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Compound (4-(3,5-di-tert-butyl-4-hydroxybenzylamine)benzenesulfonamide) (LQFM275) was designed and synthesized from darbufelone and sulfanilamide as a new multi-target for the treatment of inflammatory diseases. LQFM275 showed a great range of safe cytotoxicity profile (100-400 μM) evaluated by MTT assay, preventing damage induced by lipopolysaccharide (LPS) in EA.hy926 cell line. In mice, the acute oral treatment with LQFM275 (57, 114, and 228 mg/kg) reduced the number of writhing by 26, 37, and 49 %, respectively. LQFM275 (114 mg/kg) also presented an antinociceptive effect, reducing by 57 % the nociceptive response in the second phase of the formalin test and by 47 % the Carrageenan(Carra)-induced hyperalgesia. That effect was dependent on its anti-inflammatory activity. LQFM275 (114 mg/kg) also reduced 42 % and 31 % of the Carra and LPS-induced edema, respectively. The pleurisy test attenuated the leukocyte migration induced by Carra and LPS by reducing the number of polymorphonuclear cells (by 39 and 36 %, respectively). The production of reactive oxygen species in the pleural exudate was reduced, which is shown by a decrease in myeloperoxidase (MPO) activity (Carra = 35 % and LPS = 40 %) and in levels of pro-inflammatory cytokines TNF-α and IL-1β (Carra = 48 % and LPS = 47 e 36 %). On the other hand, it increased the levels of anti-inflammatory cytokines, IL-4, and IL-10 (Carra = 50 % and LPS = 21 and 53 %). Moreover, LQFM275 demonstrated to be a dual COX-2 and 5-LOX inhibitor (IC 50  = 81 and 167 μM, respectively). Therefore, the promising anti-inflammatory and antinociceptive effects of LQFM275 provide an opportunity for a new multi-target drug development., Competing Interests: Declaration of competing interest The authors declare that this research was conducted in the absence of any commercial, financial, or other relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

BACKGROUND: Studies evaluating sputum quality and Xpert ® MTB/RIF positivity in the context of active case finding are scarce. We aimed to determine whether sputum quality is associated with Xpert positivity and whether the association differed according to demographic and clinical characteristics. METHODS: A cross-sectional analysis using data from a mass screening programme in Brazilian prisons was conducted from 2017 to 2021. We administered a standardised questionnaire, obtained a chest X-ray and collected a spot sputum sample for Xpert testing. Sputum quality was classified as 'salivary', 'mucoid/mucopurulent' or 'blood-stained'. We used log binomial regressions to estimate the relationship between sputum quality and Xpert positivity, assessing interactions with participant characteristics. RESULTS: Among 4,368 participants for whom sputum quality was assessed, 957 (21.9%) produced salivary specimens, 3,379 (77.4%) had mucoid/mucopurulent sputum and 32 (0.7%) had blood-stained sputum. Xpert positivity was higher among those with mucoid/mucopurulent sputum than among those with salivary samples (12.0% vs. 3.7%). Mucopurulent sputum independently predicted Xpert positivity among individuals with and without symptoms, current smoking and abnormal chest radiographs on CAD4TB. CONCLUSIONS: In our study, sputum appearance independently predicted Xpert positivity, and could be used together with chest X-ray and symptom screening to inform use of Xpert in individual or pooled testing.

Previous studies have attributed the prominent analgesic, hallucinogenic, sedative, and anxiolytic properties of Salvia divinorum to Salvinorin A. However, the overall pharmacological profile of this isolate limits its clinical applications. To address these limitations, our study evaluates the C(22)-fused-heteroaromatic analogue of salvinorin A [2-O-salvinorin B benzofuran-2-carboxylate] (P-3l) in mice nociception and anxiety models while assessing possible mechanism of action. In comparison with the control group, orally administered P-3l (1, 3, 10, and 30 mg/kg) attenuates acetic acid-induced abdominal writhing, formalin-induced hind paw licking, the thermal reaction to the hotplate, and/or aversive response in the elevated plus-maze, open field, and light-dark box; and potentiates the effect of morphine and diazepam at sub-effective doses (1.25 and 0.25 mg/kg, respectively) without eliciting significant alterations in relative organ weight, or haematological or biochemical parameters. The in vivo blockade of P-3 l effects by naloxone (non-selective opioid receptor antagonist), naloxonazine (antagonist of specific subtypes mu 1 of μ-OR), and nor-binaltorphimine (selective ĸ-OR antagonist) supports initial results from binding assays and the interpretations made possible from computational modeling of the interactions of P-3 l with the opioid receptor subtypes. In addition to the opioidergic mechanism, the blockade of the P-3 l effect by flumazenil suggests benzodiazepine binding site involvement in its biological activities. These results support P-3 l potentially possessing clinical utility and substantiate the need for additional pharmacological characterization., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest for this study., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Molecular modification of compounds remains important strategy towards the discovery of new drugs. In this sense, this study presents a new pyrazole derivative 5-(1-(2-fluorophenyl)-1 H -pyrazol-4-yl)-1 H -tetrazole (LQFM039) and evaluated the anti-inflammatory, analgesic, and vasorelaxant effects of this compound as well the mechanisms of action involved in the pharmacological effects. For this, mice were orally treated with LQFM039 (17.5, 35, or 70 mg/kg) prior acetic acid-induced abdominal writhing, formalin, tail flick, and carrageenan-induced paw edema protocols. In addition, vascular reactivity protocols were made with aortic rings contraction with phenylephrine and stimulated with graded concentrations of LQFM039. Abdominal writhing and licking time in both neurogenic and inflammatory phases of formalin were reduced with LQFM039 without altering latency to nociceptive response in the tail flick test. Carrageenan-induced paw edema showed that LQFM039 reduces edema and cell migration. In addition, the mechanism of action of LQFM039 involves NO/cGMP pathway and calcium channels, since this new pyrazole derivate elicited concentration-dependent relaxation attenuated by Nω-nitro-l-arginine methyl ester and 1 H -[1,2,4] oxadiazolo [4,3-alpha]quinoxalin-1-one, and blockade of CaCl 2 -induced contraction. Altogether, our finding suggests anti-inflammatory, antinociceptive, and vasorelaxant effect of this new pyrazole derivative with involvement of NO/cGMP pathway and calcium channels.

