In Neoadjuvant FOLFIRINOX Chemotherapy for Pancreatic Ductal Adenocarcinoma, Which Response is the More Reliable Indicator for Prognosis, Radiologic or Biochemical?

BACKGROUND: In this era of increasing neoadjuvant chemotherapy, methods for evaluating responses to neoadjuvant chemotherapy are still diverse among institutions. Additionally, the efficacy of adjuvant chemotherapy for patients undergoing neoadjuvant chemotherapy remains unclear. Therefore, this retrospective study was performed to evaluate the effectiveness of methods for assessing response to neoadjuvant chemotherapy and the need for adjuvant chemotherapy in treating patients with non-metastatic pancreatic ductal adenocarcinoma. METHODS: The study identified 150 patients who underwent neoadjuvant FOLFIRINOX chemotherapy followed by curative-intent pancreatectomy. The patients were stratified by biochemical response based on the normalization of carbohydrate antigen 19-9 and by radiologic response based on size change at imaging. RESULTS: The patients were classified into the following three groups based on their response to neoadjuvant chemotherapy and prognosis: biochemical responders (BR+), radiology-only responders (BR-/RR+), and non-responders (BR-/RR-). The 3-year overall survival rate was higher for BR+ (71.0%) than for BR-/RR+ (53.6%) or BR-/RR- (33.1%) (P < 0.001). Response to neoadjuvant chemotherapy also was identified as a significant risk factor for recurrence in a comparison between BR-/RR+ and BR+ (hazard ratio [HR], 2.15; 95% confidence interval [CI] 1.19-3.88; P = 0.011) and BR-/RR- (HR, 3.82; 95% CI 2.41-6.08; P < 0.001). Additionally, regardless of the response to neoadjuvant chemotherapy, patients who completed adjuvant chemotherapy had a significantly higher 3-year overall survival rate than those who did not. CONCLUSIONS: This response evaluation criterion for neoadjuvant chemotherapy is feasible and can significantly predict prognosis. Additionally, completion of adjuvant chemotherapy could be helpful to patients who undergo neoadjuvant chemotherapy regardless of their response to neoadjuvant chemotherapy.

Self-Assembled Monolayer Doping for MoTe2 Field-Effect Transistors: Overcoming PN Doping Challenges in Transition Metal Dichalcogenides.

Transition metal dichalcogenides (TMDs) have gained significant attention as next-generation semiconductor materials that could potentially overcome the integration limits of silicon-based electronic devices. However, a challenge in utilizing TMDs as semiconductors is the lack of an established PN doping method to effectively control their electrical properties, unlike those of silicon-based semiconductors. Conventional PN doping methods, such as ion implantation, can induce lattice damage in TMDs. Thus, chemical doping methods that can control the Schottky barrier while minimizing lattice damage are desirable. Here, we focus on the molybdenum ditelluride (2H-MoTe2), which has a hexagonal phase and exhibits ambipolar field-effect transistor (FET) properties due to its direct band gap of 1.1 eV, enabling concurrent transport of electrons and holes. We demonstrate the fabrication of p- or n-type unipolar FETs in ambipolar MoTe2 FETs using self-assembled monolayers (SAMs) as chemical dopants. Specifically, we employ 1H,1H,2H,2H perfluorooctyltriethoxysilane and (3-aminopropyl)triethoxysilane as SAMs for chemical doping. The selective SAMs effectively increase the hole and electron charge transport capabilities in MoTe2 FETs by 18.4- and 4.6-fold, respectively, due to the dipole effect of the SAMs. Furthermore, the Raman shift of MoTe2 by SAM coating confirms the successful p- and n-type doping. Finally, we demonstrate the fabrication of complementary inverters using SAMs-doped MoTe2 FETs, which exhibit clear full-swing capability compared to undoped complementary inverters.

Gastric Mucosal Protective Effects of Cinnamomum cassia in a Rat Model of Ethanol-Induced Gastric Injury.

Cinnamomum cassia (cassia) is a tropical aromatic evergreen tree of the Lauraceae family well known for its fragrance and spicy flavor and widely used in Asian traditional medicine. It has recently garnered attention for its diverse potential health benefits, including anti-inflammatory, anti-cancer, and anti-diabetic properties. However, the gastroprotective effect of C. cassia, particularly against ethanol-induced gastric damage, remains unclear. We investigated the potential gastroprotective property of C. cassia and the underlying mechanisms of action in a rat model of ethanol-induced gastric injury. To assess its effectiveness, rats were fed C. cassia for a 14-day period prior to inducing gastric damage by oral administration of ethanol. Our results indicated that pre-treatment with C. cassia mitigated ethanol-induced gastric mucosal lesions and bleeding. Reduced gastric acid secretion and expression of acid secretion-linked receptors were also observed. Additionally, pretreatment with C. cassia led to decreased levels of inflammatory factors, including TNF-α, p-p65, and IκBα. Notably, C. cassia upregulated the expressions of HO1 and HSP90, with particular emphasis on the enhanced expression of PAS and MUC, the crucial gastric mucosa defense molecules. These findings suggest that C. cassia has protective effects on the gastric mucosa and can effectively reduce oxidative stress and inflammation.

