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A. The histo-pathological examination of the duodenum tissue of healthy group (HG), (H&E ×100), B. The histo-pathological examination of the jejunum tissue of healthy group (HG), (H&E ×100).
Source publication
The effect of resveratrol on the damage induced by methotrexate (MTX) in rat duodenum and jejunum tissue was investigated and evaluated in comparison with famotidine. The rats were divided into four groups as healthy group (HG), resveratrol+MTX (RMTX) group, famotidine+MTX (FMTX) group and the control group which received MTX (MTXC). RMTX group was...
Contexts in source publication
Context 1
... tissue: As is seen from Figure 4A, normal mucosa and structures are monitored on the full-thickness histopathological sections of duodenal tissue of the HG rats. Whereas on the superficial histopathological sections of duodenal tissue of the MTXC group; we observed villus epithelial damage in the muco- sa (red arrow), congestion and hemorrhage (yellow arrow) in the lamina propria and mixed inflammatory cells infiltration (blue arrow) con- taining PMNL and eosinophil leukocytes ( Figure 5A). ...
Context 2
... villus superfacial epithelial damage (red arrow), mixed inflammatory cells infiltration and mostly protected crypt structures (blue arrow) are seen in the duodenal tissue of the RMTX group ( Figure 5E). Again, we observed mild villus epithelial damage (red arrow), mixed inflammatory cells infiltration and mostly pro- tected crypt structures (blue arrow) in the FMTX group rats ( Figure 5F) Jejunal tissue: Normal jejunal tissue is seen on Figure 4B in the histopathological sections of HG group rats. Whereaes, villus epithelial (red arrow) and diffuse crypt epithelial damage are seen in the jejunal tissue of the MTXC group (blue arrow, Figure 6A). ...
Citations
... MPO is responsible for tissue damage in IBD and is inhibited effectively by resveratrol and its derivatives (143). Inhibition of IL-1, IL-6, and TNF-a release from macrophages, iNOS expression and subsequent NO production, prostaglandin production, cyclooxygenase (COX) enzyme activity, apoptosis, and MPO activity are the potential mechanisms by which RSV exerts its anti-inflammatory effect (90, 91) (Supplementary Table 1). ...
Inflammatory bowel disease (IBD) is a chronic, relapsing gastrointestinal (GI) disorder characterized by intestinal inflammation. The etiology of IBD is multifactorial and results from a complex interplay between mucosal immunity, environmental factors, and host genetics. Future therapeutics for GI disorders, including IBD, that are driven by oxidative stress require a greater understanding of the cellular and molecular mechanisms mediated by reactive oxygen species (ROS). In the GI tract, oxidative stressors include infections and pro-inflammatory responses, which boost ROS generation by promoting the production of pro-inflammatory cytokines. Nuclear factor kappa B (NF-kB) and nuclear factor erythroid 2-related factor 2 (Nrf2) represent two important signaling pathways in intestinal immune cells that regulate numerous physiological processes, including anti-inflammatory and antioxidant activities. Natural antioxidant compounds exhibit ROS scavenging and increase antioxidant defense capacity to inhibit pro-oxidative enzymes, which may be useful in IBD treatment. In this review, we discuss various polyphenolic substances (such as resveratrol, curcumin, quercetin, green tea flavonoids, caffeic acid phenethyl ester, luteolin, xanthohumol, genistein, alpinetin, proanthocyanidins, anthocyanins, silymarin), phenolic compounds including thymol, alkaloids such as berberine, storage polysaccharides such as tamarind xyloglucan, and other phytochemicals represented by isothiocyanate sulforaphane and food/spices (such as ginger, flaxseed oil), as well as antioxidant hormones like melatonin that target cellular signaling pathways to reduce intestinal inflammation occurring with IBD.
... Many studies have examined the use of RES as a therapeutic agent to treat various pathological and metabolic disorders (15). In previous studies, the protective effects of resveratrol on MTX-induced liver damage (29), intestinal damage (30,31) and ileum damage (32) has been reported. ...
