EXPERIMENTAL AND CLINICAL ENDOCRINOLOGY & DIABETES
·
2020
·Vol. 129
·期 05
·339-348
·
IF 2.058
Mao Ouyang,Tao Qin,Hengdao Liu,Junya Lu,Caixia Peng,Qin Guo
Objective High-fat diet (HFD) increases the risk of inflammatory reaction and acute arterial thrombosis. Celastrol has been confirmed to regulate inflammatory cytokine levels in atherosclerotic animal models. However, the anti-thrombotic effects of celastrol have remained to be fully demonstrated. The present study was performed to investigate the beneficial effect of celastrol in HFD-induced inflammatory reaction and thrombosis in apolipoprotein (apo)E-/- mice. Materials and Methods Thrombogenic mice model was established using HFD-fed apoE-/- mice. The levels of mRNA and protein were assayed by RT-qPCR and western blotting, respectively. Immunohistochemistry (IHC) staining was performed to measure the protein expression of matrix metalloproteinase-2 and matrix metalloproteinase-9 in the aortic endothelium of HFD-fed apoE-/- mice. Results The results demonstrated that the effect of HFD on inflammatory cytokines in mice with apoE-/- background was reversed by celastrol administration, and celastrol treatment inhibited the NOD-like receptor family, pyrin domain containing 3 (NLRP3)/caspase-1/interleukin-1β signaling cascades in peripheral blood mononuclear cells from HFD-fed apoE-/- mice. In addition, HFD enhanced adenosine diphosphate-induced platelet aggregation in normal C57BL/6 and apoE-/- mice, while celastrol administration reversed this. Furthermore, celastrol inhibited the pro-thrombotic effects of HFD in apoE-/- mice, and the underlying mechanism was mediated, at least partially, through the suppression of matrix metalloproteinase-2 and -9 expression. Conclusions Celastrol administration significantly attenuated HFD-induced inflammatory reaction, platelet aggregation and thrombosis in apoE-/- mice, and celastrol may be used as a drug for the prevention of HFD-induced inflammatory reaction and thrombus.
研究领域:
心血管疾病
·
药理学
·
炎症
·
血栓形成
✓ 已验证
DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2022
·
IF 4.46
Mengxue Pang,Songchao Duan,Mengmeng Zhao,Qingqing Jiao,Yimeng Bai,Lili Yu,Bin Du,Genyang Cheng
To treat acute kidney injury with high efficiency and low toxicity, a novel nanoplatform was developed to remove excess reactive oxygen species (ROS). Lutein (LU) and celastrol (Cel) were loaded into low molecular weight chitosan (CS) to prepare [email protected] nanomicelles . Renal tubular epithelial (HK−2) cell uptake experiments showed that the drugs could be internalized in renal tubular via the megalin receptor. In this study, the amide bond formed by the reaction of citraconic anhydride (CA) with an amino group of CS could be destroyed under acidic conditions. Therefore, the drugs were released in HK-2 cells due to the acidic environment of the lysosome . In vitro studies showed that the nanomicelles could reduce toxicity in non-target organs and enhance therapeutic efficacy in acute kidney injury (AKI). In addition, [email protected] micelles had alleviated kidney oxidative stress disorder and stabilized the mitochondrial membrane potential quickly. Next, in vivo studies proved that [email protected] micelles could inhibit the activation of the NF-κB p65 and p38 MAPK inflammatory signaling pathways. Therefore, the micelles further reduced the overexpression of related inflammatory factors. In conclusion, [email protected] nanomicelles could treat AKI with high efficiency and low toxicity, and inhibit renal fibrosis .
