JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-15
·
IF 12.6
Liu Yu,Zhang Jia,Lai Chunyu,Wang Wenjun,Huang Yangyue,Bao Xuanwen,Yan Haimeng,Sun Xuqi,Liu Qiqi,Chen Dong,Dai Xiaomeng,Qian Xinyu,Zhao Peng
Immunotherapy, exemplified by immune checkpoint blockade (ICB), has been extensively employed in antitumor treatments. Nevertheless, its efficacy in addressing low-immunogenic tumors has not yielded satisfactory results, primarily due to the depletion and inadequate infiltration of effector T cells within the tumor microenvironment (TME). Here, we construct an injectable water-in-oil emulsion hydrogel to load clinically used Celastrol (Gel@Cel), which addresses the limitations of Cel’s hydrophobicity. Cel can both inhibit tumor cell proliferation and promote tumor cell apoptosis, while simultaneously inducing immunogenic cell death, through activation of the AKT and MAPK pathways. In a model of clinically refractory hepatocellular carcinoma with malignant ascites, intraperitoneal administration of Gel@Cel significantly inhibits tumor progression and activates antitumor immune effects through lipase-controlled release of Cel, as compared to free Cel. Intriguingly, the Gel@Cel induces the activation of dendritic cells, resulting in the infiltration of cytotoxic T cells in the TME of ascites. Furthermore, the administration of Cel increases the expression of programmed cell death protein ligand-1 (PD-L1) in tumor cells. Moreover, combining the PD-1 antibody (αPD-1) with Gel@Cel further enhances the antitumor effect and amplifies the immune activation. In conclusion, Gel@Cel exhibits promising therapeutic potential in the treatment of low-immunogenic tumors, especially when combined with ICB therapy.
研究领域:
肿瘤学
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药理学
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免疫学
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生物医学工程
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DOI
PubMed
高影响因子
Materials Today Bio
·
2026
·
IF 11
Yangwang Jin,Fei Qin,Ranxing Yang,Wenzhuo Fang,Kaile Zhang,Meng Liu,Ming Yang,Ying Wang,Qiang Fu
The dynamic pathological microenvironment formed post-urethral injury drives an inflammatory-fibrotic cascade, leading to urethral stricture. Herein, we designed a novel hydrogel dressing (CPT-Cel) to modulate this dynamic urethral microenvironment for scarless reconstruction. The hydrogel responsively degrades and releases its contents upon encountering acidic environments and ROS bursts, interrupting the severe oxidative stress-inflammation cycle and creating a favorable regenerative microenvironment in the early wound phase. The incorporated celastrol continuously releases into the late repair phase, inhibiting the hyperactivation of urethral fibroblasts via the TGF-β/NF-κB pathway in urethral microenviroment, thereby preventing excessive collagen secretion. Furthermore, the dressing, featuring an ECM-mimicking microstructure, effectively adheres to and integrates with the injury site, providing hemostatic and antibacterial functions. In animal models of urethral injury, CPT-Cel accelerated urethral repair within the inflammatory milieu, significantly reduced collagen deposition and ultimately improved stricture outcomes. This study not only validates the core mechanism by which an intelligent drug-loaded hydrogel modulates the dynamic urethral microenvironment but also proposes a new paradigm for urethral tissue engineering.
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DOI
PubMed
高影响因子
OncoTargets and Therapy
·
2022
·
IF 4.345
Xiaoli Li,Guangbei Zhu,Xintong Yao,Ning Wang,Ronghui Hu,Qingxin Kong,Duanfang Zhou,Liangyuan Long,Jiali Cai,Weiying Zhou
Background Celastrol is a major active component of the thunder god vine (Tripterygium wilfordii) used in traditional Chinese medicine to treat chronic inflammatory and autoimmune diseases. Celastrol inhibits PI3K–Akt–mTOR signaling, which is frequently dysregulated in tumors and critical for tumor-cell proliferation and survival, but the underlying mechanisms are still not fully understood. In the present study, we investigated detailed mechanisms of celastrol inhibition of mTOR signaling in breast cancer cells.Methods First, we evaluated the effect of celastrol on breast cancer-cell growth using MTT assays. Second, we examined the effects of celastrol on mTOR phosphorylation and expression using Western blot. Furthermore, we investigated the cause of mTOR downregulation by celastrol using immunoprecipitation assays. In addition, we evaluated the effect of celastrol on an MDA-MB231 cell-derived xenograft model.Results Celastrol suppressed breast cancer cell growth in vitro and in vivo. Celastrol inhibited mTOR phosphorylation and induced mTOR ubiquitination, resulting in its proteasomal degradation. Mechanistically, we found that mTOR is a client of Hsp90–Cdc37 chaperone complex, and celastrol disrupts mTOR interaction with chaperone Hsp90 while promoting mTOR association with cochaperone Cdc37.Conclusion Our study reveals that celastrol suppresses mTOR signaling, at least in part through regulating its association with chaperones and inducing its ubiquitination.
