Psidium guajava leaf extract improves gastrointestinal functions in rats and rabbits: an implication for ulcer and diarrhoea management.

PURPOSE: Psidium guajava L. (Family, Myrtaceae) is reportedly used in ethnomedicine for the treatment of diarrhoea, inflammation, and gastroenteritis. OBJECTIVE: This study evaluated the gastrointestinal function of Psidium guajava leaf extract (PGLE) in rats and rabbits. MATERIALS AND METHODS: Crude ethanolic PGLE was subjected to phytochemical and toxicity tests (acute and sub-acute). Standard analytical procedures were employed to evaluate the in vivo gastrointestinal motility, and gastroprotective effect of PGLE against aspirin-induced ulcers. RESULTS: In the phytochemical analysis, phenols were the highest (48.32 mg) followed by flavonoids (32.74 mg) and least in tannins (7.31 mg). The acute toxicity of PGLE was >6000 mg/kg. Administration of PGLE decreased significantly (p < 0.05) the body weight, while the liver biomarkers were not significantly altered (p > 0.05) when compared to the control. PGLE significantly increased extractible mucus weight and lowered gastric acid secretion in rats (p < 0.05). PGLE decreased significantly (p < 0.05) ulcer scores and indexes, and increased percentage ulcer inhibition in a dose-dependent manner compared to the negative and omeprazole-treated groups. PGLE dose-dependently inhibited basal amplitudes of contractions, and significantly inhibited acetylcholine-induced contractions, terminating them completely at higher doses. CONCLUSION: PGLE may be a good anti-ulcer and anti-diarrhoeal agent, raising the prospect of novel drug development for such applications.

Caso clínico: atención integral de las necesidades paliativas en paciente nonagenario con cáncer de pene avanzado y herida tumoral / Case report: comprehensive care of palliative needs in a nonagenarian patient with advanced penile cancer and tumor ulcer

El cáncer de pene es una afección poco común que en el 4-5 % de los casos presenta recidiva local tras penectomía. Las úlceras tumorales son lesiones que aparecen en el contexto de tumores de alto grado de malignidad y/o fase avanzada de la enfermedad oncológica. Se caracterizan por tener un difícil manejo, ya que en la mayoría de los pacientes presentan dolor, mal olor, exudado abundante, sangrado y alto riesgo de infección. El objetivo de este artículo es describir el caso clínico de un varón con cáncer de pene avanzado que presentaba una lesión ulcerada tumoral con curas complejas, en el que se desestimaron medidas activas de tratamiento, optando por un enfoque paliativo. El abordaje del paciente oncológico con una úlcera tumoral supone un gran desafío para el equipo asistencial. El cuidado de las úlceras neoplásicas exige profesionales altamente cualificados en la materia debido a la complejidad y variabilidad de las curas así como la presencia de síntomas derivados. Gracias a la colaboración de todos los miembros del equipo, familia y paciente se controlaron los síntomas derivados de la úlcera tumoral, contribuyendo a la mejora en la calidad de vida en la etapa final de la enfermedad. (AU)

Cancer of the penis is a rare condition that in 4-5 % of cases presents with local recurrence after penectomy. Tumor ulcers are lesions that appear in the context of tumors with a high degree of malignancy and/or advanced phase of oncological disease. They are characterized by difficult management since in most patients they are associated with pain, bad odor, abundant exudate, bleeding, and high risk of infection. The objective of this article is to describe the clinical case of a man with advanced penile cancer who presented with an ulcerated tumor with complex management; active treatment measures were rejected, and a palliative approach was then selected. Approaching a cancer patient with a tumor ulcer is a great challenge for the healthcare team. Caring for neoplastic ulcers requires highly qualified professionals in the field due to the complexity and variability of the cures as well as the presence of derived symptoms. Thanks to the collaboration of all team members, the family, and the patient the symptoms derived from the tumor ulcer were controlled, contributing to improving quality of life in the final stage of the disease. (AU)

SHORT COMMUNICATION-Inappropriate use of proton pump inhibitor for stress ulcer prophylaxis in a tertiary care hospital in Karachi, Pakistan.