Implementation of Objective Structured Clinical Examination on Diagnostic Musculoskeletal Ultrasonography Training in Undergraduate Traditional Korean Medicine Education: An Action Research.

This study aimed to report the specific methods and investigate the educational effects of diagnostic musculoskeletal ultrasound training and the Objective Structured Clinical Examination (OSCE) for traditional medicine students. Scanning volar wrist and diagnosing carpal tunnel syndrome were selected for musculoskeletal ultrasound to train students to use the basic functions of the ultrasound device and scan various structures including tendons, nerves, and arteries. The students were divided into two groups: one group had 8 weeks of training with mock OSCE experience and received feedback about their scan images, and the other group had 3 weeks of training with flipped learning. The OSCE was implemented on the last day of the training. The subjective learning outcomes were analyzed as students' evaluation with a 5-point scale, and the objective learning outcomes were analyzed using OSCE scores evaluated with a pre-validated checklist. Of the 111 students, 60 (54.1%) responded to the questionnaire. Overall satisfaction with this ultrasound training was high (4.5 ± 0.60). The average OSCE score in the 8-week group was significantly higher than that in the 3-week group. The students' self-assessment showed no significant differences between the two groups. Proficiency in using ultrasound is affected by the practice time and feedback. Ultrasound training should be further expanded as a required curriculum to meet students' needs and achieve learning objectives in the clinical skills education of Korean medicine colleges. Further studies are needed on ultrasound education, especially guided interventions for traditional medicine students.

Potential Mechanisms of Improved Activity of Natural Killer Cells Induced by the Consumption of F-MRP for 8 weeks.

SCOPE: The authors used metabolomics to investigate the nutritional modulatory effect of fermented Maillard-reactive whey protein (F-MRP) on the activity of natural killer (NK) cells. METHODS AND RESULTS: Fifty subjects who had participated in our previous intervention study were included in the present study in the test (n = 20) and placebo groups (n = 30). Additional analyses using ultra performance liquid chromatography-mass spectrometry (UPLC-MS) and gas chromatography (GC)-MS were conducted to identify relevant metabolic features. After 8 weeks, the activity of lipoprotein-associated phospholipase A2 (Lp-PLA2) (p = 0.021), levels of interleukin (IL)-1ß (p = 0.001), and activity of NK cells were considerably increased in the test group compared with those in the placebo group. Based on the metabolites discovered by UPLC-MS, ten altered metabolic pathways were observed in the test group after 8 weeks of F-MRP consumption. Specific pathways with most pronounced associations with immune-enhancing effect of F-MRP included aminoacyl-tRNA biosynthesis, glycine/serine/threonine metabolism, arginine/proline metabolism, and sphingolipid metabolism. CONCLUSIONS: The present study demonstrated the effects of 8 weeks of F-MRP supplementation on the metabolic status manifested as changes in the Lp-PLA2 activity, IL-1ß level, and activity of NK cells. Intermediate metabolites of the identified metabolic pathways can be used to confirm the immune-enhancing efficacy of short-term supplementation.

Effects of Pancreatic Enzyme Replacement Therapy on Body Weight and Nutritional Assessments After Pancreatoduodenectomy in a Randomized Trial.

BACKGROUND & AIMS: We studied the effects of pancreatic enzyme replacement therapy (PERT) on body weight, nutritional status, and quality of life (QoL) in patients with pancreatic exocrine insufficiency after pancreatoduodenectomy. METHODS: We performed a randomized, double-blind trial of 304 patients who underwent pancreatoduodenectomy at 7 tertiary referral hospitals in South Korea. Patients with fecal levels of elastase of 200 µg/g or less, before and after surgery, were assigned randomly to groups that received PERT (a single capsule of 40,000 IU pancreatin, Norzyme (40,000 IU, Pankreatan; Nordmark Arzneimittel GmbH & Co, Uetersen, Germany), 3 times each day during meals for 3 months; n = 151) or placebo (n = 153). Protocol completion was defined as taking more than two thirds of the total dose without taking other digestive enzymes; the protocol was completed by 71 patients in the PERT group and 93 patients in the placebo group. Patients underwent a physical examination, oral glucose tolerance tests, and blood tests at baseline and at month 3 of the study period. The primary end point was change in body weight. Secondary end points were changes in bowel habits, nutritional parameters, and QoL. RESULTS: In the per-protocol analysis, 3 months after the study began, patients in the PERT group gained a mean of 1.09 kg in weight and patients in the placebo group lost a mean of 2.28 kg (difference between groups, 3.37 kg; P < .001). However, no difference in body weight was observed between groups in the intent-to-treat analysis. Three months after the study began, the mean serum levels of prealbumin increased by 10.9 mg/dL in the PERT group and increased by 7.8 mg/dL in the placebo group (P = .002). Poor compliance to PERT was a significant risk factor for weight loss (P < .001). There was no significant difference in QoL scores between groups. CONCLUSIONS: In the intent-to-treat analysis of data from a randomized trial, we found no significant effect of PERT on mean body weights of patients with pancreatic exocrine insufficiency after pancreatoduodenectomy. However, with active education and monitoring, PERT could increase body weight and nutritional parameters. ClinicalTrials.gov no: NCT02127021.

