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ScienceDirect Journal of Nutritional Biochemistry 25 (2014) 186 – 192

Feeding with olive oil attenuates inflammation in dextran sulfate sodium-induced colitis in rat☆ Toru Takashima a, b , Yasuhisa Sakata a , Ryuichi Iwakiri a , Ryosuke Shiraishi a , Yasutomo Oda a , Norie Inoue b , Atsushi Nakayama c , Shuji Toda c , Kazuma Fujimoto a,⁎ a

Department of Internal Medicine and Gastrointestinal Endoscopy, Saga Medical School, Saga 849-8501, Japan b Basic Science of Nursing, Saga Medical School, Saga 849-8501, Japan c Department of Pathology and Biodefense, Saga Medical School, Saga 849-8501, Japan

Received 9 April 2013; received in revised form 24 September 2013; accepted 4 October 2013

Abstract Chronic inflammation of long-term ulcerative colitis contributes to an increased risk of colon cancer. Few studies address whether extra-virgin olive oil (EVOO) intake suppresses inflammation, cell proliferation and signal transducers and activators of transcription (STAT) in the experimental colitis model. The aim of this study was to assess whether a 5% EVOO suppressed inflammation, increased cell proliferation and the expressions of STAT3 and STAT3 phosphorylation (pSTAT3) in dextran sulfate sodium (DSS)-induced colitis. Rats were administered DSS via drinking water (weight percentage: 4%) for 1 week with a 1-week recovery period for three cycles. Rats were divided into three groups: control group, standard diet without DSS; DSS group, standard diet+DSS; and DSS+EVOO group, EVOO diet (weight percentage: 5%)+DSS. Rats were sacrificed 5 weeks after DSS was first administered, and colonic damage was histologically and biochemically evaluated. As a result, chronic feeding of 5% EVOO attenuated inflammation. This was evaluated using a disease activity index, body weight loss and a histological score. Enhanced expressions of STAT3, pSTAT3, COX-2 and iNOS by DSS was attenuated by EVOO. In addition, EVOO attenuated increases in cell proliferation (PCNA) caused by DSS and recovered decreases in apoptosis (cleaved caspase-3). In conclusion, the study indicated that chronic feeding of 5% EVOO inhibited chronic inflammation in DSS-induced colitis in rats and also attenuated cell proliferation and recovered apoptosis in DSS colitis. © 2014 Elsevier Inc. All rights reserved. Keywords: Apoptosis; Colon cancer; Inflammatory bowel disease; Ulcerative colitis; STAT3; pSTAT3

1. Introduction Inflammatory bowel disease (IBD) includes two major chronic intestinal disorders: ulcerative colitis (UC) and Crohn’s disease (CD). The prevalence of IBD is increasing in developed countries, and one of the most serious complications of IBD is colorectal cancer (CRC) [1]. The risk of colitis-associated CRC is increased after long disease duration, especially in patients with chronic active disease [2]. Although many studies suggested that chronic inflammation might be positively correlated to the development of IBD-related carcinogenesis, the mechanisms of the IBD-related carcinogenesis process are not completely understood [3]. Many epidemiological studies indicate that dietary fat intake was a promoting factor for the incidence of CRCs [4,5]. These studies are supported by several animal studies showing that a chronic high-fat diet enhanced carcinogenesis of CRCs [6–11]. In contrast, chronic feeding of several types of fat, including fish oil and olive oil, diminish carcinogenesis of CRCs, which has been demonstrated by epidemio☆ Conflicts of interest: The authors declare that there are no conflicts of interest. ⁎ Corresponding author. Tel.: +81 952 34 2361; fax: +81 952 34 2017. E-mail address: [email protected] (K. Fujimoto).

