PHYTOMEDICINE
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2026
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IF 11.3
Li Lin,Mengjie Xia,Ruohan Liang,Mengya Zhu,Xuanyi Chen,Jisheng Zhang,Xuan Cao
Introduction Matrine, a tetracyclic quinolizidine alkaloid derived from Sophora flavescens Aiton , exhibits potent antitumor activity. However, its direct molecular targets and the mechanisms by which it reverses chemoresistance in triple-negative breast cancer (TNBC) remain poorly defined. Objectives To investigate the molecular mechanism by which matrine in reversing cisplatin (CDDP) resistance in TNBC. Methods The enhancing effects of matrine on CDDP sensitivity were evaluated in vitro and in BALB/c nude mouse xenografts. Molecular targets were identified via limited proteolysis–mass spectrometry (LiP–MS), followed by functional analyses of glycolysis, protein lactylation, and DNA repair. Results Matrine significantly sensitized CDDP-resistant TNBC cells to apoptosis and inhibited tumor growth in vivo. Mechanistically, matrine directly targeted Enolase 1 (ENO1), disrupting its interaction with PGK1 and PGAM1. This interference suppressed glycolytic enzyme complex formation, thereby reducing glycolytic flux and protein lactylation. Attenuated lactylation subsequently impaired the assembly of the NBS1-RAD50-MRE11 DNA repair complex and downregulated resistance-associated transcription factors YY1 and YBX1. Importantly, ENO1 overexpression or exogenous sodium lactate supplementation rescued cells from matrine-mediated sensitization. In vivo results confirmed that matrine targets ENO1 to inhibit glycolysis and lactate production, thereby enhancing CDDP efficacy in resistant tumors. Conclusions Matrine reverses TNBC chemoresistance by targeting ENO1 to suppress the glycolysis–lactylation–DNA repair axis. These findings highlight the therapeutic potential of this TCM-derived compound in overcoming cancer drug resistance. Download: Download high-res image (227KB) Download: Download full-size image
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KAOHSIUNG JOURNAL OF MEDICAL SCIENCES
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2021
·Vol. 37
·期 6
·505-512
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IF 2.744
Xiao-Kai Zhang,Qi-Wen Wang,Ya-Juan Xu,Hong-Mei Sun,Lei Wang,Li-Xin Zhang
Multidrug resistance (MDR) of chemotherapy is one of the significant concerns in cancer therapy. Here in our study, cisplatin (DDP) and oleanolic acid (OA) were co-loaded in mesoporous silica nanoparticles (Nsi) to construct DDP/OA-Nsi and solve the DDP-resistance in lung cancer therapy. The cytotoxicity and apoptosis assays demonstrated that in DDP-resistant A549/DDP cells, the cytotoxicity of DDP/OA-Nsi was significantly higher than that of free DDP or DDP single delivery system (DDP-Nsi). The intracellular drug accumulation study revealed that the intracellular DDP concentration in the DDP/OA-Nsi group was also higher than that in free DDP and DDP-Nsi groups. In the A549/DDP xenograft tumor model, DDP/OA-Nsi showed the best anticancer effect. In summary, DDP/OA-Nsi was a promising drug delivery system to solve MDR in lung cancer therapy.