Objective: The study aimed to evaluate the protective effects of resveratrol (RES) against methotrexate (MTX)-induced ovarian damage in female rats and were divided into 7 groups: Material and Methods: Control; MTX (15mg/kg-1st day); MTX (1st and 3rd day); MTX (1st, 3rd and 5th day); MTX (1st day) + RES (20mg/kg); MTX (1st and 3rd day) + RES; MTX (1st, 3rd and 5th day) + RES. Since there was only one animal left in groups 4 and 6 and no animals in group 7, these groups were excluded from the evaluation. Ovarian damage was evaluated by performing hematoxylin-eosin (H-E) and TUNEL staining on ovarian tissues of rats. TAS and TOS activities in ovarian tissues were evaluated spectrophotometrically. In addition, DNA damage in blood was evaluated by comet assay. Results: As a result of biochemical analyzes, TOS levels increased in MTX groups, group 2 and 3, compared to the control group, while TOS level decreased significantly in group 5. On the other hand, TAS level increased significantly in group 5 compared to groups 2 and 3. H-E staining results showed that MTX-induced damage improved with RES (group 5) treatment. Maximum positive staining in TUNEL image; observed in equal amounts in groups 2 and 3, then in group 5. In addition, the comet score, which indicates DNA damage, increased significantly in groups 2 and 3, while it decreased significantly in group 5. Conclusion: In line with the results of this study, it was observed that resveratrol may provide protective effects against methotrexate-induced ovarian damage due to its antioxidant properties.
... Methotrexate (MTX) is a chemotherapeutic folic acid antagonist that is used in the treatment of diseases 1-3 -particularly inflammatory and autoimmune diseases 2-4 -but, at high doses, it has serious toxic effects on organs and tissues. Increased levels of reactive oxygen species, oxidative stress, and inflammatory processes have emerged as key players in the pathogenesis of MTX-induced damage to organs and tissues, [5][6][7] including ovarian functional and structural disorders and, at high doses, infertility. [8][9][10] It has been reported that MTX reduces levels of the antioxidant glutathione (GSH) and increases myeloperoxidase (MPO) and malondialdehyde (MDA), 11 the latter of which is an important marker of lipid peroxidation and an indicator of oxidative tissue damage. ...
Methotrexate (MTX) has toxic effects on the uterus and ovaries via oxidative stress. Coenzyme Q10 (CoQ10) is an important component in electron transport in the mitochondria and an antioxidant in cellular metabolism through the inhibition of lipid peroxidation. The aim of this study was to investigate the preventive effects of CoQ10 on MTX-induced utero-ovarian damage and oxidative stress in rats.
In this experimental study, 30 albino Wistar female rats were divided randomly into three groups. Once a day for a month, 10 mg/kg of CoQ10 was orally administered to the rats in the MTX+CoQ10 group, while the same volume of olive oil was administered orally to the other two groups. One hour thereafter, 20 mg/kg of MTX was injected intraperitoneally into the rats in the MTX and MTX+CoQ10 groups; the remaining group was the control. At the end of the month, biochemical and histopathologic examinations were performed on the extracted uteri and ovaries. In the uterine ovarian tissues of the animals in the MTX group, there was an increase in oxidative stress mediators and a decrease in antioxidant and anti-inflammatory mediators, but these trends were reversed in the MTX+CoQ10 group, demonstrating the antioxidant effects of CoQ10. MTX leads to oxidative stress-related ovarian and uterine injury, and CoQ10 may be useful for protecting ovarian and uterine tissue from such injury.
... Mouse model (high fat diet) Cranberry extract ↓ COX-2 and TNF-α expression, LPS level; ↔ MDA and SOD levels [80] Mouse model (DSS-induced colitis) RES ↓ iNOS, COX-2 and TNF-α levels [81] Mouse Rat model (TNBS-induced colitis) RES ↓ MPO activity, IL-1β, PGE2 and PGD2 levels [93] Rat model (TNBS-induced colitis) RES ↓ MPO activity, TNF-α level, COX-1, COX-2 and NF-κB p65 expression; ↑ PGE2 level; ↔ PGD2 level [94] Rat model (TNBS-induced colitis) RES ↓ MDA level; ↑ GPx activity; ↔ MPO, SOD, CAT activities [95] Rat model (Methotrexate-induced colitis) RES ↓ MDA and GSH levels, MPO expression [96] Rat model (Oxazolone-induced colitis) RES ↓ MPO activity [97] ...