研究领域:
肿瘤学
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药理学
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分子生物学
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传统中药
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产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2024
·
IF 6.6
Bo Wang,Jiquan Shen,Changjian Zhou,Xinggao Wang,Shuanghu Wang,Ruixing Hou
Background Rheumatoid Arthritis (RA) involves prolonged inflammation of the synovium, damaging joints and causing stiffness and deformity. Celastrol (Cel), derived from the Chinese herbal medicine Tripterygium wilfordii Hook F, offers immunosuppressive effects for RA treatment but is limited by poor solubility and bioavailability.Purpose In this study, long-circulating Cel-loaded liposomes (Cel-LPs) were used to increase the pharmacokinetics of Cel, thereby improving drug delivery and efficacy for the treatment of RA.Methods Cel-LPs were prepared and administered orally and intravenously to compare the elimination half-life of drugs and bioavailability of Cel. Cel-LPs were prepared using the lipid thin-layer-hydration-extrusion method. Human rheumatoid arthritis synovial (MH7A) cells were used to investigate the compatibility of Cel-LPs. The pharmacokinetic studies were performed on male Sprague-Dawley (SD) rats.Results The Cel-LPs had an average size of 72.20 ± 27.99 nm, a PDI of 0.267, a zeta potential of −31.60 ± 6.81 mV, 78.77 ± 5.69% drug entrapment efficiency and sustained release (5.83 ± 0.42% drug loading). The cytotoxicity test showed that liposomes had excellent biocompatibility and the fluorescence microscope diagram indicated that liposome entrapment increased intracellular accumulation of Rhodamine B by MH7A cells. Furthermore, the results exhibited that Cel-LPs improved the pharmacokinetics of Cel by increasing the elimination half-life (t1/2) to 11.71 hr, mean residence time (MRT(0-∞)) to 7.98 hr and apparent volume of distribution (Vz/F) to 44.63 L/kg in rats, compared to the Cel solution.Conclusion In this study, liposomes were demonstrated to be effective in optimizing the delivery of Cel, enabling the formulation of Cel-LPs with prolonged blood circulation and sustained release characteristics. This formulation enhanced the intravenous solubility and bioavailability of Cel, developing a foundation for its clinical application in RA and providing insights on poorly soluble drug management.
研究领域:
药剂学
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药理学
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药物递送系统
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风湿病学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2020
·Vol. 24
·期 21
·12476-12490
·
IF 4.486
Zhongping Su,Pengyu Zong,Ji Chen,Shuo Yang,Yihui Shen,Yan Lu,Chuanxi Yang,Xiangqing Kong,Yanhui Sheng,Wei Sun
Vascular calcification is an important risk factor for the mortality and morbidity in chronic kidney disease (CKD). Unfortunately, until now there is no certain medication targeting vascular calcification in CKD. In this study, we explored the inhibitory effect of celastrol on high calcium–induced vascular calcification and the underlying molecular mechanisms. Cell proliferation assay showed that celastrol inhibited aortic valve interstitial cell (VIC) and vascular smooth muscle cell (VSMC) proliferation when its concentration was higher than 0.6 μmol/L. 0.8 μmol/L celastrol inhibited the expression of osteogenic genes and calcium deposition induced by high-calcium medium in both AVICs and VSMCs. In mouse vascular calcification model induced by adenine combined with vitamin D, alizarin red and immunostaining showed that celastrol inhibited pro-calcification gene expression and calcium deposition in aortic wall and aortic valve tissues. At the molecular level, celastrol inhibited the increase of BMP2, phosphorylated Smad1/5 (p-Smad1/5) and non-phosphorylated β-catenin (n-p-β-catenin) induced by high-calcium medium both in vitro and in vivo. Also, BMP2 overexpression reversed the anti-calcification effects of celastrol by recovering the decrease of p-Smad1/5 and n-p-β-catenin. Furthermore, celastrol prevented the up-regulation of BMPRII and down-regulation of Smad6 induced by high calcium, and this protectory effect can be abolished by BMP2 overexpression. In conclusion, our data for the first time demonstrate that celastrol attenuates high calcium–induced arterial and valvular calcification by inhibiting BMP2/Smad1/5 signalling, which may provide a novel therapeutic strategy for arterial and valvular calcification in patients with CKD.
