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Gastrointestinal disease is the most common health concern that occurs due to environmental, infectious, immunological, psychological, and genetic stress. Among them, the most frequent diseases are gastric ulcer (GU) and ulcerative colitis (UC). DSS-induced UC and ethanol-stimulated GU models resemble the pathophysiology of human gastrointestinal disease. The current study was designed to explore the anti-oxidation, anti-inflammation, anti-cell death properties of terazosin, an α-adrenergic receptor antagonist, in vivo and in vitro. Our results indicate that terazosin dramatically activates Pgk1, and upregulates glycose metabolism, evidenced by the enhanced ATP production and higher LDH enzymatic activity. Also, terazosin significantly enhances p-AKT expression and inhibits NF-κB p65 activation through abrogating the phosphorylation of IKBα, as well as lowers Caspase-1 and GSDMD expression. The findings in this study demonstrate that terazosin exhibits anti-inflammatory effects by downregulating NF-κB-GSDMD signal pathway, along with enhancing glycolysis for gastrointestinal disease treatment. Meanwhile, we also find terazosin ameliorates ethanol-induced gastric mucosal damage in mice. Collectively, as a clinical drug, terazosin should be translated into therapeutics for gastrointestinal disease soon.

The survival factor renalase (RNLS) is a recently discovered secretory protein with potent prosurvival and anti-inflammatory effects. Several evolutionarily conserved RNLS domains are critical to its function. These include a 20 aa site that encodes for its prosurvival effects. Its prosurvival effects are shown in GI disease models including acute cerulein pancreatitis. In rodent models of pancreatic cancer and human cancer tissues, increased RNLS expression promotes cancer cell survival but shortens life expectancy. This 37 kD protein can regulate cell signaling as an extracellular molecule and probably also at intracellular sites. Extracellular RNLS signals through a specific plasma membrane calcium export transporter; this interaction appears most relevant to acute injury and cancer. Preliminary studies using RNLS agonists and antagonists, as well as various preclinical disease models, suggest that the immunologic and prosurvival effects of RNLS will be relevant to diverse pathologies that include acute organ injuries and select cancers. Future studies should define the roles of RNLS in intestinal diseases, characterizing the RNLS-activated pathways linked to cell survival and developing therapeutic agents that can increase or decrease RNLS in relevant clinical settings.

Rho proteins operate as key regulators of the cytoskeleton, cell morphology and trafficking. Acting as molecular switches, the function of Rho GTPases is determined by guanosine triphosphate (GTP)/guanosine diphosphate (GDP) exchange and their lipidation via prenylation, allowing their binding to cellular membranes and the interaction with downstream effector proteins in close proximity to the membrane. A plethora of in vitro studies demonstrate the indispensable function of Rho proteins for cytoskeleton dynamics within different cell types. However, only in the last decades we have got access to genetically modified mouse models to decipher the intricate regulation between members of the Rho family within specific cell types in the complex in vivo situation. Translationally, alterations of the expression and/or function of Rho GTPases have been associated with several pathological conditions, such as inflammation and cancer. In the context of the GI tract, the continuous crosstalk between the host and the intestinal microbiota requires a tight regulation of the complex interaction between cellular components within the intestinal tissue. Recent studies demonstrate that Rho GTPases play important roles for the maintenance of tissue homeostasis in the gut. We will summarize the current knowledge on Rho protein function within individual cell types in the intestinal mucosa in vivo, with special focus on intestinal epithelial cells and T cells., Competing Interests: The authors declare no conflict of interest.

Genetic testing is a good predictor of lactase persistence (LP) in specific populations but its clinical utility in children is less clear. We assessed the role of lactose malabsorption in functional gastrointestinal disorders (FGID) in children and the correlation between the lactase non-persistence (LNP) genotype and phenotype, based on exhaled hydrogen and gastrointestinal symptoms, during a hydrogen breath test (HBT). We also evaluate dairy consumption in this sample. We conducted a 10-year cross-sectional study in a cohort of 493 children with suspected FGID defined by Roma IV criteria. Distribution of the C/T-13910 genotype was as follows: CC, 46.0%; TT, 14.4% (LP allele frequency, 34.1%). The phenotype frequencies of lactose malabsorption and intolerance were 36.3% and 41.5%, respectively. We observed a strong correlation between genotype and both lactose malabsorption (Cramér's V, 0.28) and intolerance (Cramér's V, 0.54). The frequency of the LNP genotype ( p = 0.002) and of malabsorption and intolerance increased with age ( p = 0.001 and 0.002, respectively). In 61% of children, evaluated dairy consumption was less than recommended. No association was observed between dairy intake and diagnosis. In conclusion, we found a significant correlation between genotype and phenotype, greater in older children, suggesting that the clinical value of genetic testing increases with age.

Bile acid metabolism by the gut microbiome exerts both beneficial and harmful effects on host health. Microbial bile salt hydrolases (BSHs), which initiate bile acid metabolism, exhibit both positive and negative effects on host physiology. In this study, 5,790 BSH homologs were collected and classified into seven clusters based on a sequence similarity network. Next, the abundance and distribution of BSH in 380 metagenomes from healthy participants were analyzed. It was observed that different clusters occupied diverse ecological niches in the human microbiome and that the clusters with signal peptides were relatively abundant in the gut. Then, the association between BSH clusters and 12 human diseases was analyzed by comparing the abundances of BSH genes in patients ( n = 1,605) and healthy controls ( n = 1,540). The analysis identified a significant association between BSH gene abundance and 10 human diseases, including gastrointestinal diseases, obesity, type 2 diabetes, liver diseases, cardiovascular diseases, and neurological diseases. The associations were further validated by separate cohorts with inflammatory bowel diseases and colorectal cancer. These large-scale studies of enzyme sequences combined with metagenomic data provide a reproducible assessment of the association between gut BSHs and human diseases. This information can contribute to future diagnostic and therapeutic applications of BSH-active bacteria for improving human health.

