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Objetivo: realizar uma revisão bibliográfica sobre o potencial antimicrobiano do carveol. É uma revisão integrativa entre os anos de 2010-2020 nas bases de dados BVS, PubMed, SciELO, ScienceDirect e Web of Science. Metodologia: dos 2753 artigos recuperados nas bases de dados, apenas 5 foram selecionados para compor os resultados, sendo os gêneros mais estudados Candida, Staphylococcus e Escherichia. A técnica de microdiluição em caldo foi a metodologia mais utilizada para determinar sua ação. Em termos de MIC, para a maioria das espécies, foram excelentes. Em relação ao teste Time-kill, o carveol teve um excelente desempenho na concentração de 4 x MIC, que mostrou uma redução de UFC de 6 log em 2 horas. Não foram encontrados na literatura estudos sobre a utilização do método Checkboard. Além disso, este composto apresentou boa atividade antibiofilme contra bactérias Staphylococcus aureus. Resultados: o possível mecanismo de ação da atividade antimicrobiana do carveol ocorre por meio dos graves danos causados às membranas citoplasmáticas, o que favorecerá a lise celular. Dessa forma, existem poucos estudos na coleção científica disponível que abordem o assunto, sendo necessária a realização de mais estudos in vitro e in vivo para melhor elucidar sua ação.

SUMMARY Aim: to carry out a bibliographic review on the antimicrobial potential of carveol. It is an integrative review between the years 2010-2020 in the BVS, PubMed, SciELO, Science-Direct and Web of Science databases. Methodology: of the 2753 articles retrieved from the databases, only 5 were selected to compose the results, the most studied genera being Candida, Staphylococcus and Escherichia. The broth microdilution technique was the most widely used methodology to determine its action. In terms of MIC, for most species, they were excellent. Regarding the Time-kill test, carveol had an excellent performance at a concentration of 4 x MIC, which showed a reduction of CFU by 6 log in 2 hours. No studies have been found in the literature on the use of the Checkboard method. Further-more, this compound had good antibiofilm activity against Staphylococcus aureus bacteria. Results: the possible mechanism of action of the antimicrobial activity of carveol occurs through the severe damage caused to the cytoplasmic membranes, which will favor cell lysis. Thus, there are few studies in the available scientific collection that address the subject, so it is necessary to carry out more in vitro and in vivo studies to better elucidate its action.

Objetivo: realizar una revisión bibliográfica sobre el potencial antimicrobiano del carveol. Se trata de una revisión integradora entre los años 2010-2020 en las bases de datos de BVS, PubMed, SciELO, ScienceDirect y Web of Science. Metodología: de los 2753 artículos recuperados de las bases de datos, solo se seleccionaron 5 para componer los resultados, siendo los géneros más estudiados Candida, Staphylococcus y Escherichia. La técnica de microdilución en caldo fue la metodología más utilizada para determinar su acción. En cuanto a CIM, para la mayoría de las especies, fueron excelentes. En cuanto al ensayo Time-kill, el carveol tuvo un excelente desempeño a una concentración de 4 x MIC, que mostró una reducción de UFC en 6 log en 2 horas. No se ha encontrado ningún estudio en la literatura sobre el uso del método Checkboard. Además, este compuesto tenía una buena actividad antibiofilm contra la bacteria Staphylococcus aureus. Resultados: el posible mecanismo de acción de la actividad antimicrobiana del carveol se produce a través del severo daño causado en las membranas citoplasmáticas, lo que favorecerá la lisis celular. Así, son pocos los estudios en la colección científica disponible que abordan el tema, por lo que es necesario realizar más estudios in vitro e in vivo para dilucidar mejor su acción.

RESUMO

Background: (-)-Carveol (p-Mentha-6,8-dien-2-ol) is a monocyclic monoterpenic alcohol, present in essential oils of plant species such as Cymbopogon giganteus, Illicium pachyphyllum and in spices such as Carum carvi (cumin). Pharmacological studies report its antitumor, antimicrobial, neuroprotective, vasorelaxant, antioxidant and anti-inflammatory activity. Hypothesis/Purpose: The objective of this study was to evaluate the acute non-clinical oral toxicity, gastroprotective activity of monoterpene (-)-Carveol in animal models and the related mechanisms of action. Methods: Acute toxicity was assessed according to OECD guide 423 in mice. Ethanol, stress, NSAIDs and pylorus ligation-induced gastric ulcer models were used to investigate antiulcer properties. The related mechanisms of action were using the ethanol-gastric lesions protocol. Results: (-)-Carveol has low toxicity, with a lethal dose 50% (LD50) equal to or greater than 2,500 mg/kg according to OECD guide nº 423. In all gastric ulcer induction methods evaluated, (-)-Carveol (25, 50, 100 and 200 mg/kg, p.o.) significantly reduced the ulcerative lesion in comparison with the respective control groups. To investigate the mechanisms involved in the gastroprotective activity, the antisecretory or neutralizing of gastric secretion, cytoprotective, antioxidant and immunoregulatory effects were evaluated. In the experimental protocol of pylorus ligation-induced gastric ulcer, (-)-Carveol (100 mg/kg) reduced (p < 0.001) the volume of gastric secretion in both routes (oral and intraduodenal). The previous administration of blockers NEM (sulfhydryl groups blocker), L-NAME (nitric oxide synthesis inhibitor), glibenclamide (KATP channel blocker) and indomethacin (cyclo-oxygenase inhibitor), significantly reduced the gastroprotection exercised by (-)-Carveol, suggesting the participation of these pathways in its gastroprotective activity. In addition, treatment with (-)-Carveol (100 mg/kg) increased (p < 0.001) mucus adhered to the gastric wall. Treatment also increased (p < 0.001) levels of reduced glutathione (GSH), superoxide dismutase (SOD) and interleukin-10 (IL-10). It also reduced (p < 0.001) malondialdehyde (MDA), myeloperoxidase (MPO), interleukin-1 beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α) levels. Conclusion: Thus, it is possible to infer that (-)-Carveol presents gastroprotective activity related to antisecretory, cytoprotective, antioxidant and immunomodulatory mechanisms.