The use of proton pump inhibitors (PPI) has been expanded inappropriately. PPI are among the most selling drugs in the world. There is growing evidence that PPI are associated with significant adverse effects along with undue financial burden. Inappropriate prescription of PPI is common in inpatients. The objective is to determine the frequency of inappropriate use of proton pump inhibitors for stress ulcer prophylaxis. This prospective observational study was conducted in the Department of Medicine of The Aga Khan University Hospital Karachi. 151 adult patients admitted in the hospital were included. All those patients who received PPI due to a condition mentioned by American Gastroenterology Association (AGA) as an indication for PPI, were labeled as PPI appropriately indicated. While those patients who received PPI without a condition mentioned by AGA as an indication for PPI, were labeled as PPI inappropriately indicated. Mean age was 57.2±18.2 years. Route of administration was oral in 110 (72.8%) and IV in 41 (27.2%) patients. Out of 151 patients, 100 (66.2%) patients were receiving PPI without any specific indication while 51 (33.8%) patients were receiving PPI with appropriate indications. Our study showed that inappropriate use of PPI is quite common among admitted patients.

Covering Post-Endoscopic Submucosal Dissection Ulcers in Miniature Swine with Hexanoyl (Hx:C6) Group-Modified Alkaline-Treated Gelatin Porous Film (HAG) Induces Proper Healing by Decreasing Inflammation and Fibrosis.

BACKGROUND AND AIMS: Hexanoyl (Hx:C6) group-modified alkaline-treated gelatin porous film (HAG) is a newly developed degradable hydrogel characterized by strong adhesiveness and high affinity for vascular endothelial growth factor (VEGF). The aim of this study was to clarify the effect of HAG sheets on the healing process of post-endoscopic submucosal dissection (ESD) porcine gastric artificial ulcers. METHODS: (1) To evaluate the adhesiveness of HAG sheets over time, we performed ESD to create 1 artificial ulcer and covered the lesion with 1 HAG sheet using 1 miniature swine. We observed 2 ulcers by endoscopic and microscopic examinations. (2) To examine the effect of HAG sheets on post-ESD ulcer healing, we performed ESD using 5 miniature swine. The artificial ulcers were covered with HAG sheets, or left uncovered after ESD (day 0), followed by macroscopic and microscopic examinations. On days 7 and 14, we observed 2 ulcers by endoscopic examinations. On day 14, the animals were sacrificed, and histological examination was performed on the 3 stomachs that could be extirpated. RESULTS: (1) On day 7, adhesion of HAG sheets was observed. (2) Gastric ulcer area on day 7 was significantly larger in the covered ulcers than in the non-covered ulcers (p = 0.046). On day 14, although there was no significant difference in ulcer area irrespective of covering (p = 0.357), the covered ulcers tended to repair less fold convergence than non-covered ulcers. The covered ulcer sheets significantly decreased inflammatory cell infiltration (p = 0.011), but significantly increased the abundance of macrophages (p = 0.033), in submucosal layers. Also, the abundance of alpha-smooth muscle actin-positive cells in submucosal layers of the covered ulcers was significantly reduced (p = 0.044), leading to a decrease in collagen accumulation. In addition, fibrosis and atrophy of the muscularis propria were significantly lower for covered ulcers than for non-covered ulcers. Furthermore, microvessels and VEGF-positive cells were significantly more abundant in the submucosal layers of the covered ulcers (p < 0.001 and p = 0.024, respectively). CONCLUSIONS: HAG sheets induced post-ESD ulcer healing with less submucosal inflammation and muscularis propria injury and have the potential to decrease excess scarring.

Protective effect and mechanism of rebamipide on NSAIDs associated small bowel injury.

PURPOSE: To investigate the protective effect and mechanism of rebamipide on NSAIDs associated intestinal injury. METHODS: Intestinal injury was induced in Sprague Dawley rats by intragastric administration of diclofenac with rebamipide intervention, and LPS and TAK-242 were given intraperitoneally respectively. The expression of TLR4/NF-κB and the related proteins in the intestinal mucosa were detected. 55 patients taking NSAIDs and diagnosed as NSAIDs associated small intestinal injury were recruited as NSAIDs group. Another 55 patients without NSAIDs and no obvious abnormality in the small bowel served as the control group. RESULTS: The macroscopic and histological scores of the small intestinal mucosa in the rebamipide pretreatment group were significantly lower compared to the diclofenac group (p < 0.01). The expressions of Tollip, ZO-1 and Claudin-1 in the diclofenac group were down-regulated compared with that in the control group, while they increased significantly in the rebamipide pretreatment group (p < 0.01). The expressions of TLR4/NF-κBp65, IL-1ß, IL-6, IL-8, and TNF-α significantly increased in the model group while they were down-regulated in the rebamipide pretreatment group (p < 0.05). Administration of LPS 1 h after diclofenac aggravated small intestinal damage, and increased expression of IL-1ß, IL-6, IL-8 and TNF-α. Administration of rebamipide did not effectively reverse intestinal injury induced by diclofenac and LPS. In contrast, pretreatment with TAK-242 significantly inhibited damage and prevented the increased expression of the cytokines. The expression of TLR4 and NF-κBp65 in the patients with NSAIDs associated intestinal injury was significantly higher than that in the control group (p < 0.01), while the expression of Tollip was decreased (p < 0.01). CONCLUSION: Rebamipide effectively alleviated intestinal mucosa injury by probably suppressing the TLR4/NF-κB signaling pathway and the decreasing of ZO-1 and Claudin-1 induced by diclofenac.

