Andrographolide: A Diterpenoid from Cymbopogon schoenanthus Identified as a New Hit Compound against Trypanosoma cruzi Using Machine Learning and Experimental Approaches.

American Trypanosomiasis, also known as Chagas disease, is caused by the protozoan Trypanosoma cruzi and exhibits limited options for treatment. Natural products offer various structurally complex metabolites with biological activities, including those with anti-T. cruzi potential. The discovery and development of prototypes based on natural products frequently display multiple phases that could be facilitated by machine learning techniques to provide a fast and efficient method for selecting new hit candidates. Using Random Forest and k-Nearest Neighbors, two models were constructed to predict the biological activity of natural products from plants against intracellular amastigotes of T. cruzi. The diterpenoid andrographolide was identified from a virtual screening as a promising hit compound. Hereafter, it was isolated from Cymbopogon schoenanthus and chemically characterized by spectral data analysis. Andrographolide was evaluated against trypomastigote and amastigote forms of T. cruzi, showing IC50 values of 29.4 and 2.9 µM, respectively, while the standard drug benznidazole displayed IC50 values of 17.7 and 5.0 µM, respectively. Additionally, the isolated compound exhibited a reduced cytotoxicity (CC50 = 92.8 µM) against mammalian cells and afforded a selectivity index (SI) of 32, similar to that of benznidazole (SI = 39). From the in silico analyses, we can conclude that andrographolide fulfills many requirements implemented by DNDi to be a hit compound. Therefore, this work successfully obtained machine learning models capable of predicting the activity of compounds against intracellular forms of T. cruzi.

Adenanthin Is an Efficient Inhibitor of Peroxiredoxins from Pathogens, Inhibits Bacterial Growth, and Potentiates Antibiotic Activities.

The emergence and re-emergence of bacterial strains resistant to multiple drugs represent a global health threat, and the search for novel biological targets is a worldwide concern. AhpC are enzymes involved in bacterial redox homeostasis by metabolizing diverse kinds of hydroperoxides. In pathogenic bacteria, AhpC are related to several functions, as some isoforms are characterized as virulence factors. However, no inhibitor has been systematically evaluated to date. Here we show that the natural ent-kaurane Adenanthin (Adn) efficiently inhibits AhpC and molecular interactions were explored by computer assisted simulations. Additionally, Adn interferes with growth and potentializes the effect of antibiotics (kanamycin and PMBN), positioning Adn as a promising compound to treat infections caused by multiresistant bacterial strains.

Biseugenol from Ocotea cymbarum (Lauraceae) attenuates inflammation, angiogenesis and collagen deposition of sponge-induced fibrovascular tissue in mice.

Several species of the genus Ocotea are used in traditional medicine due to their anti-inflammatory and analgesic properties. In this work we sought to investigate the effects of biseugenol, the main component of the hexane extract from the leaves of Ocotea cymbarum (Lauraceae), during a chronic inflammatory process induced by polyester-polyurethane sponge in mice. In addition to the inflammatory component, sponge discs also allowed us to evaluate parameters associated with the formation of new blood vessels and the deposition and organization of the extracellular matrix, processes that are related to the chronification of the inflammatory response. Daily treatment with biseugenol (0.1, 1 or 10 µg in 10 µl of 0.5% DMSO) inhibited the synthesis of inflammatory cytokines (TNF-α, CXCL-1 and CCL2) and the neutrophil and macrophage infiltrate into to the implants, indirectly evaluated by the activity of myeloperoxidase and N-acetyl-ß-D-glycosaminidase enzymes, respectively. In implants treated with biseugenol, we observed a reduction in angiogenesis, assessed through histological quantification of mean number of blood vessels, the levels of the pro-angiogenic cytokines FGF and VEGF and the activity of metalloproteinases. Except for VEGF levels, all mentioned parameters showed significant reductions after treatment with biseugenol. Finally, the administration of the compound also reduced TGF-ß1 levels, collagen synthesis and deposition, in addition to modifying the organization of the newly formed matrix, presenting a potential anti-fibrotic effect. Therefore, our results demonstrate the potential therapeutic use of biseugenol for the treatment of a series of pathological conditions, where parameters associated with inflammation, angiogenesis and fibrogenesis are deregulated.

