Journal of Materials Chemistry B
·
2018
·Vol. 6
·期 12
·1834-1843
·
IF 4.776
Chan Feng,Kun Wang,Yun Lin,Zhiwang Song,Yonglin Lu,Jie Liu,Donglei Zhu,Yongyong Li,Chunyan Dong
Compared with intracellular drug delivery, drugs with extracellular targeting sites are rarely considered. As one of these drugs, cyclopamine (CYC) is a promising anticancer drug that functions by targeting the cell membrane receptor. For improving therapeutic effect, an albumin-based nano-system (ABN) with the capacity for extracellular retention was developed. The ABN was formulated by incorporating bovine serum albumin (BSA) into nanoparticles at the denaturing temperature of BSA, with CYC acting as a hydrophobic nucleation site, followed by stabilization upon heat-induced disulfide cross-linking. The resultant ABNs are negatively charged with a nanoparticle size that can be delicately regulated by varying the reaction time. In MDA-MB-231 cells, the size and charge of ABNs significantly affected the extracellular retention capacity, with ABN-300 nm exhibiting an enhanced cytotoxic effect. In vivo fluorescence imaging revealed obvious and persistent tumor accumulation of ABNs. A therapeutic study in an orthotopic mammary fat pad tumor model shows that ABN-300 nm possesses the most remarkable antitumor effect compared with the control groups. These results provide a new strategy for improving the efficacy of drug targeting at extracellular sites.
研究领域:
药学
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纳米技术
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肿瘤学
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2017
·
IF 6.319
Jing Wang,Lifei Xie,Tao Wang,Fengxin Wu,Jie Meng,Jian Liu,Haiyan Xu
Cationic macromolecules are attractive for use as small interfering RNA (siRNA) carriers due to their performance in non-immunological reactions, customization during synthesis, and low costs compared to viral carriers. However, their low transfection efficiency substantially hinders their application in both clinical practices and academic research, which is mostly attributable to the low capacity of siRNA/cationic macromolecule complexes to escape lysosomes . To address this challenge, we designed an amphiphilic fullerene derivative (C 60 -Dex-NH 2 ) for efficient and controllable siRNA delivery. To synthesize C 60 -Dex-NH 2 , terminally aminated dextran was conjugated to C 60 . The conjugate was further cationized by covalently introducing ethylenediamine to the dextran. The physicochemical characteristics of C 60 -Dex-NH 2 was examined with elemental analyses, gel permeation chromatography , solid-state nuclear magnetic resonance ( 13 C, HPDEC), agarose gel electrophoresis , and dynamic light scattering . The cytotoxicity, cellular uptake, intracellular distribution , and in vitro RNA interference (RNAi) of siRNA/C 60 -Dex-NH 2 complex was evaluated in the human breast cancer cell line MDA-MB-231. The RNAi efficiencies mediated by C 60 -Dex-NH 2 in vivo was evaluated in subcutaneous tumor-bearing mice. The results showed that C 60 -Dex-NH 2 has a specific amphiphilic skeleton and could form micelle-like aggregate structures in water, which could prevent siRNA from destroying by reactive oxygen species (ROS). When exposed to visible light, C 60 -Dex-NH 2 could trigger controllable ROS generation which could destroy the lysosome membrane, promote the lysosomal escape, and enhance the gene silencing efficiency of siRNA in vitro and in vivo . The gene silencing efficiency could reach a maximum of 53% in the MDA-MB-231-EGFP cells and 69% in the 4T1-GFP-Luc2 tumor-bearing mice. Statement of Significance We designed a novel photosensitive amphiphilic carrier (C 60 -Dex-NH 2 ) for efficient and controllable siRNA delivery, which can be used in gene therapy. We showed that C 60 -Dex-NH 2 could destroy lysosome membrane via controllable generation of ROS when exposed to light, which can help siRNA to escape from lysosome before degradation. This can enhance the gene silencing efficiency significantly and provides a useful way to regulate RNAi efficiency by light. One advantage for C 60 -Dex-NH 2 system is C 60 has broad absorbance spectrum and can be activated by weak visible light; Furthermore, C 60 -Dex-NH 2 has a specific amphiphilic structure, which may prevent siRNA from degrading and allows C 60 -Dex-NH 2 to embed into the lipid membrane of lysosome to improve the ROS induced lysosomal disturbance after internalization .