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BIOCHEMICAL PHARMACOLOGY
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2020
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IF 4.96
Cui Li,Liping Li,Yaodong Yi,Wei Wang,Jingqun Yuan,Fuqing Tan,Danbo Fang,Su Zeng,Hui Zhou,Huidi Jiang
Cisplatin is a first-line chemotherapeutic agent that is widely used for treatment of various solid tumors. However, cisplatin-induced adverse effects, particularly severe nephrotoxicity, preclude its application. In this study, we showed that L-tetrahydropalmatine ( L-THP) could selectively inhibit organic cation transporter 2 (OCT2), which plays a crucial role in renal cisplatin uptake from the circulation. Additionally, we demonstrated that L-THP attenuated cisplatin-induced toxicity in mouse primary renal tubular cells. Subsequently, we verified that L-THP reduced the renal accumulation of cisplatin and alleviated cisplatin-induced renal injury in healthy and tumor-bearing nude mice. In healthy mice, co-treatment of L-THP at 5–40 mg/kg reduced cisplatin renal accumulation to 75.0%-49.9% of that in cisplatin alone group (10 mg/kg), and alleviated cisplatin-induced nephrotoxicity. Additionally, it did not alter Pt concentration in the tumor tissue and did not impair its antitumor efficacy in tumor bearing nude mice. The tumor inhibitory rates of cisplatin (10 mg/kg) co-treated with L-THP at 10, 20 and 40 mg/kg were 71.4%, 70.4% and 69.4%, respectively, in H460 tumor bearing nude mice, higher than that of in cisplatin alone group (60.6%), while in HCT116 tumor bearing nude mice, the tumor inhibitory rates in co-treated with 20 mg/kg L-THP was 34.7% ( vs 26.3% in cisplatin alone group). Moreover, L-THP reduced cisplatin accumulation and alleviated cisplatin-induced cytotoxicity in human primary renal tubular cells. Therefore, our findings suggested that concomitant administration of L-THP could attenuate cisplatin-induced renal injury via selective inhibition of OCT2 without impairing its antitumor efficacy.
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BIOCHEMICAL PHARMACOLOGY
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2020
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IF 4.96
Xue-qi Liu,Juan Jin,Zeng Li,Ling Jiang,Yu-hang Dong,Yu-ting Cai,Ming-fei Wu,Jia-nan Wang,Tao-tao Ma,Jia-gen Wen,Ming-ming Liu,Jun Li,Yong-gui Wu,Xiao-ming Meng
Acute kidney injury (AKI), characterized by a rapid decline in renal function, is triggered by an acute inflammatory response that leads to kidney damage . An effective treatment for AKI is lacking. Using in vitro and in vivo AKI models, our laboratory has identified a series of anti-inflammatory molecules and their derivatives. In the current study, we identified the protective role of rutaecarpine (Ru) on renal tubules. We obtained a series of 3-aromatic sulphonamide-substituted Ru derivatives exhibiting enhanced renoprotective and anti-inflammatory function. We identified Compound-6c(Cpd-6c) as having the best activity and examined its protective effect against cisplatin nephropathy both in vivo and in vitro in cisplatin-stimulated tubular epithelial cells (TECs). Our results showed that Cpd-6c restored renal function more effectively than Ru, as evidenced by reduced blood urea nitrogen and serum creatinine levels in mice. Cpd-6c alleviated tubular injury, as shown by PAS staining and molecular analysis of kidney injury molecule-1 (KIM-1), with both prevention and treatment protocols in cisplatin-treated mice. Moreover, Cpd-6c decreased kidney inflammation , oxidative stress and programmed cell death . These results have also been confirmed in cisplatin-treated TECs. Using web-prediction algorithms, molecular docking, and cellular thermal shift assay (CETSA), we identified phosphodiesterase 4B (PDE4B) as a Cpd-6c target. In addition, we firstly found that PDE4B was up-regulated significantly in the serum of AKI patients. After identifying the function of PDE4B in cisplatin-treated tubular epithelial cells by siRNA transfection or PDE4 inhibitor rolipram , we showed that Cpd-6c treatment did not protect against cisplatin-induced injury in PDE4B knockdown TECs, thus indicating that Cpd-6c exerts its renoprotective and anti-oxidative effects via the PDE4B-dependent pathway. Collectively, Cpd-6c might serve as a potential therapeutic agent for AKI and PDE4B may be highly involved in the initiation and progression of AKI.
