Gastroprotective Effects of Jujuba (Ziziphus jujuba) Fruit Extract Against the Ethanol-Related Gastric Ulcer in Rats

Abstract

Abstract Objective: Gastric ulcer is a global health problem. Alcohol consumption and nonsteroidal anti-inflammatory drugs may lead to gastric ulcers. Here, we examined the possible gastroprotective effects of Ziziphus jujuba (Zj) fruit extract on a rat model of ethanol-induced gastric ulcer. Material and Methods: Chemical properties of Zj were specified using performance liquid chromatography coupled to mass spectrometry. The animals were administered Zj extract (4-8 ml/kg) before administering absolute ethanol. Oxidative stress and proinflammatory markers, immunoexpression of NF-ĸB and caspase-3 were measured to evaluate Zj’s effects. Results: Zj fruit extract significantly reduced values of cytokines such as TNF-α, IL-1β, and IL-6 and the expressions of NF-ĸB and caspase-3 in the immunohistologic analysis. We found out ulcerative foci in the ulcer group in the histopathological analysis, while we didn’t observe ulcerative foci in the treatment groups. Conclusion: This experimental study showed that Zj fruit ameliorated the ethanol-induced gastric ulcer model in rats.

Keywords

• Ethanol
• gastric ulcer
• proinflammatory cytokines
• caspase-3
• Ziziphus jujuba

Jujuba (Ziziphus jujuba) Meyve Ekstraktının Ratlarda Etanol ile Oluşturulan Mide Ülzerine Karşı Gastroprotektif Etkileri

Abstract

Öz Amaç: Gastrik ülser global bir sağlık sorunudur. Alkol tüketimi ve nonsteroid anti-inflamatuar ilaç kullanımı mide ülserine yol açabilmektedir. Bu çalışmada, Ziziphus jujuba (Zj) meyve ekstraktının ratlarda oluşturdurğumuz etanol kaynaklı mide ülseri modeli üzerindeki olası gastroprotektif etkilerini inceledik. Gereç ve Yöntem: Zj'nin kimyasal özellikleri kütle spektrometresi ile birleştirilmiş performans sıvı kromatografisi kullanılarak belirlendi. Hayvanlara saf etanol verilmeden önce Zj ekstresi (4-8 ml/kg) uygulandı. Zj'nin etkilerini değerlendirmek için oksidatif stres ve proinflamatuar belirteçler, NF-ĸB ve kaspaz-3'ün immünoekspresyonu ölçüldü. Bulgular: Zj meyve ektraktı, immünohistolojik analizde TNF-α, IL-1β ve IL-6 gibi sitokinlerin değerlerini ve NF-ĸB ve kaspaz-3 ekspresyonlarını önemli ölçüde azaltmıştır. Histopatolojik analizde ülser grubunda ülseratif odaklar tespit edilirken, tedavi gruplarında ülseratif odaklar gözlenmedi. Sonuç: Bu deneysel çalışma, Zj meyvesinin sıçanlarda etanol ile indüklenen gastrik ülser modelini iyileştirdiğini göstermiştir.

Keywords

• Etanol
• gastrik ülser
• proinflamatuar sitokinler
• kaspaz-3
• Ziziphus jujuba

