Marine Drugs
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2022
·Vol. 20
·期 5
·284
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IF 6.085
Yuting Zhu,Shanhao Han,Jianhui Li,Hongwei Gao,Bo Dong
Marine ascidian is becoming one of the main sources of an antitumor drug that has shown high bioactivity and extensive application in cancer treatment.Halocynthia roretzi, an edible marine sea squirt, has been demonstrated to have various kinds of biological activities, such as anti-diabetic, anti-hypertension, and enhancing immunity. In this study, we reported that aqueous extracts from the edible parts ofH. roretzipresented significantly inhibiting the efficiency on HepG-2 cell viability. The separate mixed compound exhibited strong effects of inhibitory proliferation and induced apoptosis via the generation of ROS along with the concurrent loss of mitochondrial membrane potential on tumor cells. Furthermore, we found that there existed a significantly synergistic effect of the ascidian-extracted compound mixture with the anti-cancer drug doxorubicin. In the presence of the extracts fromH. roretzi, the dose of doxorubicin at the cellular level could be reduced by a half dose. The extracts were further divided by semipreparative-HPLC and the active ingredients were identified as a mixture of fatty amide, which was composed of hexadecanamide, stearamide, and erucamide by UHPLC-MS/MS. Our results suggest that the potential toxicity of ascidianH. roretziin tumor cells, and the compounds extracted fromH. roretzicould be potentially utilized on functional nutraceuticals or as an adjunct in combination with chemotherapy.Keywords:ascidian;Halocynthia roretzi;anti-tumor;drug combination;doxorubicin
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Frontiers in Cardiovascular Medicine
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2022
·
IF 5.846
Hongge Fa,Dandan Xiao,Wenguang Chang,Lin Ding,Lanting Yang,Yu Wang,Mengyu Wang,Jianxun Wang
Objective Many studies have reported that microRNAs (miRs) are involved in the regulation of doxorubicin (DOX)-induced cardiotoxicity. MiR-194-5p has been reported significantly upregulated in patients with myocardial infarction; however, its role in myocardial diseases is still unclear. Various stimuluses can trigger the endoplasmic reticulum (ER) stress and it may activate the apoptosis signals eventually. This study aims to explore the regulatory role of miR-194-5p in DOX-induced ER stress and cardiomyocyte apoptosis. Methods H9c2 was treated with 2 μM DOX to induce apoptosis, which is to stimulate the DOX-induced cardiotoxicity model. The expression of miR-194-5p was detected by quantitative real-time PCR (qRT-PCR); the interaction between miR-194-5p and P21-activated kinase 2 (PAK2) was tested by dual luciferase reporter assay; terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay and caspase-3/7 activity were used to assess apoptosis; trypan blue staining was applied to measure cell death; Western blotting was performed to detect protein expressions; and ER-related factors splicing X-box binding protein 1 (XBP1s) was detected by polyacrylamide gel electrophoresis and immunofluorescence to verify the activation of ER stress. Results MiR-194-5p was upregulated in cardiomyocytes and mouse heart tissue with DOX treatment, while the protein level of PAK2 was downregulated. PAK2 was predicted as the target of miR-194-5p; hence, dual luciferase reporter assay indicated that miR-194-5p directly interacted with PAK2 and inhibited its expression. TUNEL assay, caspase-3/7 activity test, and trypan blue stain results showed that either inhibition of miR-194-5p or overexpression of PAK2 reduced DOX-induced cardiomyocyte apoptosis. Silencing of miR-194-5p also improved DOX-induced cardiac dysfunction. In addition, DOX could induce ER stress in H9c2, which led to XBP1 and caspase-12 activation. The expression level of XBP1s with DOX treatment increased first then decreased. Overexpression of XBP1s suppressed DOX-induced caspase-3/7 activity elevation as well as the expression of cleaved caspase-12, which protected cardiomyocyte from apoptosis. Additionally, the activation of XBP1s was regulated by miR-194-5p and PAK2. Conclusion Our findings revealed that silencing miR-194-5p could alleviate DOX-induced cardiotoxicity via PAK2 and XBP1s in vitro and in vivo . Thus, the novel miR-194-5p/PAK2/XBP1s axis might be the potential prevention/treatment targets for cancer patients receiving DOX treatment.
