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Valter M Barbosa-Filho,1,2 Emily P Waczuk,2 Nadghia F Leite,3 Irwin RA Menezes,1 José GM da Costa,1 Sírleis R Lacerda,1 Isaac A Adedara,2 Henrique Douglas Melo Coutinho,4 Thais Posser,5 Jean P Kamdem2,6 1Departamento de Ciências Biológicas, Centro de Ciências Biológicas e da Saúde (CCBS), Universidade Regional do Cariri (URCA), Crato, CE, Brazil; 2Programa de Pós-Graduação em Bioquímica Toxicológica, Departamento de Bioquímica e Biologia Molecular, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil; 3Departamento de Química Biológica, Centro de Ciências Biológicas e da Saúde (CCBS), 4Laboratory of Microbiology and Molecular Biology, Universidade Regional do Cariri (URCA), Crato, CE, Brazil; 5Campus São Gabriel, Universidade Federal do Pampa, São Gabriel, RS, Brazil; 6Departamento de Bioquímica, Instituto de Ciências Básica da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil Background: The challenge of antibiotic resistance and the emergence of new infections have generated considerable interest in the exploration of natural products from plant origins as combination therapy. In this context, crude ethanolic extract (CEE), ethyl acetate fraction (EAF), and methanolic fraction (MF) from Anacardium microcarpum were tested alone or in combination with antibiotics (amikacin, gentamicin, ciprofloxacin, and imipenem) against Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. Methods: Antibiotic resistance-modifying activity was performed using the microdilution method by determining the minimal inhibitory concentration (MIC). In addition, phytochemical prospecting analyses of tested samples were carried out. Results: Our results indicated that all the extracts showed low antibacterial activity against multidrug-resistant strains (MIC =512 µg/mL). However, addition of CEE, EAF, and MF to the growth medium at the subinhibitory concentration (MIC/8=64 µg/mL) significantly modulated amikacin- and gentamicin-resistant E. coli 06. CEE and EAF also demonstrated a significant (P

Abstract: The study examined the antiinflammatory and antinociceptive effects of the sesquiterpene (−)-α-bisabolol (BISA). The antiinflammatory effect was evaluated on acute models of dermatitis induced by Croton oil, arachidonic acid, phenol and capsaicin, respectively, in mouse ear. BISA inhibited the dermatitis induced by all noxious agents, except capsaicin. BISA was assessed in two established mouse models of visceral nociception. Mice were pretreated orally with BISA, and the pain-related behavioral responses to intraperitoneal cyclophosphamide or to intracolonic mustard oil were analyzed. BISA showed a dose-unrelated significant antinociception. Collectively, the results suggest that BISA may be an topical antiinflammatory and visceral antinociceptive agent. [ABSTRACT FROM AUTHOR]

Limonene, a monoterpene found in essential oils, has various activities, such as antifungal, antioxidant, neuroprotective, gastroprotective and vasorelaxant. However, the observation of limonene's biphasic effect in preclinical studies provides crucial information about its dose-dependent actions. Understanding this behavior is essential for optimizing therapeutic doses and anticipating possible side effects prior to clinical trials. The objective of this study is to provide a more detailed characterization and investigation of the mechanisms of action of limonene on the contractile tonus of isolated aorta.The experiments were carried out on aortic rings isolated from rats, subjected to isometric recording of contractions in their circular smooth muscle and exposed to different concentrations of limonene. It was found that limonene blocked the contraction induced by KCl (60 mM), but had a biphasic effect on the contraction induced by phenylephrine (0.1 μM). At lower concentrations, limonene was able to amplify the contraction induced by phenylephrine, while at higher concentrations, it inhibited it. The nitric oxide synthase blockers L-NAME and ruthenium red, a TRP ion channel blocker, did not significantly interfere with the biphasic character of limonene. However, indomethacin, a blocker of arachidonic acid derivatives, completely blocked the amplification of contraction induced by phenylephrine. In addition, limonene promoted relaxation in contractions induced by BAY-K 8644, a calcium channel agonist and by Ba 2+ . Limonene has complex effects on aortic tone, amplifying or inhibiting contractions, suggesting that the therapeutic window should be carefully studied to optimize clinical results., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Piper tuberculatum, traditionally known as 'pimenta-d'arda,' 'pimenta-longa,' or 'pimenta de macaco,' has been used in Brazilian folk medicine to treat inflammatory symptoms, It is used for its sedative effects in pain relief. Considering this species' significant essential oil content, the present study aimed to evaluate the anti-edematogenic and anti-inflammatory effects of the essential oil Piper tuberculatum (EOPT) in vivo. To this end, Swiss mice (Mus musculus) of both sexes were treated orally with the EOPT at 50, 100, and 250 mg/Kg. The rotarod and open field evaluated the potential activity in the central nervous system. At the same time, formalin and abdominal writhing tests were carried out to perform the pharmacological screening of the essential oil. Next, the anti-edematogenic effect was assessed using paw edema models induced by carrageenan, dextran, histamine, and arachidonic acid. The anti-inflammatory activity was then characterized in peritonitis (acute) and granuloma (chronic) models.  All the EOPT doses (50, 100, and 250 mg/kg) had analgesic effects associated with anti-inflammatory mechanisms in screening models. Accordingly, the treatment (EOPT 100 mg/Kg) inhibited the inflammatory process in acute and chronic models. In conclusion, EOPT has analgesic, antiedematogenic, and anti-inflammatory effects, highlighting its potential use in developing anti-inflammatory drugs., (© 2024 Wiley‐VCH GmbH.)

