INTERNATIONAL IMMUNOPHARMACOLOGY
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2023
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IF 5.6
Tianjiao Ma,Lei Yang,Binmei Zhang,Xin Lv,Feifei Gong,Wei Yang
Aims Doxorubicin is a drug widely used in clinical cancer treatment, but severe cardiotoxicity limits its clinical application. Autophagy disorder is an important factor in the mechanism of doxorubicin-induced cardiac injury. As the smallest molecule in nature, hydrogen has various biological effects such as anti-oxidation, anti-apoptosis and regulation of autophagy. Hydrogen therapy is currently considered to be an emerging therapeutic method, but the effect and mechanism of hydrogen on doxorubicin-induced myocardial injury have not been determined. The purpose of this study was to investigate the protective effect of hydrogen inhalation on doxorubicin-induced chronic myocardial injury and its effect and mechanism on autophagy. Methods In this study, we established a chronic heart injury model by intraperitoneal injection of doxorubicin in rats for 30 days, accumulating 20 mg/kg. The effect of hydrogen inhalation on the cardiac function in rats was explored by echocardiography, Elisa, and H&E staining. To clarify the influence of autophagy, we detected the expression of LC3 and related autophagy proteins in vivo and in vitro by immunofluorescence and western blot.In order to further explore the mechanism of autophagy, we added pathway inhibitors and used western blot to preliminarily investigate the protective effect of hydrogen inhalation on myocardial injury caused by doxorubicin. Results Hydrogen inhalation can improve doxorubicin-induced cardiac function decline and pathological structural abnormalities in rats. It was confirmed by immunofluorescence that hydrogen treatment could restore the expression of autophagy marker protein LC3 (microtubule-associated protein 1 light chain 3) in cardiomyocytes reduced by doxorubicin, while reducing cardiomyocyte apoptosis. Mechanistically, Western blot results consistently showed that hydrogen treatment up-regulated the ratio of p-AMPK (phosphorylated AMP-dependent protein kinase) to AMPK and down-regulated p-mTOR (phosphorylated mammalian target of rapamycin) and mTOR ratio. Conclusions These results suggest that hydrogen inhalation can activate autophagy through the AMPK/mTOR pathway and protect against myocardial injury induced by doxorubicin. Hydrogen inhalation therapy may be a potential treatment for doxorubicin-induced myocardial injury.
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高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2026
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IF 5.7
Meng Wang,Che Wang,Zhihao Liu,Xiaoyu Du,Lu Tian,Qi Li,Feng Zhang,Yingxiang Chen,Chengzhi Lu
Acteoside attenuates doxorubicin-induced cardiotoxicity and ferroptosis. • Acteoside preserves mitochondrial function in doxorubicin-exposed cardiomyocytes. • Acteoside promotes KEAP1 degradation and activates NRF2 signaling. • NRF2 inhibition attenuates the cardioprotective and anti-ferroptotic effects of ACT. : Doxorubicin (DOX)-induced cardiotoxicity (DIC) is a major limitation to the clinical use of DOX, highlighting the need for effective cardioprotective strategies. Although acteoside (ACT), a natural compound with antioxidant properties, has shown potential cardioprotective effects, its role in DIC, particularly in the regulation of ferroptosis, remains unclear. This study therefore investigated the protective effects of ACT against DIC and the underlying molecular mechanisms. Using C57BL/6 mice in vivo and H9c2 cells in vitro, we evaluated cardiac function, myocardial injury and histopathological alterations, ferroptosis-related changes, and key regulatory proteins. ACT significantly attenuated DOX-induced cardiac dysfunction, myocardial injury, and fibrosis. These protective effects were accompanied by suppression of ferroptosis, as evidenced by reduced iron accumulation and lipid peroxidation and restored expression of glutathione peroxidase 4 (GPX4) and the cystine/glutamate transporter (xCT). ACT also preserved mitochondrial membrane potential and reduced mitochondrial reactive oxygen species (ROS) levels, thereby alleviating mitochondrial dysfunction. Mechanistically, ACT