celastrol
54632359
Molecular modulators of celastrol as the keystones for its diverse pharmacological activities.
In the recent years, much attention has been focused on identifying bioactive compounds from medicinal plants that could be employed in therapeutics, which is attributed to their potent pharmacological actions and better toxicological profile. One such example that has come into the light with considerable interest is the pentacyclic triterpenoid, celastrol, which has been found to provide substantial therapeutic properties in a variety of diseases. In an effort to further accelerate its potential to be utilized in clinical practice in the future; along with advancing technologies in the field of drug discovery and development, different researchers have been investigating on the various mechanisms and immunological targets of celastrol that underlie its broad spectrum of pharmacological properties. In this review, we have collated the various research findings related to the molecular modulators responsible for different pharmacological activities shown by celastrol. Our review will be of interest to the herbal, biological, molecular scientist and by providing a quick snapshot about celastrol giving a new direction in the area of herbal drug discovery and development.
Biomedicine pharmacotherapy Biomedecine pharmacotherapie
Sin Wi Ng Yinghan Chan Dinesh Kumar Chellappan Thiagarajan Madheswaran Farrukh Zeeshan Yik Lung Chan Trudi Collet Gaurav Gupta Brian G G Oliver Peter A B Wark Nicole G Hansbro Alan C-Y Hsu Philip Michael Hansbro Kamal Dua Jithendra Panneerselvam
145023628
Celastrol mediates autophagy and apoptosis via the ROS/JNK and Akt/mTOR signaling pathways in glioma cells
BackgroundCelastrol, a triterpene compound derived from the traditional Chinese medicine Tripterygium wilfordii, has been reported to possess potential antitumor activity towards various malignancies. However, the effect of celastrol on glioma cells and the underlying molecular mechanisms remain elusive.MethodsGlioma cells, including the U251, U87 MG and C6 cell lines and an animal model were used. The effects of celastrol on cells were evaluated by flow cytometry, confocal microscopy, reactive oxygen species production assay and immunoblotting after treatment of celastrol. Fisher's exact test, a one way ANOVA and the Mann Whitney U test were used to compare differences between groups. All data were analyzed using SPSS version 21.0 software.ResultsHere, we found that exposure to celastrol induced G2/M phase arrest and apoptosis. Celastrol increased the formation of autophagosomes, accumulation of LC3B and the expression of p62 protein. Celastrol treated glioma cells exhibited decreased cell viability after the use of autophagy inhibitors. Additionally, autophagy and apoptosis caused by celastrol in glioma cells inhibited each other. Furthermore, celastrol induced JNK activation and ROS production and inhibited the activities of Akt and mTOR kinases. JNK and ROS inhibitors significantly attenuated celastrol trigged apoptosis and autophagy, while Akt and mTOR inhibitors had opposite effects.ConclusionsIn conclusion, our study revealed that celastrol caused G2/M phase arrest and trigged apoptosis and autophagy by activating ROS/JNK signaling and blocking the Akt/mTOR signaling pathway.
Journal of experimental clinical cancer research CR
Xihong Liu Peiyuan Zhao Xiujuan Wang Lei Wang Yingjun Zhu Yadi Song Wei Gao
53761435
Celastrol inhibits microglial pyroptosis and attenuates inflammatory reaction in acute spinal cord injury rats
&NA; Pyroptosis pathway is closely related to inflammation. However, Celastrol effect on pyroptosis pathway after spinal cord injury (SCI) are poorly understood. We studied the anti inflammatory and neuroprotective effects of Celastrol on acute spinal cord injury in rats, and its anti inflammatory effects on lipopolysaccharide (LPS)/ATP induced microgliosis. Our results show that Celastrol can improve the recovery of hindlimb motor function after SCI in Sprague Dawley (SD) rats, and reduce the cavity area of spinal cord injury along with the neuronal loss. Celastrol simultaneously reduced the activation of microglia (especially M1 microglia) in the spinal cord, inhibited the pyroptosis related proteins (NLRP3 ASC Caspase 1 GSDMD) reduced the release of TNF &agr; IL 1&bgr; and IL 18 inflammatory factors, and increased the release of IL10 cytokines. In vitro studies showed that Celastrol reduced the toxicity resulting from the administration of LPS with ATP to BV 2 cells, inhibited the pyroptosis related proteins (NLRP3 Caspase 1 GSDMD) and inhibited the release of corresponding inflammatory factors. Finally, Celastrol can inhibit the expression of NF&kgr;B/p p65 in vitro and in vivo. Our results show that Celastrol can attenuate the inflammatory response of the spinal cord after SCI, which is associated with inhibition of microglial activation and pyroptosis pathway. Further study to explore the use of Celastrol to treat SCI is warranted. HighlightsPyroptosis pathway is closely related to inflammation.Celastrol can improve inflammatory response in the spinal cord after SCI.Celastrol can inhibit the pyroptosis pathway in microglia.
