Expert Opinion on Drug Metabolism & Toxicology
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2023
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IF 4.3
Xiaojuan Jiang,Caixia Yuan,Rong Ding,Di Lu,Xiaoyu Peng,Zhihao Dong,Chunyan Zhu,Yihua Lin,Caisheng Wu,Qiang Xie
Background Celastrol is known as one of the most medicinally valuable compounds. However, the pharmaceutical application of celastrol is significantly limited due to high toxicity, while there are few reports on the mechanism of toxicity.Methods This study searched for possible toxic metabolites through phase I in vitro metabolism and glutathione capture experiments. Then in vivo metabolism experiments in mice and rats were conducted to look for metabolites in vivo. Finally, mice in vivo toxicity experiment was conducted to verify the toxicity of different doses of celastrol to mice.Results In the in vivo and in vitro metabolism experiments, we found 7 phase I metabolites in vitro, 9 glutathione conjugation metabolites in vitro, and 20 metabolites in vivo. The metabolic soft points of celastrol could be the quinone methyl structure at C3-OH and C6. In vivo toxicity experiments show that celastrol causes weight loss, diarrhea, gastrointestinal tract and liver inflammation in mice.Conclusions This study analyzed the metabolites and possible metabolic soft spots of celastrol, and its hepatotoxicity and gastrointestinal toxicity were demonstrated through in vivo studies for the first time. The results might provide an important basis for potential structural modification to increase the druggability of celastrol.
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高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
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IF 4.8
Bo Wang,Jiquan Shen,Xinggao Wang,Ruixing Hou
Previous study has indicated that Celastrol (Cel) has various physiological and pharmacological effects, including antibacterial, antioxidant, pro-apoptotic, anticancer and anti-rheumatoid arthritis (RA) effects. However, low water solubility, low oral bioavailability, narrow treatment window, and high incidence of systemic adverse reactions still limit the further clinical application of Cel. Here, aiming at effectively overcome those shortcomings of Cel to boost its beneficial effects for treating RA, we developed the leukosome (LEUKO) coated biomimetic nanoparticles (NPs) for the targeted delivery of Cel to arthritis injury area in RA. LEUKO were synthesized using membrane proteins purified from activated J774 macrophage. LEUKO and Cel-loaded LEUKO (Cel@LEUKO) were characterized using dynamic light scattering and transmission electron microscopy. Our results demonstrated that Cel@LEUKO can inhibit the inflammatory response of lipopolysaccharide (LPS) induced mouse monocyte macrophage leukemia cells (RAW264.7 cells) and human rheumatoid arthritis synovial fibroblasts (MH7A) cells through the inhibition of reactive oxygen species (ROS)-NF-κB pathway. In addition, research has shown that LEUKO effectively targets and transports Cel to the inflammatory site of RA, increased drug concentration in affected areas, reduced systemic toxicity of Cel, and reduced clinical symptoms, inflammatory infiltration, bone erosion, and serum inflammatory factors in collagen-induced arthritis (CIA) rats.
研究领域:
药理学
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纳米技术
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炎症
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风湿病学
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药物递送系统
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PubMed
高影响因子
International Journal of Nanomedicine
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2021
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IF 6.4
Fen Qiu,Long Xi,Shengshuang Chen,Yonghua Zhao,Zhenping Wang,Ying Zheng
Purpose Psoriasis is an inflammatory skin disease, where keratinocytes play pivotal roles in its pathogenesis. We prepared Celastrol Noisome hydrogel (Cel Nio gel) for the treatment of psoriasis and aimed to study its target site as well as the mechanism. Methods Cel Nio was fabricated with thin-film hydration and sonication, then topically administered to imiquimod (IMQ)-induced psoriasis mice. The concentrations of Cel in the skin, blood and lymphatic system were determined using LC-MS. The anti-psoriasis effect of Cel Nio gel was studied, and the levels of inflammatory cytokines in blood were evaluated by flow cytometry. For the in vitro study, the uptake of Nio by HaCaT cells was quantified with flow cytometry, and the anti-inflammatory effect of Cel on HaCaT cells was detected with qPCR. The expressions of inflammatory factors and Ki-67 in skin were observed by immunofluorescence. Results Cel Nio possessed a particle size of 133 nm with encapsulation efficacy (EE%) of 83.2%. After topical administration of Cel Nio gel to mice, Cel was mainly accumulated in the skin instead of exposure in blood or lymphatic system, while the levels of inflammatory factors in blood had a significant decline. In addition, the preparation of Nio enhanced the uptake by HaCaT cells, and Cel obviously reduced the mRNA levels of inflammatory cytokines in HaCaT cells. Moreover, Cel Nio gel significantly decreased the expression of inflammatory cytokines and Ki-67 in the skin. Conclusion Cel Nio gel achieved the anti-psoriatic effect by inhibiting the inflammation and hyperproliferation of keratinocytes in the skin and further suppressing the systemic inflammation, thus could be a novel topical drug delivery system to treat psoriasis with topical and systemic effects.