研究领域:
纳米技术
·
药学
·
肾脏生理学
·
炎症生物学
✓ 已验证
DOI
PubMed
高影响因子
Journal of Tissue Engineering
·
2024
·
IF 6.7
Yue Zhao,Yinlian Yao,Shilong Fan,Xin Shen,Xingxing Chai,Zimin Li,Jiachun Zeng,Jiang Pi,Zhikun Zhou,Gonghua Huang,Hua Jin
The incidence of ulcerative colitis (UC) is rapidly rising worldwide. Oral drug delivery system is a promising approach for treating UC, but it often fails to accumulate to the inflammatory lesions, thus, it is impressive to develop a colon-targeted oral delivery system for preventing systemic toxicity and maintaining UC therapeutics. Here, a negative-charged PLGA nanoparticle system was designed to encapsulate celastrol (Cel), and then chitosan and mannose were coated on the surface of the nanoparticles (MC@Cel-NPs) to endow these nanoparticles with the mucosal adsorption and macrophage targeting abilities. MC@Cel-NPs demonstrate excellent resist decomposition ability against the strong acidic gastrointestinal environment, and accumulates in the specific inflammatory sites through the affinity of electrostatic reaction. After releasing the payload, MC@Cel-NPs could remarkably alleviate the colon inflammation, which was evidenced by the decrease in pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 in both blood and colon sections, and scavenging reactive oxygen species (ROS) in colon cells, including macrophage, neutrophil, T cell, and B cell. This nanoparticle system provided a new approach for treating UC through a Chinese herbal ingredient-related oral delivery manner.
研究领域:
药学
·
纳米技术
·
炎症性肠病
·
药物递送系统
·
生物医学工程
✓ 已验证
DOI
PubMed
高影响因子
BMEMat
·
2024
·
IF 0
He Ren,Zewen Wu,Jingxuan Li,Nan Zhang,Coo Yee Nah,Jiexin Li,Jingyu Zhang,Jonathan F. Lovell,Liyun Zhang,Yumiao Zhang
Rheumatoid arthritis (RA) is a systemic autoimmune disease that leads to the destruction of articular cartilage and bone. RA is characterized by immune cell infiltration and abnormal proliferation of synoviocytes in the joints. Herein, we developed a biomimetic formulation via co-loading the anti-inflammatory agent Celastrol (Cel) along with the stabilizer Vitamin K (VK) in antirheumatic methotrexate (MTX)-conjugated Pluronic F127 (F127) micelles. Micelles were then coated with B cell derived membrane, yielding MTX loaded Cel Micelle (CeViM)-micelle@B, which were investigated for RA treatment. VK, used at levels well within safety margins, was identified as a carrier compound that could stabilize Cel within micelles, increasing the encapsulation efficiency of Cel. In addition, MTX, a front-line RA therapeutic, was chemically grafted to F127 via a responsive linker sensitive to the chemically reducing environments. As such, CeViM-micelle@B released pristine MTX in response to the intracellular reducing environments, which combined with Cel to suppress pro-inflammatory responses. B cell membrane coating enhanced accumulation of CeViM-micelle@B in joints, leading to a 75% decrease of inflammatory cytokine secretion in vitro, and significantly ameliorated cartilage and bone structures in the collagen-induced arthritis murine model. Taken together, this biomimetic nanoparticle holds potential as a next-generation targeted RA treatment.