Immunization with nontreponemal antigen alters the course of experimental syphilis in the rabbit model.

The role of nontreponemal antibodies in the Treponema pallidum infection course is unclear. We investigated the effect of immunization with nontreponemal antigen on T. pallidum-challenged rabbits. Nontreponemal antigen was injected intravenously into rabbits in the nontreponemal group (n = 12) to elicit antibodies (≥1:64), and normal saline-injected rabbits were used as controls (n = 12). Then, rabbits were challenged with 106T. pallidum per site along their back. Lesion development was observed, and the injection sites were biopsied for mRNA analysis every week. Six rabbits from both groups were euthanized at 14 d and 28 d. The popliteal lymph nodes were extracted to assess infectivity using a rabbit infectivity test. The maximum lesion diameters were not different between the two groups (12.4 ± 0.9 mm in the nontreponemal group vs. 12.5 ± 1.0 mm in the control group, P = 0.386), but the time to maximum diameter appearance was delayed by approximately 4 d in the nontreponemal group (14.4 ± 1.6 d vs. 10.8 ± 1.9 d, P = 0.000). There were no significant differences in the proportions of lesions (58/60 (96.7%) vs. 59/60 (98.3%), P = 0.500) or ulcers (55/60 (91.7%) vs. 57/60 (95.0%), P = 0.359) between the two groups. An ulcer development delay of 5 d was observed in the nontreponemal group (19.3 ± 2.0 d vs. 14.0 ± 1.8 d, P = 0.000). IL-2 and IFN-γ mRNA expression in the nontreponemal group was significantly higher than that in the control group at 7 d and 14 d post-challenge. flaA mRNA expression and the rabbit infectivity test positive rate were not different between the two groups. Immunization with nontreponemal antigen altered the syphilis course in rabbits, resulting in delayed maximal lesion diameter and ulcer development, but it could not inhibit the spread of T. pallidum from primary lesion sites to viscera.

Phytochemistry, Traditional Use and Pharmacological Activity of Picrasma quassioides: A Critical Reviews.

Picrasma quassioides is a member of the Simaroubaceae family commonly grown in the regions of Asia, the Himalayas, and India and has been used as a traditional herbal medicine to treat various illnesses such as fever, gastric discomfort, and pediculosis. This study aims to critically review the presence of phytochemicals in P. quassioides and correlate their pharmacological activities with the significance of its use as traditional medicine. Data were collected by reviewing numerous scientific articles from several journal databases on the pharmacological activities of P. quassioides using certain keywords. As a result, approximately 94 phytochemicals extracted from P. quassioides were found to be associated with quassinoids, ß-carbolines and canthinones. These molecules exhibited various pharmacological benefits such as anti-inflammatory, antioxidant, anti-cancer, anti-microbial, and anti-parasitic activities which help to treat different diseases. However, P. quassioides were also found to have several toxicity effects in high doses, although the evidence regarding these effects is limited in proving its safe use and efficacy as herbal medicine. Accordingly, while it can be concluded that P. quassioides may have many potential pharmacological benefits with more phytochemistry discoveries, further research is required to determine its real value in terms of quality, safety, and efficacy of use.

Implementation of an interdisciplinary tracheostomy care protocol to decrease rates of tracheostomy-related pressure ulcers and injuries.