References

1. 1. Hosseini E, Poursina F, de Wiele TV, Safaei HG, Adibi P. Helicobacter pylori in Iran: A systematic review on the association of genotypes and gastroduodenal diseases. J Res Med Sci. 2012;17(3):280-92.
2. 2. Almasaudi SB, Abbas AT, Al-Hindi RR, et al. Manuka Honey Exerts Antioxidant and Anti-Inflammatory Activities That Promote Healing of Acetic Acid-Induced Gastric Ulcer in Rats. Evid Based Complement Alternat Med. 2017;2017:5413917.
3. 3. Elshazly SM, Abd El Motteleb DM, Ibrahim I. Hesperidin protects against stress induced gastric ulcer through regulation of peroxisome proliferator activator receptor gamma in diabetic rats. Chemico-biological interactions. 2018;291:153-61.
4. 4. Wasman SQ, Mahmood AA, Salehhuddin H, Zahra AA, Salmah I. Cytoprotective activities of Polygonum minus aqueous leaf extract on ethanol-induced gastric ulcer in rats. J Med Plants Res. 2010;4(24):2658-65.
5. 5. Taha MM, Salga MS, Ali HM, Abdulla MA, Abdelwahab SI, Hadi AH. Gastroprotective activities of Turnera diffusa Willd. ex Schult. revisited: Role of arbutin. J Ethnopharmacol. 2012;141(1):273-81.
6. 6. Riezzo G, Chiloiro M, Montanaro S. Protective effect of amtolmetin guacyl versus placebo diclofenac and misoprostol in healthy volunteers evaluated as gastric electrical activity in alcohol-induced stomach damage. Digestive diseases and sciences. 2001;46(8):1797-804.
7. 7. Wang J, Liu YT, Xiao L, Zhu L, Wang Q, Yan T. Anti-inflammatory effects of apigenin in lipopolysaccharide-induced inflammatory in acute lung injury by suppressing COX-2 and NF-kB pathway. Inflammation. 2014;37(6):2085-90.
8. 8. Lou T, Jiang W, Xu D, Chen T, Fu Y. Inhibitory Effects of Polydatin on Lipopolysaccharide-Stimulated RAW 264.7 Cells. Inflammation. 2015;38(3):1213-20.

