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Schicho R.,Snyder Institute of Infection | Schicho R.,Medical University of Graz | Shaykhutdinov R.,University of Calgary | Ngo J.,Snyder Institute of Infection | And 7 more authors.
Journal of Proteome Research | Year: 2012

Serologic biomarkers for inflammatory bowel disease (IBD) have yielded variable differentiating ability. Quantitative analysis of a large number of metabolites is a promising method to detect IBD biomarkers. Human subjects with active Crohn's disease (CD) and active ulcerative colitis (UC) were identified, and serum, plasma, and urine specimens were obtained. We characterized 44 serum, 37 plasma, and 71 urine metabolites by use of 1H NMR spectroscopy and "targeted analysis" to differentiate between diseased and non-diseased individuals, as well as between the CD and UC cohorts. We used multiblock principal component analysis and hierarchical OPLS-DA for comparing several blocks derived from the same "objects' (e.g., subject) to examine differences in metabolites. In serum and plasma of IBD patients, methanol, mannose, formate, 3-methyl-2-oxovalerate, and amino acids such as isoleucine were the metabolites most prominently increased, whereas in urine, maximal increases were observed for mannitol, allantoin, xylose, and carnitine. Both serum and plasma of UC and CD patients showed significant decreases in urea and citrate, whereas in urine, decreases were observed, among others, for betaine and hippurate. Quantitative metabolomic profiling of serum, plasma, and urine discriminates between healthy and IBD subjects. However, our results show that the metabolic differences between the CD and UC cohorts are less pronounced. © 2012 American Chemical Society. Source

Fichna J.,Snyder Institute of Infection | Fichna J.,Medical University of Lodz | Perlikowska R.,Medical University of Lodz | Gach K.,Medical University of Lodz | And 5 more authors.
Chemical Biology and Drug Design | Year: 2010

The endogenous opioid system is involved in the control of gastrointestinal (GI) motility. The potential use of endogenous MOR ligands, endomorphins (EMs), as therapeutics is limited because of their rapid enzymatic degradation and short duration of action. Targeting enzymatic degradation is an approach to prolong EM activity. In the present study, we characterized the effects of novel blockers of EM degradation in GI tissue preparation in vitro. The effects of actinonin, diprotin A (DIP) and the novel peptide EM degradation blockers Tyr-Pro-DClPhe-Phe-NH2 (EMDB-1), Tyr-Pro-Ala-NH2 (EMDB-2) and Tyr-Pro-Ala-OH (EMDB-3) on EM-2-mediated inhibition of electrically induced cholinergic twitch contractions were compared in rat ileum in vitro using an organ bath. EMDB-1 and EMDB-2 significantly prolonged the inhibitory effect of EM-2 on smooth muscle contractility in rat ileum. EMDB-2 extended the EM-2 action for up to 60 min compared to 10 min in controls and was more potent than the conventional peptidase inhibitor DIP. EMDB-1 and EMDB-2 are potent EM degradation blockers, which prolong the inhibitory effects of EM-2 on smooth muscle contractility in rat ileum. These novel compounds may be of future use when targeting the endogenous opioid system in the treatment of GI motility disorders such as diarrhea. © 2010 John Wiley & Sons A/S. Source

von der Weid P.-Y.,Snyder Institute of Infection | Muthuchamy M.,Texas A&M University
Pathophysiology | Year: 2010

The lymphatic system is composed of a dense network of lymphatic vessels, which are critical components of physiological interstitial fluid transport. These vessels possess intrinsic contractile properties providing the driving force for the fluid to be drained away from the tissues and propelled, as lymph, back into the bloodstream. Lymphatic pumping is also important to carry immune cells, bacteria, macromolecules, viruses and their products to and through lymph nodes, the other component of the lymphatic system, to initiate the adaptive immune response. In addition, among the many circulating mediators known to modulate lymphatic contractile activity and thus lymph flow, mediators of inflammation have potent excitatory or inhibitory actions. The involvement of lymphatic vessels in edema resolution, immune cell trafficking and their sensitivity to inflammatory mediators make them pivotal players of the inflammation process. The ability of lymphatic vessels to generate and regulate lymph flow is provided by the lymphatic muscle present in the vessels' wall. Although molecular studies investigating the mechanisms of lymphatic vessel contraction are still very limited, recent findings suggest that lymphatic pumping requires complicated muscle activities that have similarities to those seen in both the heart (striated muscle) and blood vessels (smooth muscle). This review article focuses on presenting and discussing the mechanisms that regulate lymphatic vessel contraction under normal and pathophysiological states, specifically pertaining to inflammatory conditions. © 2009. Source

Czako B.,Debrecen University | Marton J.,ABX Biomedizinische Forschungsreagenzien GmbH | Berenyi S.,Debrecen University | Gach K.,Medical University of Lodz | And 6 more authors.
Bioorganic and Medicinal Chemistry | Year: 2010

A set of novel 6-substituted orvinols was synthesized and pharmacologically characterized in order to explore the effect of the polarity and steric effects of these new moieties on the opioid activity. It was revealed that longer 6-O-alkyl chains led to increased agonistic activities, while the lack of C6-etheral oxygen gave rise to an antagonistic profile at the opioid receptors in the mouse ileum. © 2010 Elsevier Ltd. All rights reserved. Source

Schicho R.,Snyder Institute of Infection | Schicho R.,Medical University of Graz | Bashashati M.,University of Calgary | Bawa M.,University of Calgary | And 11 more authors.
Inflammatory Bowel Diseases | Year: 2011

Background: Cannabinoids are known to reduce intestinal inflammation. Atypical cannabinoids produce pharmacological effects via unidentified targets. We were interested in whether the atypical cannabinoid O-1602, reportedly an agonist of the putative cannabinoid receptor GPR55, reduces disease severity of dextran sulfate sodium (DSS) and trinitrobenzene sulfonic acid (TNBS)-induced colitis in C57BL/6N and CD1 mice. Methods: DSS (2.5% and 4%) was supplied in drinking water for 1 week while TNBS (4 mg) was applied as a single intrarectal bolus. Results: Both treatments caused severe colitis. Injection of O-1602 (5 mg/kg intraperitoneally) significantly reduced macroscopic and histological colitis scores, and myeloperoxidase activity. The protective effect was still present in cannabinoid receptor 1 (CB 1) and 2 (CB 2) double knockout mice and mice lacking the GPR55 gene. To investigate a potential mechanism underlying the protection by O-1602 we performed neutrophil chemotactic assays. O-1602 concentration-dependently inhibited migration of murine neutrophils to keratinocyte-derived chemokine (KC), N-formyl-methionyl- leucyl-phenylalanine (fMLP), and the N-formyl-peptide receptor ligand WKYMVm. The inhibitory effect of O-1602 was preserved in neutrophils from CB 1/CB 2 double knockout and GPR55 knockout mice. No differences were seen in locomotor activity between O-1602-treated and control mice, indicating lack of central sedation by this compound. Conclusions: Our data demonstrate that O-1602 is protective against experimentally induced colitis and inhibits neutrophil recruitment independently of CB 1, CB 2, and GPR55 receptors. Thus, atypical cannabinoids represent a novel class of therapeutics that may be useful for the treatment of inflammatory bowel diseases. Copyright © 2010 Crohn's & Colitis Foundation of America, Inc. Source

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