OBJECTIVES: Tracheostomy-related pressure injuries (TRPI) have been demonstrated to occur in approximately 10% of tracheostomy patients. In this study, we present TRPI outcomes after implementation of a standardized tracheostomy care protocol. METHODS: A tracheostomy care protocol was developed by an interdisciplinary quality improvement program and implemented on July 1, 2016. The protocol was designed to minimize factors that contribute to the development of TRPI. Rates of TRPI over the subsequent 20 months were compared to the year before implementation. RESULTS: 9 out of 85 patients (10.6%) developed TRPI in the pre-protocol cohort compared to 0 of 137 (0%) in the post-protocol cohort, which was a statistically significant decrease by Fisher's exact test with a p-value of 0.0001. Pearson's correlation coefficient demonstrated a negative correlation between age and post-operative day of diagnosis (r = -0.641, p = 0.063), indicating that older patients develop TRPI more quickly. CONCLUSIONS: Interdisciplinary peri-operative tracheostomy care protocols can be effective in decreasing rates of TRPI.

Results of Simple Conservative Treatment of Midfoot Charcot Arthropathy.

BACKGROUND: Traditionally, conservative management with an offloading orthosis, such as total contact cast (TCC), has been the standard of care for midfoot Charcot arthropathy. Considering complications of TCC and surgery, we treated midfoot Charcot arthropathy without TCC in our patients. The purpose of this study was to report clinical and radiological outcomes of conservative management of midfoot Charcot arthropathy. METHODS: A total of 34 patients (38 feet) who were diagnosed as having midfoot Charcot arthropathy between 2006 and 2014 were included. Patients started full weight bearing ambulation in a hard-soled shoe immediately after diagnosis. Outcomes such as progression of arch collapse, bony prominence, ulcer occurrence, limb amputation, and changes in Charcot stage were evaluated. RESULTS: Of 38 feet, arch collapse was observed in four while progression of bottom bump of the midfoot was observed in five feet. Foot ulcers related to bony bumps were found in two feet. CONCLUSIONS: Conservative treatment without restriction of ambulation is recommended for midfoot Charcot arthropathy because it is rarely progressive, unlike hindfoot-ankle arthropathy. In some cases, simple bumpectomy can be required to prevent catastrophic infection.

Lower odds of sole ulcers in the following lactation in dairy cows that received hoof trimming around drying off.

Sole ulcers negatively affect production and animal welfare in dairy cows. Hoof trimming around drying off is frequently recommended, but has not previously been evaluated scientifically. The association between hoof trimming around drying off and the odds of sole ulcers in the following lactation was evaluated based on recordings from 621,228 hoof trimmings in Danish dairy herds. Overall, 6.2% of cows had sole ulcers at the first hoof trimming 0-180 days in milk. The odds of sole ulcers increased with increasing days in milk, and were approximately 20% lower in cows hoof trimmed around drying off. Odds were higher in older cows, and in cows with sole ulcers in the previously lactation. Hoof trimming around drying off may help reduce the occurrence of sole ulcers in the following lactation.

Heterogeneity of treatment effect of stress ulcer prophylaxis in ICU patients: A secondary analysis protocol.

BACKGROUND: In the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial, 3291 adult ICU patients at risk for gastrointestinal (GI) bleeding were randomly allocated to intravenous pantoprazole 40 mg or placebo once daily in the ICU. No difference was observed between the groups in the primary outcome 90-day mortality or the secondary outcomes, except for clinically important gastrointestinal bleeding. However, heterogeneity of treatment effect (HTE) not detected by conventional subgroup analyses could be present. METHODS: This is a protocol and statistical analysis plan for a secondary, post hoc, exploratory analysis of the SUP-ICU trial. We will explore HTE in one set of subgroups based on severity of illness (using the Simplified Acute Physiology Score [SAPS] II) and another set of subgroups based on the total number of risk factors for GI bleeding in each patient using Bayesian hierarchical models. We will summarise posterior probability distributions using medians and 95% credible intervals and present probabilities for different levels of benefit and harm of the intervention in each subgroup. Finally, we will assess if the treatment effect interacts with SAPS II and the number of risk factors separately on the continuous scale using marginal effects plots. CONCLUSIONS: The outlined post hoc analysis will explore whether HTE was present in the SUP-ICU trial and may help answer some of the remaining questions regarding the balance between benefits and harms of pantoprazole in ICU patients at risk of GI bleeding. CLINICALTRIALS. GOV REGISTRATION: NCT02467621.

Cordycepin prevents radiation ulcer by inhibiting cell senescence via NRF2 and AMPK in rodents.

