Migyeong Jeong

Endogenous conversion of ω‐6 to ω‐3 polyunsaturated fatty acids in fat‐1 mice attenuated intestinal polyposis by either inhibiting COX‐2/β‐catenin signaling or activating 15‐PGDH/IL‐18

Omega‐3 polyunsaturated fatty acids (ω‐3PUFAs) have inhibitory effects in various preclinical cancer models, but their effects in intestinal polyposis have never been examined. As attempts have been made to use nutritional intervention to counteract colon cancer development, in this study we evaluated the effects of ω‐3 PUFAs on intestinal polyposis in the ApcMin/+ mouse model. The experimental groups included wild‐type C56BL/6 mice, ApcMin/+ mice, fat‐1 transgenic mice expressing an n‐3 desaturase to enable ω‐3 PUFA synthesis, and ApcMin/+ × fat‐1 double‐transgenic mice; all mice were 20 weeks of age. Small intestines were collected for gross and pathologic evaluation, including assessment of polyp number and size, followed by immunohistochemical staining and Western blotting. After administration of various concentrations of ω‐3 PUFAs, PUFA levels were measured in small intestine tissue by GC/MS/MS analysis to compare with PUFA synthesis of between C57BL6 and fat‐1mice. As a result, ω‐3 PUFAs significantly attenuated Apc mutation–induced intestinal polyposis accompanied with significant inhibition of Wnt/β‐catenin signaling, COX‐2 and PGE2, but induced significant levels of 15‐PGDH. In addition, significant induction of the inflammasome‐related substrates as IL‐1β and IL‐18 and activation of caspase‐1 was observed in ApcMin/+ × fat‐1 mice. Administration of at least 3 g/60 kg ω‐3 PUFAs was equivalent to ω‐3 PUFAs produced in fat‐1 mice and resulted in significant increase in the expression of IL‐1β, caspase‐3 and IL‐18, as seen in ApcMin/+ × fat‐1 mice. We conclude that ω‐3PUFAs can prevent intestinal polyp formation by inhibition of Wnt/β‐catenin signaling, but increased levels of 15‐PGDH and IL‐18.

Oxidative stress from reflux esophagitis to esophageal cancer: the alleviation with antioxidants

Abstract The incidence of reflux esophagitis increases in world, affecting approximately 20% of Western populations and its consequent lesion, Barrett’s esophagus (BE), established as the primary precursor lesion of esophageal adenocarcinoma (EAC) or Barrett associated adenocarcinoma (BAA), is also increasing in incidence in Asian countries as well as Western countries. The fact that surveillance strategies have not had a major benefit in decreasing the incidence of EAC increased attention to arrest or delay the progression of BE to EAC. Since sustained inflammation and consequent oxidative stress plays core pathogenic role in reflux esophagitis, BE, and BAA, attention paid to anti-inflammatory and antioxidative agents in the treatment of reflux esophagitis. Since the risk of esophagitis is associated with hiatal hernia, body mass index, and duodenogastric reflux, and acid exposure, lifestyle modification and agents to control gastric acidity might be mainstay for treatment, but several studies consistently showed the implication of robust oxidative stress in reflux associated esophageal diseases. In this review article, the pathogenic implication of oxidative stress will be introduced in the development of reflux esophagitis, BE, and EAC. Also, since there is great interest in complete healing of reflux esophagitis and chemoprevention to prevent or slow malignant transformation, the contribution of antioxidants or antioxidative agents, which was delivered during SFRR-Asia 2015 (Chiangmai, Thailand), will be described. Also, the molecular mechanisms how the antioxidative drugs, rebamipide, ecabet sodium, and pantoprazole exerted significant protection from acids or bile acids-associated esophagitis are included.