The misuse of antibiotics has led to an alarming increase in bacterial strains resistant to these drugs. Efflux pumps, which expel antibiotics from bacterial cells, have emerged as one of the key mechanisms of bacterial resistance. In the quest to combat and mitigate bacterial resistance, researchers have turned their attention to efflux pump inhibitors as a potential solution. Meldrum's acid, a synthetic molecule widely utilized in the synthesis of bioactive compounds, has garnered significant interest in this regard. Hence, this study aims to investigate the antibacterial activity and evaluate the efficacy of three derivatives of meldrum's acid in inhibiting efflux mechanisms, employing both in silico and in vitro approaches. The antibacterial activity of the derivatives was assessed through rigorous broth microdilution testing. While the derivatives themselves did not exhibit direct antibacterial activity, they demonstrated remarkable potential in potentiating the effects of antibiotics. Additionally, fluorescence emission assays using ethidium bromide (EtBr) revealed fluorescence levels comparable to the positive control, indicating a possible blockade of efflux pumps. Molecular docking studies conducted in silico further supported these findings by revealing binding interactions similar to norfloxacin and CCCP, known efflux pump inhibitors. These results underscore the potential of meldrum's acid derivatives as effective inhibitors of efflux pumps. By inhibiting these mechanisms, the derivatives hold promise in enhancing the effectiveness of antibiotics and combatting bacterial resistance. This study contributes valuable insights into the development of novel strategies to address the pressing issue of bacterial resistance and paves the way for further research and exploration in this field., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financialinterestsor personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Staphylococcus aureus is a bacterium responsible for resistance to multiple drugs and the efflux system is widely studied among the resistance mechanisms developed by this species. The present study evaluates the inhibition of the MepA efflux pump by thiadiazine-derived compounds. For this purpose, thiadiazine-derived compounds (IJ-14 to IJ-20) were tested against S. aureus K2068 strains. Microdilution tests were initially conducted to assess the Minimum Inhibitory Concentration (MIC) of the compounds and their efflux pump inhibition activity. In addition, fluorimetry tests were performed using BrEt emission and tests were conducted to inhibit the expression of the mepA gene. This involved comparing the bacterial gene expression with the antibiotic alone to the gene expression after combining compounds (IJ-17 and IJ-20) with the antibiotic. Furthermore, membrane permeability assessment tests and in silico molecular docking tests were performed. It was observed that the IJ17 and IJ20 compounds exhibited direct activity against the tested strain. The IJ17 compound produced significant results in the gene inhibition tests, which was also evidenced through the membrane permeability alteration test. These findings suggest that thiadiazine-derived compounds have promising effects against one of the main resistance mechanisms, with the IJ17 compound presenting observable mechanisms of action., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financialinterestsor personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The Ocimum species present active compounds with the potential to develop drugs for treating chronic disease conditions, such as anxiety and seizures. The present study aims to investigate the anticonvulsant and anxiolytic-like effect of the essential oil from O. basilicum Linn (OEFOb) leaves and its major constituent estragole (ES) in vivo on adult zebrafish (aZF) and in silico. The aZF were treated with OEFOb or ES or vehicle and submitted to the tests of toxicity, open-field, anxiety, and convulsion and validated the interactions of the estragole on the involvement of GABAergic and serotonergic receptors by molecular docking assay. The results showed that the oral administration of OEFOb and ES did not have a toxic effect on the aZF and showed anxiolytic-like effects with the involvement of GABA A , 5-HT 1 , 5-HT 2A/2C and 5-HT 3A/3B as well on anxiety induced by alcohol withdrawal. The OEFOb and ES showed anticonvulsant potential attenuating the seizures induced by pentylenetetrazole (PTZ) by modulation of the GABA A system. Both anxiolytic and anticonvulsant effects were corroborated by the potential of the interaction of ES by in silico assay. These study samples demonstrate the pharmacological evidence and potential for using these compounds to develop new anxiolytic and anticonvulsant drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The occurrence of bacterial resistance has been increasing, compromising the treatment of various infections. The high virulence of Staphylococcus aureus allows for the maintenance of the infectious process, causing many deaths and hospitalizations. The MepA and NorA efflux pumps are transporter proteins responsible for expelling antimicrobial agents such as fluoroquinolones from the bacterial cell. Coumarins are phenolic compounds that have been studied for their diverse biological actions, including against bacteria. A pharmacokinetic in silico characterization of compounds C10, C11, C13, and C14 was carried out according to the principles of Lipinski's Rule of Five, in addition to searching for similarity in ChemBL and subsequent search for publications in CAS SciFinder. All compounds were evaluated for their in vitro antibacterial and modulatory activity against standard and multidrug-resistant Gram-positive and Gram-negative strains. The effect of coumarins C9, C10, C11, C13, and C14 as efflux pump inhibitors in Staphylococcus aureus strains was evaluated using the microdilution method (MepA or NorA) and fluorimetry (NorA). The behavior of coumarins regarding the efflux pump was determined from their interaction properties with the membrane and coumarin-protein using molecular docking and molecular dynamics simulations. Only the isolated coumarin compound C13 showed antibacterial activity against standard strains of Staphylococcus aureus and Escherichia coli. However, the other tested coumarins showed modulatory capacity for fluoroquinolone and aminoglycoside antibacterials. Compounds C10, C13, and C14 were effective in reducing the MIC of both antibiotics for both multidrug-resistant strains, while C11 potentiated the effect of norfloxacin and gentamicin for Gram-positive and Gram-negative bacteria and only norfloxacin for Gram-negative. Only coumarin C14 produced synergistic effects when associated with ciprofloxacin in MepA-carrying strains. All tested coumarins have the ability to inhibit the NorA efflux pump present in Staphylococcus aureus, both in reducing the MIC and inducing increased ethidium bromide fluorescence emission in fluorimetry. The findings of this study offer an atomistic perspective on the potential of coumarins as active inhibitors of the NorA pump, highlighting their specific mode of action mainly targeting protein inhibition. In molecular docking, it was observed that coumarins are capable of interacting with various amino acid residues of the NorA pump. The simulation showed that coumarin C10 can cross the bilayer; however, the other coumarins interacted with the membrane but were unable to cross it. Coumarins demonstrated their potentiating role in the effect of norfloxacin through a dual mechanism: efflux pump inhibition through direct interaction with the protein (C9, C10, C11, and C13) and increased interaction with the membrane (C10 and C13). In the context of pharmacokinetic prediction studies, the studied structures have a suitable chemical profile for possible oral use. We suggest that coumarin derivatives may be an interesting alternative in the future for the treatment of resistant bacterial infections, with the possibility of a synergistic effect with other antibacterials, although further studies are needed to characterize their therapeutic effects and toxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financialinterestsor personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financialinterestsor personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Endotoxemia is a severe and dangerous clinical syndrome that results in elevated morbidity, especially in intensive care units. Neonates are particularly susceptible to endotoxemia due to their immature immune systems. There are few effective treatments for neonatal endotoxemia. One group of compounds with potential in the treatment of neonatal inflammatory diseases such as endotoxemia is the flavonoids, mainly due to their antioxidant and anti-inflammatory properties. Among these, naringenin (NGN) is a citrus flavonoid which has already been reported to have anti-inflammatory, antioxidant, anti-nociceptive and anti-cancer effects. Unfortunately, its clinical application is limited by its low solubility and bioavailability. However, cyclodextrins (CDs) have been widely used to improve the solubility of nonpolar drugs and enhance the bioavailability of these natural products., Objective: We, therefore, aimed to investigate the effects of NGN non-complexed and complexed with hydroxypropyl-β-cyclodextrin (HPβCD) on neonatal endotoxemia injuries in a rodent model and describe the probable molecular mechanisms involved in NGN activities., Method: We used exposure to a bacterial lipopolysaccharide (LPS) to induce neonatal endotoxemia in the mice., Results: It was found that NGN (100 mg/kg i.p.) exposure during the neonatal period reduced leukocyte migration and decreased pro-inflammatory cytokine (TNF-α, IL-1β and IL-6) levels in the lungs, heart, kidneys or cerebral cortex. In addition, NGN upregulated IL-10 production in the lungs and kidneys of neonate mice. The administration of NGN also enhanced antioxidant enzyme catalase and SOD activity, reduced lipid peroxidation and protein carbonylation and increased the reduced sulfhydryl groups in an organ-dependent manner, attenuating the oxidative damage caused by LPS exposure. NGN decreased ERK1/2, p38MAPK and COX-2 activation in the lungs of neonate mice. Moreover, NGN complexed with HPβCD was able to increase the animal survival rate., Conclusion: NGN attenuated inflammatory and oxidative damage in the lungs, heart and kidneys caused by neonatal endotoxemia through the MAPK signaling pathways regulation. Our results show that NGN has beneficial effects against neonatal endotoxemia and could be useful in the treatment of neonatal inflammatory injuries., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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., (© 2023 Wiley-VCH GmbH.)