Advances have been made in the search for new multi-target modulators to control pain and inflammation. Therefore, compound 3,5-di-tert-butyl-4-hydroxyphenyl)(4-methylpiperazin-1-yl)methanone (LQFM202) was synthesised and evaluated. First, in vitro assays were performed for COX-1, COX-2, and 5-LOX enzymes. Subsequently, adult female Swiss albino mice treated orally with LQFM202 at doses of 25-200 mg/kg were subjected to acetic acid-induced writhing, formalin-induced pain, carrageenan-induced hyperalgesia, carrageenan- or zymosan-induced paw oedema, or pleurisy. LQFM202 inhibited COX-1, COX-2, and LOX-5 (IC 50  = 3499 µM, 1565 µM, and 1343 µM, respectively). In acute animal models, LQFM202 (50, 100, or 200 mg/kg) decreased the amount of abdominal writhing (29%, 52% and 48%, respectively). Pain in the second phase of the formalin test was reduced by 46% with intermediate dose. LQFM202 (100 mg/kg) reduced the difference in nociceptive threshold in all 4 h evaluated (46%, 37%, 30%, and 26%, respectively). LQFM202 (50 mg/kg) decreased the carrageenan-oedema from the second hour (27%, 31% and 25%, respectively); however, LQFM202 (100 mg/kg) decreased the carrageenan-oedema in all hours evaluated (35%, 42%, 48% and 50%, respectively). When using zymosan, LQFM202 (50 mg/kg) decreased the oedema in all hours evaluated (33%, 32%, 31% and 20%, respectively). In the carrageenan-pleurisy test, LQFM202 (50 mg/kg) reduced significantly the number of polymorphonuclear cells (34%), the myeloperoxidase activity (53%), TNF-α levels (47%), and IL-1β levels (58.8%). When using zymosan, LQFM202 (50 mg/kg) reduced the number of polymorphonuclear and mononuclear cells (54% and 79%, respectively); and the myeloperoxidase activity (46%). These results suggest antinociceptive and anti-inflammatory effects of LQFM202., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Major depression disorder (MDD) is one of the most widespread and debilitating psychiatric diseases and may be associated with other mental disorders such as anxiety. Despite advances in neurobiology studies, currently no established mechanism can explain all facets of MDD, and available drugs often show therapeutic delay for clinical effectiveness and response rates in patients are around 50 %. Previous activities of piperazine derivatives on CNS are indicators of its therapeutic potential for treating mental disorders. In this regard, we have previously shown that the piperazine derivative 2,6-di-tert-butyl-4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenol (LQFM212) has anxiolytic-like activity which involves serotonergic pathway, nicotinic receptors and BZD-site of GABA A receptor, without cognitive impairments. Herein, was evaluated the potential antidepressant-like effect of LQFM212 on forced swimming test (FST) after a single dose of 54 μmol/kg and after repeated treatment for 15 days in mice. Pretreatment with WAY-100635, PCPA, prazosin, SCH-23390, sulpiride or AMPT reversed the antidepressant-like effect on FST, suggesting that monoaminergic pathway contributes for effects of LQFM212. Furthermore, repeated treatment with LQFM212 increased hippocampal BDNF levels dosed by ELISA kit. In assessment of possible adverse effects, repeated treatment with LQFM212 did not alter the body weight of the animals, glutathione levels in the liver, and serum levels of AST, ALT, urea, and creatinine. Taken together, the results showed that LQFM212 has an antidepressant-like effect that involves monoaminergic pathway and increased BDNF levels. This compound represents promising candidate for prototype of psychoactive drugs for treatment of anxiety and depression disorders since these pathological conditions may exist in comorbidities., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The aim of this study was to synthesise the novel di-tert-butylphenol compound, 5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-thioxo-dihydropyrimidine-4,6(1H, 5H)-dione (LQFM218), and evaluate the potential anti-nociceptive and anti-inflammatory activities in acute (mice) models in vivo. The compound was tested on acute models of pain such as acetic acid-induced abdominal writhing, formalin-induced nociception and carrageenan-induced mechanical hyperalgesia. The anti-inflammatory activity was observed in paw oedema, carrageenan-induced pleurisy tests and inflammatory mediator quantification. Key findings: oral treatment with the LQFM218 (50, 100 or 200 mg/kg) reduced abdominal writhing (18.8%, 31.6% and 48.3%). The dose intermediate (100 mg/kg) reduced the nociception in the second phase of the formalin test (61.4%), and also showed anti-hyperalgic activity in carrageenan-induced mechanical hyperalgesia (until 42.3%). In acute inflammation models, the treatment of mice LQFM218 (100 mg/kg) reduced the paw oedema all the time (33.8%, 42.6%, 37.4% and 36%) and in pleurisy test reduced: polymorphonuclear cell migration (35.4%), myeloperoxidase activity (52.2%) and the levels of inflammatory mediators such as PGE 2 (23.0%), TNF-α (67.6%) and IL-1β (53.4%). The present study showed that LQFM218 effectively reduced the nociception and inflammation in different models, and its mechanism might be related to the reduction of PGE 2 and pro-inflammatory cytokines. These findings show LQFM218 as a potential anti-inflammatory drug., (Copyright © 2020 Elsevier B.V. All rights reserved.)