An In Vivo Assessment of the Effect of Hexane Extract from Endlicheria paniculata Branches and Its Main Compound, Methyldehydrodieugenol B, on Murine Sponge-Induced Inflammation.

The present study aims to explore the anti-inflammatory potential activity of the hexane extract from branches (HEB) of Endlicheria paniculata (Lauraceae) and its main compound, methyldehydrodieugenol B, in the inflammatory response induced by a murine implant sponge model. HPLC-ESI/MS analysis of HEB led to the identification of six chemically related neolignans, with methyldehydrodieugenol B as the main compound. An in silico analysis of the pharmacokinetic parameters of the identified compounds suggested moderate solubility but good absorption and biodistribution in vivo. Thus, the treatment of mice with HEB using in vivo assays indicated that HEB promoted pro-inflammatory, antiangiogenic, and antifibrogenic effects, whereas treatment with methyldehydrodieugenol B caused anti-inflammatory, antifibrogenic, and antiangiogenic effects. The obtained results shown the therapeutic potential of HEB and methyldehydrodieugenol B in the treatment of pathologies associated with inflammation and angiogenesis, including chronic wounds.

Antiinflammatory activity of natural triterpenes-An overview from 2006 to 2021.

Terpenes are one of the most abundant classes of secondary metabolites produced by plants and can be divided based on the number of isoprene units (C5 ) in monoterpenes (2 units-C10 ), sesquiterpenes (3 units-C15 ), diterpenes (4 units-C20 ), triterpenes (6 units-C30 ), etc. Chemically, triterpenes are classified based on their structural skeleton including lanostanes, euphanes, cycloartanes, ursanes, oleananes, lupanes, tirucallanes, cucurbitanes, dammaranes, baccharanes, friedelanes, hopanes, serratanes etc. Additionally, glycosylated (saponins) or highly oxidated/degraded (limonoids) triterpenes could be found in nature. The antiinflammatory effect and action as immunomodulators of these secondary metabolites have been demonstrated in different studies. This review reports an overview of articles published in the last 15 years (from 2006 to 2021 using PubMed and SciFinder database) describing the antiinflammatory effects of different triterpenes with their presumed mechanism of action, suggesting that triterpenes could be appointed as natural products with future pharmaceutical applicability.

New perspectives on natural flavonoids on COVID-19-induced lung injuries.

The SARS-CoV-2 virus, responsible for COVID-19, spread rapidly worldwide and became a pandemic in 2020. In some patients, the virus remains in the respiratory tract, causing pneumonia, respiratory failure, acute respiratory distress syndrome (ARDS), and sepsis, leading to death. Natural flavonoids (aglycone and glycosides) possess broad biological activities encompassing antiinflammatory, antiviral, antitumoral, antiallergic, antiplatelet, and antioxidant effects. While many studies have focused on the effects of natural flavonoids in experimental models, reports based on clinical trials are still insufficient. In this review, we highlight the effects of flavonoids in controlling pulmonary diseases, particularly the acute respiratory distress syndrome, a consequence of COVID-19, and their potential use in coronavirus-related diseases. Furthermore, we also focus on establishing a relationship between biological potential and chemical aspects of related flavonoids and discuss several possible mechanisms of action, pointing out some possible effects on COVID-19.

In vivo anti-inflammatory activity of Fabaceae species extracts screened by a new ex vivo assay using human whole blood.

