Publications by authors named "Ryoung Hee Nam"

71 Publications

Nuclear Factor Erythroid 2-related Factor 2 Knockout Suppresses the Development of Aggressive Colorectal Cancer Formation Induced by Azoxymethane/Dextran Sulfate Sodium-Treatment in Female Mice.

J Cancer Prev 2021 Mar;26(1):41-53

Laboratory of Immunology, Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.

Colon tumors develop more frequently in male than in female. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays differential roles in the stage of tumorigenesis. The purpose of this study was to investigate the role of Nrf2 on colitis-associated tumorigenesis using Nrf2 knockout (KO) female mice. Azoxymethane (AOM) and dextran sulfate sodium (DSS)-treated wild-type (WT) and Nrf2 KO female mice were sacrificed at week 2 and 16 after AOM injection. Severity of colitis, tumor incidence, and levels of inflammatory mediators were evaluated in AOM/DSS-treated WT and Nrf2 KO mice. Furthermore, qRT-PCR, Western blot abnalysis, and ELISA were performed in colon tissues. At week 2, AOM/DSS-induced colon tissue damages were significantly greater in Nrf2 KO than in WT mice. At week 16, tumor numbers (> 2 mm size) were significantly lower in both the proximal and distal colon in Nrf2 KO compared to WT. The overall incidences of adenoma/cancer of the proximal colon and submucosal invasive cancer of the distal colon were reduced by Nrf2 KO. The mRNA and protein expression levels of NF-κB-related mediators (i.e., iNOS and COX-2) and Nrf2-related antioxidants (i.e., heme oxygenase-1 and glutamate-cysteine ligase catalytic subunit) were significantly lower in the Nrf2 KO than in WT mice. Interestingly, the protein level of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) was higher in AOM/DSS-treated Nrf2 KO than in WT mice. Our results support the oncogenic effect of Nrf2 in the later stage of carcinogenesis and upregulation of tumor suppressor 15-PGDH might contribute to the repression of colitis-associated tumorigenesis in Nrf2 KO female mice.
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http://dx.doi.org/10.15430/JCP.2021.26.1.41DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020176PMC
March 2021

Changes in Cecal Microbiota and Short-chain Fatty Acid During Lifespan of the Rat.

J Neurogastroenterol Motil 2021 Jan;27(1):134-146

Department of Biological Sciences and Institute of Microbiology, Seoul National University, Seoul, Korea.

Background/aims: The gut microbiota regulates intestinal immune homeostasis through host-microbiota interactions. Multiple factors affect the gut microbiota, including age, sex, diet, and use of drugs. In addition, information on gut microbiota differs depending on the samples. The aim of this study is to investigate whether changes in cecal microbiota depend on aging.

Methods: Gut microbiota in cecal contents of 6-, 31-, and 74-week-old and 2-year-old male Fischer-344 rats (corresponding to 5-, 30-, 60-, and 80-year-old humans in terms of age) were analyzed using 16S ribosomal RNA metagenome sequencing and phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) based on the Kyoto Encyclopedia of Genes and Genomes orthology. Moreover, short-chain fatty acid (SCFA) level in cecum and inflammation related factors were measured using real-time quantitative polymerase chain reaction and enzyme linked immunosorbent assay.

Results: Alpha and beta diversity did not change significantly with age. At the family level, Lachnospiraceae and Ruminococcaceae, which produce SCFAs, showed significant change in 31-week-old rats: Lachnospiraceae significantly increased at 31 weeks of age, compared to other age groups, while Ruminococcaceae decreased. Butyrate levels in cecum were significantly increased in 31-week-old rats, and the expression of inflammation related genes was increased followed aging. Especially, EU622775_s and EU622773_s, which were highly abundance species in 31-week-old rats, showed significant relationship with butyrate concentration. Enzymes required for producing butyrate-acetyl-CoA transferase, butyryl-CoA dehydrogenase, and butyrate kinase-were not predicted by PICRUSt.

Conclusions: Major bacterial taxa in the cecal lumen, such as Lachnospiraceae, well-known SCFAs-producing family, changed in 31-week-old rats. Moreover, unknown species EU622775_s and EU622773_s showed strong association with cecal butyrate level at 31 weeks of age.
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http://dx.doi.org/10.5056/jnm20148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786083PMC
January 2021

Efficacy of Tegoprazan for Improving the Susceptibility of Antimicrobial Agents against Antibiotic-Resistant .

Gut Liver 2021 Jan;15(1):53-60

Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.

Background/aims: Favorable outcomes of potassium-competitive acid blocker (PCAB)-containing eradication therapy have been reported. In fact, tegoprazan, a recently developed PCAB, was presumed to show good eradication efficacy even for resistant . We aimed to investigate the anti- efficacy of tegoprazan compared with that of vonoprazan.

Methods: A total of 220 resistant clinical isolates were utilized. The anti- efficacy of PCABs was determined by evaluating the minimum inhibitory concentrations (MICs) of clarithromycin, fluoroquinolone, metronidazole, and amoxicillin in combination with vonoprazan or tegoprazan by the agar dilution method. The impact of the mutations responsible for resistance development, such as 23S rRNA, , , , and mutations, was also analyzed.

Results: growth was significantly inhibited in a medium containing 1 μg/mL clarithromycin with tegoprazan (128 μg/mL). The MICs of clarithromycin (46.3%), fluoroquinolone (46.7%), metronidazole (55.6%), and amoxicillin (34.5%) against resistant isolates improved after tegoprazan administration. Tegoprazan demonstrated more frequent susceptibility acquisition with metronidazole than with vonoprazan (20.6% vs 4.7%, p=0.014). However, there were no significant differences depending on the mutational status of each antimicrobial agent.

Conclusions: Tegoprazan administration may improve the susceptibility of antimicrobial-resistant , independent of acid suppression.
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http://dx.doi.org/10.5009/gnl20247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817939PMC
January 2021

17β-Estradiol strongly inhibits azoxymethane/dextran sulfate sodium-induced colorectal cancer development in Nrf2 knockout male mice.

Biochem Pharmacol 2020 12 15;182:114279. Epub 2020 Oct 15.

Tumor Microenvironment Global Core Research Center, Seoul National University College of Pharmacy, Seoul, South Korea.