研究领域:
药学
·
纳米技术
·
分子生物学
·
癌症研究
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产品关联
DOI
PubMed
高影响因子
International Heart Journal
·
2024
·
IF 1.2
Xiaoyu Shen,Jiamei Zhang,Zhou Zhou,Ruiqun Yu
Cardiomyocyte lipotoxicity and ferroptosis are the key to the development of diabetic cardiomyopathy (DCM). Perilipin 5 (PLIN5) is perceived as a significant target of DCM. This study aimed to focus on the role and mechanism of PLIN5 on lipotoxicity and ferroptosis in DCM.Following transfection, mouse cardiomyocytes HL-1 were induced by 0.1 mM palmitic acid (PA) to set up lipotoxic cardiomyocyte models. The cell viability and lipid accumulation were evaluated by cell counting kit-8 assay and Oil red O staining, respectively. Ferrous ion (Fe2+), glutathione (GSH), malondialdehyde (MDA), and reactive oxygen species (ROS) levels were determined to verify the effects of PLIN5 or Pirin (PIR) on ferroptosis. Quantitative real-time reverse transcription polymerase chain reaction or Western blot was performed for quantitative analysis.PLIN5 overexpression promoted the viability, GSH level, and expression of GPX4/PIR/intracellular P65, yet suppressed lipid accumulation, level of Fe2+/MDA/ROS, and expression of interleukin (IL) -1β/IL-18/intranuclear P65 in PA-stimulated HL-1 cells. PIR silencing counteracted the roles of PLIN5 overexpression in PA-stimulated HL-1 cells.PLIN5 suppresses lipotoxicity and ferroptosis in cardiomyocyte via modulating PIR/NF-κB axis, hinting its potential as a therapeutic target in DCM.
研究领域:
心脏病学
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细胞生物学
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分子生物学
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糖尿病
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病理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BRAIN RESEARCH
·
2024
·
IF 2.7
Zhu Wang,Bowen Li,Jingrui Yang,Ying Gao,Liu Gao,Qiang Jia,Li Yu,Yunzhi Ling
The aim of this study was to examine the effects of ML365, a two-pore potassium channel (K2P) inhibitor, on postoperative cognitive impairment (POCD). A mouse model of POCD was constructed by subjecting aged C57BL/6 mice to exploratory laparotomy. Changes in cognitive function were assessed using the Morris water maze test. Western blotting and qPCR were used to detect hippocampal NLRP3, Caspase-1 and IL-1β expression levels on days 3 and 7 post-surgery. Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) expression level was also assessed by western blotting. Pathological changes and nerve damage in the hippocampal CA1 and CA3 regions were detected by H&E staining, while the concentration of malondialdehyde (MDA) in the plasma was measured. We found that pretreatment with ML365 (administered intraperitoneally at a dose of 10 mg/kg) 30 min prior to exploratory laparotomy effectively ameliorated POCD in mice. ML365 pretreatment also reduced NLRP3, Caspase-1, ASC and IL-1β expression levels in the hippocampus, improved POCD-induced pathological changes in the hippocampal CA1 and CA3 areas of aged mice, and decreased levels of plasma MDA and oxidative stress. Together, our findings indicate that ML365 can alleviate POCD in mice by inhibiting NLRP3 inflammasome activation in the hippocampus.
