Protective Effect of Perilla Seed Meal and Perilla Seed Extract against Dextran Sulfate Sodium-Induced Ulcerative Colitis through Suppressing Inflammatory Cytokines in Mice.

An excessive inflammatory response of the gastrointestinal tract is recognized as one of the major contributors to ulcerative colitis (UC). Despite this, effective preventive approaches for UC remain limited. Rosmarinic acid (RA), an enriched fraction from Perilla frutescens, has been shown to exert beneficial effects on disease-related inflammatory disorders. However, RA-enriched perilla seed meal (RAPSM) and perilla seed (RAPS) extracts have not been investigated in dextran sulfate sodium (DSS)-induced UC in mice. RAPSM and RAPS were extracted using the solvent-partitioning method and analyzed with high-pressure liquid chromatography (HPLC). Mice with UC induced using 2.5% DSS for 7 days were pretreated with RAPSM and RAPS (50, 250, 500 mg/kg). Then, the clinical manifestation, colonic histopathology, and serum proinflammatory cytokines were determined. Indeed, DSS-induced UC mice exhibited colonic pathological defects including an impaired colon structure, colon length shortening, and increased serum proinflammatory cytokines. However, RAPSM and RAPS had a protective effect at all doses by attenuating colonic pathology in DSS-induced UC mice, potentially through the suppression of proinflammatory cytokines. Concentrations of 50 mg/kg of RAPSM and RAPS were sufficient to achieve a beneficial effect in UC mice. This suggests that RAPSM and RAPS have a preventive effect against DSS-induced UC, potentially through alleviating inflammatory responses and relieving severe inflammation in the colon.

Molecular Mechanism of Antioxidant and Anti-Inflammatory Effects of Omega-3 Fatty Acids in Perilla Seed Oil and Rosmarinic Acid Rich Fraction Extracted from Perilla Seed Meal on TNF-α Induced A549 Lung Adenocarcinoma Cells.

Industrially, after the removal of oil from perilla seeds (PS) by screw-type compression, the large quantities of residual perilla seed meal (PSM) becomes non-valuable waste. Therefore, to increase the health value and price of PS and PSM, we focused on the biological effects of perilla seed oil (PSO) and rosmarinic acid-rich fraction (RA-RF) extracted from PSM for their role in preventing oxidative stress and inflammation caused by TNF-α exposure in an A549 lung adenocarcinoma culture model. The A549 cells were pretreated with PSO or RA-RF and followed by TNF-α treatment. We found that PSO and RA-RF were not toxic to TNF-α-induced A549 cells. Both extracts significantly decreased the generation of reactive oxygen species (ROS) in this cell line. The mRNA expression levels of IL-1ß, IL-6, IL-8, TNF-α, and COX-2 were significantly decreased by the treatment of PSO and RA-RF. The Western blot indicated that the expression of MnSOD, FOXO1, and NF-κB and phosphorylation of JNK were also significantly diminished by PSO and RA-RF treatment. The results demonstrated that PSO and RA-RF act as antioxidants to scavenge TNF-α induced ROS levels, resulting in decreased the expression of MnSOD, FOXO1, NF-κB and JNK signaling pathway in a human lung cell culture exposed to TNF-α.

The innovation of functional foods in Asia: IFFA 2018.

Functional foods (FF) are commonly consumed by Asians, and this trend has increased in recent years. Despite the reported health benefits of FF, it is necessary scrutiny and updates of the underpinning research are important. The first international conference on functional food innovation in Asia (IFFA 2018) took place on January 22nd- 24th, 2018, at the University of Phayao, Thailand. Domestic and international speakers, researchers, nutritionists, dieticians, research scholars and students shared their knowledge and experience in FF research. Key features were the potential beneficial roles of FF in health and disease, the current situation with FF in Asia and innovative trends. The IFFA 2018 involved 2 keynote speakers, 34 invited speakers and 10 sessions. About 250 people from across Asia participated. Key themes, discussions, innovative opportunities, and future directions to link research in academia with health-directed applications as FF are summarised.

Concerted actions of ameliorated colitis, aberrant crypt foci inhibition and 15-hydroxyprostaglandin dehydrogenase induction by sonic hedgehog inhibitor led to prevention of colitis-associated cancer.

