INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2026
·
IF 8.7
Baichuan Mu,Chuanhang Zhou,Yang Liu,Zhe Fan,Yiran Li,Ruiqi Wang,Wenlong Yan,Xicheng Duan,Wei Guo,Zongsheng Yin,Yinzhong Chen
The physical interfaces governing macromolecular protein–protein interactions dictate critical gene transcription programs, yet the structural basis of regulatory complexes inhibiting NF-κB remains partially resolved. Here, we characterize the macromolecular interaction between Smad nuclear interacting protein 1 (SNIP1) and the transcriptionally active p65 subunit of NF-κB, a regulatory axis whose pathological downregulation was identified via comparative proteomics of human osteoarthritic cartilage. GSE114007 and descriptive single-cell analyses of GSE152805 showed lower SNIP1 expression in diseased cartilage; GSE169077 showed the same direction without statistical significance. Co-immunoprecipitation confirmed the endogenous physical association of SNIP1 and p65 in human chondrocytes. Molecular docking and molecular dynamics (MD) simulations mapped a candidate SNIP1–p65 interface with a negative MM/GBSA endpoint estimate (ΔGbind = −209.6 kJ/mol, 95% CI −381.4 to −37.8 kJ/mol across three trajectory means). The computational models position SNIP1 Arg-287 and Arg-288 within a cationic interface that is sterically incompatible with the DNA-bound conformation of p65. Computational substitution analysis further identified Arg-288 as a candidate hotspot residue, with charge-reversal substitutions predicted to destabilize the complex; this residue-level prediction awaits experimental site-directed mutagenesis. An assumption-based ODE model illustrates the sensitivity of downstream outputs to imposed SNIP1-dependent inhibition without establishing clinical kinetics or residue-specific causality. Overall, the combined data define a testable structural model for SNIP1-mediated regulation of p65 while avoiding causal attribution to Arg-288 before experimental validation.
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DOI
高影响因子
BMC Pulmonary Medicine
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2020
·Vol. 20
·期 1
·1-12
·
IF 2.813
Guo Jing,Li Min,Yang Yi,Zhang Lin,Zhang Li-wei,Sun Qian-yun
Background The complement system plays a critical role as the pathogenic factor in the models of acute lung injury due to various causes. Cobra venom factor (CVF) is a commonly used complement research tool. The CVF can cause acute inflammation in the lung by producing complement activation components. Atorvastatin (ATR) is a 3-hydroxy-3-methylglutaryl coenzyme A inhibitor approved for control of plasma cholesterol levels. This inhibitor can reduce the acute pulmonary inflammatory response. However, the ability of ATR in treating acute lung inflammation caused by complement activation is still unknown. Therefore, we investigated the effect of ATR on lung inflammation in mice induced by activation of the complement alternative pathway in this study.Methods ATR (10 mg/kg/day via oral gavage) was administered for 7 days before tail vein injection of CVF (25 μg/kg). On the seventh day, all mice were sacrificed 1 h after injection. The lung lobe, bronchoalveolar lavage fluid (BALF), and blood samples were collected. The myeloperoxidase (MPO) activity of the lung homogenate, the leukocyte cell count, and the protein content of BALF were measured. The levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), P-selectin, and Intercellular cell adhesion molecule-1 (ICAM-1) in BALF and serum were determined by enzyme-linked immunosorbent assay. The pathological change of the lung tissue was observed by hematoxylin and eosin staining. The deposition of C5b-9 in the lung tissue was detected by immunohistochemistry. The phosphorylation of NF-κB p65 in the lung tissues was examined by immunohistochemistry and western blotting.Results The lung inflammation levels were determined by measuring the leukocyte cell numbers and protein content of BALF, the lung MPO activity, and expression and staining of the inflammatory mediators (IL-6 and TNF-α), and adhesion molecules (P-selectin and ICAM-1) for lung lesion. A significant reduction in the lung inflammation levels was observed after 7 days in ATR pre-treated mice with a CVF-induced lung disease. Deposition of C5b-9 was significantly alleviated by ATR pretreatment. Early intervention with ATR significantly reduced the development of acute lung inflammation on the basis of phosphorylation of NF-κB p65 in the lung.Conclusion These findings suggest the identification of ATR treatment for the lung inflammation induced by activating the complement system on the basis of its anti-inflammatory response. Together with the model replicating the complement activating characteristics of acute lung injury, the results may be translatable to the overactivated complement relevant diseases.
