Germination and Simulated Gastrointestinal Digestion of Chickpea (Cicer arietinum L.) in Exhibiting In Vitro Antioxidant Activity in Gastrointestinal Epithelial Cells.

Plant-based proteins, in particular pulse proteins, have grown in popularity worldwide. Germination, or sprouting, is an effective method to release peptides and other dietary compounds. However, the combination of germination and gastrointestinal digestion in enhancing the release of dietary compounds with potential health-beneficial biological activity has yet to be entirely elucidated. The present study illustrates the impact of germination and gastrointestinal digestion on the release of dietary compounds with antioxidant activity from chickpeas (Cicer arietinum L.). Germination up to 3 days (D0 to D3) increased the peptide content by denaturing chickpea storage proteins and increased the degree of hydrolysis (DH) in the gastric phase. The antioxidant activity was measured at three different dosages (10, 50, and 100 µg/mL) and compared between D0 and D3 on human colorectal adenocarcinoma cells (HT-29). A significant increase in antioxidant activity was observed in the D3 germinated samples in all three tested dosages. Further analysis identified 10 peptides and 7 phytochemicals differentially expressed between the D0 and D3 germinated samples. Among the differentially expressed compounds, 3 phytochemicals (2',4'-dihydroxy-3,4-dimethoxychalcone, isoliquiritigenin 4-methyl ether, and 3-methoxy-4,2',5'-trihydroxychalcone) and 1 peptide (His-Ala-Lys) were identified only in the D3 samples, indicating their potential contribution towards the observed antioxidant activity.

Comprehensive Review of γ-Glutamyl Peptides (γ-GPs) and Their Effect on Inflammation Concerning Cardiovascular Health.

γ-Glutamyl peptides (γ-GPs) are a group of peptides naturally found in various food sources. The unique γ-bond potentially enables them to resist gastrointestinal digestion and offers high stability in vivo with a longer half-life. In recent years, these peptides have caught researchers' attention due to their ability to impart kokumi taste and elicit various physiological functions via the allosteric activation of the calcium-sensing receptor (CaSR). This review discusses the various food sources of γ-glutamyl peptides, different synthesis modes, allosteric activation of CaSR for taste perception, and associated multiple biological functions they can exhibit, with a special emphasis on their role in modulating chronic inflammation concerning cardiovascular health.

Nonsupercharged Retrosternal Roux-en-Y Esophagojejunostomy for Distal Esophageal Reconstruction.

BACKGROUND: Delayed distal esophageal reconstruction with nonsupercharged jejunum is an option when gastric conduit is not available. This study aimed to describe a single-center experience with distal esophageal reconstruction with retrosternal Roux-en-Y esophagojejunostomy (RYEJ) and compare perioperative outcomes with retrosternal gastric pull-up (GP). METHODS: An Institutional Review Board-exempt retrospective chart review was conducted of patients who underwent esophagostomy closure by the retrosternal route at the University of Minnesota Medical Center (Minneapolis, MN) from January 2009 to July 2019. Patients with colonic conduits were excluded. The study compared patients with RYEJ with a contemporary cohort of patients who underwent GP. The anatomic criteria for RYEJ were the absence of a gastric conduit and an esophageal remnant that reached the sternomanubrial joint. Patient characteristics, anastomotic leak and stricture rate, postoperative complications, hospital length of stay, 30-day readmission, and 90-day mortality were recorded. Statistical analysis was performed using the Fisher exact test and the Wilcoxon rank-sum test with a significance level at P ≤.05. RESULTS: A total of 9 patients underwent RYEJ, and 10 patients had GP. Previous esophageal adenocarcinoma was more common in the RYEJ group (n = 5) compared with the GP group (n = 0) (P = .01). Patient demographics and comorbidities were comparable between the groups. No differences were found in all end points, including operating time, estimated blood loss, anastomotic leak or stricture rate, Clavien-Dindo class III to IV complications, hospital length of stay, or mortality. CONCLUSIONS: Retrosternal RYEJ without microvascular augmentation is a safe alternative for esophagostomy closure in patients with adequate esophageal length when the stomach is not available. The nonsupercharged jejunum can safely reach the level of the sternomanubrial joint.