Nuclear factor erythroid 2-related factor 2 (Nrf2) has dual effects on inflammation and cancer progression depending on the microenvironment. Estrogens have a protective effect on colorectal cancer (CRC) development. The aim of this study was to investigate CRC development in Nrf2 knockout (KO) mice. Azoxymethane (AOM) and dextran sulfate sodium (DSS)-treated wild-type (WT) and Nrf2 KO male mice were sacrificed at weeks 2 and 16 after AOM injection with/without 17β-estradiol (E2) treatment during week 1. Disease activity index and colon tissue damage at week 2 showed strong attenuation following E2 administration in WT mice but to a lesser extent in Nrf2 KO male mice. At week 16, E2 significantly diminished AOM/DSS-induced adenoma/cancer incidence at distal colon in the Nrf2 KO group, but not in the WT. Furthermore, mRNA or protein levels of NF-κB-related mediators (i.e., iNOS, TNF-α, and IL-1β) and Nrf2-related antioxidants (i.e., NQO1 and HO-1) were significantly lower in the Nrf2 KO group regardless of E2 treatment compared to the WT. The expression of estrogen receptor beta (ERβ) was higher in the Nrf2 KO group than in the WT. In conclusion, estrogen further inhibits CRC by upregulating ERβ-related alternate pathways in the absence of Nrf2.
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http://dx.doi.org/10.1016/j.bcp.2020.114279DOI Listing
December 2020

17β-Estradiol supplementation changes gut microbiota diversity in intact and colorectal cancer-induced ICR male mice.

Sci Rep 2020 07 23;10(1):12283. Epub 2020 Jul 23.

Tumor Microenvironment Global Core Research Center, Seoul National University College of Pharmacy, Seoul, South Korea.

The composition of the gut microbiota is influenced by sex hormones and colorectal cancer (CRC). Previously, we reported that 17β-estradiol (E2) inhibits azoxymethane/dextran sulfate sodium (AOM/DSS)-induced tumorigenesis in male mice. Here, we investigated whether the composition of the gut microbiota is different between male and female, and is regulated by estrogen as a secondary outcome of previous studies. We established four groups of mice based on the sex and estrogen status [ovariectomized (OVX) female and E2-treated male]. Additionally, three groups of males were established by treating them with AOM/DSS, and E2, after subjecting them to AOM/DSS treatment. The mice were sacrificed at 21 weeks old. The composition of the gut microbiota was analyzed using 16S rRNA metagenomics sequencing. We observed a significant increase in the microbial diversity (Chao1 index) in females, males supplemented with E2, and males treated with AOM/DSS/E2 compared with normal males. In normal physiological condition, sex difference and E2 treatment did not affect the ratio of Firmicutes/Bacteroidetes (F/B). However, in AOM/DSS-treated male mice, E2 supplementation showed significantly lower level of the F/B ratio. The ratio of commensal bacteria to opportunistic pathogens was higher in females and E2-treated males compared to normal males and females subjected to OVX. Unexpectedly, this ratio was higher in the AOM/DSS group than that determined in other males and the AOM/DSS/E2 group. Our findings suggest that estrogen alters the gut microbiota in ICR (CrljOri:CD1) mice, particularly AOM/DSS-treated males, by decreasing the F/B ratio and changing Shannon and Simpson index by supply of estrogen. This highlights another possibility that estrogen could cause changes in the gut microbiota, thereby reducing the risk of developing CRC.
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http://dx.doi.org/10.1038/s41598-020-69112-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378548PMC
July 2020

Sex-related Alterations of Gut Microbiota in the C57BL/6 Mouse Model of Inflammatory Bowel Disease.

J Cancer Prev 2019 Sep 30;24(3):173-182. Epub 2019 Sep 30.

Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.

Background: Gut microbiota is closely associated with development and exacerbation of inflammatory bowel diseases (IBD). The aim of this study was to investigate differences in gut microbiota depending on sex and changes of gut microbiota during IBD developments.

Methods: 16s rRNA metagenomic sequencing was performed for fecal materials from 8-week-old wild type (WT) and interleukin 10 (IL-10) knockout (KO) C57BL/6 mice of both sexes. Diversity indices, relative abundance of microbiota, and linear discriminant analysis effect size were examined to compare microbial communities between groups. Clustering of groups was performed by principal coordinates analysis (PCoA) and unweighted pair group method with arithmetic mean (UPGMA). Functional capabilities of microbiota were estimated using phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) based on Kyoto Encyclopedia of Genes and Genomes database.

Results: PCoA and UPGMA tree analysis of beta-diversity demonstrated significant differences in gut microbiota between male and female groups of WT mice, but not of IL-10 KO mice. Firmicutes to Bacteroides ratio was higher in male group than that in female group in both WT mice and IL-10 KO mice. Phylum Proteobacteria significantly increased in female IL-10 KO mice than that in female WT mice. At species level, , , and significantly increased in IL-10 KO mice than in WT mice. The relative abundance of beta-glucuronidase (K01195) was higher in female IL-10 KO mice than that in female WT mice by PICRUSt.

Conclusions: Our results suggest that microbiota-host interactions might differ between sexes during development of IBD.
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http://dx.doi.org/10.15430/JCP.2019.24.3.173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6786806PMC
September 2019

Expression of Neurotrophic Factors, Tight Junction Proteins, and Cytokines According to the Irritable Bowel Syndrome Subtype and Sex.

J Neurogastroenterol Motil 2020 Jan;26(1):106-116

Departments of Internal Medicine, Seoul National University Bundang Hospital, Seoungnam, Gyeonggi-do, Korea.

Background/aims: Emerging evidence shows that the mechanism of irritable bowel syndrome (IBS) is associated with neurotrophic factors and tight junction proteins (TJPs). It is known that there are sex differences in the pathophysiology of IBS. The aim of the present study is to determine expression levels of neurotrophic factors, TJPs, and cytokines according to IBS subtype and sex.

Methods: From 59 IBS (33 IBS-constipation, 21 IBS-diarrhea, and 5 IBS-mixed) and 36 control patients, colonic mucosa mRNA expression levels of transient receptor potential vanilloid-1 (TRPV1), nerve growth factor (NGF), glial cell-derived neurotrophic factor (GDNF), and various TJPs were assessed by real-time polymerase chain reaction. Western blot was performed to determine levels of zonular occludens-1 (ZO-1). Serum levels of cytokines were measured by enzyme-linked immunosorbent assay.

