Pharmacological potential of limonene against opportunistic fungi: Impact on Candida virulence.

The present article aims to evaluate the antifungal and antivirulence effect of the phytoconstituent Limonene against Candida spp. Antifungal assays were performed, where the concentration capable of inhibiting 50 % of fungal growth, the growth inhibition curve, the minimum fungicidal concentration, the evaluation of the modifying effect with fluconazole, the inhibitory effect of the substances on the morphological transition of Candida spp. and the statistical analysis of the results were determined. With this study, it was seen that limonene demonstrated growth inhibition for the strains tested and when associated the natural compound with Fluconazole, there was potentiation of the effect of the drug, since the inhibition of growth by the combination occurred at lower concentrations against all strains tested, when compared to the drug alone, which inhibited growth at the highest concentration. In the test to determine the Minimum Fungicidal Concentration of the products tested alone and in combination, it was found that in the case of Candida strains, growth inhibition by limonene occurred at a concentration of 1024 µg/mL. For Fluconazole, growth impairment ranged from > 1024 µg/mL to 256 µg/mL for the strains. And when combined, limonene potentiated the action of FCZ, making fungal colonization unfeasible at concentrations below 1024 µg/mL. Regarding the morphological transition from yeast to hyphae, limonene was used at concentrations of 1024 µg/mL and 512 µg/mL, and it was found that, for CA and CK, the filaments were reduced in number and size at the highest concentration and against CT, the morphological transition from yeast to hyphae/pseudohyphae was totally inhibited, and if compared to the growth control, limonene was able to reduce fungal growth at concentrations greater than 512 µg/mL. This compound has antimicrobial activity described, due to its ability to interfere in the gene expression of the fungus, the limited therapeutic options and the recent emergence of multidrug-resistant Candida species represent a significant challenge for human medicine and highlight the need for new therapeutic approaches, and in this study a great potential of limonene was revealed in relation to the perspective of increasing the efficiency of commercial drug. This work can bring an important contribution to the scientific database, while emphasizing that in-depth studies and tests on the subject, in order to better investigate its effectiveness and mechanisms by which they exert their effects, are still necessary.

Meldrum's acid derivates are MepA efflux pump inhibitors: In vitro and in silico essays.

Efflux pumps are proteins capable of expelling antibiotics from bacterial cells, have emerged as a major mechanism of bacterial resistance. In the ongoing pursuit to overcome and reduce bacterial resistance, novel substances are being explored as potential efflux pump inhibitors. Meldrum's acid, a synthetic molecule widely studied for its role in synthesizing bioactive compounds, holds promise in this regard. Therefore, the objective of this study is to evaluate the antibacterial activity of three derivatives of Meldrum's acid and assess their ability to inhibit efflux mechanisms, employing both in silico and in vitro approaches. The antibacterial activity of the derivatives was assessed using a broth microdilution testing method. Surprisingly, the derivatives did not exhibit direct antibacterial activity on their own. However, they displayed a significant effect in enhancing the efficacy of antibiotics, suggesting a potential role in potentiating their effects. Furthermore, fluorescence emission assays using ethidium bromide indicated that the derivatives could potentially block efflux pumps, as they exhibited fluorescence levels comparable to the positive control. To further investigate their inhibitory capacity, molecular docking studies were conducted in silico, revealing binding interactions similar to ciprofloxacin and carbonyl cyanide 3-chlorophenylhydrazone, known efflux pump inhibitors. These findings highlight the potential of Meldrum's acid derivatives as effective inhibitors of efflux pumps. By targeting these mechanisms, the derivatives offer a promising avenue to enhance the effectiveness of antibiotics and combat bacterial resistance. This study underscores the importance of exploring novel strategies in the fight against bacterial resistance and provides valuable insights into the potential of Meldrum's acid derivatives as efflux pump inhibitors. Further research and exploration in this field are warranted to fully exploit their therapeutic potential.

Assessment of Quercetin Antiemetic Properties: In Vivo and In Silico Investigations on Receptor Binding Affinity and Synergistic Effects.

