Study on Morphological Changes and Interference in the Development of Aedes aegypti Caused by Some Essential Oil Constituents.

Dengue, Chikungunya and Zika are arboviruses, transmitted by the mosquito Aedes aegypti, that cause high mortality and serious health consequences in human populations. Efforts to control Ae. aegypti are important for preventing outbreaks of these diseases. Essential oil constituents are known to exhibit many activities, such as their use as larvicides. Given their potential, the present study aimed to characterize the larvicidal effect of dihydrojasmone, p-cymene, carvacrol, thymol, farnesol and nerolidol on the larvae of Ae. aegypti and their interference over the morphology of the mosquitos. The essential oil constituents were dissolved in dimethylsulfoxide at concentrations of 1-100 µg/mL and were applied in the breeding environment of third-stage larvae. The larvae from bioassays were fixed, dehydrated and embedded. Ultrathin sections were contrasted using 5% uranyl acetate and 1% lead citrate for observation through transmission electron microscopy. The oil with the highest larvicidal efficiency was found to be nerolidol, followed by farnesol, p-cymene, carvacrol, thymol and dihydrojasmone, with an LC50 of 11, 21, 23, 40, 45 and 66 µg/mL, respectively. The treated Ae. aegypti larvae caused alteration to the tegument or internal portions of larvae. The present study demonstrated which of these oils-dihydrojasmone, farnesol, thymol, p-cymene, carvacrol and nerolidol-have effective larvicidal activity.

Evaluation of the antibacterial activity of hecogenin acetate and its inhibitory potential of NorA and MepA efflux pumps from Staphylococcus aureus.

Antimicrobial drugs are of great importance in the control of bacterial infections. Its indiscriminate use contributes to the consolidation of bacterial resistance. Its applicability is due to its secondary metabolites, such as saponins, which are compounds with relevant antibacterial action. Hecogenin acetate is a saponin present in plants of the agave genus with analgesic, antioxidant, antinociceptive, cardioactive, anticancer, antifungal and antimicrobial activity. The present work aimed to identify the antibacterial activity of hecogenin acetate against strains of E. coli, P. aeruginosa and S. aureus and to investigate the NorA and MepA efflux pump inhibitory activity of S. aureus strains. The Minimum Inhibitory Concentration was evaluated by broth microdilution. The Antibiotic Activity Modifier effect and the assessment of efflux pump inhibition were evaluated by microdilution with sub-inhibitory concentrations. Hecogenin acetate showed minimal inhibitory concentration without significant relevance. In the evaluation of the potentiating activity of the antibiotic action, a greater antagonistic behavior is noticed. In the analyzes performed with the efflux pump, it was noticed that the hecogenin acetate does not interfere in the efflux pump mechanism of the analyzed bacteria.

Milonine attenuates the lipopolysaccharide-induced acute lung injury in mice by modulating the Akt/NF-κB signaling pathways.

Acute lung injury is an inflammation that triggers acute respiratory distress syndrome with perialveolar neutrophil infiltration, alveolar-capillary barrier damage, and lung edema. Activation of the toll-like receptor 4 complex (TLR4/MD2) and its downstream signaling pathways are responsible for the cytokine storm and cause alveolar damage. Due to the complexity of this pulmonary inflammation, a defined pharmacotherapy has not been established. Thus, this study evaluated the anti-inflammatory potential of milonine, an alkaloid of Cissampelos sympodialis Eichl, in an experimental model of lung inflammation. BALB/c mice were lipopolysaccharide-challenged and treated with milonine at 2.0 mg/kg. Twenty-four hours later, the bronchoalveolar fluid, peripheral blood, and lungs were collected for cellular and molecular analysis. The milonine treatment decreased the cell migration (mainly neutrophils) to the alveoli, the pulmonary edema, and the cytokine levels (IL-1ß, IL-6, TNF-α). The systemic IL-6 level was also reduced. The milonine docking analysis demonstrated hydrophobic interaction at TLR4/MD2 groove with Ile124 and Phe126 amino acids. Indeed, the alkaloid downregulated the kinase-Akt and NF-κB through TLR4/MD2. Therefore, milonine is an effective inflammatory modulator being a potential molecule for the treatment of lung inflammation.

Evaluation of Progesterone Receptor Antagonist and Maxi-K Channel Agonist as Neuroprotective in Feeney's Weight Drop Model of TBI.