9. 9. Chen T, Mou Y, Tan J, et al. The protective effect of CDDO-Me on lipopolysaccharide-induced acute lung injury in mice. International immunopharmacology. 2015;25(1):55-64.
10. 10. Zhao Z, Gong S, Wang S, Ma C. Effect and mechanism of evodiamine against ethanol-induced gastric ulcer in mice by suppressing Rho/NF-small ka, CyrillicB pathway. Int Immunopharmacol. 2015;28(1):588-95.
11. 11. Mei X, Xu D, Xu S, Zheng Y, Xu S. Novel role of Zn(II)-curcumin in enhancing cell proliferation and adjusting proinflammatory cytokine-mediated oxidative damage of ethanol-induced acute gastric ulcers. Chem Biol Interact. 2012;197(1):31-9.
12. 12. Jiang M, Gao PF, Li HQ, Tian PY, Fan XM. Ghrelin inhibition of ethanol-induced gastric epithelial cell apoptosis is mediated by miR-21. International journal of clinical and experimental pathology. 2015;8(5):4662-72.
13. 13. Lakhani SA, Masud A, Kuida K, et al. Caspases 3 and 7: key mediators of mitochondrial events of apoptosis. Science. 2006;311(5762):847-51.
14. 14. Gao QH, Wu CS, Wang M. The jujube (Ziziphus jujuba Mill.) fruit: a review of current knowledge of fruit composition and health benefits. Journal of agricultural and food chemistry. 2013;61(14):3351-63.
15. 15. Al-Reza SM, Rahman A, Lee J, Kang SC. Potential roles of essential oil and organic extracts of Zizyphus jujuba in inhibiting food-borne pathogens. Food Chem. 2010;119(3):981-6.
16. 16. Huang YL, Yen GC, Sheu F, Chau CF. Effects of water-soluble carbohydrate concentrate from Chinese jujube on different intestinal and fecal indices. J Agr Food Chem. 2008;56(5):1734-9.
17. 17. Kaeidi A, Taati M, Hajializadeh Z, Jahandari F, Rashidipour M. Aqueous extract of Zizyphus jujuba fruit attenuates glucose induced neurotoxicity in an in vitro model of diabetic neuropathy. Iranian journal of basic medical sciences. 2015;18(3):301-6.
18. 18. Gupta S, Gupta YK. Combination of Zizyphus jujuba and silymarin showed better neuroprotective effect as compared to single agent in MCAo-induced focal cerebral ischemia in rats. Journal of ethnopharmacology. 2017;197:118-27.
19. 19. Yue Y, Wu S, Li Z, et al. Wild jujube polysaccharides protect against experimental inflammatory bowel disease by enabling enhanced intestinal barrier function. Food & function. 2015;6(8):2568-77.
20. 20. Yue Y, Wu S, Zhang H, et al. Characterization and hepatoprotective effect of polysaccharides from Ziziphus jujuba Mill. var. spinosa (Bunge) Hu ex H. F. Chou sarcocarp. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 2014;74:76-84.
21. 21. Awad DS, Ali RM, Mhaidat NM, Shotar AM. Zizyphus jujuba protects against ibuprofen-induced nephrotoxicity in rats. Pharmaceutical biology. 2014;52(2):182-6.
22. 22. Yu L, Jiang BP, Luo D, et al. Bioactive components in the fruits of Ziziphus jujuba Mill. against the inflammatory irritant action of Euphorbia plants. Phytomedicine : international journal of phytotherapy and phytopharmacology. 2012;19(3-4):239-44.
23. 23. Hamedi S, Arian AA, Farzaei MH. Gastroprotective effect of aqueous stem bark extract of Ziziphus jujuba L. against HCl/Ethanol-induced gastric mucosal injury in rats. J Tradit Chin Med. 2015;35(6):666-70.
24. 24. Ganachari MS, Kumar S. Anti-Ulcer Properties of Ziziphus jujuba Lam Leaves Extract in Rats. Journal of Natural Remedies. 2004;4:103-8.
25. 25. Colak AM, Kupe M, Bozhuyuk MR, Ercisli S, Gundogdu M. Identification of some Fruit Characteristics in Wild Bilberry (Vaccinium myrtillus L.) Accessions from Eastern Anatolia. Gesunde Pflanz. 2018;70(1):31-8.
26. 26. Capanoglu E, de Vos RC, Hall RD, Boyacioglu D, Beekwilder J. Changes in polyphenol content during production of grape juice concentrate. Food Chem. 2013;139(1-4):521-6.
27. 27. Re R, Pellegrini N, Proteggente A, Pannala A, Yang M, Rice-Evans C. Antioxidant activity applying an improved ABTS radical cation decolorization assay. Free Radic Biol Med. 1999;26(9-10):1231-7.
