Celastrol inhibits glucocorticoid‑induced osteoporosis in rat via the PI3K/AKT and Wnt signaling pathways

Xi, Jian-Cheng; Li, Qinggui; Luo, Xiaobo; Wang, Yipeng; Li, Jinlong; Guo, Lixin; Wu, Guangseng

doi:10.3892/mmr.2018.9436

Cited by 10 publications

(9 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Studies have found that after the AKT1 gene knockout treatment in rats, the rats have restricted bone development. It shows that AKTI may play a role in promoting bone growth in bone development [ 30 ], and at the same time, AKT1, PIK3CA, and PIK3R1 jointly act as members of the PI3K-Akt signaling pathway, and play a regulatory role in the process of bone metabolism through this pathway [ 31 , 32 ]. JAK2 is a member of the JAK/STAT signal pathway, which can cause bone destruction by participating in the inflammatory response [ 33 ].…”

Section: Resultsmentioning

confidence: 99%

Exploring the Effect of Jiawei Buguzhi Pills on TGF-β-Smad Pathway in Postmenopausal Osteoporosis Based on Integrated Pharmacological Strategy

Yuan

Yang

et al. 2021

Evidence-Based Complementary and Alternative Medicine

View full text Add to dashboard Cite

Objective. To explore the effect of Jiawei Buguzhi Pills (JWBGZP) on the TGF-β-Smad pathway in postmenopausal osteoporosis (PMO) based on integrated pharmacological strategy. Method. The ETCM database was used to collect JWBGZP. GeneCards and OMIM databases were utilized to obtain PMO-related genes. Cytoscape was used for network construction and analysis, and DAVID was used for GO and KEGG enrichment analysis of key targets. Animal experiments and cell experiments were conducted to further explore the mechanism. The bone mass density was detected by dual-energy X-ray bone densitometer. The TGF-β1 and Smad4 mRNA in bone tissue were detected by RT-qPCR. The TGF-β1 and Smad4 protein in bone tissue were detected by the western blot. The TGF-β1 and Smad4 protein in osteoblasts were determined by immunohistochemistry. Result. A total of 721 JWBGZP potential targets and 385 PMO-related genes were obtained. The enrichment analysis showed that JWBGZP may regulate the TGF-beta signaling pathway, oxidation-reduction process, aging, response to hypoxia, response to ethanol, negative regulation of cell proliferation, PI3K-Akt, HIF-1, and other signaling pathways. The animal experiments showed that compared with the model group, the femoral bone mineral density and lumbar bone mineral density of the JWBGZP group increased (P < 0.05); the expression levels of TGF-β1 and Smad mRNA and proteins in the JWBGZP group were significantly higher (P < 0.05). The cell experiment results showed a large number of osteoblast stained blue-purple and orange-red calcified nodules. The expression levels of TGF-β1 and Smad proteins in the JWBGZP group were significantly higher than those in the blank control group and the sham operation group, and the protein expression levels in the model group were the lowest (P < 0.05). Conclusion. JWBGZP may be involved in PI3K-Akt, HIF-1, estrogen, prolactin, and other signaling pathways and regulate MAPK1, AKT1, PIK3CA, JAK2, and other gene targets, regulate bone metabolism, and thereby treat PMO.

show abstract

Section: Resultsmentioning

confidence: 99%

Exploring the Effect of Jiawei Buguzhi Pills on TGF-β-Smad Pathway in Postmenopausal Osteoporosis Based on Integrated Pharmacological Strategy

Yuan

Yang

et al. 2021

Evidence-Based Complementary and Alternative Medicine

View full text Add to dashboard Cite

show abstract

“…Among them, the correlation degree of PI3K-Akt signaling pathway was the highest one, which could be considered as a potential target [ 67 – 69 ]. Revealed research indicated that the protein expression of PI3K, p-AKT, and p-GSK-3 could significantly reverse the GIOP in mice [ 70 ]. Moreover, PI3K-Akt pathway could act on specific target genes such as FOXO and GSK-3 β to reduce the oxidative damage of osteoblasts and osteoclasts [ 71 ].…”

Section: Discussionmentioning

confidence: 99%

Elaborate the Mechanism of Ancient Classic Prescriptions (Erzhi Formula) in Reversing GIOP by Network Pharmacology Coupled with Zebrafish Verification