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Chemical Biology & Drug Design
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2022
·Vol. 101
·期 1
·24-39
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IF 2.873
Donglin Zhang,Aiqin Pan,Jianke Gu,Renfeng Liao,Xueyu Chen,Zhaozhu Xu
MicroRNAs (miRs) are implicated in heart failure (HF). Thereby, we aim to uncover the role of miR-144-3p in HF. Doxorubicin (Dox)-induced HF model was constructed in rats and cardiomyocytes H9C2, and the cardiac function was determined using ultrasound cardiogram. Morphology of cardiac tissue was observed using hematoxylin–eosin (H&E) staining. The viability and apoptosis of Dox-treated and transfected cardiomyocytes were determined using Cell Counting Kit-8 (CCK-8) assay and flow cytometry. Relative expressions of the HF-associated miRs (including miR-144-3p), suppressor of cytokine signaling 2 (SOCS2), apoptosis- and phosphoinositide 3-kinase (PI3K)/AKT pathway-related factors (B-cell lymphoma 2, Bcl-2; Bcl-2 associated X protein, Bax; cleaved [C] capsase-3; phosphoinositide 3-kinase, PI3K; phosphorylated-PI3K, p-PI3K; p-AKT; AKT) were measured with quantitative real-time polymerase chain reaction or Western blot. Target gene of miR-144-3p was predicted by Starbase and TargetScan and confirmed with dual-luciferase reporter assay. Dox caused rat cardiac dysfunction, aggravated cardiac injury, decreased cardiomyocytes viability, and the expression of miR-144-3p, Bcl-2, and phosphorylation of both PI3K and AKT yet the upregulated those of Bax and C caspase-3, which was reversed by upregulating miR-144-3p, whereas downregulating miR-144-3p did oppositely. SOCS2 was the target gene of miR-144-3p, Dox promoted SOCS2 expression, which was reversed by upregulating miR-144-3p, while downregulating miR-144-3p did conversely. In addition, silencing SOCS2 reversed the effects of miR-144-3p downregulation in Dox-treated cardiomyocytes. Upregulating miR-144-3p alleviated Dox-induced cardiac dysfunction and cell apoptosis via targeting SOCS2, providing a novel evidence of miR-144-3p in HF.
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Molecular Medicine Reports
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2021
·Vol. 25
·期 2
·1-9
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IF 2.952
Fa-Xiu Chen,Qin Wan,Qing-Ling Li,Jing Fang,Le Peng,Jian Hu
The function of substance P (SP) in myocardial ischemia is well understood, but its effects on congestive heart failure are unclear. The present study aimed to use in vitro and in vivo approaches to investigate the effects of SP on doxorubicin‑induced cardiomyocyte injury. Pathological changes, apoptosis, cardiomyocyte ultrastructure and molecular mechanisms were evaluated in vitro and in vivo. The effects of SP on cell viability of H9c2 myocardial cells were evaluated using the Cell Counting Kit‑8 and flow cytometry. B‑cell lymphoma 2 (Bcl‑2), Bcl‑2‑associated X protein (Bax), Beclin‑1 and microtubule‑associated protein 1A/1B‑light chain 3 (LC3) were detected by western blotting. Heart failure in rats was established by intraperitoneal injection of doxorubicin. The in vitro data demonstrated that SP at concentrations of 1 µg/ml inhibited doxorubicin‑induced apoptosis of H9c2 cells. Administration of doxorubicin reduced Bcl‑2, Beclin‑1 and LC3 expression levels in H9c2 cells, while having no effect on Bax levels. Administration of SP to these doxorubicin‑treated cells did not affect Bcl‑2 or Bax expression, but further reduced Beclin‑1 while inhibiting the reduction in LC3 expression. In vivo, food intake was significantly increased in rats in the SP group compared with the model group. Cardiomyocytes in the heart‑failure group underwent dysfunctional autophagy as ascertained by transmission electron microscopy. Compared with the heart‑failure group, these pathological changes, including loss of striations and vacuolation, were inhibited by SP treatment, which promoted Bax expression, reduced Beclin‑1 expression and inhibited the reduction in LC3 expression. Taken together, SP reduced cardiomyocyte apoptosis in doxorubicin‑induced cardiomyocyte injury, likely by promoting autophagy, which suggested that SP is a potential therapeutic target for doxorubicin‑induced heart failure.
