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Drugs that act on α-adrenoceptors may contain morpholine and pyrimidinone heterocycles. The aim of this study was to synthesize a series of pyrimidinones (S6a-e and S8) and characterize their α-adrenoceptor activity. Cytotoxicity assays (MTT and LDH) were performed in A7r5 and HUVECs. Concentration-effect curves to phenylephrine (Phe) were performed in rat aortic rings in the presence of compounds S6a-e and S8 or vehicle. Nitric oxide (NO) production and NO stable metabolic products, nitrite and nitrate, expressed as total nitrogen oxides (NOx) were assessed in HUVECs by confocal microscopy with the DAF-2DA probe and by the Griess reaction, respectively. Molecular docking simulations were performed using the 6a compound and α 2A -adrenoceptor. In the evaluated conditions, the percentage of viable cells and the release of LDH were similar between control cells and cells exposed to the tested pyrimidinones. S6d, S6e, S8, and the positive control prazosin (but not S6a, S6b, and S6c) decreased Phe-induced contractions in endothelium-denuded aortic rings. S6a, S6b, and S6c decreased Phe-induced contractions in endothelium-intact aortic rings. The effect of S6a was abolished by L-NAME. NO production and NOx levels were inhibited in the presence of the α 2 receptor antagonist yohimbine and the NOS inhibitor L-NAME. The 6a docking simulation estimated that the mean binding free energy of the compound was lower than the estimated value for yohimbine. These data suggest that S6d, S6e, and S8 may be α 1 -adrenoceptor antagonists while S6a acts as an agonist of α 2 -adrenoceptors., Competing Interests: Declaration of competing interest The authors of the manuscript entitled “New morpholine-containing pyrimidinones act on alpha-adrenergic receptors” declare that they have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Tumor budding (TB) has been investigated in several types of solid tumors. In oral cancer, studies show its association with survival. However, for its implementation in routine histological analyses, results with a high certainty of evidence are needed. Therefore, the aim of this systematic review is to explore the association between tumor budding and overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) in oral cancer., Methods: A search was performed in Embase, PubMed, Scopus, Livivo, Web of Science, and Google Scholar. We adopted the following inclusion criteria: studies that evaluate tumor budding in oral cancer, that investigate survival, and presenting cohort design. We excluded reviews and studies without hazard-ratio (HR) data., Results: This systematic review included 22 studies and showed an association between TB and survival. High-grade TB is associated with a worse OS in univariate analysis (HR = 3.11; 95% CI: 2.06-4.69, p<0.01) and multivariate analysis (HR = 2.62; 95% CI: 1.64-4.20, p<0.01); with a poorer DSS in univariate (HR = 2.43; 95% CI: 1.94-3.03, p<0.01) and multivariate analysis (HR = 2.01; 95% CI: 1.43-2.83, p< 0.01); and with a worse DFS in univariate (HR = 1.94; 95% CI: 1.44-2.62, p<0.01) and multivariate analysis (HR = 2.15; 95% CI: 1.31-3.53, p< 0.01). Sensitivity analysis showed that the results are robust, and no significant publication bias was identified in univariate analysis for DFS (Egger's test: p = 0.94). The certainty of the evidence was graded as low or very low., Conclusion: Our findings indicate that TB is an independent prognostic factor of OS, DSS, and DFS in oral cancer. However, further studies are needed to increase the certainty of the evidence.

Objectives: To evaluate immunohistochemically the expression of GLUT-3 and GLUT-4 in oral epithelial dysplasia (OED) and the oral squamous cell carcinoma (OSCC) and assess possible involvement in the malignant transformation of oral lesions. Methods: Tissue samples of 15 cases of OSCC and 15 of OED were subjected to immunohistochemistry with anti-GLUT-3 and anti-GLUT-4 antibodies. Five fields of each case were analyzed, to provide percentages of positive cells at 400X magnification. Result: GLUT-3 and GLUT-4 were positive in 100% of the analyzed samples, the percentage immunolabeling for GLUT-3 ranging from 19% to 73% in the OED group and 10% to 89% in the OSCC group. Positive immunolabeling for GLUT-4 ranged from 15.2% to 79.9% in the OSCC group and 27.1% to 92.6% in the OED group. Statistical analysis with the Mann-Whitney test revealed that there was a higher expression of GLUT-4 in the OED group than in the OSCC group (p=0.04) without any significant difference in the GLUT-3 expression (p=0.852). Conclusion: GLUT-4 expression may indicate some role in oncogenic mechanisms which can determine a malignant phenotype. Thus, it is suggested that further studies on the role of GLUT-3 in oral carcinogenesis be conducted., (Creative Commons Attribution License)

Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity and some of these have been documented in association or preceded by oral epithelial dysplasia (OED). Aggressive cancers with fast growth have demonstrated overexpression of some glucose transporters (GLUTs). Thus, the aim of this study was to analyze the immunohistochemical expression of the glucose transporter, GLUT-1, in OEDs and OSCCs, seeking to better elucidate the biological behavior of neoplasias. Fifteen cases were selected this research of both lesions. Five areas were analyzed from each case by counting the percentage of positive cells at 400x magnification. Immunoreactivity of GLUT-1 was observed in 100% of the samples ranging from 54.2% to 86.2% for the OSCC and 73.9% to 97.4% for the OED. Statistical test revealed that there was greater overexpression of GLUT-1 in OED than the OSCC (p=0.01). It is believed the high expression of GLUT-1 may reflect the involvement of GLUT-1 in early stages of oral carcinogenesis.