INTRODUCTION: Plants have been considered a promising source for discovering new compounds with pharmacological activities. The Fabaceae family comprises a large variety of species that produce substances with diverse therapeutic potential, including anti-inflammatory activity. The limitations of current anti-inflammatories generate the need to research new anti-inflammatory structures with higher efficacy as well as develop methods for screening multiple samples, reliably and ethically, to assess such therapeutic properties. OBJECTIVE: Validate and apply a quantification method for prostaglandin E2 (PGE2 ) production from an ex vivo assay in human blood in order to screen anti-inflammatory activity present in many Fabaceae species extracts. METHODS: Human blood was incubated with extracts from 47 Fabaceae species. After lipopolysaccharide (LPS)-induced inflammation, PGE2 was quantified in the plasma by liquid chromatography with tandem mass spectrometry (LC-MS/MS). The extracts that presented PGE2 production inhibition were further assessed through in vivo assay and then chemically characterised through an analysis of ultra-performance liquid chromatography electrospray ionisation quadrupole time-of-flight tandem mass spectrometry (UPLC-ESI-QTOF-MS2 ) data. RESULTS: The new ex vivo anti-inflammatory assay showed that five out of the 47 Fabaceae species inhibited PGE2 production. Results from an in vivo assay and the metabolic profile of the active extracts supported the anti-inflammatory potential of four species. CONCLUSION: The quantification method for PGE2 demonstrated fast, sensitive, precise, and accurate results. The new ex vivo anti-inflammatory assay comprised a great, reliable, and ethical approach for the screening of a large number of samples before an in vivo bioassay. Additionally, the four active extracts in both ex vivo and in vivo assays may be useful for the development of more efficient anti-inflammatory drugs.

Sesquiterpene Polygodial from Drimys brasiliensis (Winteraceae) Down-Regulates Implant-Induced Inflammation and Fibrogenesis in Mice.

Drimys brasiliensis (Winteraceae) has been investigated in traditional medicine for its anti-inflammatory properties to treat gastric ulcers and allergic and respiratory system diseases as well as for cancer treatment. In this work, we investigate the ability of the sesquiterpene polygodial, isolated from D. brasiliensis stem barks, to modulate the chronic inflammatory response induced by polyester-polyurethane sponge implants in C57BL/6J mice. Daily treatment with polygodial inhibited the macrophage content in the implants as determined by the activity of the N-acetyl-ß-d-glucosaminidase enzyme as well as decreased the levels of CXCL1/KC and CCL2/JE/MCP-1 pro-inflammatory chemokines and the presence of mast cells along the formed fibrovascular tissue. Similarly, the deposition of a new extracellular matrix (total collagen and type I and III collagen fibers) as well as the production of the TGF-ß1 cytokine were attenuated in implants treated with polygodial, showing for the first time its antifibrogenic capacity. The hemoglobin content, the number of newly formed vessels, and the levels of VEGF cytokine, which were used as parameters for the assessment of the neovascularization of the implants, did not change after treatment with polygodial. The anti-inflammatory and antifibrogenic effects of polygodial over the components of the granulation tissue induced by the sponge implant indicate a therapeutic potential for the treatment of inflammatory diseases associated with the development of fibrovascular tissue.

Antitrypanosomal activity of epi-polygodial from Drimys brasiliensis and its effects in cellular membrane models at the air-water interface.

Epi-polygodial, a drimane sesquiterpene was isolated from Drimys brasiliensis (Winteraceae). This compound demonstrated high parasite selectivity towards Trypanosoma cruzi trypomastigotes (IC50 = 5.01 µM) with a selectivity index higher than 40. These results were correlated with the effects observed when this compound was incorporated in cellular membrane models of protozoans, represented by Langmuir monolayers of dipalmitoylphosphoethanolamine (DPPE). Surface pressure-area isotherms showed that epi-polygodial expands DPPE monolayers at higher areas and condenses them at lower areas, which was attributed to the preferential interaction with the polar heads of the lipid. This mechanism of action could be corroborated with Polarization-Modulation Reflection-Absorption Spectroscopy and Brewster Angle Microscopy. These results pointed to the fact that the interaction of epi-polygodial with DPPE monolayers at the air-water interface affects the physical chemical properties of the mixed film, which may be important to comprehend the interaction of this drug with cellular membranes at the molecular level.

Interaction of sakuranetin with unsaturated lipids forming Langmuir monolayers at the air-water interface: A biomembrane model.