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Drug Design Development and Therapy
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2022
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IF 4.319
Ruifeng Wu,Zhiqiang Zhang,Baohua Wang,Ge Chen,Yaozhong Zhang,Haowen Deng,Zilong Tang,Junjie Mao,Lei Wang
Purpose Lung cancer is the leading cause of cancer mortality worldwide. Drug resistance is the major barrier for the treatment of non-small cell lung cancer (NSCLC). The aim of this research is to develop an aptamer-decorated hybrid nanoparticle for the co-delivery of docetaxel prodrug (DTXp) and cisplatin (DDP) and to treat lung cancer.Materials and Methods Aptamer-conjugated lipid–polymer ligands and redox-sensitive docetaxel prodrug were synthesized. DTXp and DDP were loaded into the lipid–polymer hybrid nanoparticles (LPHNs). The targeted efficiency of aptamer-decorated, DTXp and DDP co-encapsulated LPHNs (APT-DTXp/DDP-LPHNs) was determined by performing a cell uptake assay by flow cytometry-based analysis. In vivo biodistribution and anticancer efficiency of APT-DTXp/DDP-LPHNs were evaluated on NSCLC-bearing mice xenograft.Results APT-DTXp/DDP-LPHNs had a particle size of 213.5 ± 5.3 nm, with a zeta potential of 15.9 ± 1.9 mV. APT-DTXp/DDP-LPHNs exhibited a significantly enhanced cytotoxicity (drug concentration causing 50% inhibition was 0.71 ± 0.09 μg/mL), synergy antitumor effect (combination index was 0.62), and profound tumor inhibition ability (tumor inhibition ratio of 81.4%) compared with the non-aptamer-decorated LPHNs and single drug-loaded LPHNs.Conclusion Since the synergistic effect of the drugs was found in this system, it would have great potential to inhibit lung tumor cells and in vivo tumor growth.
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ENVIRONMENTAL TOXICOLOGY
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2023
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IF 4.5
Weipu Mao,Lei Zhang,Yiduo Wang,Si Sun,Jianping Wu,Jie Sun,Xiangyu Zou,Ming Chen,Guangyuan Zhang
Cisplatin nephrotoxicity is an etiological factor for acute kidney injury (AKI). MicroRNA (miRNA) expression is dysregulated in cisplatin-induced AKI (cAKI) although the underlying mechanisms are unclear. A cAKI model was established by intraperitoneally injecting cisplatin, and key miRNAs were screened using high-throughput miRNA sequencing. The functions of key miRNAs were determined using the cell viability, live/dead, reactive oxygen species (ROS), and 5-ethynyl-2′-deoxyuridine (EdU) proliferation assays. Additionally, the macrophage membrane was wrapped around a metal–organic framework (MOF) loaded with miRNA agomir to develop a novel composite material, macrophage/MOF/miRNA agomir nanoparticles (MMA NPs). High-throughput miRNA sequencing revealed that miR-30e-5p is a key miRNA that is downregulated in cAKI. The results of in vitro experiments demonstrated that miR-30e-5p overexpression partially suppressed the cisplatin-induced or lipopolysaccharide (LPS)-induced downregulation of cell viability, proliferation, upregulation of ROS production, and cell death. Meanwhile, the results of in vivo and in vitro experiments demonstrated that MMA NPs alleviated cAKI by exerting anti-inflammatory effects. Mechanistically, cisplatin downregulates the expression of miR-30e-5p, and the downregulated miR-30e-5p can target Galnt3 to activate the adenosine 5‘-monophosphate activated protein kinase (AMPK) signaling pathway, which promotes the progression of AKI. Our study found that miR-30e-5p is a key downregulated miRNA in cAKI. The downregulated miR-30e-5p promotes AKI progression by targeting Galnt3 to activate the AMPK signaling pathway. The newly developed MMA NPs were found to have protective effects on cAKI, suggesting a potential novel strategy for preventing cAKI.
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ANALYTICA CHIMICA ACTA
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2023
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IF 6.2
Shengjie Ge,Gaoyang Chen,Dawei Cao,Hechuan Lin,Ziyang Liu,Meng Yu,Shiyi Wang,Zhigang Wang,Ming Zhou
Cisplatin has been widely applied in the clinical treatment of various cancers, whereas liver injury induced by its hepatotoxicity is still a severe issue. Reliable identification of early-stage cisplatin-induced liver injury (CILI) can improve clinical care and help to streamline drug development. Traditional methods, however, cannot achieve enough information at the subcellular level due to the requirement of the labeling process and low sensitivity. To overcome these, we designed an Au-coated Si nanocone array (Au/SiNCA) to fabricate the microporous chip as the surface-enhanced Raman scattering (SERS) analysis platform for the early diagnosis of CILI. A CILI rat model was established, and the exosome spectra were obtained. The principal component analysis (PCA)-representation coefficient-based k-nearest centroid neighbor (RCKNCN) classification algorithm was proposed as the multivariate analysis method to build the diagnosis and staging model. The PCA-RCKNCN model has been validated to achieve a satisfactory result, with accuracy and AUC of over 97.5%, and sensitivity and specificity of over 95%, indicating that SERS combined with the PCA-RCKNCN analysis platform can be a promising tool for clinical applications.