0955-2863/$ - see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jnutbio.2013.10.005

logical studies [12,13] and in vivo and/or in vitro studies [8,14–16]. Our previous study indicated that dietary olive oil intake inhibited formation of aberrant crypt foci and mucosal arachidonate concentrations in azoxymethane (AOM)-induced CRCs in rats [8]. Other report has indicated that hydroxytyrosol (HT) isolated from olive oil inhibited cancer cell proliferation by inducing cell apoptosis and cell cycle arrest [17]. There have been some studies that investigated the effects of dietary fat, such as n-3, n-6 and n-9 polyunsaturated fatty acids, in IBD [18–26]. However, the effect of n-9 polyunsaturated fatty acids, such as olive oil, in experimental colitis is not very clear. Cytokine signaling pathways involving transcription factors of the signal transducers and activators of transcription (STAT) family play a key role in the pathogenesis of IBD. STAT proteins are latent cytoplasmic transcription factors that induce transcription upon phosphorylation, dimerization and nuclear translocation. STAT3 and phospho-STAT3 (pSTAT3) levels were significantly increased in UC patients compared with controls [27]. Inflammation-related enzymes, including cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), are indicated to be key predisposing factors to CRCs [23], and COX-2 and iNOS expressions was closely associated with the development of cancers [28,29].

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Dextran sulfate sodium (DSS), with or without AOM, induced colon carcinogenesis in rodents [23,30,31], and the feeding of DSS enhanced cell proliferation [32]. Equability between cell proliferation and apoptosis was closely correlated to colon inflammation and carcinogenesis, as demonstrated in UC in humans and the experimental colitis model [33–35]. The aim of the present study was to demonstrate whether feeding with olive oil to rats suppressed inflammation, cell proliferation, STAT3 and pSTAT3 induced by oral administration of DSS for 1 week at a time followed by a 1-week recovery period and repeated three times. 2. Materials and methods 2.1. Experimental animals and diets Six-week-old male Sprague–Dawley rats (Japan CLEA Inc., Tokyo, Japan) were housed in an air-conditioned room that was maintained at 24°C–25°C, with constant humidity and an alternating 12-h light/dark cycle. All rats had access to food and water ad libitum. The base diet was standard laboratory diet AIN 76 (NOSAN, Kanagawa, Japan). Five percent extra-virgin olive oil (EVOO) (Ajinomoto, Tokyo, Japan) was added to diet AIN (weight percentage: 5%). EVOO contained 125±25 mg/kg total phenolics. HT in EVOO was 7.9±2.7 mg/kg (0.40±0.14 mg/kg in 5% EVOO), and tyrosol in EVOO was 15±4.1 (0.75±0.21 mg/kg in 5% EVOO). The diet was kept at 4°C and was exchanged with a fresh one every few days. Body weights, drink intake, diet consumption and survival were monitored during the experimental period. All experiments involving animals were approved by the Animal Ethics Committee of Saga Medical School. 2.2. Induction of chronic inflammation DSS (MW: 36,000–50,000, MP Biomedicals, LLC, Illkirch, France) was administered to rats via drinking water (weight percentage: 4%) for 1 week, which was followed by a 1-week recovery period. The same administration method was repeated for three times. Rats were divided into three groups at random as shown in Fig. 1: control group, standard diet and no DSS (n=12); DSS group, standard diet+DSS (n=17); and DSS +EVOO group, olive oil diet+DSS (n=12). Activity of rat DSS-induced colitis during the experimental period was evaluated using a disease activity index (DAI) [36]. This index consisted of three scales: presence of rectal bleeding, weight loss and stool consistency. 2.2.1. Macroscopic and histological evaluation. On the final day of the experimental period, the rats were sacrificed under halothane anesthesia. The entire colon was carefully removed and opened longitudinally. Samples were photographed and measured and then segmented (proximal, middle, distal) for pathological evaluation. Samples were then fixed in 4% buffered formaldehyde (pH 7.4–7.5), dehydrated by increasing the concentration of ethanol and embedded in paraffin. Paraffin sections (4 μm thick) were sliced and stained with hematoxylin and eosin (H&E) in accordance with the standard procedures for the histological evaluation of colonic damage. The histological study was representative of at least five animals per group. Evaluation was undertaken by a pathologist (A.N.) who was unaware of the experimental protocol. A histological score [37] and the efficacy of treatment were analyzed on H&E-stained tissue using a standard microscope (Olympus, Tokyo, Japan). A histological score reflecting infiltration of inflammatory cells and epithelial structure was given on a scale of 0 to 6: 0=no signs of damage; 1=few inflammatory cells, no signs of epithelial degeneration; 2=mild inflammation, few signs of epithelial degeneration; 3= moderate inflammation, few epithelial ulcerations; 4=moderate to severe inflammation, ulcerations in more than 25% of the tissue section; 5=moderate to severe inflammation, large ulcerations of more than 50% of the tissue section; 6=severe inflammation and ulcerations of more than 75% of the tissue section.

