Jong-Min Park

Quality of healing of gastric ulcers: Natural products beyond acid suppression

Gastric ulcer is a chronic disease featured with unexpected complications, including bleeding, stenosis and perforation, as well as a high incidence of recurrence. Clinical treatments for gastric ulcer have allowed the rapid development of potent anti-ulcer drugs during the last several decades. Gastric ulcer healing is successful with conventional treatments including H2-receptor antagonists, and proton pump inhibitors (PPIs) have been essential for ulcer healing and prevention of complications. Additionally, Helicobacter pylori eradication therapy is effective in reducing ulcer recurrence and leads to physiological changes in the gastric mucosa which affect the ulcer healing process. However, in spite of these advancements, some patients have suffered from recurrence or intractability in spite of continuous anti-ulcer therapy. A new concept of the quality of ulcer healing (QOUH) was initiated that considers the reconstruction of the mucosal structure and its function for preventing ulcer recurrence. Although several gastroprotection provided these achievements of the QOUH, which PPI or other acid suppressants did not accomplish, we found that gastroprotection that originated from natural products, such as a newer formulation from either Artemisia or S-allyl cysteine from garlic, were very effective in the QOUH, as well as improving clinical symptoms with fewer side effects. In this review, we will introduce the importance of the QOUH in ulcer healing and the achievements from natural products.

S-allyl cysteine alleviates nonsteroidal anti-inflammatory drug-induced gastric mucosal damages by increasing cyclooxygenase-2 inhibition, heme oxygenase-1 induction, and histone deacetylation inhibition.

Nonsteroidal anti‐inflammatory drugs (NSAIDs), the most highly prescribed drugs in the world for the treatment of pain, inflammation, and fever, are associated with gastric mucosal damages including ulcer directly or indirectly. This study was aimed to document the preventive effects of an organosulfur constituent of garlic, S‐allyl cysteine (SAC), against NSAIDs‐induced gastric damages, as well the elucidation of its pharmacological actions, such as anti‐inflammatory, anti‐oxidative, and cytoprotective actions.

Omega-3 Polyunsaturated Fatty Acids as Potential Chemopreventive Agent for Gastrointestinal Cancer

Omega-3 polyunsaturated fatty acids (n-3 PUFAs), particularly eicosapentanoic acid (EPA) and docosahexanoic acid (DHA), has been acknowledged as essential very long-chain fatty acids contributing to either achieving optimal health or protection against diseases, and even longevity. Recent high impact studies dealing with EPA and DHA have sparked a renewed interest in using n-3 PUFAs for cancer prevention and cancer treatment, for which n-3 PUFAs may exert their anticancer actions by influencing multiple targets implicated in various stages of cancer development, including cell proliferation, cell survival, angiogenesis, inflammation, and metastasis against various cancers. However, gastrointestinal cancers develop implicated with the close connection between inflammation and cancer and n-3 PUFAs especially imposed excellent actions of antiinflammation and antioxidation as well as their restorative actions. In detail, these beneficial lipids can restore or modify inflammation-associated lipid distorsion and alteration of lipid rafts. Although the chemopreventive effect of n-3 PUFAs has been studied in various experimental models, our understanding regarding the underlying mechanisms of n-3 PUFAs against GI cancer is still limited. In this review article, we described the in-detailed perspective and underlying mechanism of n-3 PUFAs application for GI cancers and added in vivo efficacy of n-3 PUFAs with Fat-1 transgenic mice experience. We suggest that future work should consider the n-6/n-3 FA ratio, combination treatment of other nutritions and alteration of lipid rafts to be a key element in experimental design and analysis.

Chemoquiescence for ideal cancer treatment and prevention: where are we now?

Cellular quiescence is a state of reversible cell cycle arrest and is associated with a low metabolic state featured with decreased glycolysis, reduced translation rates, and activation of autophagy, fundamentally to provide nutrients for cell survival similar as seen in hybernation. As signal for quiescence, inactivating the target of rapamycin kinase and resulting reduced cell growth and biosynthesis are essential, but cellular quiescence is not always associated with reduced metabolism since it is also possible to achieve a state of cellular quiescence in which glucose uptake, glycolysis and flux through central carbon metabolism are not reduced. However, in cancer cells, overcoming intrinsic and acquired resistance of cancer stem or cancer dormancy cells to current clinical treatments can be reversed with the acquisition of chemoquiesence. The development of new drug combinations or strategy to treat the highly aggressive and metastatic cancers including relapsed leukaemias, melanoma and head and neck, brain, lung, breast, ovary, prostate, pancreas as well as gastrointestinal cancers which remain incurable in the clinic in spite of aggressive therapies, can be accelerated with the introduction of chemoquiescence agent, for which cancer stem cells or tumor dormancy should be eradicated or removed. Recently potential applications of metformin or chloroquine as well as the potential drugs under investigation such as proton pump inhibitor, sonic hedgehog inhibitor, and Akt inhibitor, are actively investigated in this field of chemoquiescence to achieve cancer cure far beyond those of chemoprevention. In this review article, the evolving concept of chemoquiescence or cancer dormancy will be introduced accompanied by a description of novel target drug development.

Therapeutic effects of mouse bone marrow-derived clonal mesenchymal stem cells in a mouse model of inflammatory bowel disease

Mouse bone marrow-derived clonal mesenchymal stem cells (mcMSCs), which were originated from a single cell by a subfractionation culturing method, are recognized as new paradigm for stem cell therapy featured with its homogenous cell population. Next to proven therapeutic effects against pancreatitis, in the current study we demonstrated that mcMSCs showed significant therapeutic effects in dextran sulfate sodium (DSS)-induced experimental colitis model supported with anti-inflammatory and restorative activities. mcMSCs significantly reduced the disease activity index (DAI) score, including weight loss, stool consistency, and intestinal bleeding and significantly increased survival rates. The pathological scores were also significantly improved with mcMSC. We have demonstrated that especial mucosal regeneration activity accompanied with significantly lowered level of apoptosis as beneficiary actions of mcMSCs in UC models. The levels of inflammatory cytokines including TNF-α, IFN-γ, IL-1β, IL-6, and IL-17 were all significantly concurrent with significantly repressed NF-κB activation compared to the control group and significantly decreased infiltrations of responsible macrophage and neutrophil. Conclusively, our findings provide the rationale that mcMSCs are applicable as a potential source of cell-based therapy in inflammatory bowel diseases, especially contributing either to prevent relapse or to accelerate healing as solution to unmet medical needs in IBD therapy.

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.

Special Licorice Extracts Containing Lowered Glycyrrhizin and Enhanced Licochalcone A Prevented Helicobacter pylori-Initiated, Salt Diet-Promoted Gastric Tumorigenesis

In spite of cytoprotective and anti‐inflammatory actions, conventional licorice extracts (c‐lico) were limitedly used due to serious side effects of glycyrrhizin. As our group had successfully isolated special licorice extracts (s‐lico) lowering troublesome glycyrrhizin, but increasing licochalcone A, we have compared anti‐inflammatory, antioxidative, and cytoprotective actions of s‐lico and c‐lico against either in vitro or in vivo Helicobacter pylori infection.

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.