Introduction: Blastocystis is a common intestinal parasite of human and animal hosts. The parasite has 17 subtypes, and among those at least nine subtypes (ST1-ST9) are found in human hosts., Objective: The aim of the present study was to investigate the presence of different subtypes of Blastocystis spp. among the patients referred to Velayat hospital of Qazvin province, Iran., Methods: Overall, 864 stool samples were examined by using formalin-ethyl acetate concentration method and Trichrome staining. All specimens were cultured in clotted fetal bovine medium. Later, DNA extraction and PCR amplification of 18S ribosomal RNA gene region was conducted and phylogenetic tree constructed., Results: The results revealed 7.9% (68/864) of the study population were infected with Blastocystis . Intestinal symptoms were observed in 61% (36/59) of individuals positive for Blastocystis , with abdominal pain in 58% (21/36) of cases which was more frequent than other intestinal signs. No significant relationship was observed among the study variables. By molecular and phylogenetic analysis, three subtypes ST1 (45%), ST2 (30%) and ST3 (23%) of parasite were identified., Conclusion: This study showed ST1 subtype was the predominant subtype among the positive specimens, meanwhile the highest haplotype and nucleotide diversity were clarified in ST3 subtype., (© 2020 Delshad A et al.)

It has been hypothesized that gluten-dependent production of anti-tissue-transglutaminase 2 (anti-TG2) antibodies may occur only at an intestinal level. We have investigated intestinal production of anti-TG2 antibodies in 136 patients with normal serum levels of anti-TG2 antibodies and normal duodenal mucosa. Intestinal deposits of anti-TG2 antibodies were evaluated by immunofluorescence and anti-TG2 antibodies released in organ culture supernatants measured by ELISA. Intestinal antibody libraries were obtained from 10 subjects. Immunohistochemistry for CD25⁺, CD3⁺, and TCR-γδ⁺ was assessed in subjects with positive ( n = 32) and negative ( n = 31) intestinal anti-TG2 antibodies. Globally 33/136 (24%) seronegative patients produced anti-TG2 autoantibodies at an intestinal level. Antibody libraries analysis confirmed the anti-TG2 antibodies mucosal production in all ( n = 8) positive subjects. Lamina propria CD25⁺ cell count was significantly ( p < 0.05) higher in patients with intestinal anti-TG2. Moreover, 13/32 (41%) of them showed high TCR-γδ⁺/CD3⁺ ratios. Intestinal anti-TG2 antibody production does not show absolute specificity for CD. It is seen more often in association with inflamed mucosa. Further investigations are necessary to prove the possible role of dietary gluten.

Elevated basal serum tryptase levels are present in 4-6% of the general population, but the cause and relevance of such increases are unknown. Previously, we described subjects with dominantly inherited elevated basal serum tryptase levels associated with multisystem complaints including cutaneous flushing and pruritus, dysautonomia, functional gastrointestinal symptoms, chronic pain, and connective tissue abnormalities, including joint hypermobility. Here we report the identification of germline duplications and triplications in the TPSAB1 gene encoding α-tryptase that segregate with inherited increases in basal serum tryptase levels in 35 families presenting with associated multisystem complaints. Individuals harboring alleles encoding three copies of α-tryptase had higher basal serum levels of tryptase and were more symptomatic than those with alleles encoding two copies, suggesting a gene-dose effect. Further, we found in two additional cohorts (172 individuals) that elevated basal serum tryptase levels were exclusively associated with duplication of α-tryptase-encoding sequence in TPSAB1, and affected individuals reported symptom complexes seen in our initial familial cohort. Thus, our findings link duplications in TPSAB1 with irritable bowel syndrome, cutaneous complaints, connective tissue abnormalities, and dysautonomia.

The GI tract is the most exposed organ to proteases, both in physiological and pathophysiological conditions. For digestive purposes, the lumen of the upper GI tract contains large amounts of pancreatic proteases, but studies have also demonstrated increased proteolytic activity into mucosal tissues (both in the upper and lower GI tract), associated with pathological conditions. This review aims at outlining the evidences for dysregulated proteolytic homeostasis in GI diseases and the pathogenic mechanisms of increased proteolytic activity. The therapeutic potential of protease inhibition in GI diseases is discussed, with a particular focus on IBDs, functional GI disorders and colorectal cancer., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Purpose To review the literature surrounding the involvement of the endothelium and matrix metalloproteinases (MMP) in radiotherapy-induced gut toxicity (RIGT) and further elucidate its complex pathobiology. Results RIGT involves damage to the gastrointestinal mucosa and is associated with diarrhoea, pain, and rectal bleeding depending on the area of exposure. The mechanisms underpinning RIGT are complex and have not yet been elucidated. Members of the MMP family, particularly MMP-2 and -9, have recently been identified as being key markers in RIGT and chemotherapy-induced gut toxicity (CIGT). Furthermore, the microvasculature has long been implicated in the development of toxicities following both chemotherapy and radiotherapy, however, the mechanisms behind this are yet to be explored. Conclusions It is proposed that matrix metalloproteinases are key regulators of endothelial mediators, and may play a key role in inducing damage to intestinal microvasculature following radiotherapy.

Gastrointestinal diseases, such as irritable bowel syndrome, inflammatory bowel disease, and colorectal cancer, affect a large proportion of the population and are associated with many unpleasant symptoms. Although the causes of these diseases remain largely unknown, there is increasing evidence to suggest that dysregulated protease activity may be a contributing factor. Proteases are enzymes that cleave other proteins, and their activity is normally very tightly regulated. During disease, however, the balance between proteases and their inhibitors is often shifted, leading to altered spatial and temporal control of substrate cleavage. Evaluating protease levels in normal physiology and disease has relied heavily on the use of chemical tools. Although these tools have greatly advanced the field, they are not without caveats. This review provides an introduction to these tools, their application in the gut, and a summary of the current knowledge on the contribution of protease activity to gastrointestinal disease., (Copyright © 2016 the American Physiological Society.)

As a physiological phenomenon, acid secretion from the stomach was known already at least in the 17th century. But its mechanism was elucidated in more recent times only. At the end of the 20th century, gastric H(+)/K(+)-ATPase in the parietal cells was found to be responsible for a final step of H(+) secretion in these cells. In this century, several Cl(-)-transporting proteins for gastric acid (hydrochloric acid; HCl) secretion have been found. As inhibitors of gastric acid secretion, histamine H2 receptor antagonists (H2 blockers) were developed in the 1970's. This discovery brought a great benefit; that is, peptic ulcers became treatable by administration of a drug. In 1980's, proton pump inhibitors (PPIs) were developed. The target of PPIs is gastric H(+)/K(+)-ATPase and the PPIs exert generally more potent effects compared with H2 blockers. Most recently, several K(+)-competitive inhibitors of the ATPase are being developed. Here, we introduce gastric H(+)/K(+)-ATPase and its related proteins for gastric acid secretion, and several gastric diseases and their treatment by medicines.