The sonic hedgehog (Shh) signaling has been known to contribute to carcinogenesis in organ, where hedgehog exerted organogenesis and in cancers, which are developed based on mutagenic inflammation. Therefore, colitis-associated cancer (CAC) can be a good model to prove whether Shh inhibitors can be applied to prevent, as the efforts to discover potent anti-inflammatory agent are active to prevent CAC. Here, under the hypothesis that Shh inhibitors can prevent CAC, mouse model was generated to develop CAC by azoxymethane (AOM)-initiated, dextran sodium sulfate-promoted carcinogenesis. Shh inhibitors, cerulenin and itraconazole were treated by oral gavage and the mice were sacrificed at early phase of 3 weeks and late phase of 16 weeks. Compared to control group, the number of aberrant crypt foci at 3 weeks and tumor incidence at 16 weeks were all significantly decreased with Shh inhibitor. Significant attenuations of macrophage infiltration accompanied with significant decreases of IL-6, COX-2, STAT3 and NF-κB as well as significant ameliorations of ß-catenin nuclear translocation, cyclin D1 and CDK4 were imposed with Shh inhibitors. Especially, CAC was accompanied with significant cancellation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), but their levels were significantly preserved with Shh inhibitors. Among inflammatory mediators, significantly decreased levels of IL-6 and TNF-α, regulated with repressed NF-κb and STAT3, were prominent with Shh inhibitor, whereas significant inductions of apoptosis were noted with Shh inhibitors. In conclusion, Shh inhibitors significantly prevented CAC covering either ameliorating oncogenic inflammation or suppressing tumor proliferation, especially supported with significant inhibition of IL-6 and STAT3 signaling, 15-PGDH preservation and apoptosis induction.

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

OBJECT: 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. METHODS: Helicobacter pylori-infected and high-salt-diet-administered C57BL/6 mice were administered with Artemisia extracts (MP group) and/or green tea extracts (GT group) for 36 weeks in addition to the control group (ES group, gastroprotective drug, ecabet sodium 30 mg/kg, diet pellet). Gross and pathological gastric lesions were evaluated after 24 and 36 weeks, respectively, and their underlying molecular changes were measured in gastric homogenates. Detailed mechanisms were further evaluated in in vitro cell models. RESULTS: The erythematous and nodular changes and mucosal ulcerative and erosive lesions were noted in the control group at 24 weeks. MP, GT, MPGT, and ES groups all showed significantly ameliorated pathologic lesion compared to the control group (p < .05). After the 36 weeks, scattered nodular masses with some central ulcers and thin gastric surface were noted in the control stomach, whereas no tumorous lesion and milder atrophic changes were observed in all MP, GT, and MPGT groups except ES group (p < .05). On molecular analysis, increased expressions of COX-2, TNF-α, IL-6, lipid peroxide, and activated STAT3 relevant to H. pylori infection were significantly decreased with MPGT administration (p < .01), whereas HSP70 was significantly increased. PGDH expressions, core tumor suppressor involved in carcinogenesis, were significantly decreased with H. pylori infection (p < .05), but significantly increased in MPGT group (p < .05). Increased mucosal apoptotic index noted in the control group was significantly decreased with MP and/or GT along with significantly preserved gastric gastroprotective mediators (p < .01) such as mucins, HSP27, and HSP70. H. pylori-induced serum TNF-α and NF-κB activations were significantly decreased with MPGT administration (p < .05). CONCLUSION: Long-term dietary intake of MP and/or GT can be an effective strategy either to rejuvenate H. pylori atrophic gastritis or to suppress tumorigenesis.

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.

