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The aim of this study was to evaluate the effect of ylang-ylang ( Cananga odorata ) essential oil (YEO) on models of experimental arthritis, persistent inflammation, and nociception in mice. YEO treatment at doses of 100 and 200 mg/kg reduced the infiltration of leukocytes into the joint cavities of mice submitted to zymosan-induced arthritis 6 h and 7 days after arthritis induction. At these doses, YEO treatment reduced the formation of joint edema 4 and 6 h after arthritis induction, and at a dose of 200 mg/kg, YEO treatment reduced mechanical hyperalgesia 3 and 4 h after arthritis induction. At the dose of 200 mg/kg, YEO treatment reduced interleukin-6 (IL-6) levels and cartilage destruction in the zymosan-induced arthritis model, and reduced edema formation and mechanical hyperalgesia in the model of persistent inflammation (21 days) induced by complete Freund's adjuvant (CFA) in mice. YEO treatment at a dose of 200 mg/kg reduced the nociceptive response in experimental models of nociception induced by acetic acid and formalin. The YEO treatment reduced inflammatory parameters in the experimental arthritis model, and presented antiarthritic, anti-hyperalgesic, antinociceptive, and anti-inflammatory properties.

Snake bites are a severe problem in the countryside of Brazil and are usually attributed to snakes of the genera Bothrops, Crotalus, and Lachesis. Snake venom can release ectoenzymes and nucleotidases that modulate the purinergic system. In addition to serum therapy against snake poisoning, medicinal plants with anti-inflammatory activities, such as Tabebuia aurea, is empirically applied in accidents that occur in difficult-to-access areas. This study aimed was to verify the presence and activity of nucleotidases in the crude venom of Bothrops mattogrossensis (BmtV) in vitro and characterize the modulation of purinergic components, myeloid differentiation, and inflammatory/oxidative stress markers by BmtV in vivo and in vitro. Moreover, our study assessed the inhibitory activities of specioside, an iridoid isolated from Tabebuia aurea, against the effects of BmtV. Proteomic analysis of venom content and nucleotidase activity confirm the presence of ectonucleotidase-like enzymes in BmtV. In in vivo experiments, BmtV altered purinergic component expression (P2X7 receptor, CD39 and CD73), increased neutrophil numbers in peripheral blood, and elevated oxidative stress/inflammatory parameters such as lipid peroxidation and myeloperoxidase activity. BmtV also decreased viability and increased spreading index and phagocytic activity on macrophages. Specioside inhibited nucleotidase activity, restored neutrophil numbers, and mediate the oxidative/inflammatory effects produced by BmtV. We highlight the effects produced by BmtV in purinergic system components, myeloid differentiation, and inflammatory/oxidative stress parameters, while specioside reduced the main BmtV-dependent effects., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Leishmaniases are neglected diseases with limited therapeutic options. Diffuse cutaneous leishmaniasis can occur in Brazil due to Leishmania amazonensis . This study details the antileishmanial activity and cytotoxicity of complexes of sodium usnate (SAU) with lanthanide ions ([LnL 3 (H 2 O) x ] (Ln = La(III), Nd(III), Gd(III), Tb(III), Eu(III) and Sm(III); L = SAU). All lanthanide complexes were highly active and more potent than SAU against L. amazonensis promastigotes and intracellular amastigotes (Pro: IC 50 < 1.50 μM; Ama: IC 50 < 7.52 μM). EuL 3 ·3H 2 O and NdL 3 ·3H 2 O were the most selective and effective on intracellular amastigotes, with a selectivity index of approximately 7.0. In silico predictions showed no evidence of mutagenicity, tumorigenicity or irritation for all complexes. Treatment with EuL 3 ·3H 2 O triggered NO release even at the lowest concentration, indicating NO production as a mechanism of action against the parasite. Incubating promastigotes with the lanthanide complexes, particularly with SmL 3 ·4H 2 O and GdL 3 ·3H 2 O, led to a change in the mitochondrial membrane potential, indicating the ability of these complexes to target this essential organelle. The same complexes caused cell death through cell membrane disruption, but their relationship with early or late apoptotic processes remains unclear. Thus, the inclusion of lanthanide ions in SAU improves selectivity with a promising mechanism of action targeting the mitochondria.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes cartilage damage. Anti-inflammatories are widely used in the management of RA, but they can have side effects such as gastrointestinal and/or cardiovascular disorders. Studies published by our group showed that the synthesis of hybrid triazole analogs neolignan-celecoxib containing the substituent groups sulfonamide (L15) or carboxylic acid (L18) exhibited anti-inflammatory activity in an acute model of inflammation, inhibited expression of P-selectin related to platelet activation and did not induce gastric ulcer, minimizing the related side effects. In continuation, the present study evaluated the anti-inflammatory effects of these analogs in an experimental model of arthritis and on the functions of one of the important cells in this process, macrophages. Mechanical hyperalgesia, joint edema, leukocyte recruitment to the joint and damage to cartilage in experimental arthritis and