This study investigates the interaction between sakuranetin, a versatile pharmaceutical flavonoid, and monolayers composed of unsaturated phospholipids, serving as a surrogate for cell membranes. The phospholipids were 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE). We conducted a series of experiments to comprehensively investigate this interaction, including surface pressure assessments, Brewster angle microscopy (BAM), and polarization-modulated infrared reflection-absorption spectroscopy (PM-IRRAS). Our findings unequivocally demonstrate that sakuranetin interacts with these phospholipids, expanding the monomolecular films. Notably, regarding POPC, the presence of sakuranetin led to a reduction in stability and a decline in surface elasticity, which can likely be attributed to intricate molecular rearrangements at the interface. The visual evidence of aggregations in BAM images reinforces the interactions substantiated by PM-IRRAS, highlighting sakuranetin's interaction with the polar and nonpolar regions of POPC. However, it is worth noting that these aggregations do not appear to contribute significantly to the viscosity of the mixed film, and our investigations did not reveal any substantial hysteresis. In contrast, when examining POPE, we observed a minor reduction in thermodynamic stability, indicative of fewer rearrangements within the monolayer. This notion was further reinforced by the limited presence of aggregations in the BAM images. Sakuranetin also increased the rigidity of the lipid monolayer; nevertheless, the monolayer remained predominantly elastic, facilitating easy re-spreading on the surface, especially for the first lipid. PM-IRRAS analysis unveiled interactions between sakuranetin and POPE's polar and nonpolar segments, compellingly explaining the observed monolayer expansion. Taken together, our data suggest that sakuranetin was more effectively incorporated into the monomolecular layer of POPE, indicating that membranes comprised of POPC might exhibit a greater degree of interaction in the presence of this pharmacologically active compound.

Steam distillation, supercritical fluid extraction, and anti-Trypanosoma cruzi activity of compounds from pink pepper (Schinus terebinthifolius Raddi).

Anti-Trypanosoma cruzi activity of compounds from fruits of Schinus terebinthifolius Raddi (pink pepper) were evaluated, using sustainable techniques such as steam distillation (SD) and supercritical fluid extraction (SFE). SD was optimised using a design of experiment and SFE was carried out using supercritical CO2 solvent (300 bar and 60 °C). Results of the anti-T. cruzi activity showed that the essential oil presented high activity (IC50 = 4.5 ± 0.3 µg/mL), whereas the supercritical extract had a moderate effect (IC50 = 19.7 ± 2.9 µg/mL). The differences in the anti-T. cruzi activity can be attributed to the extraction of non-volatile compounds in the SFE, such as moronic and (Z)-masticadienoic acids. In contrast, SD extracted only volatile compounds such as monoterpenes and sesquiterpenes. Therefore, these results suggest that the volatile compounds from pink pepper are involved with the anti-T. cruzi activity.

Costic acid, a sesquiterpene from Nectandra barbellata (Lauraceae), attenuates sponge implant-induced inflammation, angiogenesis and collagen deposition in vivo.

Sesquiterpenes are a class of metabolites derived from plant species with immunomodulatory activity. In this study, we evaluated the effects of treatment with costic acid on inflammation, angiogenesis, and fibrosis induced by subcutaneous sponge implants in mice. One sponge disc per animal was aseptically implanted in the dorsal region of the mice and treated daily with costic acid (at concentrations of 0.1, 1, and 10 µg diluted in 10 µL of 0.5% DMSO) or 0.5% DMSO (control group). After 9 days of treatment, the animals were euthanized, and the implants collected for further analysis. Treatment with costic acid resulted in the reduction of the inflammatory parameters evaluated compared to the control group, with a decrease in the levels of inflammatory cytokines and chemokines (TNF, CXCL-1, and CCL2) and in the activity of MPO and NAG enzymes. Costic acid administration altered the process of mast cell degranulation. We also observed a reduction in angiogenic parameters, such as a decrease in the number of blood vessels, the hemoglobin content, and the levels of VEGF and FGF cytokines. Finally, when assessing implant-induced fibrogenesis, we observed a reduction in the levels of the pro-fibrogenic cytokine TGF-ß1, and lower collagen deposition. The results of this study demonstrate, for the first time, the anti-inflammatory, anti-angiogenic, and anti-fibrotic effects of costic acid in an in vivo model of chronic inflammation and reinforce the therapeutic potential of costic acid.

Identification of inhibitors as drug candidates against Chagas disease.