Orally administered drugs must pass through the intestinal wall and then through the liver before reaching systemic circulation. During this process drugs are subjected to different processes that may determine the therapeutic value. The intestinal barrier with active drug metabolizing enzymes and drug transporters in enterocytes plays an important role in the determination of drug bioavailability. Accumulating information demonstrates variable distribution of drug metabolizing enzymes and transporters along the human gastrointestinal tract (GI), that creates specific barrier characteristics in different segments of the GI. In this review, expression of drug metabolizing enzymes and transporters in the healthy and diseased human GI as well as their regulatory aspects: genetic, miRNA, DNA methylation are outlined. The knowledge of unique interplay between drug metabolizing enzymes and transporters in specific segments of the GI tract allows more precise definition of drug release sites within the GI in order to assure more complete bioavailability and prediction of drug interactions.

The ability of nonsteroidal anti-inflammatory drugs (NSAIDs) to inhibit cyclooxygenase (Cox)-1 and Cox-2 underlies the therapeutic efficacy of these drugs, as well as their propensity to damage the gastrointestinal (GI) epithelium. This toxic action greatly limits the use of NSAIDs in inflammatory bowel disease (IBD) and other chronic pathologies. Fatty acid amide hydrolase (FAAH) degrades the endocannabinoid anandamide, which attenuates inflammation and promotes GI healing. Here, we describe the first class of systemically active agents that simultaneously inhibit FAAH, Cox-1, and Cox-2 with high potency and selectivity. The class prototype 4: (ARN2508) is potent at inhibiting FAAH, Cox-1, and Cox-2 (median inhibitory concentration: FAAH, 0.031 ± 0.002 µM; Cox-1, 0.012 ± 0.002 µM; and Cox-2, 0.43 ± 0.025 µM) but does not significantly interact with a panel of >100 off targets. After oral administration in mice, ARN2508 engages its intended targets and exerts profound therapeutic effects in models of intestinal inflammation. Unlike NSAIDs, ARN2508 causes no gastric damage and indeed protects the GI from NSAID-induced damage through a mechanism that requires FAAH inhibition. Multitarget FAAH/Cox blockade may provide a transformative approach to IBD and other pathologies in which FAAH and Cox are overactive., (© FASEB.)

Acetylsalicylic acid (aspirin) is a prototypic cyclooxygenase (COX) inhibitor. It was synthesized serendipitously from a natural compound, i.e., salicylic acid, with known analgesic activity. This chemical modification, obtained for the first time in an industrial environment in 1897, endowed aspirin with the unique capacity of acetylating and inactivating permanently COX-isozymes. Traditional nonsteroidal anti-inflammatory drugs (tNSAIDs) were developed to mimic the pharmacological effects of aspirin, using aspirin-sensitive experimental models of pain and inflammation as the template for screening new chemical entities. Among the tNSAIDs, some were endowed with moderate COX- selectivity (e.g., diclofenac), but no studies of sufficient size and duration were performed to show any clinically relevant difference between different members of the class. Similarly, no serious attempts were made to unravel the mechanisms involved in the shared therapeutic and toxic effects of tNSAIDs until the discovery of COX-2. This led to characterizing their main therapeutic effects as being COX-2-dependent and their gastrointestinal (GI) toxicity as being COX-1-dependent, and provided a rationale for developing a new class of selective COX-2 inhibitors, the coxibs. This review will discuss the clinical pharmacology of tNSAIDs and coxibs, and the clinical read-outs of COX-isozyme inhibition. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance.", (Copyright © 2014 Elsevier B.V. All rights reserved.)

We performed a systematic review and meta-analysis of the risk of gastrointestinal (GI) toxicities associated with MEK inhibitors. Eligible studies included randomized Phase II and III trials of cancer patients on the three MEK inhibitors (trametinib, selumetinib and cobimetinib), describing events of stomatitis, diarrhea and vomiting. Our search strategy yielded 250 potentially relevant citations from Pubmed/Medline, Google scholar and CENTRAL Cochrane registry. After exclusion of ineligible studies, a total of 16 clinical trials were considered eligible for the meta-analysis. The relative risks of all-grade stomatitis, diarrhea and vomiting were 2.03 (95% CI 1.41-2.96; p = 0.002), 1.92 (95% CI 1.48-2.50; p < 0.00001) and 1.35 (95% CI 1.06-1.71; p = 0.01). Subgroup analyses according to agent used (trametinib vs Selumetinib), the regimen used (monotherapy vs combination) and the cancer treated (melanoma vs nonmelanoma) did not reveal any significant difference between the subgroups. Our meta-analysis has demonstrated that MEK inhibitor-based treatment is associated with an increased risk of stomatitis, diarrhea and vomiting compared to control. Clinicians should be aware of this risk and perform regular assessment.

Aim: To determine the alterations in rat enterocyte mitochondrial respiratory function and enzyme activities following traumatic brain injury (TBI)., Methods: Fifty-six male SD rats were randomly divided into seven groups (8 rats in each group): a control group (rats with sham operation) and traumatic brain injury groups at 6, 12, 24 h, days 2, 3, and 7 after operation. TBI models were induced by Feendy's free-falling method. Mitochondrial respiratory function (respiratory control ratio and ADP/O ratio) was measured with a Clark oxygen electrode. The activities of respiratory chain complex I-IV and related enzymes were determined by spectrophotometry., Results: Compared with the control group, the mitochondrial respiratory control ratio (RCR) declined at 6 h and remained at a low level until day 7 after TBI (control, 5.42 ± 0.46; 6 h, 5.20 ± 0.18; 12 h, 4.55 ± 0.35; 24 h, 3.75 ± 0.22; 2 d, 4.12 ± 0.53; 3 d, 3.45 ± 0.41; 7 d, 5.23 ± 0.24, P < 0.01). The value of phosphate-to-oxygen (P/O) significantly decreased at 12, 24 h, day 2 and day 3, respectively (12 h, 3.30 ± 0.10; 24 h, 2.61 ± 0.21; 2 d, 2.95 ± 0.18; 3 d, 2.76 ± 0.09, P < 0.01) compared with the control group (3.46 ± 0.12). Two troughs of mitochondrial respiratory function were seen at 24 h and day 3 after TBI. The activities of mitochondrial complex I (6 h: 110 ± 10, 12 h: 115 ± 12, 24 h: 85 ± 9, day 2: 80 ± 15, day 3: 65 ± 16, P < 0.01) and complex II (6 h: 105 ± 8, 12 h: 110 ± 92, 24 h: 80 ± 10, day 2: 76 ± 8, day 3: 68 ± 12, P < 0.01) were increased at 6 h and 12 h following TBI, and then significantly decreased at 24 h, day 2 and day 3, respectively. However, there were no differences in complex I and II activities between the control and TBI groups. Furthermore, pyruvate dehydrogenase (PDH) activity was significantly decreased at 6 h and continued up to 7 d after TBI compared with the control group (6 h: 90 ± 8, 12 h: 85 ± 10, 24 h: 65 ± 12, day 2: 60 ± 9, day 3: 55 ± 6, day 7: 88 ± 11, P < 0.01). The changes in α-ketoglutaric dehydrogenase (KGDH) activity were similar to PDH, except that the decrease in KGDH activity began at 12 h after TBI (12 h: 90 ± 12, 24 h: 80 ± 9, day 2: 76 ± 15, day 3: 68 ± 7, day 7: 90 ± 13, P < 0.01). No significant change in malate dehydrogenase (MDH) activity was observed., Conclusion: Rat enterocyte mitochondrial respiratory function and enzyme activities are inhibited following TBI. Mitochondrial dysfunction may play an important role in TBI-induced gastrointestinal dysfunction.