Results: TRPV1, GDNF, and NGF mRNA levels were significantly increased in those with IBS-constipation compared to those in controls (all < 0.05). However, they showed no significant difference between those with IBS-diarrhea and controls. Expression level of TRPV1 correlated with that of GDNF (r = 0.741, < 0.001) and NGF (r = 0.935, < 0.001). ZO-1 RNA expression levels were lower ( = 0.021) in female IBS-diarrhea than those in controls, although they showed no significant differences between male IBS-diarrhea and controls. Serum IL-1β levels in female IBS were significantly higher than those of male IBS, especially in IBS-constipation ( < 0.001).

Conclusions: Our results suggest that neurotrophic factors and IL-1β are closely related to IBS-constipation and that decrease of ZO-1 is an important factor in female with IBS-diarrhea.
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http://dx.doi.org/10.5056/jnm19099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955198PMC
January 2020

Primary and secondary antibiotic resistance of Helicobacter pylori in Korea from 2003 to 2018.

Helicobacter 2019 Dec 11;24(6):e12660. Epub 2019 Sep 11.

Department of Internal Medicine, Seoul National University Bundang Hospital, Seoungnam, South Korea.

Background: Antimicrobial resistance of Helicobacter pylori (H pylori) affects the efficacy of eradication therapy. The aim of this study was to estimate the prevalence of primary and secondary resistance of H pylori isolates to antibiotics in Korea.

Methods: The present study was performed from 2003 to 2018. Primary resistance was evaluated in 591 patients without any history of eradication and secondary resistance in 149 patients from whom Helicobacter pylori was cultured after failure of eradication. A minimal inhibitory concentration test was performed for amoxicillin, clarithromycin, metronidazole, tetracycline, levofloxacin, and rifabutin using the agar dilution method.

Results: An increase in the primary resistance rate was found in clarithromycin (P < .001), metronidazole (P < .001), and both levofloxacin (P < .001) during the study period. The primary resistance rates of amoxicillin and tetracycline were low and stable during the study period. The secondary resistance rate significantly increased in metronidazole and levofloxacin (P = .022 and .039, respectively).

Conclusions: The primary and secondary resistance rates of clarithromycin, metronidazole, and levofloxacin for Helicobacter pylori in Korea were high and increased over time. However, the primary and secondary resistance rates of amoxicillin and tetracycline were low and stable over time. These results will help in selecting effective eradication regimens of H pylori in Korea in the future.
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http://dx.doi.org/10.1111/hel.12660DOI Listing
December 2019

Gut microbiota and butyrate level changes associated with the long-term administration of proton pump inhibitors to old rats.

Sci Rep 2019 04 29;9(1):6626. Epub 2019 Apr 29.

Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea.

The association between adverse effects of PPI and gut microbiota in old age has yet to be elucidated. We assessed changes in the gut microbiota and butyrate levels following the long-term administration of PPIs to old rats and investigated their associations. F344 aged male rats were fed a PPI-supplemented diet for 50 weeks. The ileal microbiota was analysed by metagenomic sequencing of the 16S rRNA, while the butyrate concentration was measured by high-performance liquid chromatography. We observed a significant decrease in microbial diversity following PPI administration in the 2-year-old rats but not in the 74-week-old rats. PPI treatment reduced both commensal bacteria and opportunistic pathogens, particularly in the 2-year-old rats. Enterotypes comprising the majority of the control samples were enriched in Lactobacillus, while other enterotypes in the PPI group were dominated by Turicibacter or Romboutsia. The PPI treatment reduced the butyrate concentrations in the intestines and colons of 74-week-old rats compared to the control group. The abundance of Lactobacillus significantly correlated with butyrate concentrations in 74-week-old rats. In conclusion, long-term administration of PPIs alters the gut microbiota and butyrate concentrations in rats, particularly in old age, which may be an underlying mechanism of PPI-induced adverse effects such as pseudomembranous colitis.
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http://dx.doi.org/10.1038/s41598-019-43112-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488615PMC
April 2019

Rat Intestinal Acetic Acid and Butyric acid and Effects of Age, Sex, and High-fat Diet on the Intestinal Levels in Rats.

J Cancer Prev 2019 Mar 30;24(1):20-25. Epub 2019 Mar 30.

Department of Biological Sciences and Institute of Microbiology, Seoul National University, Seoul, Korea.

Background: High-fat diet is known to be implicated in the pathogenesis of various metabolic disorders related to an inflammatory response. The aim of this study was to investigate the influence of high-fat diet for intestinal acetic acid and butyric acid concentrations which are related to inflammation-associated colon cancer risk.

Methods: Both male and female rats of 6, 31, 74 and 104-week of age were fed chow diet or high-fat diet for 8 weeks. Body weight and food intake were measured weekly during the feeding period. Intestinal acetic acid and butyric acid levels were measured by high-performance liquid chromatography from luminal contents of ileum and cecum.

Results: Male rats showed greater weight change than female rats in every age. Calorie-adjusted food intake was also higher in male rats compared to female rats. Male rats showed similar intake of food in every age while 31-week old female rats showed increased intake, which was decreased at 74-week and 104-week of age. The ileal acetic acid concentration was increased in male rats fed high-fat diet, while female rats fed high-fat diet showed no significant change in the ileal acetic acid level. On the other hand, butyric acid almost disappeared in high-fat diet fed rats regardless of sex.

Conclusions: High-fat diet increases the intestinal acetic acid concentration while reducing the butyric acid concentration which may account for increased risk of inflammation-associated colon cancer.
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http://dx.doi.org/10.15430/JCP.2019.24.1.20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453582PMC
March 2019

Effects of 17β-estradiol on colorectal cancer development after azoxymethane/dextran sulfate sodium treatment of ovariectomized mice.

Biochem Pharmacol 2019 06 11;164:139-151. Epub 2019 Apr 11.

Tumor Microenvironment Global Core Research Center, Seoul National University College of Pharmacy, Seoul, South Korea.

