In conclusion, guanosine exerts beneficial effects in DNBS-induced colitis in rats, through modulation of colonic inflammation, downregulating of NFκB-mediated signaling.

Angiotensin II, the main effector of renin angiotensin system, plays an important role in the inflammatory process and most of its effects are mediated through the AT1 receptor activation. However, the knowledge about the AT2 receptor involvement in this process is still evolving. We previously found that in an experimental model of colitis, AT2 receptor activation can contribute to the impairment of the muscle contractility in vitro in the course of inflammation. Here, we investigated the potential alleviating effects of the in vivo treatment of PD123319 (1)(2)(3)(4) 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid ditrifluoroacetate), AT2 receptor antagonist, in 2,4-dinitrobenzene sulfonic acid (DNBS)-induced rat model of colitis. The effects of i.p PD123319 (0.3, 3 and 10 mg/kg) administration to rats subjected to intra-rectal DNBS instillation were investigated. The study revealed that the colon injury and the inflammatory signs were ameliorated by PD123319 when visualized by the histopathological examination. The colon shortening, myeloperoxidase activity, and colonic expression of IL-1β, IL-6 and iNOS were downregulated in a dose-dependent manner in DNBS-induced colitis rats treated with PD123319 and the anti-oxidant defense machinery was also improved. The mechanism of these beneficial effects was found in the ability of PD123319 to inhibit NF-κB activation induced by DNBS. The colonic contractility in inflamed tissues was also improved by PD123319 treatment. In conclusion, our data have demonstrated previously that undescribed proinflammatory effects for the AT2 receptors in DNBS-induced colitis in rats in which they are mediated likely by NF-κB activation and reactive oxygen species generation. Moreover, when the inflammatory process is mitigated by the AT2 receptor antagonist treatment, the smooth muscle is able to recover its functionality. Keywords Inflammation • Angiotensin • AT2 receptor • Inflammatory bowel diseaseRecent data indicate that RAS is well expressed and active in the GI tract and it can also play a major role in several gut processes, including absorption, secretion, and motility (Ewert et al. 2006;Fishlock and Gunn 1970; Mastropaolo et al. 2013 Mastropaolo et al. , 2015.Moreover, data are accumulating suggesting an involvement of RAS in diseases such as GI cancer, mesenteric ischemia, motility disorders, and particularly inflammatory diseases (Shi et al. 2016). The RAS is a multi-component cascade with renin as the rate-limiting enzyme that cleaves angiotensinogen to angiotensin (Ang) I, which is further cleaved by angiotensin-converting enzyme (ACE) to Ang II. Ang II is the main effector of the RAS, it acts by binding to the angiotensin receptors (AT1 and AT2), which are found in many cell types including intestinal epithelial cells and mucosal immune cells (Fandriks 2011). AT1 receptors mediate all classical actions of Ang II in the target cells. AT2 receptors, indeed, in many instances counteract AT1 Inflammopharmacology * Maria Grazia Zizzo

The idea of a dopaminergic enteric transmission, independent of the sympathoadrenal system, has been proposed different years ago due to the observations that neurons, expressing both the dopamine (DA)-synthesizing enzyme and the dopamine transporter, but not the norepinephrine-synthesizing enzyme, were present within the enteric nervous system (ENS) in both animal models and humans. 1,2 DA seems to be implicated in several functions in GI tract, 3 activating specific receptors belonging to the G protein-coupled receptor family categorized in two main families: D1-like receptor (D1 and D5 receptors) and D2-like receptor(D2, D3, and D4 receptors), present from the stomach through the distal colon in different animal species. 2 Abstract Background: Because dopamine (DA) has gained increasing evidence as modulator of gut motility, we aimed to characterize dopaminergic response in human colon, evaluating function and distribution of dopamine receptors in circular vs longitudinal muscle strips. Methods: Mechanical responses to DA and dopaminergic agonists on slow phasic contractions and on basal tone were examined in vitro as changes in isometric tension. RT-PCR was used to reveal the distribution of dopaminergic receptors. Key Results: In spontaneous active circular muscle, DA induced an increase in the amplitude of slow phasic contractions and of the basal tone, via activation of D1-like receptors. DA contractile responses were insensitive to neural blockers or to atropine and inhibited by phospholipase C (PLC) pathway inhibitors. In precontracted circular muscle strips, DA, at the higher concentrations tested, caused a relaxant response via activation of D2-like receptors. In the longitudinal muscle, DA caused only muscular relaxation due to activation of D2-like receptors. DA relaxant responses were insensitive to neural blockers or to nitric oxide synthase inhibitor and reduced by a wide-spectrum K + channel blockers. Transcripts encoding for all the dopaminergic receptor subtypes was observed in both circular and longitudinal preparations. Conclusions and inferences: Dopamine is able to modulate contractile activity of the human colon. In the circular muscle layer, DA induces mainly muscular contraction activating non-neural D1-like receptors, coupled to PLC/IP3 pathway. In the longitudinal muscle layer, DA induces muscular relaxation acting on non-neural D2-like receptors leading to the increase in K + conductance. K E Y W O R D S circular and longitudinal muscle, dopamine, dopaminergic receptors human colon, intestinal motility

Background: Aphanizomenon flos-aquae (AFA) is a unicellular cyanobacterium considered to be a “superfood” for its complete nutritional profile and beneficial properties. We investigated possible beneficial effects of an AFA extract, commercialized as AphaMax®, containing concentrated amount of phycocyanins and phytochrome, in 2,4 dinitrobenzensulfonic acid(DNBS)-induced colitis in rats. Methods: Effects of preventive oral treatment of AphaMax® (20, 50 or 100 mg/kg/day) in colitic rats were assessed and then macroscopic and microscopic analyses were performed to evaluate the inflammation degree. Myeloperoxidase (MPO) activity and NF-κB, pro-inflammatory citockines, cycloxygenase-2 (COX-2), and inducible NOS (iNOS) levels of expression were determined, as Reactive Oxygen Species (ROS) and nitrite levels. Results: AphaMax® treatment attenuated the severity of colitis ameliorating clinical signs. AphaMax® reduced the histological colonic damage and decreased MPO activity, NF-κB activation, as well as iNOS and COX-2 expression. AphaMax® treatment improved the altered immune response associated with colonic inflammation reducing IL-1β, IL-6 expression. Lastly, AphaMax® reduced oxidative stress, decreasing ROS and nitrite levels. Conclusions: Preventive treatment with AphaMax® attenuates the severity of the inflammation in DNBS colitis rats involving decrease of the NF-kB activation, reduction of iNOS and COX-2 expression, and inhibition of oxidative stress. Due its anti-inflammatory and antioxidant proprieties AphaMax® could be a good candidate as a complementary drug in inflammatory bowel disease (IBD) treatment.

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