Role of surgical resection in the era of FOLFIRINOX for advanced pancreatic cancer.

BACKGROUND: The introduction of FOLFIRINOX regimen greatly changed the treatment for advanced pancreatic cancers. However, detailed studies on the clinical effects and factors affecting the prognosis are insufficient. We performed this study to evaluate the effects of FOLFIRINOX and the surgical resection in advanced pancreatic cancer. METHODS: Three hundred and thirty-seven patients with advanced pancreatic cancer who initially received FOLFIRINOX, from January 2011 to December 2017, were retrospectively reviewed. Patients were evaluated according to the National Comprehensive Cancer Network guideline, responses after four to six cycles of FOLFIRINOX were re-evaluated according to the response evaluation criteria in solid tumors, and further treatment was decided in the multidisciplinary meeting. RESULTS: Sixty-seven (19.9%) patients had borderline resectable pancreatic cancer, 135 (40.1%) locally advanced pancreatic cancer, and 135 (40.1%) metastatic pancreatic cancer. The median survival period was significantly longer in the surgical group than in the nonsurgical group in each clinical stage, even in metastatic pancreatic cancer (32 vs. 14, P = 0.012). In multivariate analysis, metastatic status at diagnosis, progressive disease after FOLFIRINOX, surgical resection, and declined CA19-9 after FOLFIRINOX were significant prognostic factors. CONCLUSIONS: Surgical treatment greatly affects survival outcomes in advanced pancreatic cancer treated with FOLFIRINOX. Further studies on the optimal indication of operation and the protocol are needed.

Role of omega-3 polyunsaturated fatty acids in preventing gastrointestinal cancers: current status and future perspectives.

INTRODUCTION: Although inflammation is defensive and healing process that maintains organ homeostasis, unresolved inflammation can lead to diseases. Polyunsaturated fatty acids (PUFAs), especially n-6 PUFAs abundant in Western diet, are precursors of pro-inflammatory mediators, whereas n-3 PUFAs possess anti-inflammatory properties. Therefore, interest in the cancer-preventive effect of n-3 PUFAs is increasing. Areas covered: We have observed significant reductions of gastrointestinal tumorigenesis in the Fat-1 transgenic mouse as evidenced that the decrease in Helicobacter pylori-infected gastric tumorigenesis, colon, biliary, and pancreatic cancer was seen in Fat-1 mice producing n-3 PUFAs. However, despite many studies showing benefits, evidence-based medicine regarding molecular pathology, epidemiology, and clinical achievement of cancer prevention of n-3 PUFAs are still limited. Expert commentary: Primary deficiency of eicosapentaenoic acids and docosahexaenoic acids in Western diets can explain the risk of cancer development and the importance of n-3/n-6 PUFA ratio in reducing cancer risk. Alteration of cell membrane composition during carcinogenesis is particularly important, due to increased rate of lipid/cholesterol synthesis in cancerous tissues. Here, we discuss that direct incorporation of n-3 PUFAs in the cell membrane corrects abnormal cellular proliferation and decreases inflammation-associated carcinogenesis. This is exemplified by cancer-preventive effects of n-3 PUFAs as fat sources for gastrointestinal cancers.

Survival outcome and prognostic factors of neoadjuvant treatment followed by resection for borderline resectable pancreatic cancer.