cytotoxicity, spread of disease, phagocytic activity and nitric oxide (NO) and hydrogen peroxide production by macrophages were evaluated. Pre-treatment with L15 and L18 reduced mechanical hyperalgesia, joint edema and the influx of leukocytes into the joint cavity after different periods of the stimulus. The histological evaluation of the joint showed that L15 and L18 reduced cartilage damage and there was no formation of rheumatoid pannus. Furthermore, L15 and L18 were non-cytotoxic. The analogs inhibited the spreading, the production of NO and hydrogen peroxide. L15 decreased the phagocytosis. Therefore, L15 and L18 may be potential therapeutic prototypes to treat chronic inflammatory diseases such as RA., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Leishmaniases are among the neglected tropical diseases that still cause devastating health, social, and economic consequences to more than 350 million people worldwide. Despite efforts to combat these vector-borne diseases, their incidence does not decrease. Meanwhile, current antileishmanial drugs are old and highly toxic, and safer presentations are unaffordable to the most severely affected human populations. In a previous study by our research group, we synthesized 17 flavonoid derivatives that demonstrated impressive inhibition capacity against rCPB2.8, rCPB3, and rH84Y. These cysteine proteases are highly expressed in the amastigote stage, the target form of the parasite. However, although these compounds have been already described in the literature, until now, the amastigote effect of any of these molecules has not been proven. In this work, we aimed to deeply analyze the antileishmanial action of this set of synthetic flavonoid derivatives by correlating their ability to inhibit cysteine proteases with the action against the parasite. Among all the synthesized flavonoid derivatives, 11 of them showed high activity against amastigotes of Leishmania amazonensis , also providing safety to mammalian host cells. Furthermore, the high production of nitric oxide by infected cells treated with the most active cysteine protease B (CPB) inhibitors confirms a potential immunomodulatory response of macrophages. Besides, considering flavonoids as multitarget drugs, we also investigated other potential antileishmanial mechanisms. The most active compounds were selected to investigate another potential biological pathway behind their antileishmanial action using flow cytometry analysis. The results confirmed an oxidative stress after 48 h of treatment. These data represent an important step toward the validation of CPB as an antileishmanial target, as well as aiding in new drug discovery studies based on this protease.

Animal venoms are rich sources of neuroactive compounds, including anti-inflammatory, antiepileptic, and antinociceptive molecules. Our study identified a protonectin peptide from the wasp Parachartergus fraternus' venom using mass spectrometry and cDNA library construction. Using this peptide as a template, we designed a new peptide, protonectin-F, which exhibited higher antinociceptive activity and less motor impairment compared to protonectin. In drug interaction experiments with naloxone and AM251, Protonectin-F's activity was decreased by opioid and cannabinoid antagonism, two critical antinociception pathways. Further experiments revealed that this effect is most likely not induced by direct action on receptors but by activation of the descending pain control pathway. We noted that protonectin-F induced less tolerance in mice after repeated administration than morphine. Protonectin-F was also able to decrease TNF-α production in vitro and modulate the inflammatory response, which can further contribute to its antinociceptive activity. These findings suggest that protonectin-F may be a potential molecule for developing drugs to treat pain disorders with fewer adverse effects. Our results reinforce the biotechnological importance of animal venom for developing new molecules of clinical interest., (© 2023. The Author(s).)

Colon cancer incidence rates are increasing annually, a scenario aggravated by genetic and epigenetic alterations that promote drug resistance. Recent studies showed that novel synthetic selenium compounds are more efficient and less toxic than conventional drugs, demonstrating biocompatibility and pro-oxidant effects on tumor cells. This study aimed to investigate the cytotoxic effect of MRK-107, an imidazo [1,2- a ]pyridine derivative, in 2D and 3D cell culture models of colon cancer (Caco-2 and HT-29). Sulforhodamine B results revealed a GI50 of 2.4 µM for Caco-2, 1.1 µM for HT-29, and 22.19 µM for NIH/3T3 in 2D cultures after 48 h of treatment. Cell recovery, migration, clonogenic, and Ki-67 results corroborated that MRK-107 inhibits cell proliferation and prevents cell regeneration and metastatic transition by selectively reducing migratory and clonogenic capacity; non-tumor cells (NIH/3T3) re-established proliferation in less than 18 h. The oxidative stress markers DCFH-DA and TBARS revealed increased ROS generation and oxidative damage. Caspases-3/7 are activated and induce apoptosis as the main mode of cell death in both cell models, as assessed by annexin V-FITC and acridine orange/ethidium bromide staining. MRK-107 is a selective, redox-active compound with pro-oxidant and pro-apoptotic properties and the capacity to activate antiproliferative pathways, showing promise in anticancer drug research.

