ACS Applied Materials & Interfaces
·
2022
·
IF 10.383
Yingying Xu,Zhiguo Yu,Hao Fu,Yuedong Guo,Ping Hu,Jianlin Shi
Glucose and glutamine are two principal nutrients in mammalian cells that provide energy and biomass for cell growth and proliferation. Especially in cancer cells, glutamine could be a main alternative for energy and biomass supply once glucose metabolism is suppressed. Therefore, single inhibition of enzymes in either glucose metabolism or glutaminolysis, though maybe efficient in vitro, is far from being satisfactory for efficient in vivo cancer therapy. Here, we proposed a new strategy for dual inhibitions on both glucose and glutamine metabolisms concurrently by silencing mutated gene Kras and glutaminase 1 (GLS1) via nanomaterial-based siKras and siGLS1 delivery, rather than conventional highly toxic chemodrugs. Such a combination therapy could overcome the challenge that glucose and glutamine are alternatives to each other in the biosynthesis and energy production for cancer cells, resulting in much elevated treatment efficacy. In addition, layered double hydroxide (LDH), the siRNA carrier, enables an enhanced gene delivery efficiency compared to the commercial transfection agent Lipofectamine 2000. Briefly, Mg-Al LDH nanosheets, loaded with siKras and siGLS1 onto their surfaces by electrostatic adsorption, could release siRNA from lysosomes into the cytoplasm via the proton sponge effect of LDH, favoring the siRNA stability and gene silencing efficiency enhancements. The thus released siRNA could downregulate the expressions of Kras, GLS1, and other enzymes involved in glucose metabolism, resulting in the downregulations of ATP and other metabolites. Such a biosafe LDH/siRNA nanomedicine is able to efficiently suppress the growth of xenografts through cancer cell proliferation suppression, displaying its great potential as a simultaneous glucose/glutamine metabolism coinhibitor for treating pancreatic cancer.
研究领域:
肿瘤学
·
分子生物学
·
生物医学工程
·
纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2024
·
IF 5.3
Gang Wang,Xiao-Na Xu,Zhu Zhi-Min,Kun Wang,Fei Li
This study tried to develop the α-Hederin/Oxaliplatin (OXA) dual-loaded rHDL (α-Hederin-OXA-rHDL) modified liposomes to improve the therapeutic index on colon adenocarcinoma (COAD). The α-Hederin-OXA-rHDL were prepared and evaluated for characterizations, accumulate to tumor tissues, and antitumor activity. A thorough investigation into oxaliplatin resistant and KRAS-mutant related hub keg genes were identified and performed to assess the prognosis role of the genetic signature in COAD. The potential immune signatures and molecular docking for verifing the predicted targets of α-Hederin-OXA-rHDL in tumor-bearing mice. Results suggested that α-Hederin-OXA-rHDL could enhance the sensitivity of oxaliplatin in HCT116/L-OHP cells via the regulation of KEAP1/NRF2 -mediated signaling and HO1 or GPX4 proteins. Furthermore, α-Hederin-OXA-rHDL regulated the predicted targets of PRDM1 interaction with miR-140-5p, efficient activing CD8 T cell to improve therapeutic response in vivo . Collectively, this work provides drug delivery with rHDL dual-loaded α-Hederin and oxaliplatin synergistically targets cancer cells and effectory T cells combating COAD.
研究领域:
药学
·
癌症生物学
·
分子生物学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
DALTON TRANSACTIONS
·
2025
·
IF 3.3
Yulu Ru,Jiahui Chen,Qinxin Li,Qiyao Chen,Sihui Huang,Jiahuan Zhou,Dandan Wang,Xiaoshun Zhou,Yong Shao
Folding of nucleic acids is strongly dependent on metal ions. For example, G-quadruplex (G4) structures are usually determined by the specific K+/Na+ coordination. However, G4 constructs highly selective to high-valent metal ions (for instance, trivalent metal ions) have not been found due to their strong and nonspecific phosphate backbone interactions. Herein, a higher-order G4 structure having a heptad junction formed by GGA repeats (for example, GGA8 with eight repeats) of the human c-myb promoter region was found to stoichiometrically recruit three Tb3+ ions. The junction binding of Tb3+ did not affect the global G4 structure of GGA8 because of its high stability in K+. The three context A/A contacts with a proper stacking orientation and an appropriate interbase distance were proved to be the specific binding sites of Tb3+ (A/Tb3+/A). Other high-valent metal ions were unable to interfere with this specific Tb3+ binding, suggestive of the potential of GGA8 serving as an aptamer-like DNA for Tb3+. This A/Tb3+/A binding was also found in another KRAS promoter G4 structure with the same A/A contact, indicating the potential of Tb3+ in selectively probing G4 structures. This work will also inspire more interest in searching higher-order G4 structures for selectively coordinating high-valent metal ions with the purpose of their detection, enrichment, and recovery.
