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Copaifera duckei oleoresin is a plant product extensively used by the Brazilian population for multiple purposes, such as medicinal and cosmetic. Despite its ethnopharmacological relevance, there is no pharmacokinetic data on this important medicinal plant. Due to this, we determined the pharmacokinetic profile of the major nonvolatile compounds of C. duckei oleoresin. The diterpenes ent-polyalthic acid and dihydro-ent-agathic acid correspond to approximately 40% of the total oleoresin. Quantification was performed using LC-MS/MS, and the validated analytical method showed to be precise, accurate, robust, reliable, and linear between 0.57 and 114.74 µg/mL plasma and 0.09 to 18.85 µg/mL plasma, respectively, for ent-polyalthic acid and dihydro-ent-agathic acid, making it suitable for application in preclinical pharmacokinetic studies. Wistar rats received a single 200 mg/kg oral dose (gavage) of C. duckei oleoresin, and blood was collected from their caudal vein through 48 h. Population pharmacokinetics analysis of ent-polyalthic and dihydro-ent-agathic acids in rats was evaluated using nonlinear mixed-effects modeling conducted in NONMEN software. The pharmacokinetic parameters of ent-polyalthic acid were absorption constant rate = 0.47 h-1, central and peripheral apparent volume of distribution = 0.04 L and 2.48 L, respectively, apparent clearance = 0.15 L/h, and elimination half-life = 11.60 h. For dihydro-ent-agathic acid, absorption constant rate = 0.28 h-1, central and peripheral apparent volume of distribution = 0.01 L and 0.18 L, respectively, apparent clearance = 0.04 L/h, and elimination half-life = 3.49 h. The apparent clearance, central apparent volume of distribution, and peripheral apparent volume of distribution of ent-polyalthic acid were approximately 3.75, 4.00-, and 13.78-folds higher than those of dihydro-ent-agathic.

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Toxoplasmosis affects about one-third of the world's population. The disease treatment methods pose several side effects and do not efficiently eliminate the parasite, making the search for new therapeutic approaches necessary. We aimed to assess the anti-Toxoplasma gondii activity of four Copaifera oleoresins (ORs) and two isolated diterpene acids, named ent-kaurenoic and ent-polyalthic acid. We used HeLa cells as an experimental model of toxoplasmosis. Uninfected and infected HeLa cells were submitted to the treatments, and the parasite intracellular proliferation, cytokine levels and ROS production were measured. Also, tachyzoites were pre-treated and the parasite invasion was determined. Finally, an in silico analysis was performed to identify potential parasite targets. Our data show that the non-cytotoxic concentrations of ORs and diterpene acids controlled the invasion and proliferation of T. gondii in HeLa cells, thus highlighting the possible direct action on parasites. In addition, some compounds tested controlled parasite proliferation in an irreversible manner. An additional and non-exclusive mechanism of action involves the modulation of host cell components, by affecting the upregulation of the IL-6. Additionally, molecular docking suggested that ent-polyalthic acid has a high affinity for the active site of the TgCDPK1 protein. Copaifera ORs have great antiparasitic activity against T. gondii, and this effect can be partially explained by the presence of the isolated compounds ent-kaurenoic and ent-polyalthic acid.

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Baccharin is one of the major compounds found in Brazilian green propolis and its botanical source, Baccharis dracunculifolia. Considering the biological effects of propolis and B. dracunculifolia, this study aims to evaluate the analgesic and anti-inflammatory potential of baccharin. The neurodepressor potential was performed by the open field test, analgesia by mechanical stimulation with Dynamic Plantar Aesthesiometer, and by thermal stimulation with Hargreaves apparatus. In addition, the anti-inflammatory potential was achieved by the paw edema assay, histopathological evaluation, and NF-kB expression. Doses of 2.5, 5, and 10 mg/kg of baccharin were evaluated. After euthanasia, plantar tissue was collected and prepared for histology. As a result, analgesic activity was observed at a dose of 10 mg/kg of baccharin in thermal stimulation under an inflammatory process and anti-inflammatory potential at a dose of 5 mg/kg of baccharin from the second hour in the paw edema test. A decrease in cellular infiltrate and down-modulation of NF-kB, besides the reduction of edema in the histopathology was observed. There was no evidence of kidney and liver toxicity and neurodepressive potential at the doses tested. Thus, baccharin has a promising anti-inflammatory effect possibly associated with antiedematogenic activity by inhibiting mediators such as prostaglandins, inhibiting the migration of polymorphonuclear cells, and modulating NF-kB expression.