Chagas disease, after more than a century after its discovery, is still a major public health problem. It is estimated that approximately 10 million people worldwide are infected with T. cruzi. However, the situation is more critical in Latin America and other regions where the disease is endemic. The largest number of cases occurs in Brazil, Argentina, and Mexico as more than 100 million people in these regions are located in areas with a high risk of contamination by the vector. The need for new therapeutic alternatives is urgent, as the available drugs have severe limitations such as low efficacy and high toxicity. From this scenario, in this work, we employed the virtual screening technique using cruzain and BDF2 as key biological targets for the survival of the parasite. Our objective was to identify potential inhibitors of T. cruzi trypomastigotes, which could be considered drug candidates against Chagas disease. For this, we employed different in silico methodologies and the obtained results were corroborated using in vitro biological assays. For the VS studies, a database containing synthetic compounds was simulated at the binding site of cruzain and BDF2. In addition, pharmacophoric models were constructed in the initial phases of VS, as well as other advanced analyses (molecular dynamics simulations, calculations of binding free energy, and ADME prediction) were carried out and the results allowed the selection of potential inhibitors of T. cruzi. Based on the obtained data, 32 different compounds commercially available were subjected to biological tests against the trypomastigote form of T. cruzi. As result, 11 of those compounds displayed significant activity against T. cruzi and can be considered potential candidates for the treatment of Chagas disease.

The Potential of Secondary Metabolites from Plants as Drugs or Leads against Trypanosoma cruzi-An Update from 2012 to 2021.

BACKGROUND: Chagas disease (American Trypanosomiasis) is classified by the World Health Organization (WHO) as one of the seventeen neglected tropical diseases (NTD), affecting, mainly, several regions of Latin America. INTRODUCTION: However, immigration has expanded the range of this disease to other continents. Thousands of patients with Chagas disease die annually, yet no new therapeutics for Chagas disease have been approved, with only nifurtimox and benznidazole available. Treatment with these drugs presents several challenges, including protozoan resistance, toxicity, and low efficacy. Natural products, including the secondary metabolites found in plants, offer a myriad of complex structures that can be sourced directly or optimized for drug discovery. METHODS: Therefore, this review aims to assess the literature from the last 10 years (2012-2021) and present the anti-T. cruzi compounds isolated from plants in this period, as well as briefly discuss computational approaches and challenges in natural product drug discovery. Using this approach, more than 350 different metabolites were divided based on their biosynthetic pathway alkaloids, terpenoids, flavonoids, polyketides, and phenylpropanoids which displayed activity against different forms of this parasite epimastigote, trypomastigote and more important, the intracellular form, amastigote. CONCLUSION: In this aspect, there are several compounds with high potential which could be considered as a scaffold for the development of new drugs for the treatment of Chagas disease-for this, more advanced studies must be performed including pharmacokinetics (PK) and pharmacodynamics (PD) analysis as well as conduction of in vivo assays, these being important limitations in the discovery of new anti-T. cruzi compounds.

Effect of partial O-methylation in dehydrodieugenol on its antitrypanosomal activity - correlation with the toxicity using cell membrane models.

Biseugenol (1), a neolignan with antiprotozoal activity against Trypanosoma cruzi, was partially methylated, and the compound obtained - methyl biseugenol (2) - had its activity evaluated against the extracellular (trypomastigotes) and intracellular (amastigotes) forms of T. cruzi. It was observed that both compounds 1 and 2 exhibited similar effects against trypomastigotes (IC50 of 11.7 and 16.2 µM, respectively), whereas compound 2 displayed higher activity against amastigotes (IC50 = 8.2 µM) in comparison with biseugenol (IC50 = 15.4 µM). Additionally, reduced toxicity against NCTC cells for compound 2 was observed (CC50 > 200 µM), differently from compound 1 with CC50 = 58.0 µM. Aiming to understand better the molecular mechanism of the biological action of compound 2, the prodrug was incorporated into cellular membrane models constituted of Langmuir monolayers of the lipids dipalmitoylphosphatidylcholine (DPPC), dipalmitoylphosphatidylethanolamine (DPPE), dipalmitoylphosphatidylserine (DPPS), and dipalmitoylphosphatidylglycerol (DPPG). The lipid-drug interaction was inferred through tensiometry, surface potential, infrared spectroscopy (PM-IRRAS), and Brewster angle microscopy (BAM). The prodrug expanded DPPC and DPPG monolayers and condensed DPPE ones, as well as presented characteristic behaviors regarding the chemical structure of the lipid considering expansion-compression curves, surface potential-area isotherms, and stability of previously compressed monolayers to relevant-biological surface pressures. PM-IRRAS indicated a molecular disorder for DPPC and DPPS alkyl chains in the presence of the drug. BAM revealed the presence of domains in the DPPG and DPPE monolayers, which was probably induced by the prodrug. These data suggest, in general, that the lipid composition modulates the interaction of compound 2, whose results are expected to correlate to its trypanocidal activity, which involves the plasma membrane of T. cruzi as the primary target, i.e., the first barrier that the compound should encounter to interact with the microorganism.

