Antinociceptive Effects of Aza-Bicyclic Isoxazoline-Acylhydrazone Derivatives in Different Models of Nociception in Mice.

BACKGROUND: In a study recently published by our research group, the isoxazoline-acylhydrazone derivatives R-99 and R-123 presented promising antinociceptive activity. However, the mechanism of action of this compound is still unknown. OBJECTIVE: This study aimed to assess the mechanisms involved in the antinociceptive activity of these compounds in chemical models of pain. METHODS: Animals were orally pretreated and evaluated in the acetic acid-, formalin-, capsaicin-, carrageenan- and Complete Freund's Adjuvant (CFA)-induced pain models in mice. The effects of the compounds after pretreatment with naloxone, prazosin, yohimbine, atropine, L-arginine, or glibenclamide were studied, using the acetic acid-induced writhing test to verify the possible involvement of opioid, α1-adrenergic, α2-adrenergic or cholinergic receptors, and nitric oxide or potassium channels pathways, respectively. RESULTS: R-99 and R-123 compounds showed significant antinociceptive activity on pain models induced by acetic acid, formalin, and capsaicin. Both compounds decreased the mechanical hyperalgesia induced by carrageenan or CFA in mice. The antinociceptive effects of R-99 and R-123 on the acetic acid-induced writhing test were significantly attenuated by pretreatment with naloxone, yohimbine or atropine. R-99 also showed an attenuated response after pretreatment with atropine and glibenclamide. However, on the pretreatment with prazosin, there was no change in the animals' response to both compounds. CONCLUSION: R-99 and R-123 showed antinociceptive effects related to mechanisms that involve, at least in part, interaction with the opioid and adrenergic systems and TRPV1 pathways. The compound R-99 also interacts with the cholinergic pathways and potassium channels.

The Fatty Acid Composition of Vegetable Oils and Their Potential Use in Wound Care.

OBJECTIVE: To evaluate the similarities among fatty acid compositions of vegetable oils sold in the Brazilian market and those present in a reference health product used to treat wounds. METHODS: The relative amounts of fatty acids in 21 types of vegetable oils, purchased in the Brazilian market, were assessed using gas chromatography-mass spectrometry and flame ionization detection. MAIN RESULTS: The studied oils had similar fatty acid compositions to the reference product (caprylic acid, 18.8%; capric acid, 17.4%; oleic acid, 27.5%; and linoleic acid, 28.1%). The presence of caprylic acid (10.45% ± 0.07%), capric acid (5.8% ± 0.75%), lauric acid (45.63% ± 0.93%), and myristic acid (16.33% ± 2.23%) were detected in all the vegetable oils tested. Oleic acid (52.94% ± 12.54%) was present in andiroba, avocado, canola, copaiba, olive, palm, pequi, and pracaxi oils and featured prominently in olive oil (75.8%). Linoleic acid (57.09% ± 8.47%) was present in corn, cottonseed, grapeseed, passion fruit, and sunflower oils and in mixed oils (olive with soybean and sunflower with corn and canola). CONCLUSIONS: Most of the vegetable oils tested are products of plants from tropical climates, where they are abundant and easy to cultivate. It is possible that a balanced composition of fatty acids obtained from natural sources could be an effective alternative treatment for wounds.

Gastroprotective effect of ethyl acetate extract from Avicennia schaueriana Stapf & Leechman and underlying mechanisms.

OBJECTIVE: Avicennia schaueriana Stapf is an endemic mangrove species widely used by traditional Brazilian communities as a folk remedy for the treatment of rheumatism, ulcers, and skin wounds. The aim of the present study was to evaluate the gastroprotective potential of the ethyl acetate extract from the leaves of A. schaueriana (As-AcOEt). METHODS: Ultra-performance liquid chromatography coupled with diode-array detection and quadrupole time-of-flight mass spectrometry (UPLC-DAD-QTOF-MS/MS) was performed to identify chemical constituents of the ethyl acetate extract from the leaves ofA. schaueriana. Total phenols, flavonoids and tannins were determined and antioxidant activity was evaluated using the DPPH and ABTS methods. The acute toxicity of As-AcOEt and gastroprotective activity on HCl/ethanol-induced gastric ulcers were assessed and mechanisms of action involving the role of nitric oxide, sulfhydryl compounds, and prostaglandins were investigated. RESULTS: Terpenes, flavonoids and tannins were detected in the extract. As-AcOEt exhibited antioxidant activity, with an EC50 of 42.2 ± 4.4 µg/mL (DPPH) and 73.2% inhibition of ABTS radicals. UPLC-DAD-QTOF-MS/MS analysis identified gallic acid, gallic acid derivative, ellagic acid, myricetin pentoside, myricetin deoxyhexose, quercetin pentoside, quercetin deoxyhexose, and other compounds. Gallic acid was isolated in this species for the first time. During the acute toxicity test, no deaths or changes occurred in the variables evaluated. In the ethanol-induced ulcer model, As-AcOEt reduced the ulcerative lesion index, with 50, 100 and 200 mg/kg achieving 83.8, 88.5 and 86.9% inhibition, respectively. MPO levels decreased and the gastric mucosa of the animals treated with the extract was preserved. Pre-treatment with N-omega-nitro-l-arginine methyl ester (L-NAME; NO blocker) or carbenoxolone (CBXN; NP-SH blocker) reversed the gastroprotective effect of As-AcOEt, but this effect was not reversed with the previous administration of indomethacin. CONCLUSION: The present findings reveal that the extract from the leaves ofA. schaueriana has gastroprotective effects, suggesting the involvement of nitric oxide and nonprotein sulfhydryl compounds, but not prostaglandin. Therefore, the use of A. schaueriana in Brazilian folk medicine for the treatment of gastric disorders has a scientific basis.