Gastrointestinal (GI) anthrax results from the ingestion of Bacillus anthracis. Herein, we investigated the pathogenesis of GI anthrax in animals orally infected with toxigenic non-encapsulated B. anthracis Sterne strain (pXO1+ pXO2-) spores that resulted in rapid animal death. B. anthracis Sterne induced significant breakdown of intestinal barrier function and led to gut dysbiosis, resulting in systemic dissemination of not only B. anthracis, but also of commensals. Disease progression significantly correlated with the deterioration of innate and T cell functions. Our studies provide critical immunologic and physiologic insights into the pathogenesis of GI anthrax infection, whereupon cleavage of mitogen-activated protein kinases (MAPKs) in immune cells may play a central role in promoting dysfunctional immune responses against this deadly pathogen.

Matrix metalloproteinases (MMPs), responsible for extracellular matrix remodelling and processing of numerous soluble and cell-surface proteins, appear to play important roles in pathogenesis of gastrointestinal diseases. MMPs influence migration of inflammatory cells, mucosal destruction, matrix deposition and degradation. In this study, we analysed the expression of MMP-19 in the main forms of gastrointestinal diseases including inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease, and colorectal carcinoma. We identified prominent MMP-19 expression in unaffected areas of intestinal epithelia and macrophages but not in other cells or tissues. Abundant expression of MMP-19 was also found in the endothelium of blood and lymphatic vessels of inflamed intestinal tissue. High MMP-19 immunoreactivity was also associated with macrophages in inflamed areas and myenteric plexuses. In comparison to the intestinal epithelium, all these cell types and compartments appeared to express MMP-19 irrespective of the disease pathogenesis and progression. Intestinal epithelia exhibited striking differential immunoreactivity for MMP-19. While immunoreactivity of monoclonal antibody recognizing the propeptide domain declined in virtually all IBD and colorectal carcinoma samples, other polyclonal antibodies against the hinge region and propetide domain did not show such an obvious decrease. Additional Western blotting analysis revealed that the antibodies against MMP-19 recognize differently processed forms of this MMP. The disappearance of immunoreactivity of the monoclonal anti-propeptide domain antibody does not mean down-regulation of MMP-19, but processing of the immature form. As this processing likely leads to the activation of this MMP, the differential staining pattern may be an important sign of disease progression.

Proteases are widely distributed in the human body and are crucially involved in the modulation of physiological processes in the gastrointestinal (GI) tract. They also have a major role in the etiology and the course of GI diseases. This review discusses the pharmacology of proteases and medical application of their inhibitors in the GI tract. In particular, we focus on metabolic disorders, such as diabetes type 2, inflammatory bowel diseases (IBD), irritable bowel syndrome (IBS) and abdominal pain. Based on recent papers in the field of pharmacology and documented clinical trials, we suggest future treatment options employing protease inhibitors., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Tivantinib (formerly ARQ 197) is a selective inhibitor of c-Met mainly metabolized by CYP2C19. CYP2C19 is known for genetic polymorphisms, and ~20% of Asians are poor metabolizers (PMs), while others are extensive metabolizers (EMs). In this study, we examined the safety, pharmacokinetics (PK), and preliminary efficacy of tivantinib as a single agent to determine recommended phase II doses (RPIIDs)., Patients and Methods: Forty-seven patients (EMs, 33; PMs, 14) with solid tumors were orally treated with tivantinib, from 70 to 360 mg bid in a 3 + 3 dose-escalation scheme. EMs and PMs were separately enrolled at the doses >120 mg bid., Results: Tivantinib was well tolerated up to 360 mg bid for EMs and 240 mg bid for PMs. Neutropenia, leukopenia, anemia, fatigue, and anorexia were the frequent adverse events related to tivantinib and were commonly observed in both EMs and PMs. PMs had 1.9-fold higher AUC(0-12) compared with EMs at 240 mg bid. Regardless of CYP2C19 phenotype, Gr.4 neutropenia occurred in patients with relatively high exposure to tivantinib. A confirmed partial response was achieved in two non-small-cell lung cancer (NSCLC) patients., Conclusion: Two different settings of RPIIDs, 360 mg bid for EMs and 240 mg bid for PMs, were determined.

Matrix metalloproteinases (MMPs) are critical factors in maintaining the integrity of mucosa and mediating normal biological processes. An imbalance between tissue levels of these mediators and their natural inhibitors is believed to underlie the pathophysiology of many diseases, including those affect the gastrointestinal and oral mucosae. The ongoing development of synthetic inhibitors of these mediators may provide opportunities to develop treatment modalities for patients suffering from these diseases. Understanding the role of MMPs in the pathophysiology of many diseases, however, is far from complete, and the improvement of pharmaceutical management strategies can only be achieved if the underlying process of these diseases is completely comprehended. This paper reviews the functions of matrix metalloproteinases and addresses their role in mediating mucosal pathologies with emphasis on oral mucosa., (© 2012 John Wiley & Sons A/S.)