Cytotoxic effects of neolignans from Saururus cernuus (Saururaceae) against prostate cancer cells.

In this study, five neolignans were isolated from Saururus cernuus-threo-dihydroguaiaretic acid (1), threo-austrobailignan-6 (2), threo-austrobailignan-5 (3), verrucosin (4), and saucernetin (5)-and have their cytotoxic effects evaluated in prostate cancer cell lines (PC3 and DU145). Initially, using an in silico approach, tested compounds were predicted to be absorbed by the gastrointestinal tract, be able to permeate the blood-brain barrier and did not show any alert in PAINS (pan-assay structures interference). In vitro assays showed that compounds 2, 4, and 5 reduced cell viability of DU145 cell line at 100 µmol/L after 48 h while compounds 1 and 3 showed to be inactive at the same conditions. Furthermore, compounds 4 and 5 reduced cell number as early as in 24 h at 50 µmol/L and compound 2 showed effects at 100 µmol/L in 24 h against both cancer cell lines PC3 and DU145. Studies using flow cytometry were conducted and indicated that compound 4 induced strong necrosis and apoptosis whereas compound 5 induced strong necrosis. Otherwise, less active compound 2 did not show evidence of induction of apoptosis or necrosis, suggesting that its mechanism of action involves inhibition of cell proliferation. In conclusion, compounds 4 and 5 have been shown to be promising cytotoxic agents against prostate cancer cell lines and can be used as a starting point for the development of new drugs for the treatment of prostate cancer.

Supplementation with okra combined or not with exercise training is able to protect the heart of animals with metabolic syndrome.

The metabolic syndrome (MetS) is a clinical manifestation strongly associated with cardiovascular disease, the main cause of death worldwide. In view of this scenario, many therapeutic proposals have appeared in order to optimize the treatment of individuals with MetS, including the practice of exercise training (ET) and the consumption of okra (O). The aim of the present study was to evaluate the effect of O consumption and/or ET in animals with MetS. In all, 32 male Zucker rats (fa/fa) at 10 weeks old were randomly distributed into four groups of 8 animals each: MetS, MetS+O, MetS+ET and MetS+ET+O, and 8 lean Zucker rats (fa/ +) comprised the control group. Okra was administered by orogastric gavage 2x/day (morning and night, 100 mg/kg), 5 days/week, for 6 weeks. The ET was performed on a treadmill 1x/day (afternoon), 5 days/week, 60 min/day, in an intensity of 70% of maximal capacity, for the same days of O treatment. It was found that, O consumption alone was able to promote improved insulin sensitivity (MetS 93.93 ± 8.54 mg/dL vs. MetS+O 69.95 ± 18.7 mg/dL, p ≤ 0.05, d = 1.65, CI = 50.32 -89.58, triglyceride reduction (MetS 492.9 ± 97.8 mg/dL vs. MetS+O 334.9 ± 98.0 mg/dL, p ≤ 0.05, d = 1.61, CI = 193.2-398.7). In addition, it promoted a reduction in systolic blood pressure (MetS 149.0 ± 9.3 mmHg vs. MetS+O 132.0 ± 11.4 mmHg, p ≤ 0.05, d = 1.63, CI = 120-140), prevented an increase in cardiac collagen (MetS 12.60 ± 2.08% vs. MetS+O 7.52 ± 0.77%, p ≤ 0.05, d = 3.24, CI = 6.56-8.49). When associated with ET, the results were similar. Thus, we conclude that O consumption combined or not with aerobic ET can have a protective effect on the cardiac tissue of rats with MetS.

