Dihydromyricetin Activates AMP-Activated Protein Kinase and P38MAPK Exerting Antitumor Potential in Osteosarcoma

Zhao, Zhiqiang; Yin, Jun; Wu, Man; Song, Guohui; Xie, Xueyi; Zou, Changye; Tang, Qinglian; Wu, Yuanzhong; Lu, Jinchang; Wang, Yongqian; Wang, Jin; Kang, Tiebang; Jia, Qiang; Shen, Jingnan

doi:10.1158/1940-6207.capr-14-0067

Cited by 47 publications

(49 citation statements)

References 42 publications

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“…Owing to their safety, long-term use, and their ability to target multiple pathways, there is a renewed interest in understanding the molecular mechanisms underlying their activity. Our previous studies have also provided evidence of some natural agents having potential anti-osteosarcoma activity, such as dihydromyricetin, cinobufagin, and bufalin (19,39,40). However, there is no evidence at the cellular level or in animal models for such an effect of DGT on osteosarcoma progression.…”

Section: Discussionmentioning

confidence: 99%

“…They were treated with different concentrations of DGT for the indicated times, and the cell viability was measured by MTT assay as described previously (19).…”

Section: Cell Viability Assaymentioning

confidence: 99%

“…Then, the standard procedures as previously described were performed for Hoechst 33258 staining and caspase-3 activity assay (19).…”

Section: Cell-cycle and Apoptosis Assaysmentioning

confidence: 99%

“…Western blotting was carried out as described earlier (19). Briefly, the cells were lysed in RIPA buffer containing protease inhibitor and phosphatase inhibitor cocktails (Thermo Fisher Scientific).…”

Section: Western Blottingmentioning

confidence: 99%

“…RNA was reverse transcribed to produce cDNA and real-time PCR amplification was performed as described previously (19). The primer sequences we used are shown in Supplementary Table S1.…”

Section: Cell Transfectionmentioning

confidence: 99%

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Degalactotigonin, a Natural Compound from Solanum nigrum L., Inhibits Growth and Metastasis of Osteosarcoma through GSK3β Inactivation–Mediated Repression of the Hedgehog/Gli1 Pathway

Zhao

Jia

et al. 2018

Clinical Cancer Research

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Purpose: Agents extracted from natural sources with antitumor property have attracted considerable attention from researchers and clinicians because of their safety, efficacy, and immediate availability. Degalactotigonin (DGT), extracted from Solanum nigrum L., has anticancer properties without serious side effects. Here, we explored whether DGT can inhibit the growth and metastasis of osteosarcoma.Experimental Design: MTT, colony formation, and apoptosis assays were performed to analyze the effects of DGT on osteosarcoma cell viability in vitro. The migration and invasion abilities were measured using a Transwell assay. Animal models were used to assess the roles of DGT in both tumor growth and metastasis of osteosarcoma. Gli1 expression and function were measured in osteosarcoma cells and clinical samples. After DGT treatment, Gli1 activation and the phosphorylation status of multiple cellular kinases were measured with a luciferase reporter and phospho-kinase antibody array.Results: DGT inhibited proliferation, induced apoptosis, and suppressed migration and invasion in osteosarcoma cells. DGT, injected intraperitoneally after tumor inoculation, significantly decreased the volume of osteosarcoma xenografts and dramatically diminished the occurrence of osteosarcoma xenograft metastasis to the lungs. Mechanistically, DGT inhibited osteosarcoma growth and metastasis through repression of the Hedgehog/Gli1 pathway, which maintains malignant phenotypes and is involved in the prognosis of osteosarcoma patients. DGT decreased the activity of multiple intracellular kinases that affect the survival of osteosarcoma patients, including GSK3b. In addition, DGT represses the Hedgehog/Gli1 pathway mainly through GSK3b inactivation.Conclusions: Our studies provide evidence that DGT can suppress the growth and metastasis of human osteosarcoma through modulation of GSK3b inactivation-mediated repression of the Hedgehog/Gli1 pathway.