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Essential oils (EOs) from Citrus are the main by-product of Citrus-processing industries. In addition to food/beverage and cosmetic applications, citrus EOs could also potentially be used as an alternative to antibiotics in food-producing animals. A commercial citrus EO-Brazilian Orange Terpenes (BOT)-was fractionated by vacuum fractional distillation to separate BOT into various fractions: F1, F2, F3, and F4. Next, the chemical composition and biological activities of BOT and its fractions were characterized. Results showed the three first fractions had a high relative amount of limonene (≥10.86), even higher than the whole BOT. Conversely, F4 presented a larger relative amount of BOT's minor compounds (carvone, cis-carveol, trans-carveol, cis-p-Mentha-2,8-dien-1-ol, and trans-p-Mentha-2,8-dien-1-ol) and a very low relative amount of limonene (0.08-0.13). Antibacterial activity results showed F4 was the only fraction exhibiting this activity, which was selective and higher activity on a pathogenic bacterium (E. coli) than on a beneficial bacterium (Lactobacillus sp.). However, F4 activity was lower than BOT. Similarly, F4 displayed the highest antioxidant activity among fractions (equivalent to BOT). These results indicated that probably those minor compounds that detected in F4 would be more involved in conferring the biological activities for this fraction and consequently for the whole BOT, instead of the major compound, limonene, playing this role exclusively.

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Carveol is a monoterpene present in the structure of many plant products. It has a variety of biological activities: antioxidant, anticancer and vasorelaxation. However, studies investigating the effect of monoterpenoids on human vessels have not yet been described. Thus, the present study aimed to characterize the effect of (-)-carveol on human umbilical arteries (HUAs). HUA ring preparations were isolated and subjected to isometric tension recordings of umbilical artery smooth muscle contractions. (-)-Carveol exhibited a significant vasorelaxant effect on KCl and 5-HT-induced contractions, obtaining EC50 values of 344.25 ± 8.4 and 175.82 ± 4.05 µM, respectively. The participation of calcium channels in the relaxation produced by (-)-carveol was analyzed using vessels pre-incubated with (-)-carveol (2000 µM) in a calcium-free medium, where the induction of contractions was abolished. The vasorelaxant effect of (-)-carveol on HUAs was reduced by tetraethylammonium (TEA), which increased the (-)-carveol EC50 to 484.87 ± 6.55 µM. The present study revealed that (-)-carveol possesses a vasorelaxant activity in HUAs, which was dependent on the opening of calcium and potassium channels. These results pave the way for further studies involving the use of monoterpenoids for the vasodilatation of HUAs. These molecules have the potential to treat diseases such as pre-eclampsia, which is characterized by resistance in umbilical arteries.

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Candida is a genus of yeasts and is the most common cause of fungal infections worldwide. However, only a few antifungal drugs are currently available for the treatment of Candida infections. In the last decade, terpenophenols have attracted much attention because they often possess a variety of biological activities. In the search for new antifungals, eight carveoylphenols were synthesized and characterized by spectroscopic analysis. By using the broth microdilution assay, the compounds were evaluated for antifungal activities in vitro against four human pathogenic yeast, and structure-activity relationships (SAR) were derived. Noteworthy, in this preliminary study, compounds 5 and 6, have shown a significant reduction in the growth of all Candida strains tested. Starting from these preliminary results, we have designed the second generation of analogous in this class, and further studies are in progress in our laboratories.

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The present study used isometric tension recording to investigate the vasorelaxant effect of limonene (LM), carveol (CV), and perillyl alcohol (POH) on contractility parameters of the rat aorta, focusing in particular on the structure-activity relationship. LM, CV, and POH showed a reversible inhibitory effect on the contraction induced by electromechanical and pharmacomechanical coupling. In the case of LM, but not CV and POH, this effect was influenced by preservation of the endothelium. POH and CV but not LM exhibited greater pharmacological potency on BayK-8644-induced contraction and on electromechanical coupling than on pharmacomechanical coupling. In endothelium-denuded preparations, the order of pharmacological potency on electrochemical coupling was LM < CV < POH. These compounds inhibited also, with grossly similar pharmacological potency, the contraction induced by phorbol ester dibutyrate. The present results suggest that LM, CV and POH induced relaxant effect on vascular smooth muscle by means of different mechanisms likely to include inhibition of PKC and IP3 pathway. For CV and POH, hydroxylated compounds, it was in electromechanical coupling that the greater pharmacological potency was observed, thus suggesting a relative specificity for a mechanism likely to be important in electromechanical coupling, for example, blockade of voltage-dependent calcium channel.

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