Frontiers in Immunology
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2026
·
IF 7
Jiquan Shen,Changjian Zhou,Xinggao Wang,Yuxuan Chen,Run Liu,Liang Hong,Weiping Ji,Bo Wang
BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by severe synovial inflammation, joint deformities, and progressive tissue destruction. Celastrol (Cel), a natural triterpenoid with anti-inflammatory and antioxidant activity, is a promising therapeutic candidate for RA; however, its application is limited by poor aqueous solubility, low bioavailability, and systemic toxicity.PurposeThis study aimed to develop folate-modified liposomes encapsulating Cel (FA-Cel-LPs) to improve its solubility, stability, and joint accumulation, and to evaluate their anti-inflammatory efficacy and associated molecular changes in LPS-activated RAW264.7 macrophages and collagen-induced arthritis (CIA) rats.MethodsFA-Cel-LPs were prepared by thin-film hydration followed by extrusion and characterized for particle size, morphology, polydispersity index (PDI), encapsulation efficiency (EE), and in vitro release behavior. In LPS-activated RAW264.7 cells, cellular uptake, intracellular ROS levels, NF-κB nuclear translocation, COX-2/iNOS expression, and cytokine secretion were evaluated. In CIA rats, therapeutic efficacy was assessed by paw swelling, arthritis scores, in vivo fluorescence imaging, MRI, histological analysis, and micro-CT-based bone parameters. Safety was evaluated using hemolysis, serum biochemical analysis, and organ histology.ResultsFA-Cel-LPs showed a mean particle size of 110.65 ± 1.24 nm, an EE of 84.67 ± 2.55%, a PDI of 0.230 ± 0.018, and a sustained release profile with pH-dependent differences in vitro. In RAW264.7 cells, folate-modified liposomes showed greater cellular uptake and were associated with reduced ROS levels, attenuated NF-κB activation, and decreased COX-2, iNOS, and pro-inflammatory cytokine expression, with low cytotoxicity. In CIA rats, in vivo imaging suggested greater accumulation of FA-Cel-LPs in inflamed joints. Compared with free Cel and Cel-LPs, FA-Cel-LPs more effectively reduced paw swelling and joint inflammation while attenuating bone erosion and preserving joint architecture. Serum ALT and AST levels in the FA-Cel-LPs group remained within physiological ranges and were significantly lower than those in the free Cel group. Organ histology showed no obvious treatment-related injury, suggesting acceptable preliminary safety.ConclusionFA-Cel-LPs improved the solubility, formulation stability, and apparent joint accumulation of Cel and enhanced its anti-inflammatory and bone-protective effects in experimental RA. These effects were associated with reduced ROS/NF-κB/COX-2-related inflammatory changes, suggesting FA-Cel-LPs may represent a promising liposomal strategy for RA.
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Drug Delivery and Translational Research
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2019
·Vol. 9
·期 3
·667-678
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IF 3.111
Zhang Qian,Tian Xin,Cao Xiufeng
In this study, we developed an intravenously injectable, transferrin-functionalised microemulsion that simultaneously carries β-elemene and celastrol (called Tf-EC-MEs) for enhanced anti-lung cancer treatment and reduced systemic toxicity. These dual-drug-loaded Tf-EC-MEs not only displayed synergistic antiproliferative effects on cultured cells in vitro, but also showed enhanced efficacy in vivo via active tumour targeting. In preparatory experiments, we found that β-elemene was capable of being used as oil phase, which enhanced drug-loading efficiency and allowed the mass ratio of β-elemene and celastrol to be optimised. In cellular studies, Tf-EC-MEs exhibited significantly improved A549 cellular uptake compared with β-elemene+celastrol (conventional combination treatment) and EC-MEs (non-active targeted treatment), demonstrating remarkable synergistic antiproliferative effects and higher rates of cell apoptosis. In A549-bearing xenograft mouse tumour models, Tf-EC-MEs exhibited enhanced antitumour activity compared to all other treatments. More importantly, Tf-EC-MEs did not cause the obvious systemic toxicity commonly found with mono-celastrol treatment. Collectively, these findings suggest that Tf-EC-MEs are a promising strategy for the combination drug treatment of lung cancer.