Evaluation of anti-inflammatory activity and molecular docking study of new aza-bicyclic isoxazoline acylhydrazone derivatives.

The aim of this study was to investigate the anti-inflammatory effects of two new isoxazoline-acylhydrazone derivatives: N'-(4-methoxybenzylidene)-6-(4-nitro-benzoyl)-3a,5,6,6a-tetrahydro-4H-pyrrolo[3,2-d]isoxazole-3-carbohydrazide (R-123) and N'-(4-chlorobenzylidene)-6-(4-chlorobenzoyl)-3a,5,6,6a-tetrahydro-4H-pyrrolo[3,2-d]isoxazole-3-carbohydrazide (R-99). An air pouch induced by carrageenan was used for screening the best dose of R-99 and R-123. Using this mouse model, leukocyte migration and cytokine levels (TNF-α and IL-1ß) were determined. Paw edema induced by several phlogistic agents and vascular permeability induced by acetic acid were employed to investigate the mechanism of action of the isoxazoline-acylhydrazone derivatives. A docking study was performed with the human histamine H1 receptor to investigate potential antihistaminic activity. Treatment with the compounds reduced leukocyte migration in the air pouch at all doses tested. TNF-α and IL-1ß levels were similarly reduced by the two compounds. Vasoactive amines were inhibited in models of paw edema induced by several agents and vascular permeability induced by acetic acid. The docking study suggests that R-99 and R-123 may be inhibitors of the histamine H1 receptor. In conclusion, the results indicate that R-99 and R-123 exhibit promising anti-inflammatory activity related to their ability to inhibit TNF-α, IL-1ß, and vasoactive amine production, as well as reduce leukocyte migration and inhibit mast cell degranulation.

Anti-inflammatory and antinociceptive activities of the leaf methanol extract of Miconia minutiflora (Bonpl.) DC. and characterization of compounds by UPLC-DAD-QTOF-MS/MS.

Some species of the genus Miconia are used in Brazilian folk medicine as analgesic and anti-inflammatory; however, several species of this genus are still poorly studied. Therefore, the aims of this study were to investigate the phytochemistry characterization by UPLC-DAD-QTOF-MS/MS, acute toxicity, anti-inflammatory and antinociceptive properties of Miconia minutiflora (Bonpl.) DC. The methanol extract of M. minutiflora (Mm-MeOH) was subjected to ultra-high-performance liquid chromatography (UPLC-DAD-QTOF-MS/MS) for the identification of the main phytocompounds. The anti-inflammatory properties of the extracts were studied using several inflammation models induced by carrageenan and acetic acid-induced vascular permeability. Antinociceptive effects of Mm-MeOH were assessed in nociception induced by intraperitoneal acetic acid or subplantar formalin injection. The role of α-adrenergic, cholinergic, and opioid receptors in modulating the extract's antinociceptive activity was determined. Analyses by UPLC-DAD-QTOF-MS/MS revealed the presence of ellagic acid, gallotannin, and terpenes in the methanol extract. Mm-MeOH (100 mg/kg) reduced carrageenan-induced paw edema and vascular permeability and inhibited leukocyte migration toward the air pouch and pleural cavity. Furthermore, Mm-MeOH decreased tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) levels. Administration of Mm-MeOH reduced the number of writhes by 58.9% and increased the pain threshold in the formalin test. The anti-inflammatory action mechanism of Mm-MeOH is associated with inhibition of proinflammatory cytokines TNF-α and IL-1ß, whereas the antinociceptive actions involve peripheral and central mechanisms with participation of α2-adrenergic receptors. These effects may be attributed to the presence of polyphenolics in the extract.

