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Three new C-27-carboxylated-lupane-triterpenoid derivatives from Potentilla discolor Bunge and their in vitro antitumor activities.

ABSTRACT: Three new lupane-triterpenoids (1-3) along with six known compounds (4-9) were isolated from the ethanolic extract of whole plant of Potentilla discolor Bunge. The structures of Compounds 1-3 were established by extensive 1D and 2D NMR together with other spectrum analysis, indicating that their C-27 positions were highly oxygenated, which were rarely found in nature. Their in vitro anti-proliferative activities against HepG-2, MCF-7 and T-84 cell lines were evaluated by Cell Counting Kit-8 (CCK-8) assay, and the results showed different activities for three cell lines with IC50 values ranging from 17.84 to 40.64 μM. In addition, the results from Hoechst 33258 and AO/EB staining as well as annexinV-FITC assays exhibited Compound 1 caused a markedly increased HepG-2 cellular apoptosis in a dose-dependent manner. The further mechanisms of Compound 1-induced cellular apoptosis were confirmed that 1 induced the production of ROS and the alteration of pro- and anti-apoptotic proteins, which led to the dysfunction of mitochondria and activation of caspase-9 and caspase-3 and finally caused cellular apoptosis. These results would be useful in search for new potential antitumor agents and for developing semisynthetic lupane-triterpenoid derivatives with high antitumor activity.

SUBMITTER: Zhang J

PROVIDER: S-EPMC5384777 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Three new C-27-carboxylated-lupane-triterpenoid derivatives from Potentilla discolor Bunge and their in vitro antitumor activities.

Zhang Jing J Liu Chao C Huang Ri-Zhen RZ Chen Hui-Feng HF Liao Zhi-Xin ZX Sun Jin-Yue JY Xia Xue-Kui XK Wang Feng-Xiang FX

PloS one 20170407 4

Three new lupane-triterpenoids (1-3) along with six known compounds (4-9) were isolated from the ethanolic extract of whole plant of Potentilla discolor Bunge. The structures of Compounds 1-3 were established by extensive 1D and 2D NMR together with other spectrum analysis, indicating that their C-27 positions were highly oxygenated, which were rarely found in nature. Their in vitro anti-proliferative activities against HepG-2, MCF-7 and T-84 cell lines were evaluated by Cell Counting Kit-8 (CCK ...[more]

PMID: 28388692

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Project description:Background/aim: Potentilla discolor Bunge (PDB) is an ancient herb of traditional Chinese medicine. Studies have suggested that extracts of PDB may ameliorate diabetes mellitus (DM). This study aimed to systematically assess the efficacy of PDB extracts on glycolipid metabolism and oxidative stress in animal models of diabetes and to provide evidence-based references for the use of PDB extracts. Methods: This study followed the PRISMA 2020 guidelines. Studies were searched from eight databases until January 2023. Statistical analysis was performed using StataSE 15.0 and RevMan 5.3. The standard mean difference (SMD) and 95% confidence intervals (CI) were computed using the random-effects model. SYRCLE's risk of bias tool was used to assess the risk of bias. Results: In total, 32 studies with 574 animals were included. The findings demonstrated that PDB extracts considerably lowered fasting blood glucose (SMD: -3.56, 95%CI: -4.40 to -2.72, p < 0.00001); insulin resistance (SMD: -3.19, 95% CI: -5.46 to -0.92, p = 0.006), total cholesterol (SMD: -2.18, 95%CI: -2.89 to -1.46, p < 0.00001), triglyceride (SMD: -1.48, 95% CI: -2.01 to -0.96, p < 0.00001), low-density lipoprotein cholesterol (SMD: -1.80, 95% CI: -2.58 to -1.02], p < 0.00001), malondialdehyde (SMD: -3.46, 95% CI: -4.64 to -2.29, p < 0.00001) and free fatty acid levels (SMD: -3.25, 95%CI: -5.33 to -1.16, p = 0.002), meanwhile, increased insulin sensitivity index (SMD: 2.51 95% CI: 1.10 to 3.92, p = 0.0005), body weight (SMD:1.20, 95% CI: 0.38 to 2.01, p = 0.004), and the levels of high-density lipoprotein cholesterol (SMD: 1.04, 95% CI: 0.40 to 1.69, p = 0.001), superoxide dismutase (SMD:2.63, 95% CI: 1.53 to 3.73, p < 0.00001), glutathione peroxidase (SMD:1.13, 95%CI: 0.42 to1.83, p = 0.002), and catalase (SMD:0.75, 95% CI: 0.11 to 1.40], p = 0.02). Conclusion: These findings suggest that PDB extracts can ameliorate DM by improving glycolipid metabolism and oxidative stress. PDB may be a promising medication for DM; however, due to significant heterogeneity between studies, these findings should be interpreted with caution. In addition, future well-designed trials should determine which components of the PDB play a major role in ameliorating DM and whether these benefits persist in humans. Systematic Review Registration: https://www.crd.york.ac.uk/prospero, CRD42023379391.