BACKGROUND AND AIM: 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. METHODS: Different doses of SAC were administrated intragastrically before the indomethacin administration. After killing, in addition to gross and pathological evaluations of ulcer, the expressions of inflammatory mediators, including cyclooxygenase-2, prostaglandin E2 , IL-1ß, tumor necrosis factor-α, IL-6, and anti-oxidant capacity, were analyzed by Western blot analysis or ELISA, respectively. Transferase deoxytidyl uridine end labeling assay, periodic acid and Schiff staining, F4/80 staining, and CD31 staining were compared among doses of SAC. Detailed documentation of in vitro biological actions of SAC, including NF-κB, histone deacetylator inhibition, phase 2 enzyme, and MAPKs, was performed. RESULTS: SAC was very effective in preventing indomethacin-induced gastric damages in a low dose through significant decreases in macrophage infiltration as well as restorative action. Indomethacin-induced expressions of inflammatory mediators were all significantly attenuated with SAC in accordance with histone deacetylator inhibition. In addition, SAC significantly increased the total anti-oxidant concentration and mucus secretion, and allows for a significant induction of HO-1. However, these preventive effects of SAC were dependent on dosage of SAC; higher dose above 10 µM paradoxically aggravated NSAID-induced inflammation. CONCLUSION: Synthetic SAC can be promising therapeutics agent to provide potent anti-inflammatory, anti-oxidative, and mucosa protective effects against NSAID-induced damages.

Antibacterial activities of Miang extracts against selected pathogens and the potential of the tannin-free extracts in the growth inhibition of Streptococcus mutans.

Bacterial pathogens have remained a major public health concern for several decades. This study investigated the antibacterial activities of Miang extracts (at non-neutral and neutral pH) against Bacillus cereus TISTR 747, Escherichia coli ATCC 22595, Salmonella enterica serovar Typhimurium TISTR 292 and Streptococcus mutans DMST 18777. The potential of Polyvinylpolypyrrolidone (PVPP)-precipitated tannin-free Miang extracts in growth-inhibition of the cariogenic Streptococcus mutans DMST 18777 and its biofilms was also evaluated. The tannin-rich fermented extracts had the best bacterial growth inhibition against S. mutans DMST 18777 with an MIC of 0.29 and 0.72 mg/mL for nonfilamentous fungi (NFP) Miang and filamentous-fungi-processed (FFP) Miang respectively. This observed anti-streptococcal activity still remained after PVPP-mediated precipitation of bioactive tannins especially, in NFP and FFP Miang. Characterization of the PVPP-treated extracts using High performance liquid chromatography quadrupole-time of flight-mass spectrometry (HPLC-QToF-MS) analysis, also offered an insight into probable compound classes responsible for the activities. In addition, Crystal violet-staining also showed better IC50 values for NFP Miang (4.30 ± 0.66 mg/mL) and FFP Miang (12.73 ± 0.11 mg/mL) against S. mutans DMST 18777 biofilms in vitro. Homology modeling and molecular docking analysis using HPLC-MS identified ligands in tannin-free Miang supernatants, was performed against modelled S. mutans DMST 18777 sortase A enzyme. The in silico analysis suggested that the inhibition by NFP and FFP Miang might be attributed to the presence of ellagic acid, flavonoid aglycones, and glycosides. Thus, these Miang extracts could be optimized and explored as natural active pharmaceutical ingredients (NAPIs) for applications in oral hygienic products.

Protective Effect of Red Rice Extract Rich in Proanthocyanidins in a Murine Colitis Model.

Inflammatory bowel disease (IBD) has become a global concern. Proanthocyanidin-rich red rice extract (PRRE) has been shown to suppress the inflammatory response in cellular cultures. However, the anti-colitis effect of PRRE has never been investigated in animals. This study aimed to examine the protective effect of the PRRE against dextran sulfate sodium (DSS)-induced colitis in mice. Male mice were orally administrated with PRRE of 50, 250 and 500 mg/kg/day for 21 days. Acute colitis was subsequently induced by administrated 2.5% DSS in drinking water for the final seven days. Sulfasalazine-treated mice were the positive group. All doses of PRRE and sulfasalazine significantly ameliorated DSS-induced severity of colitis, as indicated by decreasing daily activity index and restoring colon shortening. Treatments with PRRE, but not sulfasalazine, significantly reduced the histopathological index and infiltration of inflammatory cells. Furthermore, the PRRE treatments effectively improved mucous in colonic goblet cells using PAS staining, and suppressed the production of pro-inflammatory cytokines TNF-α, IL-1ß and IL-6 induced by DSS, while sulfasalazine reduced only IL-1ß and IL-6. This study suggested that PRRE had a greater anti-colitis effect than sulfasalazine. Thus, PRRE has a potential anti-colitis effect, and should be developed in a clinical trial as a natural active pharmaceutical ingredient for IBD.