研究领域:
药学
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肿瘤学
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药物递送系统
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癌症治疗
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2023
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IF 8.2
Jing Xian,Xuemei Zhong,Qi Huang,Huan Gu,Yixuan Feng,Jiayi Sun,Di Wang,Jingjing Li,Chen Zhang,Yihan Wu,Jinming Zhang
Oral nanoparticles (NPs) are more suitable for obesity control compared to NPs administered intravenously, as their convenience increases patient compliance. Herein, we developed an oral nano-system to improve the anti-obesity efficacy of celastrol (Cel). The observed enhanced efficacy was mediated by zein core NPs decorated with adipose-homing peptides that were coated with N -trimethylated chitosan. The optimized Cel/ [email protected] exhibited spherical morphology by TEM, as well as narrow size distribution (221.76 ± 6.73 nm) and adequate stability in a gastrointestinal environment. Based on the combined delivery advantages of [email protected] – i.e. , improved cellular internalization within Caco-2 cells and enhanced white adipose tissue (WAT) vascular targeting – Cel/ [email protected] significantly reduced the body weight, blood lipid levels, adipose inflammation, and WAT distribution in diet-induced obese mice without side-effects. In short, this study provides clear evidence that TMC-based oral NPs can effectively improve celastrol for obesity treatment.
研究领域:
药学
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生物技术
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纳米医学
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肥胖研究
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Biomaterials Advances
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2026
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IF 6.7
Haoran Yang,Xue Cui,Kun Yu,Zhiwen Zhao,Longlong Jin,Qing Wang,Huiying Yang,Xinwei Li,Xuzhu Gao,Xianfu Wu
A multifunctional Fe/Cu MIL-NH 2 nanozyme for MASLD therapy • ASGR1 targeting enables hepatocyte-specific delivery and activates LXRα-mediated lipid efflux. • Synergistic ROS scavenging and anti-inflammatory action • Effective and safe therapy validated in a murine MASLD model. Metabolic dysfunction–associated steatotic liver disease (MASLD) is characterized by excessive hepatic lipid accumulation accompanied by persistent oxidative stress, posing a major challenge for effective therapeutic intervention. Here, we report a multifunctional nanozyme-based therapeutic platform, MIL@Cel-6-10/ASGR1 (MCA), designed to simultaneously address this issue through coordinated hepatocyte targeting, reactive oxygen species (ROS) scavenging, and lipid metabolism regulation. MCA is constructed from a Fe/Cu-based MIL-NH 2 metal–organic framework (MOF) with intrinsic superoxide dismutase– and catalase-like activities, encapsulating a rationally engineered Celastrol derivative (Cel-6-10) for enhanced anti-inflammatory efficacy and stability. Surface conjugation an anti-asialoglycoprotein receptor 1 (ASGR1) monoclonal antibody confers hepatocyte-targeting capability and simultaneously activates liver X receptor alpha (LXRα), thereby promoting hepatic lipid efflux. In vitro, MCA effectively attenuates palmitate-induced hepatocyte lipotoxicity by reducing oxidative stress, suppressing apoptosis, and limiting lipid accumulation. In a diet-induced murine model of MASLD, MCA demonstrates pronounced liver accumulation, markedly ameliorates hepatic steatosis, improves serum lipid profiles, and reduces liver injury markers without detectable systemic toxicity. Transcriptomic analysis reveals extensive hepatic reprogramming, characterized by suppression of pro-steatotic and pro-inflammatory pathways and enhancement of antioxidant and metabolic homeostatic programs. Collectively, this work presents a Celastrol derivative–integrated nanozyme strategy as an effective materials-based approach for MASLD management.