An increase in serum levels of pancreatic enzymes is a well-known manifestation of pancreatic disease, especially of inflammatory or neoplastic nature, even if several extrapancreatic diseases can equally cause that increase. In addition to this pathological type of hyperenzymemia, different "non-pathological" forms have also been identified, including macroamylasemia, salivary, and mixed salivary and pancreatic hyperamylasemia, in all of which only amylase elevations are seen. Nevertheless, in 1996 a new syndrome characterized by an abnormal, chronic, benign increase in levels of serum amylase, pancreatic isoamylase, lipase and trypsin, asymptomatic and usually discovered incidentally, was described for the first time by Lucio Gullo et al. Hyperamylasemia/hyperlipasemia's observation is nowadays on the increase because general practitioners tend to include more frequently amylase and lipase in routine blood tests and, moreover, because the constant evaluation of this biochemical alteration in the Emergency Unit: for this reason, this syndrome was clearly identified only recently. Therefore, it's characterized by serum elevation of all pancreatic enzymes in the absence of underlying diseases; it occurs in either sporadic or familial form and it persists over time with considerable fluctuation in serum enzyme concentrations, including frequent normalizations. Proper diagnosis of this form of hyperenzymemia is important because it reassures the subjects having this anomaly that the syndrome is benign, and because it can prevent multiple and expensive diagnostic tests or useless hospitalizations or therapies.

Background: Increased D-lactate concentrations cause neurological signs in humans with gastrointestinal disease., Hypothesis/objectives: To determine if serum D-lactate concentrations are increased in cats with gastrointestinal disease compared to healthy controls, and if concentrations correlate with specific neurological or gastrointestinal abnormalities., Animals: Systematically selected serum samples submitted to the Gastrointestinal Laboratory at Texas A&M University from 100 cats with clinical signs of gastrointestinal disease and abnormal gastrointestinal function tests, and 30 healthy cats., Methods: Case-control study in which serum D- and L-lactate concentrations and retrospective data on clinical signs were compared between 30 healthy cats and 100 cats with gastrointestinal disease. Association of D-lactate concentration with tests of GI dysfunction and neurological signs was evaluated by multivariate linear and logistic regression analyses, respectively., Results: All 100 cats had a history of abnormal gastrointestinal signs and abnormal gastrointestinal function test results. Thirty-one cats had definitive or subjective neurological abnormalities. D-lactate concentrations of cats with gastrointestinal disease (median 0.36, range 0.04-8.33 mmol/L) were significantly higher than those in healthy controls (median 0.22, range 0.04-0.87 mmol/L; P = .022). L-lactate concentrations were not significantly different between the 2 groups of cats with gastrointestinal disease and healthy controls. D-lactate concentrations were not significantly associated with fPLI, fTLI, cobalamin, folate, or neurological abnormalities (P > .05)., Conclusions and Clinical Importance: D-lactate concentrations can be increased in cats with gastrointestinal disease. These findings warrant additional investigations into the role of intestinal microbiota derangements in cats with gastrointestinal disease, and the association of D-lactate and neurological abnormalities., (Copyright © 2012 by the American College of Veterinary Internal Medicine.)

Phosphodiesterase (PDE) enzymes are widely distributed throughout the body, having numerous effects and functions. The use of on demand PDE5 inhibitors (-Is) for the treatment of erectile dysfunction (ED) has recently obtained approval for chronic daily dosing for the same indication. There are published data supporting the use of PDE5-Is for the treatment of lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH). Additional reports suggest benefit by these agents in patients with chronic heart failure, pulmonary hypertension, essential hypertension, and for the treatment of ischemia. Various central nervous system disorders have been described as targets by PDE5-Is. Sildenafil may have a potential therapeutic indication as a cognitive enhancer in age-related cerebral conditions. There is preclinical evidence for further investigation of the use of PDE5A -Is to improve recovery of cerebral function in humans after stroke by enhancing angiogenesis, neurogenesis and improving neurologic function. Sildenafil delays intestinal ulceration by an increase in the secretion of mucus/fluid and a decrease in hypermotility, and has a protective effect in reducing gastric damage. Larger scale, well designed clinical trials are needed to ascertain the safety, efficacy and cost-effectiveness of PDE5-Is in the future treatment of both urologic and non-urologic diseases. In this review, potential applications of PDE5-Is on urologic, cardiovascular, gastrointestinal, and central nervous system disorders will be updated.

Indoleamine 2,3-dioxygenase (IDO) modifies adaptive immunity, in part by determining the character of inflammatory responses in the tissue microenvironment. Small molecule inhibitors of IDO are being developed to treat cancer, chronic infections and other diseases, so the systemic effects of IDO disruption on inflammatory phenomena may influence the design and conduct of early phase clinical investigations of this new class of therapeutic agents. Here, we report cardiac and gastrointestinal phenotypes observed in IDO deficient mice that warrant consideration in planned assessments of the safety risks involved in clinical development of IDO inhibitors. Calcification of the cardiac endometrium proximal to the right ventricle was a sexually dimorphic strain-specific phenotype with ~30% penetrance in BALB/c mice lacking IDO. Administration of complete Freund's adjuvant containing Toll-like receptor ligands known to induce IDO caused acute pancreatitis in IDO deficient mice, with implications for the design of planned combination studies of IDO inhibitors with cancer vaccines. In an established model of hyperlipidemia, IDO deficiency caused a dramatic elevation in levels of serum triglycerides. In the large intestine, IDO loss only slightly increased sensitivity to induction of acute colitis, but it markedly elevated tumor incidence, multiplicity and staging during inflammatory colon carcinogenesis. Together, our findings suggest potential cardiac and gastrointestinal risks of IDO inhibitors that should be monitored in patients as this new class of drugs enter early clinical development.

Background: Acid sphingomyelinase (ASM, EC 3.1.4.12) hydrolyzes sphingomyelin to ceramide and represents a major regulator of sphingolipid metabolism. Increased activity of ASM has been observed in a variety of human diseases, and a critical contribution of ASM to medical conditions was demonstrated in several mouse models. In agreement with increased ASM activity in cell lines treated with ethanol, we have recently found higher levels of ASM activity in peripheral blood cells of active drinkers. However, the influence of ethanol on secretory ASM (S-ASM) has not been investigated so far., Methods: ASM activity and routine blood parameters were determined in plasma samples of 27 patients with alcohol dependence during physical withdrawal and compared to a group of 36 healthy volunteers., Results: Compared to the control group, patients with alcohol dependence had S-ASM activity increased by about 3-fold (141 ± 69 vs. 428 ± 220 pmol/ml/h; p < 0.001) at the beginning of physical withdrawal. During withdrawal, S-ASM activity decreased by about 50% (p < 0.001; day 0 vs. day 7 to 10) and finally approximated nearly normal values. On the day of admission, S-ASM activity correlated positively with levels of carbohydrate-deficient transferrin (r = 0.410, p = 0.034) and high-density lipoprotein cholesterol (r = 0.440, p = 0.022) and inversely with body mass index (r = -0.509; p = 0.007), glucose (r = -0.480; p = 0.011), triglycerides (r = -0.592; p = 0.001), and large unstained cells (r = -0.526; p = 0.017)., Conclusions: Activity of S-ASM is increased in alcohol-dependent patients and correlates with established biomarkers of excessive drinking. The increased S-ASM activity is implicated in alcohol-induced lipid alterations and might be relevant for the occurrence of alcohol-related disorders., (Copyright © 2011 by the Research Society on Alcoholism.)