may interact with Kelch-like ECH-associated protein 1 (KEAP1) and promoted KEAP1 degradation, thereby facilitating the nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2) and increasing the expression of downstream antioxidant proteins, including heme oxygenase-1 (HO-1). Moreover, the NRF2 inhibitor ML385 significantly attenuated the protective effects of ACT, supporting the involvement of NRF2 signaling in ACT-mediated cardioprotection. Collectively, these findings suggest that ACT protects against DIC, at least in part, by promoting KEAP1 degradation, activating NRF2 signaling, and suppressing ferroptosis. This figure summarizes the mechanism by which ACT alleviates DOX-induced cardiotoxicity through the suppression of ferroptosis. ACT promotes KEAP1 degradation, reduces KEAP1-mediated NRF2 degradation, and enhances NRF2 nuclear translocation and downstream antioxidant and anti-ferroptotic signaling. These effects upregulate HO-1, xCT, and GPX4, reduce lipid ROS accumulation, improve mitochondrial function, and suppress cardiomyocyte ferroptosis. Collectively, the cardioprotective effects of ACT are mediated, at least in part, through activation of the KEAP1/NRF2 axis. Download: Download high-res image (175KB) Download: Download full-size image
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ACS Applied Materials & Interfaces
·
2023
·
IF 9.5
Juan Cen,Xiaoying Dai,Han Zhao,Xiaohan Li,Xiaojiao Hu,Jing Wu,Shaofeng Duan
The blood–brain barrier (BBB) continues to be one of the main clinical obstacles in the treatment of glioma. Current chemotherapies always bring many different side effects, some even permanent. To date, nanomaterial-based vehicles have shown great potential in treating glioma. Herein, we developed a dual targeting liposomal delivery vector loaded with the anticancer drug doxorubicin (DOX) to treat glioma. SS31, a small peptide, has shown dual targeting effects of penetrating the BBB and specifically targeting mitochondria. In this study, a new liposomal delivery system, LS-DOX, was prepared by modifying DOX-loaded liposomes with SS31 for the treatment of in situ glioma. The liposomes demonstrated a high drug encapsulation rate and drug-loading capacity, satisfactory biocompatibility, high glioma accumulation ability, and good stability in vitro. Experimental results showed that the liposomes could effectively cross the BBB and target gliomas, and mitochondria-targeting of SS31 enhances cell uptake. In addition, the liposomes showed a good therapeutic effect on nude mice with glioma in situ with no obvious toxicity and side effects. Therefore, the present research will provide a novel alternative and reference for the effective treatment of glioma.
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ACS Nano
·
2023
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IF 17.1
Fei Peng,Jing Liu,Junjie Chen,Weiwei Wu,Yujun Zhang,Guoyan Zhao,Yi Kang,Deying Gong,Liu He,Jing Wang,Wensheng Zhang,Feng Qiu
Although surgical resection provides a straightforward and effective treatment for most malignant solid tumors, tumor recurrence and acute postoperative pain continue to be two big problems associated with this treatment. To resolve these problems, a nanocrystal composite slow-releasing ropivacaine and doxorubicin was fabricated in this study. Briefly, a self-assembling peptide was used to form nanoparticle complexes with the two drugs, based on which homogeneous nanocrystals were obtained by adjusting the pH. In cultured human melanoma cells, the nanocrystals exhibited improved antitumor activity due to a synergistic effect and enhanced cellular uptake of the two drugs. On the other hand, the nanocrystals could slowly release ropivacaine in vitro and in vivo, generating long-acting analgesia on the rat sciatic nerve block model and incisional pain model. On a nude mouse tumor resection model, the nanocrystals simultaneously suppressed the recurrence of solid tumor and relieved postoperative pain, indicating a potential postoperative treatment for tumor resection patients. This nanocrystal system also suggested a promising and facile strategy for developing multifunctional formulations combining different drugs, which could achieve better therapeutic outcomes in a synergistic and sustained manner.