Quercetin (QUA), a flavonoid compound, is ubiquitously found in plants and has demonstrated a diverse range of biological activities. The primary objective of the current study is to assess the potential antiemetic properties of QUA using an in vivo and in silico approach. In this experiment, 4-day-old chicks were purchased to induce emesis by orally administering copper sulfate pentahydrate (CuSO4·5H2O) at a dose of 50 mg/kg (orally). Domperidone (DOM) (6 mg/kg), Hyoscine (HYS) (21 mg/kg), and Ondansetron (OND) (5 mg/kg) were treated as positive controls (PCs), and distilled water and a trace amount of Tween 80 mixture was employed as a negative control (NC). QUA was given orally at two distinct doses (25 and 50 mg/kg). Additionally, QUA (50 mg/kg) and PCs were administered separately or in combination to assess their antagonistic or synergistic effects on the chicks. The binding affinity of QUA and referral ligands towards the serotonin receptor (5HT3), dopamine receptors (D2 and D3), and muscarinic acetylcholine receptors (M1-M5) were estimated, and ligand-receptor interactions were visualized through various computational tools. In vivo findings indicate that QUA (25 and 50 mg/kg) has a significant effect on reducing the number of retches (16.50 ± 4.65 and 10.00 ± 4.19 times) and increasing the chick latency period (59.25 ± 4.75 and 94.25 ± 4.01 s), respectively. Additionally, QUA (50 mg/kg) in combination with Domperidone and Ondansetron exhibited superior antiemetic effects, reducing the number of retches and increasing the onset of emesis-inducing time. Furthermore, it is worth noting that QUA exhibited the strongest binding affinity against the D2 receptor with a value of -9.7 kcal/mol through the formation of hydrogen and hydrophobic bonds. In summary, the study found that QUA exhibited antiemetic activity in chicks, potentially by interacting with the D2 receptor pathway.

Comparative Antibacterial and Efflux Pump Inhibitory Activity of Isolated Nerolidol, Farnesol, and α-Bisabolol Sesquiterpenes and Their Liposomal Nanoformulations.

The efflux systems are considered important mechanisms of bacterial resistance due to their ability to extrude various antibiotics. Several naturally occurring compounds, such as sesquiterpenes, have demonstrated antibacterial activity and the ability to inhibit efflux pumps in resistant strains. Therefore, the objective of this research was to analyze the antibacterial and inhibitory activity of the efflux systems NorA, Tet(K), MsrA, and MepA by sesquiterpenes nerolidol, farnesol, and α-bisabolol, used either individually or in liposomal nanoformulation, against multi-resistant Staphylococcus aureus strains. The methodology consisted of in vitro testing of the ability of sesquiterpenes to reduce the Minimum Inhibitory Concentration (MIC) and enhance the action of antibiotics and ethidium bromide (EtBr) in broth microdilution assays. The following strains were used: S. aureus 1199B carrying the NorA efflux pump, resistant to norfloxacin; IS-58 strain carrying Tet(K), resistant to tetracyclines; RN4220 carrying MsrA, conferring resistance to erythromycin. For the EtBr fluorescence measurement test, K2068 carrying MepA was used. It was observed the individual sesquiterpenes exhibited better antibacterial activity as well as efflux pump inhibition. Farnesol showed the lowest MIC of 16.5 µg/mL against the S. aureus RN4220 strain. Isolated nerolidol stood out for reducing the MIC of EtBr to 5 µg/mL in the 1199B strain, yielding better results than the positive control CCCP, indicating strong evidence of NorA inhibition. The liposome formulations did not show promising results, except for liposome/farnesol, which reduced the MIC of EtBr against 1199B and RN4220. Further research is needed to evaluate the mechanisms of action involved in the inhibition of resistance mechanisms by the tested compounds.

Antiedematogenic and Analgesic Activities of Abietic Acid in Mice.

Exacerbated inflammatory responses to harmful stimuli can lead to significant pain, edema, and other complications that require pharmacological intervention. Abietic acid (AA) is a diterpene found as a significant constituent in pine species, and evidence has identified its biological potential. The present study aimed to evaluate abietic acid's antiedematogenic and anti-inflammatory activity in mice. Swiss mice (Mus musculus) weighing 20-30 g were treated with AA at 50, 100, and 200 mg/kg. The central nervous system (CNS) effects were evaluated using open-field and rotarod assays. The antinociceptive and anti-inflammatory screening was assessed by the acetic acid and formalin tests. The antiedematogenic activity was investigated by measuring paw edema induced by carrageenan, dextran, histamine, arachidonic acid, and prostaglandin, in addition to using a granuloma model. The oral administration of abietic acid (200 mg/Kg) showed no evidence of CNS effects. The compound also exhibited significant antiedematogenic and anti-inflammatory activities in the carrageenan and dextran models, mostly related to the inhibition of myeloperoxidase (MOP) activity and histamine action and, to a lesser extent, the inhibition of eicosanoid-dependent pathways. In the granuloma model, abietic acid's effect was less expressive than in the acute models investigated in this study. In conclusion, abietic acid has analgesic and antiedematogenic activities related to anti-inflammatory mechanisms.