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Melanoma, an aggressive and potentially fatal skin cancer, is constrained by immunosuppression, resistance, and high toxicity in its treatment. Consequently, there is an urgent need for innovative antineoplastic agents. Therefore, this study investigated the antimelanoma potential of guttiferone E (GE). In an allogeneic murine B16 melanoma model, GE was administered subcutaneously and intraperitoneally. Antitumor evaluation included tumor volume/weight measurements and histopathological and immunohistochemical analysis. Furthermore, the toxicity of the treatments was evaluated through body/organ weights, biochemical parameters, and genotoxicity. Subcutaneous administration of 20 mg/kg of GE resulted in a significant reduction in both tumor volume and weight, effectively suppressing melanoma cell proliferation as evidenced by a decrease in mitotic figures. The tumor growth inhibition rate was equivalent to 54%. This treatment upregulated cleaved caspase-3, indicating apoptosis induction. On the other hand, intraperitoneal administration of GE showed no antimelanoma effect. Remarkably, GE treatments exhibited no toxicity, evidenced by non-significant differences in body weight gain, as well as organ weight, biochemical parameters of nephrotoxicity and hepatotoxicity, and genotoxic damage. This study revealed, for the first time, the efficacy of subcutaneous administration of GE in reducing melanoma, in the absence of toxicity. Furthermore, it was observed that the apoptotic signaling pathway is involved in the antimelanoma property of GE. These findings offer valuable insights for further exploring GE's therapeutic applications in melanoma treatment.

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The rise in antifungal resistance and side effects of conventional treatments drive the search for innovative therapies like Photodynamic Therapy (PDT). This study explored the efficacy of PDT mediated by gutiferone, an isolated compound from red propolis, for candidiasis treatment. Multiple evaluation methods were employed, including determining the minimum inhibitory concentration (MIC) via broth microdilution, quantifying biomass using crystal violet detachment, and cell counting through total plate count. PDT mediated by gutiferone was also assessed in five groups of mice, followed by histopathological examination and agar plating of lingual tissue samples. Among the seven Candida species tested, gutiferone displayed efficacy against C. albicans, C. glabrata, and C. tropicalis, with MIC values of 1000 µg/mL. In C. tropicalis biofilms, exposure to gutiferone led to a reduction of 1.61 Log10 CFU/mL. PDT mediated by gutiferone achieved an average reduction of 3.68 Log10 CFU/mL in C. tropicalis biofilm cells, underscoring its potent fungicidal activity. Histopathological analysis revealed fungal structures, such as pseudohyphae and hyphae, in infected groups (G2) and irradiated mice. In contrast, groups treated with gutiferone or subjected to gutiferone-assisted PDT (G5) exhibited only few blastoconidia. Furthermore, CFU/mL assessments in lingual tissue post-treatment demonstrated a significantly lower count (0.30 Log10 CFU/mL) in the G5 group compared to G2 (2.43 Log10 CFU/mL). These findings highlight the potential of PDT mediated by gutiferone as a promising alternative for managing denture stomatitis. Future research and clinical investigations offer the promise of validating its clinical applicability and improving outcomes in the treatment of oral candidiasis.

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Propolis is a natural product widely used in folk medicine. Among its various applications, its antiparasitic properties stand out. Due to its great biodiversity, Brazil is a major producer of several types of propolis. This study proposes to evaluate the leishmanicidal properties of the hydroalcoholic extract of propolis collected in the southern region of Brazil (Brown propolis - HEBP) and its main isolated compounds: abietic acid (1), 13-epi-cupressic acid (2), 13-epi-torulosol (3), dehydroabietic acid (4), cis-communic acid (5) and ent-agatic acid (6). In general, the diterpenes did not show activity against the promastigotes of Leishmania (Leishmania) amazonensis at the evaluated concentrations. However, the HEBP was very active with an inhibition concentration of 50% at 8.32 µg/mL. Moreover, transmission electron microscopy (TEM) and scanning electron microscopy (SEM) assays showed morphological and structural alterations in promastigote forms of L. (L.) amazonensis when incubated with HEBP.

