查找使用阿拉丁产品的科研文献

Celastrol-conjugated carboxylmethyl chitosan for oral treatment of diet-induced obesity

Qikang Tian,Qianqian Han,Xin Zhu,Lan Zhang,Kun Chen,Zhishen Xie,Pan Wang,Xiangxiang Wu,Zhenqiang Zhang,Huahui Zeng

Celastrol is a promising drug candidate for treating diet-induced obesity, but the cytotoxicity and poor water solubility limit its clinical application. We prepared a novel celastrol conjugate (Cel-CMCS) with excellent water solubility (33.94 mg/mL), and then investigated its anti-obesity and toxic activities in diet-induced obese mice. Just as the parent celastrol, Cel-CMCS reduced body weight and body fat mass in an equally effective manner, but with lower toxicity. Collectively, Cel-CMCS provides a possible solution for the treatment of obesity in humans. In addition, the present study provided a practical experience of the development of carboxymethyl chitosan-based delivery system for poorly water-soluble drugs.

Synthesis of AgInS2 quantum dots loaded with celastrol for induction of apoptosis and autophagy in hepatocellular carcinoma cells

Gong Qineng,Zhu Tianyu,Zhang Linlin,Wu Hui,Miao Yang,Hu Ye

Hepatocellular carcinoma (HCC) is a predominant form of liver cancer and one of the leading causes of cancer-related death globally. Therefore, there is an urgent need for innovative therapeutic strategies that target the molecular mechanisms underlying HCC progression and metastasis, aiming to improve treatment efficacy and patient survival. The natural product celastrol (Cel) has demonstrated inhibitory effects in various cancer cell lines. However, its clinical application has been hindered by high toxicity and a low safety threshold. Metal-free quantum dots (QDs), AgInS 2 (AIS QDs) not only eliminate toxic risks associated with heavy metals but also exhibit high biocompatibility in the biomedical field. By developing AIS QD@Cel, an AIS QDs nano-delivery system for Cel, the cell selectivity and inhibitory effects of Cel on HCC were enhanced. Fourier-transform infrared spectroscopy (FTIR) analysis revealed that AIS QDs can interact with Cel via amide bonds. The encapsulation rate of AIS QDs to Cel reached 27.5%. AIS QD@Cel eliminated toxicity on 293T and enhanced inhibition on HCC cells by over 10 times. Furthermore, the western blotting and flow cytometry experiments showed that AIS QD@Cel promoted apoptosis and autophagy signal pathway. Finally, transcriptome sequencing revealed that AIS QD@Cel effect on HCC by regulating gene expression involved in critical signaling pathways that are implicated in the progression of cancer. This strategy holds the potential to increase safety threshold and clinical applicability of Cel, offering significant clinical value for the treatment of HCC patients.

Synergistic effect of pH-sensitive PEGylated RG3-chitosan prodrug nanoparticles encapsulated celastrol on pancreatic cancer

Zheng Zhang,Jiaxing Wang,Xiaofang Li,Lingzhou Zhao,Junwei Zhao,Mengjiao Su,Xiangxiang Wu,Huahui Zeng

Celastrol (Cel) is a potential anticancer therapeutic candidate, but its limited practical applicability is due to its low solubility, poor tumor selectivity, and cytotoxicity. Clinically, ginsenoside Rg3 (RG3) is typically combined with chemotherapy to enhance antitumor effects and reduce side effects. Herein, we developed novel pH-sensitive prodrug nanoparticles (NPs) containing RG3 and Cel for the synergistic treatment of pancreatic cancer (PC). Amphiphilic prodrug, a PEGylated chitosan oligosaccharide coupled with RG3 via Schiff base bond, was self-assembled with hydrophobic Cel into NPs with drug loadings of 2.12% (Cel) and 1.63% (RG3). NPs exhibited a suitable particle size of 124.01 nm, zeta potential of −39.89 mV and good physical stability. In addition, NPs also showed a controlled drug release when the Schiff base bonds were hydrolyzed in the acidic environment. In Pan02 tumor-bearing mice, NPs exhibited a high accumulation in tumor tissues and prolonged blood circulation time. Furthermore, NPs could more effectively inhibit tumor growth and reduce systemic toxicity, compared with the free Cel, RG3, prodrug, and Cel + RG3. The results indicated that the NPs could provide a safe and promising nanoplatform for PC therapy.