Biochemical aspects of the inflammatory process: A narrative review.

Inflammation is a protective response of the body potentially caused by microbial, viral, or fungal infections, tissue damage, or even autoimmune reactions. The cardinal signs of inflammation are consequences of immunological, biochemical, and physiological changes that trigger the release of pro-inflammatory chemical mediators at the local of the injured site thus, increasing blood flow, vascular permeability, and leukocyte recruitment. The aim of this study is to give an overview of the inflammatory process, focusing on chemical mediators. The literature review was based on a search of journals published between the years 2009 and 2023, regarding the role of major chemical mediators in the inflammatory process and current studies in pathogenesis, diagnosis, and therapy. Some of the recent contributions in the study of inflammatory pathologies and their mediators, including cytokines and chemokines, the kinin system, free radicals, nitric oxide, histamine, cell adhesion molecules, leukotrienes, prostaglandins and the complement system and their role in human health and chronic diseases.

Evaluation of the antiedematogenic and anti-inflammatory properties of Ximenia americana L. (Olacaceae) bark extract in experimental models of inflammation.

Edema is one of the obvious indicators of inflammation and a crucial factor to take into account when assessing a substance's capacity to reduce inflammation. We aimed to evaluate the antiedematogenic and anti-inflammatory profile of the hydroethanolic barks extract of Ximenia americana (HEXA). The possible antiedematogenic and anti-inflammatory effect of EHXA (50, 100 mg/kg and 250 mg/kg v.o) was evaluated using the paw edema induced by carrageenan, zymosan, dextran, CFA and by different agents inflammatory (serotonin, histamine, arachidonic acid and PGE2), and pleurisy model induced by carrageenan and its action on IL-1ß and TNF-α levels was also evaluated. HEXA demonstrated a significant antiedematogenic effect at concentrations of 50, 100 and 250 mg/kg on paw edema induced by carrageenan, zymosan and dextran. However, the concentration of 50 mg/kg as standard, demonstrating the effect in the subchronic model, induced CFA with inhibition of 59.06 %. In models of histamine-induced paw edema, HEXA showed inhibition of - 30 min: 40.49 %, 60 min: 44.70 % and 90 min: 48.98 %; serotonin inhibition - 30 min: 57.09 %, 60 min: 66.04 % and 90 min: 61.79 %; arachidonic acid inhibition - 15 min: 36.54 %, 30 min: 51.10 %, 45 min: 50.32 % and 60 min: 76.17 %; and PGE2 inhibition - 15 min: 67.78 %, 30 min: 62.30 %, 45 min: 54.25 % and 60 min: 47.92 %. HEXA significantly reduced (p < 0.01) leukocyte migration in the pleurisy model and reduced TNF-α and IL-1ß levels in pleural lavage (p < 0.0001). The results showed that HEXA has the potential to have an antiedematogenic impact in both acute and chronic inflammation processes, with a putative mode of action including the suppression or regulation of inflammatory mediators.

Vasodilation promoted by (E,E)-farnesol involving ion channels in human umbilical arteries.