Fig. 1. Experiment design. DSS was administered to rats via drinking water (weight percentage: 4%) for a 1-week period followed by a 1-week recovery period. This cycle was repeated three times. Rats were divided into three groups at random as shown: control group, standard diet and no DSS; DSS group, standard diet+DSS; and DSS+EVOO group, 5% olive oil diet+DSS. −80°C for analysis. The amounts of STAT3, pSTAT3, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, COX-2, iNOS, proliferating cell nuclear antigen (PCNA) and cleaved caspase-3 in the frozen samples were determined by Western blotting using a previously described method with modification [9]. Equal quantities of protein were electrophoresed in a sodium dodecyl sulfate polyacrylamide gel and were then electroblotted onto a polyvinylidene difluoride membrane. After being blocked with PBS containing 0.1% Tween 20 (Sigma) and 5% skim milk at room temperature for 1 h, the membrane was incubated with rabbit monoclonal anti-STAT3 (Cell Signaling Technology, Beverly, MA, USA) at a dilution of 1:8000; rabbit monoclonal anti-pSTAT3 (Cell Signaling Technology) (1:1000); mouse monoclonal anti-TNF-α (Sigma-Aldrich, Saint Louis, MO, USA) (1:1000); rabbit polyclonal anti-IL-1β (Santa Cruz Biotechnology, Santa Cruz, CA, USA)(1:4000); mouse monoclonal anti-IL-6(R&D Systems, Minneapolis, MN, USA) (1:4000); rabbit polyclonal anti-COX-2 (Cell Signaling Technology) (1:1000); rabbit polyclonal anti-iNOS (Cayman, Ann Arbor, MI, USA) (1:1000); rabbit polyclonal anti-PCNA (Santa Cruz Biotechnology, Santa Cruz, CA, USA) (1:2000); rabbit polyclonal anti-cleaved caspase-3 (Cell Signaling Technology) (1:4000) and rabbit polyclonal anti-β-actin antibody (Cell Signaling Technology) (1:2000) was used as a loading control, respectively, at 4°C overnight. The antigen– antibody complex was detected with a peroxidase-conjugated secondary antibodies anti-rabbit for STAT3, pSTAT3, IL-1β, COX-2, iNOS, PCNA and cleaved caspase-3 (Cell Signaling Technology) at a dilution of 1:1000 or anti-mouse for TNF-α and IL-6(Cell Signaling Technology) (1:2000). Detection of chemiluminescence was performed using ECL Western blotting detection reagents (GE Healthcare, Buckinghamshire, UK). Densitometric assessment of the bands on the autoradiogram was done using Multi Gauge Version 3.0 (Fujifilm, Tokyo, Japan). Band intensities were quantified by measurements of absolute integrated optical intensities, estimating bands in each lane profile. Results were expressed as ratios to β-actin densitometry units. 2.4. Statistical analysis All data are expressed as the means±standard error of the mean (S.E.M.). Comparisons were done using analysis of variance (ANOVA) followed by Tukey, or repeated-measure ANOVA was used (SPSS ver. 18.0; SPSS, Chicago, IL, USA). A P value of b.05 was considered statistically significant.

3. Results

2.3. Collection of colon tissue samples and Western blotting analysis

3.1. Effect of olive oil diet on DAI score in DSS-induced colitis

The colon mucosal layer was harvested by gently scraping the epithelium using a glass slide. Mucosal scrapings were then immediately washed twice with ice-cold phosphate-buffered saline (PBS; pH 7.4) and centrifuged at 1,000g for 5 min at 4°C. The pellet was resuspended with 2 vol of buffer A and lysed at 4°C for 30 min. Buffer A consisted of 250 mM sucrose (Sigma), 20 mM N-(2-hydroxyethyl)piperazine-N-(2ethanesulfonic acid) (Sigma), KOH (pH 7.5), 10 mM KCl, 1.5 mM MgCl2, 1 mM ethylenediamine tetraacetate, 1 mM ethyleneglycoltetraacetic acid, 1 mM dithiothreitol, 1 mM phenylmethylsulfonyl fluoride, 10 g/ml aprotinin, 10 g/ml leptin and 1.8 mg/ml iodoacetamide. The homogenate was centrifuged at 1000g for 10 min at 4°C to remove nuclei before the supernatant was centrifuged at 10,000g for 15 min at 4°C to remove mitochondria. The supernatants of the 10,000g spin were further centrifuged at 1,000,000g for 1 h at 4°C. The resulting supernatant was the soluble cytosolic fraction, and the pellet was the membranous fraction. The supernatant and pellet fractions of the resuspended solution in buffer A were divided into multiple samples and frozen at