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This study aimed at evaluating the potential of Copaifera lucens, specifically its oleoresin (CLO), extract (CECL), and the compound ent-polyalthic acid (PA), in combating caries and toxoplasmosis, while also assessing its toxicity. The study involved multiple assessments, including determining the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against cariogenic bacteria. CLO and PA exhibited MIC and MBC values ranging from 25 to 50 µg/mL, whereas CECL showed values equal to or exceeding 400 µg/mL. PA also displayed antibiofilm activity with minimum inhibitory concentration of biofilm (MICB50) values spanning from 62.5 to 1000 µg/mL. Moreover, PA effectively hindered the intracellular proliferation of Toxoplasma gondii at 64 µg/mL, even after 24 h without treatment. Toxicological evaluations included in vitro tests on V79 cells, where concentrations ranged from 78.1 to 1250 µg/mL of PA reduced colony formation. Additionally, using the Caenorhabditis elegans model, the lethal concentration (LC50) of PA was determined as 1000 µg/mL after 48 h of incubation. Notably, no significant differences in micronucleus induction and the NDI were observed in cultures treated with 10, 20, or 40 µg/mL of CLO. These findings underscore the safety profile of CLO and PA, highlighting their potential as alternative treatments for caries and toxoplasmosis.

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The aim of this study was to evaluate the antimicrobial efficacy of polyhexamethylene hydrochloride guanidine (PHMGH) compared to chlorhexidine digluconate (CLX) for use as an oral antiseptic during dental procedures in wild cats. This research is crucial due to limited information on the diversity of oral microorganisms in wild cats and the detrimental local and systemic effects of oral diseases, which highlights the importance of improving prevention and treatment strategies. Samples were collected from the oral cavities of four Puma concolor, one Panthera onca, and one Panthera leo, and the number of colony-forming units per milliliter (CFU/mL) was counted and semi-automatically identified. The antimicrobial susceptibility profile of bacterial isolates was determined using minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and time-kill kinetics of PHMGH and CLX. A total of 16 bacterial isolates were identified, consisting of six Gram-positive and 10 Gram-negative. PHMGH displayed MIC and MBC from 0.24 to 125.00 µg/mL, lower than those of CLX against three isolates. Time-kill kinetics showed that PHMGH reduced the microbial load by over 90% for all microorganisms within 30 min, whereas CLX did not. Only two Gram-positive isolates exposed to the polymer showed incomplete elimination after 60 min of contact. The results could aid in the development of effective prevention and treatment strategies for oral diseases in large felids. PHMGH showed promising potential at low concentrations and short contact times compared to the commercial product CLX, making it a possible active ingredient in oral antiseptic products for veterinary use in the future.

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Polyalthic acid (PA) is a diterpene found in copaiba oil. As a continuation of our work with PA, we synthesized PA analogs and investigated their antibacterial effects on preformed biofilms of Staphylococcus epidermidis and determined the minimal inhibitory concentration (MIC) of the best analogs against planktonic bacterial cells. There was no difference in activity between the amides 2a and 2b and their corresponding amines 3a and 3b regarding their ability to eradicate biofilm. PA analogs 2a and 3a were able to significantly eradicate the preformed biofilm of S. epidermidis and were active against all the Gram-positive bacteria tested (Enterococcus faecalis, Enterococcus faecium, S. epidermidis, Staphylococcus aureus), with different MIC depending on the microorganism. Therefore, PA analogs 2a and 3a are of interest for further in vitro and in vivo testing to develop formulations for antibiotic drugs against Gram-positive bacteria.

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The technologies used to produce the different dosage forms of propolis can selectively affect the original propolis compounds and their biological activities. The most common type of propolis extract is hydroethanolic. However, there is considerable demand for ethanol-free propolis presentations, including stable powder forms. Three propolis extract formulations were developed and investigated for chemical composition and antioxidant and antimicrobial activity: polar propolis fraction (PPF), soluble propolis dry extract (PSDE), and microencapsulated propolis extract (MPE). The different technologies used to produce the extracts affected their physical appearance, chemical profile, and biological activity. PPF was found to contain mainly caffeic and p-Coumaric acid, while PSDE and MPE showed a chemical fingerprint closer to the original green propolis hydroalcoholic extract used. MPE, a fine powder (40% propolis in gum Arabic), was readily dispersible in water, and had less intense flavor, taste, and color than PSDE. PSDE, a fine powder (80% propolis) in maltodextrin as a carrier, was perfectly water-soluble and could be used in liquid formulations; it is transparent and has a strong bitter taste. PPF, a purified solid with large amounts of caffeic and p-Coumaric acids, had the highest antioxidant and antimicrobial activity, and therefore merits further study. PSDE and MPE had antioxidant and antimicrobial properties and could be used in products tailored to specific needs.

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