Ação antibacteriana e antiaderente de pithecellobium cochliocarpum (Gomez) macbr sobre microrganismos orais / Antimicrobial and antiadherent activity of pithecellobium cochliocarpum (gomez) macbr tested on oral microorganisms

O biofilme dental é o fator de maior importancia na etiologia da cárie e das doenças periodontais. Diversos produtos de origem vegetal mostraram ser potencialmente interessantes no que se refere a sua atividade antimicrobiana. O objetivo do estudo foi o de avaliar a atividade antibacteriana e antiaderente do Pithecellobium cochliocarpum (Gomez) Macbr. (babatenon) frente Streptococcus mutans, S. sanguinis, S. salivarius, S. mitis, S. oralis e Lactobacillus casei. Para a determinação da Concentraçao Inibitória Mínima (CIM), os ensaios foram realizados em triplicata, em meio sólido, através da técnica de Ágar-Difusão em placas de Petri. Em relação à determinação da Concentração Inibitória Mínima de Aderência (CIMA) da bactéria ao vidro na presença de sacarose a 5%, utilizou-se a técnica dos tubos inclinados. Em estudo comparativo, foi determinada a CIM e a CIMA do digluconato de clorexidina a 0,12%. Quanto a CIM, o Pithecellobium cochliocarpum apresentou atividade antibacteriana similar ao digluconato de clorexidina frente a todas as linhagens ensaiadas. Os halos variaram entre 10 a 30mm com resultado destacado (até a diluição 1:512) frente a S. sanguinis, S. oralis e L. casei. Já a CIMA frente ao babatenon mostrou-se efetivo na inibição da aderência até a última diluição considerada (1:512) para S. sanguinis, S. mitis e S. oralis, apresentando desempenho médio superior à clorexidina. Conclui-se que o Pithecellobium cochliocarpum apresentou potencial atividade antimicrobiana e antiaderente, ressaltando a importância de se avaliar um agente fitoterápico mais acessivel à população com perspectiva da prescrição nos serviços de Atenção Básica, estando em consonância com as novas diretrizes do Ministério da Saúde.

The dental biofilm is the major factor in the etiology of caries and periodontal diseases. Several plant products have shown to be potentially interesting with regard to its antimicrobial activity. The aim of this study was to evaluate the antibacterial and adherent the ethanol extract of Pithecellobium cochliocarpum (Gomez) Macbr (babatenon) front Streptococcus mutans, Streptococcus sanguinis, Streptococcus salivarius, Streptococcus mitis, Streptococcus oralis and Lactobacillus casei. To determine the minimum inhibitory concentration (MIC) tests were perfomed in triplicate on solid medium, using the technique of Agar Diffusion in petri dishes relation to determining the minimum inhibitory concentration of adherence (CIMA) of the bacteria to glass in the presence of sucrose at 5%, we used the technique of inclined tubes. In a comparative study, it was determined the CIM and CIMA values of chlorhexidine 0.12%. As for CIM, Pithecellobium cochliocarpum showed antibacterial activity similar to chlorhexidine gluconate against all strains tested. The zones ranged from 10 to 30 mm with outstanding results (up to dilution 1:512) against S. sanguinis, S. oralis and L. casei. Already the CIMA in relation the babatenon was effective in inhibiting adhesion to the last dilution was considered (1:512) for S. sanguinis, S.oralis and S. mitis, showing average performance than chlorhexidine. It is concluded that Pithecellobium cochliocarpum showed significant antimicrobial activity and antiadherent emphasizing the importance of evaluating an agent herbal medicine more accessible to people with perspective of the prescription in primary care services, and in line with new guidelines from the Ministry of Health.

Antitumor activity of leaves of himatanthus drasticus (mart. ) plumel-apocynaceae (janaguba) in the treatment of Sarcoma 180 tumor

Himatanthus drasticus, also known as janaguba, is used popularly in Brazil's Northeastern region in the treatment of cancer. However, no scientific reports are available. The present study is the first investigation on the antitumor activity of crude methanolic extract from Himatanthus drasticus leaves against Sarcoma 180 tumor and on its side effects including acute oral toxicity. The OECD 423 methodology was used to study acute oral toxicity, and the STOCK methodology to assess antitumor activity. The crude extract showed low toxicity at the tested doses (50, 300 and 2000 mg/kg) administered orally. The histopathological analyses demonstrated alterations in liver lung, spleen and kidney. It also showed activity against Sarcoma 180 tumor in male Swiss albino mice, evidencing tumor growth inhibition of 67.7 percent and 68 percent at 300 mg/kg and 400 mg/kg doses, respectively.

Himatanthus drasticus, conhecida popularmente como janaguba, tem uma longa história de emprego na cura do câncer no nordeste brasileiro, porém quase sem registro na literatura. O objetivo desse trabalho foi investigar a atividade antitumoral do extrato bruto metanólico das folhas de Himatanthus drasticus frente ao modelo experimental Sarcoma 180 e avaliar sua toxicidade aguda. A determinação da toxicidade aguda foi realizada segundo a metodologia da OECD 423 e o transplante do tumor sólido de sarcoma 180 foi realizado seguindo a metodologia de Stock. O extrato apresentou baixa toxicidade nas doses testadas (50, 300 e 2000 mg/kg) por via oral. A análise histopatológica apresentou alterações em nível hepático, pulmonar, baço e renal. A atividade antineoplásica apresentou inibição tumoral significativa em relação ao grupo controle nas doses de 300 mg/kg e 400 mg/kg de peso do animal com um percentual de inibição de 67.7 por cento e 68 por cento respectivamente. Na menor dose analisada, 200 mg/kg, o percentual de inibição tumoral foi apenas de 32.8 por cento.