Background: (E,E)-farnesol is a sesquiterpene alcohol derived from plants and animals that exhibits pharmacological properties in the cardiovascular system. However, its effects on human umbilical vessels remain unknown. Purpose: Thus, this study aims to characterize the vasodilatory effect of (E,E)-farnesol in human umbilical arteries (HUA). Study design: The tissue is obtained from pregnant women over 18 years of age, normotensive, and without prepartum complications. After collected, the tissue was segmented and dissected to remove Wharton's jelly and obtain the umbilical arteries segments. Methods: HUA segments were isolated and sectioned into rings that were subjected to isometric tension recordings in an organ bath. Results: (E,E)-farnesol (1 µmol/L to 1 mmol/L) promoted vasodilatory effect in HUA preparations, affecting basal tone, and inhibiting the electromechanical coupling induced by KCl 60 mmol/L with greater potency (EC50 225.3 µmol/L) than the pharmacomechanical coupling induced by 5-HT 10 µmol/L (EC50 363.5 µmol/L). In the absence of extracellular calcium, pharmacomechanical coupling was also abolished, and contractions induced by CaCl2 or BaCl2 were attenuated by (E,E)-farnesol indicating a possible direct inhibition of L-type VOCC as a mechanism of the vasodilatory effect. The vasodilator efficacy of (E,E)-farnesol on reduction of vasocontraction induced by the presence of tetraethylammonium (1 or 10 mmol/L), 4-aminopyridine (1 mmol/L) and glibenclamide (10 µmol/L) suggesting a possible influence of different potassium channels (BKCa, KV and KATP). Conclusion: These results suggest that (E,E)-farnesol may be a promising pharmacological candidate for obstetric hypertensive disorders.

Efflux Pump (QacA, QacB, and QacC) and ß-Lactamase Inhibitors? An Evaluation of 1,8-Naphthyridines against Staphylococcus aureus Strains.

The bacterial species Staphylococcus aureus presents a variety of resistance mechanisms, among which the expression of ß-lactamases and efflux pumps stand out for providing a significant degree of resistance to clinically relevant antibiotics. The 1,8-naphthyridines are nitrogen heterocycles with a broad spectrum of biological activities and, as such, are promising research targets. However, the potential roles of these compounds on bacterial resistance management remain to be better investigated. Therefore, the present study evaluated the antibacterial activity of 1,8-naphthyridine sulfonamides, addressing their ability to act as inhibitors of ß-lactamases and efflux pump (QacA/B and QacC) against the strains SA-K4414 and SA-K4100 of S. aureus. All substances were prepared at an initial concentration of 1024 µg/mL, and their minimum inhibitory concentrations (MIC) were determined by the broth microdilution method. Subsequently, their effects on ß-lactamase- and efflux pump-mediated antibiotic resistance was evaluated from the reduction of the MIC of ethidium bromide (EtBr) and ß-lactam antibiotics, respectively. The 1,8-naphthyridines did not present direct antibacterial activity against the strains SA-K4414 and SA-K4100 of S. aureus. On the other hand, when associated with antibiotics against both strains, the compounds reduced the MIC of EtBr and ß-lactam antibiotics, suggesting that they may act by inhibiting ß-lactamases and efflux pumps such as QacC and QacA/B. However, further research is required to elucidate the molecular mechanisms underlying these observed effects.

NorA, Tet(K), MepA, and MsrA Efflux Pumps in Staphylococcus aureus, their Inhibitors and 1,8-Naphthyridine Sulfonamides.

Antibiotic resistance can be characterized, in biochemical terms, as an antibiotic's inability to reach its bacterial target at a concentration that was previously effective. Microbial resistance to different agents can be intrinsic or acquired. Intrinsic resistance occurs due to inherent functional or structural characteristics of the bacteria, such as antibiotic-inactivating enzymes, nonspecific efflux pumps, and permeability barriers. On the other hand, bacteria can acquire resistance mechanisms via horizontal gene transfer in mobile genetic elements such as plasmids. Acquired resistance mechanisms include another category of efflux pumps with more specific substrates, which are plasmid-encoded. Efflux pumps are considered one of the main mechanisms of bacterial resistance to antibiotics and biocides, presenting themselves as integral membrane transporters. They are essential in both bacterial physiology and defense and are responsible for exporting structurally diverse substrates, falling into the following main families: ATP-binding cassette (ABC), multidrug and toxic compound extrusion (MATE), major facilitator superfamily (MFS), small multidrug resistance (SMR) and resistance-nodulation-cell division (RND). The Efflux pumps NorA and Tet(K) of the MFS family, MepA of the MATE family, and MsrA of the ABC family are some examples of specific efflux pumps that act in the extrusion of antibiotics. In this review, we address bacterial efflux pump inhibitors (EPIs), including 1,8-naphthyridine sulfonamide derivatives, given the pre-existing knowledge about the chemical characteristics that favor their biological activity. The modification and emergence of resistance to new EPIs justify further research on this theme, aiming to develop efficient compounds for clinical use.

