The mechanism of folic acid on N-methyl- N’-nitro-N-nitrosoguanidine-induced chronic atrophic gastritis through the PI3K/Akt pathway.

Mecanismo de acción del acido fólico en la gastritis atrófica crónica inducida por N-Metil-N’-Nitro-N-Nitrosoguanidina mediante la vía PI3K/Akt.

• Yun An Panyu District Traditional Chinese Medicine Hospital, Guangzhou,China. https://orcid.org/0000-0002-9438-2999
• Weigang Chen Panyu District Traditional Chinese Medicine Hospital, Guangzhou, China. https://orcid.org/0009-0007-9814-1037
• Yong Cao Jinan University, Guangzhou, China. https://orcid.org/0009-0004-5217-1298
• Boshen Chen Panyu District Traditional Chinese Medicine Hospital, Guangzhou,China. https://orcid.org/0009-0005-4367-4456
• Qiangbin Li Panyu District Traditional Chinese Medicine Hospital, Guangzhou,China. https://orcid.org/0009-0009-8546-734X
• Xia Zhou Panyu District Traditional Chinese Medicine Hospital, Guangzhou,China. https://orcid.org/0009-0003-3073-3512
• Weihan Huang Panyu District Traditional Chinese Medicine Hospital, Guangzhou,China. https://orcid.org/0009-0006-9402-3052

DOI: https://doi.org/10.54817/IC.v65n1a05

Keywords: folic acid, chronic atrophic gastritis, N-methyl-N’-nitro-N-nitrosoguanidine (MNNG), PI3K/Akt

Abstract

Chronic atrophic gastritis (CAG) is a precancerous atrophic gastritis of the stomach, which generates an urge to develop novel therapeutic schedules. This study aimed to investigate the effect of experimental folic acid administration on N-methyl-N’-nitro-N-nitrosoguanidine (MNNG)-induced CAG through the PI3K/ Akt pathway in rats. The rats were divided into a Model Group, a Folic Acid Group and a Blank Group. Rats in the Model Group were induced by MNNG and given 10 mL/kg/d distilled water by gavage, while rats in the Folic Acid Group were induced by MNNG and given 5 mg/kg/d folic acid suspension by gavage. As a control, rats in the Blank Group were given the same amount of distilled water as MNNG and 10 mL/kg/d distilled water by gavage. The levels of gastrin (GAS) and motilin (MTL) in serum were measured by enzyme-linked immunosorbent assay (ELISA), and the mRNA and protein expressions were detected by quantitative polymerase chain reaction (q-PCR) and Western blot. According to hematoxylin and eosin (H&E) pathological analysis, there were inflammatory factors infiltration and derangement of mucosal epithelial cells in the model group, while the gastric tissue injury in the folic acid group was improved. Folic acid could decrease the content of GAS, increase the content of MTL in the serum of the rats, and regulate the expression of PI3K and AKT signal pathways. Folic acid can have a therapeutic effect on CAG by reducing the concentration of GAS in serum and increasing the concentration of MLT in serum. Our study would lay a theoretical foundation for using folic acid to investigate new therapies for CAG in humans.

References

Lerch JM, Pai RK, Brown I, Gill AJ, Jain D, Kővári B, Kushima R, Sheahan K, Slavik T, Srivastava A, Lauwers GY, Langner C. Interobserver agreement of estimating the extent of intestinal metaplasia in patients with chronic atrophic gastritis. Virchows Arch 2022;480(6):1277-1281. doi: 10.1007/s00428-021-03245-9.

Deng D. Progress in clinical treatment of chronic Atrophic gastritis. Elec J Clin Med Literature 2018;5(85):105-106. doi: 10.3877/j.issn.2095-8242.2018.85.090

Shah SC, Piazuelo MB, Kuipers EJ, Li D. AGA Clinical Practice Update on the Diagnosis and Management of Atrophic Gastritis: Expert Review. Gastroenterology. 2021;161(4):1325-1332.e7. doi: 10.1053/j.gastro.2021.06.078.

Moazzen S, Dolatkhah R, Tabrizi JS, Shaarbafi J, Alizadeh BZ, de Bock GH, Dastgiri S. Folic acid intake and folate status and colorectal cancer risk: A systematic review and meta-analysis. Clin Nutr.2018;37(6 Pt A):1926-1934. doi: 10.1016/j.clnu.2017.10.010.

Lin Y, Chen Z. Reversal effect of folic acid and retinoic acid on gastric precancerous lesions and gastric cancer and its mechanism of anti-cancer. Chinese J Clin Gastroenterol 2001;13(01): 41-43. doi:10.3870/j. issn.1005-541X.2001.01.020. 6.

Ogino S, Liao X, Imamura Y, Yamauchi M, McCleary NJ, Ng K, Niedzwiecki D, Saltz LB, Mayer RJ, Whittom R, Hantel A, Benson AB 3rd, Mowat RB, Spiegelman D, Goldberg RM, Bertagnolli MM, Meyerhardt JA, Fuchs CS; Alliance for Clinical Trials in Oncology. Predictive and prognostic analysis of PIK3CA mutation in stage III colon cancer intergroup trial. J Natl Cancer Inst 2013;105(23):1789- 98. doi: 10.1093/jnci/djt298.

Qu Y, He Y, Ruan H, Qin L, Han Z. Abnormal downregulation of 10-formyltetrahydrofolate dehydrogenase promotes the progression of oral squamous cell carcinoma by activating PI3K/Akt/Rb pathway. Cancer Med 2023;12(5):5781-5797. doi:10.1 002/cam4.5327.

Huang X, He Z, Jiang X, Hou M, Tang Z, Zhen X, Liang Y, Ma J. Folic acid re-presses hypoxia-induced inflammation in THP-1 cells through inhibition of the PI3K/Akt/HIF-1α pathway. PLoS One 2016;11(3):e0151553. doi: 10.1371/journal.pone.0151553.

Lahner E, Zagari RM, Zullo A, Di Sabatino A, Meggio A, Cesaro P, Lenti MV, Annibale B, Corazza GR. Chronic atrophic gastritis: Natural history, diagnosis and therapeutic management. A position paper by the Italian Society of Hospital Gastroenterologists and Digestive Endoscopists [AIGO], the Italian Society of Digestive Endoscopy [SIED], the Italian Society of Gastroenterology [SIGE], and the Italian Society of Internal Medicine [SIMI]. Dig Liver Dis 2019;51(12):1621-1632. doi: 10.1016/j.dld.2019.09.016.

Zeng Q, Ou L, Wang W, Guo DY. Gastrin, cholecystokinin, signaling, and biological activities in cellular processes. Front Endocrinol (Lausanne) 2020;11:112. doi: 10.3389/fendo.2020.00112.

Kitazawa T, Kaiya H. Motilin comparative study: structure, distribution, receptors, and gastrointestinal motility. Front Endocrinol (Lausanne) 2021;12:700884. doi: 10.3389/fendo.2021.700884.

Kong W, Sun K. Roles of gastrointestinal hormone in functional disorder of colon in diabetes. World J Chin Digestion 2006;14(5):519-521. doi: 10.3969/j. issn.1009-3079.2006.05.011.