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Wubeizi Ointment Suppresses Keloid Formation through Modulation of the mTOR Pathway

ABSTRACT: Background Wubeizi (Rhus chinensis Mill.) ointment has been shown as an effective treatment for keloids. However, the protective mechanisms of Wubeizi ointment are not fully understood. The mammalian target of rapamycin (mTOR) has been demonstrated to be associated with keloid pathogenesis. In the present study, we investigated if Wubeizi ointment suppressed keloid formation through the modulation of key molecules of the rapamycin (mTOR) pathway including phosphatase and tensin homolog (PTEN), phosphatidylinositol 3-kinase (PI3K), and protein kinase B (Akt). Methods A keloid mouse model and human keloid-derived fibroblasts were developed and treated with Galla chinensis. Immunohistochemistry, western blot, and reverse transcription-PCR were used to detect PI3K, PTEN, Akt, and mTOR in keloid tissues and keloid fibroblasts. The apoptosis and proliferation rate of keloid fibroblasts was, respectively, analyzed by flow cytometry according to the MTT assay. Statistical analysis was done using SPSS version 20.0. For two variable comparisons, a two independent samples t-test was used. For multiple variable comparisons, data were analyzed by one-way analysis of variance (ANOVA) followed by pairwise q-tests. Results Our in vivo and in vitro studies showed that Wubeizi ointment suppressed keloid formation through inhibition of fibroblast proliferation and promotion of fibroblast apoptosis. The underlying basis involves downregulation of p-Akt and p-mTOR as well as upregulation of PTEN. Conclusion These findings may contribute to a better understanding of the mechanisms of Wubeizi ointment for treating keloids.

SUBMITTER: Tang Z

PROVIDER: S-EPMC7545458 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Project description:BackgroundGlioblastoma (GBM) is the most common brain tumor with the worst prognosis. Temozolomide is the only first-line drug for GBM. Unfortunately, the resistance issue is a classic problem. Therefore, it is essential to develop new drugs to treat GBM. As an oncogene, Skp2 is involved in the pathogenesis of various cancers including GBM. In this study, we investigated the anticancer effect of AAA237 on human glioblastoma cells and its underlying mechanism.MethodsCCK-8 assay was conducted to evaluate IC50 values of AAA237 at 48, and 72 h, respectively. The Cellular Thermal Shift Assay (CETSA) was employed to ascertain the status of Skp2 as an intrinsic target of AAA237 inside the cellular milieu. The EdU-DNA synthesis test, Soft-Agar assay and Matrigel assay were performed to check the suppressive effects of AAA237 on cell growth. To identify the migration and invasion ability of GBM cells, transwell assay was conducted. RT-qPCR and Western Blot were employed to verify the level of BNIP3. The mRFP-GFP-LC3 indicator system was utilized to assess alterations in autophagy flux and investigate the impact of AAA237 on the dynamic fusion process between autophagosomes and lysosomes. To investigate the effect of compound AAA237 on tumor growth in vivo, LN229 cells were injected into the brains of mice in an orthotopic model.ResultsAAA237 could inhibit the growth of GBM cells in vitro. AAA237 could bind to Skp2 and inhibit Skp2 expression and the degradation of p21 and p27. In a dose-dependent manner, AAA237 demonstrated the ability to inhibit colony formation, migration, and invasion of GBM cells. AAA237 treatment could upregulate BNIP3 as the hub gene and therefore induce BNIP3-dependent autophagy through the mTOR pathway whereas 3-MA can somewhat reverse this process. In vivo, the administration of AAA237 effectively suppressed the development of glioma tumors with no side effects.ConclusionCompound AAA237, a novel Skp2 inhibitor, inhibited colony formation, migration and invasion of GBM cells in a dose-dependent manner and time-dependent manner through upregulating BNIP3 as the hub gene and induced BNIP3-dependent autophagy through the mTOR pathway therefore it might be a viable therapeutic drug for the management of GBM.

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Wubeizi Ointment Suppresses Keloid Formation through Modulation of the mTOR Pathway

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