DAI score (Fig. 2) refers to external signs of colitis, indicating that DSS drinking induced symptoms of colitis at the beginning of week 3 and the DAI score increased in a time-dependent manner. Increases in the DAI score induced by DSS drinking were significantly attenuated by feeding with 5% olive oil (Pb.01). 3.2. Total DSS drinking, diet consumption and body weight in DSS-induced colitis DSS drinking was the same in the two groups (data not shown). Regarding diet consumption, the DSS+EVOO group significantly took diet more compared with control and DSS groups (data not shown).

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observed in the proximal and middle segments (Fig. 5B). In addition to moderate infiltration of lymphocytes and plasma cells in the lamina propria mucosa, neutrophil infiltration was observed in and around the ulcers. In the distal segment, ulcer formation was more generally observed when compared with the proximal and middle segments. Five percent olive oil intake diminished DSS-induced ulcer formation and infiltration of lymphocytes, plasma cells and neutrophils, although the inflammation caused by DSS was still observed, particularly in the distal segment (Fig. 5C). These protective effects of an olive oil diet are indicated in the histological scores (Fig. 6). Increased scores on the colon except middle segment caused by DSS were significantly attenuated by 5% olive oil feeding. Mean score of 3 segments (proximal, middle and distal segments) was significantly attenuated by a 5% olive oil diet (Pb.01 vs. DSS rats).

Fig. 2. Changes in body weight of control group, DSS group and DSS+EVOO group. Rats were weighted every week from the start of treatment. Data are expressed as the means±S.E.M.

As shown in Fig. 3, body weight was significantly reduced in DSS rats during the experimental 5-week period compared with control rats (Pb.01). Weight reduction induced by DSS was recovered by 5% olive oil feeding for 5 weeks. In DSS rats, the mortality rates at the end of the experimental period (week 6) were 0% (0/12), 23.5% (4/17) and 0% (0/12) in the control group, DSS group and DSS+olive oil group. 3.3. Lengths of colon in DSS-induced colitis As shown in Fig. 4 (macroscopic view of the colon), 4% DSS drinking significantly shortened the length of the colon. Lengths were 181.3±7.5 mm in control rats, 112.2±1.7 mm in DSS rats and 126.5± 4.2 mm in olive oil+DSS rats. Lengths of colons were significantly shortened by DSS drinking (Pb.01 vs. control). This effect was not normalized by a 5% olive oil feeding.

3.5. Effects of olive oil diet on TNF-α, IL-1β, IL-6, STAT3 and pSTAT3 expressions in DSS-induced colitis TNF-α, IL-1β, IL-6, STAT3 and pSTAT3 were assessed by Western blotting. Increased TNF-α, IL-1β and IL-6 expressions induced by DSS were not significantly suppressed by a 5% olive oil diet (data not shown). STAT3 and pSTAT3 expressions induced by DSS were clearly suppressed by a 5% olive oil diet (Fig. 7).

3.6. Effects of olive oil diet on COX-2 and iNOS expressions in DSS-induced colitis Colonic mucosal expression of COX-2 was assessed by Western blotting (Fig. 8). Administered DSS increased COX-2 expression. COX2 expression induced by DSS was clearly suppressed by a 5% olive oil diet. On the other hand, colonic expression of iNOS was examined for evaluation of oxidative stress by Western blotting (Fig. 8). Administered DSS significantly increased iNOS expression. iNOS expression induced by DSS was clearly suppressed by a 5% olive oil diet.