... Despite that, the MPO, SOD and CAT activities were unaffected [95]. In rats with methotrexate-induced or oxazolone-induced colitis, MPO activity was suppressed by RES administration [96,97]. Furthermore, the expression of pro-inflammatory cytokines, like IL-6, TNF-α and IL-1β, was decreased in a peptidoglycan-polysaccharide-induced colitis rat model [99]. ...
Oxidative stress plays an important role in the onset as well as the progression of inflammation. Without proper intervention, acute inflammation could progress to chronic inflammation, resulting in the development of inflammatory diseases. Antioxidants, such as polyphenols, have been known to possess anti-oxidative properties which promote redox homeostasis. This has encouraged research on polyphenols as potential therapeutics for inflammation through anti-oxidative and anti-inflammatory pathways. In this review, the ability of polyphenols to modulate the activation of major pathways of inflammation and oxidative stress, and their potential to regulate the activity of immune cells are examined. In addition, in this review, special emphasis has been placed on the effects of polyphenols on inflammation in the brain-liver-gut axis. The data derived from in vitro cell studies, animal models and human intervention studies are discussed.
... Oxidative stress is one of the main mechanisms responsible for the intestinal mucositis due to MTX. Oxidants such as myeloperoxidase (MPO) which is the marker of inflammatory response and malondialdehyde (MDA) which is the product of lipid peroxidation are increased and antioxidants such as glutathione (tGSH) are decreased in MTX induced mucositis [2]. It is also shown that MTX increases the production of proinflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in the small intestine tissue of rats [19]. ...
... Arslan et al. reported that MDA level which is the end product of lipid peroxidation was increased; tGSH, glutathione reductase, glutathione peroxidase, catalase and superoxide dismutase which are antioxidants were decreased in the small intestine mucositis caused by MTX [3]. MTX caused oxidative stress by increasing MDA levels and decreasing tGSH levels in the small intestine tissue and confirmed histopathological changes [2]. It has been also reported that MTX caused increased MDA and decreased tGSH levels in the other organs [13]. ...
Intestinal mucositis is an important problem in the patients receiving cancer treatment. We aimed to investigate the effect of anakinra, which is a well known anti-oxidant and anti-inflammatory agent, on methotrexate-induced small intestine mucositis in rats. Forty rats were divided into 4 groups with 10 in each group. The healthy group (HG) and the methotrexate group (MTXG) were given distilled water, while the methotrexate+anakinra 50 (MTX+ANA50) and the methotrexate+anakinra 100 (MTX+ANA100) groups were intraperitoneally administered 50 and 100 mg/kg of anakinra. After one hour, the MTXG, MTX+ANA50 and MTX+ANA100 groups were given oral methotrexate at a dose of 5 mg/kg. This procedure was repeated once a day for 7 days. After the rats had been sacrificed, the small intestine tissue of rats were removed for the assesment of biochemical markers, histopathological evaluation and gene expression analyze. Statistical analyses of the data were performed using one-way ANOVA. Malondialdehyde (MDA), myeloperoxidase (MPO) and interleukin-6 (IL-6) levels were significantly higher, whereas total glutathione (tGSH) levels were significantly lower in MTXG (P<0.001) compared to other groups. MTX also increased IL-1β and TNF-α gene expression levels in MTXG (P<0.001). Inflammatory cell infiltration and damage to the villus were observed histopathologically in the MTXG group, whereas only mild inflammation was seen in the MTX+ANA100 group. A dose of 100 mg/kg of anakinra prevented the increase of the biochemical markers and gene expression levels better than a dose of 50 mg/kg. Intestinal mucositis caused by MTX may be preventible by co-administered anakinra.
... In addition to this, a previous study has reported that RSV protects against MTX induced oxidative stress in the small intestines of rats [41]. An interesting protective effect, since gastro-intestinal side effects from MTX are reported as a major reason for treatment discontinuation in RA patients [42]. ...
Background
Resveratrol is a natural polyphenol found in berries, roots and wine that is well known to have anti-inflammatory and anti-oxidative properties. The anti-inflammatory effect has been reported for both immune cells and connective tissues, but only few studies have investigated effects on immune mediated inflammatory arthritis. None of which have studied this effect when combining resveratrol with methotrexate or adalimumab, two major drugs in the treatment of immune mediated inflammatory arthritis.