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JOURNAL OF NANOBIOTECHNOLOGY
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2021
·Vol. 19
·期 1
·1-16
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IF 10.435
Xiao Jianmin,Yan Miao,Zhou Ke,Chen Hui,Xu Zhaowei,Gan Yuehao,Hong Biao,Tian Geng,Qian Junchao,Zhang Guilong,Wu Zhengyan
The cell membrane is widely considered as a promising delivery nanocarrier due to its excellent properties. In this study, self-assembled Pseudomonas geniculate cell membranes were prepared with high yield as drug nanocarriers, and named BMMPs. BMMPs showed excellent biosafety, and could be more efficiently internalized by cancer cells than traditional red cell membrane nanocarriers, indicating that BMMPs could deliver more drug into cancer cells. Subsequently, the BMMPs were coated with nanoselenium (Se), and subsequently loaded with Mn2+ ions and doxorubicin (DOX) to fabricate a functional nanoplatform (BMMP-Mn2+/Se/DOX). Notably, in this nanoplatform, Se nanoparticles activated superoxide dismutase-1 (SOD-1) expression and subsequently up-regulated downstream H2O2 levels. Next, the released Mn2+ ions catalyzed H2O2 to highly toxic hydroxyl radicals (·OH), inducing mitochondrial damage. In addition, the BMMP-Mn2+/Se nanoplatform inhibited glutathione peroxidase 4 (GPX4) expression and further accelerated intracellular reactive oxygen species (ROS) generation. Notably, the BMMP-Mn2+/Se/DOX nanoplatform exhibited increased effectiveness in inducing cancer cell death through mitochondrial and nuclear targeting dual-mode therapeutic pathways and showed negligible toxicity to normal organs. Therefore, this nanoplatform may represent a promising drug delivery system for achieving a safe, effective, and accurate cancer therapeutic plan.
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POLYMER INTERNATIONAL
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2021
·Vol. 70
·期 12
·1717-1724
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IF 2.99
Lei Wang,Yifan Huang,Binjie Xin,Tingxiao Li
Electrospun core–shell nanofibers have aroused attention in drug delivery systems and tissue engineering because of the latent structures which can encapsulate various drugs and obtain tailored release profiles. Here, poly( l -lactide- co -ε-caprolactone) (PLCL) with gelatin (GE) blends were employed to electrospin the shell of core–shell nanofibers which could act as a protection layer for the controlled released behavior of the model drug doxorubicin hydrochloride (DOX). Core–shell nanofiber membranes with different drug loaded amounts were fabricated and the corresponding drug release behaviors were researched. The surface morphology of the obtained nanofibers was assessed by SEM and the structure of the core–shell nanofibers were observed by inverted fluorescence microscopy and TEM. The hydrophilicity was evaluated by water contact angle testing and the results indicated that the obtained fibers all possess good hydrophilicity. The mechanical properties of the fiber membranes were evaluated by tensile testing. Exploring the composition of the fiber membranes by Fourier transform infrared spectroscopy proved that DOX existed in the drug-loaded fiber membranes. In vitro release was evaluated by UV–visible spectroscopy and the accumulative release curves of DOX showed that increasing drug rates would lead to increasing cumulative release amounts but decreasing cumulative drug release rates. The results indicated that drugs encapsulated in PLCL/GE core–shell nanofiber material would be efficient and a potential material for drug delivery systems. © 2021 Society of Chemical Industry
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JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
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2021
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IF 3.935
Ya Zhang,Qian Zhou,Xin Ding,Haibo Wang,Guangguo Tan
Doxorubicin (DOX) is widely used against cancer but carries the risk of a progressive cardiomyopathy. Astragalus polysaccharides (ASP) is the main active ingredient of Astragalus membranaceus Bunge. It has been proved to be effective against DOX-induced cardiomyopathy. However, its therapeutic mechanism is not yet well explored. In this study, a metabolomics approach based on hydrophilic interaction liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (HILIC-Q-TOFMS) was developed to characterize the metabolic fluctuations associated with DOX cardiomyopathy and elucidate the underlying mechanisms of the protective effects of ASP. By the combination of HILIC-Q-TOFMS and multivariate and univariate data analysis, we identified 22 polar serum metabolites associated with DOX cardiomyopathy, 12 of which were significantly reversed when the animals were co-treated with ASP through two main metabolic pathways, i.e., sphingolipid and glycerophospholipid metabolism. Furthermore, it was found that ASP could alleviate DOX-induced cardiomyopathy by decreasing the levels of acid sphingomyelinase, acid ceramidase and phospholipase A2 and increasing the levels of sphingomyelin synthase to regulate the sphingolipid and glycerophospholipid metabolic disorder. These results revealed that sphingolipid and glycerophospholipid metabolism may be significantly responsible for DOX cardiomyopathy, which is also a major mechanism for the action of ASP against DOX cardiomyopathy.
