Moghadam Delaram, Zarei Reza, Vakili Sina, Ghojoghi Rozita, Zarezade Vahid, Veisi Ali, Sabaghan Mohamad, Azadbakht Omid, Behrouj Hamid
Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
Infertility Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
Mol Biol Rep. 2023 Jan;50(1):77-84. doi: 10.1007/s11033-022-08031-7. Epub 2022 Oct 28.
There is evidence that low doses or physiological concentrations of certain natural polyphenols enhance the activity of telomerase. However, the precise mechanism by which natural polyphenols regulate telomerase activity remains unclear. Recent research indicates that NF-E2 related factor 2 (Nrf2) and silent information regulator 1 (SIRT1) are involved in human telomerase reverse transcriptase (hTERT) regulation. Thus, in order to better comprehend the mechanism by which polyphenols regulate hTERT, the present study investigated the effects of the natural polyphenols Resveratrol, Gallic acid, and Kuromanin chloride on hTERT, Nrf2, and SIRT1 expression as well as oxidative stress in HepG2 hepatocellular carcinoma.
The trypan blue dye exclusion assay was used to assess cell viability. The level of mRNA for hTERT, Nrf2, and SIRT1 was then determined using real-time PCR. A spectrophotometric analysis was conducted to quantify oxidative stress markers.
The results demonstrated that Resveratrol induces the expression of hTERT and the SIRT1/Nrf2 pathway in a dose-dependent manner. Gallic acid at concentrations of 10 and 20 μM also increased the expression of the hTERT and SIRT1/Nrf2 pathway. Furthermore, dose-dependent overexpression of hTERT and Nrf2 was induced by Kuromanin chloride at 10 and 20 µM. Moreover, we found that Resveratrol and Kuromanin chloride ameliorated oxidative stress, whereas Gallic acid exacerbated it.
This study demonstrates that low doses of polyphenols (Resveratrol, Gallic acid, and Kuromanin chloride) upregulate the expression of the hTERT gene in the HepG2 hepatocellular carcinoma cell line, possibly via induction of the SIRT1/Nrf2 signaling pathway. Therefore, by targeting this pathway or hTERT, the anti-cancer effect of polyphenols can be enhanced.
有证据表明，某些天然多酚的低剂量或生理浓度可增强端粒酶的活性。然而，天然多酚调节端粒酶活性的确切机制仍不清楚。最近的研究表明，核因子E2相关因子2（Nrf2）和沉默信息调节因子1（SIRT1）参与人类端粒酶逆转录酶（hTERT）的调控。因此，为了更好地理解多酚调节hTERT的机制，本研究调查了天然多酚白藜芦醇、没食子酸和氯化天竺葵素对hTERT、Nrf2和SIRT1表达以及HepG2肝癌细胞氧化应激的影响。
采用台盼蓝染料排除法评估细胞活力。然后使用实时PCR测定hTERT、Nrf2和SIRT1的mRNA水平。进行分光光度分析以量化氧化应激标志物。
结果表明，白藜芦醇以剂量依赖性方式诱导hTERT的表达以及SIRT1/Nrf2信号通路。浓度为10和20μM的没食子酸也增加了hTERT的表达以及SIRT1/Nrf2信号通路。此外，10和20μM的氯化天竺葵素诱导了hTERT和Nrf2的剂量依赖性过表达。此外，我们发现白藜芦醇和氯化天竺葵素可改善氧化应激，而没食子酸则加剧了氧化应激。
本研究表明，低剂量的多酚（白藜芦醇、没食子酸和氯化天竺葵素）可上调HepG2肝癌细胞系中hTERT基因的表达，可能是通过诱导SIRT1/Nrf2信号通路。因此，通过靶向该信号通路或hTERT，可以增强多酚的抗癌作用。
