This study investigated the gastrointestinal (GI) protective effect of water and ethanol extracts of Morus alba leaves in rats who received indomethacin. Rats were randomly distributed into nine groups: a control group, an indomethacin group, and seven groups pre-treated orally with either water and ethanol extracts of M. alba leaves (500, 1,000, and 2,000 mg/kg) or omeprazole (100 mg/kg) for 5 days before receiving oral indomethacin (40 mg/kg). After 24-hour treatment, GI lesions, apoptotic proteins, and prostaglandin E2 (PGE2) in gastric and jejunal tissues were evaluated by macro- and microscopic assessments, western blot analysis, and ELISA, respectively. Both extracts prevented ulcerative lesions in rat jejunum, but not in the stomach. Their intestinal protection involved suppressing protein kinase R-like ER kinase/C/EBP homologous protein signaling and the Bcl-2-associated X protein/B-cell leukemia/ lymphoma 2 protein (Bax/Bcl-2) ratio. Both extracts did not affect PGE2 levels in rat GI tissues, which might explain their inability to prevent gastric ulcers.
Boonyong C, Angkhasirisap W, Lertnitikul N, Kengkoom K, Suttisri R, Jianmongkol S. Morus alba leaf extracts prevent indomethacin-induced intestinal ulcers via suppression of endoplasmic reticulum stress. J Appl Pharm Sci. 2024. Online First. http://doi.org/10.7324/JAPS.2025.210080
1. Bielsa-Fernández MV, Tamayo-de la Cuesta JL, Lizárraga-López J, Remes-Troche JM, Carmona-Sánchez R, Aldana-Ledesma JM, et al. The Mexican consensus on the diagnosis, treatment, and prevention of NSAID-induced gastropathy and enteropathy. Rev Gastroenterol Mex. (Engl Ed). 2020;85(2):190–206. doi: https://doi.org/10.1016/j.rgmx.2019.11.003
2. Bjarnason I, Scarpignato C, Holmgren E, Olszewski M, Rainsford KD, Lanas A. Mechanisms of damage to the gastrointestinal tract from nonsteroidal anti-inflammatory drugs. Gastroenterology. 2018;154(3):500–14. doi: https://doi.org/10.1053/j.gastro.2017.10.049
3. Chávez-Piña AE, Abril-Urías RR, Cerecedo D. Mechanisms of damage involved in small intestinal tract caused by nonsteroidal anti-inflammatory drugs. Mex J Med Res ICSA. 2018;6(12):1–5. doi: https://doi.org/10.29057/mjmr.v6i12.3162
4. Liu YH, Zhang ZB, Zheng YF, Chen HM, Yu XT, Chen XY, et al. Gastroprotective effect of andrographolide sodium bisulfite against indomethacin-induced gastric ulceration in rats. Int Immunopharmacol. 2015;26(2):384–91. doi: https://doi.org/10.1016/j.intimp.2015.04.025
5. Boonyong C, Vardhanabhuti N, Jianmongkol S. Modulation of non-steroidal anti-inflammatory drug-induced, ER stress-mediated apoptosis in Caco-2 cells by different polyphenolic antioxidants: a mechanistic study. J Pharm Pharmacol. 2020;72(11):1574–84. doi: https://doi.org/10.1111/jphp.13343
6. Liang HW, Yang TY, Teng CS, Lee YJ, Yu MH, Lee HJ, et al. Mulberry leaves extract ameliorates alcohol-induced liver damages through reduction of acetaldehyde toxicity and inhibition of apoptosis caused by oxidative stress signals. Int J Med Sci. 2021;18(1):53–64. doi: https://doi.org/10.7150/ijms.50174
7. Ranjan B, Pranab L, Pakrasi PL, Kumar RV. Antioxidant and anti-diabetic potential of MR-1 mulberry variety. Int J Pharm Biol Sci. 2018;8(4):904–14.
8. Wang Y, Li M, Yu X, He S, Wu X, Wang Y. Mulberry leaf flavonoids protect against glucotoxicity-induced INS-1 cell apoptosis. J Tradit Chin Med. 2019;39(2):153–9.