研究领域:
免疫学
·
药理学
·
纳米医学
·
自身免疫疾病
✓ 已验证
DOI
BIOLOGICAL & PHARMACEUTICAL BULLETIN
·
2025
·Vol. 48
·期 7
·1096-1106
·
IF 1.7
Tao Feng,Guofang Hu,Yinjun Luo,Xin Zhang,Hong Chen,Zuoren Liang,Xianjiao He,Shijing Ma,Jinting Wei,Xiaoyan Fang,Biao Li,Jinhua Wang,Suchan Liao
Nasopharyngeal carcinoma (NPC) is a highly invasive form of head and neck cancer that arises from nasopharyngeal epithelial cells. Celastrol and curcumin, both derived from traditional Chinese medicine, have demonstrated antitumor potential. However, the clinical application of these compounds is limited by their low bioavailability and/or toxicity. Cancer cell viability, apoptosis, autophagy, ferroptosis, and mitochondrial fission- and fusion-related proteins were evaluated following treatment with celastrol alone, curcumin alone, and their combination. The results indicated that low doses of celastrol (0.7 μM) alone do not inhibit proliferation in NPC cells. However, when combined with curcumin, there is a significant enhancement of the antiproliferative effect. There was no significant alteration in the expression levels of the apoptosis-related proteins BCL2-associated X and cleaved caspase 3 in either the curcumin alone or the combined treatment groups compared to the control group. Interestingly, the combined treatment significantly increased the ferroptosis contributor acyl-CoA synthetase long-chain family member 4 while notably decreasing solute carrier family 7 member 11 and glutathione peroxidase 4, accompanied by increased phosphorylation of dynamin-related protein 1. Furthermore, the combined treatment exhibited significant antitumor efficacy with low toxic side effects in a xenograft model. In conclusion, our study provides new insights into combination therapies to enhance anti-NPC efficacy.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
传统中医药学
·
转化医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2024
·
IF 6.6
Yunyan Chen,Ziwei Zhang,Zhilei Qian,Rui Ma,Minna Luan,Yu Sun
Background A sequential release co-delivery system is an effective strategy to improve anti-cancer efficacy. Herein, multicomponent-based liposomes (TET-CTM/L) loaded with tetrandrine (TET) and celastrol (CEL)-loaded coix seed oil microemulsion (CTM) were fabricated, which showed synergistic anti-liver cancer activities. By virtue of Enhanced Permeability and Retention (EPR) effect, TET-CTM/L can achieve efficient accumulation at the tumor site. TET was released initially to repair abnormal vessels and decrease the fibroblasts, and CTM was released subsequently for eradication of tumor tissue.Methods TEM (transmission electron microscopy) and DLS (dynamic light scattering) were adopted to characterize the TET-CTM/L. Flow cytometry was adopted to examine the cellular uptake and cytotoxicity of HepG2 cells. The HepG2 xenograft nude mice were adopted to evaluate the anti-tumor efficacy and systemic safety of TET-CTM/L.Results TEM images of TET-CTM/L showed the structure of small particle size of CTM within large-size liposomes, indicating that CTM can be encapsulated in liposomes by film dispersion method. In in vitro studies, TET-CTM/L induced massive apoptosis toward HepG2 cells, indicating synergistic cytotoxicity against HepG2 cells. In in vivo studies, TET-CTM/L displayed diminished systemic toxicity compared to celastrol or TET used alone. TET-CTM/L showed the excellent potential for tumor-targeting ability in a biodistribution study.Conclusion Our study provides a new strategy for combining anti-cancer therapy that has good potential not only in the treatment of liver cancer but also can be applied to the treatment of other solid tumors.
研究领域:
药学
·
肿瘤学
·
纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-29
·
IF 12.6
Li Yang,Xue Xiaoxia,Yu Liuchunyang,Qian Jinxiu,Li Xiaoyu,Tian Meng,Yang Jue,Deng Rongjun,Lu Cheng,Xiao Cheng,Liu Yuanyan