研究领域:
生物化学
·
分子生物学
·
无机化学
·
结构生物学
·
核酸研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Death Discovery
·
2025
·Vol. 11
·期 1
·1-15
·
IF 7
Cheng Mengting,Wu Wentong,Li Qing,Tao Xinyu,Jiang Feng,Li Jinjin,Shen Nonger,Wang Fei,Luo Peihua,He Qiaojun,huang Ping,Xu Zhifei,Zhang Yiwen
Sotorasib, the inaugural targeted inhibitor sanctioned for the management of patients afflicted with locally advanced or metastatic non-small cell lung cancer presenting the KRAS G12C mutation, has encountered clinical application constraints due to its potential for cardiac injury as evidenced by safety trials. This investigation has elucidated that the heightened expression of neuraminidase-1 (NEU1) constitutes the principal etiology of cardiac damage induced by sotorasib. Mechanistically, sotorasib treatment inhibited the ubiquitinated degradation of NEU1, leading to its elevated expression, which induced downstream AKT signaling pathway inhibition and mitochondrial dysfunction leading to cardiomyocyte apoptosis. Meanwhile, in vivo and in vitro studies showed that D-pantothenic acid (D-PAC) alleviated sotorasib-induced cardiac damage by promoting NEU1 degradation. In conclusion, this study revealed that NEU1 is a key protein in sotorasib cardiotoxicity and that reducing the level of this protein is a critical strategy for the clinical treatment of sotorasib-induced cardiac injury. Schematic representation of a mechanism.
研究领域:
肿瘤学
·
心脏病学
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SENSORS AND ACTUATORS B-CHEMICAL
·
2025
·
IF 7.7
Li Meng,Mingzhong Li,Zhenyu Xu,Tianlan Chen,Meiwan Chen,Joana Vaz Pinto,Bruno Veigas,Man-Kay Law
Precise temperature control and measurement are crucial for in vitro nucleic acid denaturation, especially in melting curve analysis (MCA). However, the inherent cumbersome multi-step calibration process required to obtain an accurate spatial temperature gradient can be a major limitation for the study of MCA on existing microfluidic chips. This work proposes to obtain a highly linear temperature gradient with a functional substrate for achieving high-resolution MCA on a digital microfluidics (DMF) platform. Taking advantage of the high thermal conductivity of aluminum, we employ a thin trapezoidal aluminum plate as the DMF substrate to compensate for the uneven heat transfer caused by temperature differences at different substrate positions and the ambient environment. We further pattern a banded superhydrophilic thread on the superhydrophobic surface to passively achieve a liquid thread by driving the mother droplet through the electrowetting on dielectric (EWOD) effect. With a heater and a cooler positioned at the opposite ends of the substrate, we can create a highly linear (simulated R 2 = 1 and experimental R 2 = 0.9998) temperature gradient from 40°C to 90°C across the liquid thread, requiring only temperature calibration at the two end points. The elimination of laborious temperature calibration steps can effectively enable rapid, continuous and reliable nucleic acid amplification as well as MCA on DMF. The high temperature accuracy also ensures simultaneous multiple hybrid DNA detection for rapid one-time discrimination of single nucleotide mutations in KRAS gene targets. This innovation underscores the DMF platform's potential in the realms of biomedical research and clinical diagnostics.
研究领域:
生物医学工程
·
微流控技术
·
分子诊断学
·
生物化学
·
遗传学
·
芯片实验室技术
·
临床诊断学
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2024
·
IF 9.4
Jianan Qiao,Shuhui Liu,Yanfeng Huang,Xiang Zhu,Chenyang Xue,Yan Wang,Hui Xiong,Jing Yao
Clinical pancreatic ductal adenocarcinoma (PDAC) treatment is severely limited by lack of effective KRAS suppression strategies. To address this dilemma, a reactive oxygen species (ROS)-responsive and PDAC-targeted nanodrug named Z/B-PLS was constructed to confront KRAS through dual-blockade of its downstream PI3K/AKT/mTOR and RAF/MEK/ERK for enhanced PDAC treatment. Specifically, photosensitizer zinc phthalocyanine (ZnPc) and PI3K/mTOR inhibitor BEZ235 (BEZ) were co-loaded into PLS which was constructed by click chemistry conjugating MEK inhibitor selumetinib (SEL) to low molecular weight heparin with ROS-responsive oxalate bond. The BEZ and SEL blocked PI3K/AKT/mTOR and RAF/MEK/ERK respectively to remodel glycolysis and non-canonical glutamine metabolism. ZnPc mediated photodynamic therapy (PDT) could enhance drug release through ROS generation, further facilitating KRAS downstream dual-blockade to create treatment-promoting drug delivery-therapeutic positive feedback. Benefiting from this broad metabolic modulation cascade, the metabolic symbiosis between normoxic and hypoxic tumor cells was also cut off simultaneously and effective tumor vascular normalization effects could be achieved. As a result, PDT was dramatically promoted through glycolysis-non-canonical glutamine dual-metabolism regulation, achieving complete elimination of tumors in vivo . Above all, this study achieved effective multidimensional metabolic modulation based on integrated smart nanodrug delivery, helping overcome the therapeutic challenges posed by KRAS mutations of PDAC.