研究领域:
药剂学
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皮肤病学
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药理学
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生物技术
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高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2020
·Vol. 18
·期 1
·1-15
·
IF 6.518
Jin Tian,Wu Di,Liu Xiao-Ming,Xu Jiang-Tao,Ma Bing-Jie,Ji Yun,Jin Yu-Ying,Wu Si-Yin,Wu Tao,Ma Ke
Background Celastrol has been proven effective in anti-inflammatory but was limited in the clinic due to the poor solubility and side effects induced by low bioavailability. Osteoarthritis has acidic and inflammatory environment. Our aim was to load celastrol into HMSNs and capped with chitosan to construct a pH-responsive nanoparticle medicine (CSL@HMSNs-Cs), which is of high solubility for osteoarthritis intra-articular injection treatment.Methods The CSL@HMSNs-Cs were assembled and the characteristics were measured. The CSL@HMSNs-Cs was applied in vitro in the chondrocytes collected from rats cartilage tissue and in vivo in the MIA induced knee osteoarthritis rats via intra-articular injection. Cytotoxicity assay, pH-responsive release, pain behavior, MRI, safranin o fast green staining, ELISA and western blot analysis were applied to evaluate the bioavailability and therapeutic effect of CSL@HMSNs-Cs.Results CSL@HMSNs-Cs was stable due to the protection of the chitosan layers in alkaline environment (pH = 7.7) but revealed good solubility and therapeutic effect in acidic environment (pH = 6.0). The cytotoxicity assay showed no cytotoxicity at relatively low concentration (200 μg/mL) and the cell viability of chondrocytes stimulated by IL-1β was increased in CSL@HMSNs-Cs group. Paw withdrawal threshold in CSL@HMSNs-Cs group is increased, and MRI and Safranin O Fast Green staining showed improvements in articular surface erosion and joint effusion. The upregulated expression levels of IL-1β, TNF-α, IL-6, MMP-3 and MMP-13 and NF-κB signaling pathway of chondrocytes were inhibited in CSL@HMSNs-Cs group.Conclusion Hollow mesoporous silica nanoparticles were an ideal carrier for natural drugs with poor solubility and were of high biocompatibility for intra-articular injection. These intra-articular injectable CSL@HMSNs-Cs with improved solubility, present a pH-responsive therapeutic strategy against osteoarthritis.
研究领域:
药学
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纳米技术
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骨科
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药物递送系统
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PubMed
高影响因子
Bioactive Materials
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2024
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IF 18
Peng Hua,Ruifeng Liang,Suleixin Yang,Yanbei Tu,Meiwan Chen
Abnormal proliferation of aggressive fibroblast-like synoviocytes (FLS) and perpetuate synovial inflammation can inevitably accelerate the progression of rheumatoid arthritis (RA). Herein, a strategy of simultaneously promoting FLS apoptosis and inhibiting inflammation as mediated by macrophages is proposed to restore synovial homeostasis for effective RA therapy. A hyaluronic acid-based dissolvable microneedle (MN) is fabricated for transdermal delivery of dual human serum albumin (HSA)-contained biomimetic nanocomplexes to regulate RA FLS and macrophages. Upon skin insertion, dual nanocomplexes are released rapidly from the MN and accumulate in RA joint microenvironment through both passive and active targeting as mediated by HSA. Thioketal-crosslinked fluorinated polyethyleneimine 1.8 K ( TK PF) was constructed to bind the plasmid encoding pro-apoptotic gene PUMA with HSA coating layer ( TK PF/pPUMA@HSA, TPH). TPH nanocomplexes can upregulate PUMA through RA FLS transfection to trigger efficient apoptosis. Also, HSA nanocomplexes encapsulating the classic anti-inflammatory natural product celastrol (Cel@HSA, CH) can inhibit inflammation of macrophages through blocking NF-κB pathway activation. TPH/CH MN can deplete RA FLS and inhibit M1 macrophage activation, suppress synovial hyperplasia as well as reduce bone and cartilage erosion in a collagen-induced arthritis (CIA) mouse model, demonstrating a promising strategy for efficient RA treatment.
