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Background: Recent studies suggest that lipids, including free fatty acids (FFAs), are necessary for proper μ opioid receptor (MOR) binding and that activation of opioid receptors (ORs) improves intestinal inflammation. The objective of the study was to investigate a possible interaction between the ORs and FFA receptors (FFARs) ligands in the colitis. Methods: The potential synergistic effect of ORs and FFARs ligands was evaluated using mouse model of acute colitis induced by dextran sulfate sodium (DSS, 4%). Compounds were injected intraperitoneally (i.p.) once or twice daily at the doses of 0.01 or 0.02 mg/kg body weight (BW) (DAMGO—an MOR agonist), 0.3 mg/kg BW (DPDPE—a δ OR (DOR) agonist) and 1 mg/kg BW (naloxone—a non-selective OR antagonist, GLPG 0974—a FFAR2 antagonist, GSK 137647—a FFAR4 agonist and AH 7614—a FFAR4 antagonist) for 4 days. Results: Myeloperoxidase (MPO) activity was significantly decreased after DAMGO (0.02 mg/kg BW) and GSK 137647 (1 mg/kg BW) administration and co-administration as compared to DSS group. Conclusions: Treatment with ligands of ORs and FFARs may affect the immune cells in the inflammation; however, no significant influence on the severity of colitis and no synergistic effect were observed.

Introduction: Adiponectin is a hormone secreted by adipocytes, which exhibits insulin-sensitizing and anti-inflammatory properties and acts through adiponectin receptors: AdipoR1 and AdipoR2. The aim of the study was to evaluate whether activation of adiponectin receptors AdipoR1 and AdipoR2 with an orally active agonist AdipoRon has gastroprotective effect and to investigate the possible underlying mechanism. Methods: We used two well-established mouse models of gastric ulcer (GU) induced by oral administration of EtOH (80% solution in water) or diclofenac (30 mg/kg, p.o.). Gastroprotective effect of AdipoRon (dose 5 and 50 mg /kg p.o) was compared to omeprazole (20 mg/kg p.o.) or 5% DMSO solution (control). Clinical parameters of gastroprotection were assessed using macroscopic (gastric lesion area) and microscopic (evaluation of the gastric mucosa damage) scoring. To establish the molecular mechanism, we measured: myeloperoxidase (MPO), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) activities; glutathione (GSH) level; and IL-1β, adenosine monophosphate-activated protein kinase (AMPK), and phosphorylated AMPK expression in gastric tissue. Results: AdipoRon produced a gastroprotective effect in both GU mouse models as evidenced by significantly lower macroscopic and microscopic damage scores. AdipoRon exhibited anti-inflammatory effect by reduction in MPO activity and IL-1β expression in the gastric tissue. Moreover, AdipoRon induced antioxidative action, as demonstrated with higher GSH levels, and increased SOD and GPX activity. Conclusions: Activation of AdipoR1 and AdipoR2 using AdipoRon reduced gastric lesions and enhanced cell response to oxidative stress. Our data suggest that AdipoR1 and AdipoR2 activation may be an attractive therapeutic strategy to inhibit development of gastric ulcers.

Background: the pharmacological treatment and/or maintenance of remission in inflammatory bowel diseases (IBDs) is currently one of the biggest challenges in the field of gastroenterology. Method: our aim was the synthesis of homo- and heterodimers of natural enkephalinase inhibitors (opiorphin; sialorphin; spinorphin) and the in vitro characterization of their effect on the degradation of enkephalin by neutral endopeptidase (NEP) and stability in human plasma. We investigated the in vivo heterodimer of Cys containing analogs of sialorphin and spinorphin (peptide X) in a mouse model of colitis. The extent of inflammation was evaluated based on the microscopic score; macroscopic score; ulcer score, colonic wall thickness, colon length and quantification of myeloperoxidase activity. Results: we showed that the homo- and heterodimerization of analogs of sialorphin, spinorphin and opiorphin containing Cys residue at the N-terminal position resulted in dimeric forms which in vitro exhibited higher inhibitory activity against NEP than their parent and monomeric forms. We showed that peptide X was more stable in human plasma than sialorphin and spinorphin. Peptide X exerts potent anti-inflammatory effect in the mouse model of colitis. Conclusion: we suggest that peptide X has the potential to become a valuable template for anti-inflammatory therapeutics for the treatment of gastrointestinal (GI) tract inflammation.