Anti-hypertensive Peptide Predictor: A Machine Learning-Empowered Web Server for Prediction of Food-Derived Peptides with Potential Angiotensin-Converting Enzyme-I Inhibitory Activity.

Angiotensin converting enzyme-I (ACE-I) is a key therapeutic target of the renin-angiotensin-aldosterone system (RAAS), the central pathway of blood pressure regulation. Food-derived peptides with ACE-I inhibitory activities are receiving significant research attention. However, identification of ACE-I inhibitory peptides from different food proteins is a labor-intensive, lengthy, and expensive process. For successful identification of potential ACE-I inhibitory peptides from food sources, a machine learning and structural bioinformatics-based web server has been developed and reported in this study. The web server can take input in the FASTA format or through UniProt ID to perform the in silico gastrointestinal digestion and then screen the resulting peptides for ACE-I inhibitory activity. This unique platform provides elaborated structural and functional features of the active peptides and their interaction with ACE-I. Thus, it can potentially enhance the efficacy and reduce the time and cost in identifying and characterizing novel ACE-I inhibitory peptides from food proteins. URL: http://hazralab.iitr.ac.in/ahpp/index.php.

Bioactivity of Cooked Standard and Enriched Whole Eggs from White Leghorn and Rhode Island Red in Exhibiting In-Vitro Antioxidant and ACE-Inhibitory Effects.

Hen breed, diet enrichment, cooking methods, and gastrointestinal (GI) digestion modulates the bioaccessibility of the bioactive compounds in eggs, but their synergistic role in modulating bioactivity is still unclear. The present study evaluates the effect of hen breed, diet enrichment, and GI digestion on the cooked whole egg-derived peptides in-vitro antioxidant and antihypertensive activities. Standard and enriched whole eggs from White Leghorn (WLH) and Rhode Island Red (RIR) hens were boiled or fried and subjected to GI digestion. Antioxidant activity was measured through oxygen radical absorbance capacity (ORAC) and gastrointestinal epithelial cell-based assays, and the antihypertensive capacity by in-vitro Angiotensin-I Converting Enzyme (ACE) inhibition assay. WLH fried standard egg hydrolysate showed a high ORAC antioxidant activity but failed to show any significant antioxidant effect in the cell-based assay. No significant differences were observed in the antihypertensive activity, although enriched samples tended to have a higher ACE-inhibitory capacity. The peptide profile explained the antioxidant capacities based on antioxidant structural requirements from different peptide fractions, while previously reported antihypertensive peptides were found in all samples. The study validates the importance of physiologically relevant models and requires future studies to confirm mechanisms that yield bioactive compounds in whole egg hydrolysates.

Evaluating the effect of high-pressure processing in contrast to boiling on the antioxidant activity from alcalase hydrolysate of Great Northern Beans (Phaseolus vulgaris).

Food processing can alter protein structure, modulate enzyme accessibility, and therefore the release of bioactive peptides. Thus, processing techniques, boiling, high-pressure processing (HPP), and a combination of both, were compared for their efficiency to release antioxidant peptides after alcalase hydrolysis of Great Northern Beans (GNBs). The oxygen radical absorbance capacity (ORAC) indicated that boiled hydrolysates had the highest antioxidant activity (370.9 ± 43.8 µmol TEAC/g). Mass spectrometry-based analysis suggested that di- and tri-peptide expression were significantly altered among the three treatments, and either Ile, Leu, Phe, and Arg containing peptides potentially contributed toward the enhanced antioxidant activity. Furthermore, the total phenolic content of the HPP-treated hydrolysate was higher than the other two treatments, with ferulic acid being the most prominent phenolic compound present in the bean hydrolysates. This study indicates that thermal processing such as boiling is more effective in modulating the release of antioxidant peptides. PRACTICAL APPLICATIONS: Common beans (Phaseolus vulgaris), such as Great Northern Beans (GNBs) are one of the major pulse crops in the United States. Storage proteins in beans can release peptides with biological activities after enzymatic hydrolysis. However, processing conditions can modulate the release of peptides. The present study is primarily focused on comparing the two processing methods, boiling and HPP, and their combination for the generation of peptides with potential antioxidant activity in alcalase-digested GNBs. Data from the study suggest that thermal treatment such as boiling is more effective in modulating the release of peptides from alcalase hydrolysate of GNBs with antioxidant activity. This is particularly important because over different cultures around the world, boiling is the most widely used processing method for the cooking of beans, and hence, these data also ensure that boiling is the most effective method in getting the most beneficial effects from the consumption of beans.