Dietary prevention of Helicobacter pylori -associated gastric cancer with kimchi

To prove whether dietary intervention can prevent Helicobacter pylori-induced atrophic gastritis and gastric cancer, we developed cancer preventive kimchi (cpKimchi) through special recipe and administered to chronic H. pylori-initiated, high salt diet-promoted, gastric tumorigenesis mice model. H. pylori-infected C57BL/6 mice were administered with cpKimchi mixed in drinking water up to 36 weeks. Gross and pathological gastric lesions were evaluated after 24 and 36 weeks, respectively and explored underlying molecular changes to explain efficacies. Cancer preventive actions of anti-inflammation and anti-mutagenesis were compared between standard recipe kimchi (sKimchi) and special recipe cpKimchi in in vitro H. pylori-infected cell model. The erythematous and nodular changes, mucosal ulcerative and erosive lesions in the stomach were noted at 24th weeks, but cpKimchi administration significantly ameliorated. After 36th weeks, scattered nodular masses, some ulcers, and thin nodular gastric mucosa were noted in H. pylori-infected mice, whereas these gross lesions were significantly attenuated in cpKimchi group. On molecular analysis, significant expressions of COX-2 and IL-6, activated NF-κB and STAT3, increased apoptosis, and marked oxidative stresses were noted in H. pylori-infected group relevant to tumorigenesis, but these were all significantly attenuated in cpKimchi group. cpKimchi extracts imparted significant selective induction of apoptosis only in cancer cells, led to inhibition of H. pylori-induced proliferation, while no cytotoxicity through significant HO-1 induction in non-transformed gastric cells. In conclusion, daily dietary intake of cpKimchi can be an effective way either to rejuvenate H. pylori-atrophic gastritis or to prevent tumorigenesis supported with the concerted actions of anti-oxidative, anti-inflammatory, and anti-mutagenic mechanisms.

Sonic hedgehog inhibitors prevent colitis-associated cancer via orchestrated mechanisms of IL-6/gp130 inhibition, 15-PGDH induction, Bcl-2 abrogation, and tumorsphere inhibition

Sonic hedgehog (SHH) signaling is essential in normal development of the gastrointestinal (GI) tract, whereas aberrantly activated SHH is implicated in GI cancers because it facilitates carcinogenesis by redirecting stem cells. Since colitis-associated cancer (CAC) is associated with inflammatory bowel diseases, in which SHH and IL-6 signaling, inflammation propagation, and cancer stem cell (CSC) activation have been implicated, we hypothesized that SHH inhibitors may prevent CAC by blocking the above SHH-related carcinogenic pathways. In the intestinal epithelial cells IEC-6 and colon cancer cells HCT-116, IL-6 expression and its signaling were assessed with SHH inhibitors and levels of other inflammatory mediators, proliferation, apoptosis, tumorsphere formation, and tumorigenesis were also measured. CAC was induced in C57BL/6 mice by administration of azoxymethane followed by dextran sodium sulfate administration. SHH inhibitors were administered by oral gavage and the mice were sacrificed at 16 weeks. TNF-α–stimulated IEC-6 cells exhibited increased levels of proinflammatory cytokines and enzymes, whereas SHH inhibitors suppressed TNF-α–induced inflammatory signaling, especially IL-6/IL-6R/gp130 signaling. SHH inhibitors significantly induced apoptosis, inhibited cell proliferation, suppressed tumorsphere formation, and reduced stemness factors. In the mouse model, SHH inhibitors significantly reduced tumor incidence and multiplicity, decreased the expression of IL-6, TNF-α, COX-2, STAT3, and NF-κB, and significantly induced apoptosis. In colosphere xenografts, SHH inhibitor significantly suppressed tumorigenesis by inhibiting tumorsphere formation. Taken together, our data suggest that administration of SHH inhibitors could be an effective strategy to prevent colitis-induced colorectal carcinogenesis, mainly by targeting IL-6 signaling, ablating CSCs, and suppressing oncogenic inflammation, achieving chemoquiescence ultimately.

Dietary Intervention of Artemisia and Green Tea Extracts to Rejuvenate Helicobacter pylori-Associated Chronic Atrophic Gastritis and to Prevent Tumorigenesis.

As nonmicrobial dietary approach is capable of controlling Helicobacter pylori infection, we evaluated the efficacy of long‐term dietary administration of Artemisia and/or green tea extracts on H. pylori‐initiated, high‐salt‐promoted chronic atrophic gastritis and gastric tumorigenesis mouse model.