Background: Neuroprotection in traumatic brain injury (TBI) is an unmet medical need. Objective: We evaluated two agents, aglepristone (progesterone receptor antagonist) and N-salicyloyltryptamine (STP) (activator of Maxi-K channel in GH3 cells), for neuroprotection in Feeney's weight drop model of TBI. Material and Methods: Forty-eight male Wistar rats were divided into six groups (n = 8 per group). A battery of six neurobehavioral tests was evaluated at the end of the first week (EO1W), second week (EO2W), and third week (EO3W). In addition, histopathological and immunohistochemistry (BAX, Bcl-2, and M30 Cytodeath) tests were performed at EO3W. Results: Aglepristone at 10 mg/kg showed significant neuroprotection compared to control as assessed by Rota-rod test at EO1W, VEFP right paw and 28-point neurobehavioral test at EO2W, MWM test at EO3W, and positive histopathological and IHC findings. Aglepristone at 20 mg/kg showed negative results as assessed by BAX expression, downregulation of Bcl-2, and positive M30 Cytodeath, thereby suggesting toxicity at higher doses. STP 100 mg/kg showed modest neuroprotective activity but failed to show a dose-response relationship at a dose of 50 mg/kg. Conclusion: The study shows that progesterone receptor antagonists have neuroprotection at lower doses and toxicity at higher doses.

Avaliação da citotoxicidade em hemácias de humanos do extrato etanólico de Praxelis clematidea (Griseb.)

Introdução: Espécies da família Asteraceae são conhecidas por apresentarem propriedades aromática, cosmética e terapêutica; tendo diversas pesquisas que evidenciou potencial medicinal dessa família. Dentre as espécies de Asteraceae, está Praxelis clematidea, que é rica em substâncias químicas como flavonoides, terpenóides e esteroides, as quais podem desempenhar uma série de atividades biológicas. Objetivo: Verificar o potencial tóxico do extrato etanólico das folhas de P. clematidea frente à células sanguíneas humanas, afim de determinar a toxicidade teórica dessa espécie. Métodos: Para a realização do teste de atividade citotóxica foram preparadas suspensões sanguíneas dos tipos A, B e O, que posteriormente foram misturadas a concentrações distintas do extrato etanólico por 1 (uma) hora. A hemólise foi quantificada por espectrofotometria em comprimento de onda de 540 nm. Resultados: O extrato etanólico das folhas de P. clematidea em diferentes concentrações apresentou baixa citoxicidade contra os eritrócitos humanos in vitro, enfatizando o produto como uma possível opção viável para a indústria de medicamentos fitoterápicos. No entanto, é importante elucidar que mais estudos in vivo precisam ser realizados para confirmar esse perfil toxicológico do extrato.

SUMMARY Introduction: Species of the Asteraceae family are known to have aromatic, cosmetic and therapeutic properties; having several researches that evidenced medicinal potential of this family. Among the species of Asteraceae, there is Praxelis clematidea, which is rich in chemical substances such as flavonoids, terpenoids and steroids, which can perform a series of biological activities. Aim: To verify the toxic potential of the ethanolic extract of P. clematidea leaves against human blood cells, in order to determine the theoretical toxicity of this species. Method: For the performance of the cytotoxic activity test, blood suspensions of types A, B and O were prepared, which were subsequently mixed at different concentrations of the ethanolic extract for 1 (one) hour. Hemolysis was quantified by spectrophotometry at a wavelength of 540 nm. Results: The ethanolic extract of P. clematidea leaves in different concentrations showed low cytotoxicity against human erythrocytes in vitro, emphasizing the product as a possible viable option for the herbal medicine industry. However, it is important to clarify that more in vivo studies need to be carried out to confirm this toxicological profile of the extract.

Introducción: Se sabe que las especies de la familia Asteraceae tienen propiedades aromáticas, cosméticas y terapéuticas; habiendo varias investigaciones que evidenciaron el potencial medicinal de esta familia. Entre las especies de Asteraceae, se encuentra Praxelis clematidea, que es rica en sustancias químicas como flavonoides, terpenoides y esteroides, que pueden realizar una serie de actividades biológicas. Objetivo: Verificar el potencial tóxico del extracto etanólico de hojas de P. clematidea contra las células sanguíneas humanas, con el fin de determinar la toxicidad teórica de esta especie. Metodos: Para realizar la prueba de actividad citotóxica se prepararon suspensiones de sangre de los tipos A, B y O, que luego se mezclaron a diferentes concentraciones del extracto etanólico durante 1 (una) hora. La hemólisis se cuantificó mediante espectrofotometría a una longitud de onda de 540 nm. Resultados: El extracto etanólico de hojas de P. clematidea a diferentes concentraciones mostró baja citotoxicidad contra eritrocitos humanos in vitro, destacando el producto como una posible opción viable para la industria de la fitoterapia. Sin embargo, es importante aclarar que es necesario realizar más estudios in vivo para confirmar este perfil toxicológico del extracto.