We therefore aimed to investigate the anti-inflammatory effect of resveratrol alone and in combination with methotrexate or adalimumab in ex vivo models of immune mediated inflammatory arthritis. We furthermore aimed to describe any variations in this effect based on disease activity and cellular composition of the synovial fluid infiltrate.
Methods
Synovial fluid mononuclear cells from patients with rheumatoid arthritis (n = 7) and spondyloarthritis (n = 7) were cultured for either 48 h or 21 days. In both models, synovial fluid mononuclear cells were treated with resveratrol alone or in combination with methotrexate or adalimumab. Monocyte chemoattractant protein 1, matrix metalloproteinase 3 and tartrate resistant acidic phosphatase were measured to quantify inflammation, enzymatic degradation and osteoclast differentiation, respectively.
Results
Resveratrol reduced monocyte chemoattractant protein 1 production by synovial fluid mononuclear cells significantly (p = 0.005) compared to untreated controls. The effect of resveratrol was greatest in cultures from patients with low disease activity, i.e. DAS28CRP ≤ 3.2 (p = 0.022), and in cultures dominated by lymphocytes (p = 0.03). Further, the combination of methotrexate and resveratrol significantly reduced monocyte chemoattractant protein 1 levels compared with methotrexate alone in cultures from patients with low disease activity (p = 0.016), and in cultures with high lymphocyte count (p = 0.011). Resveratrol did not significantly affect matrix metalloproteinase 3 and tartrate resistant acidic phosphatase production.
Conclusion
Resveratrol has anti-inflammatory properties in our ex vivo model of immune mediated inflammatory arthritis. Results show an additive effect of resveratrol, when combined with methotrexate in samples dominated by lymphocytes and samples from patients with low disease activity. This suggests further investigations in vitro and whether this effect may also be present in a clinical setting.
Electronic supplementary material
The online version of this article (10.1186/s41927-018-0036-5) contains supplementary material, which is available to authorized users.
... Arslan et al. (94) found that resveratrol is able to protect against gastrointestinal toxicity of chemotherapeutic agents such as methotrexate, demonstrating that it can reduce the oxidative stress and induce antioxidant responses in duodenal and jejunal tissues. ...
Despite the fact that inflammatory bowel disease (IBD) has still no recognised therapy, treatments which have proven at least mildly successful in improving IBD symptoms include anti-inflammatory drugs and monoclonal antibodies targeting pro-inflammatory cytokines. Resveratrol, a natural (poly)phenol found in grapes, red wine, grape juice and several species of berries, has been shown to prevent and ameliorate intestinal inflammation. Here, we discuss the role of resveratrol in the improvement of inflammatory disorders involving the intestinal mucosa. The present review covers three specific aspects of resveratrol in the framework of inflammation: (i) its content in food; (ii) its intestinal absorption and metabolism; and (iii) its anti-inflammatory effects in the intestinal mucosa in vitro and in the very few in vivo studies present to date. Actually, if several studies have shown that resveratrol may down-regulate mediators of intestinal immunity in rodent models, only two groups have performed intervention studies in human subjects using resveratrol as an agent to improve IBD conditions. The effects of resveratrol should be further investigated by conducting well-designed clinical trials, also taking into account different formulations for the delivery of the bioactive compound.
... Therefore, MTX therapy results in decreased effectiveness of the antioxidant defense system that protects the cells against reactive oxygen radicals [25]. Recent studies have underlined that MTX increases the amount of MDA and decreases the amount of tGSH in the intestinal mucosal tissue [26]. Information obtained from the literature and our experimental results indicates that oxidative stress developed in the oropharyngeal tissue of the animals given MTX. ...
Objectives:
The objective of this study is to investigate and evaluate the effect of Hippophae rhamnoides extract (HRE) on oropharyngeal mucositis induced in rats with methotrexate (MTX) through biochemical, gene expression, and histopathological examinations.
Methods:
Experimental animals were divided into a healthy group (HG), a HRE+MTX (HREM) group, HRE group (HREG), and a control group that received MTX (MTXG). The HREM and HREG groups of rats was administered 50 mg/kg HRE, while the MTXG and HG groups were given an equal volume distilled water with gavage. Then, the HREM and MTXG rat groups were given oral MTX at a dose of 5 mg/kg 1 hour after HRE and distilled water was administered. This procedure was repeated for 1 month. At the end of this period, all of the animals were sacrificed with a high dose of anesthesia. Then, the amounts of malondialdehyde (MDA) and total glutathione (tGSH) were determined in the removed oropharyngeal tissues. Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) gene expressions were measured, and all the tissues were studied histopathologically.