Ethnopharmacological Relevance: The leaves of Miconia albicans have been extensively used as a traditional medicine to treat inflammation, infection, arthritis, joint pain, and analgesia, which can be purchased easily. Nevertheless, the scientific evidence of chemical profile identification and toxicity investigation is meager., Aim of the Study: This study aimed to determine the chemical profile of Miconia albicans aqueous extract (MAAE), to investigate its anti-inflammatory and hyperalgesic effects, and toxicity (acute and repeated-dose oral) in vivo studies., Materials and Methods: MAAE was obtained by infusion method and its chemical constituents were analyzed and annotated by LC-DAD-MS. The in vivo tests were performed with male and female Swiss mice. Toxicity studies were examined by acute (2000 mg/kg) and repeated-dose oral assays (51.2; 256; 1280 mg/kg); anti-inflammatory evaluation was performed by paw edema and leukocyte migration, and anti-hyperalgesic properties were analyzed by abdominal writhing induced by acetic acid and formalin. The animals were treated by oral means with 51.2, 256, and 1280 mg/kg of MAAE., Results: Twenty-four compounds were annotated from MAAE by LC-DAD-MS, such as ellagitannins, ellagic acid derivatives, flavan-3-ol, and O-glycosylated compounds, including flavonols, triterpenes, and megastigmanes. MAAE induced no significant toxicological effects in the acute and repeated-dose oral assays at lower doses and no histological changes were observed. Hematological and biochemical showed no significant alterations. The oral administration of MAAE 256 mg/kg inhibited the edematogenic effect and reduced the leukocyte migration. In addition, MAAE decreased the abdominal writhings induced by acetic acid and the paw-licking time by formalin assay., Conclusion: MAAE showed a significant reduction in inflammatory levels and leukocyte migration, revealing anti-hyperalgesic properties. Additionally, MAAE revealed no acute and repeated-doses toxicities., Competing Interests: Declaration of competing interest All authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Libidibia ferrea (Mart. ex. Tul.) L.P. Queiroz is a Brazilian native tree locally known as jucá and pau-ferro, and it has been used in folk medicine for relieving, asthma, bronchitis, sore throat, rheumatism, enterocolitis and fever. The anti-inflammatory properties of L. ferrea were confirmed for its stem, fruit, leaves, bark and seeds extracts, however little is known about the natural compounds that may be associated with that response., Aim of This Study: In a normal physiological condition, many enzymes play an important role in catalyzing biological functions. Among them, proteases are of great interest. Although they take part of many biological systems, as the inflammatory process, when deregulated, proteases may cause system malfunctions, such as under- or overproduction of cytokines, or immune cells activation. Thus, protease inhibitors prevent these immune responses by regulating proteases. The objective of this study was to evaluate the anti-inflammatory and anti-nociceptive response of a protease inhibitor purified from L. ferrea seeds (LfTI)., Materials and Methods: In vitro (5, 50 and 250 μg/mL of LfTI) and in vivo (0.6, 3 e 15 mg/kg of LfTI) assays were performed. Male Swiss mice weighing 18-25 g were used for cell harvesting and for the in vivo assays. The anti-inflammatory activity was analyzed in vitro by macrophage cytotoxicity, hydrogen peroxide (H 2 O 2 ) production, and cell adhesion assays; and in vivo by leukocyte recruitment, nitric oxide (NO) production, vascular permeability, paw edema and mast cell degranulation assays. The anti-nociceptive activity was evaluated through abdominal writhing test induced by acetic acid and formalin sensitization., Results: Our results showed that, in vitro, LfTI is not cytotoxic. Also, LfTI (50 μg/mL) inhibited macrophage H 2 O 2 production (48.2%), and adhesion (48.4%). LfTI (0.6, 3 e 15 mg/kg) decreased polymorphonuclear cell recruitment dose-dependently, and it inhibited NO production (53%), vascular permeability (40.7%) and paw edema at 3 mg/kg at different time, but it did not inhibit mast cell degranulation. Besides, LfTI did not inhibit either the number of writhing or the licking time in the formalin test in the second phase (inflammatory). However, LfTI (3 mg/kg) inhibited licking time at the first phase (neurogenic) in the formalin sensitization (46.1%)., Conclusions: Our results show that LfTI has anti-inflammatory and antinociceptive (neurogenic pain) effects, and these effects might be associated with the inhibition of inflammatory proteases and/or protease-activated receptors activation hindering., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The aim of this study is to evaluate the efficacy of Baccharis trimera infusion on high-fat diet-induced metabolic disorders in mice and macrophages activation. This study evaluated obesity, insulin resistance, dyslipidemia and hepatic steatosis induced by a high-fat diet in Swiss mice. Cellular parameters in macrophages, such as cell viability (MTT), the production and release of nitric oxide (NO) and hydrogen peroxide (H 2 O 2 ), cell spreading, cell adhesion and phagocytosis were determined. Our results showed that treatment with B. trimera prevented the mentioned conditions, except for the production of hydrogen peroxide. B. trimera prevented the development of obesity and associated comorbidities, as well as activation of macrophages. In conclusion, B. trimera is able to prevent obesity and metabolic disorders and macrophages activation, minimizing inflammation and validating the popular use of this plant tea.