Omega-3 Polyunsaturated Fatty Acids Intake to Regulate Helicobacter pylori-Associated Gastric Diseases as Nonantimicrobial Dietary Approach

Omega-3 polyunsaturated fatty acids (n-3 PUFAs), commonly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been acknowledged as essential long-chain fatty acids imposing either optimal health promotion or the rescuing from chronic inflammatory diseases such as atherosclerosis, fatty liver, and various inflammatory gastrointestinal diseases. Recent studies dealing with EPA and DHA have sparked highest interests because detailed molecular mechanisms had been documented with the identification of its receptor, G protein coupled receptor, and GPR120. In this review article, we have described clear evidences showing that n-3 PUFAs could reduce various Helicobacter pylori- (H. pylori-) associated gastric diseases and extended to play even cancer preventive outcomes including H. pylori-associated gastric cancer by influencing multiple targets, including proliferation, survival, angiogenesis, inflammation, and metastasis. Since our previous studies strongly concluded that nonantimicrobial dietary approach for reducing inflammation, for instance, application of phytoceuticals, probiotics, natural products including Korean red ginseng, and walnut plentiful of n-3 PUFAs, might be prerequisite step for preventing H. pylori-associated gastric cancer as well as facilitating the rejuvenation of precancerous atrophic gastritis, these beneficial lipids can restore or modify inflammation-associated lipid distortion and correction of altered lipid rafts to send right signaling to maintain healthy stomach even after chronic H. pylori infection.

Heme Oxygenase-1 Induction and Anti-inflammatory Actions of Atractylodes macrocephala and Taraxacum herba Extracts Prevented Colitis and Was More Effective than Sulfasalazine in Preventing Relapse

Background/Aims In inflammatory bowel disease (IBD), repeated bouts of remission and relapse occur in patients and can impose a risk of colitis-associated cancer. We hypothesized that plant extracts of Atractylodes macrocephala (AM) or Taraxacum herba (TH) may be better than sulfasalazine for treating this disease because these extracts can promote additional regeneration. Methods Murine intestinal epithelial IEC-6 cells were pretreated with AM or TH before a lipopolysaccharide (LPS)-induced challenge. Acute colitis was induced with 7 days of dextran sulfate sodium (DSS) in male C57BL/6 mice, and extracts of AM and TH were administered for 2 weeks before DSS administration. Results In vitro studies demonstrated that AM or TH treatment reduced LPS-induced COX-2 and tumor necrosis factor-α mRNA levels but increased heme oxygenase-1 (HO-1). Oral preadministration of AM and TH rescued mice from DSS-induced colitis by inhibiting inflammatory mediators via inactivated extracellular signal regulated kinase and repressed nuclear factor κB and signal transducer and activator of transcription 3, but the effect was weaker for sulfasalazine than that for the extracts. Anti-inflammatory activities occurred via the inhibition of macrophage and T lymphocyte infiltrations. Unlike sulfasalazine, which did not induce HO-1, TH extracts afforded significant HO-1 induction. Conclusions Because the AM or TH extracts were far superior in preventing DSS-induced colitis than sulfasalazine, AM or TH extracts can be considered natural agents that can prevent IBD relapse.

The role of chronic inflammation in the development of gastrointestinal cancers: reviewing cancer prevention with natural anti-inflammatory intervention

Inflammatory mediators alter the local environment of tumors, known as the tumor microenvironment. Mechanistically, chronic inflammation induces DNA damage, but understanding this hazard may help in the search for new chemopreventive agents for gastrointestinal (GI) cancer which attenuate inflammation. In the clinic, GI cancer still remains a major cause of cancer-associated mortality, chemoprevention with anti-inflammatory agents is thought to be a realistic approach to reduce GI cancer. Proton pump inhibitors, monoclonal antibodies targeting tumor necrosis factor-alpha, anti-sense targeted smad7 and non-steroidal anti-inflammatory agents have been investigated for their potential to prevent inflammation-based GI cancer. Besides these, a wide variety of natural products have also shown potential for the prevention of GI cancer. In this review, the authors will provide insights to explain the mechanistic connection between inflammation and GI cancer, as well as describe a feasible cancer prevention strategy based on anti-inflammatory treatments.