Background: Perillyl alcohol (POH) is a monoterpenoid found in plant essential oils and has been shown to relax murine vessels, but its effect on human vessels remains poorly studied., Objective: The study aimed to characterize the effect of POH on human umbilical arteries (HUA)., Methods: Rings of HUA were obtained from uncomplicated patients and suspended in an organ bath for isometric recording. The vasorelaxant effect of POH in HUA was evaluated on basal tone and electromechanical or pharmacomechanical contractions, and possible mechanisms of action were also investigated., Results: POH (1-1000 μM) altered the basal tone of HUA and completely relaxed HUA rings precontracted with KCl (60 mM) or 5-HT (10 μM), obtaining greater potency in the pharmacomechanical pathway (EC 50 110.1 μM), suggesting a complex interference in the mobilization of extra- and intracellular Ca 2+ . POH (1000 μM) inhibited contractions induced by BaCl 2 (0.1-30 mM) in a similar way to nifedipine (10 μM), indicating a possible blockade of L-type VOCC. In the presence of potassium channel blockers, tetraethylammonium (1 mM), 4-aminopyridine (1 mM), or glibenclamide (10 μM), an increase in the EC 50 value of the POH was observed, suggesting a modulation of the activity of BK Ca , K V , and K ATP channels., Conclusion: The data from this study suggest that POH modulates Ca 2+ and K + ion channels to induce a relaxant response in HUA., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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 (CuSO 4 ·5H 2 O) 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.

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., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

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.

The NorA efflux pump of Staphylococcus aureus is known to play a major role in the development of resistance against quinolone drugs by reducing their concentration inside target pathogens. The objective of this study was to evaluate the ability of tannic acid to inhibit the gene expression of the NorA efflux pump in Staphylococcus aureus and to evaluate the in silico effect on the pump. Efflux pump inhibition was evaluated by fluorimetry. The checkerboard method evaluates the effect of the test substance in combination with an antimicrobial at different concentrations. To gene expression evaluation NorA the assay was performed using: a sub-inhibitory concentration preparation (MIC/4) of the antibiotic; a sub-inhibitory concentration preparation (MIC/4) of the antibiotic associated with tannic acid at a sub-inhibitory concentration (MIC/4). In this study, docking simulations were performed by the SWISSDOCK webserver. The ability of tannic acid to inhibit the NorA efflux pump can be related to both the ability to inhibit the gene expression of this protein, acting on signaling pathways involving the ArlRS membrane sensor. As well as acting directly through direct interaction with the NorA protein, as seen in the approach and in silico and in vitro per checkerboard method and fluorimetry of bromide accumulated in the cell., (© 2023. Springer Nature Limited.)