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Journal of Nanomaterials
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2017
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IF 1.871
Juan Zhang,Huanhuan Weng,Xiangwan Miao,Quanming Li,Siqi Wang,Huifen Xie,Tao Liu,Minqiang Xie
A novel folate (FA) receptor-targeted superparamagnetic Fe3O4 nanoparticles (SPIONs) codelivering cisplatin (CDDP) and tissue factor pathway inhibitor-2 (TFPI-2) plasmid DNA (pDNA) was constructed. The core shell nanocomposites ([email protected]) were composed of superparamagnetic Fe3O4 core that binds CDDP and TFPI-2 shell that combines with folate-polyethylene glycol-polyethyleneimine (FA-PEG-PEI) via electrostatic interaction. The shell containing FA-PEG-PEI and TFPI-2 plasmid was synthesized through amidation reaction and electrostatic adsorption and the core containing SPION-CDDP was modified by aldehyde sodium alginate. Proton nuclear magnetic resonance and Fourier transform infrared spectra on FA-PEG-PEI polymers showed characteristic peaks of various metabolites in corresponding frequency. Transmission electron microscopy image of [email protected] nanoparticles demonstrated a near-monodisperse spherical morphology, while dynamic light scattering studies indicated an intensity-average diameter of 149.5 nm. Zeta potential was 14.89 ± 1.83 mv and the final concentration of loaded CDDP was 100 ug/ml. Gel electrophoresis data showed that the nanocomposite would protect TFPI-2 pDNA from being digested by DNases. Compared with CNE-2 cells, the good targetability and better gene transfection efficiency (57.9%) were detected by Prussian blue iron stain and fluorescence analysis in HNE-1 cells in vitro. The results suggested the potential application of [email protected] as a multifunctional anticancer nanomedicine on targeting therapy for FR positive NPC.
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ANTI-CANCER DRUGS
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2024
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IF 1.8
Yang Lulu,Meng Bo,Gong Xiaoyun,Jiang You,Shentu Xuping,Xue Zhichao
Chemoresistance largely hampers the clinical use of chemodrugs for cancer patients, combination or sequential drug treatment regimens have been designed to minimize chemotoxicity and resensitize chemoresistance. In this work, the cytotoxic effect of cisplatin was found to be enhanced by palbociclib pretreatment in HeLa cells. With the integration of liquid chromatography–mass spectrometry-based proteomic and N-glycoproteomic workflow, we found that palbociclib alone mainly enhanced the N-glycosylation alterations in HeLa cells, while cisplatin majorly increased the different expression proteins related to apoptosis pathways. As a result, the sequential use of two drugs induced a higher expression level of apoptosis proteins BAX and BAK. Those altered N-glycoproteins induced by palbociclib were implicated in pathways that were closely associated with cell membrane modification and drug sensitivity. Specifically, the top four frequently glycosylated proteins FOLR1, L1CAM, CD63, and LAMP1 were all associated with drug resistance or drug sensitivity. It is suspected that palbociclib-induced N-glycosylation on the membrane protein allowed the HeLa cell to become more vulnerable to cisplatin treatment. Our study provides new insights into the mechanisms underlying the sequential use of target drugs and chemotherapy drugs, meanwhile suggesting a high-efficiency approach that involves proteomic and N-glycoproteomic to facilitate drug discovery.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2024
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IF 7.7
Mohamed Eid,Jingsong Zhu,Muhammad Asif Ismail,Bin Li
Chemically cross-linked hydrogel nanoparticles (HGNPs) offer enhanced properties over their physical counterparts, particularly in drug delivery and cell encapsulation. This study applied pH-thermal dual responsive bio-adhesive HGNPs for dual complexation and enhanced the controlled release and bioavailability of cisplatin (CDDP) and Vitamin E (VE) drugs. The CDDP was loaded into the HGNPs via chemical conjugation with the carboxyl groups in the HGNPs surface by soy polysaccharides (SSPS). At the same time, the host-guest interaction complexed the VE through the β-cyclodextrin (β-CD). The HGNPs showed a uniform HGNPs size distribution of 90.77 ± 14.77 nm and 81.425 ± 13.21 nm before and after complexation, respectively. The FTIR, XRD , XPS , and zeta potential confirmed the conjugation. The cumulative release percent of CDDP reached 98 % at pH 1.2, while <45 % was released at pH 7.4. Our HGNPs enhance the incorporation of CDDP by substituting its chlorides with carboxyl groups of the SSPS; the loading of CDDP and VE was 15 ± 0.33 and 11.32 ± 0.25 wt%, respectively. Moreover, the CDDP and VE also released slower from the HGNPs at 25 °C than at 37 °C and 42 °C. The (VE/CDDP)-loaded HGNPs exhibited longer circulation time in vivo than free CDDP and free VE suspension.