研究领域:
肿瘤学
·
药理学
·
纳米技术
·
代谢调控
·
光疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2025
·
IF 14.1
Hongrui Fan,Hongyi Chen,Haolin Song,Chufeng Li,Yu Wang,Zhenhao Zhao,Qin Guo,Xuwen Li,Mingxuan Liu,Tao Sun,Chen Jiang
KRAS mutations are find in over 90% of pancreatic ductal adenocarcinoma (PDAC) cases, making PDAC exhibit intrinsic resistance to chemotherapy and reshape the immunosuppressive tumor microenvironment (TME), disappointing the clinically preferred chemotherapy-immunotherapy combination. Standing on the cross point of therapeutic resistance, the aberrant adenosine metabolism contributes greatly to chemo- and immunotherapy tolerance. KRAS mutation-induced over-expression of key enzyme CD39 is believed to be involved in shaping the immunosuppressive TME, as it catalyzes the hydrolysis of extracellular ATP into immunosuppressive adenosine. Meanwhile, the loss of equilibrative nucleoside transporters (ENTs) leads to the accumulation of adenosine and the intracellular delivery difficulty of gemcitabine, further vanishing patients’ hope of benefiting from either chemotherapy or immunotherapy. The key challenge is to modulate the aberrant metabolism, also enhance gemcitabine intracellular delivery. Therefore, ROS-responsive positively-charged polymer B-PDEA is prepared and assembled into polyplexes for loading CD39-down-regulating small interfering RNA. Gemcitabine-loaded albumin is coupled with the polyplexes through enzyme-cleavable peptide, forming the intact nanoparticles for the co-delivery of the first-line chemotherapeutic drug and CD39-regulating nucleic acid, showing enhanced gemcitabine intracellular delivery and adenosine metabolism regulating capacity. This approach activated antitumor immunity while achieving chemosensitization by changing the metabolic-immune crosstalk of TME, showcasing great potential for PDAC treatment.
研究领域:
纳米医学
·
肿瘤学
·
药剂学
·
分子生物学
·
免疫治疗
·
药物递送
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2022
·
IF 15.304
Xiuna Jia,Mengmeng Lv,Yunwei Fei,Qing Dong,Hao Wang,Qiong Liu,Dan Li,Jin Wang,Erkang Wang
Diagnosis-guided synergistic treatment based on innovative nanomaterials is of great significance for the development of anti-cancer therapies. However, the low delivery efficiency of therapeutic gene and the inability to trigger release on demand are still major obstacles impeding its wide application. Herein, we report an ultra-fast one-step method within 2 min to prepare a smart carrier, liposome-coated Prussian blue @ gold nano-flower, which is named LPAR after linking with tumor-targeting peptide. The versatile LPAR not only can respond to near-infrared (NIR) light, achieve the selective delivery and the controlled release of siRNA targeting the mutant gene of Kras at its codon-12 from Glycine (G) to Aspartic acid (D) (named as G12D mutant gene) in the malignant pancreatic tumors, but also efficiently convert the absorbed NIR light into the heat to realize gene-photothermal synergistic therapy both in vitro and in vivo . Theoretical simulation results reveal that the outstanding photothermal conversion efficiency of LPAR is mainly due to its higher electric field intensity and power density distributions . Furthermore, the LPAR possesses the capabilities for triple-modal imaging. Therefore, the developed NIR light-responsive LPAR has the potential to be served as a tumor-targeted nano-delivery system for imaging-guided synergistic therapy of cancers.
研究领域:
癌症治疗
·
纳米技术
·
生物医学工程
·
分子生物学
·
药学
·
材料科学
✓ 已验证
DOI
PubMed
高影响因子
AQUATIC TOXICOLOGY
·
2023
·
IF 4.5
Yingying Zhang,Yinan Jiang,Zhu Zhu,Xinrui Xu,Hui Yang
Microplastic pollution, especially microfibers (MFs), presents a critical global environmental challenge in natural water bodies. Yet, research on the toxic effects of MFs, particularly during early fish development, is limited. This study aimed to investigate MFs' toxic effects and mechanisms on early-stage zebrafish. Zebrafish embryos were exposed to varying concentrations of polyacrylonitrile microfibers (PanMfs) for 7 days. Results revealed PanMfs adhering to the embryos' surface, with higher concentrations accelerating heart rate and causing pericardial edema in post-hatching larvae. Larvae ingested PanMfs, leading to their accumulation in the intestines and increased levels of reactive oxygen species (ROS) and mitochondrial quantity. Notably, lipid metabolism and calcium ion related signaling pathways underwent significant changes. Low concentration MFs affected glycometabolism pathways, with potential roles for aldob and cacng1a , exhibiting pronounced increases in ROS levels. High concentration of MFs had the most profound impact on signal transduction-related pathways, and possibly triggering micromitophagy and apoptosis in zebrafish intestinal epithelial cells through the Kras/MAPK signaling pathway, with potential roles for kras and mapk9 . Although ROS increase was somewhat alleviated, it resulted in decreased survival rates and restricted growth in high concentration of MFs group. These findings highlight the significant threat of MFs to the early survival of fish. MFs pollution prevention and control hold great significance in the conservation of fishery resources.
研究领域:
环境科学
·
毒理学
·
水生生物学
·
渔业
·
发育生物学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）