研究领域:
药理学
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免疫学
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病理学
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呼吸医学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CELLULAR BIOCHEMISTRY
·
2018
·Vol. 120
·期 6
·9648-9655
·
IF 2.959
Chaozhi Ma,Liyuan Zou,Yu Xia,Yijun Tu,Daquan Xue,Yanfang Yang,Dan Liu,Yanwen Liu,Hezhen Wu,Hanxiong Dan,Pengtao You
Asthma is characterized by airway inflammatory infiltration, which leads to airway remodeling and airway hyperreactivity. Coleus forskohlii (CFK) has been used to treat asthma, however, the mechanism involved is not clear. To explore the antiasthma mechanism of extracts of Coleus forskohlii (ECFK), guinea pigs were administered with a spray of phosphoric acid histamine, and rats were sensitized with ovalbumin (OVA). Hematoxylin and eosin staining (H&E) were used to evaluate pathological changes in lung tissue. Enzyme-linked immunosorbent assay (ELISA) was used to determine cytokine levels in serum and bronchoalveolar lavage fluid (BALF). Immunohistochemistry and Western blot analysis were used to assess the expression of intercellular cell adhesion molecule-1 (ICAM-1), phosphorylation of p65 (p-p65), matrix metallopeptidase 9 (MMP-9), and tissue inhibitor of metalloproteinase 1 (TIMP-1). After ECFK treatment, the asthma incubation period of guinea pigs was significantly prolonged. The H&E results showed that the number of eosinophils in the 12.8 g/kg ECFK group was significantly lower when compared with the control group. Moreover, ELISA results demonstrated that interleukin (IL)-4, IL-5, and IL-17 in serum and BALF were significantly decreased, and interferon-γ (IFN-γ) and IL-10 were increased after ECFK treatment. In addition, ECFK treatment resulted in downregulation of ICAM-1, p-p65, MMP-9, and TIMP-1 in lung tissue after being sensitized by OVA. In conclusion, our findings indicated that ECFK significantly alleviated OVA-induced inflammatory infiltration and airway remodeling in asthma. This study laid a theoretical foundation for the clinical use of ECFK.
研究领域:
药理学
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免疫学
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呼吸医学
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DOI
PubMed
高影响因子
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
·
2023
·
IF 3.9
Yinzhong Chen,Wei Guo,Weizhao Lu,Xiucheng Guo,Weilu Gao,Zongsheng Yin
Osteoarthritis (OA), the most common joint disease, is characterized by inflammation and cartilage degradation. Previous studies illustrated that Smad nuclear-interacting protein 1 (SNIP1) is an inhibitor of the TGF-β signal transduction pathway and SNIP1 has been reported as an anti-inflammatory factor. This study aimed to explore the role of SNIP1 in OA progression. In this study, the SNIP1 expression was evaluated in OA human and OA mice tissue and interleukin-1 beta (IL-1β)-induced chondrocytes . The Safranin-O (SO) staining and osteoarthritis research society international (OARSI) scoring system was used to evaluate cartilage injury. The gain- and loss-of-function studies for SNIP1 were performed in chondrocytes. The SNIP1 overexpression adenovirus was injected into mice by intra-articular injection. The SNIP1 expression was decreased in OA patients, OA mice, and IL-1β-stimulated chondrocytes. The cartilage injury of medial meniscus-induced OA (DMM-OA) mice at 8 weeks showed more severe than that at 4 weeks. The expression of SNIP1 was lower at 8 weeks than that at 4 weeks. In IL-1β-stimulated chondrocytes, SNIP1 overexpression reduced the expression of TNF-α and IL-6, alleviated ECM degradation, reduced the phosphorylation levels of p65 and IκBα , and decreased the p65 level in nuclear. Moreover, overexpression of SNIP1 alleviated cartilage injury in DMM-OA mice. In brief, our study suggested that SNIP1 alleviated OA and repressed inflammation by inhibiting the activation of NF-κB. This study might provide a new insight into OA treatment.