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 PGE 2 ), and pleurisy model induced by carrageenan and its action on IL-1β 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 PGE 2 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-1β 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Valencene and nootkatone are aromatic sesquiterpenes with known biological activities, such as antimicrobial, antioxidant, anti-inflammatory, and antitumor. Given the evidence that encapsulation into nanosystems, such as liposomes, could improve the properties of several compounds, the present study aimed to evaluate the activity of these sesquiterpenes in their isolated state or in liposomal formulations against strains of Staphylococcus aureus carrying efflux pumps. The broth microdilution method evaluated the antibiotic-enhancing activity associated with antibiotics and ethidium bromide (EtBr). The minimum inhibitory concentration was assessed in strains of S. aureus 1199B, IS-58, and RN4220, which carry the efflux proteins NorA, Tet(K), and MsrA. In tests with strain 1199B, valencene reduced the MIC of norfloxacin and EtBr by 50%, while the liposomal formulation of this compound did not show a significant effect. Regarding the strain IS-58, valencene, and its nanoformulation reduced norfloxacin MIC by 60.3% and 50%, respectively. In the non-liposomal form, the sesquiterpene reduced the MIC of EtBr by 90%. Against the RN4220 strain, valencene reduced the MIC of the antibiotic and EtBr by 99% and 93.7%, respectively. Nootkatone and its nanoformulation showed significant activity against the 1199B strain, reducing the EtBr MIC by 21.9%. Against the IS-58 strain, isolated nootkatone reduced the EtBr MIC by 20%. The results indicate that valencene and nootkatone potentiate the action of antibiotics and efflux inhibitors in strains carrying NorA, Tet(K), and MsrA proteins, which suggests that these sesquiterpenes act as efflux pump inhibitors in S. aureus . Therefore, further studies are needed to assess the impact of incorporation into liposomes on the activity of these compounds in vivo.

The discovery of antibiotics has significantly transformed the outcomes of bacterial infections in the last decades. However, the development of antibiotic resistance mechanisms has allowed an increasing number of bacterial strains to overcome the action of antibiotics, decreasing their effectiveness against infections they were developed to treat. This study aimed to evaluate the antibacterial activity of synthetic coumarins Staphylococcus aureus in vitro and analyze their interaction with the MepA efflux pump in silico. The Minimum Inhibitory Concentration (MIC) determination showed that none of the test compounds have antibacterial activity. However, all coumarin derivatives decreased the MIC of the standard efflux inhibitor ethidium bromide, indicating antibacterial synergism. On the other hand, the C14 derivative potentiated the antibacterial activity of ciprofloxacin against the resistant strain. In silico analysis showed that C9, C11, and C13 coumarins showed the most favorable interaction with the MepA efflux pump. Nevertheless, due to the present in silico and in vitro investigation limitations, further experimental research is required to confirm the therapeutic potential of these compounds in vivo., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The use of medicinal plants to treat inflammatory conditions and painful processes has attracted the attention of scientists and health professionals due to the evidence that natural products can promote significant therapeutic benefits associated with fewer adverse effects compared to conventional anti-inflammatory drugs. The genus Plectranthus is composed of various plants with pharmacological potential, which are used to treat various diseases in traditional communities worldwide. The present study systematically reviewed Plectranthus species with anti-inflammatory and analgesic potential. To this end, a systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol. The search was conducted on the following databases: PubMed, ScienceDirect, SciVerse Scopus, and Web of Science. Different combinations of search terms were used to ensure more excellent article coverage. After the selection, a total of 45 articles were included in this review. This study identified twelve Plectranthus species indicated for the treatment of different inflammatory conditions, such as wounds, fever, bronchitis, abscess, asthma, hepatitis, labyrinthitis, tonsillitis, and uterine inflammation. The indications for pain conditions included headache, sore throat, heartburn, menstrual cramp, colic, toothache, stomachache, migraine, chest pain, abdominal pain, local pain, labor pain, and recurring pain. Among the listed species, ten plants were found to be used according to traditional knowledge, although only four of them have been experimentally studied. When assessing the methodological quality of preclinical in vivo assays, most items presented a risk of bias. The SR results revealed the existence of different Plectranthus species used to treat inflammation and pain. The results of this systematic review indicate that Plectranthus species have the potential to be used in the treatment of diseases with an inflammatory component, as well as in the management of pain. However, given the risk of biases, the experimental analysis of these species through preclinical testing is crucial for their safe and effective use.

Antimicrobial resistance has become a growing public health concern in recent decades, demanding a search for new effective treatments. Therefore, this study aimed to elucidate the phytochemical composition and evaluate the antibacterial activity of the essential oil obtained from the fruits of Piper tuberculatum Jacq. (EOPT) against strains carrying different mechanisms of antibiotic resistance. Phytochemical analysis was performed using gas chromatography-mass spectrometry (GC/MS). The antibacterial activity of EOPT and its ability to inhibit antibiotic resistance was evaluated through the broth microdilution method. The GC-MS analysis identified 99.59% of the constituents, with β-pinene (31.51%), α-pinene (28.38%), and β-cis-ocimene (20.22%) being identified as major constituents. The minimum inhibitory concentration (MIC) of EOPT was determined to assess its antibacterial activity against multidrug-resistant strains of Staphylococcus aureus (IS-58, 1199B, K2068, and K4100). The compound showed a MIC of ≥ 1024 μg/mL, suggesting a lack of intrinsic antibacterial activity. However, when the EOPT was associated with antibiotics and EtBr, a significant decrease in antibiotic resistance was observed, indicating the modulation of efflux pump activity. This evidence was corroborated with the observation of increased fluorescent light emission by the bacterial strains, indicating the involvement of the NorA and MepA efflux pumps. Additionally, the significant potentiation of ampicillin activity against the S. aureus strain K4414 suggests the β-lactamase inhibitory activity of EOPT. These results suggest that the essential oil from P. tuberculatum fruits has antibiotic-enhancing properties, with a mechanism involving the inhibition of efflux pumps and β-lactamase in MDR S. aureus strains. These findings provide new perspectives on the potential use of EOPT against antibiotic resistance and highlight the importance of Piper species as sources of bioactive compounds with promising therapeutic activities against MDR bacteria. Nevertheless, further preclinical (in vivo) studies remain necessary to confirm these in vitro-observed results.

