The Impact of Resveratrol on Oxidative Stress Induced by Methotrexate in Rat Ileum Tissue: Evaluation of Biochemical and Histopathological Features and Analysis of Gene Expression

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Abstract

Objective

The aim of this study was to assess the impact of resveratrol (RST) on oxidative stress induced by methotrexate in rat ileum tissue.

Materials and Methods

Twenty-four rats were divided into 4 groups with 6 in each group. Each rat was orally administered the following every day for 30 days: group 1 (MTXG), methotrexate (MTX; 5 mg/kg); group 2 (RMTXG), MTX (5 mg/kg) plus RST (25 mg/kg/day); group 3 (RSTG), RST alone (25 mg/kg/day), and group 4 (controls), distilled water. After the rats had been sacrified, the ilea were removed for the assessment of malondialdehyde (MDA), total glutathione (tGSH) and glutathione peroxidase (GSH-Px). Gene expression analyses for interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and myeloperoxidase (MPO) were also performed. Hematoxylin and eosin-stained paraffin-embedded sections of the ileum were analyzed under a light microscope and the findings were recorded. Statistical analyses of the data were performed using one-way ANOVA.

Results

The administration of MTX in group 1 yielded a higher level of MDA (8.33 ± 2.5 μmol/g protein, p < 0.001) and lower levels of tGSH (0.97 ± 0.29 nmol/g protein) and GSH-Px (5.22 ± 0.35 U/g protein, p < 0.001) compared to the other groups. MTX also increased IL-1β (40.33 ± 5.43 gene expression levels), TNF-α (6.08 ± 0.59) and MPO gene expression (9 ± 1.41) in group 1 compared to the controls (11.33 ± 2.07, 2.15 ± 0.33 and 3.43 ± 0.48, respectively, p < 0.001). The impact of RST on IL-1β, TNF-α and MPO gene expression induced by MTX was observed as a reversal of these findings (p < 0.05). Severe inflammation, damage to the villus epithelium and crypt necrosis was observed histopathologically in the MTXG group, whereas only mild inflammation was seen in the RMTXG group.

Conclusion

In this study, ileal damage caused by MTX was inhibited by RST.

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Most cited references 22

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To review the concept of proinflammatory cytokines. Review of published literature. Academic (university hospital). Cytokines are regulators of host responses to infection, immune responses, inflammation, and trauma. Some cytokines act to make disease worse (proinflammatory), whereas others serve to reduce inflammation and promote healing (anti-inflammatory). Attention also has focused on blocking cytokines, which are harmful to the host, particularly during overwhelming infection. Interleukin (IL)-1 and tumor necrosis factor (TNF) are proinflammatory cytokines, and when they are administered to humans, they produce fever, inflammation, tissue destruction, and, in some cases, shock and death. Reducing the biological activities of IL-1 and TNF is accomplished by several different, but highly specific, strategies, which involve neutralizing antibodies, soluble receptors, receptor antagonist, and inhibitors of proteases that convert inactive precursors to active, mature molecules. Blocking IL-1 or TNF has been highly successful in patients with rheumatoid arthritis, inflammatory bowel disease, or graft-vs-host disease but distinctly has not been successful in humans with sepsis. Agents such as TNF-neutralizing antibodies, soluble TNF receptors, and IL-1 receptor antagonist have been infused into > 10,000 patients in double-blind, placebo-controlled trials. Although there has been a highly consistent small increase (2 to 3%) in 28-day survival rates with anticytokine therapy, the effect has not been statistically significant. Anticytokine therapy should be able to "rescue" the patient whose condition continues to deteriorate in the face of considerable support efforts. Unfortunately, it remains difficult to identify those patients who would benefit from anticytokine therapy for septic shock.

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Glutathione peroxidase activity in selenium-deficient rat liver.

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Quercetin is equally or more effective than resveratrol in attenuating tumor necrosis factor-{alpha}-mediated inflammation and insulin resistance in primary human adipocytes.