Is IFN expression by NK cells a hallmark of severe COVID-19?

Natural Killer cells (NK) are crucial in host defense against viruses. There are many unanswered questions about the immune system in COVID-19, especially the mechanisms that contribute to the development of mild or severe forms of the disease. Although NK cells may have an essential role in the pathogenesis of COVID-19, the mechanisms involved in this process are not yet fully elucidated. Here, we demonstrate that CD3-CD56+ NK cells frequency in the volunteers who recovered from mild COVID-19 (Mild CoV) presented a significant increase compared to the healthy control (HC) and individuals recovering from severe COVID-19 (Severe CoV) groups. Furthermore, distinct IFN profiles in recovered COVID-19 patients with mild or severe clinical forms of the disease were observed in the total NK cells (CD3-CD56+). In the first group, NK cells express increased levels of IFN-α compared to the severe CoV, while higher production of IFN-γ in severe CoV was found. Moreover, NK cells in mild CoV express more cytolytic granules depicted by granzyme B and perforin. Compared to HC, PBMCs from mild CoV presented higher Ki-67 and TIM-3 production after Pool CoV-2 and Pool Spike CoV-2 peptides stimulus. In addition, non-stimulated PBMCs in the mild CoV group had higher NK TIM-3+ frequency than severe CoV. In the mild CoV group, Pool Spike CoV-2 and Pool CoV-2 peptides stimuli elicited higher granzyme B and perforin coexpression and IFN-α production by PBMCs. However, in severe CoV, Pool Spike CoV-2 reduced the coexpression of granzyme B, perforin, and CD107a suggesting a decrease in the cytotoxic activity of NK cells. Therefore, our study shows that NK cells may have a crucial role in COVID-19 with the involvement of IFN-α and cytotoxic properties that aid in developing qualified immune responses. Furthermore, the data suggest that higher amounts of IFN-γ may be linked to the severity of this disease.

Coumarin Derivatives Exert Anti-Lung Cancer Activity by Inhibition of Epithelial-Mesenchymal Transition and Migration in A549 Cells.

A series of coumarin derivatives and isosteres were synthesized from the reaction of triflic intermediates with phenylboronic acids, terminal alkynes, and organozinc compounds through palladium-catalyzed cross-coupling reactions. The in vitro cytotoxic effect of the compounds was evaluated against two non-small cell lung carcinoma (NSCLC) cell lines (A-549 and H2170) and a normal cell line (NIH-3T3) using cisplatin as a reference drug. Additionally, the effects of the most promising coumarin derivative (9f) in reversing the epithelial-to-mesenchymal transition (EMT) in IL-1ß-stimulated A549 cells and in inhibiting the EMT-associated migratory ability in A549 cells were also evaluated. 9f had the greatest cytotoxic effect (CC50 = 7.1 ± 0.8 and 3.3 ± 0.5 µM, respectively against A549 and H2170 cells) and CC50 value of 25.8 µM for NIH-3T3 cells. 9f inhibited the IL-1ß-induced EMT in epithelial cells by inhibiting the F-actin reorganization, attenuating changes in the actin cytoskeleton reorganization, and downregulating vimentin in A549 cells stimulated by IL-1ß. Treatment of A549 cells with 9f at 7 µM for 24 h significantly reduced the migration of IL-1ß-stimulated cells, which is a phenomenon confirmed by qualitative assessment of the wound closure. Taken together, our findings suggest that coumarin derivatives, especially compound 9f, may become a promising candidate for lung cancer therapy, especially in lung cancer promoted by NSCLC cell lines.