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Section: Discussionmentioning

confidence: 99%

“…They were treated with different concentrations of DGT for the indicated times, and the cell viability was measured by MTT assay as described previously (19).…”

Section: Cell Viability Assaymentioning

confidence: 99%

“…Then, the standard procedures as previously described were performed for Hoechst 33258 staining and caspase-3 activity assay (19).…”

Section: Cell-cycle and Apoptosis Assaysmentioning

confidence: 99%

Section: Western Blottingmentioning

confidence: 99%

“…RNA was reverse transcribed to produce cDNA and real-time PCR amplification was performed as described previously (19). The primer sequences we used are shown in Supplementary Table S1.…”

Section: Cell Transfectionmentioning

confidence: 99%

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Degalactotigonin, a Natural Compound from Solanum nigrum L., Inhibits Growth and Metastasis of Osteosarcoma through GSK3β Inactivation–Mediated Repression of the Hedgehog/Gli1 Pathway

Zhao

Jia

et al. 2018

Clinical Cancer Research

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Effects of preheating temperatures on β‐lactoglobulin structure and binding interaction with dihydromyricetin

Zhang

Guan

Huang

et al. 2022

eFood

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Low aqueous solubility limits the bioactivity and bioaccessibility of dihydromyricetin (DHM). Preheating treatment affects the loading efficiency of β-lactoglobulin (β-Lg) to polyphenols, but the mechanism remained unclear. In this study, a serial of temperatures (298 K, 318 K, 338 K, 358 K, and 373 K) were set to analyze the preheating effects on the loading efficiency of β-Lg to DHM, and secondary structure change, binding interactions, and particle size distribution were measured and compared with discover the effects. β-Lg preheated at 358 K possessed the highest binding percentage of 0.45, higher than 0.27, 0.30, 0.36, and 0.40 at 298 K, 318 K, 338 K, and 373 K, the exposure of inside hydrophobic residues contribute the hydrophobic interaction with DHM. Fluorescence quenching and molecular docking analysis showed that DHM tend to bind to β-Lg preheated at 358 K with a binding constant of 1.76 × 10 5 L mol −1 and a binding score of −5.84 kcal mol −1 , higher than that of other temperatures. Particle size distribution showed that Z-average size at 358 K was 16.34 nm, significantly higher than others of 7.64, 8.06, 6.84, and 13.4 nm. Preheating unfolded the structure of β-Lg, exposing the internal residues and enhancing the interaction with DHM.

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Construction of microRNA–messenger networks for human osteosarcoma

Zhang

Luo

et al. 2019

Journal Cellular Physiology

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Osteosarcoma is the most common bone tumor in children and young adults. Although the microRNAs (miRNA) expression analyses of osteosarcoma have been performed previously, the construction of miRNA–messenger RNA (mRNA) networks for osteosarcoma is needed. This study aimed to identify osteosarcoma‐related miRNAs through analyzing the microarray datasets and to construct the regulatory network of miRNA–mRNA for human osteosarcoma. The datasets were extracted from the Gene Expression Omnibus and the differentially expressed miRNAs were screened through the limma package in Bioconductor. Genes targeted by the differentially expressed miRNAs were screened out by using the Miranda, MirTarget2, PicTar, PITA, and TargetScan databases. The predicted target genes were further analyzed by Gene Ontology and pathway enrichment analysis and a regulatory network of differentially expressed miRNAs and their target osteosarcoma‐associated genes was constructed. A total of 36 downregulated miRNAs and 182 upregulated miRNAs were identified in osteosarcoma samples compared with normal samples and 397 target genes for upregulated miRNAs and 222 target genes for downregulated miRNAs were obtained. The enriched pathways for target genes of differentially expressed miRNAs included transcriptional misregulation in cancer, the AMPK signaling pathway, and MAPK signaling pathway. In the regulatory network, has‐miR‐199a‐5p targeted the highest number of genes and nemo‐like kinase (NLK) was targeted by five miRNAs (hsa‐miR‐140‐5p, hsa‐miR‐107, hsa‐miR‐324‐5p, hsa‐miR‐199a‐5p, and hsa‐miR‐28‐5p). The has‐miR‐324‐5p targets NLK, TGFB2, and PPARG. These miRNAs and their target genes may serve as potential therapeutic targets of osteosarcoma.

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Dihydromyricetin Activates AMP-Activated Protein Kinase and P38MAPK Exerting Antitumor Potential in Osteosarcoma

Cited by 47 publications

References 42 publications

Degalactotigonin, a Natural Compound from Solanum nigrum L., Inhibits Growth and Metastasis of Osteosarcoma through GSK3β Inactivation–Mediated Repression of the Hedgehog/Gli1 Pathway

Degalactotigonin, a Natural Compound from Solanum nigrum L., Inhibits Growth and Metastasis of Osteosarcoma through GSK3β Inactivation–Mediated Repression of the Hedgehog/Gli1 Pathway

Effects of preheating temperatures on β‐lactoglobulin structure and binding interaction with dihydromyricetin

Construction of microRNA–messenger networks for human osteosarcoma

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