3.4. Histological analysis of colonic lesions in DSS-induced colitis Histological features in each group are shown in Fig. 5. Fig. 5A indicates the control group in each segment and shows mild infiltration of lymphocytes and plasma cells in the lamina propria mucosa but no clear ulcer formation. Small ulcer formation was partly

Fig. 3. DAI of control group, DSS group and DSS+EVOO group. The DAI consisted of three scales: presence of rectal bleeding, weight loss and stool consistency. Rats were weighted every week from the start of treatment. Data are expressed as the means±S.E.M.

Fig. 4. Macroscopic view and lengths of colon on day of sacrifice. (A) Control group; (B) DSS group; (C) DSS+EVOO group. Data are expressed as the means±S.E.M. ⁎Pb.01 vs. control.

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Fig. 5. Representative images showing colon segments on day of sacrifice. (A) Control group, (B) DSS group, (C) DSS+EVOO group.

3.7. Effects of olive oil diet on cell proliferation and apoptosis in DSS-induced colitis

polyphenol extract [26] in the experimental colitis. A previous study indicates that a 10% EVOO intake attenuated colon mucosal inflammation in DSS-induced colitis of mice with reduction in

Colonic expression of PCNA was examined for evaluation of cell proliferation, and colonic expression of cleaved caspase-3 was examined for evaluation of apoptosis (Fig. 9). Increased PCNA induced by DSS was significantly reduced by a 5% olive oil diet, whereas decreased cleaved caspase-3 almost recovered following a 5% olive oil diet. As a result, the PCNA/cleaved caspase-3 ratio increased in DSSinduced colitis and was recovered by a 5% olive oil diet (4.1±1.6 vs. 0.57±0.11). 4. Discussion This study indicates that chronic feeding of a 5% olive oil diet for 5 weeks attenuates inflammation in DSS-induced colitis of rat colons. This finding is based on evaluation using the DAI score, body weight loss, histological scores, STAT3, pSTAT3, COX-2 and iNOS. There have been some studies that investigated the effects of dietary fat, such as n-3, n-6 and n-9 polyunsaturated fatty acids, in IBD [18–26]. With regard to n-9 polyunsaturated fatty acids such as olive oil, there are not yet very clear, although previous studies investigated about 10% EVOO [23], 10% EVOO+0.04% HT, which polyphenol in EVOO [24], unsaponifiable fraction isolated from EVOO [25] and

Fig. 6. Histological scores on day of sacrifice. Histological scores of proximal, middle and distal colon segments of control group, DSS group and DSS+EVOO group. Data are expressed as the means±S.E.M. ⁎Pb.01 vs. control. ⁎⁎Pb.05 vs. DSS rats.

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Fig. 7. Expressions of STAT3 and pSTAT3. Effects of 5% EVOO diet on STAT3 and pSTAT3 proteins using anti-STAT3 and anti-pSTAT3 antibodies. Control group; DSS group; DSS+EVOO group. The bands were quantified. β-Actin was used as the loading control. Data are expressed as the means±S.E.M. ⁎Pb.01 vs. control. ⁎⁎Pb.05 and ⁎⁎⁎Pb.01 vs. DSS rats.

enzyme expressions in both COX-2 and iNOS, which might be key predisposing factors to CRCs of DSS-induced colitis [23]. The present results are in accordance with the previous study, although the experimental conditions were different including animal models (mouse vs. rat), the way DSS was administered (0.7% DSS for 15 cycles vs. 4% DSS for 3 cycles) and olive oil concentration (10% vs. 5%). With regard to olive oil, 4%–5% olive oil, not 10%, is recommended for longterm feeding studies on rats [38]. Therefore, the present study indicates that chronic feeding of 5% olive oil is effective to attenuate chronic inflammation caused by DSS administered for 5 weeks. EVOO contains an abundance of phenolic antioxidants including simple phenols, such as HT and tyrosol, aldehydic secoiridoids, flavonoids and lignans [39]. Among these phenolic compounds, HT had antioxidant capacities and anti-inflammatory and antiplatelet aggregation actions [40], leading to protective effects on human peripheral blood mononuclear cells against oxidative stress [41]. Tyrosol had antioxidant, anti-inflammatory and neuroprotective effects [42]. In the present study, the concentration of HT was 7.9±