Coumarin (2H-1-Benzopyran-2-one) act against planktonic and biofilm forms of Staphylococcus aureus, Klebsiellapneumoniae and Pseudomonas aeruginosa

SUMMARY Introduction: biofilm-related infections caused by Staphylococcus aureus, Klebsiella pneumoniae and Pseudomonas aeruginosa are difficult to treat and few effective pharmacological options are currently available for this purpose. In this context, coumarin (2H-1-Benzopyran-2-one) has been reported to have antibacterial and antibiofilm activity, but this potential remains poorly understood. Aim: to investigate the action of coumarin on planktonic and biofilm forms of S. aureus, K. pneumoniae and P. aeruginosa. Results: a minimum inhibitory concentration (MIC) of coumarin ranging from 256 to 1024 fig/mL was observed, with a remarkable ability to inhibit the formation of biofilms and to act on mature biofilms in concentrations close to MIC. Conclusion: coumarin has strong activity against planktonic and biofilm forms on the three species of great relevance in the clinical scenario. These results are interesting to enable a pharmacological alternative for the treatment of these infections.

Introducción: las infecciones relacionadas con la biopelícula causadas por Staphylococcus aureus, Klebsiella pneumoniae y Pseudomonas aeruginosa son difíciles de tratar y actualmente existen pocas opciones farmacológicas eficaces para este propósito. En este contexto, se ha informado que la cumarina (2H-1-Benzopiran-2-ona) tiene actividad antibacteriana y antibiofilm, pero este potencial sigue siendo poco conocido. Objetivo: investigar la acción de la cumarina sobre formas planctónicas y de biopelículas de S. aureus, K. pneumoniae y P. aeruginosa. Resultados: se observó una concentración inhibitoria mínima (CMI) de cumarina en el rango de 256 a 1024 µg/mL, con una notable capacidad para inhibir la formación de biofilms y actuar sobre biofilms maduros en concentraciones cercanas a la CMI. Conclusión: la cumarina tiene una fuerte actividad contra las formas planctónicas y biofilm sobre las tres especies de gran relevancia en el escenario clínico. Estos resultados son interesantes para habilitar una alternativa farmacológica para el tratamiento de estas infecciones.

Introdução: as infecções relacionadas ao biofilme causadas por Staphylococcus aureus, Klebsiella pneumoniae e Pseudomonas aeruginosa são difíceis de tratar e poucas opções farmacológicas eficazes estão disponíveis atualmente para esse propósito. Nesse contexto, foi relatado que a cumarina (2H-1-benzopirano-2-ona) tem atividade antibacteriana e antibiofilme, mas esse potencial permanece pouco conhecido. Objetivo: investigar a ação da cumarina sobre as formas planctónicas e de biofilme de S. aureus, K. pneumoniae e P. aeruginosa. Resultados: observou-se uma concentração inibitória mínima (CIM) de cumarina variando de 256 a 1024 µg/mL, com notável capacidade de inibir a formação de biofilmes e de atuar sobre biofilmes maduros em concentrações próximas à CIM. Conclusão: a cumarina possui forte atividade contra as formas planctónicas e de biofilme sobre as três espécies de grande relevância no cenário clínico. Esses resultados são interessantes para possibilitar uma alternativa farmacológica para o tratamento dessas infecções.

Plant-Derived Pesticides as an Alternative to Pest Management and Sustainable Agricultural Production: Prospects, Applications and Challenges.

Pests and diseases are responsible for most of the losses related to agricultural crops, either in the field or in storage. Moreover, due to indiscriminate use of synthetic pesticides over the years, several issues have come along, such as pest resistance and contamination of important planet sources, such as water, air and soil. Therefore, in order to improve efficiency of crop production and reduce food crisis in a sustainable manner, while preserving consumer's health, plant-derived pesticides may be a green alternative to synthetic ones. They are cheap, biodegradable, ecofriendly and act by several mechanisms of action in a more specific way, suggesting that they are less of a hazard to humans and the environment. Natural plant products with bioactivity toward insects include several classes of molecules, for example: terpenes, flavonoids, alkaloids, polyphenols, cyanogenic glucosides, quinones, amides, aldehydes, thiophenes, amino acids, saccharides and polyketides (which is not an exhaustive list of insecticidal substances). In general, those compounds have important ecological activities in nature, such as: antifeedant, attractant, nematicide, fungicide, repellent, insecticide, insect growth regulator and allelopathic agents, acting as a promising source for novel pest control agents or biopesticides. However, several factors appear to limit their commercialization. In this critical review, a compilation of plant-derived metabolites, along with their corresponding toxicology and mechanisms of action, will be approached, as well as the different strategies developed in order to meet the required commercial standards through more efficient methods.