Over the past years, the incidence of yeast infections, especially candidiasis, has increased. It is known that birds, including cockatiels, harbor potentially pathogenic yeasts to human beings in their gastrointestinal tract. Thus, this work aims at determining the in vitro antifungal susceptibility and phospholipase activity of Candida spp. isolated from the gastrointestinal tract and stools of cockatiels. Sixty cockatiels were assessed and samples were collected from oral cavity, crop and cloaca and stools were collected from cages where birds were kept. Yeast species were identified according to morphological and biochemical characteristics. Amphotericin B, itraconazole and fluconazole were tested against 39 C. albicans; 12 C. tropicalis; 7 C. parapsilosis and 1 C. krusei, through broth microdilution test. These same isolates were also tested for phospholipase production, on egg yolk agar. For amphotericin B, itraconazole and fluconazole, MICs were 0.25-1 μg/mL, 0.03125 to ≥16 μg/mL and 0.5 to ≥64 μg/mL, respectively, and resistance to itraconazole and fluconazole was observed in 14 (35.89%) and 4 (10.26%) C. albicans isolates, respectively. All C. albicans were positive for phospholipase production, out of which 74.36% presented high enzymatic activity. Among non-albicans Candida species, 40% produced phospholipase. The results show that cockatiels might represent a hazard to human health, as sources of infections caused by resistant Candida spp., especially to immunocompromised individuals, children and elderly., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Gastrointestinal (GI) dysfunction occurs frequently in early Parkinson's disease (PD) and it is supposed to anticipate motor symptoms. About 80% of PD patients suffer from constipation before the onset of movement disorders. Despite such a high prevalence of gut impairment in PD, the molecular mechanisms remain poorly investigated. This is also due to the scarcity of experimental studies. In the present work, we tried to reproduce digestive abnormalities observed in PD patients by administering the parkinsonism-inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) to C57BL mice. We show that in these mice, MPTP (20mg/kg × 3) while producing the classic striatal dopamine (DA) denervation, persistently delays colonic motility, produces constipation, and reduces the number of enteric TH-positive neurons. The loss of TH-positive cells in the gut is selectively due to the disappearance of DA neurons within both myenteric and mostly submucosal plexus in the intestine, while no change is detected in the esophagus and stomach. In contrast, norepinephrine (NE) neurons are not affected. These data were confirmed by immunohistochemistry and by HPLC showing the significant loss of DA levels while NE and 5-HT content was not affected. Dopamine cell loss was associated with increased α-synuclein levels. These functional, biochemical, and morphological findings extend the PD-mimicking effects of MPTP to GI dysfunctions and provide a useful experimental model to understand gut dysfunction in PD and to find effective treatments for digestive symptoms., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Heme oxygenase (HO)-1 is the inducible isoform of the first and rate-limiting enzyme of heme degradation. HO-1 not only protects against oxidative stress and apoptosis, but has received a great deal of attention in recent years because of its potent anti-inflammatory functions. Studies with HO-1 knockout animal models have led to major advances in the understanding of how HO-1 might regulate inflammatory immune responses, although little is known on the underlying mechanisms. Due to its beneficial effects the targeted induction of this enzyme is considered to have major therapeutic potential for the treatment of inflammatory disorders. This review discusses current knowledge on the mechanisms that mediate anti-inflammatory protection by HO-1. More specifically, the article deals with the role of HO-1 in the pathophysiology of viral hepatitis, inflammatory bowel disease, and pancreatitis. The effects of specific HO-1 modulation as a potential therapeutic strategy in experimental cell culture and animal models of these gastrointestinal disorders are summarized. In conclusion, targeted regulation of HO-1 holds major promise for future clinical interventions in inflammatory diseases of the gastrointestinal tract.

Since the discovery of two cyclooxygenase isoforms (COX-1, COX-2), efforts have been made to characterize the roles played by these enzymes in the regulation of physiological functions, as well as to explore their involvement in the pathophysiology of inflammatory disorders. In the digestive tract, the majority of evidence has been obtained at mucosal level, where both isoforms regulate various functions, and contribute to the development of inflammatory and neoplastic disorders. The role of COX isoforms in the gut neuromuscular compartment, where their expression has been detected in different species, is still unclear. However, the characterization of actions exerted by COX-derived prostanoids on gut motility has been under investigation for many years, and it is becoming increasingly appreciated that these mediators subserve complex regulatory patterns of COX on digestive motility. More recently, several studies have strengthened the concept that both COX-1 and COX-2 are involved in the modulation of gastrointestinal neuromuscular activity under normal conditions, and that changes in their regulatory activities occur in the presence of various digestive disorders, including inflammatory bowel diseases and postoperative ileus. Despite a large body of preclinical evidence, studies aimed at translating these findings into clinically relevant applications are needed, in an attempt to identify novel therapeutic approaches for treatment of gut disorders associated with motility alterations. This review illustrates and discusses current knowledge of the roles played by COX pathways in the regulation of gastrointestinal neuromuscular functions, both under normal conditions and in the presence of gut disorders.

Rosacea is a common inflammatory condition of the facial skin of unknown etiology, which frequently occurs in combination with gastrointestinal disorders. Many dietary and hormonal factors are known to affect the severity of rosacea symptoms, several of which also modulate the activity of the enzyme intestinal alkaline phosphatase (IAP). The role of IAP in inhibiting an inflammatory response to intestinal bacteria suggests a mechanism by which intestinal pathologies may be linked to the skin inflammation characteristic of rosacea. Analysis of alkaline phosphatase activity is routinely performed on blood samples, and methods to quantify enzyme activity of the intestinal isoform specifically have been described. Correlations between IAP activity and rosacea symptoms in patients and controls can thus be screened by noninvasive and inexpensive means. If IAP activity is found to be low in rosacea patients, acute symptoms could be treated with oral IAP supplementation, and trials of IAP-activating medications currently used in gastrointestinal disease could be initiated in rosacea patients. More importantly, the safe and long-term control of rosacea could be undertaken by patients themselves through dietary modification to naturally increase IAP activity.