研究领域:
风湿病学
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分子生物学
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炎症
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软骨生物学
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DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
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2012
·
IF 2.999
Hua-Zhong Ying,Yue-Huan Liu,Bing Yu,Zhi-Yuan Wang,Jia-Na Zang,Chen-Huan Yu
Dietary quercetin is highly abundant in edible plants, which possesses a wide range of pharmacological properties. This study was to investigate hepatoprotective effects of quercetin in the nonalcoholic steatohepatitis (NASH) gerbils induced by a high-fat diet (HFD), and to evaluate its regulatory mechanism on hepatic inflammatory response. The gerbils were fed with HFD for 28 days to induce NASH. From 15th day to 28th day, the treated drugs were given daily to each animal, respectively. The lipid profiles and biochemical markers were determined at the end of the experiment. The expressions of Sirt1, NF-κB p65 and iNOS were detected by immunohistochemistry and Western blot analysis. The results showed that oral administration of quercetin at doses of 30–60 mg/kg to hyperlipidemia rats for 14 days were highly effective in decreasing the levels of serum total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), alanine aminotransferase (ALT) and aspartate aminotransferase (AST). It could decrease lipid accumulation in the hepatocytes, and reduce serum levels of pro-inflammatory cytokines TNF-α and IL-6 via regulating the expressions of Sirt1, NF-κB p65 and iNOS. Thus, dietary quercetin had significant therapeutic benefits and could be explored as a potential promising candidate for the prevention of NASH.
研究领域:
药理学
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肝病学
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营养学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2023
·
IF 6.7
Yihang Wu,Zixiu Liu,Zhenxiu He,Jumei Yi,Xingfang Qiao,Chunbin Tan,Yajing Xing,Yaobo Zeng,Dajian Yang,Junlin Yin,Baomin Fan,Guangzhi Zeng
Ulcerative colitis is a chronic inflammatory disease with a remitting-relapsing clinical course, it has evolved into a global burden given its high incidence worldwide. Cantharidin (CTD) derivatives are a class of compounds whose structures characterized with a 7-oxabicyclo [2.2.1]heptane core. Though potent cytotoxicity CTD and its derivatives showed, their clinical usage as anti-cancer drugs was limited by the toxicity in organs. In order to find new CTD analogues with good activity and lower toxicity, 21 CTD analogues with or without alkynyl substitution at C5 position of 7-oxabicyclo [2.2.1]heptane core were synthesized, some compounds showed better in vitro anti-inflammatory activity compared to CTD and norcantharidin (NCTD). Based on the structure-activity relationship results of in vitro experiment, analogue 3i was chosen for further study. Results from the acute toxicity in mice showed that 3i was hypotoxic with the single-dose MTD (maximum tolerated dose) for oral administration is over 1852 mg/kg, at least 35-fold lower than that of NCTD. Mechanism study indicated that 3i could potently inhibit TNF-α induced activation of NF-κB signaling by down-regulation the expression levels of phosphor- IKK, IκBα , and NF-κB p65 , and alleviated dextran sulfate sodium-induced colitis in mice. This study indicated that CTD analogues with alkynyl substitution at C5 position of 7-oxabicyclo [2.2.1]heptane core is a kind of new compounds with good anti-inflammatory activity and lower toxicity in vivo, and might be used as therapeutic agents for inflammatory diseases.