Effect of p-cymene and rosmarinic acid on gastric ulcer healing - Involvement of multiple endogenous curative mechanisms.

BACKGROUND: p-Cymene and rosmarinic acid are secondary metabolites found in several medicinal plants and spices. Previous studies have demonstrated their anti-inflammatory, antioxidant, and cytoprotective effects. PURPOSE: To evaluate their gastroduodenal antiulcer activity, gastric healing and toxicity in experimental models. METHODS: Preventive antiulcer effects were assessed using oral pre-treatment on HCl/ethanol-induced gastric lesions and cysteamine-induced duodenal lesions models. Gastric healing, the underlining mechanisms and toxicity after repeated doses were carried out using the acetic acid-induced gastric ulcer rat model and oral treatment for 14 days. RESULTS: In the HCl/ethanol-induced gastric ulcer and cysteamine-induced duodenal injury, p-cymene and rosmarinic acid (50-200 mg/kg) decreased significantly the ulcer area, and so prevented lesions formation. In the acetic acid-induced ulcer model, both compounds (200 mg/kg) markedly reduced the ulcerative injury. These effects were related to an increase in the levels of reduced glutathione (GSH) and interleukin (IL)-10, and due to a decrease in malondialdehyde (MDA), IL-1ß, tumor necrosis factor (TNF)-α, total and mitochondrial reactive oxygen species (ROS) levels. Downregulation of factor nuclear kappa B (NFκB) and enhanced expression of suppressor of cytokine signaling (SOCS)3 were also demonstrated. Furthermore, positive vascular endothelial growth factor (VEGF), metalloproteinase (MMP)-2, and cyclooxygenase (COX-2)-stained cells were increased in treated groups. Treatment also upregulated the platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), transforming growth factor (TGF)-ß and epidermal growth factor receptor (EGFR) in gastric tissues. In isolated gastric epithelial cells this healing effect seems to be linked to a modulation of apoptosis, proliferation, survival and protein phosphorylation, such as the extracellular signal-regulated kinases (ERK)1/2 and p38 mitogen-activated protein kinase (MAPK). Oral toxicity investigation for 14 days revealed no alterations in heart, liver, spleen, and kidneys weight nor the biochemical and hematological assessed parameters. p-Cymene and rosmarinic acid also protected animals from body weight loss maintaining feed and water intake. CONCLUSIONS: Data altogether suggest low toxicity, antiulcer and gastric healing activities of p-cymene and rosmarinic acid. Antioxidant and immunomodulatory properties seem to be involved in the curative effect as well as the induction of different factors linked to tissue repair.

In vitro antileishmanial and immunomodulatory activities of the synthetic analogue riparin E.

Leishmaniases are infectious diseases caused by protozoa of the genus Leishmania, that may have different clinical manifestations. First line drugs used in the treatment of leishmaniosis are high costly, and are very aggressive requiring medical monitoring. Thus new therapeutic alternatives are needed and, in this context, natural products have been considered as a source of new antileishmania agents. Riparins are alkamides found in the unripe fruits of Aniba riparia. Several biological activities are described for this group of compounds, such as antimicrobial and antiparasitic potential. The objective of this work was to evaluate the anti-leishmania activity riparin E (Rip-E) in vitro, against promastigotes and internalized amastigotes of Leishmania amazonensis. Rip-E was able to inhibit promastigote cell growth (IC50 4.7 µg/ml) and to reduce the percentage of macrophages infected with amastigotes, reducing its infectivity (survival index) (IC50 1.3 µg/ml). The cytotoxicity against BALB/c murine macrophages was also assessed (CC50 50.6 µg/ml) and the selectivity index was 38.9. Rip-E also demonstrated immunomodulatory activity, evidenced by the increase of the phagocytic capacity and lysosomal activity. However, Rip-E did not affect directly the production of nitric oxide. These results suggest that Rip-E has antileishmania potential, by both its direct inhibitory effect and its ability to activate macrophages.

p-Cymene and Rosmarinic Acid Ameliorate TNBS-Induced Intestinal Inflammation Upkeeping ZO-1 and MUC-2: Role of Antioxidant System and Immunomodulation.