Transport of Dietary Anti-Inflammatory Peptide, γ-Glutamyl Valine (γ-EV), across the Intestinal Caco-2 Monolayer.

The present study analyzed the transepithelial transport of the dietary anti-inflammatory peptide, γ-glutamyl valine (γ-EV). γ-EV is naturally found in dry edible beans. Our previous study demonstrated the anti-inflammatory potency of γ-EV against vascular inflammation at a concentration of 1mM, and that it can transport with the apparent permeability coefficient (Papp) of 1.56 × 10-6 ± 0.7 × 10-6 cm/s across the intestinal Caco-2 cells. The purpose of the current study was to explore whether the permeability of the peptide could be enhanced and to elucidate the mechanism of transport of γ-EV across Caco-2 cells. The initial results indicated that γ-EV was nontoxic to the Caco-2 cells up to 5 mM concentration and could be transported across the intestinal cells intact. During apical-to-basolateral transport, a higher peptide dose (5 mM) significantly (p < 0.01) enhanced the transport rate to 2.5 × 10-6 ± 0.6 × 10-6 cm/s. Cytochalasin-D disintegrated the tight-junction proteins of the Caco-2 monolayer and increased the Papp of γ-EV to 4.36 × 10-6 ± 0.16 × 10-6 cm/s (p < 0.001), while theaflavin 3'-gallate and Gly-Sar significantly decreased the Papp (p < 0.05), with wortmannin having no effects on the peptide transport, indicating that the transport route of γ-EV could be via both PepT1-mediated and paracellular.

Dietary γ-Glutamyl Valine Ameliorates TNF-α-Induced Vascular Inflammation via Endothelial Calcium-Sensing Receptors.

γ-Glutamyl valine (γ-EV), commonly found in edible beans, was shown to reduce gastrointestinal inflammation via activation of calcium-sensing receptors (CaSRs). The present study aimed to evaluate the efficacy of γ-EV in modulating the tumor necrosis factor-α-induced inflammatory responses in endothelial cells (ECs) via CaSR-mediated pathways. Human aortic ECs (HAoECs) were pretreated (2 h) with γ-EV (0.01, 0.1, and 1 mM). 1 mM pretreatment of γ-EV significantly reduced the upregulation of inflammatory adhesion molecules, VCAM-1 and E-selectin, by 44.56 and 57.41%, respectively. The production of cytokines IL-8 and IL-6 was significantly reduced by 40 and 51%, respectively, with 1 mM pretreatment of γ-EV. Similarly, there was a significant reduction in chemokine MCP-1 from a positive control of 9.70 ± 0.52 to 6.6 ± 0.43 ng/mL, after γ-EV treatment. The anti-inflammatory effect of γ-EV was attenuated by the treatment of the CaSR-specific inhibitor, NPS-2143, suggesting the involvement of CaSR-mediated pathways. Further studies identified the critical role of key modulators, such as ß-arrestin2 and cyclic adenosine monophosphate response element-binding protein, in mediating the CaSR-dependent anti-inflammatory effect of γ-EV. Finally, the transport efficiency of γ-EV was evaluated through a monolayer of intestinal epithelial cells (Caco-2), and the apparent permeability (Papp) of the peptide was found to be 1.56 × 10-6 cm/s.

γ-Glutamylvaline Prevents Low-Grade Chronic Inflammation via Activation of a Calcium-Sensing Receptor Pathway in 3T3-L1Mouse Adipocytes.