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REACTIVE & FUNCTIONAL POLYMERS
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2021
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IF 3.975
Yue Zhang,Lizhen Yu,Jun Zhu,Renmin Gong
In this paper, a novel grafted polymer (folate and carboxymethyl-β-cyclodextrin grafted trimethyl chitosan, FCT) was synthesized. Then the FCT nanoparticles (FCT NPs) were fabricated by ionic gelation and the potential of NPs as co-carrier of doxorubicin and siRNA was evaluated. The physicochemical properties of grafted polymer and NPs were characterized and analyzed by fourier transforms infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR), transmission electron microscopy (TEM), dynamic light scattering (DLS), zeta potential and polydispersity index (PDI). The results showed the diameter of NPs ranged from 190 to 240 nm with polydispersity index of 0.192 and zeta potential of +21mv. The prepared NPs exhibited satisfactory drug loading capacity and encapsulation efficiency to doxorubicin and siRNA-survivin. Meanwhile, the prepared NPs could effectively protect siRNA-survivin from degradation of serum RNAase for a long time. Both drugs encapsulated in NPs all exhibited pH-dependent controlled sustained release characteristics and the cytotoxicity study testified that drug drug-loaded FCT NPs significantly improved the efficacy of antitumor drugs . The novel graft polymer was expected to become the co-carrier of anticancer and gene drugs in future with broad application prospects.
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JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2021
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IF 8.128
Yalei Miao,Yecheng Feng,Jie Bai,Zhongyi Liu,Xubo Zhao
Rapid progress has been made for mesoporous silica nanoparticle (MSN) in recent years; however, efforts to fabricate MSN with adjustable size have been met with limited advancement in drug delivery, especially for the synthesis of MSN with adjustable size in the range of 150–300 nm. Herein we report the construction of a series of MSNs with adjustable specific surface area, size, and pore structure, depending on the different silicon monomers selected. The optimized MSN showed large specific surface area and appropriate size distribution for efficiently anchoring doxorubicin (DOX) through the imine linkage formed. Based on the remarkable features of the unique MSN, a novel MSN-based drug delivery system was prepared through the introduction of polydopamine/manganese oxide (PDA/MnO 2 ) coating, which reduced the premature leakage of drugs in physiological environments, and yet facilitated drug release when destroyed by responding to endogenous glutathione (GSH) at the tumor sites. Notably, the transformation of MnO 2 to Mn 2+ resulted in the collapse of the PDA/MnO 2 coating, which facilitated drug release and therefore indicated the controlled release feature. It was demonstrated that the drug-loaded MSN-based drug delivery system delivered drugs into cancer cells and showed effective inhibition against cancer cell growth. These results suggested that the emergence of MSN with adjustable size can expand the application of MSN in drug delivery.
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NANOTECHNOLOGY
·
2021
·Vol. 32
·期 18
·185702
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IF 3.874
Mingxiu Tang,Mengjia Yang,Kaiyong He,Ran Li,Xiaojie Chen,Yaowen Wang,Xueqiong Zhang,Tong Qiu
We aimed to combine glycyrrhetinic acid with doxorubicin to prepare, characterize and evaluate a drug delivery nano-system with REDOX sensitivity for the treatment of breast cancer. M-DOX-GA NPs prepared by nano sedimentation were spherical, with a particle size of 181 nm. And the maximum encapsulation efficiency and drug loading in M-DOX-GA NPs were 89.28% and 18.22%, respectively. Cytotoxicity and cellular uptake experiments of nanoparticles to KC cells, Cal-27 cells and 4T1 cells were studied by the CCK-8 method. The result indicated that M-DOX-GA NPs could accurately release the drug into the tumor cells, thus achieving the targeted release of the drug. Comparing the survival rate of the above three cells, it was found that M-DOX-GA NPs had a good tumor selectivity and had a more significant therapeutic effect on breast cancer. A 4T1-bearing mouse model was established, and the tumor inhibition rate was 77.37% after injection of nanoparticle solution for 14 d. Normal tissue H&E stained sections and TUNEL assay were verified M-DOX-GA NPs have excellent tumor suppressive effect, and can efficiently reduce the toxic side effects on normal organisms, and effectively avoided 4T1 cells metastasis. Immunofluorescence detection and Western-blot analysis figured a decline in both CUGBP1 and α-SMA, which verifying the TME remodeling induced by glycyrrhetinic acid. Collectively, the combination of doxorubicin and glycyrrhetinic acid is an effective and safe strategy for remodeling fibrotic TME by improving the therapeutic outcome for breast cancer.