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 (EC 50 225.3 μmol/L) than the pharmacomechanical coupling induced by 5-HT 10 μmol/L (EC 50 363.5 μmol/L). In the absence of extracellular calcium, pharmacomechanical coupling was also abolished, and contractions induced by CaCl 2 or BaCl 2 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 (BK Ca , K V and K ATP )., Conclusion: These results suggest that ( E , E )-farnesol may be a promising pharmacological candidate for obstetric hypertensive disorders., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Species belonging to the genus Lippia are used worldwide as foods, beverages, and seasonings. Studies have demonstrated that these species have antioxidant, sedative, analgesic, anti-inflammatory, and antipyretic activities. This work aimed to evaluate the antibacterial activity and anxiolytic effect by different pathways of essential oils and ethanolic extracts of three species of Lippia ( Lippia alba , Lippia sidoides , and Lippia gracilis ). The ethanolic extracts were characterized by HPLC-DAD-ESI-MS n and their phenolics were quantified. The antibacterial activity was evaluated by determining the minimal inhibitory concentration and modulation of antibiotic activity, and toxic and anxiolytic effects were evaluated in the zebrafish model. The extracts showed compositions with a low ratio and shared compounds. L. alba and L. gracilis showed higher amounts of phenols and flavonoids, respectively. All extracts and essential oils presented antibacterial activity, especially those obtained from L. sidoides . On the other hand, L. alba extract presented the most significant antibiotic-enhancing effect. The samples were not toxic after 96 h of exposure, but showed an anxiolytic effect through modulation of the GABA A receptor, while L. alba extract acted via modulation of the 5-HT receptor. This new pharmacological evidence opens horizons for therapeutic approaches targeting anxiolytic and antibacterial therapies and food conservation using these species and their constituents.

The increase in antibiotic resistance rates has attracted the interest of researchers for antibacterial compounds capable of potentiating the activity of conventional antibiotics. Coumarin derivatives have been reported to develop effective antibacterials with possible new mechanisms of action for treating infectious diseases caused by bacteria with a profile of drug resistance. In this context, the aim of the present study we have now prepared one variety of new synthetic coumarins evaluating the pharmacokinetic and chemical similarity in silico, their antimicrobial activity against Staphylococcus aureus (ATCC 25923) and Escherichia coli (ATCC 25922), and potential for the modulation of antibiotic resistance against Staphylococcus aureus (SA10) and Escherichia coli (EC06) clinical isolate bacteria by in vitro assay. The antibacterial activity and antibiotic-enhancing properties were evaluated by the broth microdilution method and pharmacokinetically characterized according to the Lipinsk rule of 5 and had their similarity analyzed in databases such as ChemBL and CAS SciFinder. The results demonstrated that only compound C13 showed significant antibacterial activity (MIC ≤256 μg/mL), and all other coumarins did not display relevant antibacterial activity (MIC ≥1024 μg/mL). However, they did modulate the antibiotics activities to norfloxacin and gentamicin, except, compound C11 to norfloxacin against Staphylococcus aureus (SA10). The in silico properties prediction and drug-likeness results demonstrated that all coumarins presented a good drug-likeness score with no violations and promising in silico pharmacokinetic profiles showing that they have the potential to be developed into an oral drug. The results indicate that the coumarin derivatives showed good in vitro antibacterial activity. These new coumarin derivatives also demonstrated the capacity to modulate antibiotic resistance with potential synergy action for current antimicrobials assayed, as antibiotic adjuvants, to reduce the emergence of antimicrobial resistance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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., (© 2022 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

The bacterial species Staphylococcus aureus presents a variety of resistance mechanisms, among which the expression of β-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 β-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 β-lactamase- and efflux pump-mediated antibiotic resistance was evaluated from the reduction of the MIC of ethidium bromide (EtBr) and β-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 β-lactam antibiotics, suggesting that they may act by inhibiting β-lactamases and efflux pumps such as QacC and QacA/B. However, further research is required to elucidate the molecular mechanisms underlying these observed effects.

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., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Post-traumatic stress disorder (PTSD) is an anxiety disorder with manifestations somatic resulting from reliving the trauma. The therapy for the treatment of PTSD has limitations, between reduced efficacy and "PTSD pharmacotherapeutic crisis". Scientific evidence has shown that the use of ketamine has benefits for the treatment of depressive disorders and other symptoms present in PTSD compared to other conventional therapies. Therefore, this study aims to analyze the available evidence on the effect of ketamine in the treatment of post-traumatic stress. The systematic review and the meta-analysis were conducted following PRISMA guidelines and RevManager software, using randomized controlled trials and eligible studies of quality criteria for data extraction and analysis. The sample design evaluated included the last ten years, whose search resulted in 594 articles. After applying the exclusion criteria, 35 articles were selected, of which 14 articles were part of the sample, however, only six articles were selected the meta-analysis. The results showed that the ketamine is a promising drug in the management of PTSD with effect more evident performed after 24 h evaluated by MADRS scale. However, the main limitations of the present review demonstrate that more high-quality studies are needed to investigate the influence of therapy, safety, and efficacy.