研究领域:
药理学
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炎症
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药物发现
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胃肠病学
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DOI
PubMed
高影响因子
Journal of Biomedical Nanotechnology
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2020
·Vol. 16
·期 10
·1463-1470
·
IF 4.483
Ding Xiangyu,Wang Yuan,Wen Chunmei,Wang Silu,Ruan Qingqing,Li Zhaofeng,Xu Jinzhong,Xu Zheng,Deng Jie
Rhein is a potential anti-inflammatory agent, but its poor water solubility significantly restricts its clinical application. In this study, rhein micelles (RMs) with improved water solubility were fabricated on Pluronic F127 (F-127). Transmission electron microscopy showed that the
as-prepared RMs displayed a mean diameter of approximately 20 nm and a spherical morphology. The encapsulation efficiency of the micelles towards drugs varied from 81.38 ± 4.35% to 24.87 ± 4.32%. The RMs exhibited a burst release during the first 6 h and a following sustained
release up to 96 h with a biphasic drug release pattern as suggested by the drug release assay. Cytotoxicity assessment showed that the RMs caused no change in cell viability at drug concentrations below 40 μM after 24 and 48 h of incubation. In RAW264.7 macrophages, the RMs inhibited the
lipopolysaccharide-induced activation of p65/NF-κB, which in turn suppressed the transcription of its downstream inducible nitric oxide synthase, and cytokine genes such as interleukin-1β and tumor necrosis factor-α . Simultaneously, the RMs led to reduced cytokine secretions,
including cyclooxygenase-2, prostaglandin E2, nitric oxide, and interleukin-6 in a dose-dependent manner. The RMs reported herein may be a promising candidate for developing anti-inflammatory therapeutic formulations.
研究领域:
药学
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纳米技术
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炎症研究
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DOI
PubMed
高影响因子
PHARMACOLOGICAL RESEARCH
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2022
·
IF 10.334
Yuhang Li,Yitian Li,Sennan Xu,Yue Chen,Pan Zhou,Ting Hu,Hua Li,Ying Liu,Yaping Xu,Jie Ren,Yan Qiu,Canzhong Lu
Psoriasis is an incurable autoimmune disease that affects 2–3% of the world’s population. Limited understanding of its pathogenesis hinders the development of therapies for the disease. Herein, we reported that N-acylethanolamine acid amidase (NAAA), a cysteine enzyme that catalyzes the hydrolysis of fatty acid ethanolamides (FAEs), was upregulated in psoriasis patients and imiquimod (IMQ)-induced mouse model of psoriasis. The upregulated NAAA contributes to the progression of psoriasis via enhancing dendritic cell (DCs) maturation. Transgenic expression of NAAA in mice accelerated the development of psoriasis, whereas genetic ablation of NAAA or local administration of NAAA inhibitor F96 ameliorated psoriasis. NAAA expressed in dendritic cells (DCs), but not in macrophages, T cells, or keratinocytes plays a critical role in psoriasis development. In addition, the results showed that NAAA degrades palmitoylethanolamide (PEA) and reduces PEA-PPARα-mediated dissociation of NF-κB p65 from Sirtuin 1 (SIRT1), subsequently, repressing the acetylation of p65 and down-regulating IL10 production. The decreased IL10 then leads to the maturation of DCs, thus promoting the development of psoriasis. These results provide new insights into the pathophysiological mechanism of psoriasis and identify NAAA as a novel target for the treatment of psoriasis.