Estrogen is known to have a protective effect in colorectal cancer (CRC) development. Previously, we reported the anti-inflammatory and antitumorigenic effects of 17β-estradiol (E2) in azoxymethane (AOM)/dextran sulfate sodium (DSS)-treated male mice. The aim of this study was to investigate whether ovariectomy in a female AOM/DSS mouse model increases colorectal tumorigenesis and whether tumorigenesis is reduced by estrogen supplementation after ovariectomy. Clinical symptoms and histological severity of colitis and the levels of inflammatory mediators were evaluated in the colon of AOM/DSS-treated ovariectomized (OVX) mice. The levels of E2, myeloperoxidase (MPO), and NF-κB-dependent cytokines (interleukin (IL)-1β and IL-6) were measured by ELISA. Furthermore, quantitative real-time (qRT) PCR and Western blot analysis were performed. Ovariectomy did not aggravate AOM/DSS-induced colitis at 2 weeks. At weeks 10 and 16, ovariectomy significantly increased tumor number and incidence rate in only the proximal colon after AOM/DSS treatment (F_AOM/DSS vs OVX_AOM/DSS), and these increases were significantly reduced by E2 supplementation (OVX_AOM/DSS vs OVX_AOM/DSS/E2). However, ovariectomy did not affect CRC development in the distal colon (F_AOM/DSS vs OVX_AOM/DSS). At week 2, E2 administration to AOM/DSS-treated OVX mice attenuated the histological severity of colitis by decreasing the protein and/or mRNA levels of estrogen receptor alpha (ERα) and NF-κB-related mediators (i.e., COX-2, TNF-α, and IL-6) and by enhancing estrogen receptor beta (ERβ) and nuclear Nrf2 protein expression and the mRNA expression of related antioxidant enzyme genes (i.e., HO-1, GCLC, GCLM, and NQO1). Endogenous estrogen in females protects against the development of proximal colon cancer, and exogenous E2 replacement in OVX female mice showed protective effects against AOM/DSS-induced colitis and carcinogenesis. The mechanism could involve modulating ERs-, NF-κB- and Nrf2-mediated pathways.
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http://dx.doi.org/10.1016/j.bcp.2019.04.011DOI Listing
June 2019

Risk factors of rescue bismuth quadruple therapy failure for Helicobacter pylori eradication.

J Gastroenterol Hepatol 2019 Apr 25;34(4):666-672. Epub 2019 Feb 25.

Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.

Background And Aim: Failure of bismuth quadruple therapy for Helicobacter pylori eradication is frequently observed. To increase the eradication rate, comprehensive analyses need to be performed regarding risk factors of bismuth quadruple therapy failure based on complete standard culture and antimicrobial susceptibility testing results.

Methods: Patients with history of failed first therapy who had H. pylori colonies isolated from culture and successful minimum inhibitory concentration (MIC) test were enrolled. Esomeprazole, bismuth, metronidazole, and tetracycline (quadruple) therapies for 7 or 14 days were given. Eradication rate, treatment compliance, adverse events, and risk factors for the failure of bismuth quadruple therapy were analyzed.

Results: A total 54 patients were enrolled. Overall eradication rate in the present study was 88.8%. The eradication rate for cases with metronidazole resistance such as MIC 8-16 μg/mL or 16-32 μg/mL was 92.8% (13/14). For cases with high level metronidazole resistance (MIC > 32 μg/mL), the eradication rate was only 60% (6/10). Multivariate analysis regarding compliance, treatment duration, age > 60, three kinds of metronidazole MICs, tetracycline MIC > 4 μg/mL, adverse events and any other parameters, "metronidazole resistance, high level (MIC > 32 μg/mL)" was the only independent risk factor for eradication failure (P = 0.007).

Conclusion: For cases with metronidazole resistance at MIC > 32 μg/mL, rescue therapy other than bismuth-containing quadruple therapy is needed.
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http://dx.doi.org/10.1111/jgh.14625DOI Listing
April 2019

Effects of 17β-Estradiol on Colonic Permeability and Inflammation in an Azoxymethane/Dextran Sulfate Sodium-Induced Colitis Mouse Model.

Gut Liver 2018 11;12(6):682-693

Tumor Microenvironment Global Core Research Center, Seoul National University College of Pharmacy, Seoul, Korea.

Background/aims: Intestinal barrier dysfunction is a hallmark of inflammatory bowel diseases (IBDs) such as ulcerative colitis. This dysfunction is caused by increased permeability and the loss of tight junctions in intestinal epithelial cells. The aim of this study was to investigate whether estradiol treatment reduces colonic permeability, tight junction disruption, and inflammation in an azoxymethane (AOM)/dextran sodium sulfate (DSS) colon cancer mouse model.

Methods: The effects of 17β-estradiol (E2) were evaluated in ICR male mice 4 weeks after AOM/DSS treatment. Histological damage was scored by hematoxylin and eosin staining and the levels of the colonic mucosal cytokine myeloperoxidase (MPO) were assessed by enzyme-linked immunosorbent assay (ELISA). To evaluate the effects of E2 on intestinal permeability, tight junctions, and inflammation, we performed quantitative real-time polymerase chain reaction and Western blot analysis. Furthermore, the expression levels of mucin 2 (MUC2) and mucin 4 (MUC4) were measured as target genes for intestinal permeability, whereas zonula occludens 1 (ZO-1), occludin (OCLN), and claudin 4 (CLDN4) served as target genes for the tight junctions.

Results: The colitis-mediated induced damage score and MPO activity were reduced by E2 treatment (p<0.05). In addition, the mRNA expression levels of intestinal barrier-related molecules (i.e., MUC2, ZO-1, OCLN, and CLDN4) were decreased by AOM/DSS-treatment; furthermore, this inhibition was rescued by E2 supplementation. The mRNA and protein expression of inflammation-related genes (i.e., KLF4, NF-κB, iNOS, and COX-2) was increased by AOM/DSS-treatment and ameliorated by E2.

Conclusions: E2 acts through the estrogen receptor β signaling pathway to elicit anti-inflammatory effects on intestinal barrier by inducing the expression of MUC2 and tight junction molecules and inhibiting pro-inflammatory cytokines.
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http://dx.doi.org/10.5009/gnl18221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6254630PMC
November 2018

Microbial Changes and Host Response in F344 Rat Colon Depending on Sex and Age Following a High-Fat Diet.

Front Microbiol 2018 21;9:2236. Epub 2018 Sep 21.

Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea.