LQFM219 is a molecule designed from celecoxibe (COX-2 inhibitor) and darbufelone (inhibitor of COX-2 and 5-LOX) lead compounds through a molecular hybridisation strategy. Therefore, this work aimed to investigate the antinociceptive and anti-inflammatory activities of this new hybrid compound. The acute oral systemic toxicity of LQFM219 was evaluated via the neutral red uptake assay. Acetic acid-induced abdominal writhing and CFA-induced mechanical hyperalgesia were performed to evaluate the antinociceptive activity, and the anti-oedematogenic activity was studied by CFA-induced paw oedema and croton oil-induced ear oedema. Moreover, the acute anti-inflammatory activity was determined by carrageenan-induced pleurisy. In addition, cell migration, myeloperoxidase enzyme activity, and TNF-α and IL-1β levels were determined in pleural exudate. Moreover, a redox assay was conducted using electroanalytical and DPPH methods. The results demonstrated that LQFM219 was classified as GHS category 4, and it showed better free radical scavenger activity compared to BHT. Besides, LQFM219 decreased the number of writhings induced by acetic acid and the response to the mechanical stimulus in the CFA-induced mechanical hyperalgesia test. Furthermore, LQFM219 reduced oedema formation, cell migration, and IL-1β and TNF-α levels in the pleural cavity and inhibited myeloperoxidase enzyme activity. Thus, our study provides that the new pyrazole derivative, LQFM219, demonstrated low toxicity, antinociceptive and anti-inflammatory potential in vitro and in vivo., (Copyright © 2020. Published by Elsevier B.V.)

Aims: This study investigated the antinociceptive and anti-inflammatory effects of new pyrazole compounds LQFM011(5), LQFM043(6) and LQFM044(7) as well as the mechanisms of action and acute in vitro toxicity., Main Methods: The antinociceptive activity was evaluated using the acetic acid-induced abdominal writhing test, formalin-induced pain test and the Randall-Selitto test. The anti-inflammatory activity was evaluated using models of paw oedema and pleurisy induced by carrageenan; cell migration, the levels of tumour necrosis factor α (TNF-α) and myeloperoxidase (MPO) enzyme activity were evaluated. In addition, the ability to inhibit phospholipase A2 (PLA2) in vitro and docking in PLA2 were used. Acute oral systemic toxicity in mice was evaluated through the neutral red uptake assay., Key Findings: The synthesised compounds (5-7), delivered via gavage (p.o.) at 70, 140 or 280 µmol/kg, decreased the number of writhings induced by acetic acid; the three compounds (280 µmol/kg p.o.) reduced the paw licking time in the first and second phase of the formalin test and decreased the nociceptive threshold variation in the Randall-Selitto test. Furthermore, this dose reduced oedema formation, leucocyte migration (specifically through reduction in polymorphonuclear cell movement) and increased mononuclear cells. MPO activity and the levels of pro-inflammatory cytokines TNF-α were decreased. Evaluation of PLA2 inhibition via the docking simulation revealed more interactions of LQFM043R(6) and LQFM044(7), data that corroborated the half-maximal inhibitory concentration (IC 50 ) of PLA2 inhibition in vitro. Therefore, LQFM011(5), LQFM043(6) and LQFM044(7) were classified with the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) as category 4.