研究领域:
神经科学
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药理学
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外科手术
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炎症
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认知障碍
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产品关联
DOI
PubMed
高影响因子
CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY
·
2021
·Vol. 99
·期 12
·
IF 2.273
Weimin Xu,Peng Wang,Dalong Wang,Ke Liu,Shuaishuai Zhang,Wei Zhao,Guoqing Liu
The aim of the present study was to investigate the protective effect of S-ketamine (S-KET) against carbon tetrachloride (CCl4) – induced liver damage and oxidative stress, as well as to elucidate the related underlying mechanisms. Blood was collected to measure biochemical parameters (alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), total bilirubin (TB) and γ-glutamyltransferase (γ-GT)) and the liver was harvested for histopathological analysis of enzymes related to the antioxidant response (malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GSH-PX)). Liver cell apoptosis was evaluated using the TUNEL assay. In addition, the expression levels of apoptosis-related proteins and the nuclear factor erythroid 2–related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway were detected by Western blot analysis to explore potential mechanisms. S-KET protected the liver from CCl4-induced damage. The changes to the liver biochemical parameters (increased ALT, AST, ALP, TB, and γ-GT) and oxidative stress-related indicators (increased MDA; depleted SOD, GSH, and GSH-PX) induced by CCl4 were inhibited by S-KET. S-Ket also inhibited CCl4-induced cell apoptosis, the changes in expression of related proteins, and blocked CCl4-induced liver injury and oxidative stress via activation of the Nrf2/HO-1 signaling pathway. S-KET effectively protected the liver by inhibition of CCl4-induced damage via upregulation the Nrf2/HO-1 signaling pathway.
研究领域:
药理学
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肝病学
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分子生物学
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毒理学
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DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2018
·
IF 5.158
Zheng-Nan Cai,Wan Li,Shomaila Mehmood,Wen-Juan Pan,Ya Wang,Fan-Ju Meng,Xiao-Fang Wang,Yong-Ming Lu,Yan Chen
This study aimed to investigate the structural features, in vitro and in vivo antioxidant activities of a heteropolysaccharide from the fruiting bodies of Morchella esculenta (FMP-1). FMP-1 had an average molecular weight of 4.7 × 10 3 Da and consisted of mannose, glucose and galactose. By methylation and NMR analysis, the backbone of FMP-1 was deduced to be made up of 1,4-linked Glc p and 1,6-linked Gal p . Hydroxyl, DPPH and superoxide radicals could be efficiently scavenged by FMP-1, with IC 50 values of 74.26, 119.32 and 161.49 μg/mL, respectively. Furthermore, FMP-1 could significantly protect zebrafish embryos against AAPH-induced oxidative damage. Decrease in malformations and mortalities was observed along with the reduction of ROS production, NO production and cell death. The protective effects were by decreasing MDA content and increasing SOD, CAT and GSH-Px levels. The current work provided a good suggestion of the potential utilization of FMP-1 as an attractive natural antioxidant.
研究领域:
药理学
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生物化学
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真菌学
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毒理学
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产品关联
DOI
PubMed
高影响因子
CHEMBIOCHEM
·
2018
·Vol. 19
·期 10
·1060-1065
·
IF 2.774
Xueyu Zhao,Gaochao Lv,Ying Peng,Qingzhu Liu,Xi Li,Shanshan Wang,Ke Li,Ling Qiu,Jianguo Lin
Graphical Active duty : An activatable fluorescent probe consisting of a peptide, Arg-Val-Arg-Arg (RVRR), and an aminoluciferin fluorophore is designed and prepared for the responsive and activatable detection of furin activity in living cells. This probe is shown to have “off–on” florescence properties, and in the presence of furin in vitro, its fluorescence intensity is increased by a factor of ≈3.58. Furin, a protein convertase, plays a crucial role in the progression of tumors. In this work, a new fluorescent probe consisting of a peptide, Arg-Val-Arg-Arg (RVRR), and an aminoluciferin fluorophore was designed and prepared for the responsive and activatable detection of furin activity in vitro and in living cells. We demonstrated that this probe could be responsive toward furin with an “off–on” florescence signal and generated an approximately 3.58-fold enhancement in the fluorescence intensity in vitro. Fluorescence imaging in MDA-MB-468 and LoVo cells showed that the probe could be cleaved by overexpressed furin with fluorescence turn-on in MDA-MB-468 cells, and this probe was also found to be capable of discriminating between furin-overexpressing and furin-deficient cell lines. Our research indicates that this probe has great potential for the detection of furin activity in living cells.