Cai

Wang

Jiang

et al. 2022

Evidence-Based Complementary and Alternative Medicine

View full text Add to dashboard Cite

Osteoporosis is a degenerative disease that endangers human health. At present, chemical drugs used for osteoporosis have serious side effects. Therefore, it is valuable to search herbs with high safety and good curative effect in antiosteoporosis. Erzhi formula (EZF), an ancient classic compound, has been reported to have a beneficial effect in antiosteoporosis, but its mechanism is unclear. In this paper, the active compounds of EZF were found in Systems Pharmacology Database, and gene targets related to osteoporosis were obtained in GeneCards. The GO functional and KEGG pathway enrichment analysis were performed by Metascape. The network of “components-targets-signal pathway” was constructed by Cytoscape. Next, molecular docking between the active components and hub genes related to the PI3K-Akt signaling pathway was conducted by Autodock. In the verification experiment, the zebrafish induced by prednisolone (PNSL) was used to reproduce glucocorticoid-induced osteoporosis (GIOP) model, and then the reversal effects of EZF were systematically evaluated according to the behavior, skull staining area, bone mineralization area (BMA), average optical density (AOD), and cumulative optical density (COD). Finally, it was shown that 24 components in EZF could regulate 39 common gene targets to exert antiosteoporosis effect. Besides, the main regulatory mechanisms of EZF were 4 signaling pathways: PI3K-Akt, JAK-STAT, AGE-RAGE, and cancer pathway. In PI3K-Akt signaling pathway, wedelolactone, dimethyl wedelolactone, specnuezhenide, ursolic acid, acacetin, beta-sitosterol, apigenin, and kaempferol can bind tightly with EGF, IL-2, and IL-4 genes. Compared with the model group, the moving distance, swimming speed, and cumulative swimming time of zebrafish in EZF group were significantly increased ( P < 0.05 ). Meanwhile, the BMA and COD of zebrafish were significantly improved after the intervention of EZF ( P < 0.05 ). In summary, the 24 components of EZF exert their antiosteoporosis effects by regulating 39 related gene targets, among which the PI3K signaling pathway is crucial. EZF can promote bone formation and reversed GIOP through “multicomponent/multitarget/multipathway” and the medium dose of EZF may be the most suitable concentration for the treatment of GIOP in zebrafish model.

show abstract

“…Celastrol, as an effective ingredient of Tripterygium wilfordii (Thunder god vine), has a long history in the treatment of in ammatory and autoimmune disease. Pharmacologically, celastrol exhibits anti-cancer, anti-in ammatory, and antioxidant properties (17)(18)(19). In in ammatory disease, celastrol had been found to ameliorate myelin oligodendrocyte glycoprotein (MOG)-induced EAE development by reducing Th17 responses in both the periphery and central nervous system (CNS) (20).…”

Section: Discussionmentioning

confidence: 99%

Celastrol ameliorates experimental autoimmune neuritis by shifting the polarization of M1/M2 macrophages via the hypoxic response pathway

Qian¹,

Tang²,

Min-hai³

et al. 2020

Preprint

View full text Add to dashboard Cite

BackgroundGBS is an autoimmune disease characterized by inflammatory infiltration and demyelination of peripheral nerves. Macrophage polarization is involved in different stages of GBS. Altering the polarization of macrophages may be an effective therapeutic strategy for GBS. Celastrol was previously shown to contribute to anti-neuroinflammation. However, the mechanism underlying the effect of celastrol in GBS animal model experimental autoimmune neuritis (EAN) is unclear. We hypothesized that celastrol may shift the polarization of macrophages through the NRF /HIF-1αpathway.MethodsClinical scores, weight and histological changes were assessed to investigate the effects of celastrol on EAN. To detect the polarization state of macrophages, flow cytometry and immunofluorescence staining were applied. Inflammation cytokines were evaluated by ELISA. The expression of NRF2 and HIF-1α were detected by western-blot and immunofluorescence staining.ResultsCelastrol treatment significantly ameliorates the severity and neuroinflammation of EAN. The polarization state of macrophages from M1 to M2 was observed upon celastrol application. Consistently, pro-inflammatory cytokines were decreased, whereas anti-inflammatory cytokines were increased upon celastrol treatment. Furthermore, we found that celastrol treatment may increase expression of Nrf2 and decrease the expression of HIF-1α. ConclusionTaken together, these data demonstrate that celastrol may ameliorate the severity and neuroinflammation of EAN via promoting the polarization state of macrophages into M2, likely by modulating the hypoxic response. Celastrol may therefore serve as a novel therapeutic agent for GBS.

show abstract

Celastrol inhibits glucocorticoid‑induced osteoporosis in rat via the PI3K/AKT and Wnt signaling pathways

Cited by 10 publications

References 21 publications

Exploring the Effect of Jiawei Buguzhi Pills on TGF-β-Smad Pathway in Postmenopausal Osteoporosis Based on Integrated Pharmacological Strategy

Exploring the Effect of Jiawei Buguzhi Pills on TGF-β-Smad Pathway in Postmenopausal Osteoporosis Based on Integrated Pharmacological Strategy

Elaborate the Mechanism of Ancient Classic Prescriptions (Erzhi Formula) in Reversing GIOP by Network Pharmacology Coupled with Zebrafish Verification

Celastrol ameliorates experimental autoimmune neuritis by shifting the polarization of M1/M2 macrophages via the hypoxic response pathway

Contact Info

Product

Resources

About