was synthesized and investigated as a potential apoptosis inducer in chemotherapy. Spectroscopy and molecular docking simulations show that1exhibits moderated binding affinity toKRASG-quadruplex DNA by groove mode. Further, in vitro studies reveal that1displays inhibitory activity against MCF-7 growth with IC50= 3.7 ± 0.2 μM. Flow cytometric analysis, comet assay, and immunofluorescence confirm that1can induce the apoptosis of MCF-7 cells and G0/G1 phase arrest through DNA damage. In summary, the prepared arene Ru(II) complexes can be developed as a promising candidate for targeting G-quadruplex structure to induce the apoptosis of breast cancer cells via binding and stabilizingKRASG-quadruplex conformation on oncogene promoter.Keywords:arene ruthenium complex;KRASG-quadruplex DNA;breast cancer;apoptosis;DNA damage
研究领域:
药理学
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肿瘤学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
AQUATIC TOXICOLOGY
·
2024
·
IF 4.1
Afrasyab Khan,Bibimaryam Khan,Shakeel Hussain,Yuhan Wang,Weijun Mai,Yongzhong Hou
Permethrin (Per) is a widely used and frequently detected pyrethroid pesticide in agricultural products and the environment. It may pose potential toxicity to non-target organisms. Per has been reported to affect lipid homeostasis, although the mechanism is undefined. This study aims to explore the characteristic transcriptomic profiles and clarify the underlying signaling pathways of Per-induced lipid metabolism disorder in zebrafish liver. The results showed that environmental exposure to Per caused changes in the liver index, histopathology, and oxidative stress in zebrafish. Moreover, transcriptome results showed that Per heavily altered the pathways involved in metabolism, the immune system, and the endocrine system. We conducted a more in-depth analysis of the genes associated with lipid metabolism. Our findings revealed that exposure to Per led to a disruption in lipid metabolism by activating the KRAS-PPAR-GLUT signaling pathways through oxidative stress. The disruption of lipid homeostasis caused by exposure to Per may also contribute to obesity, hepatitis, and other diseases. The results may provide new insights for the risk of Permethrin to aquatic organisms and new horizons for the pathogenesis of hepatotoxicity.
研究领域:
毒理学
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分子生物学
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环境科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2024
·
IF 4.8
Li-Ying Han,Hao Yu,Shuai Wang,Yong-Rui Bao,Tian-Jiao Li,Ying Zheng,Xi Luo,Meng-Nan Jia,Qiang Zhang,Xian-Sheng Meng
Ethnopharmacological relevance Colorectal cancer (CRC) belongs to the category of intestinal wind, anal ulcer, abdominal mass and other diseases in traditional Chinese medicine (TCM). Floris Sophorae Powder (F.S), is a classical prescription is recorded in Puji Benshi Fang for the treatment of intestinal carbuncle. It has been incorporated into the prescriptions for the treatment of intestinal diseases and achieved remarkable results in modern medicine. However, the mechanism of F.S in the treatment of colorectal cancer remains unclear and requires further study. Aim of the study To investigate F.S in treating CRC and clarify the underlying mechanism. Materials and methods This study was based on Dextran Sulfate Sodium Salt (DSS) combined with Azoxymethane (AOM) induced CRC mouse model to clarify the pharmacological effects of F.S. The serum metabolomics was used to study the mechanism of action, and the chemical composition of F.S was found by UPLC-Q-TOF-MS. The rationality of serm metabolomics results was verified through the clinical target database of network pharmacology, and the upstream and downstream targets of related pathways were found. The mechanism pathway was verified by Western blot to clarify its mechanism of action. Results In vivo pharmacological experiments showed that F.S inhibited tumor growth and improved hematochezia. The vital signs of mice in the high-dose F.S group approached to those in the control group. A total of 43 differential metabolites were found to be significantly changed by serum metabolomics. F.S could modulate and recover most of the differential metabolites, which proved to be closely related to the KRAS/MEK-ERK signaling pathway. A total of 46 compounds in F.S were identified, and the rationality of serm metabolic pathway was verified by network pharmacology. Western blot results also verified that the expression of KRAS, E2F1, p-MEK and p-ERK were significantly decreased after F.S treatment. Conclusion Classical prescription Floris Sophorae Powder treat colorectal cancer by regulating KRAS/MEK-ERK signaling pathway.
研究领域:
药理学
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肿瘤学
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中医
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代谢组学
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信号转导
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
·
2025
·Vol. 16
·期 1
·1-18
·
IF 9.6
Zhou Chao,Liu Yuqing,Liu Hongyu,Lu Jun,Zhang Bo,Zhu Liang,Wang Shuyuan,Lei Huimin,Han Baohui
The clinical effect of KRAS G12C inhibitors (G12Ci) as monotherapy is poor, prompting the development of combination treatment strategies. Here, we demonstrate that the WEE1 kinase inhibitor (WEE1i), Adavosertib, can sensitize the effect of G12Ci through the MYBL2-RRM2 axis, which is associated with poor prognosis in lung cancer. Overexpressing the MYBL2-RRM2 axis or supplementing the products of the RRM2 enzyme, dNTPs/dNs, can partially reverse this synergistic inhibitory effect. We also observed marked effects of the combination therapy in tumor xenografts models. Collectively, these results uncover the WEE1 kinase inhibitors, some of which are available clinically, as effective enhancers for G12Ci therapy.