研究领域:
生物化学
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分子生物学
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癌症研究
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
BIOLOGICAL TRACE ELEMENT RESEARCH
·
2017
·Vol. 181
·期 1
·62-70
·
IF 2.399
Zhang Hui,Chang Zhenyu,Mehmood Khalid,Abbas Rao Zahid,Nabi Fazul,Rehman Mujeeb Ur,Wu Xiaoxing,Tian Xinxin,Yuan Xiaodan,Li Zhaoyang,Zhou Donghai
Nano-sized copper particles are widely used in various chemical, physical, and biological fields. However, earlier studies have shown that nano copper particles (40–100 μg/mL) can induce cell toxicity and apoptosis. Therefore, this study was conducted to investigate the role of nano copper in mitochondrion-mediated apoptosis in PK-15 cells. The cells were treated with different doses of nano copper (20, 40, 60, and 80 μg/mL) to determine the effects of apoptosis using acridine orange/ethidium bromide (AO/EB) fluorescence staining and a flow cytometry assay. The levels of malondialdehyde (MDA) and superoxide dismutase (SOD) in the PK-15 cells were examined using commercially available kits. Moreover, the mRNA levels of the Bax, Bid, Caspase-3, and CYCS genes were assessed by real-time PCR. The results revealed that nano copper exposure induced apoptosis and changed the mitochondrial membrane potential. In addition, nano copper significantly altered the levels of the Bax, Bid, Caspase-3, and CYCS genes at a concentration of 40 μg/mL. To summarize, nano copper significantly ( P < 0.05) decreased the level of SOD and increased the level of MDA in PK-15 cells. Altogether, these results suggest that nano copper can play an important role in inducing the apoptotic pathway in PK-15 cells, which may be the mechanism by which nano copper induces nephrotoxicity.
研究领域:
细胞生物学
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毒理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2022
·
IF 5.714
Shu-ping Yang,Qing Su,Ya-ru Zhang,Yun Sun,Yu-rong Chai
As the main lymphoid organ, the thymus degenerates with age. The loss of thymic epithelial cells is mainly related to thymus degeneration and reduced T cells development. As an insulin sensitizer, metformin is a first-line drug for the treatment of diabetes and has been shown to prolong the lifespan of mice, but the mechanism is still unclear. In this study, we explored the therapeutic effect of metformin on thymus degeneration in the accelerated aging mice, which was established by intraperitoneal injection D-galactose (120 mg/kg/day) for eight weeks. Metformin was intragastrically given with 100 or 300 mg/kg body weight per day, respectively, for six weeks. Histological examination showed that metformin administration could alleviate thymus atrophy caused by D-galactose. In addition, metformin therapy increased mitochondrial membrane potential, with a reduction in mitochondrial reactive oxygen species, MDA and SOD levels, and restored mitochondrial balance through enhanced expression of dynamin-related protein 1 (Drp1). Furthermore, metformin altered T lymphocyte subsets and cellular senescent cells; the expression of FoxN1, Aire and Sox2 of thymic epithelial cells also increased. Thus, metformin presented a positive effect on thymic degeneration through improving mitochondrial function. Taken together, these findings revealed an unexpected complexity in the anti-aging of this widely used drug.
研究领域:
药理学
·
免疫学
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老年学
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细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
MOLECULES
·
2024
·Vol. 29
·期 18
·4375
·
IF 4.2
Ran Luo,Haoyi Zhao,Siqi Deng,Jiale Wu,Haijun Wang,Xiaoshan Guo,Cuicui Han,Wenkang Ren,Yinglong Han,Jianwen Zhou,Yu Lin,Ming Bu
In this study, novel ergosterol peroxide (EP) derivatives were synthesized and evaluated to assess their antiproliferative activity against four human cancer cell lines (A549, HepG2, MCF-7, and MDA-MB-231). Compound3gexhibited the most potent antiproliferative activity, with an IC50value of 3.20 µM against MDA-MB-231. This value was 5.4-fold higher than that of the parental EP. Bioassay optimization further identified3gas a novel glutaminase 1 (GLS1) inhibitor (IC50= 3.77 µM). In MDA-MB-231 cells,3greduced the cellular glutamate levels by blocking the glutamine hydrolysis pathway, which triggered reactive oxygen species production and induced caspase-dependent apoptosis. Molecular docking indicated that3ginteracts with the reaction site of the variable binding pocket by forming multiple interactions with GLS1. In a mouse model of breast cancer,3gshowed remarkable therapeutic effects at a dose of 50 mg/kg, with no apparent toxicity. Based on these results,3gcould be further evaluated as a novel GLS1 inhibitor for triple-negative breast cancer (TNBC) therapy.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
