Berberine protects against esophageal mucosal damage in reflux esophagitis by suppressing proinflammatory cytokines

Choo,Byung  Kil; Roh,Seong‑Soo

doi:10.3892/etm.2013.1202

Berberine protects against esophageal mucosal damage in reflux esophagitis by suppressing proinflammatory cytokines

Authors:
- Byung Kil Choo
- Seong‑Soo Roh
View Affiliations

Affiliations: Department of Crop Agriculture and Life Science, Chonbuk National University, Jeonju 561‑756, Republic of Korea, Department of Herbology, College of Korean Medicine, Daegu Haany University, Gyeongsan 712‑715, Republic of Korea
Published online on: July 4, 2013 https://doi.org/10.3892/etm.2013.1202
Pages: 663-670

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

This study was performed to investigate the effects of berberine (BB) in a rat model of gastroesophageal reflux disease (GERD), induced by pylorus and forestomach ligation. We evaluated cytotoxicity and proinflammatory biomarkers (nitric oxide, interleukin (IL)‑1β and prostaglandin E2) in RAW 264.7 cells in vitro and anti‑inflammatory effects in vivo. A total of 54 Sprague Dawley rats were divided into six groups: intact control rats; reflux esophagitis (RE) control rats; RE rats treated with 20 mg/kg omeprazole and RE rats treated with BB at doses of 20, 40 and 60 mg/kg, respectively. All rats were fasted. RE was induced by pylorus and forestomach ligation one hour subsequent to the oral treatment. Six hours subsequent to the surgery, the rats were sacrificed, blood was collected from the abdominal vein and the esophagus and stomach were dissected. The gastric volume and the pH of the gastric juice were evaluated, prior to the esophagus being cut longitudinally and an inner mucosal area being imaged, to analyze mucosal damage indices. Proinflammatory biomarkers in the serum, including tumor necrosis factor (TNF)‑α, IL‑1β, IL‑6 and monocyte chemoattractant protein (MCP)‑1 were analyzed using an enzyme-linked immunosorbent assay (ELISA) kit, while the mRNA expression of TNF‑α, IL‑1β, IL‑6 and plasminogen activator inhibitor (PAI)‑1 was analyzed using a quantitative polymerase chain reaction (qPCR). Esophagic tissue damage in the BB groups was dose‑dependently decreased compared with that in the RE control group. This result was consistent with significant reductions in the levels of proinflammatory biomarkers in the serum and in the expression of proinflammatory mRNA, specifically, TNF‑α, IL‑1β, IL‑6 and PAI‑1. The results suggest that the anti‑inflammatory and protective effects of BB may attenuate the severity of RE and prevent esophageal mucosal damage, in addition to validating the use of BB as a pharmacological treatment for esophageal reflux disease.