研究领域:
免疫学
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皮肤病学
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药理学
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DOI
PubMed
高影响因子
JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION
·
2024
·
IF 2
Zhen Qin,Qiang-qiang Chu,An-lan Ding,Chuan-Ying Li,Mao-yan Zhang
Sirtuin 3 involved in development of various diseases, but its role in inflammatory bowel disease is still unknown. We used inflammatory bowel disease biopsies, colitis animal model, and vitro cells RAW264.7 to study the role of Sirtuin 3 in the pathophysiology of inflammatory bowel disease. Sirtuin 3 negatively correlated with intestinal TNF-α. Sirt3 was less pronounced in pediatric and adult inflammatory bowel disease patients compared with corresponding control group. Sirtuin 3 activator Honokiol suppressed dextran sulfate sodium induced colonic manifestations, while Sirt3 inhibitor caused opposite results. Honokiol inhibited colonic oxidative stress by and reduced intestinal permeability. Honokiol repressed inflammatory response by reducing macrophage infiltration, pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 levels, and inhibiting activation of NF-κB p65 in the colitis mice. However, Sirt3 inhibitor amplified colonic oxidative stress and inflammatory response. In vitro study, Sirt3 inhibitor or siRNA Sirtuin 3 activated NF-κB p65 and enhanced TNF-α, IL-1β, and IL-6 secretion from LPS stimulated RAW264.7, while Honokiol remarkably attenuated these pro-inflammatory cytokines secretion. Finally, knockdown of Sirt3 in Caco-2 cells enhanced TNF-α induced intestinal barrier integrity injury. Sirtuin 3 negatively regulates inflammatory bowel disease progression via reducing colonic inflammation and oxidative stress. Sirtuin 3 is a promising therapeutic target in clinical application for inflammatory bowel disease therapy.
研究领域:
胃肠病学
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免疫学
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药理学
·
分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF FOOD SCIENCE
·
2021
·Vol. 86
·期 5
·2118-2130
·
IF 3.167
Lingyu Zhu,Yang Song,Huilin Liu,Min Wu,Haizhou Gong,Hainan Lan,Xin Zheng
β-Carotene displays antioxidant and anti-inflammatory activities and prevents the development of cancer. Ulcerative colitis (UC) is a kind of inflammatory bowel disease that is accompanied by a certain risk of colon cancer. However, the role of β-carotene in the modulation of gut microbiota and UC improvement is unclear. In this research, the properties of β-carotene on anti-inflammatory and the composition of gut microbiota were evaluated in a rat model of UC induced by dextran sulfate sodium (DSS). The results revealed that β-carotene significantly ( p < 0.05) decreased the severity of colitis in rats, as assessed using body weight (6.00 ± 1.73%), colon length (22.23 ± 0.53%), and disease activity index, and improved the structure of the colon damaged. Moreover, colonic levels of proinflammatory cytokines were significantly lower following β-carotene supplementation. β-Carotene intervention also lowered the expression levels of phosphorylated p65 (0.60 ± 0.02), p38 (0.57 ± 0.00), Erk (0.63 ± 0.04), and JNK (0.70 ± 0.00). The result of the relative abundance of gut microbiota showed that DSS administration significantly changed the microbial structure at the phylum and genus levels of rats. Furthermore, β-carotene treatment significantly increased the abundance of Faecalibacterium , the levels of which negatively correlated with the levels of inflammatory cytokines. Faecalibacterium may be a potential target in the alleviation of DSS-induced UC. β-Carotene can alleviate DSS-induced UC through the regulation of gut microbiota. This study provides a reference for the rational use of β-carotene in the treatment of UC. Practical Application β-Carotene can relieve ulcerative colitis and regulate the gut microbiota; the nutritional intervention of β-carotene enhancing animal health.