Photobiological effect of eugenol-derived 3-benzoylcoumarin associated with led lights against MDR microorganisms.

The problem of antibiotic resistance by bacteria threatens human health. Therefore, studies in this area seek alternatives to circumvent it. The study with coumarins and eugenol has already proven that these classes of compounds act against bacteria. In this same aspect, exposure to LED also shows a bactericidal effect. Seeking a possible enhancement of this effect, the present work studied coumarins derived from eugenol in association with LED to investigate the bactericidal effect. Four compounds were tested. For this, minimum inhibitory concentrations (MICs) and modulation with three antibiotics against Escherichia coli and Staphylococcus aureus bacteria were determined. To test the behavior of the activity against exposure to LED, the plates were exposed for 20 min to blue light, 415 nm and then incubated at 37°C for 24 h. For control, duplicates were made, and one of them did not undergo this exposure. C1 exhibited better activity against S. aureus, as synergism prevailed under the conditions tested. C3 and C4 were promising against E. coli as they showed synergism in association with the three antibiotics both with and without LED exposure. Thus, the compounds showed bactericidal activity, and LED was shown to enhance synergism.

Mechanisms of Actions Involved in The Antinociceptive Effect of Estragole and its ß-Cyclodextrin Inclusion Complex in Animal Models.

(1) Background: estragole is a monoterpene found in the essential oils of several aromatic plants, which can be used for several pharmacological activities. The aim of this study was to evaluate the antinociceptive effect of estragole (Es) and its ß-cyclodextrins inclusion complex (Es/ß-CD). (2) Methods: the effects of Es and Es/ß-CD on the central nervous system (CNS) were evaluated through open field and rota-rod assays, and the antinociceptive effect in formalin models, abdominal writhing induced by acetic acid, hot plate, tail flick test and plantar mechanical hyperalgesia. (3) Results: Es and Es/ß-CD showed no alterations on the CNS evaluated parameters and the results suggested there was an antinociceptive action in the formalin, abdominal writhing, hot plate, tail flick tests and plantar mechanical hyperalgesia, proposing the involvement of the nitric oxide, glutamatergic signaling pathways, cyclic guanosine monophosphate and vanilloid pathways. (4) Conclusion: the results suggest that Es and Es/ß-CD have a promising antinociceptive potential as a possible alternative for the pharmacological treatment of pain, also showing that the encapsulation of Es in ß-cyclodextrins probably improves its pharmacological properties, since the complexation process involves much lower amounts of the compound, contributing to better bioavailability and a lower probability of adverse effect development.

In vivo and in silico anti-inflammatory properties of the sesquiterpene valencene.

Valencene (VLN) is a sesquiterpene found in juices and essential oils of citrus species such as Cyperus rotundus. Considering the evidence that this species has anti-inflammatory effects, the present study aims to evaluate the anti-inflammatory activity of VLN in vivo and in silico. Swiss mice (n = 6) were orally treated according to their treatment groups as follows: VLN (10, 100 or 300 mg/kg), negative control (0.9% saline), and positive controls (indomethacin 25 mg/kg or promethazine 6 mg/kg). The anti-inflammatory activity was evaluated in murine models of acute and chronic inflammation. The inhibition of acute inflammation was evaluated in models of paw edema induced by different inflammatory agents (carrageenan, dextran, histamine, and arachidonic acid (AA)) and carrageenan-induced pleurisy and peritonitis. The modulation of chronic inflammation was evaluated in a granuloma model induced cotton pellets implantation. The interaction with inflammatory targets was evaluated in silico using molecular docking analysis. The administration of VLN to challenged mice significantly inhibited paw edema formation with no significant difference between the administered doses. The compound also reduced albumin extravasation, leukocyte recruitment, and the production of myeloperoxidase (MPO), IL-1ß, and TNF-α in both pleural and peritoneal lavages. According to the mathematical-statistical model observed in silico analysis, this compound has favorable energy to interact with the cyclooxygenase enzyme (COX-2) and the histamine 1 (H1) receptor. Finally, animals treated with the sesquiterpene showed a reduction in both granuloma weight and concentration of total proteins in a chronic inflammation model. Given these findings, it is concluded that NLV presents promising pharmacological activity in murine models of acute and chronic inflammation.

Vaccination for COVID-19 in children: Denialism or misinformation?