The aim of this study was to design, synthesize and evaluate the potential analgesic and anti-inflammatory effects of 5-[1-(4-fluorphenyl)-1H-1,2,3-triazol-4-yl]-1H-tetrazole-(LQFM-096: a new triazole compound) as well as to elucidate its possible mechanisms of action. The oral administration of LQFM-096 (10, 20 or 40 mg/kg) decreased the number of writhing in mice. At the dose of 20 mg/kg, LQFM-096 reduced the licking time at both neurogenic and inflammatory phases of the formalin test. Pretreatment with naloxone (3 mg/kg) and glibenclamide (3 mg/kg) attenuated the antinociceptive effect of LQFM-096 in the first phase of the formalin test. At the dose of 20 mg/kg, LQFM-096 also decreased the licking time in the acidified saline-induced and capsaicin-induced nociception. This effect was blocked by naloxone (3 mg/kg) pretreatment prior to the administration of LQFM-096. In addition, LQFM-096 inhibited hyperalgesia induced by carrageenan and PGE2. Naloxone (3 mg/kg) attenuated the effect of LQFM-096 through disinhibition of PGE2-induced hyperalgesia. The anti-inflammatory effect of LQFM-096 was demonstrated in carrageenan-induced oedema or pleurisy as well as CFA-induced arthritis. The hyperalgesia and cellular migration in CFA-induced arthritis were reduced significantly. Altogether, these findings suggest antinociceptive effect of LQFM-096 and implicate the modulation of ASICs/TRPV1 channels by opioid/KATP pathway. The anti-inflammatory effect of LQFM-096 was mediated by a reduction in oedema, leukocytes migration, TNF-α, PGE 2 levels and myeloperoxidase activity.

Distinct architectures of layer-by-layer (LbL) films made of carbon nanotubes and gold nanoparticles were investigated to serve as the matrix to immobilize cholesterol oxidase, with which cholesterol could be detected using amperometry. The gold nanoparticles were synthesized by metal reduction stabilized in poly(allylamine hydrochloride) (PAH) providing a stable AuNPs-PAH suspension, while multi-walled carbon nanotubes (CNTs) were functionalized with carboxylic groups to obtain an aqueous suspension. The LbL films were deposited on ITO, with a cushion film of PAH and poly(vinyl sulfonic acid) (PVS). Owing to the synergy between CNTs and AuNPs, the electrode ITO/(PAH/PVS)₂ (AuNPs-PAH/CNTs) 10 was selected for immobilization of cholesterol oxidase (ChO x ). This sensor could detect cholesterol with a limit of detection of 14.8 μmol L -1 and sensitivity of 36.47 (μA cm -2 )·(mmol L -1 ) -1 . It was also able to determine cholesterol in egg yolk with a recovery of 97.7%.

Pyrazoles are potent medicinal scaffolds and exhibit a wide spectrum of biological activities, such as analgesic, anti-inflammatory and antipyretic. In this paper we report on research we have performed with the aim of continuing the biological evaluation of the regio-isomeric pyrazole compounds, LQFM-020 (fluorine, para position), LQFM-021 (fluorine, meta position), and LQFM-039 (fluorine, ortho position) in models of pain induced by acidified saline, capsaicin, and formalin. We also investigated the mechanisms of action of these compounds via electrophysiological analyses using the two-electrode voltage-clamp technique and heterologous expression in Xenopus laevis oocytes. This enabled us to study different potassium channel subtypes: the ASIC-1α channel, TRPV-1, and μMOR receptors. Our results indicate that LQFM-020, LQFM-021, and LQFM-039 (15, 30 or 60 mg.kg -1 ) compounds inhibited the nociceptive response induced by acidified saline in a dose-dependent manner. The dose of 30 mg.kg -1 inhibited the nociceptive response induced by capsaicin by 53.3%, 51.4%, and 52.1%, respectively. In addition, we found that naloxone reverses the antinociceptive effect produced by the compounds in both phases of the formalin test. In electrophysiological analyses, we observed that the LQFM-020, LQFM-021, and LQFM-039 compounds did not modulate voltage-gated K + channel subtypes. In contrast, all the compounds tested inhibited the ASIC-1α channel at pH 4.5, with IC50-values of 96.1, 91.6, and 235.2 μM, respectively. All compounds also inhibited the TRPV-1 channel with IC50-values of 139.1, 212.5, and 159.1 μM, respectively. In contrast to the ASIC-1α and TRPV-1 targets, all compounds showed agonist activity on the μMOR receptor with an EC50-value of 117.4, 98.9, and 86.3 μM, respectively. We thus conclude that the ASIC-1α, TRPV-1, and μMOR channels are targets that are directly involved in the antinociceptive effect of LQFM-020, LQFM-021, and LQFM-039. Furthermore, the modifications of the fluorine positions in the phenyl analogs do not change the analgesic effect. However, LQFM-039 showed lower interaction with ASIC-1α channel., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Nonsteroidal anti-inflammatory drugs are commonly used worldwide; however, they have several adverse effects, evidencing the need for the development of new, more effective and safe anti-inflammatory and analgesic drugs. This research aimed to design, synthesize and carry out a pharmacological/toxicological investigation of LQFM-102, which was designed from celecoxib and paracetamol by molecular hybridization. To evaluate the analgesic effect of this compound, we performed formalin-induced pain, hot plate and tail flick tests. The anti-inflammatory effect of LQFM-102 was evaluated in carrageenan-induced paw oedema and pleurisy tests. The biochemical markers indicative of toxicity-AST, ALT, GSH, urea and creatinine-as well as the index of gastric lesion after prolonged administration of LQFM-102 were also analyzed. In addition, the interaction of LQFM-102 with COX enzymes was evaluated by molecular docking. In all experimental protocols, celecoxib or paracetamol was used as a positive control at equimolar doses to LQFM-102. LQFM-102 reduced the pain induced by formalin in both phases of the test. However, this compound did not increase the latency to thermal stimuli in the hot plate and tail flick tests, suggesting an involvement of peripheral mechanisms in this effect. Furthermore, LQFM-102 reduced paw oedema, the number of polymorphonuclear cells, myeloperoxidase activity and TNF-α and IL-1β levels. Another interesting finding was the absence of alterations in the markers of hepatic and renal toxicity or lesions of gastric mucosa. In molecular docking simulations, LQFM-102 interacted with the key residues for activity and potency of cyclooxygenase enzymes, suggesting an inhibition of the activity of these enzymes.