研究领域:
药理学
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风湿病学
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纳米技术
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基因治疗
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炎症研究
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高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
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2024
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IF 4.4
Yinlian Yao,Shilong Fan,Yinqiang Fan,Xin Shen,Xingxing Chai,Yiming Shao,Jiang Pi,Xueqin Huang,Yiming Shao,Zhikun Zhou,Yue Zhao,Hua Jin
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common causes of respiratory failure in critically ill patients. There is still a lack of definitive and effective treatment options, and the mortality rate remains as high as 30% to 40%. Effective therapeutics for ALI/ARDS are greatly hindered by the side effects resulting from inefficient delivery to the disease lesions and off-targeting biodistribution of drugs. Macrophages play an integral role in maintaining the steady state of the immune system and are involved in inflammation processes. Thus, nanodrug to accurately target macrophages have the potential to transform disease treatment. Here, we developed an mannosylated drug delivery system to target and deliver celastrol (Cel) to the alveolar macrophages for enhanced alleviating the cytokines in LPS-induce ALI mice. In vitro data demonstrated that the as-synthesized Man@Cel-NPs significantly improved the targeting of Cel into the inflammatory macrophages via mannose receptor-mediated phagocytosis. In vivo experiments further showed that intratracheal delivery of Man@Cel-NPs can improve the dysregulation of inflammatory response in LPS-induced mice by inhibiting the release of inflammatory cytokines and increasing autophagy and decreasing apoptosis in lungs. This work provides a potential NP platform for the locally tracheal delivery of herbal ingredients and exhibits promising clinical potential in the treatment of numerous respiratory diseases, including ALI/ARDS.
研究领域:
药理学
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纳米技术
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免疫学
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呼吸医学
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2026
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IF 6
Nuannuan Li,Ye Jin,Yating Zhao,Bo Li,Wenjun Yu,Xinfeng Liu,Jinguang Liu,Yuanlei Fu
Celastrol (Cel), a highly promising natural product isolated from traditional Chinese medicine, exhibits potent therapeutic efficacy against ulcerative colitis (UC). Nevertheless, its poor colon-targeting efficiency, insufficient capacity to penetrate the intestinal mucus layer, and low cellular internalization significantly compromise therapeutic outcomes in UC treatment. To address these critical limitations, herein we rationally designed a exosome-hydrogel hybrid system (Cel-GDNPs@Gel) by first encapsulating Cel into ginger-derived exosome-like nanoparticles (GDNPs), which were subsequently dispersed within a glycyrrhizic acid (GA) hydrogel matrix. Experimental studies confirmed that GDNPs were successfully isolated and characterized with uniform size distribution and round- or cup-shaped morphology, and Cel was successful encapsulated into GDNPs. The GA hydrogel endowed the system with excellent pH-sensitivity and robust mucoadhesive properties, thereby facilitating enhanced accumulation and prolonged retention at the colon site. Moreover, GDNPs promoted efficient mucus penetration and cellular uptake of Cel. Notably, both GDNPs and GA could exert synergistic therapeutic effects with Cel. Accordingly, in vitro and in vivo studies demonstrated that Cel-GDNPs@Gel significantly alleviated colitis symptoms, suppressed the expression of pro-inflammatory cytokines, attenuated oxidative stress, regulated macrophage polarization, promoted intestinal mucosal barrier repair, and restored intestinal homeostasis. Furthermore, this delivery system exhibited favorable biosafety with no obvious systemic toxicity. Collectively, this multifunctional Cel-GDNPs@Gel platform offers a safe and effective strategy for the oral treatment of UC. Herein we rationally designed a hydrogel-integrated ginger-derived exosome-like nanoparticles system (Cel-GDNPs@Gel) by first encapsulating celastrol (Cel) into ginger-derived exosome-like nanoparticles (GDNPs), which were subsequently dispersed within a self-assembled glycyrrhizic acid (GA) hydrogel matrix. The GA hydrogel displayed excellent pH-responsiveness, enabling enhanced accumulation of Cel in the colon. Meanwhile, the hydrogel component endowed the system with mucoadhesion, thereby significantly prolonging the intestinal retention of Cel. Moreover, the GDNPs facilitated efficient mucus penetration and cellular uptake. Notably, both GDNPs and GA could exert synergistic therapeutic effects with Cel. Accordingly, Cel-GDNPs@Gel significantly alleviated colitis symptoms, suppressed pro-inflammatory cytokine expression, attenuated oxidative stress via inhibiting ROS overproduction, regulated macrophage polarization by restraining M1 polarization, promoted intestinal mucosal barrier repair by up-regulating tight junction proteins, and remodeled gut microbiota to restore intestinal homeostasis. Furthermore, this delivery system exhibited favorable biosafety. Collectively, this multifunctional Cel-GDNPs@Gel platform offers a safe and effective strategy for the oral treatment of UC. Download: Download high-res image (110KB) Download: Download full-size image