The aim of this study is to evaluate the phytochemical profile, oral acute toxicity, and the effect of ylang-ylang ( Cananga odorata Hook. F. & Thomson) essential oil (YEO) on acute inflammation. YEO was analyzed by gas chromatography/mass spectrometry. For in vitro tests, YEO was assessed using cytotoxicity, neutrophil chemotaxis induced by N -formyl methionyl leucyl phenylalanine (fMLP), and phagocytic activity tests. YEO was orally administered in zymosan-induced peritonitis, carrageenan-induced leukocyte rolling, and adhesion events in the in situ microcirculation model and in carrageenan-induced paw edema models. YEO (2000 mg/kg) was also tested using an acute toxicity test in Swiss mice. YEO showed a predominance of benzyl acetate, linalool, benzyl benzoate, and methyl benzoate. YEO did not present in vitro cytotoxicity. YEO reduced the in vitro neutrophil chemotaxis induced by fMLP and reduced the phagocytic activity. The oral treatment with YEO reduced the leukocyte recruitment and nitric oxide production in the zymosan-induced peritonitis model, reduced rolling and adherent leukocyte number induced by carrageenan in the in situ microcirculation model, and reduced carrageenan-induced edema and mechanical hyperalgesia. YEO did not present signs of toxicity in the acute toxicity test. In conclusion, YEO affected the leukocyte activation, and presented antiedematogenic, anti-hyperalgesic, and anti-inflammatory properties.

This study reports the synthesis of novel neolignans-celecoxib hybrids and the evaluation of their biological activity. Analogs8-13(L13-L18) exhibited anti-inflammatory activity, inhibited glycoprotein expression (P-selectin) related to platelet activation, and were considered non- ulcerogenic in the animal model, even with the administration of 10 times higher than the dose used in reference therapy. In silico drug-likeness showed that the analogs are compliant with Lipinski's rule of five. A molecular docking study showed that the hybrids8-13(L13-L18) fitted similarly with celecoxib in the COX-2 active site. According to this data, it is possible to infer that extra hydrophobic interactions and the hydrogen interactions with the triazole core may improve the selectivity towards the COX-2 active site. Furthermore, the molecular docking study with P-selectin showed the binding affinity of the analogs in the active site, performing important interactions with amino acid residues such as Tyr 48. Whereas the P-selectin is a promising target to the design of new anti-inflammatory drugs with antithrombotic properties, a distinct butterfly-like structure of 1,4-diaryl-1,2,3-triazole neolignan-celecoxib hybrids synthesized in this work may be a safer alternative to the traditional COX-2 inhibitors., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Ethnopharmacological Relevance: Lantana canescens is popularly known in Brazil as "cidreirinha" or "chumbinho-branco". It is found in Pantanal biome and its flowers and leaves are used in traditional medicine to treat pain and inflammation. Information about this species is limited to the activity of isolated essential oils. Studies with different extracts, composition, and biological properties are still scarce., Aim of This Study: The objective of this study was to evaluate the anti-inflammatory and anti-hyperalgesic activity of the hydroethanolic extract of L. canescens aerial parts., Materials and Methods: The hydroethanolic extract L. canescens aerial parts (HELc) was analyzed using HPLC-DAD-EM. Male and female Swiss mice weighing 18-25 g were used in the in vivo assays. Acute toxicity was assessed (2000 mg/kg); anti-inflammatory activity through paw edema, mast cell degranulation and peritonitis, and anti-hyperalgesic activity through abdominal writhing assays induced by acetic acid and formalin sensitization, were evaluated using the doses of 3, 30 and 300 mg/kg., Results: The phytochemical characterization of HELc confirmed the presence of glycosylated iridoids (theveside, theviridoside), verbascosides and flavonoids. The HELc did not present toxicity in the evaluated dose. HELc reduced formation of paw edema, degranulation of peritoneal mast cells and infiltration of polymorphonuclear cells into the animals peritoneal cavity. In addition, HELc decreased the number of abdominal writhing induced by acetic acid and the time of paw licking in the evaluation of formalin sensitization., Conclusions: These results confirm the anti-inflammatory and anti-hyperalgesic effects of hydroethanolic extract of L. canescens, validating the use of this plant in folk medicine., (Copyright © 2021. Published by Elsevier B.V.)