研究领域:
药理学
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胃肠病学
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微生物学
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营养学
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产品关联
DOI
PubMed
高影响因子
HUMAN & EXPERIMENTAL TOXICOLOGY
·
2021
·
IF 2.903
Hai-Yan Jiang,Yan-Ni Bao,Feng-Mei Lin,Yong Jin
Triptolide (TP), the main active compound extracted from medicine- tripterygium wilfordii Hook f. (TWHF). It has anti-tumor and immunomodulatory properties. Our study aimed to investigate the mechanisms of hepatotoxicity treated with TP in vivo and in vitro, as well as their relationship with the NF-κB (p65) signal pathway; and to assess TP-induced hepatotoxicity after CYP2E1 modulation by the known inhibitor, clomethiazole, and the known inducer, pyrazole. Mice were given TP to cause liver injury and IHHA-1 cells were given TP to cause hepatocyte injury. The enzyme activity and hepatotoxicity changed dramatically when the CYP2E1 inhibitor and inducer were added. In comparison to the control group, the enzyme inducer increased the activity of CYP2E1, whereas the enzyme inhibitor had the opposite effect. Our findings suggest that TP is an inducer of CYP2E1 via a time-dependent activation mechanism. In addition, TP can promote oxidative stress, inflammatory and involving the NF-κB (p65) signal pathway. Therefore, we used triptolide to stimulate C57 mice and IHHA-1 cells to determine whether TP can promote oxidative stress and inflammation by activating CYP2E1 in response to exacerbated liver damage and participate in NF-κB (p65) signaling pathway.
研究领域:
药理学
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毒理学
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分子生物学
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DOI
PubMed
高影响因子
Acta Biomaterialia
·
2018
·
IF 6.383
Feihu Wang,Qian Huang,Yun Wang,Wenjun Zhang,Ran Lin,Yanna Yu,Yuanyuan Shen,Honggang Cui,Shengrong Guo
Simultaneous inhibition of both tumor growth and metastasis is the key to treating metastatic cancer, yet the development of effective drug delivery systems represents a great challenge since multimodal therapeutic agents must be rationally combined to overcome the biological mechanisms underpinning tumor cell proliferation and invasion. In this context, we report a hybrid therapeutic nanoscale platform that incorporates an anti-proliferative drug, doxorubicin (DOX), and an anti-NF-κB agent, p65-shRNA, for effective treatment of metastatic breast cancer. In our design, we first conjugated DOX via an acid-labile linker onto gold nanorods that were pre-modified with the tumor targeting peptide RGD and a positively charged, disulfide cross-linked short polyethylenimines (DSPEI), and then incorporated shRNA through electrostatic complexation with DSPEI. We show that this “all in one” nanotherapeutic system (RDG/shRNA@DOX) can be effectively internalized through RGD-mediated endocytosis , followed by stimuli-responsive intracellular co-release of DOX and shRNA. Our in vitro experiments suggest that this multimodal system can significantly inhibit cell proliferation, angiogenesis , and invasion of metastatic MDA-MB-435 cancer cells. Systemic administration of RDG/shRNA@DOX into a metastatic mouse model led to enhanced tumor accumulation, and, most importantly, significant inhibition of in situ tumor growth and almost complete suppression of tumor metastasis. We believe this hybrid multimodal nanotherapeutic system provides important insight into the rational design of therapeutic systems for the effective treatment of metastatic carcinoma. Statement of Significance The key to successfully treat metastatic cancer is the simultaneous inhibition of both tumor growth and metastasis. This represents a great challenge for the design of drug delivery systems since multimodal therapeutic agents must be rationally combined to overcome the respective biological mechanisms underpinning tumor cell proliferation and invasion. Toward this end, we developed a hybrid nanomedicine platform that incorporates an anti-proliferative drug, doxorubicin (DOX), and an anti-NF-κB agent, p65-shRNA, for effective treatment of metastatic breast cancer. We showed that this multimodal system (RDG/shRNA@DOX) enhanced tumor accumulation, led to prolonged circulation, and most importantly, significant inhibition of in situ tumor growth and almost complete suppression of tumor metastasis. We believe this hybrid multimodal nanotherapeutic system provides significant insight into the rational design of therapeutic systems for the effective treatment of metastatic cancer.
研究领域:
纳米医学
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肿瘤学
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药物递送系统
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分子生物学
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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）