p-Cymene (p-C) and rosmarinic acid (RA) are secondary metabolites that are present in medicinal herbs and Mediterranean spices that have promising anti-inflammatory properties. This study aimed to evaluate their intestinal anti-inflammatory activity in the trinitrobenzene sulphonic acid (TNBS)-induced colitis model in rats. p-C and RA (25-200 mg/kg) oral administration reduced the macroscopic lesion score, ulcerative area, intestinal weight/length ratio, and diarrheal index in TNBS-treated animals. Both compounds (200 mg/kg) decreased malondialdehyde (MDA) and myeloperoxidase (MPO), restored glutathione (GSH) levels, and enhanced fluorescence intensity of superoxide dismutase (SOD). They also decreased interleukin (IL)-1ß and tumor necrosis factor (TNF)-α, and maintained IL-10 basal levels. Furthermore, they modulated T cell populations (cluster of differentiation (CD)4+, CD8+, or CD3+CD4+CD25+) analyzed from the spleen, mesenteric lymph nodes, and colon samples, and also decreased cyclooxigenase 2 (COX-2), interferon (IFN)-γ, inducible nitric oxide synthase (iNOS), and nuclear transcription factor kappa B subunit p65 (NFκB-p65) mRNA transcription, but only p-C interfered in the suppressor of cytokine signaling 3 (SOCS3) expression in inflamed colons. An increase in gene expression and positive cells immunostained for mucin type 2 (MUC-2) and zonula occludens 1 (ZO-1) was observed. Altogether, these results indicate intestinal anti-inflammatory activity of p-C and RA involving the cytoprotection of the intestinal barrier, maintaining the mucus layer, and preserving communicating junctions, as well as through modulation of the antioxidant and immunomodulatory systems.

Rosmarinic acid prevents gastric ulcers via sulfhydryl groups reinforcement, antioxidant and immunomodulatory effects.

Rosmarinic acid (RA) is a secondary metabolite present in several plant species that has already demonstrated antioxidant, antiallergic, anticancer, antimicrobial, neuroprotective, and hepatoprotective effects experimentally. Due to the promising pharmacological properties found previously, this study aimed to assess the oral acute toxicity and the gastroprotective effect of RA using animal models. Acute toxicity was assessed according to OECD guide 423. Ethanol, stress, NSAIDs, and pylorus ligature-induced gastric ulcer models were used to investigate antiulcer properties. The related mechanisms of action were also evaluated from ethanol-induced gastric lesions protocol. RA (300 and 2000 mg/kg) showed no changes in behavioral, water and food intake, body and organs weight parameters with LD50 set around 2500 mg/kg. RA presented gastroprotective activity in all assessed doses (25, 50, 100, and 200 mg/kg) using different animal models. Besides, it was observed that this effect is not related to the modulation of gastric juice parameters (pH, volume, and [H+]), the participation of nitric oxide, mucus, and prostaglandins. However, increased sulfhydryl groups, GSH and IL-10 levels as well as reduced of proinflammatory cytokine (TNF-α and IL-1ß) levels were found for RA-treated groups. RA presents low acute toxicity and gastroprotective activity, preventing ulcer formation via cytoprotective, antioxidant, and anti-inflammatory mechanisms. Graphical abstract.

Pharmacological applications of farnesol (C15H26O): a patent review.

Introduction: Farnesol (C15H26O) is a sesquiterpene alcohol found in essential oils. This substance is reported to have different pharmacological activities such as antimicrobial, antitumor and antioxidant effects, as well as actions in different body systems.Areas covered: This study aimed to analyze pharmaceutical patents containing this substance in their formulations. Patent search was carried out through the WIPO (World Intellectual Property Organization), LatiPat and INPI (National Institute of Industrial Property) electronic banks using the following descriptors and combinations: 'farnesol', 'pharmaceutical product', 'pharmacology' and 'pharmacy'.Expert opinion: Primary research identified 54 patents, from which 17 were selected for the final analysis after applying the inclusion criteria. The selected patents referred to products presenting different pharmaceutical activities of interest such as the prevention and treatment of diseases affecting the dermis, central nervous and cardiovascular systems, diseases caused by different microorganisms and cancers, among others. A minority of the articles included in this review reported the type of farnesol isomer that was investigated, this becoming a major limitation for the development of future pharmaceutical products. With the completion of this study, farnesol presents itself as a potential agent with pharmacological application both in the prevention and treatment of different diseases.