Parachartergus fraternus wasp induces inflammation with a predominance of mononuclear cells, that can acquire macrophage functions at the sting site, amplifying the response. These cells can be activated by venomous animals and are involved in destruction of injurious agents and release of inflammatory mediators. The objective of this work was to evaluate the activity of P. fraternus venom (Pfv) on isolated murine macrophage function. The cells were obtained from peritoneal cavity of Swiss male mice and incubated with Pfv (2.5, 5 and 10 μg/mL). Cytotoxicity was determined using MTT assay. Adhesion and detachment were evaluated using violet crystal dye. Spreading was evaluated based on morphological parameters. Phagocytosis was performed with opsonized zymosan. Production of hydrogen peroxide (H 2 O 2 ) and nitric oxide (NO) were quantified using the phenol red and Griess assays, respectively. Pfv at concentrations evaluated was not cytotoxic in MTT assay and did not cause macrophage detachment in cell culture plates. However, it increased adhesion of macrophage, spreading and phagocytosis of opsonized zymosan, as well as induced production of H 2 O 2 and NO. Therefore, Pfv induces macrophage activation in vitro and the response of these cells can be correlated with the previously reported inflammatory process triggered by this wasp., (Copyright © 2021. Published by Elsevier Ltd.)

Agelaia-MPI and protonectin are antimicrobial peptides isolated from the wasp Parachartergus fraternus that show antimicrobial and neuroactive activities. Previously, two analogues of these peptides, neuroVAL and protonectin-F, were designed to reduce nonspecific toxicity and improve potency. Here, the three-dimensional structures of neuroVAL, protonectin and protonectin-F were determined by using circular dichroism and NMR spectroscopy. Antibacterial, antifungal, cytotoxic and hemolytic activities were tested for the parent peptides and analogues. All peptides showed moderate antimicrobial activity against Gram-positive bacteria, with agelaia-MPI being the most active. Protonectin and protonectin-F were found to be toxic to cancerous and noncancerous cell lines. Internalization experiments revealed that these peptides accumulate inside both cell types. By contrast, neuroVAL was nontoxic to all tested cells and was able to enter cells without accumulating. In summary, neuroVAL has potential as a nontoxic cell-penetrating peptide, while protonectin-F needs further modification to realize its potential as an antitumor peptide., (© 2020 Wiley-VCH GmbH.)

The sting of different wasp species triggers local and systemic reactions in victims that can lead to death. Parachartergus fraternus is responsible for frequent accidents in Latin America; however, few studies have been conducted on this insect and its venom. In this study, the inflammatory process induced by the venom of the P. fraternus wasp (Pfv; 100, 200, and 400 μg/kg) was characterized. Mice were used to assess paw edema, vascular permeability, mast cell degranulation, leukocyte influx, nitric oxide (NO) production, expression of inflammatory genes, and histopathological changes. Pfv triggered edema formation with a peak dose of 200 μg/kg at 10 min. There was an increase in permeability in all periods and doses evaluated, with no differences between them. The 200 μg/kg dose induced mast cell degranulation in all periods, with a peak at 15 min. This same dose induced leukocyte influx with a predominance of mononuclear cells and triggered a peak in NO production in the 12th hour. The increase in COX-2, iNOS, and IFN-γ mRNA expression occurred after 1 and 6 h, and there was an increase in IL-10 expression after 48 h. In addition, Pfv triggered edema and induced an influx of macrophages and mast cells into the injection site. Therefore, Pfv induces an inflammatory process from the first 5 min of inoculation that can persist for up to 48 h., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Stings from the wasp Parachartergus fraternus occur throughout Latin America, and edema followed by pain is the main symptom presented by victims. This often limited inflammatory event has not been characterized for this species. In this work, we identified the mechanisms and possible mediators involved in this response. P. fraternus venom (100, 200, and 400 μg/kg) was injected into the hind paws of mice, and edema was evaluated at intervals of 10 min for up to 60 min and at 120, 240, and 1440 min using a digital plethysmometer. The peak of edema was observed at 10 min with a dose of 200 μg/kg. A reduction in edema was observed with indomethacin (58.1%), celecoxib (44.5%), MK886 (30.8%), and dexamethasone (53.2%). Loratadine, cimetidine, and cyproheptadine treatment reduced the edema by 54.2%, 63.9%, and 84.4%, respectively, compared with the control. Captopril and L-NAME inhibited 42.5% and 69.8%, respectively, of the edema. These results showed that the edema induced in mice by P. fraternus venom occurs early and is mediated by arachidonic acid derivatives, vasoactive amines, and nitric oxide. Together, these mediators amplify the inflammatory process, with emphasis on histamine and serotonin in triggering the edematogenic response, being more effective the use of cyproheptadine in the therapeutic approach.