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BIOMEDICINE & PHARMACOTHERAPY
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2024
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IF 6.9
Qiaofeng Zhou,Xiying Guo,Tu Chen,Yumin Liu,Huimin Ji,Yixuan Sun,Xiaosong Yang,Changhan Ouyang,Xiufen Liu,Min Lei
Celastrol, the primary constituent of Tripterygium wilfordii , has demonstrated neuroprotective properties in rats with dementia by reducing inflammation. A high-fat diet and streptozotocin injection were utilized to establish a diabetic rat model, which was then employed to investigate the possible protective effect of celastrol against the development of diabetes-induced learning and memory deficits. Afterwards, the experimental animals received a dose of celastrol by gavage (4 mg/kg/d). An animal study showed that celastrol enhanced insulin sensitivity and glucose tolerance in diabetic rats. In the Morris water maze test, rats with diabetes performed poorly in terms of spatial learning and memory; treatment with celastrol improved these outcomes. Additionally, administration of celastrol downregulated the expression of inflammatory-related proteins (NF-κB, IKKα, TNF-α, IL-1β, and IL-6) and greatly reduced the generation of Aβ in the diabetic hippocampus tissue. Moreover, the insulin signaling pathway-related proteins PI3K, AKT, and GSK-3β were significantly upregulated in diabetic rats after celastrol was administered. Also, celastrol prevented damage to the brain structures and increased the synthesis of synaptic proteins like PSD-95 and SYT1. In conclusion, celastrol exerts a neuroprotective effect by modulating the insulin signaling system and reducing inflammatory responses, which helps to ameliorate the cognitive impairment associated with diabetes.
研究领域:
神经科学
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药理学
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糖尿病研究
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神经保护
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TALANTA
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2021
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IF 6.057
Fei Li,Xiaoxuan Li,Jie Su,Yijun Li,Xiwen He,Langxing Chen,Yukui Zhang
In this work, a novel strategy to prepare molecularly imprinted polymers (MIPs) functionalized magnetic carbon nanotubes (MCNTs) via a facile sol-gel polymerization by adopting Cu 2+ -mediating interaction was presented for selective recognition of celastrol (Cel), in the traditional Chinese medicines (TCM). Firstly, template Cel, 3-aminopropyltriethoxysilane (APTES) as monomer and Cu 2+ (co-monomer) were mixed to form a self-assembled pre-complex, in which Cu 2+ could coordinate with Cel. Meanwhile, APTES plays a role of bridge between APTES and Cel. Secondly, carboxyl modified MCNTs as substrate was added into the pre-complex solution. After that, a multi-step sol-gel polymerization process was occurred in the presence of tetraethylorthosilicate as cross-linker and acetic acid as catalyst. Finally, MIPs layer was formed on the surface of the MCNTs (Cel-MIPs@MCNTs) after the removal of template with methanol/acetic. The morphology and structure of Cel-MIPs@MCNTs was investigated by various characterization techniques. The adsorption performance of Cel-MIPs@MCNTs to Cel was illustrated by kinetic, isothermal and selective binding experiments. The results displayed that the Cel-MIPs@MCNTs possessed fast kinetic equilibrium time (40 s), high adsorption capacity (13.35 μg mg −1 ), good imprinting factor of 3.41, and high magnetic responsivity (44.38 emu·g -1 ), which can be used as an ideal adsorbent for rapid isolation and enrichment of target analytes. A selective and sensitive method based on Cel-MIPs@MCNTs coupling with HPLC was developed for Cel determination including a wide linear range (0.15–200 μg mL −1 ) with correlation coefficient of 0.9998, a low limit of detection (0.05 μg mL −1 ). Furthermore, the applicability of Cel-MIPs@MCNTs was demonstrated to isolate and determine Cel in TCM samples with satisfactory recoveries ranged from 84.47% to 91.5% (RSD<5.35%). The results revealed that Cel-MIPs@MCNTs offer great potential as an adsorbent for selective and efficient isolation of Cel from complex TCM samples.