Lippia alba is popularly known as lemon balm, with its essential oil (EO) cited for displaying antimicrobial, sedative, and vasorelaxant effects. Yet, its action on isolated human vessels has not been described in the literature. Thus, we evaluated the vasorelaxant effect of essential oil of L. alba (EOLa) on human umbilical arteries (HUA) isolated in organ baths. HUA rings were isolated, subjected to contractions induced by potassium chloride (KCl), serotonin (5-HT), or histamine (HIST) to record the isometric tension, and then treated with EOLa (30-1000 µg/mL). The EOLa showed a more prominent inhibitory effect on the pharmacomechanical coupling contraction via HIST with an EC 50 value of 277.1 ± 8.5 µg/mL and maximum relaxant effect at 600 µg/mL. The addition of tetraethylammonium (TEA) or 4-aminopyridine (4-AP) in HUA preparations did not inhibit EOLa total relaxant effect at 1000 µg/mL. In the presence of gliblenclamide (GLI), the oil relaxed the HUA rings by 90.8% at maximum concentration. The EOLa was also investigated for its effects on voltage-operated calcium channels (VOCCs), where the HUA preincubation with this oil at 1000 μg/mL inhibited BaCl 2 (0.1-30 mM)-induced contractions. This study demonstrates for the first time that EOla has a vasorelaxant effect on HUA and its particular blockade of VOCCs.

(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 β -cyclodextrins inclusion complex (Es/β-CD). (2) Methods: the effects of Es and Es/β-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/β-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/β-CD have a promising antinociceptive potential as a possible alternative for the pharmacological treatment of pain, also showing that the encapsulation of Es in β-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.

Competing Interests: MLRN, the corresponding author of this manuscript, certify that the contributors' and conflicts of interest statements included in this paper are correct and have been approved by all co-authors.

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-1β, 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., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Hyptis martiusii Benth. also known as "cidreira brava", has some activities verified in the literature, such as antiulcerogenic, antimicrobial and antiedematogenic. This study aimed to verify the anti-inflammatory and antinociceptive effect of the leaves essential oil. For the evaluation of the anti-inflammatory activity of OEHM (100 mg/kg/p.o.), models paw edema induced by dextran and histamine, peritonitis and vascular permeability were used. Regarding the anti-nociceptive activity of the OEHM, abdominal contortion tests by acetic acid, formalin, hot plate (50.75 and 100 mg/kg/p.o.), open field and mechanical plantar hyper-nociception (100 mg/kg/p.o.) were carried out. OEHM (100 mg/kg) showed anti-inflammatory activity, being able to remarkably deducing the paw edema induced by dextran and histamine, the total number of cell leukocytes/neutrophils in peritonitis, and exudate in vascular permeability. In antinociceptive activity, the OEHM did not promote significant effect in central nervous system in the open field assay, remarkably reduced abdominal contortions (50, 75 and 100 mg/kg), the time in the formalin assay and the mechanical hyper-nociception (100 mg/kg); however, only doses between 75 and 100 mg/kg were capable of ameliorating the reponse latency time. Regarding the probable mechanism of action, the antinociceptive activity includes the participation in the activation of opioid, TRPV1, and α2-noradrenergic systems. In short, data obtained here reveal that OEHM has anti-inflammatory and antinociceptive activity, implying that its action may be involved in the mechanism of inhibition or liberation of pro-inflammatory mediators involved in pain and inflammation., Competing Interests: The authors declare that they have no known competing financialinterestsor personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

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, β, and δ-damascone and inclusion complexes with β-cyclodextrin against different Candida spp. The inclusion complex of β-damascone was prepared by the co-evaporation method using three molar proportions (1:1; 2:1; 3:1 (βDA-βCD)) 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 IC 50 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, β, and δ-DA isolated or in combination with fluconazole (FCZ) showed significant antifungal activity. β-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., (© 2022. Institute of Microbiology, Academy of Sciences of the Czech Republic, v.v.i.)

Osteoarthritis (OA) is a degenerative joint disease that occurs when there is a change in the mechanical and biological properties of the articular cartilage and the subchondral bone; The condition is more prevalent in women than in men. Pequi oil (PO), which is extracted from the fruits of the pequi tree (Caryocar coriaceum Wittm), is widely used in traditional medicine in the Brazilian northeast for the management of inflammation and joint pain. The aim of this study was to develop a pharmaceutical formulation containing Carbopol® hydrogel nanoencapsulated with pequi pulp fixed oil (PeONC) and evaluate its therapeutic effect on functionality and pain in women with knee osteoarthritis. The study was divided into two stages: Stage 1 - preparation and physico-chemical characterization of the pharmaceutical formulation containing PeONC, cell viability assays and skin irritability testing. Step 2 - A double-blind randomized clinical trial evaluating knee symptoms, quality of life, pressure pain, function, muscle strength and range of motion. The nanoformulation was in a gel form, with a particle size of 209.5 ± 1.06 nm, a pH of 6.23 ± 0.45, a zeta potential of - 23.1 ± 0.4 mV, a polydispersity index of 0.137 ± 0.52, and containing nanocapsules with a spherical shape a polymeric wall and an oily nucleus. The gel showed no cytotoxicity and was not irritating to human skin. The treatment with PeONC increased the strength of the knee flexor and extensor muscles and the total motion range of the knee. In addition, the treatment reduced knee instability, pain, swelling, and locking; There was also an improvement in some items of the SF-36 quality of life questionnaire such as in respect of functional capacity and social aspects. In conclusion, PeONC was found to be a stable, safe formulation with no toxicity in respect of topical use in humans. Additionally, the treatment produced an increase in muscle strength and functionality that was associated with reduced knee symptoms and improved quality of life. Our findings showed that in a group of women treated with PeONC mitigated the symptoms of knee osteoarthritis., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Eugenol (EUG) is a phenylpropanoid widely used in the food and cosmetic industries. It is commonly referred to in the literature by its biological activities such as antioxidant, anti-inflammatory, antimicrobial, and relaxing in organs of laboratory animals, especially in rodent vessels. However, its vasorelaxant potential in human tissue, has not been investigated. Thus, this study characterizes the vasodilatory effect of EUG in the human umbilical artery (HUA). HUAs were isolated, cleaned, sectioned (3-4 mm) and placed in an organ bath (10 mL Krebs Henseleit, 37 °C; and carbogenic mixture). EUG (100-1400 μM), obtained total relaxation of electromechanical contractions induced by KCl (60 mM), and pharmacomechanical contractions (30-1200 μM), induced by serotonin (10 μM) and by histamine (10 μM), showing statistically significant concentrations: 600 μM, 400 μM and 200 μM, and EC 50 values: 759.8 ± 6.5 μM, 229.9 ± 7.9 and 279.0 ± 3.4 μM, respectively. EUG (1200 and 1400 μM) prevented the contraction promoted by BaCl 2 (0.1-30 mM), similar to the effects of nifedipine (10 μM), sugesting the involvement of EUG in blocking VOCCs. In the presence of tetraethylammonium (10 μM), EUG (30-1200 μM) did not produce a total relaxation (88.6%), suggesting that an alternative pathway where potassium channels, may partially mediate EUG effect. In the presence of 4-aminopyridine (1 mM), glibenclamide (10 μM), and tetraethylammonium (1 mM), EUG relaxed HUAs 100%, although the pharmacological potency was statistically altered, demonstrating the participation of K + channels (Kv, KATP, BKCa). Our data indicates that EUG has a vasorelaxant effect on HUAs, had a greater pharmacological potency in the serotoninergic pathway, showing effective participation of VOCCs and a partial modulation of K + channels. These data suggest new possibilities for the use of EUG in human vascular dysfunctions, such as preeclampsia. More studies are necessary to confirm the safety and effectivity in future treatments., (Copyright © 2022 Elsevier B.V. All rights reserved.)

