Pharmacological research : the official journal of the Italian Pharmacological Society
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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.
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Type 2 diabetes is characterized by insulin resistance in target tissues and hyperglycemia. Catalpol is a natural product isolated from the root of Rehmannia glutinosa, which has been reported to produce the effect of anti-diabetes in recent reports. The goal of the current study is to investigate the therapeutic effects of catalpol on hepatic insulin resistance in type 2 diabetes and elucidate the underlying cellular mechanisms. ⋯ Furthermore, the effect of catalpol on depriving glucosamine-induced insulin resistance was prevented by knockdown of NOX4 or AMPK with short interfering RNA (siRNA) in HepG2 cells. Moreover, the suppressive effect of catalpol on glucosamine-induced NOX4 over-expression was weakened by knockdown of AMPK with siRNA. Taken together, these findings suggested that catalpol ameliorated hepatic insulin resistance in type 2 diabetes through acting on AMPK/NOX4/PI3K/AKT pathway.
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Review
Role of RET protein-tyrosine kinase inhibitors in the treatment RET-driven thyroid and lung cancers.
RET is a transmembrane receptor protein-tyrosine kinase that is required for the development of the nervous system and several other tissues. The mechanism of activation of RET by its glial-cell derived neurotrophic factor (GDNF) ligands differs from that of all other receptor protein-tyrosine kinases owing to the requirement for additional GDNF family receptor-α (GFRα) co-receptors (GFRα1/2/3/4). RET point mutations have been reported in multiple endocrine neoplasia (MEN2A, MEN2B) and medullary thyroid carcinoma. ⋯ Currently the number of new cases of neoplasms bearing RET mutations or RET-fusion proteins is estimated to be about 10,000 per year in the United States. This is about the same as the incidence of chronic myelogenous leukemia for which imatinib and second and third generation BCR-Abl non-receptor protein-tyrosine kinase antagonists have proven clinically efficacious and which are commercially successful. These findings warrant the continued development of specific antagonists targeting RET-driven neoplasms.
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Melanoma originated from melanocytes is the most aggressive type of skin cancer. Despite considerable progresses in clinical treatment with the discovery of BRAF or MEK inhibitors and monoclonal antibodies, the durability of response to treatment is often limited to the development of acquired resistance and systemic toxicity. ⋯ In this review, we will discuss the main influence of tumor microenvironment in melanoma growth and treatment outcome. Furthermore, third generation loaded nanotechnologies represent an exciting tool for detection, treatment, and escape from possible mechanism of resistance mediated by tumor microenvironment, and will be highlighted in this review.