Precise delivery of celastrol by PEGylated aptamer dendrimer nanoconjugates for enormous therapeutic effect via superior intratumor penetration over antibody counterparts

Boning Niu,Yuehuang Wu,Min Zhou,Ruimiao Lin,Pengjin Ge,Xiaohui Chen,Hu Zhou,Xiaokun Zhang,Jingjing Xie

Antibody-coated nanoparticles have been reported to have the extremely low delivery efficiency in solid tumors in preclinical trials. Though aptamers were considered to be superior over antibodies in cancer theranostics, whether PEGylated aptamer nanoparticles are better than antibody nanoparticles in improving delivery specificity and penetration efficiency of chemotherapeutics is still unknown. Here, we conjugate celastrol , a natural product with anti-tumor effect, onto PEGylated EpCAM aptamer or antibody dendrimers to obtain two nanoconjugates , and for the first time, conduct a comprehensive study to compare their performance in delivery specificity, intratumoral penetration ability and therapeutic outcomes. Our results showed that compared to antibody counterparts, PEGylated aptamer nanoconjugates exhibited the enhanced accumulation and retention specificities at tumor sites and the stronger intratumoral penetration capabilities by reducing the macrophage reservoir effects in solid tumors . When delivered celastrol to a colorectal xenograft tumor mice model by PEGylated aptamer dendrimers , 20 % of enhanced therapeutic efficiency was achieved compared to that by antibody-modified ones. Moreover, celastrol at 2 mg/kg delivered by PEGylated aptamer dendrimers showed the prominent anticancer efficiency (nearly 92 %) but without obvious side effects. These data firstly provide the proof-of-concept implementation that PEGylated aptamer nanoconjugates will display the great potential in the effective and safe cancer treatment with regard to the superiority over antibody ones in penetration abilities.

Bone-targeted celastrol nanocarrier suppresses osteoclastogenesis in postmenopausal osteoporosis

Yu Xiaolong,Zhang Shengtao,Wei Zhiqi,Xu Qiang

Osteoporosis is a metabolic disorder characterized by progressive bone loss, particularly affecting postmenopausal women. Excessive osteoclast activity contributes to bone resorption and skeletal fragility. Celastrol, a natural triterpene, has demonstrated anti-inflammatory and anti-resorptive effects, but its clinical application is limited by poor solubility and systemic toxicity. In this study, we engineered a bone-targeted nano-sustained-release system using mesoporous silica nanoparticles loaded with celastrol. The nanocarrier displayed high bone affinity, sustained drug release, and favorable biocompatibility. In vitro, it suppressed RANKL-induced osteoclast formation and function by downregulating NF-κB and MAPK signaling. In vivo, treatment of ovariectomized rats improved bone mineral density, preserved trabecular microarchitecture, and reduced osteoclast numbers without apparent systemic toxicity. These findings demonstrate that bone-targeted celastrol nanoparticles provide an efficient and safe therapeutic strategy for postmenopausal osteoporosis by inhibiting osteoclastogenesis and protecting bone structure.

Celastrol ameliorates acute liver injury through modulation of PPARα

Qi Zhao,Ping Tang,Ting Zhang,Jian-Feng Huang,Xue-Rong Xiao,Wei-Feng Zhu,Frank J. Gonzalez,Fei Li

Celastrol , derived from the roots of the Tripterygium Wilfordi , has attracted interest for its potential anti-inflammatory and lipid-lowering activities. In the present study, the protective effect of celastrol on carbon tetrachloride (CCl 4 )-induced acute liver injury was investigated. Celastrol improved the increased transaminase activity, inflammation, and oxidative stress induced by CCl 4 , resulting in improved metabolic disorders found in mice with liver injury. Dual-luciferase reporter assays and primary hepatocyte studies demonstrated that the peroxisome proliferator-activated receptor α (PPARα) signaling mediated the protective effect of celastrol, which was not observed in Ppara -null mice, and co-treatment of wild-type mice with the PPARα antagonist GW6471. Mechanistically, PPARα deficiency potentiated CCl 4 -induced liver injury through a deoxycholic acid (DCA)-EGR1-inflammatory factor axis. These data demonstrate a novel role for celastrol in protection against acute liver injury through modulating PPARα signaling.