The pathological mechanisms of radiation ulcer remain unsolved and there is currently no effective medicine. Here, we demonstrate that persistent DNA damage foci and cell senescence are involved in radiation ulcer development. Further more, we identify cordycepin, a natural nucleoside analogue, as a potent drug to block radiation ulcer (skin, intestine, tongue) in rats/mice by preventing cell senescence through the increase of NRF2 nuclear expression (the assay used is mainly on skin). Finally, cordycepin is also revealed to activate AMPK by binding with the α1 and γ1 subunit near the autoinhibitory domain of AMPK, then promotes p62-dependent autophagic degradation of Keap1, to induce NRF2 dissociate from Keap1 and translocate to the nucleus. Taken together, our findings identify cordycepin prevents radiation ulcer by inhibiting cell senescence via NRF2 and AMPK in rodents, and activation of AMPK or NRF2 may thus represent therapeutic targets for preventing cell senescence and radiation ulcer.

Bifidobacteriumbreve Bif195 Protects Against Small-Intestinal Damage Caused by Acetylsalicylic Acid in Healthy Volunteers.

BACKGROUND & AIMS: Enteropathy and small-intestinal ulcers are common adverse effects of nonsteroidal anti-inflammatory drugs such as acetylsalicylic acid (ASA). Safe, cytoprotective strategies are needed to reduce this risk. Specific bifidobacteria might have cytoprotective activities, but little is known about these effects in humans. We used serial video capsule endoscopy (VCE) to assess the efficacy of a specific Bifidobacterium strain in healthy volunteers exposed to ASA. METHODS: We performed a single-site, double-blind, parallel-group, proof-of-concept analysis of 75 heathy volunteers given ASA (300 mg) daily for 6 weeks, from July 31 through October 24, 2017. The participants were randomly assigned (1:1) to groups given oral capsules of Bifidobacterium breve (Bif195) (≥5 × 1010 colony-forming units) or placebo daily for 8 weeks. Small-intestinal damage was analyzed by serial VCE at 6 visits. The area under the curve (AUC) for intestinal damage (Lewis score) and the AUC value for ulcers were the primary and first-ranked secondary end points of the trial, respectively. RESULTS: Efficacy data were obtained from 35 participants given Bif195 and 31 given placebo. The AUC for Lewis score was significantly lower in the Bif195 group (3040 ± 1340 arbitrary units) than the placebo group (4351 ± 3195) (P = .0376). The AUC for ulcer number was significantly lower in the Bif195 group (50.4 ± 53.1 arbitrary units) than in the placebo group (75.2 ± 85.3 arbitrary units) (P = .0258). Twelve adverse events were reported from the Bif195 group and 20 from the placebo group. None of the events was determined to be related to Bif195 intake. CONCLUSIONS: In a randomized, double-blind trial of healthy volunteers, we found oral Bif195 to safely reduce the risk of small-intestinal enteropathy caused by ASA. ClinicalTrials.gov no: NCT03228589.

Stress ulcer prophylaxis in critically ill children: Protocol for a systematic review.

BACKGROUND: Stress ulcer prophylaxis is the considered standard of care in many critically ill patients in the intensive care unit (ICU). Whether there is overall benefit or harm of stress ulcer prophylaxis in critically ill children is unknown. Accordingly, we aim to assess patient-important benefits and harms of stress ulcer prophylaxis versus placebo or no treatment in critically ill children in the ICU. METHODS/DESIGN: We will conduct a systematic review of randomized clinical trials with meta-analysis and trial sequential analysis and assess the use of proton pump inhibitors (PPIs) or histamine-2-receptor antagonists (H2RAs) versus placebo or no prophylaxis. We will systematically search the Cochrane Library, MEDLINE, EMBASE, Science Citation Index, BIOSIS, and Epistemonikos for relevant literature. We will follow the recommendations by the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The risk of systematic errors (bias) and random errors will be assessed, and the overall quality of evidence will be evaluated according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. DISCUSSION: There is a need for an updated systematic review to summarize the benefits and harms of stress ulcer prophylaxis in critically ill children to inform practice and future research.

Preventive effect of ecabet sodium on low-dose aspirin-induced small intestinal mucosal injury: a randomized, double-blind, pilot study.