Gut microbiota, an important component that affects host health, change rapidly and directly in response to altered diet composition. Recently, the role of diet-microbiome interaction on the development of colon cancer has been the focus of interest. Colon cancer occurs more frequently in an aged population, and in males. However, the effect of dietary changes on the gut microbiome has been studied mainly in young males, even though it may vary with age and sex. The aim of this study was to investigate microbial changes and host response in the colons of male and female 6-week-old (young) and 2-year-old (old) Fisher-344 rats exposed to a high-fat diet (HFD). Our results showed that exposure to HFD for 8 weeks decreased the species richness of microbiota (Chao1) and increased / ratio only in aged rats, and not in young rats. Sex differences underlying the alteration by HFD in the gut microbiome were observed in the microbiome of aged rats. For instance, the abundance ratio of and spp. increased in response to HFD in young rats and female aged rats, but not in male aged rats. Histological inflammation and cell proliferation of colon mucosa (indexed by Ki67) were significantly increased by HFD even in young rats; aged rats showed significantly higher cell proliferation in the HFD group than in the control. The HFD-induced decrease of species richness and the increase in specific species ( spp. and ), which produce carcinogenic compounds such as HS and -nitroso compounds, were significantly correlated with Ki67 index. In colon mucosa, the concentration of myeloperoxidase was increased by HFD only in males, and not in females. In conclusion, the results suggest a link between HFD-induced gut dysbiosis (particularly the low species richness and high abundance ratios of spp. and ) and cell proliferation of colon mucosa (indicated by Ki67 IHC). In addition, sex differences influence the response of gut microbiome to HFD particularly in old age. Such sex differences in the gut microbiota might be related to sex differences in inflammation in the colon mucosa.
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http://dx.doi.org/10.3389/fmicb.2018.02236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160749PMC
September 2018

Effect of Estradiol in an Azoxymethane/Dextran Sulfate Sodium-Treated Mouse Model of Colorectal Cancer: Implication for Sex Difference in Colorectal Cancer Development.

Cancer Res Treat 2019 Apr 1;51(2):632-648. Epub 2018 Aug 1.

Tumor Microenvironment Global Core Research Center, Seoul National University College of Pharmacy, Seoul, Korea.

Purpose: This study demonstrates that estradiol downregulates inflammation and inhibits colorectal cancer (CRC) development in azoxymethane/dextran sulfate sodium (AOM/DSS) mouse model.

Materials And Methods: AOM/DSS-treated male and female mice were sacrificed at weeks 2, 10, and 16, to assess estrogen effects on colitis and carcinogenesis. Macroscopic and histologic severity of colitis and Western blot and quantitative real-time polymerase chain reaction were evaluated, to measure inflammatory mediators and cytokines.

Results: Compared with AOM/DSS-treated male mice (M-AOM/DSS group), AOM/DSS-treated male mice with estradiol administration (M-AOM/DSS+estr group) displayed at week 2 significantly decreased severity of colitis. At weeks 10 and 16, AOM/DSS-treated female mice (F-AOM/DSS group) and the M-AOM/DSS+estr group showed significantly lower tumor multiplicity compared with the M-AOM/DSS group. At week 2, F-AOM/DSS group had a lower level of nuclear factor-κB (NF-κB) expression and higher level of nuclear factor erythroid 2-related factor 2 (Nrf2) expression, compared to the M-AOM/DSS group. At week 2, expression levels of NF-κB and its related mediators decreased in the M-AOM/DSS+estr group, while levels of Nrf2 and Nrf2-related anti-oxidant enzymes increased. In addition, estradiol significantly increased Nod-like receptor protein 3 (NLRP3) inflammasome expressions in AOM/DSS-treated male mice. In contrast, at weeks 10 and 16, Nrf2 and its-related anti-oxidant enzymes and NLRP3 inflammasome were highly expressed in M-AOM/DSS group and in F-AOM/DSS group, who developed cancer.

Conclusion: The data suggest that estradiol inhibits the initiation of CRC by regulating Nrf2-related pathways. Moreover, these imply the dual role of Nrf2 and NLRP3 inflammasome, including promotion of tumor progression upon tumor initiation.
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http://dx.doi.org/10.4143/crt.2018.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473282PMC
April 2019

Comparative Analysis of Ileal and Cecal Microbiota in Aged Rats.

J Cancer Prev 2018 Jun 30;23(2):70-76. Epub 2018 Jun 30.

Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.

Background: Gut microbiota contributes to intestinal and immune homeostasis through host-microbiota interactions. Distribution of the gut microbiota differs according to the location in the gastrointestinal tract. Although the microbiota properties change with age, evidence for the regional difference of gut microbiota has been restricted to the young. The aim of this study is to compare the gut microbiota between terminal ileum and cecum of old rats.

Methods: We analyzed gut microbiome of luminal contents from ileum and cecum of 74-week-old and 2-year-old rats (corresponding to 60-year and 80-year-old of human age) by metagenome sequencing of 16S rRNA.

Results: Inter-individual variation (beta diversity) of microbiota was higher in ileum than in cecum. Conversely, alpha diversity of microbiota composition was higher in cecum than in ileum. were more abundant in ileum compared to cecum while and were more enriched in cecum. The proportions of were increased in cecal microbiota of 2-year-old rats compared to 74-week-old rats.

Conclusions: Major regional distinctions of microbiota between ileum and cecum of old rats appear consistent with those of young rats. Age-related alterations of gut microbiota in old rats seem to occur in minor compositions.
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http://dx.doi.org/10.15430/JCP.2018.23.2.70DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6037205PMC
June 2018

Erratum: Analysis of Gastric Body Microbiota by Pyrosequencing: Possible Role of Bacteria Other Than in the Gastric Carcinogenesis.

J Cancer Prev 2017 Dec 30;22(4):267. Epub 2017 Dec 30.

Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.

[This corrects the article on p. 115 in vol. 22, PMID: 28698866.].
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http://dx.doi.org/10.15430/JCP.2017.22.4.267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5751846PMC
December 2017

Probiotics reduce repeated water avoidance stress-induced colonic microinflammation in Wistar rats in a sex-specific manner.

PLoS One 2017 15;12(12):e0188992. Epub 2017 Dec 15.

Departments of Internal Medicine, Seoul National University Bundang Hospital, Seoungnam, South Korea.