Protective Effect of Probiotics Isolated from Traditional Fermented Tea Leaves (Miang) from Northern Thailand and Role of Synbiotics in Ameliorating Experimental Ulcerative Colitis in Mice.

This study aimed to investigate the protective effect of probiotics and synbiotics from traditional Thai fermented tea leaves (Miang) on dextran sulfate sodium (DSS)-induced colitis in mice, in comparison to sulfasalazine. C57BL/6 mice were treated with probiotics L. pentosus A14-6, CMY46 and synbiotics, L. pentosus A14-6 combined with XOS, and L. pentosus CMY46 combined with GOS for 21 days. Colitis was induced with 2% DSS administration for seven days during the last seven days of the experimental period. The positive group was treated with sulfasalazine. At the end of the experiment, clinical symptoms, pathohistological changes, intestinal barrier integrity, and inflammatory markers were analyzed. The probiotics and synbiotics from Miang ameliorated DSS-induced colitis by protecting body weight loss, decreasing disease activity index, restoring the colon length, and reducing pathohistological damages. Furthermore, treatment with probiotics and synbiotics improved intestinal barrier integrity, accompanied by lowing colonic and systemic inflammation. In addition, synbiotics CMY46 combined with GOS remarkedly elevated the expression of IL-10. These results suggested that synbiotics isolated from Miang had more effectiveness than sulfasalazine. Thereby, they could represent a novel potential natural agent against colonic inflammation.

Perilla Seed Oil Alleviates Gut Dysbiosis, Intestinal Inflammation and Metabolic Disturbance in Obese-Insulin-Resistant Rats.

BACKGROUND: High-fat diet (HFD) consumption induced gut dysbiosis, inflammation, obese-insulin resistance. Perilla seed oil (PSO) is a rich source of omega-3 polyunsaturated fatty acids with health promotional effects. However, the effects of PSO on gut microbiota/inflammation and metabolic disturbance in HFD-induced obesity have not been investigated. Therefore, we aimed to compare the effects of different doses of PSO and metformin on gut microbiota/inflammation, and metabolic parameters in HFD-fed rats. METHODS: Thirty-six male Wistar rats were fed either a normal diet or an HFD for 24 weeks. At week 13, HFD-fed rats received either 50, 100, and 500 mg/kg/day of PSO or 300 mg/kg/day metformin for 12 weeks. After 24 weeks, the metabolic parameters, gut microbiota, gut barrier, inflammation, and oxidative stress were determined. RESULTS: HFD-fed rats showed gut dysbiosis, gut barrier disruption with inflammation, increased oxidative stress, metabolic endotoxemia, and insulin resistance. Treatment with PSO and metformin not only effectively attenuated gut dysbiosis, but also improved gut barrier integrity and decreased gut inflammation. PSO also decreased oxidative stress, metabolic endotoxemia, and insulin resistance in HFD-fed rats. Metformin had greater benefits than PSO. CONCLUSION: PSO and metformin had the beneficial effect on attenuating gut inflammation and metabolic disturbance in obese-insulin resistance.

Anti-inflammatory effect of Perilla frutescens seed oil rich in omega-3 fatty acid on dextran sodium sulfate-induced colitis in mice.