研究领域:
药理学
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心血管疾病
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肾病学
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分子生物学
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DOI
PubMed
高影响因子
Science Advances
·
2024
·Vol. 10
·期 28
·
IF 11.7
Hanrong Li,Yifan Li,Lingpu Zhang,Nan Wang,Dong Lu,Dongsheng Tang,Yitong Lv,Jinbo Zhang,Heben Yan,He Gong,Ming Zhang,Kaili Nie,Yi Hou,Yingjie Yu,Haihua Xiao,Chaoyong Liu
Celastrol (CEL), an active compound isolated from the root of Tripterygium wilfordii, exhibits broad anticancer activities. However, its poor stability, narrow therapeutic window and numerous adverse effects limit its applications in vivo. In this study, an adenosine triphosphate (ATP) activatable CEL-Fe(III) chelate was designed, synthesized, and then encapsulated with a reactive oxygen species (ROS)–responsive polymer to obtain CEL-Fe nanoparticles (CEL-Fe NPs). In normal tissues, CEL-Fe NPs maintain structural stability and exhibit reduced systemic toxicity, while at the tumor site, an ATP-ROS–rich tumor microenvironment, drug release is triggered by ROS, and antitumor potency is restored by competitive binding of ATP. This intelligent CEL delivery system improves the biosafety and bioavailability of CEL for cancer therapy. Such a CEL-metal chelate strategy not only mitigates the challenges associated with CEL but also opens avenues for the generation of CEL derivatives, thereby expanding the therapeutic potential of CEL in clinical settings.
研究领域:
药理学
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纳米技术
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癌症研究
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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
Biomedicines
·
2026
·Vol. 14
·期 7
·1488
·
IF 4.5
Jiayi Li,Xiaoyao Fu,Zhonghuan Qu,Yanjun Yang
Background: Psoriasis is a chronic inflammatory skin disease characterized by abnormal epidermal hyperplasia and immune-inflammatory imbalance. Although celastrol (Cel) exhibits potent anti-inflammatory activity, its strong hydrophobicity and low local delivery efficiency limit its therapeutic application.Methods: To enhance its transdermal delivery and topical therapeutic efficacy, a Cel-loaded liposomal hydrogel microneedle system (Cel-lipo-MNs) was developed in this study. Cel-loaded liposomes were first prepared by the thin-film dispersion method, and Cel-lipo-MNs were subsequently fabricated using a multistep vacuum micromolding process combined with UV-induced photocrosslinking.Results: In vivo studies demonstrated that, in an imiquimod-induced psoriasis-like mouse model, Cel-lipo-MNs markedly alleviated erythema, scaling, and skin thickening, reduced PASI-like scores. Further investigation revealed that Cel-lipo-MNs significantly downregulated the serum levels of IL-17, IL-23, and IFN-γ, and exhibited superior therapeutic efficacy compared with free celastrol, conventional liposomes, and blank microneedles.Conclusions: These findings indicate that Cel-lipo-MNs can substantially enhance the therapeutic effect of celastrol against psoriasis-like skin lesions, possibly through suppression of the IL-23/IL-17 inflammatory axis and related immune-inflammatory responses, and provide a promising transdermal delivery strategy for topical psoriasis treatment.