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MOLECULES
·
2023
·Vol. 28
·期 18
·6443
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IF 4.6
Chaoyan Zhang,Xiaoyu Zhou,Fei Yan,Jing Lin
Herein, we describe a fast and highly sensitive electrochemical sensor for doxorubicin (DOX) detection based on the indium tin oxide (ITO) modified with a binary material consisting of vertically-ordered mesoporous silica films (VMSFs) and N-doped graphene quantum dots (NGQDs). VMSFs, with high permeability and efficient molecular transport capacity, is attached to the ITO electrode via a rapid and controllable electrochemical method, which can serve as a solid template for the confinement of numerous NGQDs through facile electrophoresis. By virtue of the excellent charge transfer capacity, π-π and electrostatic preconcentration effects of NGQDs, as well as the electrostatic enrichment ability of VMSF, the presented NGQDs@VMSF/ITO shows amplified electrochemical signal towards DOX with a positive charge, resulting in good analytical performance in terms of a wide linear range (5 nM~0.1 μM and 0.1~1 μM), high sensitivity (30.4 μA μM−1), and a low limit of detection (0.5 nM). Moreover, due to the molecular sieving property of VMSF, the developed NGQDs@VMSF/ITO sensor has good selectivity and works well in human serum and urine samples, with recoveries of 97.0~109%, thus providing a simple and reliable method for the direct electrochemical analysis of DOX without complex sample pretreatment procedures.
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PHYTOMEDICINE
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2021
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IF 5.34
Yang Zhang,Shan Liu,Jiu-Long Ma,Chen Chen,Peng Huang,Jia-Hua Ji,Di Wu,Li-Qun Ren
Background Doxorubicin (DOX) is a broad-spectrum anti-tumor drug that has been associated with cardiotoxicity. Plant extracts have been shown to confer protection against DOX-induced cardiotoxicity. Apocynum venetum L . belongs to the Apocynaceae family. Flavonoid extracted from Apocynum venetum L . possess various biological effects, such as lowering blood pressure levels, sedation, diuresis, anti-aging, and improving immunity. Purpose This study investigated the mechanism by which dry leaf extract of Apocynum venetum L. (AVLE) alleviates DOX-induced cardiomyocyte apoptosis. Methods HPLC-MS/MS and HPLC methods were used to analyze the components of AVLE. The effects of DOX and AVLE on apoptosis of H9c2 and HMC cells were assessed using the MTT assay. Calcein AM/PI, TUNEL, and flow cytometry were carried out to determine the effects of AVLE on DOX-induced apoptosis. The effect of AVLE on DOX-induced oxidative stress in cardiomyocytes was investigated using ELISA test. Mito-Tracker Red CMXRos, JC-1, and RT-qPCR assays were performed to evaluate the impact of AVLE on DOX-induced cardiomyocyte mitochondrial activity and membrane permeability. Western blot assay was carried out to determine the activation of multiple signaling molecules, including phosphorylated-protein kinase B (p-AKT), Cytochrome c, Bcl-2 family, and caspase family in the apoptosis pathway. The AKT inhibitor was used to block AKT/Bcl-2 signaling pathway to investigate the role of AKT in the protection conferred by AVLE against DOX-induced cardiotoxicity. Results A total of 8 compounds, including rutin, hyperoside, isoquercetin, unidentified compounds, myricetin, quercetin, quercetin-3-O-glucuronide and kaempferol, were detected in AVLE. Of note, DOX suppressed lactate dehydrogenase (LDH) levels, aggravated oxidative stress, and promoted cardiomyocyte apoptosis. It also upregulated the mRNA expression levels of voltage-dependent anion channel 1 (VDAC1), adenosine nucleotide transporter 1 (ANT1), and cyclophilin D (CYPD), while suppressing mitochondrial activity and mitochondrial membrane permeability. Treatment with DOX altered the expression levels of apoptosis-associated proteins, Bcl-2 and Bax. However, AVLE treatment alleviated DOX-induced effects on cardiomyocytes. In addition, application of AKT inhibitors promoted DOX-induced apoptosis and reversed the inhibitory effects of AVLE on DOX-induced apoptosis. Conclusions AVLE confer cardio protection by suppressing oxidative stress and apoptosis of cardiomyocytes via AKT/Bcl-2 signaling pathway.