The colonic response to stress is greater in female rats than in male rats. The aim of this study was to evaluate the effect of probiotics in the repeated water avoidance stress (rWAS)-induced colonic microinflammation model of Wistar rats in a sex-specific manner. The three groups (no-stress, WAS, and WAS with probiotics) were exposed to r-WAS for 1 h daily for 10 days, and Lactobacillus farciminis was administered by oral gavage for 10 days to animals in the probiotics group. The visceromotor response (VMR) to colorectal distension (CRD) was assessed using a barostat and noninvasive manometry before and after WAS exposure. Immunohistochemistry for mast cells and real-time polymerase chain reaction (RT-PCR) for detection of mucosal cytokines were performed using distal colon tissue after the animals were sacrificed. Significant reduction of VMR to CRD (visceral analgesia) was observed at 60 mmHg in the female WAS group (P = 0.045), but not in males. In addition, the female WAS with probiotics group showed a significantly lower colonic mucosal mast cell count in comparison to the female WAS group (P = 0.013), but this phenomenon was not observed in the male group. The colonic mucosal mRNA levels of interferon-γ (IFNR), tumor necrosis factor-α (TNFA), interleukin (IL) 6, and IL17 were higher in the female WAS group than in the male WAS group. The mRNA levels of IFNR, TNFA, and IL6 were significantly decreased in WAS females who received probiotics (all P < 0.050). In conclusion, rWAS is induced in a sex-specific manner. A 10-day-long treatment with L. farciminis is an effective therapy for rWAS-induced colonic microinflammation in female rates, but not in male rats.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0188992PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731730PMC
January 2018

Changes in the interstitial cells of Cajal and neuronal nitric oxide synthase positive neuronal cells with aging in the esophagus of F344 rats.

PLoS One 2017 28;12(11):e0186322. Epub 2017 Nov 28.

Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, S. Korea.

The aging-associated cellular and molecular changes in esophagus have not been established, yet. Thus we evaluated histological structure, interstitial cells of Cajal (ICCs), neuronal nitric oxide synthase (nNOS)-positive cells, and contractility in the esophagus of Fischer 344 rat at different ages (6-, 31-, 74-weeks, and 2-years). The lamina propria thickness and endomysial area were calculated. The immunoreactivity of c-Kit, nNOS and protein gene product (PGP) 9.5 was counted after immunohistochemistry. Expression of c-Kit, stem cell factor (SCF), nNOS and PGP 9.5 mRNA was measured by real-time PCR, and expression of c-Kit and nNOS protein was detected by Western blot. Isovolumetric contractile force measurement and electrical field stimulation (EFS) were conducted. The lamina propria thickness increased (6 week vs 2 year, P = 0.005) and the endomysial area of longitudinal muscle decreased with aging (6 week vs 2 year, P<0.001), while endomysial area of circular muscle did not significantly decrease. The proportions of NOS-immunoreactive cells and c-Kit-immunoreactive areas declined with aging (6 week vs 2 year; P<0.001 and P = 0.004, respectively), but there was no significant change of PGP 9.5-immunopositiviy. The expressions of nNOS, c-Kit and SCF mRNA also reduced with aging (6 week vs 2 year; P = 0.006, P = 0.001 and P = 0.006, respectively), while the change of PGP 9.5 mRNA expression was not significant. Western blot showed the significant decreases of nNOS and c-Kit protein expression with aging (6 week vs 2 year; P = 0.008 and P = 0.012, respectively). The EFS-induced esophageal contractions significantly decreased in 2-yr-old rat compared with 6-wk-old rats, however, L-NG-Nitroarginine methylester did not significantly increase the spontaneous and EFS-induced contractions in the 6-wk- and 2-yr-old rat esophagus. In conclusion, an increase of lamina propria thickness, a decrease of endomysial area, c-Kit, SCF and NOS expression with preserved total enteric neurons, and contractility in aged rat esophagus may explain the aging-associated esophageal dysmotility.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0186322PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705109PMC
December 2017

Specific mutations of penicillin-binding protein 1A in 77 clinically acquired amoxicillin-resistant Helicobacter pylori strains in comparison with 77 amoxicillin-susceptible strains.

Helicobacter 2017 Dec 25;22(6). Epub 2017 Aug 25.

Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea.

Background: Amoxicillin (Amx) is one of the most important antibiotics for eradication of Helicobacter pylori (H. pylori). Main determinants of genetically stable Amx resistance are mutations in the C-terminus of penicillin-binding protein 1A (pbp1A). However, contribution of individual mutation remains unclear.

Methods: 77 Amx-resistant (Amx ) and 77 Amx-susceptible (Amx ) H. pylori strains were isolated from gastric tissues, and DNA sequencing was performed to compare C-terminus sequences of pbp1A gene between Amx and Amx strains. Natural transformation of these mutated genes into amoxicillin-susceptible strains was performed.

Results: Among many mutations in pbp1A, D479E (OR: 37.4, 95% CI: 5.53-252.49, P < .001), and T593 mutation (OR: 32.0, 95% CI: 4.04-252.86, P < .001) independently contributed to Amx resistance in H. pylori strains. In the transformation experiment, T593 mutations were identified in their transformants showing Amx resistance. However, PCR product of D479E was not inserted into recipient (ATCC 43504) resulting in transformation failure.

Conclusion: Amx resistance is associated with various substitutions in pbp1A and T593 mutation contributes to Amx resistance of H. pylori.
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http://dx.doi.org/10.1111/hel.12437DOI Listing
December 2017

Comparison of Changes in the Interstitial Cells of Cajal and Neuronal Nitric Oxide Synthase-positive Neuronal Cells With Aging Between the Ascending and Descending Colon of F344 Rats.

J Neurogastroenterol Motil 2017 Oct;23(4):592-605

Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Korea.

Background/aims: Neuronal degeneration and changes in interstitial cells of Cajal (ICCs) are important mechanisms of age-related constipation. This study aims to compare the distribution of ICCs and neuronal nitric oxide synthase (nNOS) with regard to age-related changes between the ascending colon (AC) and descending colon (DC) in 6-, 31-, and 74-week old and 2-year old male Fischer-344 rats.

Methods: The amount of fecal pellet and the bead expulsion times were measured. Fat proportion in the muscle layer of the colon was analyzed by hematoxylin and eosin staining. Proto-oncogene receptor tyrosine kinase (KIT) and neuronal nitric oxide synthase (nNOS) expression were analyzed with Western blotting and immunohistochemistry. Isovolumetric contractile measurements and electrical field stimulation were used to assess smooth muscle contractility.