28. 28. Celik SE, Ozyurek M, Guclu K, Apak R. Determination of antioxidants by a novel on-line HPLC-cupric reducing antioxidant capacity (CUPRAC) assay with post-column detection. Anal Chim Acta. 2010;674(1):79-88.
29. 29. Folin OC, V. On tyrosine and tryptophane determinations in proteins. J Biol Chem. 1927;73:627-50.
30. 30. Singleton VL. Citation Classic - Colorimetry of Total Phenolics with Phosphomolybdic-Phosphotungstic Acid Reagents. Cc/Agr Biol Environ. 1985(48):18
31. 31. Aksak Karamese S, Toktay E, Unal D, Selli J, Karamese M, Malkoc I. The protective effects of beta-carotene against ischemia/reperfusion injury in rat ovarian tissue. Acta Histochem. 2015;117(8):790-7.
32. 32. Ikeda M, Ohkawa S, Okusaka T, et al. Japanese phase I study of GC33, a humanized antibody against glypican-3 for advanced hepatocellular carcinoma. Cancer Sci. 2014;105(4):455-62.
33. 33. Cadirci E, Halici Z, Yayla M, et al. Blocking of urotensin receptors as new target for treatment of carrageenan induced inflammation in rats. Peptides. 2016;82:35-43.
34. 34. Xie P-j, You F, Huang L-x, Zhang C-h. Comprehensive assessment of phenolic compounds and antioxidant performance in the developmental process of jujube (Ziziphus jujuba Mill.). Journal of Functional Foods. 2017;36(Supplement C):233-42.
35. 35. Stermer E. Alcohol consumption and the gastrointestinal tract. The Israel Medical Association journal : IMAJ. 2002;4(3):200-2.
36. 36. Amirshahrokhi K, Khalili AR. Gastroprotective effect of 2-mercaptoethane sulfonate against acute gastric mucosal damage induced by ethanol. International immunopharmacology. 2016;34:183-8.
37. 37. Bagchi D, Carryl OR, Tran MX, et al. Stress, diet and alcohol-induced oxidative gastrointestinal mucosal injury in rats and protection by bismuth subsalicylate. J Appl Toxicol. 1998;18(1):3-13.
38. 38. El-Maraghy SA, Rizk SM, Shahin NN. Gastroprotective effect of crocin in ethanol-induced gastric injury in rats. Chem Biol Interact. 2015;229:26-35.
39. 39. Arab HH, Salama SA, Omar HA, Arafa el SA, Maghrabi IA. Diosmin protects against ethanol-induced gastric injury in rats: novel anti-ulcer actions. PLoS One. 2015;10(3):e0122417.
40. 40. Zhang H, Tsao R. Dietary polyphenols, oxidative stress and antioxidant and anti-inflammatory effects. Curr Opin Food Sci. 2016;8:33-42.
41. 41. Ma N, Sun Y, Yi J, Zhou L, Cai S. Chinese sumac (Rhus chinensis Mill.) fruits alleviate indomethacin-induced gastric ulcer in mice by improving oxidative stress, inflammation and apoptosis. J Ethnopharmacol. 2022;284:114752.
42. 42. Li NS, Luo XJ, Dai Z, et al. Beneficial effects of capsiate on ethanol-induced mucosal injury in rats are related to stimulation of calcitonin gene-related Peptide release. Planta Med. 2012;78(1):24-30.
43. 43. Al Batran R, Al-Bayaty F, Abdulla MA, et al. Gastroprotective effects of Corchorus olitorius leaf extract against ethanol-induced gastric mucosal hemorrhagic lesions in rats. J Gastroenterol Hepatol. 2013;28(8):1321-9.
44. 44. Rao Ch V, Vijayakumar M. Protective effect of (+)-catechin against gastric mucosal injury induced by ischaemia-reperfusion in rats. The Journal of pharmacy and pharmacology. 2007;59(8):1103-7.
45. 45. Asokkumar K, Sen S, Umamaheswari M, Sivashanmugam AT, Subhadradevi V. Synergistic effect of the combination of gallic acid and famotidine in protection of rat gastric mucosa. Pharmacological reports : PR. 2014;66(4):594-9.
46. 46. Sen S, Asokkumar K, Umamaheswari M, Sivashanmugam AT, Subhadradevi V. Antiulcerogenic effect of gallic Acid in rats and its effect on oxidant and antioxidant parameters in stomach tissue. Indian journal of pharmaceutical sciences. 2013;75(2):149-55.