In the current pandemic scenario, vaccines for children have been scientifically approved; however, there is a challenge faced globally: parents' hesitation about vaccinating their children for COVID-19, which can hamper adherence to vaccine campaigns. This issue is due to the lack of information or access to fake news that affects the parents' power of judgment. The experience of the vaccine process with Pfizer's immunizer in several countries successfully reduced the number of hospitalized and prevented hundreds of child deaths from COVID-19. All health professionals must encourage the vaccination of children from the age of 5, sharing reliable scientific data, thus reducing the spread of fake news.

Evaluation of the antifungal activity of α, ß, and δ-damascone and inclusion complexes in ß-cyclodextrin against Candida spp.

Due to the increase in fungal resistance to existing drugs, a need exists to search for new antifungals. This study aimed to evaluate the antifungal activity of α, ß, and δ-damascone and inclusion complexes with ß-cyclodextrin against different Candida spp. The inclusion complex of ß-damascone was prepared by the co-evaporation method using three molar proportions (1:1; 2:1; 3:1 (ßDA-ßCD)) and analyzed using Fourier transform infrared spectroscopy (FTIR). Standard Candida albicans (CA INCQS 40,006), Candida krusei (CK INCQS 40,095), and Candida tropicalis (CT INCQS 40,042) strains were used to evaluate antifungal activity. The substances were tested individually or in association with fluconazole (FCZ). The IC50 and cell viability curve constructions were performed using the microdilution method. The minimum fungicidal concentration (MFC) was determined by the subculture method in a solid medium. The α, ß, and δ-DA isolated or in combination with fluconazole (FCZ) showed significant antifungal activity. ß-damascone showed effective complexation in the three molar proportions assayed; however, none of the inclusion complexes was demonstrated clinically significant effects against the fungal tested. Then, all compounds have shown promising antifungal activities; however, in vivo assays are necessary to have therapeutical application in the future.

Inhibition of the MepA efflux pump by limonene demonstrated by in vitro and in silico methods.

Bacterial resistance is a natural process carried out by bacteria, which has been considered a public health problem in recent decades. This process can be triggered through the efflux mechanism, which has been extensively studied, mainly related to the use of natural products to inhibit this mechanism. To carry out the present study, the minimum inhibitory concentration (MIC) tests of the compound limonene were performed, through the microdilution methodology in sterile 96-well plates. Tests were also carried out with the association of the compound with ethidium bromide and ciprofloxacin, in addition to the ethidium bromide fluorimetry, and later the molecular docking. From the tests performed, it was possible to observe that the compound limonene presented significant results when associated with ethidium bromide and the antibiotic used. Through the fluorescence emission, it was observed that when associated with the compound limonene, a greater ethidium bromide fluorescence was emitted. Finally, when analyzing the in silico study, it demonstrated that limonene can efficiently fit into the MepA structure. In this way, it is possible to show that limonene can contribute to cases of bacterial resistance through an efflux pump, so that it is necessary to carry out more studies to prove its effects against bacteria carrying an efflux pump and assess the toxicity of the compound.

Biological properties of terpinolene evidenced by in silico, in vitro and in vivo studies: A systematic review.

BACKGROUND: Terpinolene, a monoterpene that is naturally found in a variety of herbs, is widely used as a flavoring agent in the industry. Although it's well established in the literature that terpinolene is an important component of plant extracts, the biological properties and the potential therapeutic use of this compound remain poorly explored. PURPOSE: This work aimed to answer the following guiding question: "What are the biological activities of terpinolene demonstrated through in silico, in vitro, and in vivo assays?". STUDY DESIGN AND METHODOLOGY: A systematic review was carried out in four electronic databases (Embase, Web of Science, Scopus, and PubMed) according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, using the following search terms: terpinolene "AND" activity "OR" properties "OR" therapeutic "OR" treatment. This search included manuscripts published between 1960 and June 2020. Study selection was conducted by two independent reviewers according to predefined criteria. RESULTS: The initial search found a total of 2449 articles. However, only 57 of them were selected as they met the inclusion criteria and answered the guiding question. The analysis of these studies indicated that terpinolene presents a series of biological effects, from which the antioxidant, larvicide, and insecticide activities stand out. Despite the evidence demonstrating that terpinolene has the potential to be used in a broad pharmacological context, the mechanisms underlying its cellular and molecular effects remain to be better elucidated. In addition, the in vivo efficacy and safety of the administration of this compound have been poorly evaluated through either preclinical and clinical trials. Therefore, this study highlights the importance of characterizing the biological aspects and mechanisms of action of this natural compound. CONCLUSION: The data summarized in the present systematic review demonstrates the pharmacological potential of terpinolene. Nevertheless, most studies included in this review provide a superficial characterization of terpinolene biological effects and therefore, further research elucidating its mechanism of action and potential therapeutic benefits through preclinical and clinical trials are required. Nevertheless, due to its wide range of different biological activities, terpinolene will certainly attract the interest of scientific research, which could significantly contribute to the development of new products with both therapeutic and environmental applications.