Introduction Atherosclerosis serving as the main underlying factor of cardiovascular disease (CVD) remains the primary cause of mortality and morbidity globally, while the deposition of massive cholesterol in macrophage-derived foam cells exerts pivotal roles in the occurrence and progression of atherosclerosis. Celastrol (CEL) is a bioactive ingredient owning potent capability to modulate lipid metabolism, whereas the poor bioavailability and potential toxicity limit its clinical application. Objectives This study aims to design a CEL-loaded recombinant high-density lipoprotein (rHDL) delivery platform for active targeting, which may effectively promote lipid degradation in foam cells and reversely transport excessive cholesterol to the liver for metabolism in time. Methods The rHDL loaded with CEL (CEL-rHDL) was prepared by the thin film dispersion method. Then the anti-atherosclerotic efficacy and targeted delivery to foam cells of atherosclerotic lesions were verified both in vitro and in vivo. RNA-sequence was applied to reveal the potential mechanism against early atherosclerosis, which was further validated through several molecular biology experiments. Results The prepared CEL-rHDL increased the targeting efficiency to foam cells of atherosclerotic lesions, mitigated its off-target toxicity, and improved anti-atherosclerotic efficacy. Importantly, CEL-rHDL decreased lipid storage in foam cells by triggering lipophagy via the activation of Ca 2+ /CaMKKβ/AMPK/mTOR signaling pathway and reverse cholesterol transport (RCT). Conclusion A combination of hypolipidemic chemo-intervention with rHDL participated specific and reverse delivery may offer a promising strategy for biocompatible treatment of early atherosclerosis. Graphical abstract
研究领域:
心血管疾病
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2017
·
IF 8.402
Yanan Tan,Yun Zhu,Yue Zhao,Lijuan Wen,Tingting Meng,Xuan Liu,Xiqin Yang,Suhuan Dai,Hong Yuan,Fuqiang Hu
Mitochondria, crucial regulators of inducing tumor cells apoptosis, can be treated as the prime target for tumor therapy. The selective and responsive release of proapoptotic therapeutics into mitochondria may notably improve antitumor efficiency. Herein, (4-Carboxybutyl) triphenylphosphonium bromide (CTPP), a lipophilic cation, was conjugated with glucolipid-like conjugates (CSOSA) to produce mitochondria-targeted conjugates (CTPP-CSOSA). Loading with weakly acidic drug Celastrol (Cela), CTPP-CSOSA/Cela micelles could selectively respond to mitochondrial alkaline pH (pH 8.0), controlled by the weaker interaction between hydrophobic core of micelles and Cela with higher solubility at pH 8.0. However, there was a slow drug release behavior at pH 7.4 and pH 5.0. It illustrated that CTPP-CSOSA/Cela could realize mitochondrial fast drug release, and decrease drug leakage in the cytoplasm and lysosome . CTPP-CSOSA/Cela highly enhanced ROS levels, which further induced mitochondria membrane potential decreasing and more Cytochrome C releasing into cytoplasm, then promoted tumor cells apoptosis notably. In vivo , CTPP-CSOSA had an enhanced accumulation in tumor tissue, compared with CSOSA. Moreover, the tumor-inhibition rate of CTPP-CSOSA/Cela was 80.17%, which was significantly higher than CSOSA/Cela (58.35%) and Cela (54.89%). Thus, CTPP-CSOSA/Cela micelles with mitochondrial targeting and alkaline pH-responsive release capability could provide a new strategy for tumor therapy.
研究领域:
药学
·
生物医学工程
·
肿瘤学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2019
·
IF 3.973
Shikang Meng,Lin Sun,Lun Wang,Zibei Lin,Zeyu Liu,Long Xi,Zhenping Wang,Ying Zheng
Psoriasis is a severe disfiguring skin disease affecting approximately 3% of people worldwide and negatively affecting their daily lives. The pathogenesis of psoriasis is complicated, and typical therapeutic strategies for psoriasis mainly focus on anti-inflammation. Considering the side effects, withdrawal rebound, high cost, and many other disadvantages of existing treatments, we developed a new topical therapeutic formulation consisting of niosomes loaded with celastrol, a triterpenoid extracted from Tripterygium . Celastrol niosomes were prepared by the thin film hydration method and probe sonication. The niosomes were composed of Span 20, Span 60, and cholesterol at a weight ratio of 3:1:1. The particle size of the niosomes was approximately 147 nm, with yield of up to 90%. Celastrol niosomes showed improved in vitro permeation ability compared to the raw drug. In our in vivo study, celastrol niosomes effectively alleviated erythema and scaling on the dorsal skin of psoriasis mouse models. Spleen weight and the levels of cytokines, including IL-22, IL-23, and IL-17, decreased after the treatment, indicating the high therapeutic potential of this formulation for psoriasis. In conclusion, encapsulation of celastrol by niosomes increased the water-solubility and permeation of celastrol into the skin, significantly improving its anti-psoriasis activity in mice.