Results:
The amount of MDA was significantly increased in the MTXG group compared to the HREM, HREG, and HG groups (P<0.001). MTX significantly decreased the amount of tGSH in the MTXG group compared to the HREM, HREG, and HG groups (P<0.001). In this study, there were no visible ulcers in the animal group in which the levels of MDA, IL-1β, and TNF-α were high and the level of tGSH was low. However, histopathologic examination revealed mucin pools in wide areas due to ruptured oropharynx glands, and proliferated, dilated, and congested blood vessels and dilated ductal structures in some areas.
Conclusion:
HRE protected oropharyngeal oxidative damage induced by MTX. As an inexpensive and natural product, HRE has important advantages in the prevention of oropharyngeal damage induced by MTX.
... It has been reported that berberine exerts many pharmacological activities such as anti-oxidative, anti-bacterial, and other organ function protective activity. 2,4,32) Considering that intestinal oxidative stress injury plays an important role in the pathogenesis of several gastrointestinal diseases and that reducing intestinal oxidative stress could improve various gastrointestinal injury, [33][34][35] we measured some typical biomarkers, such as MDA and SOD in the intestine, for evaluating the status of oxidative stress in the setting of uremia, 36,37) . The results revealed that the intestinal MDA level was significantly increased in the uremic group, compared with that in the control group. ...
Berberine is one of the main active constituents of Rhizoma coptidis, a traditional Chinese medicine, and has long been used for the treatment of gastrointestinal disorders. The present study was designed to investigate the effects of berberine on the intestinal mucosal barrier damage in a rat uremia model induced by the 5/6 kidney resection. Beginning at postoperative week 4, the uremia rats were treated with daily 150 mg/kg berberine by oral gavage for 6 weeks. To assess the intestinal mucosal barrier changes, blood samples were collected for measuring the serum D-lactate level, and terminal ileum tissue samples were used for analyses of intestinal permeability, myeloperoxidase activity, histopathology, malondialdehyde (MDA) level, and superoxide dismutase (SOD) activity. Berberine treatment resulted in significant decreases in the serum D-lactate level, intestinal permeability, intestinal myeloperoxidase activity, and intestinal mucosal and submucosal edema and inflammation, and the Chiu's scores assessed for intestinal mucosal injury. The intestinal MDA level was reduced and the intestinal SOD activity was increased following berberine treatment. In conclusion, berberine reduces intestinal mucosal barrier damage induced by uremia, which is most likely due to its anti-oxidative activity. It may be developed as a potential treatment for preserving intestinal mucosal barrier function in patients with uremia.
This study evaluated the potential of a treatment of honey, ginger and, turmeric against methotrexate-(MTX) induced intestinal toxicity. Rats were randomly split into five groups (n = 7) as follows: the control group was administrated placebo (physiologic saline) for seven days; the MTX groups were injected with vehicle intraperitoneally for one day followed by a single dose of MTX (20 mg/kg body weight). Animals in the treated groups were treated orally with honey solution, an aqueous extract of ginger, or turmeric. Body weight gain was significantly reduced at (p<0.05) after the injection of MTX for all treated groups. However, the total antioxidant capacity was significantly (p<0.05) higher for groups treated with honey, ginger and turmeric (1.70 ± 0.24; 1.4 ± 0.2; 1.70 ± 0.6 mM/L, respectively) compared with rats treated with MTX alone (0.97 ± 0.2 mM/L). Also, those who received honey and MTX had liver and kidney enzymes closer to normal levels, with better hematology parameters and morphological structure of the intestines. Treatment with aqueous extract of ginger and/or turmeric appeared to significantly ameliorate the toxic effects of MTX via an increase in total antioxidant capacity and decreased formation of malondialdehyde. There were also significant improvements in hematology results for rats treated with aqueous extract of ginger and/or turmeric. Finally, combined treatment with honey, ginger, and turmeric led to lower toxicity than treatment with MTX alone.
