ABSTRACT
Uvaol is a natural pentacyclic triterpene that is widely found in olives and virgin olive oil, exerting various pharmacological properties. However, information remains limited about how it affects fibroblasts and endothelial cells in events associated with wound healing. Here, we report the effect of uvaol in the in vitro and in vivo healing process. We show the positive effects of uvaol on migration of fibroblasts and endothelial cells in the scratch assay. Protein synthesis of fibronectin and laminin (but not collagen type I) was improved in uvaol-treated fibroblasts. In comparison, tube formation by endothelial cells was enhanced after uvaol treatment. Mechanistically, the effects of uvaol on cell migration involved the PKA and p38-MAPK signaling pathway in endothelial cells but not in fibroblasts. Thus, the uvaol-induced migratory response was dependent on the PKA pathway. Finally, topical treatment with uvaol caused wounds to close faster than in the control treatment using experimental cutaneous wounds model in mice. In conclusion, uvaol positively affects the behavior of fibroblasts and endothelial cells, potentially promoting cutaneous healing.
Subject(s)
Endothelial Cells/drug effects , Fibroblasts/drug effects , Skin/drug effects , Triterpenes/pharmacology , Wound Healing/drug effects , Animals , Cell Movement/drug effects , Cell Survival/drug effects , Endothelial Cells/cytology , Extracellular Matrix/drug effects , Extracellular Matrix/metabolism , Fibroblasts/cytology , Kinetics , MAP Kinase Signaling System/drug effects , Mice , Skin/pathology , Skin/physiopathology , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
Cyclo-Gly-Pro (CGP) attenuates nociception, however its effects on salivary glands remain unclear. In this study, we investigated the acute effects of CGP on salivary flow and composition, and on the submandibular gland composition, compared with morphine. Besides, we characterized the effects of naloxone (a non-selective opioid receptor antagonist) on CGP- and morphine-induced salivary and glandular alterations in mice. After that, in silico analyses were performed to predict the interaction between CGP and opioid receptors. Morphine and CGP significantly reduced salivary flow and total protein concentration of saliva and naloxone restored them to the physiological levels. Morphine and CGP also reduced several infrared vibrational modes (Amide I, 1687-1594cm-1; Amide II, 1594-1494cm-1; CH2/CH3, 1488-1433cm-1; C = O, 1432-1365cm-1; PO2 asymmetric, 1290-1185cm-1; PO2 symmetric, 1135-999cm-1) and naloxone reverted these alterations. The in silico docking analysis demonstrated the interaction of polar contacts between the CGP and opioid receptor Cys219 residue. Altogether, we showed that salivary hypofunction and glandular changes elicited by CGP may occur through opioid receptor suggesting that the blockage of opioid receptors in superior cervical and submandibular ganglions may be a possible strategy to restore salivary secretion while maintaining antinociceptive action due its effects on the central nervous system.
Subject(s)
Ganglia, Parasympathetic/drug effects , Naloxone/pharmacology , Narcotic Antagonists/pharmacology , Peptides, Cyclic/pharmacology , Salivary Glands/drug effects , Analgesics, Opioid/pharmacology , Animals , Binding Sites , Ganglia, Parasympathetic/metabolism , Ganglia, Parasympathetic/physiology , Male , Mice , Morphine/pharmacology , Nociception , Protein Binding , Receptors, Opioid/chemistry , Receptors, Opioid/metabolism , Saliva/metabolism , Salivary Glands/metabolism , Salivary Glands/physiologyABSTRACT
High glucose concentration in the airway surface liquid (ASL) is an important feature of diabetes that predisposes to respiratory infections. We investigated the role of alveolar epithelial SGLT1 activity on ASL glucose concentration and bacterial proliferation. Non-diabetic and diabetic rats were intranasally treated with saline, isoproterenol (to increase SGLT1 activity) or phlorizin (to decrease SGLT1 activity); 2 hours later, glucose concentration and bacterial proliferation (methicillin-resistant Sthaphylococcus aureus, MRSA and Pseudomonas aeruginosa, P. aeruginosa) were analyzed in bronchoalveolar lavage (BAL); and alveolar SGLT1 was analyzed by immunohistochemistry. BAL glucose concentration and bacterial proliferation increased in diabetic animals: isoproterenol stimulated SGLT1 migration to luminal membrane, and reduced (50%) the BAL glucose concentration; whereas phlorizin increased the BAL glucose concentration (100%). These regulations were accompanied by parallel changes of in vitro MRSA and P. aeruginosa proliferation in BAL (r = 0.9651 and r = 0.9613, respectively, Pearson correlation). The same regulations were observed in in vivo P. aeruginosa proliferation. In summary, the results indicate a relationship among SGLT1 activity, ASL glucose concentration and pulmonary bacterial proliferation. Besides, the study highlights that, in situations of pulmonary infection risk, such as in diabetic subjects, increased SGLT1 activity may prevent bacterial proliferation whereas decreased SGLT1 activity can exacerbate it.