The calcium-sensing receptor (CaSR), a G-protein receptor, is well recognized for its role in the regulation of adipocyte proliferation, in modulating adipose tissue dysfunction, and as a potential target for therapeutic intervention. In the present study, we investigate the anti-inflammatory effect of γ-glutamylvaline (γ-EV) on mouse adipocytes and explore the role of γ-EV-activated CaSR in the regulation of cellular homeostasis using the mouse 3T3-L1 cell line in vitro model. Our results indicate that the 3T3-L1 adipocyte-like cells accumulated lipids and expressed CaSR after 2 days of differentiation and 7 days of maturation period. The pretreatment with γ-EV (10 µM) suppressed the production of TNF-α-induced pro-inflammatory cytokines, i.e., IL-6 (23.92 ± 5.45 ng/mL, p < 0.05)) and MCP-1 (101.17 ± 39.93 ng/mL, p < 0.05), while enhancing the expression of PPARγ (1.249 ± 0.109, p < 0.001) and adiponectin (7.37 ± 0.59 ng/mL, p < 0.05). Elevated expression of Wnt5a was detected in γ-EV-treated cells (115.90 ± 45.50, p < 0.001), suggesting the involvement of the Wnt/ß-catenin pathway. Also, phosphorylation of ß-catenin was shown to be significantly inhibited (0.442 ± 0.034) by TNF-α but restored when cells were pretreated with γ-EV (0.765 ± 0.048, p < 0.05). These findings suggest that γ-EV-induced CaSR activation not only prevents TNF-α-induced inflammation in adipocytes but also modulates the cross-talk between Wnt and PPARγ pathways. Concentrations of serine phosphorylated IRS-1 were shown to be lower in γ-EV-treated cells, indicating γ-EV may also prevent inflammation in the context of insulin resistance. Thus, γ-EV-activated CaSR plays a significant role in the cross-talk between adipocyte inflammatory and metabolic pathways through the regulation of extracellular sensing.

Food-derived bioactive peptides and their role in ameliorating hypertension and associated cardiovascular diseases.

Non-communicable diseases including cardiovascular diseases (CVDs) and associated metabolic disorders are responsible for nearly 40 million deaths globally per year. Hypertension or high blood pressure (BP) is one of the primary reasons for the development of CVDs. A healthy nutritional strategy complementing with physical activity can substantially reduce high BP and prevent the occurrence of CVD-associated morbidity and mortality. Bioactive peptides currently are the next wave of the promising bench to clinic options for potential targeting chronic and acute health issues including hypertension. Peptides demonstrating anti-inflammatory, anti-oxidant, and angiotensin-converting enzyme-I inhibitory activity are widely studied for the amelioration of hypertension and associated CVDs. Isolating these potent bioactive peptides from different food sources is a promising endeavor toward nutraceutical based dietary management and prevention of hypertension. Understanding the pathophysiology of hypertension and the action mechanisms of the bioactive peptides would complement in designing and characterizing more potent peptides and suitable comprehensive dietary plans for the prevention of hypertension and associated CVDs.

Structural-features of food-derived bioactive peptides with anti-inflammatory activity: A brief review.

Chronic inflammatory conditions such as obesity, type-2 diabetes, and cardiovascular diseases are the leading causes of mortality worldwide. Hence, much research interest in bioactive peptides has been stimulated due to lack of potent pharmacological interventions. Although many such peptides have been identified from food proteins, insufficient information is available on their structure-function relationship. Presence of hydrophobic and positively charged amino acids is a common occurrence for the peptides with anti-inflammatory properties. However, inconsistent findings have also been reported. Most of the food-derived peptides exhibited their anti-inflammatory activities primarily by inhibiting signaling components of either NF-κB or MAPK pathway, which are the two major pathways involved in chronic inflammation following uncontrolled signal activation. This review highlighted the structural requirements of the peptides to exhibit anti-inflammatory activity based on the current knowledge about food-derived anti-inflammatory peptides and their underlying molecular mechanisms of action. PRACTICAL APPLICATIONS: While research in the food-derived bioactive peptide is gaining momentum, but the ability to translate these new findings into the commercial product such as nutraceuticals and functional foods, remains delayed. The most prominent reasons for this delay are the lack of detailed research on, (i) the structure-function relationship of the peptide and the underlying molecular mechanisms of these bioactive peptides, and (ii) the interaction of these peptides with different cellular elements in the disease pathophysiology. This review gives an insight into the structure-activity relationship of bioactive peptides involved in anti-inflammatory responses. The information provided here would be highly beneficial to describe the possible anti-inflammatory activity of any newly identified peptides from different food sources.

Food-Derived Bioactive Peptides in Human Health: Challenges and Opportunities.