BACKGROUND AND PURPOSE: Ulcerative colitis is a chronic inflammatory bowel disease that involves diffused inflammation of the large intestine. Omega-3 fatty acid (FA) has been known to regulate the inflammatory response associated with ulcerative colitis pathogenesis. Perilla frutescens is a valuable source of omega-3 FA and α-linolenic acid (ALA) contained in its seed oil. Therefore, the aim of this study was to evaluate the anti-inflammatory effect of Perilla seed oil (PSO) on colitis induced by dextran sulfate sodium (DSS) in a mouse model. EXPERIMENTAL APPROACH: PSO was extracted using a cold-pressed extractor and FA composition of PSO was analyzed by GC-MS. Acute colitis in mice was induced with 3% DSS in drinking water for 7 days. Some mice were treated with PSO (20, 100, 200 mg/kg BW) for 3 weeks before the DSS administration. Sulfasalazine was used as a positive control. The clinical features, histopathologic, serum, and gene expression of proinflammatory cytokines in the colon were assessed. FINDING/RESULTS: PSO contained the highest proportion of ALA (61.51%). Furthermore, PSO pretreatment evidently reduced body weight loss, diminished diarrhea, gross bleeding, and DSS-induced colon shortening. PSO pretreatment attenuated histopathological changes in response to DSS-induced colitis. PSO pretreatment also markedly decreased inflammatory response in serum and the colon tissue of DSS-induced mice. CONCLUSION AND IMPLICATION: ALA in PSO is suggested to be mainly responsible for the reduction of DSS-induced colitis through suppressing inflammatory markers. PSO could be further developed as a functional health supplement, which would be beneficial for anti-inflammation in the colonic mucosa.

Rosmarinic Acid Enriched Fraction from Perilla frutescens Leaves Strongly Protects Indomethacin-Induced Gastric Ulcer in Rats.

Gastric ulcers are a common problem in upper gastrointestinal tract (GI) disorders. Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most aggressive factors leading to inducing gastric ulcers. Natural products with lower toxicity and safety are currently sought as a potential source to minimize the effect of the gastric ulcers. Perilla frutescens or Nga-mon (in Thai) leaves are rich in rosmarinic acid (RA), which has antioxidant, anti-inflammatory, and anticancer effects. This study investigates the protective effect of ethanolic extract (EE) and aqueous fraction (AF) from Perilla frutescens leaves, which are rich in RA, on indomethacin- (IND-) induced gastric ulcer in a rat model. The EE at the doses of 50 and 500 mg/kg body weight, AF at the doses of 50, 250, and 500 mg/kg body weight, or famotidine (a standard drug) were administered for 14 days prior to ulcer induction. The ulceration was performed by intragastric administration of IND. Gross gastric ulcers and biological and histological parameters were examined. The pretreatment with AF had more significant effects than EE, including reduced ulcer index, decreased gastric secretion volume and decreased acidity, but it had an elevated gastric pH relative to the IND-induced gastric ulcer. In a histopathological study, the EE and AF decreased mucosal ulcer, inflammatory infiltration, and degenerative lining cells. The IND-induced expression of inflammatory mediators was significantly attenuated with EE and AF. The experiment also remarkably showed the preservation of mucus and apoptosis protection of EE and AF on a gastric mucosal ulcer. The findings demonstrated that the EE and AF of perilla leaves were capable of protecting the stomach against gastric ulcers induced by IND through anti-inflammatory and antiapoptotic mechanisms that should be further investigated. It is suggested that Perilla frutescens leaf could be a potential alternative source of RA as a therapeutic agent and food supplement for NSAID-induced gastric injuries.

Targeted molecular ablation of cancer stem cells for curing gastrointestinal cancers.

INTRODUCTION: Abundance of the ATPase-binding cassette (ABC) transporters and deranged self-renewal pathways characterize the presence of cancer stem cells (CSCs) in gastrointestinal cancers (GI cancers), which play crucial roles in tumorigenesis, chemotherapy resistance, tumor recurrence, and cancer metastasis. Therefore, in order to ensure high cure rates, chemoquiescence, CSCs should be ablated. Recent advances in either understanding CSCs or biomarker identification enable scientists to develop techniques for ablating CSCs and clinicians to provide cancer cure, especially in GI cancers characterized by inflammation-driven carcinogenesis. Areas covered: A novel approach to ablate CSCs in GI cancers, including esophageal, gastric, and colon cancers, is introduced along with explored underlying molecular mechanisms. Expert commentary: Though CSC ablation is still in the empirical stages and not in clinical practice, several strategies for ablating CSCs in GI cancers had been published, proton-pump inhibitors (PPIs) that regulate the membrane-bound ABC transporters, which underlie drug resistance; chloroquine (CQ) that inhibits autophagy, which is responsible for tumor survival; Hedgehog/Wnt/Notch inhibitors that influence the underlying stem-cell growth, and some natural products including Korean red ginseng, cancer-preventive kimchi, Artemisia extract, EGCG from green tea, and walnut extracts.