Celastrol-Loaded Zwitterionic Nanogels Trigger Pyroptosis for Potent Antitumor Effects

Shaoqi Sheng,Jiaxin Zhang,Licheng Yang,Zhuofan Diao,Yichen Zhang,Yue Wang,Haibao Peng,Wuli Yang

Pyroptosis has recently emerged as a promising therapeutic strategy owing to its unique advantages in inducing lytic cell death and eliciting immunogenic responses. Moderate induction of pyroptosis not only directly eliminates cancer cells but also activates antitumor immunity through the release of tumor-associated antigens and proinflammatory cytokines. However, most available pyroptosis inducers suffer from poor solubility, instability, and nonspecific biodistribution, which significantly hinder their translational potential. To address these challenges, we developed a pyroptosis-inducing delivery platform based on carboxybetaine zwitterionic nanogels for the efficient encapsulation of celastrol. These zwitterionic nanogels exhibit excellent resistance to protein adsorption and prolonged circulation in vivo. Upon drug release, celastrol promotes mitochondrial reactive oxygen species (ROS) accumulation, activates the caspase-3/GSDME axis, and triggers pyroptosis accompanied by immunogenic signals, including adenosine triphosphate (ATP) secretion, lactate dehydrogenase (LDH) release, and calreticulin (CRT) exposure. When combined with the anti-PD-1 checkpoint blockade, this platform further enhances dendritic cell maturation and antigen presentation, thereby amplifying pyroptosis-driven immune responses. In summary, our study demonstrates an effective strategy for inducing pyroptosis by integrating zwitterionic nanogel-mediated celastrol delivery with immune checkpoint inhibition, providing new insights and potential breakthroughs for cancer immunotherapy.

Celastrol-conjugated chitosan oligosaccharide for the treatment of pancreatic cancer

Xiaohu Zeng,Xin Zhu,Qikang Tian,Xiaoke Tan,Ning Sun,Min Yan,Junwei Zhao,Xiangxiang Wu,Ruiqin Li,Zhenqiang Zhang,Huahui Zeng

Celastrol Derivative/DOX Co-Assembled Nanodrug for Enhanced Antitumor Therapy

Jiangtao Su,Xue Chen,Fan Ye,Chuchu Liu,Jiahao Liang,Xuejun Zhang,Xiaoxia Guo

Background: Multidrug resistance (MDR) is a key challenge in clinical chemotherapy. The combination of drugs can effectively reverse multi-drug resistance. Objective: In this study, doxorubicin (DOX) was capsulated into nanoparticles formed by an amphiphilic PEGylated-poly (α-lipoic acid)-methanamide analogue of celastrol (mPEG-PαLA-CEN) prodrug polymer. CEN was linked to the branched chain of poly (α-lipoic acid) by forming ester bonds. DOX was physically trapped inside the nanoparticles via electrostatic interaction. Both drugs can be simultaneously released in response to low pH and high GSH in order to overcome DOX resistance. Methods: The chemical structure of the mPEG-PαLA-CEN-DOX NPs was confirmed through 1H NMR, FT-IR spectroscopy, UV-Vis spectrum, DLS, and TEM. Drug-loading content, efficacy, and drug release were measured using HPLC. Cell toxicity was examined using an MTT assay. Results: CEN/DOX-loaded nanoparticles were found to have spherical shapes with diameters of around 229.7 nm. The NPs exhibited high biocompatibility and released 92% DOX and 71.8% CEN in response to low pH and high GSH of tumor microenvironments. As dual drug-loaded nanoparticles, the efficacy of mPEG-PαLA-CEN-DOX NPs against tumor cell lines in vitro was enhanced for both MCF-7 and MCF-7/ADR compared to free DOX. Compared to free DOX, the IC50 of mPEG-PαLA-CEN-DOX NPs reduced from 46.10 μM to 8.36 μM for the MCF-7/ADR cell line. Conclusion: In conclusion, this study demonstrated that PEGylated poly (α-lipoic acid)-CEN copolymers can be used not only as biocompatible, stimulation-responsive anticancer drug nanocarriers but also as chemosensitizers to overcome multidrug resistance, which provide a theoretical base for clinical application of CEN/DOX nanodrug.

Celastrol inhibits Streptococcus suis infection through disrupting arginine metabolism pathway

Hongdou Liu,Shichao Xu,Rui Lei,Xiaoying Yu,Yi Lu,Yandi Pan,Bo Su,Shiqi Lang,Hongkai Ren,Rendong Fang,Jialu Zhang,Lianci Peng