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JOURNAL OF NANOBIOTECHNOLOGY
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2025
·Vol. 23
·期 1
·1-23
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IF 12.6
Su Yanguo,Chen Rui,Wang Bingjie,Wang Teng,Tao Jiaojiao,Diao Qijie,Jiang Tianze,Zhao Xia
Activation of cGAS-STING signaling pathway and accumulation of reactive oxygen and nitrogen species (RONS) are important issues facing the treatment of rheumatoid arthritis (RA). Here, we report a biomimetic nano-Chinese medicine (HA-RM-Cel-BR) for RA immunotherapy based on STING inhibition of celastrol (Cel) and RONS clearance of bilirubin (BR). HA-RM-Cel-BR is constructed by the carrier-free self-assembly of active ingredients Cel and BR from traditional Chinese medicine, and then camouflaged by hyaluronic acid (HA)-modified red blood cell membranes (RM). HA-RM-Cel-BR prolongs circulation time through RM camouflage, targets inflamed joints by HA modification, and remodels the joint immune microenvironment by STING inhibition and RONS clearance. More importantly, HA-RM-Cel-BR shows excellent therapeutic effects on RA rat model, and significantly reduces hepatotoxicity associated with Cel. Our work provides a new strategy for RA immunotherapy with traditional Chinese medicine ingredients.
研究领域:
药理学
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免疫学
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纳米医学
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高影响因子
JOURNAL OF MOLECULAR STRUCTURE
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2023
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IF 3.8
Jiangtao Su,Dan Li,Yuchen Hu,Xiangyu You,Xiaoxia Guo,Xican Li,Ban Chen
To improve the application prospects of celastrol (CE), a novel C 6 -sulfonated CE analog (called CENFN in this study) was designed via quantum chemical calculations. On this basis, CENFN was synthesized and clarified by spectroscopic methods (IR, 1 H NMR, UV–Vis and fluorescence spectra). Subsequently, the tyrosinase and melanin inhibitory effects of CE and CENFN were comparably explored in silico and in vitro . The calculation and spectroscopy results confirmed the rationality of the synthetic reactions of CENFN. The molecular simulation results showed that CENFN possessed a higher level of tyrosinase and melanin inhibition than CE, which was consistent with the experimental results. All these findings can help to design and synthesize CE analogs as tyrosinase and melanin inhibitors.
研究领域:
药物化学
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生物化学
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皮肤病学
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高影响因子
Scientific Reports
·
2020
·Vol. 10
·期 1
·1-11
·
IF 3.998
Chen Minjian,Yang Jing,Li Lei,Hu Yanhui,Lu Xiaomei,Sun Rongli,Wang Yubang,Wang Xinru,Zhang Xiaoling
Recently, celastrol has shown great potential for inducing apoptosis in acute myeloid leukemia cells, especially acute promyelocytic leukaemia cells. However, the mechanism is poorly understood. Metabolomics provides an overall understanding of metabolic mechanisms to illustrate celastrol's mechanism of action. We treated both nude mice bearing HL-60 cell xenografts in vivo and HL-60 cells as well as NB-4 cells in vitro with celastrol. Ultra-performance liquid chromatography coupled with mass spectrometry was used for metabolomics analysis of HL-60 cells in vivo and for targeted L-cysteine analysis in HL-60 and NB-4 cells in vitro . Flow cytometric analysis was performed to assess mitochondrial membrane potential, reactive oxygen species and apoptosis. Western blotting was conducted to detect the p53, Bax, cleaved caspase 9 and cleaved caspase 3 proteins. Celastrol inhibited tumour growth, induced apoptosis, and upregulated pro-apoptotic proteins in the xenograft tumour mouse model. Metabolomics showed that cysteine metabolism was the key metabolic alteration after celastrol treatment in HL-60 cells in vivo . Celastrol decreased L-cysteine in HL-60 cells. Acetylcysteine supplementation reversed reactive oxygen species accumulation and apoptosis induced by celastrol and reversed the dramatic decrease in the mitochondrial membrane potential and upregulation of pro-apoptotic proteins in HL-60 cells. In NB-4 cells, celastrol decreased L-cysteine, and acetylcysteine reversed celastrol-induced reactive oxygen species accumulation and apoptosis. We are the first to identify the involvement of a cysteine metabolism/reactive oxygen species/p53/Bax/caspase 9/caspase 3 pathway in celastrol-triggered mitochondrial apoptosis in HL-60 and NB-4 cells, providing a novel underlying mechanism through which celastrol could be used to treat acute myeloid leukaemia, especially acute promyelocytic leukaemia.