Recent scientific evidence suggests that food proteins not only serve as nutrients, but can also modulate the body's physiological functions. These physiological functions are primarily regulated by some peptides that are encrypted in the native protein sequences. These bioactive peptides can exert health beneficial properties and thus are considered as a lead compound for the development of nutraceuticals or functional foods. In the past few decades, a wide range of food-derived bioactive peptide sequences have been identified, with multiple health beneficial activities. However, the commercial application of these bioactive peptides has been delayed because of the absence of appropriate and scalable production methods, proper exploration of the mechanisms of action, high gastro-intestinal digestibility, variable absorption rate, and the lack of well-designed clinical trials to provide the substantial evidence for potential health claims. This review article discusses the current techniques, challenges of the current bioactive peptide production techniques, the oral use and gastrointestinal bioavailability of these food-derived bioactive peptides, and the overall regulatory environment.

Moderation of hyperuricemia in rats via consuming walnut protein hydrolysate diet and identification of new antihyperuricemic peptides.

In this study, walnut meal hydrolysates (WMH) and dephenolized walnut meal hydrolysates (DWMH) were found to effectively decrease the serum uric acid level and protect the renal function in potassium oxonate-induced hyperuricemic rats in vivo as well as inhibit xanthine oxidase in vitro. Two novel antihyperuricemic peptides including WPPKN (640.8 Da) and ADIYTE (710.7 Da) were purified from DWMH via Sephadex G-15 gel filtration and reverse-phase high-performance liquid chromatography and identified by LC-ESI-MS/MS. These peptides displayed high in vitro xanthine oxidase inhibition (XOI) activity with IC50 values of 17.75 ± 0.12 mg mL-1 (WPPKN) and 19.01 ± 0.23 mg mL-1 (ADIYTE). Based on the results of molecular simulation, WPPKN entered into the hydrophobic channel and even obstructed the interaction between xanthine and xanthine oxidase (XO), while ADIYTE was positioned on the surface of the B-chain and blocked the entrance of the substrate to the hydrophobic channel. Therefore, the two peptides are partially responsible for the antihyperuricemic properties of DWMH.

Obesity is Independently Associated With Increased Risk of Hepatocellular Cancer-related Mortality: A Systematic Review and Meta-Analysis.

OBJECTIVE: Excess body weight is associated with increased risk of developing hepatocellular cancer (HCC), but its effect on HCC-related mortality remains unclear. We performed a systematic review and meta-analysis to assess the association between premorbid obesity and HCC-related mortality. MATERIALS AND METHODS: Through a systematic literature search-up to March 2016, we identified 9 observational studies (1,599,453 individuals, 5705 HCC-related deaths) reporting the association between premorbid body mass index (BMI), and HCC-related mortality. We estimated summary adjusted hazard ratio (aHR) with 95% confidence intervals (CIs), comparing obese (BMI>30 kg/m(2)) and overweight (BMI, 25 to 29.9 kg/m(2)) individuals with normal BMI individuals using random-effects model. RESULTS: On meta-analysis, compared with individuals with normal BMI, obese (aHR, 1.95; 95% CI, 1.46-2.46), but not overweight individuals (aHR, 1.08; 95% CI, 0.97-1.21), had higher HCC-related mortality, with moderate heterogeneity. On subgroup analysis, magnitude of increased mortality was higher in obese men (aHR, 2.50; 95% CI, 2.02-3.09; 3 studies) as compared with obese women (aHR, 1.45; 95% CI, 1.08-1.97; 2 studies). The impact of premorbid obesity on HCC-related mortality was observed only in western populations (aHR, 2.10; 95% CI, 1.77-2.48; 4 studies), but not Asian populations (aHR, 1.10; 95% CI, 0.63-1.92; 1 study). There was limited assessment of competing risk because of advanced liver disease. CONCLUSIONS: On the basis of this meta-analysis, premorbid obesity may be independently associated with a 2-fold risk of HCC-related mortality. This association was more pronounced in men and western populations. Strategies targeting obesity-associated metabolic abnormalities may provide novel pathways for HCC therapy.

Impact of Postoperative Liver Dysfunction on Survival After Left Ventricular Assist Device Implantation.