Involvement of monoaminergic targets in the antidepressant- and anxiolytic-like effects of the synthetic alkamide riparin IV: Elucidation of further mechanisms through pharmacological, neurochemistry and computational approaches.

Despite recent advances, current antidepressants have considerable limitations: late onset of action and the high profile of refractoriness. Biomedical research with natural products has gained growing interest in the last years, and had provide useful candidates for new antidepressants. Riparins are a group of natural alkamides obtained from Aniba riparia, which had marked neuroactive effects, mainly as antidepressant and antinociceptive agents. We made modifications of the basic structure of riparins, originating a synthetic alkamide, also known as riparin IV (RipIV). RipIV demonstrated a superior analgesic effect than its congeners and a marked antidepressant-like effect. However, the basic mechanism for the central effects of RipIV remains unknown. Here, we aimed to investigate the participation of monoaminergic neurotransmission targets in the antidepressant-like effects of RipIV. To do this, we applied a combined approach of experimental (classical pharmacology and neurochemistry) and computer-aided techniques. Our results demonstrated that RipIV presented antidepressant- and anxiolytic-like effects without modifying locomotion and motor coordination of mice. Also, RipIV increased brain monoamines and their metabolite levels. At the higher dose (100 mg/kg), RipIV increased serotonin concentrations in all studied brain areas, while at the lower one (50 mg/kg), it increased mainly dopamine and noradrenaline levels. When tested with selective receptor antagonists, RipIV antidepressant effect showed dependence of the activation of multiple targets, including D1 and D2 dopamine receptors, 5-HT2A/2, 5-HT3 receptors and α2 adrenergic receptors. Molecular docking demonstrated favorable binding conformation and affinity of RipIV to monoamine oxidase B (MAO-B), serotonin transporter (SERT), α1 receptor, D2 receptor, dopamine transporter (DAT) and at some extent GABA-A receptor. RipIV also presented a computationally predicted favorable pharmacokinetic profile. Therefore, this study demonstrated the involvement of monoaminergic targets in the mechanism of RipIV antidepressant-like action, and provide evidence of it as a promising new antidepressant.

GC-MS-FID characterization and antibacterial activity of the Mikania cordifolia essential oil and limonene against MDR strains.

The present study evaluated the effect of the essential oil of Mikania cordifolia (EOMc) and its major constituent limonene alone or associated with antibacterial drugs against Multidrug Resistant Bacteria (MDR). To evaluate the antibacterial activity, the minimum inhibitory concentrations (MIC) of the oil and limonene against Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus were determined. The antibiotic-modulating activity was assessed using subinhibitory concentrations (MIC/8) of these substances in combination with conventional antibacterial drugs. Although no relevant antibacterial activity of the natural products was detected, both substances modulated the action of antibiotics against resistant bacteria. The EOMc demonstrated the best modulating effect against P. aeruginosa, presenting synergistic effects when associated with gentamicin and norfloxacin. In addition, the oil reduced the MIC of norfloxacin against E. coli as well as reduced the MIC of gentamicin against S. aureus. On the other hand, the best effect of limonene was obtained against S. aureus. Thus, it is concluded that the essential oil Mikania cordifolia and the isolated compound limonene do not have clinically significant antibacterial effect, but modulate the action of antibiotics against MDR bacteria.

Ethanol extract of Cissampelos sympodialis ameliorates lung tissue damage in streptozotocin-induced diabetic rats

Diabetes Mellitus (DM) is a metabolic syndrome characterized by hyperglycemia. Chronic complications affect a number of organs, including the lungs. Cissampelos sympodialis Eichl (Menispermaceae) is a plant used to treat respiratory diseases. The aim of this study was to evaluate the effect of Cissampelos sympodialis extract (CSE) in lungs of diabetic rats. We used 30 Wistar rats divided into three groups: control group (CG), diabetic group (DG) and diabetic Cissampelos sympodialis treatment group (DTG). Diabetes was induced by streptozotocin (40 mg/kg i.v.). The CSE (400 mg/kg, po) was administered daily, during four weeks, beginning one week after the onset of DM. The treatment with CSE was not able to reduce blood glucose levels after streptozotocin injection. However, it was able to decrease cholesterol and triglycerides and prevent damage on pancreatic islets morphology. Additionally, morphological alterations such as alveolar septa loss, inflammatory infiltrate and fibrosis were seen in lung tissue of rats with DM, and treatment with CSE apparently reversed these histopathological findings. Thus, CSE treatment reduced the lipid profile and restored the lung architecture of diabetic animals by a mechanism independent of glycemia and which might be associated with the reduction of the damage on the pancreatic islets.