研究领域:
材料科学
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分析化学
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药学
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中医药
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2024
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IF 5.3
Xiang Zhang,Zhixing Long,Zixu Qin,Hongyan Ran,Sha Wu,Muxin Gong,Jing Li
As one of the most common brain tumors, glioblastoma (GBM) lacks efficient therapeutic treatment and remains lethal. Extracellular vesicles (EVs) have emerged as a promising platform for GBM therapies. Nevertheless, the properties of EVs are significantly influenced by their cell origins. This study aimed to evaluate the advantages of EVs derived from bone marrow mesenchymal stem cells (BMSCs), human glioblastoma cells (U-87 MG) and macrophage cells (RAW264.7) to develop a more effective strategy for the delivery of anti-GBM drug celastrol (Cel). Three kinds of EVs exhibited spherical- or oval-shapes with an average size ranging from 90 to 140 nm. Western blot analysis confirmed the presence of specific EV markers (ALIX, CD63 or TSG101). Notably, the yield of BMSCs-derived EVs (BMSC-EVs) significantly surpassed that of U-87 MG and RAW264.7 cells. Furthermore, BMSC-EVs demonstrated the highest entrapment efficiency for Cel (72 %) and enhanced internalization into the target cells U-87 MG. The increased cytotoxicity and cell apoptosis further confirmed that Cel-loaded BMSC-EVs (BMSC-EVs-Cel) were more potent for killing U-87 MG cells compared with free Cel. In vivo studies utilizing both orthotopic and subcutaneous GBM models revealed facilitated blood–brain barrier penetration and transportation of cargo into tumor tissue by BMSC-EVs. Importantly, BMSC-EVs-Cel could effectively inhibit GBM growth, induce tumor tissue apoptosis and suppress intratumoral microvessel density in comparison with free Cel and temozolomide, while successfully decrease systemic toxicity. Overall, this study elucidates the properties of EVs derived from distinct cell origins and highlights the great potential of BMSC-EVs for brain tumor treatment.
研究领域:
肿瘤学
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神经科学
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药理学
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干细胞研究
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ACS Applied Materials & Interfaces
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2023
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IF 9.5
Yuehuang Wu,Min Zhou,Ruimiao Lin,Lixue Yu,Xiaokun Zhang,Jingjing Xie
Combination of chemotherapeutics with polypeptide/protein drugs has been demonstrated to be an effective approach for treatment against cancer multidrug resistance. However, due to the low biostability and weak cell penetrating ability of biomacromolecules, intracellular delivery and release of biomacromolecules in a spatiotemporally controllable manner in target sites in vivo face great challenges, and synergistic effects will not be achieved as expected just by simple drug combination. Here, we conceived an inspired strategy to combat the drug-resistant tumors by fabricating multiarm PEG-gated large pore-sized mesoporous silica nanoparticles for the Bcl-2-functional-converting peptide (denoted as N9@M-CA∼8P) payload and controlled release and realizing synergistic effects with celastrol integration at a low dosage as a curative sensitizer. Our results demonstrated that the N9 peptide could be pH-responsively released from the macropores of the M-CA∼8P nanosystem both in simulated physiological environments and in cancer cells and at tumor sites. Biosafe and enhanced therapeutic outcomes (90% tumor inhibition) were obtained by combination of the N9@M-CA∼8P nanosystem with celastrol coordinatively inducing mitochondrion-mediated cell apoptosis in resistant cancer cell lines and in the corresponding xenografted mice models. Overall, this study provides convincing evidence for effective and safe resistant cancer treatment through a stimulus-responsive biomacromolecule nanosystem combined with a low dosage of a natural compound.