BACKGROUND: Liver dysfunction in left ventricular assist device (LVAD) recipients is common both before and after implantation. Postoperative liver dysfunction (PLD) develops in some LVAD recipients without preoperative liver dysfunction. The aim of this study was to assess clinical outcomes in such patients. METHODS: Records of all patients undergoing implantation of a HeartMate II (HM II, St. Jude Medical, Inc, Minneapolis, MN) LVAD at a single center at the University of Minnesota from January 2005 through June 2014 were analyzed. PLD was defined by hypertransaminasemia or hyperbilirubinemia, or both, during the hospitalization for LVAD implantation. RESULTS: During the study period, 284 patients underwent HM II implantation. Excluded from analysis were 14 recipients with preoperative liver dysfunction. In the final cohort (n = 270), there were no major difference in preoperative characteristics among those patients with versus without PLD. PLD developed in 129 (47.8%) recipients: 16 (12.4%) had isolated hypertransaminasemia (group I), 76 (58.9%) had isolated hyperbilirubinemia (group II), and 37 (28.7%) had combined hypertransaminasemia and hyperbilirubinemia (group III). Group III LVAD recipients had significantly greater rates of 30-day, 90-day, and 1-year mortality, along with significantly higher transfusion requirements and higher rates of renal replacement therapy, prolonged ventilation, and vasopressor use. Moreover, their mortality risk was significantly higher than that of PLD-free LVAD recipients (hazard ratio, 4.6; 95% confidence interval, 2.1 to 10.1; p < 0.001). CONCLUSIONS: Isolated hyperbilirubinemia is common after LVAD implantation. In this study, it was not associated with an increase in early or midterm postoperative mortality. However, postoperative combined transaminasemia and hyperbilirubinemia was associated with a significant increase in early and midterm morbidity and mortality. Further research into the pathogenesis of post-LVAD PLD is necessary.

Intervention of Dietary Dipeptide Gamma-l-Glutamyl-l-Valine (γ-EV) Ameliorates Inflammatory Response in a Mouse Model of LPS-Induced Sepsis.

Sepsis, the systemic inflammatory response syndrome (SIRS) with infection is one of the leading causes of death in critically ill patients in the developed world due to the lack of effective antisepsis treatments. This study examined the efficacy of dietary dipeptide gamma-l-glutamyl-l-valine (γ-EV), which was characterized previously as an anti-inflammatory peptide, in an LPS-induced mouse model of sepsis. BALB/c mice were administered γ-EV via oral gavage followed by an intraperitoneal injection of LPS to induce sepsis. The γ-EV exhibited antisepsis activity by reducing the expression of pro-inflammatory cytokines TNF-α, IL-6, and IL-1ß in plasma and small intestine. γ-EV also reduced the phosphorylation of the signaling proteins JNK and IκBα. We concluded that γ-EV could possess an antisepsis effect against bacterial infection in intestine. This study proposes a signaling mechanism whereby the calcium-sensing receptor (CaSR) allosterically activated by γ-EV stimulates the interaction of ß-arrestin2 with the TIR(TLR/IL-1R) signaling proteins TRAF6, TAB1, and IκBα to suppress inflammatory signaling.

Prostate Cancer: How Young is too Young?

Prostate cancer is the most common non-cutaneous malignancy in men. It is generally considered a cancer of the elderly, and the median age of presentation is 68 years. However 10% of new diagnoses in the USA occur in men aged ≤ 55 years. This may be due to more prevalent screening nowadays, and may also reflect the diagnosis of an increasingly recognized but underappreciated entity, i.e. early-onset prostate cancer. Patients with early onset prostate cancer pose unique challenges. Current data suggest that early-onset prostate cancer is a distinct phenotype-from both an etiological and clinical perspective- that deserves further attention. We present a case of a 28-year-old man who presented with lower urinary tract symptoms and was diagnosed with advanced stage prostate cancer.

Downregulation of Sp1 by Minnelide leads to decrease in HSP70 and decrease in tumor burden of gastric cancer.