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DOI
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2024
·Vol. 28
·期 14
·e18375
·
IF 4.3
Dandan Wang,Shan Jin,Hanye Liu,Xinyi Song,Hongyu Jin,Yilan Song,Hongwei Zhao,Liangchang Li,Guanghai Yan
Celastrol, a bioactive molecule extracted from the plant Tripterygium wilfordii Hook F., possesses anti-inflammatory, anti-obesity and anti-tumour properties. Despite its efficacy in improving erythema and scaling in psoriatic mice, the specific therapeutic mechanism of celastrol in atopic dermatitis (AD) remains unknown. This study aims to examine the role and mechanism of celastrol in AD using TNF-α-stimulated HaCaT cells and DNCB-induced Balb/c mice as in vitro and in vivo AD models, respectively. Celastrol was found to inhibit the increased epidermal thickness, reduce spleen and lymph node weights, attenuate inflammatory cell infiltration and mast cell degranulation and decrease thymic stromal lymphopoietin (TSLP) as well as various inflammatory factors (IL-4, IL-13, TNF-α, IL-5, IL-31, IL-33, IgE, TSLP, IL-17, IL-23, IL-1β, CCL11 and CCL17) in AD mice. Additionally, celastrol inhibited Ezrin phosphorylation at Thr567, restored mitochondrial network structure, promoted translocation of Drp1 to the cytoplasm and reduced TNF-α-induced cellular reactive oxygen species (ROS), mitochondrial ROS (mtROS) and mitochondrial membrane potential (MMP) production. Interestingly, Mdivi-1 (a mitochondrial fission inhibitor) and Ezrin-specific siRNAs lowered inflammatory factor levels and restored mitochondrial reticular formation, as well as ROS, mtROS and MMP production. Co-immunoprecipitation revealed that Ezrin interacted with Drp1. Knocking down Ezrin reduced mitochondrial fission protein Drp1 phosphorylation and Fis1 expression while increasing the expression of fusion proteins Mfn1 and Mfn2. The regulation of mitochondrial fission and fusion by Ezrin was confirmed. Overall, celastrol may alleviate AD by regulating Ezrin-mediated mitochondrial fission and fusion, which may become a novel therapeutic reagent for alleviating AD.
研究领域:
药理学
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免疫学
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细胞生物学
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皮肤科
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DOI
PubMed
高影响因子
JOURNAL OF PROTEOME RESEARCH
·
2021
·
IF 4.466
Shaohua Xu,Liwei Lyu,Huaichang Zhu,Xiaoqiang Huang,Wei Xu,Wen Xu,Yaqian Feng,Yong Fan
The antiobesity effect of celastrol has been reported in numerous studies, but the underlying mechanism remains unclear. It is widely accepted that gut dysbiosis is closely related to obesity. The potential effect of celastrol on microbiota is worth exploring. In this study, the celastrol-induced weight loss was validated in high-fat diet (HFD)-induced obese mice, with the detection of reported phenotypes including a reduction in food intake, augments in dyslipidemia and glucose metabolism, and adipose thermogenesis. The anti-inflammatory effect of celastrol was also proved based on the alterations in serum cytokines. Antibiotic interference showed that gut microbiota contributes to celastrol-induced weight loss. Several key bacteria were identified using shotgun metagenomic sequencing to display the alterations of the intestinal microbiome in obese mice treated with celastrol. Meanwhile, the fecal and serum metabolic profiles were generated by pseudotargeted metabolomics, and changes in some critical metabolites related to appetite and metabolism were detected. Importantly, we applied in silico bidirectional mediation analysis to identify the precise connections among the alterations in gut microbes, serum metabolome, and host phenotypes induced by celastrol treatment for the first time. Therefore, we concluded that the celastrol-induced microbial changes partially contribute to the antiobesity effect via the serum metabolome. The mass spectrometry data are deposited on MetaboLights (ID: MTBLS3278).