Serological and molecular epidemiology of the Dengue, Zika and Chikungunya viruses in a risk area in Brazil.

BACKGROUND: The co-circulation of types of arbovirus in areas where they are endemic increased the risk of outbreaks and limited the diagnostic methods available. Here, we analyze the epidemiological profile of DENV, CHIKV and ZIKV at the serological and molecular level in patients with suspected infection with these arboviruses in the city of Juazeiro do Norte, Ceará, Brazil. METHODS: In 2016, the Central Public Health Laboratory (LACEN) of Juazeiro do Norte received 182 plasma samples from patients who visited health facilities with symptoms compatible with arbovirus infection. The LACEN performed serological tests for detection of IgM/IgG to DENV and CHIKV. They then sent these samples to the Retrovirology Laboratory of the Federal University of São Paulo and Faculty of Medical of the ABC where molecular analyses to confirm the infection by DENV, ZIKV and CHIKV were performed. The prevalence of IgM/IgG antibodies and of infections confirmed by RT-qPCR were presented with 95% confidence interval. RESULTS: In serologic analysis, 125 samples were positive for antibodies against CHIKV and all were positive for antibodies against DENV. A higher prevalence of IgG against CHIKV (63.20% with 95% CI: 45.76-70.56) than against DENV (95.05% with 95% CI: 78.09-98.12) was observed. When the samples were submitted to analysis by RT-qPCR, we observed the following prevalence: mono-infection by ZIKV of 19.23% (95% CI: 14.29-34.82) patients, mono-infection by CHIKV of 3.84% (95% CI: 2.01-5.44) and co-infection with ZIKV and CHIKV of 1.09% (95% CI: 0.89-4.56). CONCLUSION: The serologic and molecular tests performed in this study were effective in analyzing the epidemiological profile of DENV, CHIKV and ZIKV in patients with suspected infection by these arboviruses in the city of Juazeiro do Norte, Ceará/Brazil.

Effect of Carvacrol and Thymol on NorA efflux pump inhibition in multidrug-resistant (MDR) Staphylococcus aureus strains.

Undue exposure to antimicrobials has led to the acquisition and development of sophisticated bacterial resistance mechanisms, such as efflux pumps, which are able to expel or reduce the intracellular concentration of various antibiotics, making them ineffective. Therefore, inhibiting this mechanism is a promising way to minimize the phenomenon of resistance in bacteria. In this sense, the present study sought to evaluate the activity of the Carvacrol (CAR) and Thymol (THY) terpenes as possible Efflux Pump Inhibitors (EPIs), by determining the Minimum Inhibitory Concentration (MIC) and the association of these compounds in subinhibitory concentrations with the antibiotic Norfloxacin and with Ethidium Bromide (EtBr) against strains SA-1199 (wild-type) and SA-1199B (overexpresses NorA) of Staphylococcus aureus. In order to verify the interaction of the terpenes with the NorA efflux protein, an in silico molecular modeling study was carried out. The assays used to obtain the MIC of CAR and THY were performed by broth microdilution, while the Efflux Pump inhibitory test was performed by the MIC modification method of the antibiotic Norfloxacin and EtBr. docking was performed using the Molegro Virtual Docker (MVD) program. The results of the study revealed that CAR and THY have moderate bacterial activity and are capable of reducing the MIC of Norfloxacin antibiotic and EtBr in strains of S. aureus carrying the NorA efflux pump. The docking results showed that these terpenes act as possible competitive NorA inhibitors and can be investigated as adjuvants in combined therapies aimed at reducing antibiotic resistance.