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International Journal of Medical Sciences
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2020
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IF 2.523
Ke Li,Wenhua Zhan,Min Jia,Yufeng Zhao,Yingguang Liu,Rajiv Kumar Jha,Liansuo Zhou
Background : Combination chemotherapy plays an important role in the clinical therapy of non-small cell lung cancer (NSCLC). However, the pharmacokinetic differences between drugs are an insurmountable barrier in traditional treatment. For the synergistic therapy of NSCLC, synergistic nanoparticles (EDS NPs) loaded with both an EGFR inhibitor and doxorubicin (DOX) were designed and prepared. Methods : Erlotinib, apatinib and icotinib were evaluated for optimal combination with DOX in treatment of NSCLC via CCK-8 assay. Then the cationic amphipathic starch (CSaSt) and hyaluronic acid (HA) were applied to coencapsulate DOX and EGFR inhibitor to form the EDS NPs. EDS NPs were evaluated in NSCLC cell lines (A549, NCI-H1975 and PC9) and NSCLC xenograft mouse models. Results : Icotinib was found to be the optimal synergistic drug in combination with DOX in the tested. Subsequently, icotinib and DOX were coencapsulated in the NPs. EDS NPs were roughly spherical with an average size of 65.7±6.2 nm and possessed stable loading and releasing properties. In the in vitro investigation, EDS NPs could efficiently deliver payloads into cells, exhibited cytotoxicity and produced strong anti-migration properties. In vivo hypotoxicity was confirmed by acute toxicity and hemolytic assays. The in vivo distribution showed that EDS NPs could enhance accumulation in tumors and decrease nonspecific accumulation in normal organs. EDS NPs significantly promoted the in vivo synergistic effects of icotinib and DOX in the mouse model. Conclusions : The study suggests that EDS NPs possess noteworthy potential for development as therapeutics for NSCLC clinical chemotherapy.
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JOURNAL OF PHARMACY AND PHARMACOLOGY
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2020
·Vol. 72
·期 4
·496-506
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IF 2.571
Zha Liqiong,Wang Beilei,Qian Jiajia,Fletcher Brock,Zhang Caiyun,Dong Qiannian,Chen Weidong,Hong Lufeng
ObjectivesZein nanoparticles (Zein NPs) were used as a hydroxyapatite (HA) biomineralization template to generate HA/Zein NPs. Doxorubicin hydrochloride (DOX) was loaded on HA/Zein NPs (HA/Zein-DOX NPs) to improve its pH-sensitive release, bioavailability and decrease cardiotoxicity.MethodsHA/Zein-DOX NPs were prepared by phase separation and biomimetic mineralization method. Particle size, polydispersity index (PDI), Zeta potential, transmission electron microscope, X-ray diffraction and Fourier-transform infrared spectroscopy of HA/Zein-DOX NPs were characterized. The nanoparticles were then evaluated in vitro and in vivo.Key findingsThe small PDI and high Zeta potential demonstrated that HA/Zein-DOX NPs were a stable and homogeneous dispersed system and that HA was mineralized on Zein-DOX NPs. HA/Zein-DOX NPs showed pH-sensitive release. Compared with free DOX, HA/Zein-DOX NPs increased cellular uptake which caused 7 times higher in-vitro cytotoxicity in 4T1 cells. Pharmacokinetic experiments indicated the t1/2β and AUC0–t of HA/Zein-DOX NPs were 2.73- and 3.12-fold higher than those of DOX solution, respectively. Tissue distribution exhibited HA/Zein-DOX NPs reduced heart toxicity with lower heart targeting efficiency (18.58%) than that of DOX solution (37.62%).ConclusionIn this study, HA/Zein-DOX NPs represented an antitumour drug delivery system for DOX in clinical tumour therapy with improved bioavailability and decreased cardiotoxicity.
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