The piperazine derivatives correspond to an extensive chemical class of compounds with numerous neuropharmacological activities, including antidepressant (e.g., nefazodone, trazodone) and anxiolytic (e.g., buspirone) properties. Therefore, aiming to identify a new antidepressant and antianxiety lead-compound, our group designed, synthesized, and investigated the effects of a new piperazine compound, namely, LQFM104, on the behavior of mice. Male albino Swiss mice were treated with LQFM104 prior to predictive behavioral tests as open field (OFT), elevated plus maze (EPM), forced swimming (FST), and tail suspension tests (TST). The participation of the serotonergic system was evaluated by pretreatment with a 5-HT1A antagonist receptor (WAY100635) and serotonin (5-HT) synthesis inhibitor (p-chlorphenylalanine, pCPA) before oral administration of LQFM104 and behavioral tests. The treatment with LQFM104 did not interfere with locomotor activity but revealed suggestive data of anxiolytic-like effects by the increase in the time spent in the center of the OFT. This activity was confirmed by the results obtained in the EPM, and it was abolished after pretreatment with WAY100635 and pCPA. The immobility time decreased in both the FST and TST. The antidepressant-like activity was completely abolished after WAY100635 pretreatment. Altogether, these data revealed that LQFM104 possesses anxiolytic and antidepressant-like properties in behavioral tests on mice, and these activities are possibly mediated, directly and/or indirectly, by serotonergic pathways., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Ethnopharmacological Relevance: The cashew gum (Anacardium occidentale L.) is used in traditional Brazilian medicine in the treatment of inflammatory conditions, asthma, diabetes, and gastrointestinal disturbances., Aim of the Study: In the present study, we aimed at forming a chemical characterization and investigation of the antinociceptive and anti-inflammatory activities of the aqueous extract of cashew gum without the presence of polysaccharides in its composition (CGE)., Materials and Methods: The CGE was obtained after the precipitation and removal of polysaccharides through the use of acetone. After, the acetone was removed by rotaevaporation, and the concentrated extract was lyophilized. The chemical characterization of CGE was performed by liquid chromatography mass spectrometry (LC-MS) and tandem mass spectrometry (MS/MS) analyses. Mice were used for the evaluation of the antinociceptive and anti-inflammatory activities. CGE was analyzed via the Irwin test, acetic acid-induced writhing test, formalin-induced pain test, and carrageenan-induced paw edema test. The motor activity or probable sedation was verified through the chimney, open-field, and sodium pentobarbital-induced sleep tests. We investigated if the analgesic and anti-inflammatory effects of CGE depend of reduction in PGE 2 levels, were performed the carrageenan or PGE 2 -induced hyperalgesia tests., Results: The chemical characterization of CGE showed the presence of anacardic acids as the predominant phytoconstituents. The treatment with CGE (75, 150, and 300mg/kg, p.o.) inhibited the number of writhing in a dose-dependent manner. With an intermediate dose, CGE did not cause motor impairment with the chimney test or alterations in either the open-field or sodium pentobarbital-induced sleep. In the formalin-induced pain test, CGE (150mg/kg, p.o.) produced an antinociceptive effect only in the first phase of the test, suggesting anti-inflammatory activity. With the same dosage, CGE also reduced the carrageenan-induced paw edema at all hours of the test, confirming its anti-inflammatory effect. Furthermore, CGE (150mg/kg, p.o.) presented an antihyperalgic effect at all hours of the carrageenan-induced hyperalgesia test. However, this dose of CGE was not able to reduce the hyperalgesia induced by PGE 2 , suggesting that the anti-inflammatory effect of this extract depends on the reduction in the PGE 2 levels., Conclusion: The anacardic acids are the predominant phytoconstituents identified in the CGE. The action mechanisms of CGE suggest the reduction in the PGE 2 levels. These findings support the use of cashew gum in popular medicine and demonstrate that part of its antinociceptive and anti-inflammatory effects should also be attributed to the presence of anacardic acids in its composition, independent of the presence of polysaccharides., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In the scope of a research program aimed at developing new drugs for the treatment of central nervous system diseases, we describe herein the synthesis and pharmacological evaluation of 1-(4-(3,5-di-tert-butyl-4-hydroxybenzyl) piperazin-1-yl)-2-methoxyethan-1-one (LQFM180). This compound showed antioxidant activity in two models, electroanalytical assays, and DPPH activity. Moreover, in behavioral tests as the open field test LQFM180 (9.4, 18.8, and 37.6 mg/kg, per oral (p.o.)), we detected anxiolytic-like activity. In the sodium pentobarbital-induced sleep test, LQFM180, in all doses, decreased the latency to sleep and increased sleep duration, indicating central depressant activity; moreover, in the chimney test, LQFM180 did not alter motor activity. LQFM180 (18.8 mg/kg, p.o.) increased the time and number of entries on open arms in the elevated plus maze test, suggesting anxiolytic-like activity, which was reversed by NAN-190 and p-chlorophenylalanine, indicating a role of the serotonergic pathway on this effect. In the forced swimming test, LFQM180 (18.8 mg/kg, p.o.) decreased immobility time, suggesting antidepressant-like activity, which was reversed by monoaminergic antagonists, indicating a role for the serotonergic, noradrenergic, and dopaminergic pathways. Competition binding assays showed that LQFM180 was able to bind to the α 1B , 5-HT 1A , and D 2 receptors, however, within the low micromolar range. We conclude that LQFM180 should be considered as a scaffold for drug candidate development.