研究领域:
肿瘤学
·
分子生物学
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药理学
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES A-PHYSICOCHEMICAL AND ENGINEERING ASPECTS
·
2025
·
IF 5.4
Qingxiang Wang,Hezhong Ouyang,Wentao Li,Hexiao Zhang,Aolin He,Ruijiang Liu
The Kirsten Rat Sarcoma Viral Oncogene (KRAS) represents one of the most frequently mutated oncogenes in a variety of malignant tumors, including non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC). Therefore, it is regarded as a pivotal tumor marker, and the detection of it holds immense significance in the realm of tumor prevention, diagnosis, and disease monitoring. In this project, an α-Fe 2 O 3 /Fe 3 O 4 @Au-DNA/BSA probe was progressively constructed to capture KRAS, and the binding probe was immobilized onto the surface of magnetic glass carbon electrodes (MGCE) through magnetic self-assembly for detection purposes. The fabrication process was validated by changes observed in cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) data. Differential pulse voltammetry (DPV) was employed to optimize crucial experimental conditions and analyze biosensor performance. This condition optimization resulted in enhanced sensitivity of the biosensor, leading to improved linearity of data obtained. The limit of detection (LOD) achieved was 1.93 pM, with a limit of quantification (LOQ) at 5.84 pM, and a linear range ranging from 10 pM to 1 μM. Additionally, the stability (the current maintaining stability during the initial eight days), reproducibility (RSD = 2.47 %), selectivity, and real sample analysis (recovery rates ranging from 95.26 % to 109.80 %, RSD ≤ 1.22 %) were found to be favorable. These findings suggest promising prospects for practical applications of this biosensor.
研究领域:
肿瘤学
·
生物医学工程
·
分析化学
✓ 已验证
产品关联
DOI
高影响因子
MOLECULAR CARCINOGENESIS
·
2023
·
IF 4.6
Miao Deng,Jiaxin Guo,Zihang Ling,Chi Zhang,Lihong He,Zhaona Fan,Bin Cheng,Juan Xia
Gene mutations play an important role in head and neck squamous cell carcinoma (HNSCC) by not only promoting the occurrence and progression of HNSCC but also affecting sensitivity to treatment and prognosis. KRAS is one of the most frequently mutated oncogenes, which has been reported to have a mutation rate from 1.7% to 12.7% and may lead to poor prognosis in HNSCC, but its role remains unclear. Here, we found that the KRAS mutation can promote HNSCC generation through synergism with 4-Nitroquinoline-1-Oxide(4NQO). Mechanistically, KRAS mutations can significantly upregulate Runx1 to promote oral epithelial cell proliferation and migration and inhibit apoptosis. Runx1 inhibitor Ro 5-3335 can effectively inhibit KRAS -mutated HNSCC progression both in vitro and in vivo. These findings suggest that the KRAS mutation plays an important role in HNSCC and that Runx1 may be a novel therapeutic target for KRAS -mutated HNSCC.
研究领域:
肿瘤学
·
分子生物学
·
癌症遗传学
✓ 已验证
DOI
PubMed
高影响因子
DRUG DEVELOPMENT RESEARCH
·
2024
·Vol. 85
·期 5
·e22241
·
IF 3.5
Xiaowen Wang,Linyu Su,Chong Niu,Xiao Li,Ruijie Wang,Bo Li,Sha Liu,Yuwen Xu
The role of KRAS mutation in non-small cell lung cancer (NSCLC) initiation and progression is well-established. However, “undruggable” KRAS protein poses the research of small molecule inhibitors a significant challenge. Addressing this, proteolysis-targeting chimeras (PROTACs) have become a cutting-edge treatment method, emphasizing protein degradation. A modified ethanol injection method was employed in this study to formulate liposomes encapsulating PROTAC drug LC-2 (LC-2 LPs). Precise surface modifications using cell-penetrating peptide R8 yielded R8-LC-2 liposomes (R8-LC-2 LPs). Comprehensive cellular uptake and cytotoxicity studies unveiled that R8-LC-2 LPs depended on concentration and time, showcasing the superior performance of R8-LC-2 LPs compared to normal liposomes. In vivo pharmacokinetic profiles demonstrated the capacity of DSPE-PEG2000 to prolong the circulation time of LC-2, leading to higher plasma concentrations compared to free LC-2. In vivo antitumor efficacy research underscored the remarkable ability of R8-LC-2 LPs to effectively suppress tumor growth. This study contributed to the exploration of enhanced therapeutic strategies for NSCLC, specifically focusing on the development of liposomal PROTACs targeting the “undruggable” KRAS protein. The findings provide valuable insights into the potential of this innovative approach, offering prospects for improved drug delivery and heightened antitumor efficacy.
研究领域:
肿瘤学
·
药学
·
分子生物学
✓ 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）