Chemical annotation of the infusion of Jungia floribunda Less and its inhibitory potential on the elastase enzyme.

Jungia floribunda Less. is a shrub belonging to the Asteraceae. The infusion of its leaves has been used, in folk medicine of several South American countries, as anti-inflammatory and hypoglycaemic agent. In the present study, the infusion of leaves from J. floribunda was obtained and its chemical composition was determined by UHPLC-MS associated with molecular network allowing the annotation of flavonoids, sesquiterpene lactones, coumarins, and chlorogenic acid derivatives. Besides, in vitro elastase activity assay was carried out with the infusion. As observed, elastase was inhibited at concentrations ranging from 15 to 240 µg/mL, reaching to 71% of inhibition at the maximum of evaluated concentration. Given that species of plants are promising sources for the discovery of new drugs, these results corroborate the infusion of J. floribunda as a potential source of bioactive compounds for the discovery of new inhibitors for elastase, besides its ethnopharmacological aspects.

Potential anti-inflammatory biomarkers from Myrtaceae essential oils revealed by untargeted metabolomics.

Many species from Myrtaceae have traditionally been used in traditional medicine as anti-inflammatory, antimicrobial, antidiarrheal, antioxidant and antirheumatic, besides in blood cholesterol reduction. In the present work, the anti-inflammatory activity of essential oils from eighteen Myrtaceae spp. were evaluated according to their ex-vivo anti-inflammatory activity in human blood, and the corresponding biomarkers were determined using untargeted metabolomics data and multivariate data analysis. From these studied species, six displayed anti-inflammatory activity with percentage rates of inhibition of PGE2 release above 70%. Caryophyllene oxide (1), humulene epoxide II (2), ß-selinene (3), α-amorphene (4), α-selinene (5), germacrene A (6), ß-bisabolene (7), α-muurolene (8), α-humulene (9), ß-gurjunene (10), myrcene (11), ß-elemene (12), α-cadinol (13), α-copaene (14), E-nerolidol (15) and ledol (16) were annotated as potential anti-inflammatory biomarkers. The results obtained in this study point to essential oils from species of the Myrtaceae family as a rich source of anti-inflammatory agents.

Therapeutic Activity of a Topical Formulation Containing 8-Hydroxyquinoline for Cutaneous Leishmaniasis.

Cutaneous leishmaniasis exhibits a wide spectrum of clinical manifestations; however, only a limited number of drugs are available and include Glucantime® and amphotericin B, which induce unacceptable side effects in patients, limiting their use. Thus, there is an urgent demand to develop a treatment for leishmaniasis. Recently, it was demonstrated that 8-hydroxyquinoline (8-HQ) showed significant leishmanicidal effects in vitro and in vivo. Based on that, this work aimed to develop a topical formulation containing 8-HQ and assess its activity in experimental cutaneous leishmaniasis. 8-HQ was formulated using a Beeler base at 1 and 2% and showed an emulsion size with a D50 of 25 and 51.3 µm, respectively, with a shear-thinning rheological behaviour. The creams were able to permeate artificial Strat-M membranes and excised porcine skin without causing any morphological changes in the porcine skin or murine skin tested. In BALB/c mice infected with L. (L.) amazonensis, topical treatment with creams containing 1 or 2% of 8-HQ was found to reduce the parasite burden and lesion size compared to infected controls with comparable efficacy to Glucantime® (50 mg/kg) administered at the site of the cutaneous lesion. In the histological section of the skin from infected controls, a diffuse inflammatory infiltrate with many heavily infected macrophages that were associated with areas of necrosis was observed. On the other hand, animals treated with both creams showed only moderate inflammatory infiltrate, characterised by few infected macrophages, while tissue necrosis was not observed. These histological characteristics in topically treated animals were associated with an increase in the amount of IFN-γ and a reduction in IL-4 levels. The topical use of 8-HQ was active in decreasing tissue parasitism and should therefore be considered an interesting alternative directed to the treatment of leishmaniasis, considering that this type of treatment is non-invasive, painless, and, importantly, does not require hospitalisation, improving patient compliance by allowing the treatment to be conducted.