研究领域:
药剂学
·
皮肤病学
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2018
·Vol. 6
·期 12
·3284-3299
·
IF 5.831
Ding Qu,Lixiang Wang,Yue Qin,Mengfei Guo,Jian Guo,Mengmeng Huang,Yuping Liu,Congyan Liu,Hui Li,Yan Chen
A codelivery system that sequentially releases its contents is an effective strategy to enhance anticancer efficacy. Here, we fabricated multicomponent-based liposomes (T/CM-L) loaded with sodium tanshinone IIA sulfonate (STS) and a small-sized microemulsion of celastrol (CM), which shows synergistic anti-breast cancer activity through the initial release of STS for modulation of the tumor microenvironment, and subsequent release of CM (and its payloads) for eradication of tumor tissues. In vitro studies exhibited that T/CM-L induced massive apoptosis of MCF-7 cells, indicating a coordinated cytotoxicity against cancer cells. Once the liposomes had accumulated at the tumor site, STS was released from T/CM-L in the first place to repair abnormal vessels as well as to decrease the level of fibroblasts. Owing to the barriers of the microemulsion and the liposomes, the celastrol was then unloaded at a moderate rate to kill the tumor cells, which resulted in the shrinkage of the tumor size. Furthermore, T/CM-L displayed diminished systemic toxicity compared to celastrol used alone. Our work offers a novel strategy for combination anticancer treatment and holds promising potential not only for breast cancer treatment, but also for the treatment of other solid tumors.
研究领域:
药学
·
肿瘤学
·
药物递送系统
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2022
·
IF 9.965
Yilin Liu,Junbai Li
Celastrol , extracted from Tripterygium wilfordii Hook F, is one of the most promising natural extract for cancer treatment. Nevertheless, insufficient tumor retention and severe systemic toxicity still hinder its application. Herein, we report for the first time that Celastrol can directly self-assemble into size-controllable nanoparticles through the anti-solvent method by using different good solvent or by the variation of Celastrol concentrations. In vitro anti-cancer experiment revealed that the as-prepared nanoparticles can kill MCF-7 cells more effectively. Moreover, the nanoparticles can efficiently accumulate in tumors of the tumor bearing mice after tail vein injection. Under the administration of lethal dosage of Celastrol, the tumors are greatly suppressed and the mice maintain the activity. These results demonstrate that anti-solvent method may be a promising strategy to fabricate Celastrol nano-drugs with controllable size and less systemic toxicity for further clinical cancer treatment.
研究领域:
药学
·
肿瘤学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2021
·
IF 6.514
Fan-Fan Shang,Jing Ying Wang,Qian Xu,Hao Deng,Hong-Yan Guo,Xuejun Jin,Xiaoting Li,Qing-Kun Shen,Zhe-Shan Quan
Four series of hypoxia-inducible factor-1 alpha (HIF-1α) functioning derivatives stemming from modifications to the C-29 carboxyl group of celastrol were designed and synthesized, and their anticancer activities were evaluated. To address the structure and activity relationship of each derivative, extensive structural changes were made. HRE luciferase reporter assay demonstrated that 12 modified compounds showed superior HIF-1α inhibitory activity. Among them, compound C6 exhibited the best features: firstly, the strongest HIF-1α inhibitory activity (IC 50 = 0.05 μM, 5-fold higher than that of celastrol); secondly, lower cytotoxicity (22-fold lower, C6-16.85 μM vs celastrol-0.76 μM). Thus, the safety factor of C6 was about 112 times higher than that of celastrol. Western blot assay indicated that C6 may inhibit the expression of HIF-1α protein in cells. Additionally, C6 hindered tumor cell cloning , migration and induced cell apoptosis . It is worth mentioning that in the mouse tumor xenograft model, C6 (10 mg/kg) displayed good antitumor activity in vivo , showing a better inhibition rate (74.03%) than the reference compound 5-fluorouracil (inhibition rate, 59.58%). However, the celastrol treatment group experienced collective death after four doses of the drug. Moreover, C6 minimally affected the mouse weight, indicating that its application in vivo has little toxic effect. H&E staining experiments show that it could also exacerbate the degree of tumor cell damage. The results of water solubility experiment show that the solubility of C6 is increased by 1.36 times than that of celastrol. In conclusion, C6 is a promising antitumor agent through HIF-1α pathway.
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）