Hesperidin Reversed Long-Term N-methyl-N-nitro-N-Nitroguanidine Exposure Induced EMT and Cell Proliferation by Activating Autophagy in Gastric Tissues of Rats

Abstract

Gastric cancer is a common malignant tumor worldwide. N-methyl-N-nitro-N-nitroguanidine (MNNG) is one of the most important inducing factors of gastric cancer. Autophagy can affect the occurrence and development of gastric cancer, but the mechanism is not clear. Chemoprevention has been shown to be a rational and very promising approach to the prevention of gastric cancer. Hesperidin is a citrus flavone, an abundant polyphenol in citrus fruits and traditional Chinese medicine. It has an excellent phytochemistry that plays an intervention role in gastric cancer. However, it is unclear whether long-term exposure to MNNG will affect the occurrence of gastric cancer by regulating autophagy and whether hesperidin can play an intervention role in this process. In the present study, we demonstrated that long-term MNNG exposure inhibits autophagy in stomach tissues of rats, promotes the epithelial–mesenchymal transition (EMT) process and cell proliferation and suppresses the activity of the PI3K/AKT pathway. We further found that after rapamycin-activated autophagy, long-term MNNG exposure promoted cell proliferation and EMT were inhibited. In addition, hesperidin promotes autophagy and the activity of the PI3K/AKT pathway, as well as the suppression of proliferation and EMT in the stomach tissues of rats. Our findings indicate that hesperidin reverses MNNG-induced gastric cancer by activating autophagy and the PI3K/AKT pathway, which may provide a new basis for the early prevention and treatment of MNNG-induced gastric cancer.

Recent understanding of the mechanisms of the biological activities of hesperidin and hesperetin and their therapeutic effects on diseases

“… [ 181 ] Gastric cancer Hsd MNNG-induced rats Activate autophagy and the PI3K/AKT pathway. [ 182 ] Esophageal cancer Hst Eca109 cells Human xenograft tumor nude mice Depletion of GSH, accumulation of ROS, increase of cleaved caspase-9 and cleaved caspase-3 [ 183 ] Ehrlich ascites carcinoma Hsd Ehrlich ascites carcinoma (EAC) mice Down-regulate Bcl2 and Stimulate Caspase3 and Bax genes expression [ 184 ] Liver cancer Hsd DEN/CCl4-induced rats Activate Nrf2/ARE/HO-1 and PPARγ pathways. [ 185 ] Gastric cancer Hsd Xenograft tumor nude mice Activate the mitochondrial pathway by increasing the ROS.…”

The effect of phytochemicals in N-methyl-N-nitro-N-nitroguanidine promoting the occurrence and development of gastric cancer

“…MNNG can induce gastric cancer by regulating inflammation, cell damage, cell differentiation mitochondrial dysfunction, glycolysis pathogenesis and oxidative stress processes ( Cai et al, 2018 ; Zhao et al, 2019a ; Cai et al, 2019 ; Cui et al, 2021 ; Wen et al, 2021 ; Gunes-Bayir et al, 2022 ). MNNG promotes the occurrence and development of gastric cancer by regulating processes such as autophagy, EMT, apoptosis, proliferation, angiogenesis, gastric epithelial dysplasia, malignant transformation and change endogenous metabolites ( Zhao et al, 2019b ; Deng et al, 2019 ; Wu and Hui, 2020 ; Liang et al, 2022a ; Cai et al, 2022 ; Chen et al, 2022 ; Peng et al, 2022 ; Yang et al, 2022 ; Xie et al, 2023 ).Therefore, there is an urgent need to find an effective and low side effect intervention or treatment strategy. In recent years, phytochemicals and active ingredients of herbal medicine have showed excellent application prospects in the prevention and treatment of gastric cancer.…”

“…A large number of studies have showed that phytochemicals play a very important intervention effect on gastric cancer ( Mao et al, 2020 ; Liang et al, 2022a ; Zhao et al, 2023 ). The effects of phytochemicals on the treatment and prevention of MNNG exposure related gastric cancer also have been studied.…”

“…N-nitrosamines is one of the main risk factors of gastric cancer, which widely exists in the living environment and various food. N-methyl-N-nitro-N-nitroguanidine (MNNG) is a common N-nitrosamine chemical that is often used to study the role and mechanism of N-nitrosamines in inducing gastric cancer ( Cai et al, 2019 ; Liang et al, 2022a ). Studies have showed that MNNG promotes the occurrence of gastric cancer ( Isyraqiah et al, 2019 ; Lin et al, 2019 ; Gunes-Bayir et al, 2022 ).…”

“…Vegetables, fruits, tea, spices, nuts, soybeans, edible fungi and grains are rich in phytochemicals ( Bastos et al, 2010 ; Mao et al, 2020 ; Liang et al, 2022b ). Supplement of phytochemicals have been proved to be a safe and promising method for the prevention and treatment of cancers such as gastric cancer ( Lu et al, 2016 ; Liang et al, 2022a ). Studies have demonstrated that phytochemicals have excellent efficacy in the prevention and treatment of MNNG related gastric cancer ( Nagata et al, 2002 ; Bastos et al, 2010 ; Mao et al, 2020 ) ( Figure 1 ).…”