BACKGROUND: We aimed to investigate how high-dose ecabet sodium affects low-dose aspirin-induced small intestinal mucosal injury in healthy volunteers. METHODS: Healthy volunteers were enrolled randomly into one of two groups with the following drug regimens for 2 weeks: group A, low-dose aspirin once per day and group B, low-dose aspirin and 4.0 g of ecabet sodium. Small bowel capsule endoscopy was performed before and 2 weeks after low-dose aspirin administration. RESULTS: A significant difference was found in the median number [range] of small intestinal lesions between baseline and two weeks after low-dose aspirin administration in group A (baseline: 1 [0-5], after: 5 [1-11]; p = 0.0059) but not in group B (baseline: 0.5 [0-9], after: 3 [0-23]; p = 0.0586). In group B, although the median number [range] of lesions in the first tertile of the small intestine did not increase two weeks after low-dose aspirin administration (baseline: 0 [0-4], after: 1.5 [0-8]; p = 0.2969), the number of lesions in the second and third tertiles of the small intestine increased significantly (baseline: 0 [0-5], after: 2 [0-15]; p = 0.0469). CONCLUSIONS: Ecabet sodium had a preventive effect on low-dose aspirin-induced small intestinal mucosal injury in the upper part of the small intestine. TRIAL REGISTRATION: ISRCTN 99322160 , 01/10/2018.

Biological agent in prevention of ocular recurrence in Behçets disease: a case report.

INTRODUCTION: Ocular involvement in Behçets disease (BD) is characterized by recurrent inflammatory attacks leading to poor long-term visual prognosis. The development of biologic agents has heralded a new era in the management of BD uveitis enabling more targeted immune modulation with greater efficacy and has now become the first line agents. OBJECTIVE: To report a case of young gentleman with Behçets disease whose ocular recurrence was controlled with injection Adalimumab. CASE: A 31-year-old male with recurrent oral and genital ulcers with bilateral recurrent uveitis was diagnosed as bilateral ocular Behçet's disease based on positive HLA B51typing and ferning pattern in FFA. He was on oral Prednisolone and Cyclosporine and was advised for biological agents. On presentation to us, he had anterior uveitis with pseudophakia and secondary open angle glaucoma in right eye and posterior sub capsular cataract in left eye. After starting Inj Adalimumab with oral Methotrexate, he ocular inflammation was under control and patient underwent uneventful cataract surgery in left eye. Over 1-year follow-up, the patient is on remission, on injection Adalimumab with the steroid tapered off. CONCLUSION: Biological agents like Adalimumab is effective in controlling recurrences in Behçet's disease.

Antiulcerative Activity of Milk Proteins Hydrolysates.

Several studies have shown the protective effect of dairy products, especially α-lactalbumin and derived hydrolysates, against induced gastric ulcerative lesions. The mucus strengthening represents an important mechanism in the defense of gastrointestinal mucosa. Previously, a hydrolysate from casein (CNH) and a hydrolysate from whey protein concentrate rich in ß-lactoglobulin (WPH) demonstrated a stimulatory activity on mucus production in intestinal goblet cells. The aim of this work was to evaluate the possible antiulcerative activity of these two hydrolysates in an ethanol-induced ulcer model in rats. All tested samples significantly reduced the ulcerative lesions index (ULI), compared with the saline solution, using doses of 300 and 1000 mg kg-1 body weight with decreases up to 66.3% ULI. A dose-response relationship was found for both hydrolysates. The involvement of endogenous sulfhydryl (SH) groups and prostaglandins (PGs) in the antiulcerative activity was evaluated using their blockage. The antiulcerative activity of WPH showed a drastic decrease in presence of N-ethylmaleimide (from 41.4% to 9.2% ULI). However, the CNH antiulcerative properties were not significantly affected. The cytoprotective effect of WPH appears to depend on a PG-mediated mechanism. In conclusion, CNH and WPH demonstrated in vivo antiulcerative properties and represent a promising alternative as protectors of the gastric mucosa.

A New Polyoxygenated Flavonol Gossypetin-3-O-ß-d-Robinobioside from Caesalpinia gilliesii (Hook.) D. Dietr. and In Vivo Hepatoprotective, Anti-Inflammatory, and Anti-Ulcer Activities of the Leaf Methanol Extract.