9. Suthamwong P, Minami M, Okada T, Shiwaku N, Uesugi M, Yokode M, et al. Administration of mulberry leaves maintains pancreatic β-cell mass in obese/type 2 diabetes mellitus mouse model. BMC Complement. Med Ther 2020;20(1):136. doi: https://doi.org/10.1186/s12906-020-02933-4
10. Chen C, Mohamad Razali UH, Saikim FH, Mahyudin A. Mohd Noor NQI. Morus alba L. plant: bioactive compounds and potential as a functional food ingredient. Foods. 2021;10(3):689. doi: https://doi.org/10.3390/foods10030689
11. Ji S, Zhu C, Gao S, Shao X, Chen X, Zhang H, et al. Morus alba leaves ethanol extract protects pancreatic islet cells against dysfunction and death by inducing autophagy in type 2 diabetes. Phytomedicine. 2021;83:153478. doi: https://doi.org/10.1016/j.phymed.2021.153478
12. Kujawska M, Ewertowska M, Adamska T, Ignatowicz E, Flaczyk E, Przeor M, et al. Protective effect of Morus alba leaf extract on N-nitrosodiethylamine-induced hepatocarcinogenesis in rats. In vivo. 2016;30(6):807–12. doi: https://doi.org/10.21873/invivo.10998
13. Boonyong C, Vardhanabhuti N, Jianmongkol S. Natural polyphenols prevent indomethacin-induced and diclofenac-induced Caco-2 cell death by reducing endoplasmic reticulum stress regardless of their direct reactive oxygen species scavenging capacity. J Pharm Pharmacol. 2020;72(4):583–91. doi: https://doi.org/10.1111/jphp.13227
14. Koudoufio M, Desjardins Y, Feldman F, Spahis S, Delvin E, Levy E. Insight into polyphenol and gut microbiota crosstalk: are their metabolites the key to understand protective effects against metabolic disorders? Antioxidants. 2020;9(10):982. doi: https://doi.org/10.3390/antiox9100982
15. Farzaei MH, Abdollahi M, Rahimi R. Role of dietary polyphenols in the management of peptic ulcer. World J Gastroenterol. 2015;21(21):6499–517. doi: https://doi.org/10.3748/wjg.v21.i21.6499
16. Sembiring EN, Elya B, Sauriasari R. Phytochemical screening, total flavonoid and total phenolic content and antioxidant activity of different parts of Caesalpinia bonduc (L.) Roxb. Pharmacogn J. 2018;10(1):123–7. doi: https://doi.org/10.5530/pj.2018.1.22
17. Carrasco-Pozo C, Castillo RL, Beltrán C, Miranda A, Fuentes J, Gotteland M. Molecular mechanisms of gastrointestinal protection by quercetin against indomethacin-induced damage: role of NF-κB and Nrf2. J Nutr Biochem. 2016;27:289–98. doi: https://doi.org/doi/10.1016/j.jnutbio.2015.09.016
18. Mabeku LBK, Nana BN, Bille BE, Tchuenguem RT. Anti-Helicobacter pylori and antiulcerogenic activity of Aframomum pruinosum seeds on indomethacin-induced gastric ulcer in rats. Pharm Biol. 2017;55(1):929–36. doi: https://doi.org/10.1080/13880209.2017.1285326
19. Sabiu S, Garuba T, Sunmonu T, Ajani E, Sulyman A, Nurain I, et al. Indomethacin-induced gastric ulceration in rats: protective roles of Spondias mombin and Ficus exasperata. Toxicol Rep. 2015;2:261–7. doi: https://doi.org/10.1016/j.toxrep.2015.01.002
20. Boonyong C, Angkhasirisap W, Kengkoom K, Jianmongkol S. Different protective capability of chlorogenic acid and quercetin against indomethacin-induced gastrointestinal ulceration. J Pharm Pharmacol. 2023;75(3):427–36. doi: https://doi.org/10.1093/jpp/rgac098
21. USFDA. Guidance for industry: estimating the maximum safe starting dose in adult healthy volunteer. Rockville, MA: 2005.
22. Chinese Pharmacopoeia Commission. Pharmacopoeia of the People’s Republic of China. Chin Med Sci Technol Press. 2020;1:310–1.
23. AlKreathy HM, Alghamdi MK, Esmat A. Tetramethylpyrazine ameliorates indomethacin-induced gastric ulcer in rats: impact on oxidative, inflammatory, and angiogenic machineries. Saudi Pharm J. 2020;28(8):916–26. doi: https://doi.org/10.1016/j.jsps.2020.06.012
24. Liu R, Zhu N, Hao Y, Liu X, Kang J, Mao R, et al. The protective effect of walnut oligopeptides against indomethacin-induced gastric ulcer in rats. Nutrients. 2023;15(7):1675. doi: https://doi.org/10.3390/nu15071675
25. Pérez Guerrero C, Martín MJ, Marhuenda E. Prevention by rutin of gastric lesions induced by ethanol in rats: role of endogenous prostaglandins. Gen Pharmacol. 1994;25(3):575–80. doi: https://doi.org/10.1016/0306-3623(94)90217-8
26. Motilva V, Alarcón de la Lastra C, Martín MJ. Ulcer-protecting effects of naringenin on gastric lesions induced by ethanol in rat: role of endogenous prostaglandins. J Pharm Pharmacol. 1994;46(2):91–4. doi: https://doi.org/10.1111/j.2042-7158.1994.tb03747.x
27. Di Sotto A, Locatelli M, Macone A, Toniolo C, Cesa S, Carradori S, et al. Hypoglycemic, antiglycation, and cytoprotective properties of a phenol-rich extract from waste peel of Punica granatum L. var. Dente di Cavallo DC2. Molecules. 2019;24(17):3103. doi: https://doi.org/10.3390/molecules24173103
28. Han D, Gu X, Gao J, Wang Z, Liu G, Barkema HW, et al. Chlorogenic acid promotes the Nrf2/HO-1 anti-oxidative pathway by activating p21Waf1/Cip1 to resist dexamethasone-induced apoptosis in osteoblastic cells. Free Radic Biol Med. 2019;137:1–12. doi: https://doi.org/10.1016/j.freeradbiomed.2019.04.014
29. Hua FZ, Ying J, Zhang J, Wang XF, Hu YH, Liang YP, et al. Naringenin pre-treatment inhibits neuroapoptosis and ameliorates cognitive impairment in rats exposed to isoflurane anesthesia by regulating the PI3/Akt/PTEN signalling pathway and suppressing NF-κB-mediated inflammation. Int J Mol Med. 2016;38(4):1271–80. doi: https://doi.org/10.3892/ijmm.2016.2715
30. Li Y, Qin L, Ying L, Dong H, Wang D. Rutin prevents retinal ganglion cell death and exerts protective effects by regulating transforming growth factor-β2/Smad2/3Akt/PTEN signaling in experimental rat glaucoma. Trop J Pharm Res. 2019;18(5):985–93. doi: https://doi.org/10.4314/tjpr.v18i5.11
Year
Month