Pharmacological research : the official journal of the Italian Pharmacological Society
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Autism-spectrum disorder (ASD) is a neurodevelopmental disorder characterized by persistent deficits in social communication and repetitive patterns of behavior. ASD is, however, often associated with medical comorbidities and gastrointestinal (GI) dysfunction is among the most common. Studies have demonstrated a correlation between GI dysfunction and the degree of social impairment in ASD. ⋯ This paper reviews the role of serotonin in ASD from the perspective of the ENS. A murine model that has been demonstrated to possess brain, behavioral and GI abnormalities mimicking those seen in ASD harbors the most common serotonin transporter (SERT) based mutation (SERT Ala56) found in children with ASD. Discussion of the gut-brain manifestations in the SERT Ala56 mice, and their correction with developmental administration of a 5-HT4 agonist, are also addressed in conjunction with other future directions for diagnosis and treatment.
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N-Acylethanolamine acid amidase (NAAA) is a cysteine enzyme that catalyzes the hydrolysis of palmitoylethanolamide (PEA). Pharmacological blockage of NAAA elevates PEA levels and exerts powerful anti-inflammatory activities. We have recently identified a highly potent NAAA inhibitor F215. ⋯ The inflammation-restricted effect of F215 was further confirmed in the alveolar macrophage, F215 only increased PEA levels and exerted anti-inflammatory effects in activated macrophages, but not in unstimulated macrophages. Moreover, we also showed that the pharmacological effects of F215 were restricted to the local inflamed skin elicited by 12-o-tetradecanoylphorbol-13-acetate (TPA), but not the normal tissues. We believe that F215 could be a useful probe to investigate the function of NAAA, as well as a potent anti-inflammatory agent, and its inflammation-restricted feature might offer a new approach to prevent potential side effects of systemic enzyme inhibition.
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1,4-benzothiazines have ameliorative effects through inhibition of COX-2 mediated STAT-3 pathways at G-protein couple receptor site. As per this scenario, we recently prepared and tested novel 1,4-benzothiazine derivatives against HT-29 human colon cancer cell line. Two compounds namely AR13 and AR15 showed higher inhibitions among all the synthesized compounds. ⋯ This action was substansiated by immunohistochemistry using JAK2, p-JAK2, STAT3 and p-STAT3 targets in colon tissue. Finally, score plots of PLS-DA models exhibited significant metabolic discriminations between the treated and CRC groups, and both compounds showed ability to restore the imbalance of multiple metabolites during CRC. In conclusion, our study provided the evidence towards better antiproliferative effect of AR13 and AR15 in DMH-induced CRC through the blockade of COX-2/JAK-2/STAT-3 signal transduction pathway and could be demonstrated as useful anti-CRC candidate molecules for future anticancer therapy.