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Materials Science & Engineering C-Materials for Biological Applications
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2020
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IF 5.88
Yuanfeng Pan,Junren Liu,Kunni Yang,Pingxiong Cai,Huining Xiao
Nanogel based on polysaccharides has attracted the tremendous interest due to its unique performance as drug carrier for in vivo release. In this work, the multi-responsive nanogels were developed based on the tailor-modified sugarcane bagasse cellulose (SBC). In the presence of crosslinking agent cystamine bisacrylamide (CBA), the in-situ free radical copolymerization of methacrylated monocarboxylic sugarcane bagasse cellulose (MAMC-SBC) and N-isopropylacrylamide (NIPAM) in aqueous phase was conducted, thus leading to redox, pH and thermal-responsive nanogels. The results obtained from FT-IR, SEM and particle sizer showed that the nanogels were highly stable with the desired particle size ranging from 90 to 180 nm and contained targeted polymeric segments and linkage for multi-responsivity. Doxorubicin hydrochloride (DOX) as a model drug was effectively loaded into the nanogels, partly driven by strong electrostatic association; and the loading efficiency reached up to 82.7%. Moreover, the drug release could be readily manipulated by the addition of reducing agent, pH and temperature, which is attributed to the multi-responsive behavior of nanogels as carrier and synergetic effects. The performance of nanogels was also governed by the ratio of reactive MAMC-SBC and NIPAM during polymerization; and the ratio at 1:1(wt) led to the optimal structure of nanogels.
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ACS Applied Polymer Materials
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2020
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IF 0
Wei Zhang,Yi Li,Lanju Xu,Dou Wang,Jing Long,Meng Zhang,Yufei Wang,Yuxiao Lai,Xing-Jie Liang
Combination therapy based on a nanoscale drug delivery system (nDDS) shows great promise in cancer therapy. We report herein the development of a nanotherapeutic that combines photothermal therapy (PTT) and chemotherapy into one nanoformula to achieve combinatorial anticancer capacity. Near-infrared (NIR)-absorbing conjugated polymers (CPs) were used as the PTT agents and coloaded with chemotherapeutic drug doxorubicin (Dox) to afford the multifunctional delivery system DCP NPs. The strong NIR absorbance of CPs endows DCP NPs with excellent photothermal capacity and NIR laser triggered drug release property. The fluorescence of Dox was quenched after encapsulation because of the fluorescence resonance energy transfer (FRET) effect between Dox and CPs, which could be used to monitor the intracellular Dox release from DCP NPs. As a result of these properties, DCP NPs exhibited very potent anticancer capacity against osteosarcoma 143B cells. This study demonstrates the great potential of CPs-based nanotherapeutic for combined photothermal-chemotherapy to combat cancer.
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Science Advances
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2020
·Vol. 6
·期 18
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IF 13.117
Chen-Cheng Xue,Meng-Huan Li,Yang Zhao,Jun Zhou,Yan Hu,Kai-Yong Cai,Yanli Zhao,Shu-Hong Yu,Zhong Luo
The rapid development of treatment resistance in tumors poses a technological bottleneck in clinical oncology. Ferroptosis is a form of regulated cell death with clinical translational potential, but the efficacy of ferroptosis-inducing agents is susceptible to many endogenous factors when administered alone, for which some cooperating mechanisms are urgently required. Here, we report an amorphous calcium carbonate (ACC)–based nanoassembly for tumor-targeted ferroptosis therapy, in which the totally degradable ACC substrate could synergize with the therapeutic interaction between doxorubicin (DOX) and Fe2+. The nanoplatform was simultaneously modified by dendrimers with metalloproteinase-2 (MMP-2)–sheddable PEG or targeting ligands, which offers the functional balance between circulation longevity and tumor-specific uptake. The therapeutic cargo could be released intracellularly in a self-regulated manner through acidity-triggered degradation of ACC, where DOX could amplify the ferroptosis effects of Fe2+ by producing H2O2. This nanoformulation has demonstrated potent ferroptosis efficacy and may offer clinical promise.