研究领域:
纳米医学
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癌症研究
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药学
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生物技术
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材料科学
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高影响因子
MOLECULAR MEDICINE
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2025
·Vol. 31
·期 1
·1-15
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IF 6.4
Pei Lipeng,Zhu Yan,Li Wenpeng,Xu Bin,Sun Jingli
Background Uterine corpus endometrial carcinoma (UCEC) is one of the most frequent female genital malignant tumors. Targeting DNA damage and cell apoptosis are regarded as effective ways for UCEC therapy. Celastrol is a natural anti-cancer product from the Celastraceae plant family, while its role in UCEC has not been investigated. Methods UCEC cell lines Ishikawa and HEC-1-A were applied and treated with different concentrations of Celastrol. The appropriate and nontoxic concentrations were used for the subsequent experiments. Functional experiments analyzed the cell viability, cell cycle distribution, DNA damage, apoptosis and the expression of related proteins. We determined tumor growth in xenograft nude mice. Bioinformatic analysis, protein coimmunoprecipitation (Co-IP), luciferase assay, cell experiments were performed to reveal the relationship of Celastrol/KAT2B/RBPJ/MCM4 in UCEC. Results Treatment of Celastrol inhibited cell viability in a dose-dependent manner, and caused cell cycle arrest, accompanied by the downregulation of CDK2 and cyclin E expression and the upregulation of p21. Celastrol treatment resulted DNA damage and apoptosis in cultured cells, as demonstrated by increased number of TUNEL-positive cells, activity of caspase-3 and expression of cleaved-caspase-9, cleaved PARP1 and γ-H2AX. In xenograft nude mice, Celastrol also repressed tumor growth. Furthermore, lysine acetyltransferase KAT2B was a putative target of Celastrol, and its expression was upregulated by Celastrol in vitro and in vivo. Overexpression of KAT2B in UCEC inhibited cell proliferation and increased DNA damage and apoptosis. KAT2B knockdown overcame the anti-proliferative and pro-apoptotic roles of Celastrol. Moreover, Co-IP demonstrated that KAT2B bound to RBPJ, a transcriptional repressor, and increased the acetylation of RBPJ. RBPJ could bind to the MCM4 promoter to suppress the luciferase activity. Further functional analysis revealed that the functions of KAT2B in UCEC cell proliferation, DNA damage and apoptosis were mediated by MCM4, and Celastrol enhanced RBPJ acetylation and reduced MCM4 expression. Conclusions These results underscore that Celastrol is a promising anti-cancer agent in UCEC with preferential anti-proliferative, pro-apoptotic and DNA damage effects through the KAT2B/RBPJ/MCM4 axis, and KAT2B is a promising therapeutic target for UCEC. Graphical abstract
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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药理学
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JOURNAL OF NANOBIOTECHNOLOGY
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2024
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IF 10.6
Jinfeng Shi,Jiahui Zhou,Bo Liu,Kezhou Lin,Xingliang Xie,Xue Han,Yanmei Sheng,Yihan Liu,Congjian He,Yujin Zhou,Nan Zhu,Qian Yang,Ruifeng Luo,Yi Li
Background The oral administration of drugs for treating ulcerative colitis (UC) is hindered by several factors, including inadequate gastrointestinal stability, insufficient accumulation in colonic lesions, and uncontrolled drug release. Methods A multiple sensitive nano-delivery system comprising β-cyclodextrin (CD) and 4-(hydroxymethyl)phenylboronic acid (PAPE) with enzyme/reactive oxygen species (ROS) sensitivity was developed to load celastrol (Cel) as a comprehensive treatment for UC. Results Owing to the positive charge in the site of inflamed colonic mucosa, the negatively charged nanomedicine (Cel/NPs) could efficiently accumulate. Expectedly, Cel/NPs showed excellent localization ability to colon in vitro and in vivo tests. The elevated concentration of ROS and intestinal enzymes in the colon microenvironment quickly break the CD, resulting in Cel release partially to rebalance microbiota and recover the intestinal barrier. The accompanying cellular internalization of residual Cel/NPs, along with the high concentration of cellular ROS to trigger Cel burst release, could decrease the expression of inflammatory cytokines, inhibit colonic cell apoptosis, promote the macrophage polarization, scavenge ROS, and regulate the TLR4/NF-κB signaling pathway, which certified that Cel/NPs possessed a notably anti-UC therapy outcome. Conclusions We provide a promising strategy for addressing UC symptoms via an enzyme/ROS-sensitive oral platform capable of releasing drugs on demand. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1186/s12951-024-02725-9.