47. 47. Siddaraju MN, Dharmesh SM. Inhibition of gastric H+, K+-ATPase and Helicobacter pylori growth by phenolic antioxidants of Zingiber officinale. Molecular nutrition & food research. 2007;51(3):324-32.
48. 48. Siddaraju MN, Dharmesh SM. Inhibition of gastric H(+),K(+)-ATPase and Helicobacter pylori growth by phenolic antioxidants of Curcuma amada. Journal of agricultural and food chemistry. 2007;55(18):7377-86.
49. 49. Chatterjee A, Chatterjee S, Das S, Saha A, Chattopadhyay S, Bandyopadhyay SK. Ellagic acid facilitates indomethacin-induced gastric ulcer healing via COX-2 up-regulation. Acta Biochim Biophys Sin (Shanghai). 2012;44(7):565-76.
50. 50. Li Q, Hu X, Xuan Y, et al. Kaempferol protects ethanol-induced gastric ulcers in mice via pro-inflammatory cytokines and NO. Acta biochimica et biophysica Sinica. 2018;50(3):246-53.
51. 51. Dubey S, Ganeshpurkar A, Shrivastava A, Bansal D, Dubey N. Rutin exerts antiulcer effect by inhibiting the gastric proton pump. Indian journal of pharmacology. 2013;45(4):415-7.
52. 52. Lee JS, Oh TY, Kim YK, et al. Protective effects of green tea polyphenol extracts against ethanol-induced gastric mucosal damages in rats: stress-responsive transcription factors and MAP kinases as potential targets. Mutat Res. 2005;579(1-2):214-24.
53. 53. Li W, Yao H, Niu X, et al. Protective effect of delta-amyrone against ethanol-induced gastric ulcer in mice. Immunobiology. 2015;220(6):798-806.
54. 54. Wang T, Leng YF, Zhang Y, Kang YQ, Xue X, Zhang Y. [Preventive effects of ischemic postconditioning and penehyclidine hydrochloride on gastric against ischemia-reperfusion injury in rats]. Zhonghua Yi Xue Za Zhi. 2011;91(16):1130-5.
55. 55. Zeng M, Su Y, Li K, et al. Gallic Acid Inhibits Bladder Cancer T24 Cell Progression Through Mitochondrial Dysfunction and PI3K/Akt/NF-kappaB Signaling Suppression. Front Pharmacol. 2020;11:1222.
56. 56. Lakshmi SP, Reddy AT, Kodidhela LD, Varadacharyulu NC. The tea catechin epigallocatechin gallate inhibits NF-kappaB-mediated transcriptional activation by covalent modification. Arch Biochem Biophys. 2020;695:108620.
57. 57. Ahad A, Ganai AA, Mujeeb M, Siddiqui WA. Ellagic acid, an NF-kappaB inhibitor, ameliorates renal function in experimental diabetic nephropathy. Chem Biol Interact. 2014;219:64-75.
58. 58. Somade OT, Oyinloye BE, Ajiboye BO, Osukoya OA. Syringic acid demonstrates an anti-inflammatory effect via modulation of the NF-kappaB-iNOS-COX-2 and JAK-STAT signaling pathways in methyl cellosolve-induced hepato-testicular inflammation in rats. Biochem Biophys Rep. 2023;34:101484.
59. 59. Tehami W, Nani A, Khan NA, Hichami A. New Insights Into the Anticancer Effects of p-Coumaric Acid: Focus on Colorectal Cancer. Dose Response. 2023;21(1):15593258221150704.
60. 60. Kim JM, Lee EK, Kim DH, Yu BP, Chung HY. Kaempferol modulates pro-inflammatory NF-kappaB activation by suppressing advanced glycation endproducts-induced NADPH oxidase. Age (Dordr). 2010;32(2):197-208.
61. 61. Chen J, Du CY, Lam KY, et al. The standardized extract of Ziziphus jujuba fruit (jujube) regulates pro-inflammatory cytokine expression in cultured murine macrophages: suppression of lipopolysaccharide-stimulated NF-kappaB activity. Phytotherapy research : PTR. 2014;28(10):1527-32.
62. 62. Brunelle JK, Letai A. Control of mitochondrial apoptosis by the Bcl-2 family. J Cell Sci. 2009;122(Pt 4):437-41.
63. 63. Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G. Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol. 2010;11(10):700-14.
64. 64. D'Amelio M, Cavallucci V, Cecconi F. Neuronal caspase-3 signaling: not only cell death. Cell Death Differ. 2010;17(7):1104-14.
65. 65. Wakeyama H, Akiyama T, Kadono Y, et al. Posttranslational regulation of Bim by caspase-3. Ann N Y Acad Sci. 2007;1116:271-80.
66. 66. McIlwain DR, Berger T, Mak TW. Caspase functions in cell death and disease. Cold Spring Harb Perspect Biol. 2013;5(4):a008656.