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., (© 2021. Institute of Microbiology, Academy of Sciences of the Czech Republic, v.v.i.)

The increase in antibiotic resistance and the emergence of new bacterial infections have intensified the research for natural products from plants with associated therapy. This study aimed to verify the antibacterial and antioxidant activity of crude extracts of the genus Plectranthus species, being the first report on the modulation of aminoglycosides antibiotic activity by Plectranthus amboinicus extracts. The chemical composition was obtained by chemical prospecting and High-Performance Liquid Chromatography with diode arrangement detector (HPLC/DAD). The antibacterial activities of the extracts alone or in association with aminoglycosides were analyzed using the microdilution test. The antioxidant activity was evaluated by 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging. The phytochemical prospection allowed the flavonoids, saponins, tannins and triterpenoids to be identified. Quercetin, rutin, gallic acid, chlorogenic acid, caffeic acid, catechin, kaempferol, glycosylated kaempferol, quercitrin, and isoquercitrin were identified and quantified. The principal component analysis (PCA) observed the influence of flavonoids and phenolic acids from Plectranthus species on studied activities. Phytochemical tests with the extracts indicated, especially, the presence of flavonoids, confirmed by quantitative analysis by HPLC. The results revealed antibacterial activities, and synergistic effects combined with aminoglycosides, as well as antioxidant potential, especially for P. ornatus species, with IC 50 of 32.21 µg/mL. Multivariate analyzes show that the inclusion of data from the antioxidant and antibacterial activity suggests that the antioxidant effect of these species presents a significant contribution to the synergistic effect of phytoconstituents, especially based on the flavonoid contents. The results of this study suggest the antibacterial activity of Plectranthus extracts, as well as their potential in modifying the resistance of the analyzed aminoglycosides.

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., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Mercury chloride (HgCl 2 ) acts as a bioaccumulator capable of causing numerous neurological and physiological changes in organisms in a negative way. However, rutin has been considered a very effective antioxidant compound in the treatment of neurodegenerative diseases, as it can neutralize radicals capable of damaging neuronal cells. In this context, this study aimed to evaluate rutin as a neoprotective agent against the damage induced by HgCl 2 in Drosophila melanogaster. The exposure of the flies to the agents was carried out in triplicate, and about 150 adult flies were evaluated. To assess the antioxidant action of rutin, MTT, phenanthroline, nitric oxide, total thiols and NPSH tests were carried out in the following concentrations: Control (1500 μL of distilled water), 1 mg/g of HgCl 2 , 0.5 mg/g of Rutin + HgCl 2 , 1 mg/g of Rutin + HgCl 2 , 2 mg/g of Rutin + HgCl 2 . The locomotion test was verified by negative geotaxis, the result of which showed that flies exposed to HgCl 2 had difficulties in flight. The group treated with HgCl 2 alone had a high mortality rate, while in combination with different concentrations of rutin, it heard a moderate reduction in the number of deaths, as well as in the negative geotaxis data in which the rutin had a positive effect. An increase in iron (II) levels was observed at the highest concentrations of rutin, while at low concentrations, rutin significantly decreased nitric oxide levels. The HgCl 2  + R group (2 mg/g) showed a significant increase in the total thiols content, while for the NPSH all rutin concentrations showed a significant increase in the levels of non-protein thiols. Our results demonstrate that mercury chloride can cause oxidative stress in D. melanogaster. However, the results suggest that rutin has antioxidant and protective effects against the damage caused by HgCl 2 ., (Copyright © 2021. Published by Elsevier Inc.)

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., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The antibacterial activity of the monoterpene estragole was evaluated against two strains of bacteria with an efflux pump mechanism, which are Staphylococcus aureus 1199B and S. aureus K2068, which have a NorA and MepA pump, respectively. For that, the methodology proposed by CLSI with modifications was followed, and to evaluate the reversal of the efflux pump, subinhibitory concentrations (MIC/8) of estragole and standard pump inhibitors, CCCP and Chlorpromazine were used and it was verified whether they managed to modulate the action of Norfloxacin, Ciprofloxacin and Ethidium Bromide, an indicator of an efflux pump. It was observed that estragole positively modulated norfloxacin and ethidium bromide against the strain of S. aureus 1199B and that it also managed to reduce the MIC of ethidium bromide against the strain of S. aureus K2068. In the non-clinical acute toxicity tests with estragole, the animals treated with the dose of 625 mg/kg/v.o. showed no clinical signs of toxicity, according to the parameters evaluated. These results are promising, since it places estragole as a possible inhibitor of the efflux pump, thus managing to inhibit this mechanism of action in the strains tested., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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., (© 2021. The Author(s).)