研究领域:
药理学
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微生物学
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代谢组学
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营养学
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肥胖研究
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产品关联
DOI
PubMed
高影响因子
International Journal of Pharmaceutics-X
·
2023
·
IF 4.7
Ping Sheng,Chao Bu,Tanyue Hui,Lili Zhou,Hao Chen,Guoliang Zhou
Synergistic chemotherapy and photothermal therapy (PTT) holds the promise of addressing the weakness of individualized chemotherapy and PTT. In this study, we synthesized a chemotherapeutic agent, PDA-Ce-CDs, which combines the photothermal conversion ability and the generation of hydroxyl radicals (•OH), enabling synergistic enhancement of antitumor effects. Furthermore, the localized heating effect of NIR radiation promoted the uptake of the PDA-Ce-CDs and enhances the sensitivity of intracellular reactive oxygen species (ROS). Finally, the antitumor activity of the PDA-Ce-CDs was evaluated through cell experiments and tumor-bearing mice experiments, confirming its excellent antitumor efficacy in vivo and in vitro . Our work presents a new strategy in cancer treatment by utilizing carbon dots in combination with photothermal agents for synergistic chemotherapy-photothermal therapy. This innovative approach offers a new therapeutic avenue for synergistic tumor treatment by harnessing the combined effects of photothermal therapy and chemotherapy.
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2023
·
IF 5.6
Shengjin Xiang,Jinrun Chen,Mengyun Deng,Zixiang Wang,Xingyi Li,Dan Lin,Jianhong Zhou
Background Extensive research has revealed the favorable effects of celastrol (CEL) against various diseases, but the role of CEL in autoimmune uveitis remains unexplored. Methods We first assessed the prophylactical and therapeutical effects of CEL on autoimmune uveitis via rat experimental autoimmune uveitis model. After network pharmacology, functional enrichment and molecular docking analyses, we predicted the potential target of CEL and validated its effect on EAU by clinical and histopathological scores, Evans blue staining, immunofluorescence assay and western blotting. Then we evaluated the role of CEL in the gut environment by 16S rRNA sequencing and untargeted metabolomic analysis. Results We confirmed that CEL treatment suppressed the pathological TH17 response, inhibited the migration of inflammatory cells, and preserved the integrity of BRB via targeting STAT3-IL17 pathway. Furthermore, CEL was found to reduce the relative abundance of opportunistic pathogenic bacteria including Clostridium_sensu_stricto_1 , Parasutterella and GCA-900066575 , and enrich the relative abundance of beneficial Oscillospirales and Ruminococcus_torques_group in EAU rats by fecal 16S rRNA sequencing. Meanwhile, CEL treatment reshaped the gut metabolites in the EAU rats by increasing the relative concentrations of cholic acid, progesterone and guggulsterone, and decreasing the relative levels of isoproterenol, creatinine and phenylacetylglutamine. Conclusions CEL exerts its ameliorative effects on the experimental autoimmune uveitis through the dual mechanisms of targeting STAT3 and reprofiling the gut microenvironment.
研究领域:
免疫学
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药理学
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微生物学
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分子生物学
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眼科学
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DOI
PubMed
高影响因子
MATERIALS & DESIGN
·
2024
·
IF 7.6
Jie Chen,Yan Liu,Yanting You,Ruisi Zhou,Yanchun Li,Xinghong Zhou,Xiaohu Chen,Ying Yang,Jinxiang Chen,Hiu Yee Kwan,Xiaoshan Zhao,Yuyao Wu
Celastrol (CEL) has garnered significant interest for its anti-tumour properties and potential for colorectal cancer (CRC) treatment. However, its clinical use is constrained by its limited bioavailability and potential toxicity. Herein, a biotin-decorated CEL nano-drug delivery system using a zeolitic imidazolate framework (ZIF-8) as a carrier was synthesized, named CEL@ZIF-8@BIO. It exhibits excellent water solubility, efficient loading of CEL, and a high release rate in acidic environments. In vitro experiments demonstrated that CEL@ZIF-8@BIO inhibited proliferation, induced cell cycle arrest in G0/G1 phase, increased ROS production and reduced mitochondrial membrane potential in CRC cells. RNA-Seq analysis indicated that the anticancer mechanism of CEL@ZIF-8@BIO may be linked to ferroptosis as indicated by a significant increase in Fe 2 + levels, oxidative stress, lipid peroxidation, and mitochondrial dysfunction in CRC cells. Furthermore, these effects could be reversed by ferroptosis inhibitor. In vivo research revealed that CEL@ZIF-8@BIO significantly inhibited the growth of CRC tumours and reduced the toxicity associated with CEL treatment. Taken together, the CEL@ZIF-8@BIO nano-drug delivery system shows great promise for CRC therapy due to its improved efficacy and reduced toxicity.
研究领域:
癌症研究
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纳米技术
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药学
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分子生物学
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细胞生物学
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产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）