Celastrol exhibits effective anti- S. suis efficacy both in vitro and in vivo. • Celastrol potentiates the anti- S. suis efficacy of antibiotics. • Celastrol potentially targets arginine deiminase (ADI) and disrupts arginine metabolism of S. suis . • Celastrol disrupts cytoplasmic membrane function of S. suis . Objectives : Given the rising prevalence of Streptococcus suis ( S. suis ) infection and the reduced effectiveness of traditional antibiotics, the development of novel alternative therapeutics or synergistic adjuvants to improve antimicrobial efficacy is urgently required. Celastrol displays antibacterial effects, but the specific mechanism by which celastrol exerts its anti- S. suis activity through interference with arginine metabolism remains unexplored. Purpose : This study investigated the antibacterial mechanism of celastrol against S. suis and further demonstrated its potential as an adjuvant to conventional antibiotics. Methods : The in vitro and in vivo anti- S. suis efficacy of celastrol were evaluated through time-killing curves, drug resistance, biofilm formation assays and mice infection model. The synergistic efficacy of celastrol and antibiotics against S. suis was evaluated through checkerboard microdilution assay. Transcriptomic analysis was performed to analyze the potential anti- S. suis pathways of celastrol. Anti- S. suis target of celastrol was elucidated using Δ arcA mutant strain, CETSA and DARTS assays. Celastrol-disrupted membrane integrity and function of S. suis were employed. Results : Celastrol exerted potent anti- S. suis efficacy in vitro and in vivo , and combination with antibiotics exhibited synergistic antibacterial efficacy. We found that celastrol treatment downregulated arginine-metabolism genes including arcA, argF , and argR . Importantly, celastrol physically interacted with recombinant ADI, the key enzyme catalyzing arginine degradation. Meanwhile, celastrol destroyed membrane integrity, induced ROS accumulation, caused proton motive force (PMF) dissipation, impaired ATP production and inhibited efflux pump activity. Conclusion : This study demonstrates that celastrol exerts anti- S. suis efficacy by disrupting arginine metabolism and compromising membrane function. Download: Download high-res image (259KB) Download: Download full-size image

Celastrol Attenuates FGF23 Expression in Osteoblasts by Inhibiting STAT3 Activation

Jiawei Cao,Yuewen Tang,Feng Wan,Tingjiao Xu,Ruchun Yang

Introduction In this study, we aim to investigate the mechanism by which extracellular phosphate (Pi) regulates the transcription of fibroblast growth factor 23 (FGF23) in osteoblasts and the effects of celastrol on FGF23 expression in UMR-106 cells and in chronic kidney disease (CKD) rat models. Methods We used Pi to induce FGF23 expression in a rat osteoblastic cell line as a model and then treated the cells with celastrol. The cytotoxicity of Pi and celastrol was assessed using the CCK-8 assay. FGF23 expression was measured using real-time quantitative PCR (RT-qPCR), and its promoter activity was evaluated using luciferase reporter assays. To detect active signal transducer and activator of transcription 3 (STAT3), immunofluorescence and Western blotting were performed. The 5/6 nephrectomized rat model was established to investigate the effects of celastrol on FGF23 expression in vivo. An enzyme-linked immunosorbent assay was carried out to examine serum FGF23 levels in rats. RT-qPCR detected the mRNA levels of FGF23 and STAT3 in the femurs of CKD rats. Results We found that high Pi activated STAT3 and promoted its nuclear translocation, leading to elevated FGF23 expression, which was suppressed by celastrol. Additionally, in rats subjected to 5/6 nephrectomy with high serum Pi levels, serum FGF23 levels and skeletal STAT3 expression were significantly decreased after celastrol treatment. Discussion Therefore, celastrol could have therapeutic effects on CKD by decreasing serum FGF23. Conclusion High Pi activates STAT3 and induces FGF23 expression. Furthermore, celastrol can attenuate increased FGF23 expression induced by high Pi, potentially via inhibition of STAT3 activation.

Celastrol-encapsulated microspheres prepared by microfluidic electrospray for alleviating inflammatory pain

Huiyu Zheng,Cheng Zhao,Yitian Lu,Jun Cao,Fanning Zeng,Huan Wang,Zaisheng Qin,Tao Tao

Inflammatory pain is induced by trauma, infection, chemical stimulation, etc. It causes severe physical and psychological agony to patients. Celastrol has powerful anti-inflammatory property and has achieved good results in various inflammation-related diseases. However, the low water solubility and multi-system toxicity limit its clinical application. Herein, we proposed alginate microspheres with core-shell structure which encapsulated celastrol by microfluidic electrospray to effectively overcome the shortcomings and improve the therapeutic effect. The microspheres had uniform size and good biocompatibility, and could release the loaded drugs in the gut. The behavioral tests showed that the celastrol-loaded microspheres effectively alleviated inflammatory pain, and the hematoxylin and eosin staining (HE staining), immunofluorescence and detection of inflammatory cytokines showed the anti-inflammatory effect. These results indicated that the microspheres could reduce dose and toxicity without affecting efficacy, and facilitate the application of celastrol in different clinical situations.