研究领域:
药学
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纳米技术
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胃肠病学
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炎症研究
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2021
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IF 6.953
Yun Qian,Jun Zhang,Rui Xu,Qiang Li,Qi Shen,Guofu Zhu
Triple negative breast cancer (TNBC) metastasis is still one of the obstacles in clinical treatment, while highly-effective cancer drugs usually cannot be used for their hydrophobicity and comprehensive system toxicity. This study built a kind of pH-sensitive nanoparticles (PP/H NPs) constructed by poly (lactic- co -glycolic acid) modified with β-cyclodextrin (PLGA-β-CD), polyethyleneimine grafted with benzimidazole (PEI-BM) and low molecular weight heparin (LMWH) to delivery Celastrol (Cela) and ferrocene (Fc) for breast cancer therapy. PLGA-β-CD and PEI-BM were synthesized by amidation reaction, the amphipathic polymer nanoparticles with 108.37 ± 1.02 nm were self-assembled in water. After PP/H NPs treatment, the half maximal inhibitory concentration (IC 50 ) decreased by 91% compared with Cela, and ROS level was also elevated. PP/H NPs led to substantial tumor inhibiting rate (TIR, 65.86%), utilized LMWH to strengthen the anti-metastasis effect of PP/H NPs. PP/H NPs took advantage of exogenous chemotherapeutics and endogenous ROS to inhibit tumor growth, and combined with LMWH to hinder breast cancer metastasis.
研究领域:
纳米技术
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药学
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肿瘤学
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材料科学
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化学
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高影响因子
International Journal of Nanomedicine
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2026
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IF 8.7
Jinfeng Shi,Xueqian Zhang,Linxing Yang,Wei Wang,Lingling Liu,Tian Lu,Xing Xu,Yan Xu,Shiyu Ren,Ruifeng Luo
Introduction: Conventional oral nanocarriers for intestinal diseases rely on single-responsive mechanisms and target a single pathological stage, failing to address the inflammation–carcinoma continuum. Celastrol (Cel)’s oral translation is limited by poor bioavailability and lack of lesion-specific targeting. To overcome these barriers, we constructed a hyaluronic acid (HA)-functionalized platform featuring dual enzyme/ROS-triggered release and CD44-mediated active targeting (HA@Cel/NPs) for treating ulcerative colitis (UC), colitis-associated colorectal cancer (CAC), and colon cancer.Methods: HA@Cel/NPs were fabricated using β-cyclodextrin and 4-(hydroxymethyl) phenylboronic acid as dual-responsive linkers. Physicochemical properties, drug release profiles, cellular uptake, anti-inflammatory activity, macrophage polarization, and anticancer activity were systematically evaluated in vitro. In vivo biodistribution and therapeutic efficacy were assessed in UC, CAC, and colon cancer mouse models, with anti-PD-L1 combination therapy in the colon cancer setting.Results: HA@Cel/NPs exhibited uniform size (76.87 ± 2.65 nm, PDI 0.166 ± 0.012), stayed stable for 14 days, and achieved ~71% Cel release under high H2O2/α-amylase conditions within 8 h. The nanocarriers enhanced cellular uptake and promoted M1-to-M2 macrophage polarization in inflamed macrophages, while inducing potent CT26 cell apoptosis. Orally administered HA@Cel/NPs alleviated UC severity and suppressed CAC progression, with significantly reduced tumor burden. In colon cancer, intravenous HA@Cel/NPs combined with intraperitoneal anti-PD-L1 significantly boosted CD8⁺ and CD4⁺ T cell infiltration and effectively eradicated established tumors compared with HA@Cel/NPs monotherapy.Conclusion: HA@Cel/NPs offer a versatile, dual-route platform that bridges inflammation management and cancer immunotherapy, distinguishing itself from single-mechanism or single-disease nanocarriers.
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