B. K. McIntosh, Chia-Hua Chuang, S A Overman … (2010)

Quercetin and trans-resveratrol (trans-RSV) are plant polyphenols reported to reduce inflammation or insulin resistance associated with obesity. Recently, we showed that grape powder extract, which contains quercetin and trans-RSV, attenuates markers of inflammation in human adipocytes and macrophages and insulin resistance in human adipocytes. However, we do not know how quercetin and trans-RSV individually affected these outcomes. The aim of this study was to examine the extent to which quercetin and trans-RSV prevented inflammation or insulin resistance in primary cultures of human adipocytes treated with tumor necrosis factor-α (TNF-α)-an inflammatory cytokine elevated in the plasma and adipose tissue of obese, diabetic individuals. Cultures of human adipocytes were pretreated with quercetin and trans-RSV followed by treatment with TNF-α. Subsequently, gene and protein markers of inflammation and insulin resistance were measured. Quercetin, and to a lesser extent trans-RSV, attenuated the TNF-α-induced expression of inflammatory genes such as interleukin (IL)-6, IL-1β, IL-8, and monocyte chemoattractant protein-1 (MCP-1) and the secretion of IL-6, IL-8, and MCP-1. Quercetin attenuated TNF-α-mediated phosphorylation of extracellular signal-related kinase and c-Jun-NH₂ terminal kinase, whereas trans-RSV attenuated only c-Jun-NH₂ terminal kinase phosphorylation. Quercetin and trans-RSV attenuated TNF-α-mediated phosphorylation of c-Jun and degradation of inhibitory κB protein. Quercetin, but not trans-RSV, decreased TNF-α-induced nuclear factor-κB transcriptional activity. Quercetin and trans-RSV attenuated the TNF-α-mediated suppression of peroxisome proliferator-activated receptor γ (PPARγ) and PPARγ target genes and of PPARγ protein concentrations and transcriptional activity. Quercetin prevented the TNF-α-mediated serine phosphorylation of insulin receptor substrate-1 and protein tyrosine phosphatase-1B gene expression and the suppression of insulin-stimulated glucose uptake, whereas trans-RSV prevented only the TNF-α-mediated serine phosphorylation of insulin receptor substrate-1. These data suggest that quercetin is equally or more effective than trans-RSV in attenuating TNF-α-mediated inflammation and insulin resistance in primary human adipocytes.

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Author and article information

Journal

Journal ID (nlm-ta): Med Princ Pract

Journal ID (iso-abbrev): Med Princ Pract

Journal ID (publisher-id): MPP

Title: Medical Principles and Practice

Publisher: S. Karger AG (Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch )

ISSN (Print): 1011-7571

ISSN (Electronic): 1423-0151

Publication date (Print): February 2016

Publication date (Electronic): 30 October 2015

Publication date PMC-release: 30 October 2015

Volume: 25

Issue: 2

Pages: 181-186

Affiliations

[1] ^aDepartment of Internal Medicine, Istanbul Medeniyet University, Istanbul, Turkey

[2] ^bDepartment of Pharmacology, Faculty of Medicine, Erzincan University, Istanbul, Turkey

[3] ^cDepartment of Pathology, Mengucek Gazi Training and Research Hospital, Erzincan, Departments of, Istanbul, Turkey

[4] ^dDepartment of Anatomy, Faculty of Medicine, Istanbul Medeniyet University, Istanbul, Turkey

[5] ^eDepartment of Biochemistry, Faculty of Pharmacy, Ataturk University, Erzurum, Istanbul, Turkey

[6] ^fDepartment of Histology and Embryology, Faculty of Medicine, Recep Tayyip Erdogan University, Rize, Istanbul, Turkey

[7] ^gDepartment of Department of Medical Genetics, Goztepe Training and Research Hospital, Istanbul Medeniyet University, Istanbul, Turkey

Author notes

*Dr. Adalet Ozcicek, Department of Internal Medicine, Faculty of Medicine, Erzincan University, Haci Ali Akin Street, TR—24030 Erzincan (Turkey), E-Mail draozcicek@ 123456hotmail.com

Article

Publisher ID: mpp-0025-0181

DOI: 10.1159/000442020

PMC ID: 5588348

PubMed ID: 26517535

SO-VID: bde6f294-b006-4218-b75e-1971c5dfd5ae

License:

This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Distribution permitted for non-commercial purposes only.

History

Date received : 15 April 2015

Date accepted : 29 October 2015

Page count

Figures: 1, Tables: 2, References: 30, Pages: 6

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The Impact of Resveratrol on Oxidative Stress Induced by Methotrexate in Rat Ileum Tissue: Evaluation of Biochemical and Histopathological Features and Analysis of Gene Expression

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Abstract

Objective

Materials and Methods

Results

Conclusion

Related collections

Stress signalling in stem cells

Most cited references 22

Proinflammatory cytokines.

Glutathione peroxidase activity in selenium-deficient rat liver.

Quercetin is equally or more effective than resveratrol in attenuating tumor necrosis factor-{alpha}-mediated inflammation and insulin resistance in primary human adipocytes.

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Cited by 4

Most referenced authors 524