Results: Colon transit and bead expulsion slowed with senescence. Fat in the muscle layer accumulated with age in the AC, but not in the DC. The proportion of KIT-immunoreactive ICCs in the submucosal and myenteric plexus was higher in the DC than in the AC, and it declined with age, especially in the AC. In contrast, the proportion of NOS-immunoreactive neurons in the myenteric plexus was higher in the AC than in the DC, and both decreased in older rats. Nitric oxide levels declined with age in the DC. Muscle strip experiments showed that the inhibitory response mediated by nitric oxide in the circular direction of the DC was reduced in 2-year old rats.

Conclusion: The AC and DC differ in their distribution of ICCs and nNOS, and age-related loss of nitrergic neurons more severely affects the DC than the AC.
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http://dx.doi.org/10.5056/jnm17061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5628993PMC
October 2017

rdxA, frxA, and efflux pump in metronidazole-resistant Helicobacter pylori: Their relation to clinical outcomes.

J Gastroenterol Hepatol 2018 Mar;33(3):681-688

Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Korea.

Background And Aim: rdxA and frxA mutations and enhancement of efflux pump have been suggested as the cause of metronidazole resistance in Helicobacter pylori. This study was performed to investigate the resistance mechanisms related to clinical eradication outcome, and to examine direct involvement of hefA in metronidazole-resistant isolates with intact rdxA and frxA.

Methods: A total of 53 H. pylori-positive patients who were treated with metronidazole-containing sequential or quadruple therapy from 2011 to 2015 were enrolled. The metronidazole susceptibility of H. pylori isolates was examined by agar dilution test. Mutations in rdxA and frxA, were analyzed with DNA sequencing, and impact of hefA on metronidazole resistance was examined with quantitative real-time reverse transcription polymerase chain reaction, knockout and genetic complementation test for hefA.

Results: Seven mutation types of rdxA and/or frxA were found in H. pylori isolated from non-eradicated subjects. rdxA mutation was associated with eradication failure (P = 0.002), and nonsense mutation in rdxA reduced eradication efficacy (P = 0.009). hefA expression was significantly higher in resistant isolates (P < 0.001), especially in rdxA(-)frxA(-) as compared to rdxA(+)frxA(+) (P = 0.027). Resistant isolates with no mutation in rdxA and frxA became susceptible after hefA knockout. Genetic complementation for hefA recovered metronidazole resistance in all of three hefA knockout mutants.

Conclusions: These results suggest that rdxA mutations play a critical role in metronidazole resistance as well as the outcomes of eradication therapy. In addition, hefA seems to be directly involved in metronidazole resistance, which explains the resistance in clinical isolates with intact rdxA and frxA.
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http://dx.doi.org/10.1111/jgh.13906DOI Listing
March 2018

Analysis of Gastric Body Microbiota by Pyrosequencing: Possible Role of Bacteria Other Than in the Gastric Carcinogenesis.

J Cancer Prev 2017 Jun 30;22(2):115-125. Epub 2017 Jun 30.

Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.

Background: Gastric microbiota along with (HP) plays a key role in gastric disease. The aim of our study is to investigate the difference of human gastric microbiota between antrum and body according to disease (control vs. gastric cancer) and HP status.

Methods: Each antrum and body biopsy was collected from 12 subjects at Seoul National University Bundang Hospital. Gastric microbiota was analyzed by bar-coded 454 pyrosequencing of the 16S rRNA gene. Twelve subjects consisted of HP-negative control (n = 2), HP-negative cancer (n = 2), HP-positive control (n = 3), and HP-positive cancer (n = 5). The analysis was focused on non-HP urease-producing bacteria (UB) and non-HP nitrosating or nitroreducing bacteria (NB) between antrum and body.

Results: Gastric body samples showed higher diversity compared to gastric antrum mucosa samples but there was no significant difference. The mean of operational taxonomic units was higher in HP(-) cancer than HP(+) cancer (antrum, 273.5 vs. 228.2, = 0.439; body, 585.5 vs. 183.2, = 0.053). The number of non-HP UB and non-HP NB was higher in HP(-) cancer groups than the others. These differences were more pronounced in the body ( = 0.051 and = 0.081, respectively). Analysis of overlap of non-HP UB and non-HP NB revealed the higher composition of , and in HP(-) cancer groups than the others, only in the body ( = 0.030) but not in the antrum ( = 0.123).

Conclusions: Higher diversity and higher composition of , and in HP(-) cancer group than the other groups in the body suggest that analysis of microbiota from body mucosa could be beneficial to identify a role of non-HP bacteria in the gastric carcinogenesis.
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http://dx.doi.org/10.15430/JCP.2017.22.2.115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503224PMC
June 2017

Pantoprazole Does Not Reduce the Antiplatelet Effect of Clopidogrel: A Randomized Controlled Trial in Korea.

Gut Liver 2017 Jul;11(4):504-511

Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.

Background/aims: Concerns that proton pump inhibitors (PPIs) diminish the efficacy of clopidogrel could hamper the appropriate prescription of PPIs. We evaluated the influence of pantoprazole on the antiplatelet effect of clopidogrel compared with ranitidine, which is regarded as safe, after stratification of the population according to the presence of a cytochrome (CYP) 2C19 polymorphism in Korea.

Methods: Forty patients who underwent dual antiplatelet therapy were randomized to receive pantoprazole (n=20) or ranitidine (n=20). Platelet aggregation was evaluated by impedance aggregometry at baseline (D0) and 8 days after acid-lowering treatments (D9). CYP2C19 was genotyped by polymerase chain reaction-restriction fragment length polymorphism.

Results: After co-treatment, the percentage of clopidogrel low-response was 11.1% (2/18) in the pantoprazole group and 10.5% (2/19) in the ranitidine group (p=0.954). The impedance values with adenosine diphosphate stimulus after acid-lowering treatments did not significantly differ between the two groups. In a multiple regression analysis, only ST-elevation myocardial infarction was marginally associated with a reduced antiplatelet effect (odds ratio, 12.07; 95% confidence interval, 0.84 to 173.78). However, pantoprazole use did not affect the antiplatelet effect after correction for the polymorphism.

Conclusions: This study showed that pantoprazole does not increase platelet aggregation in patients receiving dual antiplatelet therapy (ClinicalTrials.gov number: NCT02733640).
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http://dx.doi.org/10.5009/gnl16352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491085PMC
July 2017

The Effect of Sex on the Azoxymethane/Dextran Sulfate Sodium-treated Mice Model of Colon Cancer.

J Cancer Prev 2016 Dec 30;21(4):271-278. Epub 2016 Dec 30.

Receptor Cell Biology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD 20852, USA.