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.

Development of GI-safe NSAID; progression from the bark of willow tree to modern pharmacology.

Non-steroidal anti-inflammatory drugs (NSAIDs) have been used for analgesic, anti-inflammatory and antithrombotic actions and recently for cancer prevention, but they carries a risk of major gastroduodenal damages from symptomatic ulcers to serious complications leading to fatal outcomes. Therefore, the novel strategies to rescue long-term NSAID requiring patients from NSAID-associated gastroduodenal damages are essential. Besides of current drugs based on classic damaging mechanisms attributable to the decline of gastric mucosal prostaglandin synthesis, reductions of mucosal blood flow, attenuated bicarbonate secretion and mucus synthesis related with prostaglandin levels, effective therapeutics targeted for update mechanisms of NSAID-induced gastroduodenal damages are introduced in this paper based on recent advances in basic science and biotechnology exploring deeper molecular mechanisms of NSAID-induced gastroduodenal damage beyond COX inhibition.

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.

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.

Non-microbial approach for Helicobacter pylori as faster track to prevent gastric cancer than simple eradication.

Although the International Agency for Research on Cancer declared Helicobacter pylori (H. pylori) as a definite human carcinogen in 1994, the Japanese Society for Helicobacter Research only recently (February 2013) adopted the position that H. pylori infection should be considered as an indication for either amelioration of chronic gastritis or for decreasing gastric cancer mortality. Japanese researchers have found that H. pylori eradication halts progressive mucosal damage and that successful eradication in patients with non-atrophic gastritis most likely prevents subsequent development of gastric cancer. However, those who have already developed atrophic gastritis/gastric atrophy retain potential risk factors for gastric cancer. Because chronic perpetuated progression of H. pylori-associated gastric inflammation is associated with increased morbidity culminating in gastric carcinogenesis, a non-microbial approach to treatment that provides long-term control of gastric inflammation through nutrients and other interventions may be an effective way to decrease this morbidity. This non-microbial approach might represent a new form of prerequisite "rescue" therapy that provides a quicker path to the prevention of gastric cancer as compared to simple eradication.

Anti-inflammatory and carbonic anhydrase restoring actions of yam powder (Dioscorea spp) contribute to the prevention of cysteamine-induced duodenal ulcer in a rat model.

Increased acid output, accompanied with a defective defense system, is considered a fundamental pathogenesis of duodenal ulcer (DU). However, relapse of DU occurs despite proton pump inhibitors and H2 receptor antagonists, hence imposing the enforcement of the defense system. Dried powder of the yam tuber (Dioscorea spp) has been used in traditional folk medicine as a nutritional fortification. We hypothesized that dried-yam powder would prevent DU through improvement of anti-inflammatory actions and carbonic anhydrase (CA) activity. Therefore, we investigated the preventive effects of dried-yam powder against the cysteamine-induced DU and elucidated the underlying mechanisms. Duodenal ulcers were induced in Sprague-Dawley rats by intragastric administration of 500 mg/kg cysteamine-HCl. The dried-yam powder was used as a pretreatment before the cysteamine-HCl. The number and size of DU were measured. The expressions of inflammation mediators were checked in duodenal tissues, and the expressions of CAs and malondialdehyde levels were also examined. Cysteamine provoked perforated DU, whereas dried-yam powder significantly prevented DU as much as pantoprazole and significantly reduced the incidence of perforation. The messenger RNA expressions of cyclooxygenase-2 and inducible nitric oxide synthase were remarkably decreased in the yam group compared with the cysteamine group, and the serum levels of proinflammatory cytokines including interleukin-1ß, interleukin-6, and tumor necrosis factor were significantly attenuated in the yam group. Cysteamine significantly decreased the expression of CAs, whereas yam treatment significantly preserved the expressions of CA IX, XII, and XIV. In conclusion, dried-yam powder exerts a significant protective effect against cysteamine-induced DU by lowering the activity of inflammatory cytokines and free radicals and restoring the activity of CAs, except in CA IV.