Betulinic Acid Derivative BA5, Attenuates Inflammation and Fibrosis in Experimental Chronic Chagas Disease Cardiomyopathy by Inducing IL-10 and M2 Polarization.

Chronic Chagas disease cardiomyopathy (CCC) is a major cause of heart disease in Latin America and treatment for this condition is unsatisfactory. Here we investigated the effects of BA5, an amide semi-synthetic derivative betulinic acid, in a model of CCC. Mice chronically infected with T. cruzi were treated orally with BA5 (10 or 1 mg/Kg), three times per week, for 2 months. BA5 treatment decreased inflammation and fibrosis in heart sections but did not improve exercise capacity or ameliorate cardiac electric disturbances in infected mice. Serum concentrations of TNF-α, IFN-γ, and IL-1ß, as well as cardiac gene expression of pro-inflammatory mediators, were reduced after BA5 treatment. In contrast, a significant increase in the anti-inflammatory cytokine IL-10 concentration was observed in BA5-treated mice in both tested doses compared to vehicle-treated mice. Moreover, polarization to anti-inflammatory/M2 macrophage phenotype was evidenced by a decrease in the expression of NOS2 and proinflammatory cytokines and the increase in M2 markers, such as Arg1 and CHI3 in mice treated with BA5. In conclusion, BA5 had a potent anti-inflammatory activity on a model of parasite-driven heart disease related to IL-10 production and a switch from M1 to M2 subset of macrophages.

Toxicological and pharmacologic effects of farnesol (C15H26O): A descriptive systematic review.

The objective of the present study was to perform a systematic review (SR) composed of preclinical and clinical studies which investigated the toxicological and pharmacologic effects of farnesol [Molecular formula: C15H26O; IUPAC: (3,7,11-Trimethyl-2,6,10-dodecatrien-1-ol]. This SR was performed according to PRISMA guidelines. Literature research was performed using PubMed, MEDLINE, Scopus and Web of Science databases using the descriptor combinations: "farnesol and pharmacological effect" and "farnesol and toxicology". The inclusion criteria used were original articles from preclinical and clinical studies investigating the pharmacological and toxicological effects of farnesol, published between January 1960 and December 2017 which were written in English, Portuguese and Spanish. Primary research identified 414 articles, from which 76 articles were selected for final analysis following the inclusion criteria. After grouping, 51.32 and 22.37% of the articles investigated the antimicrobial and antitumor effect, respectively. Methodological biases have been observed both in pre-clinical studies with non-human animals and in clinical trials, mainly in group allocation and blinding. This SR is the first study developed to compile the studies concerning the pharmacological and toxicological effects of farnesol. This study concludes that farnesol possesses different pharmacological and toxicological features, which permit its use as an active or a coadjuvant drug.

Th1-Biased Immunomodulation and In Vivo Antitumor Effect of a Novel Piperine Analogue.

Natural products have an important role as prototypes in the synthesis of new anticancer drugs. Piperine is an alkaloid amide with antitumor activity and significant toxicity. Then, the N-(p-nitrophenyl)acetamide piperinoate (HE-02) was synthesized, and tested for toxicological and antitumor effects. The toxicity was evaluated in vitro (on RAW 264.7 cells and mice erythrocytes) and in vivo (acute toxicity in mice). The Ehrlich ascites carcinoma model was used to evaluate the antitumor activity of HE-02 (6.25, 12.5 or 25 mg/kg, intraperitoneally, i.p.), as well as toxicity. HE-02 induced only 5.01% of hemolysis, and reduced the viability of RAW 264.7 cells by 49.75% at 1000 µg/mL. LD50 (lethal dose 50%) was estimated at around 2000 mg/kg (i.p.). HE-02 reduced Ehrlich tumor cell viability and peritumoral microvessels density. There was an increase of Th1 helper T lymphocytes cytokine profile levels (IL-1ß, TNF-α, IL-12) and a decrease of Th2 cytokine profile (IL-4, IL-10). Moreover, an increase was observed on reactive oxygen species and nitric oxide production. Weak in vivo toxicological effects were recorded. Our data provide evidence that the piperine analogue HE-02 present low toxicity, and its antitumor effect involves modulation of immune system to a cytotoxic Th1 profile.