International immunopharmacology
Wangying Dai Xingguo Wang Honglin Teng Chi Li Bin Wang Jing Wang
58568464
Celastrol Protects From Cholestatic Liver Injury Through Modulation of SIRT1 FXR Signaling*
The present study used metabolomics, transcriptomics, protein analysis by immunoblots, chemical inhibition and gene knockout mice to determine the effects of celastrol on cholestasis and its mechanisms. Samples from patients were used to validate our findings, and the data supported the conclusions that celastrol protected against cholestatic liver injury through modulation of the SIRT1 and FXR. Graphical Abstract Highlights 1. Celastrol alleviated cholestatic liver injury. 2. Celastrol inhibited the decrease of SIRT1 induced by deoxycholic acid. 3. SIRT1 FXR signaling pathway mediated the effect of celastrol. Celastrol, derived from the roots of the Tripterygium Wilfordi, shows a striking effect on obesity. In the present study, the role of celastrol in cholestasis was investigated using metabolomics and transcriptomics. Celastrol treatment significantly alleviated cholestatic liver injury in mice induced by a naphthyl isothiocyanate (ANIT) and thioacetamide (TAA) Celastrol was found to activate sirtuin 1 (SIRT1) increase farnesoid X receptor (FXR) signaling and inhibit nuclear factor kappa B and P53 signaling. The protective role of celastrol in cholestatic liver injury was diminished in mice on co administration of SIRT1 inhibitors. Further, the effects of celastrol on cholestatic liver injury were dramatically decreased in Fxr null mice, suggesting that the SIRT1 FXR signaling pathway mediates the protective effects of celastrol. These observations demonstrated a novel role for celastrol in protecting against cholestatic liver injury through modulation of the SIRT1 and FXR.
Molecular Cellular Proteomics
Qi Zhao Fang Liu Yan-Wei Cheng Xue-rong Xiao Dandan Hu Ying-mei Tang Wei-min Bao Jin-hui Yang Tao Jiang Jia-Peng Hu Frank J Gonzalez Fei Li
58587483
Celastrol loaded PEG b PPS nanocarriers as an anti inflammatory treatment for atherosclerosis.
In this work, the hydrophobic small molecule NF kB inhibitor celastrol was loaded into poly(ethylene glycol) b poly(propylene sulfide) (PEG b PPS) micelles. PEG b PPS micelles demonstrated high loading efficiency, low polydispersity, and no morphological changes upon loading with celastrol. Encapsulation of celastrol within these nanocarriers significantly reduced cytotoxicity compared to free celastrol, while simultaneously expanding the lower concentration range for effective inhibition of NF kB signaling by nearly 50 000 fold. Furthermore, celastrol loaded micelles successfully reduced TNF a secretion after LPS stimulation of RAW 264.7 cells and reduced the number of neutrophils and inflammatory monocytes within atherosclerotic plaques of ldlr mice. This reduction in inflammatory cells was matched by a reduction in plaque area, suggesting that celastrol loaded nanocarriers may serve as an anti inflammatory treatment for atherosclerosis.
Biomaterials science
Sean D Allen Yu-gang Liu Taehyeung Kim Sharan Bobbala Sijia Yi Xiaohan Zhang Jaehyuk Choi Evan Alexander Scott
53262251
Celastrol strongly inhibits proliferation, migration and cancer stem cell properties through suppression of Pin1 in ovarian cancer cells
Abstract Ovarian cancer is one of the most serious diseases worldwide and the fifth most common cancer among women. Celastrol, extracted from Thunder God Vine, exerts anti cancer effects on various cancers; however, the mechanism underlying these anti cancer effects in ovarian cancer needs further investigation. Herein, we investigated the anti cancer efficacy of celastrol and its underlying mechanism in human ovarian cancer cell lines A2780, OVCAR3, and SKOV3. Celastrol significantly suppressed cell proliferation and migration in a dose dependent manner. Celastrol resulted in a G2/M cell cycle arrest, accompanied with the down regulation of Cyclin D1, CDK2, and CDK4. Celastrol induced apoptosis primarily via up regulation of caspase 3, caspase 8, and Bax, and down regulation of Bcl 2. Celastrol treatment inhibited the expression of stem cell marker CD44, Nanog, Klf4, and Oct4, and reduced a portion of the CD44highCD24low cell population. To further understand the cancer therapeutic target, we assessed the effect of celastrol on expression of Pin1, which is reportedly overexpressed in many human cancers and activates more than 40 oncogenes or inactivates more than 20 tumor suppressor genes. We report that celastrol particularly suppressed Pin1 expression, thereby inhibiting Akt, STAT3, P38, JNK, P65, and IL 6 expression. Taken together, these findings indicate that celastrol is a potential therapeutic agent for ovarian cancer in humans via inhibition of Pin1 expression.