Hymenaea martiana is a species popularly known in Northeastern Brazil as "jatobá" and used in folk medicine to treat pain and inflammation. The aim of this work was to evaluate the antinociceptive and anti-inflammatory activity of H. martiana. In the present study, we carried out an investigation about the effects of the crude ethanolic extract (Hm-EtOH) and the ethyl acetate fraction (Hm-AcOEt) in models of nociception and inflammation in mice. Chemical (acetic acid-induced writhing and formalin) and thermal stimuli (hot plate) were used for the evaluation of antinociceptive activity, while for the anti-inflammatory profile paw edema induced by carrageenan was used, along with leukocyte migration to the peritoneal cavity. The presence of the flavonoid astilbin in the samples was characterized through HPLC-DAD-MS analysis. Hm-EtOH and Hm-AcOEt (100, 200 and 400 mg.kg-1, i.p.) significantly reduced the number of abdominal contortions and decreased the paw licking time in the formalin test. In the hot plate, the extract increased the latency time of animals. Hm-EtOH and Hm-AcOEt inhibited significantly the increase in the edema after the administration of carrageenan. Hm-EtOH and Hm-AcOEt inhibited leukocyte migration in the peritonitis test. HPLC-DAD-MS analysis of Hm-EtOH and Hm-AcOEt revealed the presence of the flavonoid astilbin in the samples. According to the results of this study, both Hm-EtOH and Hm-AcOEt have antinociceptive and anti-inflammatory activities, which could be related with the presence of flavonoid in the extracts. The results reinforce the popular use of this plant.

Human activities, especially in industry, have contributed to soil contamination with heavy or toxic metals. The objective of this study was to determine the chelating effect and antioxidant activity of pyrogallol, as well as to evaluate its cytoprotective activity in prokaryotic and eukaryotic models, animal and plant, respectively, against toxic mercury chloride action. Antioxidant activity was determined by DPPH where pyrogallol showed considerable action, chelating even iron ions. For the microbiologic activity assays, microdilution was performed to obtain the minimal inhibitory concentration, minimum bactericidal and minimum fungicide concentration, from which the sub-inhibitory concentrations were determined. The product did not conferred cytoprotection to the tested bacteria and fungi. To evaluate plant cytoprotection, Lactuta sativa seeds were used together with the product at a sub-allelopathic concentration with different HgCl 2 concentrations. In this case, the tannin conferred cytoprotection to the plant model, allowing the best growth and development of caulicles and radicles, thus preserving tissues necessary for plant survival. From the results, it is observable that pyrogallol possesses cytoprotective action in the eukaryotic plant model, this action being useful as an alternative which favors the growth of plants in contaminated areas, as the recovering of crop fields or reforestation projects.

This study aimed to evaluate the antibacterial activity and to verify, in silico and in vitro, the inhibition of efflux mechanisms using a series of synthesized 1,8-naphthyridines sulfonamides against Staphylococcus aureus strains carrying MepA efflux pumps. The chemical synthesis occurred through the thermolysis of the Meldrum's acid adduct. The sulfonamide derivatives were obtained by the sulfonylation of 2-amino-5‑chloro-1,8-naphthyridine with commercial benzenesulfonyl chloride. Antibacterial activity was assessed by the broth microdilution test. Efflux pump inhibitory capacity was evaluated in silico by molecular docking and in vitro by analyzing synergistic effects on ciprofloxacin and ethidium bromide (EtBr) and by EtBr fluorescence emission assays. The following 1,8-naphthyridines were synthesized: 4-methyl-N-(5‑chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Compound 10a); 2,5-dichloro-N-(5‑chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Compound 10b); 4-fluoro-N-(5‑chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Compound 10c); 2,3,4-trifluoro-N-(5‑chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Compound 10d); 3-trifluoromethyl-N-(5‑chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Compound 10e); 4‑bromo-2,5-difluoro-N-(5‑chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Compound 10f). The 1,8-naphthyridines derivatives associated with sulfonamides did not show antibacterial activity. However, they showed a favorable pharmacokinetic profile with possible MepA efflux pump inhibitory action, demonstrated in molecular docking. In addition to the promising results in reducing the concentration of intracellular EtBr. 1,8-naphthyridines act as putative agents in the inhibitory action of the MepA efflux pump., (Copyright © 2021. Published by Elsevier B.V.)

Mercury is widely found in nature, however, in low concentrations, but anthropological activities have increased its concentration considerably. This causes various environmental hazards and human health. Many substances are capable of reversing the toxicity of mercuric chloride in the environment. The aim of the present study was to determine the chelating effect of vanillin, as well as to evaluate its capacity for cytoprotection in prokaryotic and eukaryotic plant models. Chelating activity was determined from vanillin's ability to reduce iron III ions. To evaluate cytoprotection in a unicellular prokaryotic and eukaryotic model, Escherichia coli and Candida albicans, respectively, were used. And to evaluate the cytoprotective activity in vegetables, lettuce seeds were submitted to different concentrations of mercuric chloride and its association with the sub-allelopathic concentration of vanillin (32 µg/mL). Vanillin has been found to have antioxidant activity as it can reduce iron III ions. The use of vanillin also allows for better growth and development of Lactuca sativa seed root and stem, also allowing better preservation of its biochemical structures. These results are quite important, as environmental contamination by heavy metals has increased dramatically and finding a viable alternative to grow vegetables in contaminated areas is very valid.