Ethnopharmacological Relevance: Tabebuia aurea (Silva Manso) Benth. & Hook. f. ex S. Moore is used as anti-inflammatory, analgesic and antiophidic in traditional medicine, though its pharmacological proprieties are still underexplored. In the bothropic envenoming, pain is a key symptom drove by an intense local inflammatory and neurotoxic event. The antivenom serum therapy is still the main treatment despite its poor local effects against pain and tissue injury. Furthermore, it is limited to ambulatorial niches, giving space for the search of new and more inclusive pharmacological approaches., Aim of the Study: evaluation of Tabebuia aurea hydroethanolic extract (HEETa) in hyperalgesia and neuronal injury induced by Bothrops mattogrossensis venom (VBm)., Materials and Methods: Stem barks from Tabebuia aurea were extracted with ethanol and water (7:3, v/v) to yield the extract HEETa. Then, HEETa was analyzed by LC-DAD-MS and its constituents were identified. Snake venoms were extracted from adult specimens of Bothrops mattogrossensis, lyophilized and kept at -20 °C until use. Male Swiss mice, weighting 20-25 g, were used to hyperalgesia (electronic von Frey), motor impairment (Rotarod test) and tissue injury evaluation (histopatology and ATF-3 immunohistochemistry). Therefore, three experimental groups were formed: VBm (1 pg, 1 ng, 0.3 μg, 1 μg, 3 and 6 μg/paw), HEETa orally (180, 540, 720, 810 or 1080 mg/kg; 10 mL/kg, 30 min prior VBm inoculation) and VBm neutralized (VBm: HEETa, 1:100 parts, respectively). In all set of experiments a control (saline group) was used. First, we made a dose-time-response course curve of VBm's induced hyperalgesia. Next, VBm maximum hyperalgesic dose was employed to perform HEETa orally dose-time-response course curve and analyses of VBm neutralized. Paw tissues for histopathology and DRGs were collected from animals inoculated with VBm maximum dose and treated with HEETa antihyperalgesic effective dose or neutralized VBm. Paws were extract two or 72 h after VBm inoculation and DRGs, in the maximum expected time expression of ATF-3 (72 h)., Results: From HEETa extract, glycosylated iridoids were identified, such as catalpol, minecoside, verminoside and specioside. VBm induced a time and dose dependent hyperalgesia with its highest effect seen with 3 µg/paw, 2 h after venom inoculation. HEETa effective dose (720 mg/kg) decreased significantly VBm induced hyperalgesia (3 µg/paw) with no motor impairment and signs of acute toxicity. HEETa antihyperalgesic action starts 1.5 h after VBm inoculation and lasted up until 2 h after VBm. Hyperalgesia wasn't reduced by VBm: HEETa neutralization. Histopathology revealed a large hemorragic field 2 h after VBm inoculation and an intense inflammatory infiltrate of polymorphonuclear cells at 72 h. Both HEETa orally and VBm: HEETa groups had a reduced inflammation at 72 h after VBm. Also, the venom significantly induced ATF-3 expression (35.37 ± 3.25%) compared with saline group (4.18 ± 0.68%) which was reduced in HEETa orally (25.87 ± 2.57%) and VBm: HEETa (19.84 ± 2.15%) groups., Conclusion: HEETa reduced the hyperalgesia and neuronal injury induced by VBm. These effects could be related to iridoid glycosides detected in HEETa and their intrinsic reported mechanism., (Copyright © 2019 Elsevier B.V. All rights reserved.)

In recent years, the fruits of native Brazilian plant species with anti-inflammatory property have gained prominence due to their properties comparable to traditional medicines. This study aimed to chemically characterize and evaluate the anti-inflammatory and antihyperalgesic activity of Byrsonima cydoniifolia fruit, which is widely used to manufacture ice cream and jellies. Our results revealed that the fruit exhibits flavonoid derivatives and stilbenes, as trans-piceatannol and resveratrol, as main secondary metabolites. In mice, the hydroethanolic extract of fruit reduced the edema, migration of polymorphonuclear leukocytes into the peritoneal cavity, as well as abdominal writhings. The results demonstrated, for the first time, the presence of stilbenoids in the Byrsonima genus and the anti-inflammatory and antihyperalgesic effect of Byrsonima cydoniifolia fruits, supporting its potential as a nutraceutical food., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The Hymenaea stigonocarpa and Hymenaea martiana species, commonly known as "jatobá," produce a sap which is extracted by perforation of the trunk and is commonly used in folk medicine as a tonic. For this study, the authenticity of commercial samples of jatobá was verified by the identification of the main compounds and multivariate analysis and contamination by microbial presence analysis. The acute toxicity of the authentic jatobá sap was also evaluated. The metabolites composition and multivariate analysis revealed that none of the commercial samples were authentic. In the microbiological contamination analysis, five of the six commercial samples showed positive cultures within the range of 1,700-100,000 CFU/mL and the authentic sap produced no signs of toxicity, and from a histological point of view, there was the maintenance of tissue integrity. In brief, the commercial samples were deemed inappropriate for consumption and represent a danger to the population., Competing Interests: The authors declare that there are no competing interests regarding the publication of this paper.