Gastric ulcer affects people worldwide, and its inefficacy and recurrence have fueled the search for new therapeutic strategies. Despite the well-known use of allantoin in medicines and cosmetic products, its effect has not yet been studied with regard to gastric ulcer. Hence, the aim of the present study was to explore the pharmaco-mechanistic efficacy of allantoin against commonly harmful agents that cause injuries to the stomach. Ethanol, indomethacin, and stress-induced gastric ulcer models were adopted, in addition to pylorus ligature, a quantification of vascular permeability, glutathione (GSH), gastric adhered mucus, prostaglandin (PGE 2 ), pro-inflammatory cytokines levels, myeloperoxidase (MPO), and catalase (CAT) activities. The gastric lesions were examined by gross, histological, and ultrastructural features. The results showed that treatment with allantoin (60mg/kg, per oral) reduced the gastric ulcer formation in all models. Furthermore, allantoin reduced the parameters of gastric acid secretion and attenuated both the vascular permeability and MPO activity. The levels of pro-inflammatory cytokines were also reduced, accompanied by a restoration of CAT activity and GSH levels. Notably, allantoin treatment preserved the gastric-adhered mucus and PGE 2 levels after ethanol administration. Microscopic and ultrastructural analysis revealed that allantoin maintained tissue integrity and prevented morphological changes in cells caused by ethanol. In summary, we demonstrated for the first time that allantoin possesses gastroprotective activity through anti-inflammatory, anti-oxidative, antisecretory, and cytoprotective mechanisms. The antisecretory and cytoprotective mechanisms are probably associated with an increase in PGE 2 levels., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aims: This study investigates the anti-nociceptive and anti-inflammatory effects of new piperazine compound (LQFM182) as well as the toxicity acute in vitro., Main Methods: To evaluate the anti-nociceptive activity, the acetic acid-induced abdominal writhing test, tail flick test and formalin-induced pain test were used. The anti-inflammatory activity was evaluated using the models of paw oedema and pleurisy induced by carrageenan and some inflammatory parameters were evaluated, including cell migration, myeloperoxidase enzyme activity and the levels of TNF-α and IL-1β cytokines in pleural exudate. The acute oral systemic toxicity of LQFM182 in mice was evaluated through the neutral red uptake (nru) assay., Key Findings: LQFM182 (50, 100 or 200 mg/kg, p.o.) decreased the number of writhings induced by acetic acid in a dose-dependent manner, and an intermediate dose (100 mg/kg, p.o.) reduced the paw licking time of animals in the second phase of the formalin test. Furthermore, LQFM182 (100 mg/kg, p.o.) reduced oedema formation at all hours of the paw oedema induced by carrageenan test and in pleurisy test reduced cell migration from the reduction of polymorphonuclear cells, myeloperoxidase enzyme activity and the levels of pro-inflammatory cytokines IL-1β and TNF-α. Therefore, it was classified in GHS category 300 < LD 50  < 2000 mg/kg., Significance: Reduction of the TNF-α and IL-1β levels.