The influence of genetic polymorphism in inosine triphosphate pyrophosphatase (ITPA) on thiopurine-induced adverse events has not been investigated in the context of combination chemotherapy for acute lymphoblastic leukemia (ALL). This study investigated the effects of a common ITPA variant allele (rs41320251) on mercaptopurine metabolism and toxicity during treatment of children with ALL. Significantly higher concentrations of methyl mercaptopurine nucleotides were found in patients with the nonfunctional ITPA allele. Moreover, there was a significantly higher probability of severe febrile neutropenia in patients with a variant ITPA allele among patients whose dose of mercaptopurine had been adjusted for TPMT genotype. In a cohort of patients whose mercaptopurine dose was not adjusted for TPMT phenotype, the TPMT genotype had a greater effect than the ITPA genotype. In conclusion, genetic polymorphism of ITPA is a significant determinant of mercaptopurine metabolism and of severe febrile neutropenia, after combination chemotherapy for ALL in which mercaptopurine doses are individualized on the basis of TPMT genotype.

Purpose of Review: To describe recent advances in the processing of gastrointestinal hormones, and the consequences for human disease of mutations in the enzymes involved., Recent Findings: Although gastrointestinal prohormones were long regarded as devoid of biological activity, recent data indicate that the prohormones for both gastrin and gastrin-releasing peptide are bioactive, through different receptors from the mature hormones. Mutations in the family of prohormone convertases responsible for the initial steps in the processing of gastrointestinal hormones are associated with several different pathophysiological conditions in humans., Summary: Human mutational studies, when taken together with the phenotypes observed in mice deficient in the prohormone convertases, emphasize the crucial importance of the processing enzymes in mammalian biology. Although the phenotypes may often be ascribed to defective production of a mature hormone or growth factor, the recognition that the precursors are independently bioactive suggests that the increased precursor concentrations may also contribute to the symptoms. The observation that the precursors often act through different receptors from the mature hormones may permit the development of precursor-selective antagonists for therapeutic use.

Examination of 101 patients with pathological processes induced by caustic substances included measurement of serum enzyme activities (lactate dehydrogenase, creatine phosphokinase, aminotransferase , alkaline phosphatase), De Ritis index, and free hemoglobin. It was found that caustic lesions in splanchnic organs were associated with enhanced enzymatic activities the spectra of which were different in patients with acetic acid poisoning and poisoning from other caustic substances (inorganic acids, alkalis, oxidizing agents). It is concluded that a rise in creatine phosphokinase activity may be used as an indicator of the severity of lesion in the walls of the digestive tract.

Breath tests provide a valuable non-invasive diagnostic strategy to in vivo assess a variety of enzyme activities, organ functions or transport processes. Both the hydrogen breath tests and the (13)C-breath tests using the stable isotope (13)C as tracer are non-radioactive and safe, also in children and pregnancy. Hydrogen breath tests are widely used in clinical practice to explore gastrointestinal disorders. They are applied for diagnosing carbohydrate malassimilation, small intestinal bacterial overgrowth and for measuring the orocecal transit time. (13)C-breath tests non-invasively monitor the metabolisation of a (13)C-labelled substrate. Depending on the choice of the substrate they enable the assessment of gastric bacterial Helicobacter pylori infection, gastric emptying, liver and pancreatic function as well as measurements of many other enzyme activities. The knowledge of potential pitfalls and influencing factors are important for correct interpretation of breath test results before drawing clinical conclusions.

Cyclooxygenase (COX) catalyzes the conversion of arachidonic acid into prostaglandins (PGs), which play a significant role in health and disease in the gastrointestinal tract (GI) and in the renal, skeletal, and ocular systems. COX-1 is constitutively expressed and found in most normal tissues, whereas COX-2 can be expressed at low levels in normal tissues and is highly induced by pro-inflammatory mediators. Inhibitors of COX activity include: (1) conventional nonselective, nonsteroidal anti-inflammatory drugs (ns-NSAIDs) and (2) COX-2 selective nonsteroidal anti-inflammatory drugs (COX-2 s-NSAIDs). Inhibition of COX-1 often elicits GI toxicity in animals and humans. Therefore, COX-2 s-NSAIDs were developed to provide a selective COX-2 agent, while minimizing the attendant COX-1-mediated GI toxicities. Rats and dogs overpredict COX inhibition for renal effects such as renal handling of electrolytes in humans. COX inhibitors are shown to have both beneficial and detrimental effects, such as on healing of ligament or tendon tears, on the skeletal system in animal models. Certain ophthalmic conditions such as glaucoma and keratitis are associated with increased COX-2 expression, suggesting a potential role in their pathophysiology.

The discovery of a novel class of peripheral tryptophan hydroxylase (TPH) inhibitors is described. This class of TPH inhibitors exhibits excellent potency in in vitro biochemical and cell-based assays, and it selectively reduces serotonin levels in the murine intestine after oral administration without affecting levels in the brain. These TPH1 inhibitors may provide novel treatments for gastrointestinal disorders associated with dysregulation of the serotonergic system, such as chemotherapy-induced emesis and irritable bowel syndrome.

It is known that the overproduction of nitric oxide (NO) by nitric oxide synthase (NOS) occurs during the progression of various inflammatory diseases in intestinal tract. NOS inhibitors or inducible nitric oxide synthase (iNOS) gene expression inhibitors should be considered as potential anti-inflammatory agents, as NO synthesized by iNOS is related to various pathophysiological processes including inflammation. In order to understand the relationship between iNOS and pathological reactions such as the inflammatory process and malign transformation clearly, the existence and amount of constitutive expression should be determined. It is crucial to comprehend the harmful and protective amounts of iNOS expressions in order to clarify the relationship between iNOS and pathological processes. Evidently, only after this inspection is it possible to utilize iNOS as a marker and treatment instrument during the diagnosis and treatment of malign transformation and the inflammatory process.