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高影响因子
COLLOID AND POLYMER SCIENCE
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2020
·Vol. 298
·期 3
·303-312
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IF 1.536
Gao Feng,Wang Qiang,Yang Xiaochun
Synthesis of amphiphilic poly( β -amino esters) (PBAE) was optimized by stepwise feeding of monomers (PBAE-(P-H)) compared with one-pot synthesis (PBAE-(P&H)) based on poly(ethylene glycol) diacrylate (PEGDA) and 1,6-hexanediol diacrylate (HDDA). Interestingly, optimized synthetic PBAE-(P-H) had smaller critical micelle concentration (CMC) of 6.6 μg/mL on average than one-pot synthetic PBAE-(P&H) (10.4 μg/mL). Nanoparticles were prepared based on PBAE-(P-H) and PBAE-(P&H), respectively. PBAE-(P-H) nanoparticles exhibited more narrow size distribution (average size, 105.3 nm; PDI, 0.103) than PBAE-(P&H) nanoparticles (average size, 117.8 nm; PDI, 0.233) demonstrated by dynamic light scattering and transmission electron microscopy. Afterward, PBAE-(P-H) and PBAE-(P&H) nanoparticles were selected to further investigate the properties including charge conversion and pH responsiveness. Doxorubicin (DOX) was encapsulated into nanoparticles. DOX release in vitro was enhanced as the decrease of pH value. Furthermore, DOX-loaded PBAE-(P-H) and PBAE-(P&H) nanoparticles exhibited enhanced cytotoxicity and cellular uptake against HCT116 cells compared with DOX under tumor microenvironment.
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International Journal of Nanomedicine
·
2021
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IF 6.4
Ronghua Tan,Danlei Tian,Jiaoyan Liu,Congcong Wang,Ying Wan
Background Chemotherapeutic drugs used for tumor treatments often show limited efficiency due to their short lifetime, nonspecific delivery, and slow or insufficient intracellular drug release, and also, they can cause severe system or organ toxicity. The development of chemotherapeutic nanomedicines with high efficacy and satisfactory safety still remains a challenge for current tumor chemotherapy.Methods A novel type of conjugate was synthesized using hydroxyethyl starch (HES) as a carrier while binding doxorubicin (DOX) onto HES backbone through a pH/redox responsive linker containing both disulfide and hydrazone bonds in series. The built conjugates were self-assembled into nanoparticles (NPs) (HES-SS-hyd-DOX NPs) for achieving enhanced antitumor therapy and adequate safety.Results HES-SS-hyd-DOX NPs had a certain ability for the tumor-orientated drug accumulation and were capable of releasing DOX itself rather than DOX derivatives. It was found that the pH/redox responsive linkage enabled the NPs to achieve fast and sufficient intracellular drug release. Based on the tumor-bearing mouse model, antitumor results demonstrated that these NPs were able to inhibit the growth of the advanced tumors with significantly enhanced efficacy when compared to free DOX, and to those conjugate NPs containing only a single responsive or unresponsive bond. Besides, HES-SS-hyd-DOX NPs also showed adequate safety to the normal organs of the treated mice.Conclusion The pH/redox responsive linkage in HES-SS-hyd-DOX was found to play a critical role in mediating the drug accumulation and the fast and sufficient intracellular drug release. The HES-exposed surface of HES-SS-hyd-DOX NPs endowed the NPs with long circulation capability and remarkably reduced the DOX-induced side effects.
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ChemNanoMat
·
2019
·Vol. 5
·期 12
·1531-1539
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IF 3.431
Licheng Wang,Hanyi Hou,Xinqi Jiao,Tianyin Shen,Yingying Liu,Yida Qiao,Yu Liu,Yuan Lu,Jun Ge
Graphical Irresistible : An antineoplastic chemotherapeutic nanoparticle (NP) is constructed based on zinc-cobalt bimetal-organic frameworks encapsulated with doxorubicin (DOX). Therapeutic effects are tested on cancer cell lines and its DOX-resistant counterparts, and cellular characteristics are further examined to demonstrate the effectiveness of NPs in overcoming drug-resistance. Drug resistance is a major challenge in antineoplastic chemotherapy, which could be possibly solved through multifunctional anti-cancer therapy. This study constructs a drug delivery system with Zn(II)-Co(II) bimetal-organic framework nanoparticles with encapsulated doxorubicin (DOX), a model chemotherapeutic molecule. Beyond conventional therapeutic mechanisms powered by DOX, the newly applied Co(II) to the drug delivery system catalyzes the generation of reactive oxygen species (ROS) through a Fenton-like process, leading to necrosis due to oxidative stress beyond threshold. The system displayed DOX-based and Co(II)-based dual mechanism anti-cancer therapy to overcome DOX-resistance while demonstrating significant cytotoxicity promotion in non-resistant cell lines, as effects of ROS were further acknowledged by following cell characteristic examinations. This bifunctional DOX-encapsulated bimetal-organic framework nanoparticle opens a new strategy to construct multiple anti-cancer mechanism drug delivery systems with great simplicity.
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