Background: The colitis-associated cancer exhibits different characteristics according to sex in the initiation and progression of the tumors. The aim of this study was to investigate the sex-associated difference in the azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colitis-associated cancer model.

Methods: The AOM/DSS ICR mouse model was established to compare male with female, and then the severity of colitis-associated carcinogenesis was examined macroscopically and histologically regarding the number, size, and location of tumors. Subsequently, levels of colonic mucosal cytokine, interleukin (IL)-1β and myeloperoxidase (MPO) were assessed.

Results: At the 16th week, the tumor multiplicity and the pro-inflammatory factors differed according to sex. The total tumor number was significantly higher in male ( = 0.020) and the number of large tumors (diameter > 2 mm) was higher in male ( = 0.026). In male, the tumors located more in distal colon ( = 0.001). MPO was significantly higher in AOM/DSS-treated male mice compared to the control group ( = 0.003), whereas the corresponding female group showed no significant change ( = 0.086). Colonic IL-1β level significantly increased in AOM/DSS groups compared to control groups both in male and female (male, = 0.014; female, = 0.005). It was higher in male group; however, there was no statistical significance ( = 0.226).

Conclusions: In AOM/DSS murine model, colitis-associated colon tumorigenesis are induced more severely in male mice than female probably by way of inflammatory mediators such as IL-1β and MPO. The sex-related differences at the animal model of colon cancer suggest the importance of approach to disease with sex-specific medicine in human.
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http://dx.doi.org/10.15430/JCP.2016.21.4.271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5207612PMC
December 2016

Change in the Interstitial Cells of Cajal and nNOS Positive Neuronal Cells with Aging in the Stomach of F344 Rats.

PLoS One 2017 3;12(1):e0169113. Epub 2017 Jan 3.

Departments of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.

The gastric accommodation reflex is an important mechanism in gastric physiology. However, the aging-associated structural and functional changes in gastric relaxation have not yet been established. Thus, we evaluated the molecular changes of interstitial cell of Cajal (ICC) and neuronal nitric oxide synthase (nNOS) and the function changes in the corpus of F344 rats at different ages (6-, 31-, 74-wk and 2-yr). The proportion of the c-Kit-positive area in the submucosal border (SMB) and myenteric plexus (MP) layer was significantly lower in the older rats, as indicated by immunohistochemistry. The density of the nNOS-positive immunoreactive area also decreased with age in the SMB, circular muscle (CM), and MP. Similarly, the percent of nNOS-positive neuronal cells per total neuronal cells and the proportion of nNOS immunoreactive area of MP also decreased in aged rats. In addition, the mRNA and protein expression of c-Kit and nNOS significantly decreased with age. Expression of stem cell factor (SCF) and the pan-neuronal marker PGP 9.5 mRNA was significantly lower in the older rats than in the younger rats. Barostat studies showed no difference depending on age. Instead, the change of volume was significantly decreased by L-NG63-nitroarginine methyl ester in the 2-yr-old rats compared with the 6-wk-old rats (P = 0.003). Taken together, the quantitative and molecular nNOS changes in the stomach might play a role in the decrease of gastric accommodation with age.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0169113PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5207530PMC
September 2017

Açaí Berries Inhibit Colon Tumorigenesis in Azoxymethane/Dextran Sulfate Sodium-Treated Mice.

Gut Liver 2017 Mar;11(2):243-252

Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.

Background/aims: The aim of this study was to investigate the protective effect of açaí against azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colorectal cancer development.

Methods: The effect of açaí on tumorigenesis was assessed by evaluating tumor incidence, multiplicity and invasiveness in the mouse colon. The levels of myeloperoxidase (MPO) and proinflammatory cytokines (tumor necrosis factor α [TNF-α], interleukin [IL]-1β, and IL-6) were measured via enzyme-linked immunosorbent assay. Protein levels of cyclooxygenase 2 (COX-2), proliferating cell nuclear antigen (PCNA), B-cell lymphoma 2 (Bcl-2), Bcl-2-associated death promoter (Bad) and cleaved-caspase-3 were assessed by immunoblotting.

Results: Administration of pellets containing 5% açaí powder reduced the incidences of both colonic adenoma and cancer (adenoma, 23.1% vs 76.9%, respectively, p=0.006; cancer, 15.4% vs 76.9%, respectively, p=0.002). In the açaí-treated mice, the MPO, TNF-α, IL-1β and IL-6 levels in the colon were significantly down-regulated. Açaí inhibited PCNA and Bcl-2 expression and increased Bad and cleaved-caspase-3 expression. studies demonstrated that açaí treatment reduced lipopolysaccharide-induced expression of TNF-α, IL-1β, IL-6 and COX-2 in murine macrophage RAW 264.7 cells.

Conclusions: Açaí demonstrated protective effects against AOM/DSS-induced colon carcinogenesis, which suggests that the intake of açaí may be beneficial for the prevention of human colon cancer.
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http://dx.doi.org/10.5009/gnl16068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347649PMC
March 2017

Impact of Long-Term Proton Pump Inhibitor Therapy on Gut Microbiota in F344 Rats: Pilot Study.

Gut Liver 2016 Nov;10(6):896-901

Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.

Background/aims: To evaluate changes in gut microbiota composition following long-term proton pump inhibitor (PPI) treatment.

Methods: Twenty-four-week-old F344 rats were fed diets with (n=6) or without (n=5) lansoprazole for 50 weeks. Profiles of luminal microbiota in the terminal ileum were then analyzed. Pyrosequencing of the 16S rRNA gene was performed using an FLX genome sequencer (454 Life Sciences/Roche).

Results: Rats treated with lansoprazole showed significantly reduced body weights compared to controls (lansoprazole-treated rats and controls, 322.3±15.3 g vs 403.2±5.2 g, respectively, p<0.001). However, stool frequencies and consistencies did not differ between the two groups. The composition of the gut microbiota in lansoprazole-treated rats was quite different from that of the controls. In the controls, the microbiota profiles obtained from the terminal ileum showed a predominance of (93.9%) due to the abundance of and genera. Conversely, lansoprazole-treated rats showed an elevated population of (66.9%), which was attributed to an increased ratio of to genera.

Conclusions: This preliminary study suggests that long-term administration of PPI may cause weight loss and changes to the microbiota in the terminal ileum.
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http://dx.doi.org/10.5009/gnl15529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5087928PMC
November 2016