Celastrol inhibits the proliferation and angiogenesis of high glucose-induced human retinal endothelial cells

Fang, Jian; Chang, Xiaoke

doi:10.1186/s12938-021-00904-5

Cited by 13 publications

(8 citation statements)

References 30 publications

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“…Some studies have found that high glucose promotes endothelial proliferation, invasion and angiogenesis (Li et al, 2016;Fang and Chang, 2021;Wang et al, 2022;Yang et al, 2022). Our investigation focussed on HRMECs cultured under high glucose conditions for over 60 days, while most previous studies exposed cells for a maximum of 2 weeks.…”

Section: Discussionmentioning

confidence: 99%

Long term high glucose exposure induces premature senescence in retinal endothelial cells

et al. 2022

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Purpose: Features of cellular senescence have been described in diabetic retinal vasculature. The aim of this study was to investigate how the high glucose microenvironment impacts on the senescence program of retinal endothelial cells.Methods: Human retinal microvascular endothelial cells were cultured under control and high glucose conditions of 5 mM and 25 mM D-glucose, respectively. Isomeric l-glucose was used as the osmotic control. Cells were counted using CASY technology until they reached their Hayflick limit. Senescence-associated β-Galactosidase was used to identify senescent cells. Endothelial cell functionality was evaluated by the clonogenic, 3D tube formation, and barrier formation assays. Cell metabolism was characterized using the Seahorse Bioanalyzer. Gene expression analysis was performed by bulk RNA sequencing. Retinal tissues from db/db and db/+ mice were evaluated for the presence of senescent cells. Publicly available scRNA-sequencing data for retinas from Akimba and control mice was used for gene set enrichment analysis.Results: Long term exposure to 25 mM D-Glucose accelerated the establishment of cellular senescence in human retinal endothelial cells when compared to 5 mM D-glucose and osmotic controls. This was shown from 4 weeks, by a significant slower growth, higher percentages of cells positive for senescence-associated β-galactosidase, an increase in cell size, and lower expression of pRb and HMGB2. These senescence features were associated with decreased clonogenic capacity, diminished tubulogenicity, and impaired barrier function. Long term high glucose-cultured cells exhibited diminished glycolysis, with lower protein expression of GLUT1, GLUT3, and PFKFB3. Transcriptomic analysis, after 4 weeks of culture, identified downregulation of ALDOC, PFKL, and TPI1, in cells cultured with 25 mM D-glucose when compared to controls. The retina from db/db mice showed a significant increase in acellular capillaries associated with a significant decrease in vascular density in the intermediate and deep retinal plexuses, when compared to db/+ mice. Senescent endothelial cells within the db/db retinal vasculature were identified by senescence-associated β-galactosidase staining. Analysis of single cell transcriptomics data for the Akimba mouse retina highlighted an enrichment of senescence and senescence-associated secretory phenotype gene signatures when compared to control mice.Conclusion: A diabetic-like microenvironment of 25 mM D-glucose was sufficient to accelerate the establishment of cellular senescence in human retinal microvascular endothelial cells.

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Section: Discussionmentioning

confidence: 99%

Long term high glucose exposure induces premature senescence in retinal endothelial cells

et al. 2022

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“…For decades, celastrol has been used in folk medicine and clinical practice to treat cancer, including HCC. Because of its broad beneficial biological effects, such as inflammation suppression, cellular proliferation inhibition ( Fang and Chang, 2021 ; Chen et al, 2022 ), the lipid absorption alleviation ( Zhang et al, 2019 ; Hu et al, 2021 ), celastrol has garnered the research focuses of natural medicinal agents. Studies unveiling the mechanism of the hepato-protective effect of celastrol have demonstrated that its functions are mainly regulated via caspase-dependent apoptosis ( Shen et al, 2021 ) and mTOR/AKT-associated proliferation ( Li et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Celastrol-regulated gut microbiota and bile acid metabolism alleviate hepatocellular carcinoma proliferation by regulating the interaction between FXR and RXRα in vivo and in vitro

Zeng

Zhang²,

Luo³

2023

Front. Pharmacol.