研究领域:
肿瘤学
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药理学
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代谢组学
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细胞生物学
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高影响因子
JOURNAL OF GENE MEDICINE
·
2020
·Vol. 22
·期 9
·e3201
·
IF 3.258
Liping Ma,Yanjing Cao,Lin Zhang,Ketao Li,Laixing Yan,Yizhan Pan,Jianhua Zhu
Background Celastrol (Cel) has been corroborated as an anti-inflammatory and anti-apoptotic agent in multiple cell damage models. However, the protective effect of Cel in high glucose (HG)-induced cardiomyocyte injury is still unclear. The present study aimed to determine whether Cel can mitigate HG-stimulated cardiomyocyte injury via regulating the miR-345-5p/growth arrest-specific 6 (Gas6) signaling pathway. Methods Cardiomyocytes were exposed to normal glucose (NG; 5 mmol/l) or HG (30 mmol/l) and then administered with Cel. Cell counting kit-8 and flow cytometry assays were used to detect cell proliferative activity and apoptosis. mRNA and protein expression were analyzed using a quantitative reverse transcriptase-polymerase chain reaction and western blotting, respectively. A bioinformatics algorithm and a luciferase reporter gene assay were used to determine whether Gas6 is a direct target of miR-345-5p. Results The present study confirmed the inhibitory effects of Cel in HG-induced inflammation in cardiomyocytes. Moreover, Cel exhibited the ability to antagonize HG-induced cardiomyocyte apoptosis and suppress the elevated Bax/Bcl-2 ratio elicited by HG stimulation. Intriguingly, Cel treatment revoked the HG-triggered repression of Gas6 protein expression, and Gas6 loss-of-function accelerated HG-induced cardiomyocyte apoptosis. HG-triggered up-regulation of miR-345-5p expression was depressed following Cel treatment. Importantly, we validated that Gas6 is a direct target of miR-345-5p. Transfection with miR-345-5p inhibitors restrained HG-induced release of pro-inflammatory cytokines and cell apoptosis. Conclusions The findings of the present study demonstrate that Cel administration antagonized HG-induced cardiomyocyte apoptosis and inflammation through up-regulating Gas6 expression by restraining miR-345-5p.
研究领域:
心脏病学
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分子生物学
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药理学
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PubMed
高影响因子
LANGMUIR
·
2024
·
IF 3.7
Jianbin Deng,Mengqi Liu,Shiqi Gao,Dongjie Lei,Zhicheng Su,Fuqing Liang,Songyun Tang,Huiyuan Yang,Yuan-Yuan Huang,Weiquan Xie,Guang-Yu Pan
The urgent need for new antimicrobial drugs arises from the limited efficacy of traditional antibiotics against emerging drug-resistant strains. Celastrol (CSL) demonstrates an exceptional antibacterial property that remains unaffected by bacterial resistance, but its poor water solubility limits its wide applications. This study uses the hydrophobic inner cavity of mono-(6-diethylenetriamine-6-deoxy)-β-cyclodextrin (mβ-CD) (a derivative of cyclodextrin) to encapsulate CSL, constructing an inclusion complex (CSL@mβ-CD) to enhance the water solubility of CSL. The obtained inclusion complex is further incorporated into a swellable hydrogel microneedle (MN) to obtain CSL@mβ-CD/MN. The fabricated CSL@mβ-CD/MN can enable the sustained release of CSL, achieving effective bacterial eradication at infected sites. In vivo experiments demonstrate that CSL@mβ-CD/MN has a remarkable efficacy in the treatment of methicillin-resistant Staphylococcus aureus-induced subcutaneous abscesses and wound infections. Specifically, CSL@mβ-CD/MN can effectively penetrate the stratum corneum of the skin to realize rapid elimination of the bacteria in wounds. Moreover, CSL@mβ-CD/MN can efficiently scavenge reactive oxygen species, promote M2 polarization of macrophages, and relieve local inflammation at the wound sites. These results reveal that CSL@mβ-CD/MN holds great promise in the clinical treatment of acute skin infections induced by drug-resistant bacteria.
研究领域:
药剂学
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微生物学
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皮肤科学
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高影响因子
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