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COLLOIDS AND SURFACES A-PHYSICOCHEMICAL AND ENGINEERING ASPECTS
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2025
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IF 5.4
Lei Yang,Lang Ran,Yu Li,Yi’ao Tan,Dian Xia,Tao Huang,Jing Wang,Tingting Jiang,Tao Tao,Jianmin Xiao,Shuhan Liu
Cisplatin as a first-line drug showed some significant limitations in clinical use owing to seriously systemic toxicity, and acquired drug-resistance. Herein, we utilized PC-3 cell membrane camouflaged Mn-doped metal-organic framework to deliver low toxic tetravalent cisplatin prodrug (mMOF-Pt) for synergistic chemodynamic therapy (CDT) and chemotherapy of prostate tumor. Owing to homologous targeting action, the mMOF-Pt actively recognized prostate tumor. Upon special tumor microenvironment, the mMOF-Pt released ciplatin prodrug. Next, the tetravalent cisplatin prodrug could be reduced into high toxic cisplatin by over-expressed GSH, effective killing tumor cells. Meanwhile, the MOF catalyzed endogenous H 2 O 2 into highly toxic ·OH via Fenton-like reaction, which induced intracellular ROS production and significantly elevated oxidative stress level. Strong oxidative stress dramatically enhanced the sensitivity of tumor cells to chemotherapeutic drug, further amplifying the toxicity of cisplatin to tumor cells. In vivo experiment results demonstrated that the mMOF-Pt effectively accumulated in tumor site and significantly inhibited the growth of prostate tumor within low systemic toxicity. Moreover, the mMOF-Pt could be completely excreted out from body, which avoided potential risk for body. Overall, we considered that this work provided a great strategy for improving therapy of prostate cancer.
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MACROMOLECULAR BIOSCIENCE
·
2016
·Vol. 17
·期 4
·1600262
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IF 3.68
Qin Yun,Si Song Wang,Shan Xu,Jin Ping Yang,Juan Fan,Ling Lin Yang,Yue Chen,Shao Zhi Fu,Jing Bo Wu
Colorectal peritoneal carcinomatosis (CRPC) is a common systemic metastasis of intra-abdominal cancers. Intraperitoneal chemotherapy against CRPC is at present the preferred treatment. The aim of this study is to develop a novel hydrogel drug delivery system through the combination of 5-fluorouracil (5-FU) loaded polymeric micelles and cisplatin (DDP) in biodegradable thermosensitive chitosan (CS) hydrogel. The prepared CS hydrogel drug is a free-flowing solution at room temperature and forms a stationary gel at body temperature. Therefore, a CRPC mouse model is established to investigate the antitumor activity of CS hydrogel drug system. The results suggest that intraperitoneal administration of CS hydrogel drug can inhibit tumor growth and metastasis, and prolong survival time compared with other groups, thus improving the chemotherapeutic effect. Ki-67 immunohistochemical analysis reveals that tumors in the CS hydrogel drug group has lower cell proliferation in contrast to other groups ( P < 0.001). Furthermore, hematoxylin-eosin staining of liver and lung tissue indicates that the CS hydrogel drug has also a certain inhibitory effect on colorectal cancer metastasis to the liver and lung. Hence, the work highlights the potential clinical applications of the CS hydrogel drug.
研究领域:
肿瘤学
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药剂学
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