Digestive tract proteases are best known for their proteolytic activity in the digestion of alimentary proteins. However, during the last decade, a possible role of proteases as signalling molecules has been emphasized with the discovery of a novel class of G-protein coupled receptors located on cell membranes that may be activated by proteolytic cleavage of their N-terminal extracellular domain. Type 2 protease-activated receptors (PAR-2) are cleaved by serine-proteases such as trypsin and tryptase. PAR-2 is present in many intestinal cell types and particularly on epithelial cells. Multiple functions have been demonstrated in the gut for PAR-2, including epithelial permeability, mainly the intercellular permeability that is of paramount importance in the equilibrium between the external milieu (digestive contents) and the submucosal immune system. Alterations of both tissue and luminal levels of proteases or serine-protease activity may affect gut permeability and subsequently the immune status of the mucosa. Activation of PAR-2 on epithelial cells may directly affect cytoskeleton contraction by triggering phosphorylation of myosin light chain with subsequent changes in tight junction permeability. Enhanced fecal protease level has been recently reported in both organic (ulcerative colitis) and functional (irritable bowel syndrome) intestinal disorders and may play a role in the pathogenesis of such diseases.

Gastrointestinal disorders, especially strangulating intestinal obstructions, are still a major cause of illness and death in the horse. Circulating lipopolysaccharides may activate both neutrophils and monocytes. The activated neutrophils release myeloperoxidase (MPO), a specific enzyme with strong oxidative activity. The aim of this study was to evaluate MPO concentrations in the plasma and peritoneal fluid (PF) of horses with colic and to check the hypothesis that these concentrations would be higher in a case of strangulating obstruction than in cases of nonstrangulating disease. By using a specific enzyme-linked immunosorbent assay for equine MPO, we determined the MPO concentrations in horses admitted to a clinic for colic. Horses with nonstrangulating or strangulating obstruction of the large intestine (NSLI or SLI), strangulating obstruction of the small intestine (SSI), or inflammatory bowel disease (IBD) were compared with healthy horses. The horses with SLI, SSI, or IBD had significantly higher MPO levels in plasma and PF than did those in the other 2 groups. The mean plasma level was significantly higher in the horses with NSLI than in the healthy horses. High MPO values in PF indicated necrotic bowel. These results show that neutrophil activation occurs during nonstrangulating and strangulating intestinal obstruction in horses and that the plasma and PF MPO concentrations may be a marker of the severity of the disease.

The gastrointestinal mucosa is an extremely soft, highly vascularised tissue, with a single layer of epithelium separating the gut lumen from the host. Epithelial cells adhere to a thin basement membrane that is produced by both epithelial cells and the underlying stromal cells. Signals passing between epithelial cells and stromal cells are needed for normal gut structure. In gut diseases, however, epithelial cells and stromal cells produce large amounts of matrix degrading enzymes (matrix metalloproteinases), the function of which is only beginning to be elucidated. Here, we review the role of matrix metalloproteonases (MMPs) in the gut in health, in gut inflammation, and in cancer.

Variants within the human UGT1A1 gene are associated with irinotecan induced severely adverse reactions and hyperbilirubinemia. Intra-ethnic differences in the genetic variation and haplotypes of UGT1A1 gene have been analyzed in the present study. Relationship between the concentrations of total serum bilirubin (T-bil) and haplotype structure of UGT1A1 in healthy people were also evaluated. We genotyped five functional polymorphisms including -3279T>G and -3156G>A in the enhancer region, (TA)6>7 in the TATA box, and 211G>A (G71R), 686C>A (P229Q) in the exon1 region of UGT1A1 in three groups of healthy Chinese ethnic populations, consisting of 264 subjects of She origin, 539 of Han origin and 273 of Dong origin. The distribution of -3279T>G, (TA)6>7, 211G>A of UGT1A1 differed greatly as between the three ethnic groups. All of six haplotypes differed considerably between at least two of the three groups, which highlighted the need to analyze clinically irinotecan toxicity relevant SNPs and haplotypes in a variety of different racial groups within the Chinese population. Total bilirubin concentration in homozygous carriers of the -3279G and (TA)7 allele were significantly higher than those in heterozygous carriers or homozygous carriers of wild-type alleles. Carriers of the variant haplotypes (-3279G; -3156A; (TA)7; 211G; 686C) had higher serum T-Bil concentrations compared with the other groups. Our results indicate that heterogeneity among different ethnic populations is possibly the result of microevolution and is relevant to studies into the effect of tailored drug treatment.

Our previous work has demonstrated that weaning at 19 days of age has deleterious effects on mucosal barrier function in piglet intestine that are mediated through peripheral CRF receptor signaling pathways. The objectives of the present study were to assess the impact of piglet age on weaning-associated intestinal dysfunction and to determine the role that mast cells play in weaning-induced breakdown of mucosal barrier function. Nursing Yorkshire-cross piglets were either weaned at 19 days of age (early-weaned, n = 8) or 28 days of age (late-weaned, n = 8) and housed in nursery pens. Twenty-four hours postweaning, segments of midjejunum and ascending colon from piglets within each weaning age group were harvested and mounted on Ussing chambers for measurements of transepithelial electrical resistance and serosal-to-mucosal [(3)H]mannitol fluxes. Early weaning resulted in reductions in transepithelial electrical resistance and increases in mucosal permeability to [(3)H]mannitol in the jejunum and colon (P < 0.01). In contrast, postweaning reductions in intestinal barrier function were not observed in piglets weaned at 28 days of age. Early-weaned piglet intestinal mucosa had increased expression of CRF receptor 1 protein, increased mucosal mast cell tryptase levels, and evidence of enhanced mast cell degranulation compared with late-weaned intestinal mucosa. Pretreatment of piglets with the mast cell stabilizer drug cromolyn, injected intraperitoneally 30 min prior to weaning, abolished the early-weaning-induced intestinal barrier disturbances. Our results indicate that early-weaning stress induces mucosal dysfunction mediated by intestinal mast cell activation and can be prevented by delaying weaning.

Flavin-containing monooxygenase 3 (FMO3) is a hepatic microsomal enzyme that oxidizes a host of drugs, xenobiotics and other chemicals. Numerous variants in the gene encoding FMO3 have been identified, some of which result in altered enzymatic activity and, consequently, altered substrate metabolism. Studies also implicate individual and ethnic differences in the frequency of FMO3 polymorphisms. In addition, new variants continue to be identified with potentially important clinical implications. For example, the role of FMO3 variants in the pathophysiology of gastrointestinal diseases is an evolving area of research. Two commonly occurring polymorphisms of FMO3, E158K and E308G, have been associated with a reduction in polyp burden in patients with familial adenomatous polyposis who were treated with sulindac sulfide, an FMO3 substrate. These findings suggest a potential role for prospective genotyping of common FMO3 polymorphisms in the treatment of disease states that involve the use of drugs metabolized by FMO3. This review summarizes the current state of research on the genetic polymorphisms of FMO3, with a focus on their clinical implications in gastrointestinal diseases.