Dietary, non-microbial intervention to prevent Helicobacter pylori -associated gastric diseases

Since the discovery of Helicobacter pylori (H. pylori) infection as the major cause of gastroduodenal disorders including acute and chronic gastritis, gastroduodenal ulcer, chronic atrophic gastritis, and gastric cancer almost three decades ago, the possibility of preventing these clinical diseases through eradicating H. pylori has been the focus of active research, but soon debate in the scientific community, though eradication opens the feasibility of cancer prevention and the removal of bacteria significantly prevents development or recurrence of peptic ulcer diseases and some clinical diseases, was proposed due to uncertainty in either achievement of complete eradication or inefficacy in cancer prevention with eradication alone. Still its linkage to gastric cancer is incontestable. Since the multiple combination of bacterial factors, environmental insults, and the host immune response that drives the initiation and progression of mucosal atrophy, metaplasia, and dysplasia toward gastric cancer is intervened, simple eradication deemed the feasibility of cancer prevention. Therefore, our group open strong hypothesis that non-microbial, dietary approach might be the alternate, for which several interventions of nutritional components can highlight rejuvenation of chronic atrophic gastritis as well as amelioration of H. pylori-associated procarcinogenic inflammation. In this review article, the experience and outcome regarding nutritional application to rejuvenate gastric atrophy will be introduced, using Korean red ginseng, garlic extracts, cancer preventive Korea kimchi, n-3 polyunsaturated fatty acids (PUFA), special form of licorice, and probiotics. The detailed influence of dietary intervention and bacterial eradication therapy on disease progression and reversibility of premalignant lesions are discussed.

Synthetic 8-hydroxydeoxyguanosine inhibited metastasis of pancreatic cancer through concerted inhibitions of ERM and Rho-GTPase

Abstract 8‐hydroxydeoxyguanosine (8‐OHdG) is generated consequent to oxidative stress, but its paradoxical anti‐oxidative, anti‐inflammatory, and anti‐mutagenic effects via Rho‐GTPase inhibition were noted in various models of inflammation and cancer. Metastasis occurs through cell detachment, epithelial–mesenchymal transition (EMT), and cell migration; during these processes, changes in cell morphology are initiated through Rho‐GTPase‐dependent actin cytoskeleton polymerization. In this study, we explored the anti‐metastatic mechanisms of 8‐OHdG in Panc‐1 pancreatic cancer cells. 8‐OHdG inhibits cell migration by inactivating ERM and Rho‐GTPase proteins, and inhibiting focal adhesion kinase (FAK) and matrix metalloproteinases (MMPs). At 15 min, 8‐OHdG significantly inactivated ERM (p < 0.05) and led to a significant retardation of wound healing; siERM and H1152 (ROCK inhibitor) had similar effects (p < 0.05). However, FAK inhibitor 14, DPI (NOX inhibitor), and NAC (antioxidant) significantly delayed wound healing without inhibiting ERM or CD44 (p < 0.05). In the experiments on cell migration, siERM, siCD44, DPI, and 8‐OHdG significantly inhibited MMPs. 8‐OHdG significantly decreased DCF‐DA activation in Panc‐1 pancreatic cancer cells and down‐regulated NOXs (nox‐1, nox‐2, and nox‐3). Finally, all of these anti‐migration actions of 8‐OHdG resulted in significant inhibition of EMT, as evidenced by the up‐regulation of ZO‐1 and claudin‐1 and down‐regulation of vimentin. We found significant inhibition of lung metastasis of Panc‐1 cells by 8‐OHdG. In conclusion, exogenous 8‐OHdG had potent anti‐metastasis effects mediated by either ERM or Rho GTPase inhibition in metastasis‐prone pancreatic cancer cells. Graphical abstract Figure. No caption available. Highlights8‐OHdG, oxidative DNA adduct, inhibits metastasis of pancreatic cancer.8‐OHdG decreases CD44 expression via inhibiting of ERM and Rho‐GTP activation.8‐OHdG inhibits EMT via reducing of ERM and FAK pathway.8‐OHdG inhibits MMP expression via decreasing of NOXs expression and ROS generation.8‐OHdG blocks metastasis by inhibiting RhoA‐ERM‐CD44‐EMT, ROS and FAK, independently