An ethnopharmacological survey indicates that the genus Byrsonima has some medicinal species that are commonly found in the Brazilian Cerrado and has been used as an anti-inflammatory and for gastroduodenal disorders. The aim of this study was to evaluate the anti-inflammatory and antioxidant activity along with qualitative chemical characterization of the methanolic extract of the leaves of Byrsonima verbascifolia (BvME) obtained by exhaustive percolation. The data from the chemical analyses by liquid chromatography-mass spectrometry led to tentative identification of 42 compounds belonging to proanthocyanidins, galloyl quinic acid derivatives, flavonoids, and triterpene glycoside derivatives. BvME contain flavonoids and show an antioxidative activity. The methanolic extract administered intraperitoneally at doses of 50, 100, or 300 mg/kg showed a significant reduction in paw edema and modulated the neutrophil influx in a mouse model. Furthermore, the anti-edematogenic activity of the extract provided in smaller doses (12.5 and 25 mg/kg) was also demonstrated in a mouse paw edema model. The extract inhibited NO production by macrophages induced by lipopolysaccharide. We presume that the anti-inflammatory effects of BvME are due to a combination of compounds present in B. verbascifolia, including catechins (procyanidins), flavonoids, and triterpene glycosides and that these anti-inflammatory actions should be mediated, at least partly, through the inhibition of NO production. This study supports and validates the ethnopharmacological uses of B. verbascifolia as an anti-inflammatory.

Ethnopharmacological Relevance: Croton urucurana (Euphorbiaceae) is popularly used in Brazil to treat inflammatory processes, pain, and gastric ulcers., Aim of Study: To evaluate the anti-inflammatory and antinociceptive properties of the methanol extract from the bark of C. urucurana (MECu) in mice and identify its chemical constituents., Materials and Methods: The extract was characterized by UHPLC-DAD-ESI-Q-TOF-MS/MS. Extract doses of 25, 100, and 400mg/kg were employed in the biological assays. Evaluation of anti-inflammatory activity was based on paw edema and leukocyte recruitment into the peritoneal cavity of mice, both induced by carrageenan. Abdominal writhing caused by acetic acid and duration of formalin-induced paw-licking were the models employed to evaluate antinociceptive activity., Results: Ten compounds were identified in the extract: (+)-gallocatechin (1), procyanidin B3 (2), (+)-catechin (3), (-)-epicatechin (4), tembetarine (5), magnoflorine (6), taspine (7), methyl-3-oxo-12-epi-barbascoate (8), methyl-12-epi-barbascoate (9), and hardwickiic acid (10). This is the first report of compounds 2, 4, 6, 7, and 10 in C. urucurana and compound 5 in the genus Croton. In addition to inhibiting paw edema and leukocyte recruitment (particularly of polymorphonuclear cells) into the peritoneal cavity of mice, MECu reduced the number of abdominal writhings induced by acetic acid and the duration of formalin-induced paw licking., Conclusions: The methanol extract of C. urucurana bark exhibited anti-inflammatory and antinociceptive properties, corroborating its use in folk medicine. These effects may be related to the presence of diterpenes, alkaloids, and flavonoids., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Achyrocline alata, known as Jateí-ka-há, is traditionally used to treat several health problems, including inflammations and infections. This study aimed to optimize an active extract against Streptococcus mutans, the main bacteria that causes caries. The extract was developed using an accelerated solvent extraction and chemometric calculations. Factorial design and response surface methodologies were used to determine the most important variables, such as active compound selectivity. The standardized extraction recovered 99% of the four main compounds, gnaphaliin, helipyrone, obtusifolin and lepidissipyrone, which represent 44% of the extract. The optimized extract of A. alata has a MIC of 62.5 μg/mL against S. mutans and could be used in mouth care products.