癌症研究
✓ 已验证
DOI
PubMed
高影响因子
INFLAMMOPHARMACOLOGY
·
2024
·
IF 4.6
Iqbal Urooj,Malik Abdul,Sial Nabeela Tabassum,Mehmood Malik Hassan,Nawaz Shoaib,Papadakis Marios,Fouad Dalia,Ateyya Hayam,Welson Nermeen N.,Alexiou Athanasios,Batiha Gaber El-Saber
Background The current study aimed to evaluate the anti-inflammatory, anti-oxidant, and pronounced gastro-protective activities of β- Citronellol using in vitro , in vivo assays and in silico approaches. Methods In vitro assays, denaturation of bovine serum albumin, egg protein, and human Red Blood Cells (RBCs) membrane stabilization were performed, using Piroxicam as standard. For in vivo assessment, Histamine (0.1 ml from 1% w/v) and Formaldehyde (0.1 ml from 2% v/v) were used to mediate inflammation. In silico molecular docking and network pharmacology were employed to probe the possible target genes mediating gastroprotective effect of β-Citronellol at 25, 50, and 100 mg/kg, using indomethacin-induced (25 mg/kg i.p) gastric ulcer in rats. Moreover, Gastric tissues were evaluated for morphological, histopathological, and bio-chemical analysis of PGE 2, COX-I, COX-II, 5-LOX, eNOS, ICAM-1, oxygen-free radical scavengers (SOD, CAT), and oxidative stress marker (MDA). Results β - Citronellol prevented denaturation of proteins and RBCs membrane stabilization with maximum effect observed at 6,400 µg/mL. Citronellol decreased rat’s paw edema. Network pharmacology and docking studies revealed gastro-protective potential of Citronellol possibly mediated through arachidonic acid pathways by targeting COX-I, COX-II, PGE 2 , and 5-LOX. Citronellol reduced the ulcer indices, and histopathological changes. Further, β - Citronellol (50 and 100 mg/kg) increased gastric PGE 2, COX-1, and eNOS; while suppressing COX-2, 5-LOX and ICAM-1. Citronellol markedly enhanced the oxidative balance in isolated rat stomach tissues. Conclusions The anti-inflammatory, anti-oxidant, and gastro-protective effects of β - Citronellol against indomethacin-induced gastric ulcer model in rats through mediating COX-I, COX-II, PGE 2, 5-LOX, eNOS, and ICAM-1 inflammatory markers. Graphical abstract
研究领域:
药理学
·
炎症
·
胃肠病学
·
分子生物学
·
生物化学
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产品关联
DOI
PubMed
高影响因子
FEBS Open Bio
·
2024
·
IF 2.8
Linqian Chen,Meifeng Chen,Yan Xie,Yuyan Zhang,Shutian Mo,Yongfei He,Tianyi Liang,Yuan Liao,Renbin Huang,Guodong Huang,Chuangye Han,Thi Thai Hoa Pham
Several studies have suggested a potential antitumor effect of 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione (DMDD). To further understand the mechanism of action of this compound, we investigated its effect on the phosphatidylinositol-3-kinase (PI3K)/serine–threonine kinase (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. We show that DMDD application significantly inhibited the proliferation of breast cancer cell lines MDA-MB-231 and ER-α positive MCF-7. Furthermore, DMDD application resulted in increased intracellular reactive oxygen species (ROS) levels, apoptosis and autophagy, whereas it downregulated the expression of PI3K, Akt and mTOR mRNA and proteins, and increased the expression of LC3II/I and p62 proteins. In a mouse breast cancer xenograft model, DMDD inhibited tumor growth. Expression analyses suggest that ROS levels were higher in DMDD treated tumor tissues, whereas immunohistochemical analyses suggest that apoptotic cells were more prevalent in the DMDD treated group compared to the control group. Taken together, our results suggest that the molecular mechanism of action of DMDD may involve the enhancement of breast cancer autophagy through the PI3K/Akt/mTOR signaling pathway by mediating ROS expression.
研究领域:
肿瘤学
·
细胞生物学
·
药理学
·
癌症研究
✓ 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）