Background: Major depressive disorder is a psychiatric disorder that affects 4.4% of the population worldwide. Although the majority of antidepressant drugs ameliorate depressive symptoms, there is still a need for safer and more effective antidepressant., Objective: Evaluate the antidepressant-like activity of sesquiterpene compound β-caryophyllene (BCP) for the possible contribution of the monoamine and hippocampal levels of brain-derived neurotrophic factor (BDNF)., Methods: Male albino Swiss mice were subjected to the forced swimming test after acute treatment and to the tail suspension test after repeated treatment. Hippocampal levels of BDNF were assayed by enzyme-linked immunosorbent assay., Results: The anti-immobility effect of BCP was reverted by pretreatment with an inhibitor of catecholamine synthesis α-methyl-p-tyrosine (100 mg/kg, i.p.), α2-adrenergic antagonist yohimbine (1 mg/kg, i.p.), and β-adrenergic antagonist propranolol (2 mg/kg, i.p.), but not by pretreatment with either α1-adrenergic antagonist prazosin (1 mg/kg, i.p.) or 5-HT1A antagonist NAN-190 (0.5 mg/kg, i.p.), thereby suggesting the involvement of α2 and β-adrenergic receptors, but not of the α1-adrenergic and 5-HT1A serotonergic receptors, in BCP's antidepressive-like activity. Furthermore, BCP increased BDNF levels in the hippocampus after 14 days of treatment. No treatments in this study altered locomotor activity in the open field test., Conclusion: This study provides a new mechanism of BCP-induced antidepressant-like effect mediated by some sub-types of catecholaminergic neurotransmitter system that could be a candidate for clinical tests of new treatments for depressive disorders., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

The pyrazole compound LQFM-021 exhibits vasorelaxant, antinociceptive and anti-inflammatory activities. Furthermore, it has low toxicity, indicating that this compound may be considered to be a good prototype for the development of new analgesic/anti-inflammatory drugs. Therefore, the aim of this study was to investigate the potential anti-inflammatory activity of LQFM-021 using a model of carrageenan-induced inflammation as well as the mechanism of action and role of nitric oxide in this effect. Acute treatments with LQFM-021 (30 and 60 mg/kg p.o.) reduced paw edema formation dose-dependently 2 h after carrageenan injection. In the carrageenan-induced pleurisy test, LQFM-021 (30 mg/kg p.o.) reduced the leukocyte (polymorphonuclear) count in the pleural cavity, as well as decreased protein extravasation and myeloperoxidase activity. This dose of LQFM-021 increased the NO (nitrite/nitrate) and IL-4 levels and decreased the TNF-α and IL-1β levels in the pleural cavity. Moreover, pre-treatment with L-NAME reversed the effect of LQFM-021 on NO, leukocyte migration, and the TNF-α and IL-1β levels. Additionally, we observed that LQFM-021 showed weak inhibitory activity on cyclooxygenases, but reduced the PGE 2 levels in the pleural cavity. Immunoblot analyses showed that LQFM-021 promoted a decrease in COX-2 levels and increase in iNOS levels. In conclusion, we demonstrated that LQFM-021 has marked anti-inflammatory activity by reducing polymorphonuclear recruitment, which is associated with the inhibition of the production of inflammatory cytokines and eicosanoids. In addition, we found that the synthase/release of nitric oxide promoted by LQFM-021 is essential for the anti-inflammatory effect observed., (Copyright © 2017 Elsevier Inc. All rights reserved.)

In this study, we proposed the design, synthesis of a new compound 2-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)ethan-1-ol (LQFM032), and pharmacological evaluation of its anxiolytic-like effect. This new compound was subjected to pharmacological screening referred to as Irwin test, prior to sodium pentobarbital-induced sleep, open-field and wire tests. The anxiolytic-like effect of this compound was evaluated using elevated plus maze and light-dark box tests. In addition, the mnemonic activity was evaluated through step-down test. In sodium pentobarbital-induced sleep test, LQFM032 decreased latency and increased duration of sleep. In the open-field test, LQFM032 altered behavioral parameter, that suggested anxiolytic-like activity, as increased in crossings and time spent at the center of open field. In the plus maze test and light-dark box test, the LQFM032 showed anxiolytic-like activity, increased entries and time spent on open arms, and increased in number of transitions and time spent on light area, respectively. Those effects was antagonized by flumazenil but not with 1-(2-Methoxyphenyl)-4-(4-phthalimidobutyl)piperazine (NAN-190). The LQFM032 did not alter mnemonic activity. Moreover, the anxiolytic-like activity of LQFM032 was antagonized by mecamylamine. In summary, LQFM032 showed benzodiazepine and nicotinic pathways mediated anxiolytic-like activity without altering the mnemonic activity., (© 2017 John Wiley & Sons A/S.)