Ethnopharmacological Relevance: Ethnobotanical studies show that Tabebuia aurea has been used as anti-inflammatory and for snake bite. Evaluate the effect of treatment with the hydroethanolic extract of Tabebuia aurea (HETa) on inflammatory, hemorrhagic and myotoxic activities induced by Bothrops neuwiedi (BnV) in mice., Materials and Methods: The anti-inflammatory, antihemorragic and antimyotoxic properties of the HETa 100, 200 and 400mg/kg or BnV neutralized with HETa (1:50) were evaluated using the following animal models: BnV-induced paw edema, BnV-induced recruitment of polymorphonuclear cells into the peritoneal cavity, hemorrhagic activity, myotoxic activity and hydrogen peroxide production by peritoneal macrophages in vitro., Results: HETa inhibited the paw edema and polymorphonuclear cell recruitment into the peritoneal cavity. BnV neutralized with HETa reduced the hemorrhagic activity and histopathological analysis of skeletal muscle tissue showed that the hemorrhagic area was smaller and multifocal. The leukocyte infiltrate was less intense and muscle necrosis discrete. BnV induced hydrogen peroxide production and BnV neutralized reduced this production. In addition, the HETa was nontoxic to macrophages., Conclusions: The activities of the HETa presented herein justify the popular use of Tabebuia aurea in inflammatory situations from snake bite., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Ethnopharmacological Relevance: Achyrocline alata is a locally marketed (Mato Grosso do Sul/ Brazil) herb used in folk medicine as an anti-inflammatory and a sedative. Evaluate the anti-inflammatory properties of Achyrocline alata in both in vivo and in vitro models., Materials and Methods: A hydroethanolic extract from inflorescences of Achyrocline alata (HEAa) was characterized by HPLC-DAD and compared to standards (chlorogenic acid; isoquercetrin; quercetin; 4,2',4'-trihydroxy-6'-methoxychalcone; gnaphalin; 3-O-methyl-quercetin; 3,5-dicaffeoyl-quinic acid and 4,5-dicaffeoyl-quinic acid). The in vivo anti-inflammatory properties of the HEAa (4, 20 and 100 mg/kg, per os) were evaluated using the following animal models: carrageenan-induced paw edema in rats, carrageenan-induced vascular permeability and peritonitis in mice and an acetic acid-induced writhing model to test antihyperalgesic activity in mice. In vitro assays were performed to study the effects of the HEAa (0.16, 0.8 and 4 mg/ml) on the cell viability, cell spreading and production of NO and H2O2 in stimulated macrophages., Results: The A. alata extract inhibited the development of edema and vascular permeability, reduced polymorphonuclear cell recruitment in the acute peritonitis assay and decreased the amount of writhing induced by acetic acid. The HEAa did not increase NO/H2O2 production, while it did inhibit production when the macrophages were stimulated by LPS or PMA at all tested concentrations. In the presence of HEAa, macrophage spreading did not increase even after stimulation with LPS. Additionally, the HEAa was nontoxic to macrophages at all tested concentrations., Conclusions: The HEAa displayed anti-inflammatory and antihyperalgesic effects, which supports the use of this plant in folk medicine. These effects might be due to the flavonoids and phenylpropanoids derivatives present in the HEAa., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: To characterize drug prescriptions in a university hospital adult intensive care unit., Methods: Single-center, observational, descriptive, cross-sectional study conducted at an adult general intensive care unit. The study population included all of the unit's inpatients from January to March 2011. The following characteristics for all prescriptions recorded during this period were examined: drug name (generic, brand name or abbreviation), dosage strength, pharmaceutical form, dose, route of administration, patient name, patient registration in the institution, clinic and hospital bed as well as the name, board license number, signature of the prescriber and date of the prescription. It was quantified the percentage of prescribed drugs included in the National List of Essential Drugs, the World Health Organization Model List of Essential Medicines and the University Hospital Center Pharmacotherapy Guide. The prescribed drugs were classified based on the Anatomical Therapeutic Chemical classification system (levels 1 and 2)., Results: Eight hundred forty-four prescriptions were reviewed from 72 patients (mean age: 59.04 ± 21.80), 54.92% of whom were female. The mean number of prescriptions per patient was 11.72 ± 11.68. The total number of drugs prescribed was 12,052 and 9,571 (79.41%) of the drugs were prescribed using the generic name. The most frequent absent information in the drug description was the pharmaceutical form of the drug (8,829/73.26%). The dosage strength was indicated in 7,231 (60%) of the prescriptions, and the prescriber and patient information were indicated in over 96% of the prescriptions. The prescribed drugs were classified in 13 therapeutic groups and 55 subgroups. Systemic antibacterials represented one of the most frequently prescribed subgroups., Conclusion: Most of the reviewed information was present in the prescriptions. However, the dosage strength and pharmaceutical form were absent in many prescriptions. The characterization of prescriptions at different hospital units is essential for the development of strategies that reduce drug utilization problems.