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.

Suppressed Helicobacter pylori-associated gastric tumorigenesis in Fat-1 transgenic mice producing endogenous ω-3 polyunsaturated fatty acids.

Dietary approaches to preventing Helicobacter pylori (H. pylori)-associated gastric carcinogenesis are widely accepted because surrounding break-up mechanisms are mandatory for cancer prevention, however, eradication alone has been proven to be insufficient. Among these dietary interventions, omega-3-polyunsaturated-fatty acids (ω-3 PUFAs) are often the first candidate selected. However, there was no trial of fatty acids in preventing H. pylori-associated carcinogenesis and inconclusive results have been reported, likely based on inconsistent dietary administration. In this study, we developed an H. pylori initiated-, high salt diet promoted-gastric tumorigenesis model and conducted a comparison between wild-type (WT) and Fat-1-transgenic (TG)-mice. Gross and pathological lesions in mouse stomachs were evaluated at 16, 24, 32, and 45 weeks after H. pylori infection, and the underlying molecular changes to explain the cancer preventive effects were investigated. Significant changes in: i) ameliorated gastric inflammations at 16 weeks of H. pylori infection, ii) decreased angiogenic growth factors at 24 weeks, iii) attenuated atrophic gastritis and tumorigenesis at 32 weeks, and iv) decreased gastric cancer at 45 weeks were all noted in Fat-1-TG-mice compared to WT-mice. While an increase in the expression of Cyclooxygenase (COX)-2, and reduced expression of the tumor suppressive 15-PGDH were observed in WT-mice throughout the experimental periods, the expression of Hydroxyprostaglandin dehydrogenase (15-PGDH) was preserved in Fat-1-TG-mice. Using a comparative protein array, attenuated expressions of proteins implicated in proliferation and inflammation were observed in Fat-1-TG-mice compared to WT-mice. Conclusively, long-term administration of ω-3 PUFAs can suppress H. pylori-induced gastric tumorigenesis through a dampening of inflammation and reduced proliferation in accordance with afforded rejuvenation.

The ω-3 polyunsaturated fatty acids prevented colitis-associated carcinogenesis through blocking dissociation of ß-catenin complex, inhibiting COX-2 through repressing NF-κB, and inducing 15-prostaglandin dehydrogenase.

Numerous studies have demonstrated that diets containing an increased ratio of ω-6 : ω-3 polyunsaturated fatty acids (PUFAs) are a risk factor for colon cancer and might affect tumorigenesis. Therefore, dietary ω-3 PUFA administration may be a preventive strategy against colon cancer. Until now, the exact molecular mechanisms and required dietary doses of ω-3 PUFAs for cancer prevention were unknown. In this study, we explored the anti-tumorigenic mechanisms of ω-3 PUFAs against a colitis-associated cancer (CAC) model. Through in vitro cell models involving docosahexaenoic acid (DHA) administration, down-regulation of survivin and Bcl-2, and up-regulation of Bax, accompanied by blockage of ß-catenin complex dissociation, the main mechanisms responsible for DHA-induced apoptosis in HCT116 cells were determined. Results included significant reduction in azoxymethane-initiated, dextran sodium sulfate-promoted CACs, as well as significant preservation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and significant inhibition of Cyclooxyganase-2 (COX-2) and Prostaglandin E2(P < 0.01). Additional mechanisms and significant induction of apoptosis in both tumor and non-tumor tissues were also noted in fat-1 transgenic (TG) mice. The lipid profiles of colon tissues measured in all specimens revealed that intake greater than 3 g ω-3 PUFA/60 kg of body weight showed tissue levels similar to those seen in fat-1 TG mice, preventing cancer. Our study concluded that COX-2 inhibition, 15-PGDH preservation, apoptosis induction, and blockage of ß-catenin complex dissociation contributed to the anti-tumorigenesis effect of ω-3 PUFAs, and an intake higher than 3g ω-3 PUFAs/60 kg of body weight can assist in CAC prevention.

Korean red ginseng ameliorated experimental pancreatitis through the inhibition of hydrogen sulfide in mice.

AIM: Effective therapy to treat acute pancreatitis (AP) or to prevent its recurrence/complication is still not available. Based on previous results that suggest that: i) hydrogen sulfide (H2S) levels were significantly increased in pancreatitis and gastritis and ii) Korean red ginseng (KRG) efficiently attenuated Helicobacter pylori-associated gastritis through the suppressive actions of H2S, we hypothesized that KRG can ameliorate experimental pancreatitis through suppression of H2S generation. METHODS: C57BL/6 mice were pre-administered KRG and then subjected to cerulein injection or pancreatic duct ligation (PDL) to induce pancreatitis. Blood and pancreas tissues were collected and processed to measure serum levels of amylase, lipase and myeloperoxidase and the concentration of H2S and the levels of various inflammatory cytokine in pancreatic tissues of mice with induced AP. RESULTS: KRG significantly inhibited NaHS-induced COX-2 and TNF-α mRNA in pancreatic cells, but dl-propargylglycine did not. KRG ameliorated cerulein-induced edematous pancreatitis accompanied with significant inactivation of NF-κB and JNK in pancreatic tissues of C57BL/6 mice (p < 0.001) and also significantly ameliorated PDL-induced necrotizing pancreatitis (p<0.01); in both conditions, the significant suppression of H2S resulting from KRG pretreatment afforded rescuing outcomes. Along with suppressed levels of H2S consequent to depressed expressions of CBS and CSE mRNA, KRG administration efficiently decreased the serum level of amylase, lipase, and myeloperoxidase and the expression of inflammatory cytokines in animal models of mild or severe AP. CONCLUSIONS: These results provide evidence for the preventive and therapeutic roles of KRG against AP mediated by H2S suppression.

Endogenous conversion of ω-6 to ω-3 polyunsaturated fatty acids in fat-1 mice attenuated intestinal polyposis by either inhibiting COX-2/ß-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 Apc(Min/+) mouse model. The experimental groups included wild-type C56BL/6 mice, Apc(Min/+) mice, fat-1 transgenic mice expressing an n-3 desaturase to enable ω-3 PUFA synthesis, and Apc(Min/+) × 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/ß-catenin signaling, COX-2 and PGE2, but induced significant levels of 15-PGDH. In addition, significant induction of the inflammasome-related substrates as IL-1ß and IL-18 and activation of caspase-1 was observed in Apc(Min/+) × 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-1ß, caspase-3 and IL-18, as seen in Apc(Min/+) × fat-1 mice. We conclude that ω-3PUFAs can prevent intestinal polyp formation by inhibition of Wnt/ß-catenin signaling, but increased levels of 15-PGDH and IL-18.