Dual 5-LOX/COX inhibitors are potential new dual drugs to treat inflammatory conditions. This research aimed to design, synthesis and to evaluate the anti-inflammatory and antinociceptive effects of the new compound, which is derived from nimesulide and darbufelone lead compounds. The new dual inhibitor 5-LOX/COX has the possible advantage of gastrointestinal safety. A voltammetric experiment was conducted to observe the drug's antioxidative effect. A formalin test, a hot plate test and carrageenan-induced mechanical hyperalgesia were employed to evaluate the analgesic nature of LQFM-091. To evaluate anti-inflammatory activity, we measured edema, leukocyte count, myeloperoxidase activity and cytokines levels in carrageenan-induced inflammation tests. We elucidated the underlying mechanisms by assessing the interaction the with COXs and LOX enzymes by colorimetric screening assay and molecular docking. The lethal dose (LD 50 ) was estimated using 3T3 Neutral Red Uptake assay. Our results indicate that the LQFM-091 prototype is a powerful antioxidant, as well as able to inhibit COX-1, COX-2 and LOX activities. LQFM091 was classified in GHS category 4 (30050 <2000mg/Kg). This prototype showed analgesic activity in the formalin test and decreased carrageenan-induced mechanical hyperalgesia. Furthermore, LQFM-091 reduced the paw edema induced by carrageenan and reduced the leukocyte count, myeloperoxidase activity, TNF-α and IL-1β levels in the pleural exudate. Another interesting finding was the absence of gastrointestinal lesions. These data indicate that LQFM-091 produced antinociceptive and anti-inflammatory effects while maintaining gastrointestinal safety. Furthermore, this compound presented a safe toxicological profile. Blocked COXs and LOX enzymes are important targets for manipulating the mechanism of this compound., (Copyright © 2017. Published by Elsevier B.V.)

Inflammatory diseases and pain are among the main problems that significantly influence the lifestyle of millions of people and existing therapies are not always effective and can cause several adverse effects. In this context, the molecular modifications or synthesis of compounds continue being the best strategies for the identification of new compounds for the treatment of pain and inflammation. The aim of this study was to evaluate the analgesic and anti-inflammatory activities of new analogues of pyrazole compounds containing subunits N-phenyl-1-H-pirazoles and 1,3,4-oxadiazole-2(3H)-thione, LQFM-146, LQFM-147 and LQFM-148. In the acetic acid-induced abdominal writhing test, treatments with LQFM-146, LQFM-147 or LQFM-148 at doses 89, 178 and 356µmol/kg p.o. reduced the abdominal writhing in a dose-dependent manner. In the formalin test, these compounds at dose 178µmol/kg p.o. reduced the licking time only in inflammatory phase of this test, suggesting an antinociceptive effect dependent of the anti-inflammatory effect. The treatment with the three compounds in intermediate dose (178µmol/kg p.o.) reduced the edema at all tested time points in the carrageenan-induced paw edema test and reduced polymorphonuclears cell migration, activity myeloperoxidase and TNF-α levels in the carrageenan-induced pleurisy test. Our date suggest that the new compounds LQFM-146, LQFM-147 and LQFM-148 possess satisfactory anti-inflammatory and antinociceptive effects that involves the reduction of pro-inflammatory cytokines and inhibition of the myeloperoxidase enzyme., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: The leaves and stems bark of Memora nodosa (Silva Manso) Miers (Bignoniaceae) are used in Brazilian traditional medicine in the treatment of external ulcers and wounds; its roots are used to treat abdominal pain and scabies., Aim of the Study: Our aim was to evaluate the antinociceptive and anti-inflammatory activities of Memora nodosa roots ethanolic extract (EMN) and allantoin, a secondary metabolite isolated from this plant., Materials and Methods: The EMN and allantoin antinociceptive activity were evaluated in mice using both chemical and heat-induced pain models such as acetic acid-induced writhing, formalin and tail-flick tests. In the formalin test, a pre-treatment with naloxone was used to verify an involvement of opioid receptor in the antinociceptive effect of EMN and allantoin. Pre-treatment with glibenclemide was used to verity an involvement of ATP-sensitive K(+)channel in the allantoin antinociceptive effect. EMN and allantoin anti-inflammatory activity were assessed by carrageenan-induced paw edema and pleurisy tests., Results: The treatment with EMN (250, 500 and 1000mg/kg, p.o.) inhibit the acetic acid and formalin (both phases)-induced nociception. However, just at doses 500 and 1000mg/kg increased the latency time in tail-flick test. These results suggest the involvement of both peripheral and central antinociceptive mechanisms. The treatment with allantoin (40, 60 and 80mg/kg p.o.) produced a dose-dependent antinociceptive effect in both phases of formalin-induced nociception test; allantoin (60mg/kg) was not able to increase the latency time in tail flick-test. The pre-treatment with naloxone completely reversed the EMN (1000mg/kg) and allantoin (60mg/kg) effect in the first phase of formalin test; and glibenclamide reversed the allantoin effect. The administration of EMN (250, 500 and 1000mg/kg) and allantoin (60mg/kg) showed significant anti-inflammatory activity in the whole carrageenan-induced paw edema. Furthermore, EMN and allantoin reduced the leukocytes migration and pleural exudate to the pleural cavity., Conclusion: EMN have significant antinociceptive and anti-inflammatory effects, which appear to be, at least in part, due to the presence of allantoin. However, allantoin is not responsible for the EMN central antinociceptive activity. Allantoin has peripheral antinociceptive activity that involves the opioid receptor and ATP-sensitive K(+)channels. Opioid receptors are also involved in the EMN antinociceptive activity. These findings support the use of Memora nodosa in popular medicine and demonstrate that this plant has therapeutic potential for the development of antinociceptive and anti-inflammatory phytomedicines., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)