BACKGROUND: Gastric cancer is the third leading cause of cancer related mortality worldwide with poor survival rates. Even though a number of chemotherapeutic compounds have been used against this disease, stomach cancer has not been particularly sensitive to these drugs. In this study we have evaluated the effect of triptolide, a naturally derived diterpene triepoxide and its water soluble pro-drug Minnelide on several gastric adenocarcinoma cell lines both as monotherapy and in combination with CPT-11. METHODS: Gastric cancer cell lines MKN28 and MKN45 were treated with varying doses of triptolide in vitro. Cell viability was measured using MTT based assay kit. Apoptotic cell death was assayed by measuring caspase activity. Effect of the triptolide pro-drug, Minnelide, was evaluated by implanting the gastric cancer cells subcutaneously in athymic nude mice. RESULTS: Gastric cancer cell lines MKN28 and MKN45 cells exhibited decreased cell viability and increased apoptosis when treated with varying doses of triptolide in vitro. When implanted in athymic nude mice, treatment with Minnelide reduced tumor burden in both MKN28 derived tumors as well as MKN45 derived tumors. Additionally, we also evaluated Minnelide as a single agent and in combination with CPT-11 in the NCI-N87 human gastric tumor xenograft model. CONCLUSION: Our results indicated that the combination of Minnelide with CPT-11 resulted in significantly smaller tumors compared to control. These studies are extremely encouraging as Minnelide is currently undergoing phase 1 clinical trials for gastrointestinal cancers.

Total Pancreatectomy With Islet Autotransplantation Resolves Pain in Young Children With Severe Chronic Pancreatitis.

OBJECTIVES: Fear of diabetes and major surgery may prohibit referral of young children severely affected by pancreatitis for total pancreatectomy with islet autotransplant (TPIAT). We evaluated outcomes in our youngest TPIAT recipients, 3 to 8 years of age at surgery. METHODS: Medical records were reviewed for 17 children (9 girls) ages 8 years or younger undergoing TPIAT from 2000 to 2014. Most (14/17) had genetic risk factors for pancreatitis. Since 2006, TPIAT recipients were followed prospectively with health questionnaires including assessments of pain and narcotic use, and scheduled hemoglobin A1c (HbA1c) and mixed-meal tolerance tests (6 mL/kg Boost HP) before surgery, and at regular intervals after. Patients are 1 to 11 years post-TPIAT (median 2.2 years). Data are reported as median (25th, 75th percentile). RESULTS: All had relief of pain, with all 17 patients off narcotics at most recent follow-up. Hospitalization rates decreased from 5.0 hospitalization episodes per person-year of follow-up before TPIAT, to 0.35 episodes per person-year of follow-up after TPIAT. Fourteen (82%) discontinued insulin, higher than the observed insulin independence rate of 41% in 399 patients older than 8 years of age undergoing TPIAT over the same interval (P = 0.004). Median post-TPIAT HbA1c was 5.9% (5.6%, 6.3%), and within patient post-TPIAT mean HbA1c was ≤6.5% for all but 2 patients. CONCLUSIONS: Young children with severe refractory chronic pancreatitis may be good candidates for TPIAT, with high rates of pain relief and insulin independence, and excellent glycemic control in the majority.

Intervention of Isomaltodextrin Mitigates Intestinal Inflammation in a Dextran Sodium Sulfate-Induced Mouse Model of Colitis via Inhibition of Toll-like Receptor-4.

Isomaltodextrin (IMD), a highly branched α-glucan, is a type of resistant starch. Earlier studies have indicated that polysaccharides could prevent inflammation and can be effective in reducing the complications of chronic gastrointestinal diseases such as inflammatory bowel disease (IBD). Therefore, the aim of the present study was to evaluate the anti-inflammatory effect of IMD in dextran sodium sulfate (DSS)-induced colitis in a mouse model. IMD (0.5, 1.0, 2.5, and 5.0% (w/v)) was given orally for 23 days to female Balb/c mice, and then 5% DSS was administered to induce colitis (from day 15 onward to the end of the trial). IMD could not prevent DSS-induced weight loss or colon shortening. However, IMD could reduce inflammatory cytokines, TNF-α and IL-6, in the colon. Gene expression indicated the tendency of IMD to suppress pro-inflammatory cytokines IL-1ß, MCP-1, and IL-17 and to increase an anti-inflammatory cytokine, IL-10. Further study revealed that the anti-inflammatory action of IMD mediates through inhibition of the expression of Toll-like receptor-4.