Oxidative stress (OS) has been proposed as a significant causative and propagating factor in inflammatory bowel diseases (IBDs). Modulation of OS is possible through antioxidants and inhibition of oxidizing enzymes. Thirty-one IBD patients and thirty-two controls were included in the study. The aim was to examine the levels of OS in colonic tissue of IBD requiring surgical intervention and control group, and their association with pain intensity. Total antioxidant capacity (TAC), superoxide dismutase (SOD) and catalase (CAT) activity, glutathione (GSH) and oxidized glutathione (GSSG) levels, and glutathione peroxidase (GPX) activity as markers of antioxidant defense were determined. Cyclooxygenases activities (Total COX, COX-1 and COX-2) were measured as prooxidant enzymes. Thiobarbituric acid reactive substances (TBARS) concentrations were measured to evaluate lipid peroxidation. Disease activity was assessed, and each subject filled out VAS and Laitinen’s pain assessment scales. Correlation between the OS, pain intensity, disease activity parameters, C-reactive protein (CRP), number of stools passed daily, disease duration, and dietary habits was investigated. No TAC differences were found between the groups. A significant decrease of SOD activity and GSH and GSSG levels was seen in IBD patients vs. controls, while GPX activity was diminished significantly only in CD patients. CAT and COX-1 activity was increased, and COX-2 significantly decreased in IBD. TBARS were significantly higher in CD patients compared to control group. No correlation was found between pain scores, inflammatory status, disease activity, disease duration, or dietary habits and OS markers. In our study, OS did not influence pain sensation reported by IBD patients.

Due to its immunomodulatory effect, vitamin D has been associated with clinical parameters and outcomes in inflammatory bowel diseases (IBDs) which are chronic conditions of the gastrointestinal tract. Upon synthesis or digestion, vitamin D is metabolized in the liver to form 25(OH)D3, the major circulating metabolite. Further renal hydroxylation generates 1,25(OH)2D3, the most potent metabolite. Our aim was to examine the association between vitamin D levels, and its supplementation and pain intensity in 39 IBD patients and 33 healthy individuals. 25(OH)D3 and 1,25(OH)2D3 serum levels were measured. Each subject filled out visual analog scale (VAS) and Laitinen’s pain assessment scales. Laboratory results were obtained, and disease activity was assessed. Linear regression was employed to investigate the correlation between 25(OH)D3, 1,25(OH)2D3 and pain intensity, clinical activity parameters, C-reactive protein, disease duration, and dietary habits. In IBD patients, 25(OH)D3 was increased, whereas 1,25(OH)2D3 was not. Vitamin D3 supplementation did not influence their levels. No correlation was found between pain scores, disease activity, inflammatory status, disease duration or dietary habits and both forms of vitamin D. Elevated 25(OH)D3 and normal 1,25(OH)D3 were found in IBD patients as compared to the controls. We discovered no effect from supplementation and no association between pain severity and vitamin D.

Red cabbage is an important source of vitamins, micro- and macroelements and polyphenols. The aim of our study was to evaluate the anti-inflammatory effect of red cabbage extract (RCE) in mouse models of inflammatory bowel disease (IBD). The effect of RCE on experimental colitis was determined using clinical, macro- and microscopic parameters of inflammation. To study the mechanism of RCE action, the expression of pro-inflammatory cytokines and parameters of oxidative stress were assessed. RCE produced a potent anti-inflammatory action in the mouse model of Crohn's disease, as shown by decreased macroscopic damage score in acute (2.70 ± 0.24 vs. 5.78 ± 0.58 for control group) and chronic (1.81 ± 0.38 vs. 2.94 ± 0.29) colitis model. In the animal model of ulcerative colitis, total macroscopic score was decreased after prophylactic and therapeutic administration (11.9 ± 0.5 and 11.2 ± 0.9 vs. 14.2 ± 0.4 in control group, respectively). Red cabbage extract may be applied as a potential dietary supplement in IBD therapy.

AIMS: Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder, associated with alterations of bowel function, abdominal pain and other symptoms related to the GI tract. Recently the endogenous cannabinoid system (ECS) was shown to be involved in the physiological and pathophysiological control of the GI function. The aim of this pilot study was to investigate whether IBS defining symptoms correlate with changes in endocannabinoids or cannabinoid like fatty acid levels in IBS patients. METHODS: AEA, 2-AG, OEA and PEA plasma levels were determined in diarrhoea-predominant (IBS-D) and constipation-predominant (IBS-C) patients and were compared to healthy subjects, following the establishment of correlations between biolipid contents and disease symptoms. FAAH mRNA levels were evaluated in colonic biopsies from IBS-D and IBS-C patients and matched controls. RESULTS: Patients with IBS-D had higher levels of 2AG and lower levels of OEA and PEA. In contrast, patients with IBS-C had higher levels of OEA. Multivariate analysis found that lower PEA levels are associated with cramping abdominal pain. FAAH mRNA levels were lower in patients with IBS-C. CONCLUSION: IBS subtypes and their symptoms show distinct alterations of endocannabinoid and endocannabinoid-like fatty acid levels. These changes may partially result from reduced FAAH expression. The here reported changes support the notion that the ECS is involved in the pathophysiology of IBS and the development of IBS symptoms.