PURPOSE: Neoadjuvant treatment may provide improved survival outcomes for patients with borderline resectable pancreatic cancer (BRPC). The purpose of this study is to evaluate the clinical outcomes of neoadjuvant treatment and to identify prognostic factors. METHODS: Forty patients who met the National Comprehensive Cancer Network definition of BRPC and received neoadjuvant treatment followed by surgery between 2007 and 2015 were evaluated. Prospectively collected clinicopathological outcomes were analyzed retrospectively. RESULTS: The mean age was 61.7 years and the male-to-female ratio was 1.8:1. Twenty-six, 3, and 11 patients received gemcitabine-based chemotherapy, 5-fluorouracil, and FOLFIRINOX, respectively. The 2-year survival rate (2YSR) was 36.6% and the median overall survival (OS) was 20 months. Of the 40 patients, 34 patients underwent resection and the 2YSR was 41.2% while the 2YSR of patients who did not undergo resection was 16.7% (P = 0.011). The 2YSR was significantly higher in patients who had partial response compared to stable disease (60.6% vs. 24.3%, P = 0.038), in patients who did than did not show a CA 19-9 response after neoadjuvant treatment (40.5% vs. 0%, P = 0.039) and in patients who did than did not receive radiotherapy (50.8% vs. 25.3%, P = 0.036). Five patients had local recurrence and 17 patients had systemic recurrence with a median disease specific survival of 15 months. CONCLUSION: Neoadjuvant treatment followed by resection is effective for BRPC. Pancreatectomy and neoadjuvant treatment response may affect survival. Effective systemic therapy is needed to improve long-term survival since systemic metastasis accounts for a high proportion of recurrence.

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.

Emerging Targets to Relieve Fat Stress-Induced Liver Diseases: UDCA, Tocotrienol, ω-3 PUFAs, and IgY Targeted NPC1L1 Cholesterol Transporter.

Fat stress-induced liver disease is a hepatic manifestation of metabolic syndrome initiated by excess fat accumulation and encompasses a wide spectrum of diseases from non-alcoholic fatty liver disease to nonalcoholic steatohepatitis, a precursor lesion progressing to more aggressive liver cirrhosis and hepatocellular carcinoma. Although the incidence of these fat stress-induced liver diseases is rapidly increasing worldwide in parallel with the growing epidemics of obesity and metabolic diseases, its exact pathogenesis is not well defined. Although obesity, sedentary life-style, altered dietary pattern, insulin resistance, altered intestinal barrier function, inflammatory cytokines, and oxidative stress have been acknowledged as contributing factors because of the indefinite pathogenesis of metabolic diseases, the only reliable treatment is lifestyle intervention composed of restrictive diet and exercise. Additionally, some existing medications such as pioglitazone and antioxidants such as vitamin E were reported to be effective; in this review, several novel agents especifically targeting nonalcoholic fatty liver disease pathogenesis under clinical trial will be introduced. These include an NPC1L1 blocker (ezetimibe), which significantly improved histological and symptomatic scores associated with steatohepatitis and fibrosis; clofibrate, phentoxyfylline, ursodeoxycholic acid, and tocopherol, all of which are prescribed to relieve fat stress; and additional IgY targeted NPC1L1, tocotrienol, ursodeoxycholic acid, and ω-3 polyunsaturated fatty acids, which are actively under investigation to confirm the safety of long-term use.

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.

Amelioration of non-alcoholic fatty liver disease with NPC1L1-targeted IgY or n-3 polyunsaturated fatty acids in mice.

Patients with non-alcoholic fatty liver disease (NAFLD) have an increased risk for progression to hepatocellular carcinoma in addition to comorbidities such as cardiovascular and serious metabolic diseases; however, the current therapeutic options are limited. Based on our previous report that omega-3 polyunsaturated fatty acids (n-3 PUFAs) can significantly ameliorate high fat diet (HFD)-induced NAFLD, we explored the therapeutic efficacy of n-3 PUFAs and N-IgY, which is a chicken egg yolk-derived IgY specific for the Niemann-Pick C1-Like 1 (NPC1L1) cholesterol transporter, on NAFLD in mice. We generated N-IgY and confirmed its efficient cholesterol transport-blocking activity in HepG2 and Caco-2 cells, which was comparable to the effect of ezetimibe (EZM). C57BL/6 wild type and fat-1 transgenic mice, capable of producing n-3 PUFAs, were fed a high fat diet (HFD) alone or supplemented with N-IgY. Endogenously synthesized n-3 PUFAs combined with N-IgY led to significant decreases in hepatic steatosis, fibrosis, and inflammation (p<0.01). The combination of N-IgY and n-3 PUFAs resulted in significant upregulation of genes involved in cholesterol uptake (LDLR), reverse cholesterol transport (ABCG5/ABCG8), and bile acid metabolism (CYP7A1). Moreover, fat-1 transgenic mice treated with N-IgY showed significant downregulation of genes involved in cholesterol-induced hepatic stellate cell activation (Tgfb1, Tlr4, Col1a1, Col1a2, and Timp2). Collectively, these data suggest that n-3 PUFAs and N-IgY, alone or in combination, represent a promising treatment strategy to prevent HFD-induced fatty liver through the activation cholesterol catabolism to bile acids and by decreasing cholesterol-induced fibrosis.

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.

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.

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.

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.

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.

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.

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.