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Celastrol, a triterpene derived from Thunder God Vine (Tripterygium wilfordii Hook f; Celastraceae), a traditional Chinese herb, has promising anticancer activity. The present study aimed to elucidate an indirect mechanism of celastrol-mediated alleviation of hepatocellular carcinoma (HCC) via gut microbiota-regulated bile acid metabolism and downstream signaling. Here, we constructed a rat model of orthotopic HCC and performed 16S rDNA sequencing and UPLC-MS analysis. The results showed that celastrol could regulate gut bacteria; suppress the abundance of Bacteroides fragilis; raise the levels of glycoursodeoxycholic acid (GUDCA), a bile acid; and alleviate HCC. We found that GUDCA suppressed cellular proliferation and induced the arrest of mTOR/S6K1 pathway-associated cell cycle G0/G1 phase in HepG2 cells. Further analyses using molecular simulations, Co-IP, and immunofluorescence assays revealed that GUDCA binds to farnesoid X receptor (FXR) and regulates the interaction of FXR with retinoid X receptor a (RXRα). Transfection experiments using the FXR mutant confirmed that FXR is essential for GUCDA-mediated suppression of HCC cellular proliferation. Finally, animal experiments showed that the treatment with the combination of celastrol/GUDCA alleviated the adverse effects of celastrol alone treatment on body weight loss and improved survival in rats with HCC. In conclusion, the findings of this study suggest that celastrol exerts an alleviating effect on HCC, in part via regulation of the B. fragilis-GUDCA-FXR/RXRα-mTOR axis.

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“…For the VEGF signaling pathway, one study's results suggested that the inhibition of the VEGF signaling pathway could protect diabetic retina, and this protective effect might be related to anti-inflammatory and antioxidative activities [ 57 ]. In vivo studies indicated that downregulation of the VEGF and HIF1 signaling pathway could inhibit the proliferation and angiogenesis of high-glucose-induced human retinal endothelial cells [ 58 – 60 ]. Additionally, lots of studies and experiments results have confirmed that downregulation of the VEGF and HIF1 signaling pathway could also prevent hypoxia-induced retinal angiogenesis [ 61 – 63 ].…”

Section: Discussionmentioning

confidence: 99%

Investigating the Mechanisms of Pollen Typhae in the Treatment of Diabetic Retinopathy Based on Network Pharmacology and Molecular Docking

Zhou

Jin

Zhang

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Objective. To explore the main bioactive compounds and investigate the underlying mechanism of Pollen Typhae (PT) against diabetic retinopathy (DR) by network pharmacology and molecular docking analysis. Methods. Bioactive ingredients and the target proteins of PT were obtained from TCMSP, and the related target genes were acquired from the SwissTargetPrediction database. The target genes of DR were obtained from GeneCards, TTD database, DisGeNET database, and DrugBank. The compound-target interaction network was established based on Cytoscape 3.7.2. The protein-protein interaction (PPI) network was constructed via STRING database and Cytoscape 3.7.2. Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were visualized through DAVID database and Bioinformatics. Ingredient-gene-pathway network analysis was conducted to further screen the ingredients, target proteins, and pathways closely related to the biological mechanism on PT for DR, and molecular docking analysis was performed by SYBYL-X 2.1.1 software. Finally, the mechanism and underlying targets of PT in the treatment of DR were predicted. Results. A total of 8 compounds and 171 intersection targets were obtained based on the online network database. 7 main compounds were screened from compound-target network, and 53 targets including the top six key targets (PTGS2, AKT1, VEGFA, MAPK3, TNF, and EGFR) were further acquired from PPI analysis. The 53 key targets covered 80 signaling pathways, among which PI3K-Akt signaling pathway, focal adhesion, Rap1 signaling pathway, VEGF signaling pathway, and HIF-1 signaling pathway were closely connected with the biological mechanism involved in the alleviation of DR by PT. Ingredient-gene-pathway network shows that AKTI, EGFR, and VEGFA were core genes, kaempferol and isorhamnetin were pivotal ingredients, and VEGF signaling pathway and Rap1 signaling pathway were closely involved in anti-DR. The docking results indicated that five main compounds (arachidonic acid, isorhamnetin, quercetin, kaempferol, and (2R)-5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one) had good binding activity with EGFR and AKT1 targets. Conclusion. The active ingredients in PT may regulate the levels of inflammatory factors, suppress the oxidative stress, and inhibit the proliferation, migration, and invasion of retinal pericytes by acting on PTGS2, AKT1, VEGFA, MAPK3, TNF, and EGFR targets through VEGF signaling pathway, PI3K-Akt signaling pathway, Rap1 signaling pathway, and HIF-1 signaling pathway to play a therapeutic role in diabetic retinopathy.

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Celastrol inhibits the proliferation and angiogenesis of high glucose-induced human retinal endothelial cells

Cited by 13 publications

References 30 publications

Long term high glucose exposure induces premature senescence in retinal endothelial cells

Long term high glucose exposure induces premature senescence in retinal endothelial cells

Celastrol-regulated gut microbiota and bile acid metabolism alleviate hepatocellular carcinoma proliferation by regulating the interaction between FXR and RXRα in vivo and in vitro

Investigating the Mechanisms of Pollen Typhae in the Treatment of Diabetic Retinopathy Based on Network Pharmacology and Molecular Docking

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