View Figures

View References

1	Mahattanadul S, Ridtitid W, Nima S, Phdoongsombut N, Ratanasuwon P and Kasiwong S: Effects of Morinda citrifolia aqueous fruit extract and its biomarker scopoletin on reflux esophagitis and gastric ulcer in rats. J Ethnopharmacol. 134:243–250. 2011.
2	Fujiwara Y, Higuchi K, Hamaguchi M, Takashima T, Watanabe T, Tominaga K, Oshitani N, Matsumoto T and Arakawa T: Increased expression of transforming growth factor-alpha and epidermalgrowthfactor receptors in rat chronic reflux esophagitis. J Gastroenterol Hepatol. 19:521–517. 2004. View Article : Google Scholar : PubMed/NCBI
3	Yoshida N: Inflammation and oxidative stress in gastroesophageal reflux disease. J Clin Biochem Nutr. 40:13–23. 2007. View Article : Google Scholar : PubMed/NCBI
4	Labenz J, Blum AL, Bayendörffer E, Meining A, Stolte M and Börsch G: Curing Helicobacter pylori infection in patients with duodenal ulcer disease may provoke reflux esophagitis. Gastroenterology. 112:1442–1447. 1997.
5	Varanasi RV, Fantry GT and Wilson KT: Decreased prevalence of Helicobacter pylori infection in gastroesophageal reflux disease. Helicobacter. 3:188–194. 1998.
6	Haruma K, Hamada H, Mihara M, Kamada T, Yoshihara M, Sumii K, Kajiyama G and Kawanishi M: Negative associated between Helicobacter pylori infection and reflux esophagitis in older patients: case-control study in Japan. Helicobacter. 5:24–29. 2000.
7	Shin JM and Kim N: Pharmacokinetics and pharmacodynamics of the proton pump inhibitors. J Neurogastroenterol Motil. 19:25–35. 2013. View Article : Google Scholar : PubMed/NCBI
8	Carling L, Axelsson CK, Forssell H, Stubberöd A, Kraglund K, Bonnevie O and Ekström P: Lansoprazole and omeprazole in the prevention of relapse of reflux oesophagitis: a long-term comparative study. Aliment Pharmacol Ther. 12:985–990. 1998. View Article : Google Scholar : PubMed/NCBI
9	Youssef SS, Iskandar SB, Scruggs J and Roy TM: Acute pancreatitis associated with omeprazole. Int J Clin Pharmacol Ther. 43:558–561. 2005. View Article : Google Scholar : PubMed/NCBI
10	Katz PO: Optimizing medical therapy for gastroesophageal reflux disease: state of the art. Rev Gastroenterol Disord. 3:59–69. 2003.PubMed/NCBI
11	Lahiri S, Singh P, Singh S, Rasheed N, Palit G and Pant KK: Melatonin protects against experimental reflux esophagitis. J Pineal Res. 46:207–213. 2009. View Article : Google Scholar : PubMed/NCBI
12	Colin-Jones DG: Histamine-2-receptor antagonists in gastro- oesophageal reflux. Gut. 30:1305–1308. 1989. View Article : Google Scholar : PubMed/NCBI
13	Doornebal J, Bijlsma R and Brouwer RM: An unknown but potentially serious side effect of proton pump inhibitors: hypomagnesaemia. Ned Tijdschr Geneeskd. 153:A7112009.(In Dutch).
14	Ku SK, Kim JS, Seo YB, et al: Effect of Curculigo orchioides on reflux esophagitis by suppressing proinflammatory cytokines. Am J Chin Med. 40:1241–1255. 2012.
15	Compare D, Pica L, Rocco A, De Giorgi F, Cuomo R, Sarnelli G, Romano M and Nardone G: Effects of long-term PPI treatment on producing bowel symptoms and SIBO. Eur J Clin Invest. 41:380–386. 2011. View Article : Google Scholar : PubMed/NCBI
16	Allescher HD and Wagner H: STW 5/Iberogast: multi-target-action for treatment of functional dyspepsia and irritable bowel syndrome. Wien Med Wochenschr. 157:301–307. 2007.(In German).
17	Wang XH, Jiang SM and Sun QW: Effects of berberine on human rheumatoid arthritis fibroblast-like synoviocytes. Exp Biol Med (Maywood). 236:859–866. 2011. View Article : Google Scholar : PubMed/NCBI
18	Lou T, Zhang Z, Xi Z, Liu K, Li L, Liu B and Huang F: Berberine inhibits inflammatory response and ameliorates insulin resistance in hepatocytes. Inflammation. 34:659–667. 2011. View Article : Google Scholar : PubMed/NCBI
19	Kuo CL, Chi CW and Liu TY: The anti-inflammatory potential of berberine in vitro and in vivo. Cancer Lett. 203:127–137. 2004. View Article : Google Scholar : PubMed/NCBI
20	Jeong HW, Hsu KC, Lee JW, Ham M, Huh JY, Shin HJ, Kim WS and Kim JB: Berberine suppresses proinflammatory responses through AMPK activation in macrophages. Am J Physiol Endocrinol Metab. 296:E955–E964. 2009. View Article : Google Scholar : PubMed/NCBI
21	Lu DY, Tang CH, Chen YH and Wei IH: Berberine suppresses neuroinflammatory responses through AMP-activated protein kinase activation in BV-2 microglia. J Cell Biochem. 110:697–705. 2010. View Article : Google Scholar : PubMed/NCBI
22	Wang Q, Zhang M, Liang B, Shirwany N, Zhu Y and Zou MH: Activation of AMP-activated protein kinase is required for berberine-induced reduction of atherosclerosis in mice: the role of uncoupling protein 2. PLoS One. 6:e254362011. View Article : Google Scholar : PubMed/NCBI