2.7 mg/kg in EVOO and tyrosol was 15±4.1 mg/kg, which were almost equivalent to the concentration of these compounds in the previous study [39]. A recent study found that STAT3 and pSTAT3 levels were significantly higher in UC patients in comparison with controls [27]. Another study found that STAT3 was constitutively activated in CD patients but not in healthy volunteers, but other STAT proteins were not constitutively activated [43]. Therefore, STAT3 might be one of the crucial targets for the treatment of IBD. In the experimental colitis model, STAT3 antisense oligonucleotide inhibited the expressions of STAT3 and pSTAT3 in inflamed colonic mucosa of trinitrobenzene sulfonic acid, not DSS [44]. In our results, olive oil attenuated the expressions of STAT3 and pSTAT3, although TNF-α, IL-1β or IL-6 was not influenced. This finding suggests that olive oil has an important beneficial ability in the treatment of IBD. However, more studies are needed to gain further insight into this mechanism. This study also indicates that a 5% olive oil diet attenuated increases in PCNA expression and recovered the decrease in cleaved

Fig. 8. Expressions of inflammatory proteins. Effects of 5% EVOO diet on expressions of inflammatory proteins using anti-COX-2 and anti-iNOS antibodies. (A) Images of each protein. Lanes A–C, control group; DSS group; DSS+EVOO group. (B) The bands were quantified. β-Actin was used as the loading control. Data are expressed as the means±S.E.M. ⁎Pb.01 vs. control. ⁎⁎Pb.01 vs. DSS rats.

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Fig. 9. Cell proliferation and apoptosis. Effects of 5% EVOO diet on cell proliferation and apoptosis using anti-PCNA and anti-cleaved caspase-3 antibodies. (A) Images of each protein. Lanes A–C, control group; DSS group; DSS+EVOO group. (B) The bands were quantified. β-Actin was used as the loading control. Data are expressed as the means±S.E.M. ⁎Pb.05 and ⁎⁎Pb.01 vs. DSS rats.

caspase-3. These data suggest that feeding with olive oil attenuates both increases in cell proliferation and decreases in apoptosis induced in rat colons by DSS. The attenuation effect was demonstrated in other animal models with different diets, including polysaccharides from fruit body extract and mycelia extract, resveratrol derivative and EVOO polyphenol extract [45,46,26]. Increases in cell proliferation and deceases in apoptosis were observed in the precancerous state induced by colon carcinogen. Our previous studies indicated that colon carcinogen AOM induced CRCs in rats, which was attenuated by olive oil and fish oil [8] but enhanced by beef tallow and corn oil [7,8]. From these data, it is possible that olive oil might attenuate DSSinduced CRCs. This possibility warrants further exploration. The administration of DSS increased STAT3 expression and decreased apoptosis in comparison with the control group (Figs. 7 and 9). However, a 5% olive oil attenuated increases in STAT3 expression and recovered the decrease in apoptosis. STAT3 possesses antiapoptotic activity [47] and oncogenic potential [48]. Therefore, olive oil might prevent DSS-induced CRCs by inhibiting STAT3 activation. However, more studies are needed to gain further insight into this mechanism. In the present study, the administration of DSS increased COX-2 expression and decreased apoptosis (Figs. 8 and 9). However, 5% olive oil attenuated increases in COX-2 expression and recovered the decrease in apoptosis. These results are in accordance with a previous study which showed that enhanced COX-2 expression inhibited apoptosis [49]. Olive oil intake attenuated enhanced COX-2 expression by DSS and might result in recover decreases in apoptosis. The experimental period of this study was for 5 weeks. More studies are needed to investigate whether the long-term administration of 5% olive oil intake is more effective to attenuate inflammation in the DSS-induced colitis. In conclusion, the present findings suggest that 5% olive oil is an effective inhibitor of DSS-induced colitis in the rat colon. Chronic feeding of olive oil attenuated chronic inflammation in the colon and might reverse the precancerous state induced by DSS. Acknowledgments The authors thank Prof. Hitoshi Kawano and Ms. Yumiko Tsugitomi for their invaluable advice. This work was supported in

part by Grants-in-Aid for Scientific Research from Japan Society for the Promotion of Science (KAKEN) 20590728, (KF) 24590889 and (RI) 20590745.

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Feeding with olive oil attenuates inflammation in dextran sulfate sodium-induced colitis in rat.

Chronic inflammation of long-term ulcerative colitis contributes to an increased risk of colon cancer. Few studies address whether extra-virgin olive ...
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