European journal of pharmacology
Xiaojing Li Hongmin Wang Jie Ding Shaozhen Nie Li Wang Lili Zhang Shaoda Ren
84846197
Friedelane type triterpene cyclase in celastrol biosynthesis from Tripterygium wilfordii and its application for triterpenes biosynthesis in yeast.
Celastrol is a promising bioactive compound isolated from Tripterygium wilfordii and has been shown to possess many encouraging preclinical applications. However, the celastrol biosynthetic pathway is poorly understood, especially the key oxidosqualene cyclase (OSC) enzyme responsible for cyclisation of the main scaffold. Here, we report on the isolation and characterisation of three OSCs from T. wilfordii: TwOSC1, TwOSC2 and TwOSC3. Both TwOSC1 and TwOSC3 were multiproduct friedelin synthases, while TwOSC2 was a b amyrin synthase. We further found that TwOSC1 and TwOSC3 were involved in the biosynthesis of celastrol and that their common product, friedelin, was a precursor of celastrol. We then reconstituted the biosynthetic pathway of friedelin in engineered yeast constructed by the CRISPR/Cas9 system, with protein modification and medium optimisation, leading to heterologous production of friedelin at 37.07 mg l 1 in a shake flask culture. Our study was the first to identify the genes responsible for biosynthesis of the main scaffold of celastrol and other triterpenes in T. wilfordii. As friedelin has been found in many plants, the results and approaches described here have laid a solid foundation for further explaining the biosynthesis of celastrol and related triterpenoids. Moreover, our results provide insights for metabolic engineering of friedelane type triterpenes.
The New phytologist
Jiawei Zhou Tianyuan Hu Linhui Gao Ping Su Yifeng Zhang Yu-jun Zhao Shang Chen Lichan Tu Yadi Song Xing Wang Luqi Huang Wei Gao
196811662
Loading of water insoluble celastrol into niosome hydrogels for improved topical permeation and anti psoriasis activity.
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.
Colloids and surfaces. B, Biointerfaces
Shikang Meng Lin Sun Lun Wang Zibei Lin Zeyu Liu Long Xi Zhenping Wang Ying Zheng
71147347
IL1R1 is required for celastrol's leptin sensitization and anti obesity effects
Celastrol, a pentacyclic triterpene, is the most potent antiobesity agent that has been reported thus far1. The mechanism of celastrol's leptin sensitizing and antiobesity effects has not yet been elucidated. In this study, we identified interleukin 1 receptor 1 (IL1R1) as a mediator of celastrol's action by using temporally resolved analysis of the hypothalamic transcriptome in celastrol treated DIO, lean, and db/db mice. We demonstrate that IL1R1 deficient mice are completely resistant to the effects of celastrol in leptin sensitization and treatment of obesity, diabetes, and nonalcoholic steatohepatitis. Thus, we conclude that IL1R1 is a gatekeeper for celastrol's metabolic actions.IL1R1 is a gatekeeper for celastrol's metabolic actions.
Nature Medicine
Xudong Feng Dongxian Guan Thomas Auen Jae Won Choi Mario Andres Salazar Hernandez Jaemin Lee Hyonho Chun Farhana Faruk Esther Kaplun Zachary T Herbert Kyle D Copps Umut Ozcan
3589804
A Mechanistic Overview of Triptolide and Celastrol, Natural Products from Tripterygium wilfordii Hook F
Triptolide and celastrol are predominantly active natural products isolated from the medicinal plant Tripterygium wilfordii Hook F. These compounds exhibit similar pharmacological activities, including anti cancer, anti inflammation, anti obesity, and anti diabetic activities. Triptolide and celastrol also provide neuroprotection and prevent cardiovascular and metabolic diseases. However, toxicity restricts the further development of triptolide and celastrol. In this review, we comprehensively review therapeutic targets and mechanisms of action, and translational study of triptolide and celastrol. We systemically discuss the structure activity relationship of triptolide, celastrol, and their derivatives. Furthermore, we propose the use of structural derivatives, targeted therapy, and combination treatment as possible solutions to reduce toxicity and increase therapeutic window of these potent natural products from T. wilfordii Hook F.
Front. Pharmacol.
Shao-Ru Chen Yan Dai Jing Zhao Ligen Lin Yitao Wang Ying Wang