23	Shang W, Liu J, Yu X and Zhao J: Effects of berberine on serum levels of inflammatory factors and inflammatory signaling pathway in obese mice induced by high fat diet. Zhongguo Zhong Yao Za Zhi. 35:1474–1477. 2010.(In Chinese).
24	Shen YB, Piao XS, Kim SW, Wang L and Liu P: The effects of berberine on the magnitude of the acute inflammatory response induced by Escherichia coli lipopolysaccharide in broiler chickens. Poult Sci. 89:13–19. 2010. View Article : Google Scholar : PubMed/NCBI
25	Singh P, Singh N and Palit G: Analysing the role of COX-2 in acute oesophagitis and in melatonin-exerted protection against experimental reflux oesophagitis in rats. J Pharm Pharmacol. 63:1572–1580. 2011. View Article : Google Scholar : PubMed/NCBI
26	US Environmental Protection Agency. Health Effects Test Guidelines OPPTS 870.100. Washington: US EPA; 2012
27	McAdam E, Haboubi HN, Forrester G, Eltahir Z, Spencer-Harty S, Davies C, Griffiths AP, Baxter JN and Jenkins GJ: Inducible nitric oxide synthase (iNOS) and nitric oxide (NO) are important mediators of reflux-induced cell signalling in esophageal cells. Carcinogenesis. 33:2035–2043. 2012. View Article : Google Scholar : PubMed/NCBI
28	Lee CH, Chen JC, Hsiang CY, Wu SL, Wu HC and Ho TY: Berberine suppresses inflammatory agents-induced interleukin-1beta and tumor necrosis factor-alpha productions via the inhibition of IkappaB degradation in human lung cells. Pharmacol Res. 56:193–201. 2007. View Article : Google Scholar
29	Choi BH, Ahn IS, Kim YH, Park JW, Lee SY, Hyun CK and Do MS: Berberine reduces the expression of adipogenic enzymes and inflammatory molecules of 3T3-L1 adipocyte. Exp Mol Med. 38:599–605. 2006. View Article : Google Scholar : PubMed/NCBI
30	Xiao HB, Sun ZL, Zhang HB and Zhang DS: Berberine inhibits dyslipidemia in C57BL/6 mice with lipopolysaccharide induced inflammation. Pharmacol Rep. 64:889–895. 2012. View Article : Google Scholar : PubMed/NCBI
31	Jia L, Liu J, Song Z, Pan X, Chen L, Cui X and Wang M: Berberine suppresses amyloid-beta-induced inflammatory response in microglia by inhibiting nuclear factor-kappaB and mitogen-activated protein kinase signalling pathways. J Pharm Pharmacol. 64:1510–1521. 2012.
32	Yan F, Wang L, Shi Y, et al: Berberine promotes recovery of colitis and inhibits inflammatory responses in colonic macrophages and epithelial cells in DSS-treated mice. Am J Physiol Gastrointest Liver Physiol. 302:G504–G514. 2012. View Article : Google Scholar : PubMed/NCBI
33	Jeong HW, Hsu KC, Lee JW, Ham M, Huh JY, Shin HJ, Kim WS and Kim JB: Berberine suppresses proinflammatory responses through AMPK activation in macrophages. Am J Physiol Endocrinol Metab. 296:E955–E964. 2009. View Article : Google Scholar : PubMed/NCBI
34	Yoon HD, Jeong EJ, Choi JW, Lee MS, Park MA, Yoon NY, Kim YK, Cho DM, Kim JI and Kim HR: Anti-inflammatory effects of ethanolic extracts from Codium fragile on LPS-stimulated RAW 264.7 macrophages via nuclear factor kappaB inactivation. Fish Aquat Sci. 14:267–274. 2011.
35	Rodríguez-Hernández H, Simental-Mendía LE, Rodríguez-Ramírez G and Reyes-Romero MA: Obesity and inflammation: epidemiology, risk factors, and markers of inflammation. Int J Endocrinol. 2013:6781592013.PubMed/NCBI
36	Rieder F, Biancani P, Harnett K, Yerian L and Falk GW: Inflammatory mediators in gastroesophageal reflux disease: impact on esophageal motility, fibrosis, and carcinogenesis. Am J Physiol Gastrointest Liver Physiol. 298:G571–G581. 2010. View Article : Google Scholar : PubMed/NCBI
37	Gruol DL and Nelson TE: Physiological and pathological roles of interleukin-6 in the central nervous system. Mol Neurobiol. 15:3307–3339. 1997. View Article : Google Scholar
38	Heinrich PC, Castell JV and Andus T: Interleukin-6 and acute phase response. Biochem J. 265:621–636. 1990.PubMed/NCBI
39	Allan EH and Martin TJ: Prostaglandin E2 regulates production of plasminogen activator isoenzymes, urokinase receptor, and plasminogen activator inhibitor-1 in primary cultures of rat calvarial osteoblasts. J Cell Physiol. 165:521–529. 1995. View Article : Google Scholar
40	Ortiz-Muñoz G, Martin-Ventura JL, Hernandez-Vargas P, et al: Suppressors of cytokine signaling modulate JAK/STAT-mediated cell responses during atherosclerosis. Arterioscler Thromb Vasc Biol. 29:525–531. 2009.PubMed/NCBI
41	Wu AC, Morrison NA, Kelly WL and Forwood MR: MCP-1 expression is specifically regulated during activation of skeletal repair and remodeling. Calcif Tissue Int. 92:566–575. 2013. View Article : Google Scholar : PubMed/NCBI
42	Dawson SJ, Wiman B, Hamsten A, Green F, Humphries S and Henney AM: The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene respond differently to interleukin-1 in HepG2 cells. J Biol Chem. 268:10739–10745. 1993.PubMed/NCBI