Project description:PurposeType 2 diabetes mellitus (T2DM) is associated with reduced insulin uptake and glucose metabolic capacity. Potentilla discolor Bunge (PDB) has been used to treat T2DM; however, the fundamental biological mechanisms remain unclear. This study aimed to understand the active ingredients, potential targets, and underlying mechanisms through which PDB treats T2DM.MethodsComponents and action targets were predicted using network pharmacology and molecular docking analyses. PDB extracts were prepared and validated through pharmacological intervention in a Cg>InRK1409A diabetes Drosophila model. Network pharmacology and molecular docking analyses were used to identify the key components and core targets of PDB in the treatment of T2DM, which were subsequently verified in animal experiments.ResultsNetwork pharmacology analysis revealed five effective compounds made up of 107 T2DM-related therapeutic targets and seven protein-protein interaction network core molecules. Molecular docking results showed that quercetin has a strong preference for interleukin-1 beta (IL1B), IL6, RAC-alpha serine/threonine-protein kinase 1 (AKT1), and cellular tumor antigen p53; kaempferol exhibited superior binding to tumor necrosis factor and AKT1; β-sitosterol demonstrated pronounced binding to Caspase-3 (CASP3). High-performance liquid chromatography data quantified quercetin, kaempferol, and β-sitosterol at proportions of 0.030%, 0.025%, and 0.076%, respectively. The animal experiments revealed that PDB had no effect on the development, viability, or fertility of Drosophila and it ameliorated glycolipid metabolism disorders in the diabetes Cg>InRK1409A fly. Furthermore, PDB improved the body size and weight of Drosophila, suggesting its potential to alleviate insulin resistance. Moreover, PDB improved Akt phosphorylation and suppressed CASP3 activity to improve insulin resistance in Drosophila with T2DM.ConclusionOur findings suggest that PDB ameliorates diabetes metabolism disorders in the fly model by enhancing Akt activity and suppressing CASP3 expression. This will facilitate the development of key drug targets and a potential therapeutic strategy for the clinical treatment of T2DM and related metabolic diseases.

Project description:Melanoma is the most aggressive and lethal type of skin cancer, responsible for approximately 60,000 deaths annually. The main strategy for treating melanoma is surgery to completely remove the lesion and its margins. However, for more advanced cases with a high recurrence rate, the preferred approach is to combine chemotherapy with immunotherapy treatments. Tumor-associated macrophages (TAMs) are the most abundant leukocytes in solid tumors. Current immunotherapy approaches target TAMs by inhibiting pro-tumoral TAMs and activating anti-tumoral TAMs, repolarizing them to the M1 phenotype. The antitumor and immunomodulatory activities of molecules derived from 1,2,4-oxadiazole, as demonstrated in the literature, highlight the potential of this class as a source of promising candidates for therapeutic applications. Thus, the present study aims to evaluate the antitumor and immunomodulatory effects of the synthetic derivative 1,2,4-oxadiazole, N-cyclohexyl-3-(3-methylphenyl)-1,2,4-oxadiazole-5-amine (1,2,4-oxadiazole derivative 2), in melanoma cells and murine Bone Marrow-Derived Macrophages (BMDMs). Cytotoxicity in B16-F10 and BMDMs cells was assessed using the (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) MTT method. 1,2,4-oxadiazole derivative 2 exhibited antiproliferative effects on both cell lines, being 2.6 times more selective for B16-F10. Necrosis was identified as the active induced death pathway. BMDMs isolated and exposed to 1,2,4-oxadiazole derivative 2 polarize to the M1 phenotype and induce TNF-α at a concentration of 64.34 μM. Exposure to melanoma murine supernatants also promotes M1 polarization. Supernatants containing traces of 1,2,4-oxadiazole derivative 2 (Supernatants B, C, and D) increased the percentage of M1 cells compared to Supernatant A, as well as elevated levels of nitrite, TNF-α, and IL-12. 1,2,4-oxadiazole derivative 2 combined with Supernatant A and 1,2,4-oxadiazole derivative 2 combined with LPS also resulted in higher M1 polarization, suggesting a synergistic effect on M1 polarization and TNF-α production. Our findings underscore the significance of the 1,2,4-oxadiazole compound class and highlight the potential of 1,2,4-oxadiazole derivative 2 as an antitumoral and immunotherapeutic agent.

Dataset Information

Three new C-27-carboxylated-lupane-triterpenoid derivatives from Potentilla discolor Bunge and their in vitro antitumor activities.

Publications

Three new C-27-carboxylated-lupane-triterpenoid derivatives from Potentilla discolor Bunge and their in vitro antitumor activities.

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