A hitherto unknown polyoxygenated flavonol robinobioside (gossypetin-3-O-ß-d-robinobioside) was isolated from the leaves of Caesalpinia gilliesii along with thirteen known phenolic secondary metabolites. The isolated compounds were characterized using spectroscopic analysis, including 1D and 2D NMR and mass spectrometry (MS) analyses. The extract reduced the level of liver damage in CCl4-induced liver injury in rats. A decrease of the liver biomarkers-aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and an increase of total antioxidant capacity (TAC) levels-were observed similar to the liver protecting drug silymarin. In addition, the extract showed promising activity against carrageenan-induced paw edema in rats and protected their stomachs against ethanol-induced gastric ulcers in a concentration dependent fashion. The observed activities could be attributed to the high content of antioxidant polyphenols. Our results suggest that the C. gilliesii has the capacity to scavenge free radicals and can protect against oxidative stress, and liver and stomach injury.

FFA3 Activation Stimulates Duodenal Bicarbonate Secretion and Prevents NSAID-Induced Enteropathy via the GLP-2 Pathway in Rats.

BACKGROUND: Therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with enteropathy in humans and experimental animals, a cause of considerable morbidity. Unlike foregut NSAID-associated mucosal lesions, most treatments for this condition are of little efficacy. We propose that the endogenously released intestinotrophic hormone glucagon-like peptide-2 (GLP-2) prevents the development of NSAID-induced enteropathy. Since the short-chain fatty acid receptor FFA3 is expressed on enteroendocrine L cells and on enteric nerves in the gastrointestinal tract, we further hypothesized that activation of FFA3 on L cells protects the mucosa from injury via GLP-2 release with enhanced duodenal HCO3- secretion. We thus investigated the effects of synthetic selective FFA3 agonists with consequent GLP-2 release on NSAID-induced enteropathy. METHODS: We measured duodenal HCO3- secretion in isoflurane-anesthetized rats in a duodenal loop perfused with the selective FFA3 agonists MQC or AR420626 (AR) while measuring released GLP-2 in the portal vein (PV). Intestinal injury was produced by indomethacin (IND, 10 mg/kg, sc) with or without MQC (1-10 mg/kg, ig) or AR (0.01-0.1 mg/kg, ig or ip) treatment. RESULTS: Luminal perfusion with MQC or AR (0.1-10 µM) dose-dependently augmented duodenal HCO3- secretion accompanied by increased GLP-2 concentrations in the PV. The effect of FFA3 agonists was inhibited by co-perfusion of the selective FFA3 antagonist CF3-MQC (30 µM). AR-induced augmented HCO3- secretion was reduced by iv injection of the GLP-2 receptor antagonist GLP-2(3-33) (3 nmol/kg), or by pretreatment with the cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor CFTRinh-172 (1 mg/kg, ip). IND-induced small intestinal ulcers were dose-dependently inhibited by intragastric administration of MQC or AR. GLP-2(3-33) (1 mg/kg, ip) or CF3-MQC (1 mg/kg, ig) reversed AR-associated reduction in IND-induced enteropathy. In contrast, ip injection of AR had no effect on enteropathy. CONCLUSION: These results suggest that luminal FFA3 activation enhances mucosal defenses and prevents NSAID-induced enteropathy via the GLP-2 pathway. The selective FFA3 agonist may be a potential therapeutic candidate for NSAID-induced enteropathy.

Microbiota Plays a Key Role in Non-Steroidal Anti-Inflammatory Drug-Induced Small Intestinal Damage.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) damage the small intestine by causing multiple erosions and ulcers. However, to date, no established therapies and prophylactic agents are available to treat such damages. We reviewed the role of intestinal microbiota in NSAID-induced intestinal damage and identified potential therapeutic candidates. SUMMARY: The composition of the intestinal microbiota is an important factor in the pathophysiology of NSAID-induced small intestinal damage. Once mucosal barrier function is disrupted due to NSAID-induced prostaglandin deficiency and mitochondrial malfunction, lipopolysaccharide from luminal gram-negative bacteria and high mobility group box 1 from the injured epithelial cells activate toll-like receptor 4-signaling pathway and nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 inflammasome; this leads to the release of proinflammatory cytokines such as tumor necrosis factor-α and interleukin-1ß. Proton pump inhibitors (PPIs) are often used for the prevention of NSAID-induced injuries to the upper gastrointestinal tract. However, several studies indicate that PPIs may induce dysbiosis, which may exacerbate the NSAID-induced small intestinal damage. Our recent research suggests that probiotics and rebamipide could be used to prevent NSAID-induced small intestinal damage by regulating the intestinal microbiota. Key Messages: Intestinal microbiota plays a key role in NSAID-induced small intestinal damage, and modulating the composition of the intestinal microbiota could be a new therapeutic strategy for treating this damage.