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In this paper, we measured B cell function in elderly healthy individuals (EH) and in elderly patients with Type-2 Diabetes Mellitus (T2DM, ET2DM), which are treatment-naive, as compared to healthy young (YH) individuals. Results show a higher serum inflammatory status of elderly versus young individuals, and especially of ET2DM versus EH. This status is associated with a reduced response to the seasonal influenza vaccine and with increased frequencies of the circulating pro-inflammatory B cell subset called Double Negative (DN) B cells. B cells from ET2DM patients are not only more inflammatory but also hyper-metabolic as compared to those from EH controls. The results herein are to our knowledge the first to show that T2DM superimposed on aging further increases systemic and B cell intrinsic inflammation, as well as dysfunctional humoral immunity. Our findings confirm and extend our previously published findings showing that inflammatory B cells are metabolically supported. [ABSTRACT FROM AUTHOR]

Objective: This systematic review aimed to analyze the clinical (survival rate, failure risk, or fracture) and laboratory performance (fracture mode or failure) of rehabilitations of endodontically treated teeth, with and without posts. Materials and Methods: A systematic search was conducted in the Pubmed, Scopus, Web of Science, Embase, Cochrane Library, and OpenGrey databases up to March 2023, according to PRISMA guidelines. In vitro and clinical studies that compared the clinical and laboratory performance of endodontically treated teeth with and without intraradicular posts were included. Studies selection, data extraction, and risk of bias analysis were performed. Results: Thirty‐one in vitro and 7 clinical studies were included. For in vitro studies, fiberglass post (n = 24) was the most mentioned. The follow‐up time of the clinical studies ranged from 1 to 17 years, with the fiber‐reinforced composite post (n = 3) being the most evaluated, and only failure risk proved to be more favorable for using intraradicular posts. Conclusion: Rehabilitations of endodontically treated teeth with and without intraradicular retainers showed no difference in fracture resistance and failure mode, evaluated by in vitro studies. Clinical studies showed no difference in survival rate, but failure risk proved to be more favorable for the use of posts. Clinical Significance: This analysis revealed significant variability between results, however, most laboratory and clinical studies revealed no difference with using the post. Furthermore, it is important to emphasize the need to evaluate the coronary remnant and the general characteristics of the tooth in each situation. [ABSTRACT FROM AUTHOR]

This study aims to analyze, through an experimental study with a quantitative and descriptive approach, the toxicity and identification of the 50% Lethal Concentration (LC50) of the reference and generic paracetamol drops, both commercially available and produced in Brazil, comparing them with each other. The lethality test was performed on Artemia salina according to the methodology described by Meyer (1982), with some modifications. When performing the toxicity test on Artemia salina, for generic paracetamol, the LC50 obtained after 24 hours was 998.3 ± 0.2μg/ mL. The reference paracetamol presented LC50 of 612.2 ± 1.3μg/mL. Based on the analysis of this research, it was found that the reference paracetamol presented signs of toxicity in nauplii of the microcrustacean Artemia salina, presenting a LC50 ≤1000μg/mL. Generic paracetamol showed a LC50 ≤1000μg/mL with a range above 1000 ug/mL indicating non-toxicity for this sample [ABSTRACT FROM AUTHOR]

Introduction: The final step of irrigation has been considered to of increase the bonding strength of filling material to dentin. This study investigated the impact of three final-step irrigation methods on the endodontic sealer bond strength to dentin by using a micro push-out test. Materials and Methods: Palatal roots of human maxillary molars were cleaned and shaped and randomly divided in six groups (n=15) according to the final-step irrigation method and the type of root canal sealer used. The solutions used for the final-step irrigation were 17% ethylenediaminetetraacetic acid and 2.5% sodium hypochlorite, which underwent three methods: 1) syringe-needle irrigation/conventional, 2) passive ultrasonic irrigation, and 3) XP-endo Finisher agitation. The root canal sealers used were: EndoSequence BC Sealer, and AH-Plus sealer. Roots were obturated with the single cone technique and then, cross-sectioned in 2-mm-thick slices (3 slices from each root). Push-out test was performed on the sliced specimens (cervical, middle, and apical thirds) with a universal testing machine. Bond strength values were recorded in megapascal (MPa). Subsequently, each specimen was longitudinally split to verify the type of failure. Data analysis was performed using Johnson transformation, three-way analysis of variance, Tukey's post-hoc tests, and the partial Eta squared test. Results: There were significant differences in bond strength between the sealers [AH: 4.46±2.24 and BC: 3.47±2.19 MPa (P<0.001)]; between final-step irrigation methods [passive ultrasonic irrigation: 4.52±2.25, XP-endo Finisher: 3.93±3.93 and syringe-needle irrigation/conventional: 3.37±2.51 MPa (P<0.001)], and between the root canal thirds represented by the sliced specimens [cervical: 5.45±2.39, middle: 4.14±1.99 and apical: 2.30±1.30 MPa (P<0.001)]. The interaction between the variables had no significance (P>0.05). Conclusion: Agitation of the final irrigating solution may improve the bonding of the sealer to canal walls. AH-Plus sealer had the highest bond strength. The bond strength reduced significantly towards the apical third. [ABSTRACT FROM AUTHOR]

Simple Summary: Adrenocortical tumors are rare neoplasms with an uncertain prognosis. A greater understanding of the biology of these tumors will allow new therapeutic targets to be identified and the prognosis of these patients to be better understood, enabling more precise therapeutic targeting. Our study sought to evaluate the expression of the PRKAB2 gene as a prognostic biomarker in 63 cases of pediatric adrenocortical tumors and to analyze how efficient Rottlerin is in altering the tumorigenic profile of the NCI-H295R adrenocortical carcinoma (ACC) cell line. Pediatric adrenocortical tumors (ACTs) are rare, highly heterogeneous neoplasms with limited therapeutic options, making the investigation of new targets with potential therapeutic or prognostic purposes urgent. The PRKAB2 gene produces one of the subunits of the AMP-activated protein kinase (AMPK) complex and has been associated with cancer. However, little is known about the role AMPK plays in ACTs. We have evaluated how PRKAB2 is associated with clinical and biological characteristics in 63 pediatric patients with ACTs and conducted in vitro studies on the human NCI-H295R ACC cell line. An analysis of our cohort and the public ACC pediatric dataset GSE76019 showed that lower PRKAB2 expression was associated with relapse, death, metastasis, and lower event-free and overall survival rates. Multivariate analysis showed that PRKAB2 expression was an independent prognostic factor when associated with age, tumor weight and volume, and metastasis. In vitro tests on NCI-H295R cells demonstrated that Rottlerin, a drug that can activate AMPK, modulated several pathways in NCI-H295R cells, including AMPK/mTOR, Wnt/β-catenin, SKP2, HH, MAPK, NFKB, and TNF. Treatment with Rottlerin decreased cell proliferation and migration, clonogenic capacity, and steroid production. Together, these results suggest that PRKAB2 is a potential prognostic marker in pediatric ACTs, and that Rottlerin is promising for investigating drugs that can act against ACTs. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the penetration of hydrogen peroxide (HP) into the pulp chamber and the color change of different bleaching varnishes in low concentrations used for at‐home bleaching. Materials and Methods: Ninety healthy premolars were used, randomly distributed into nine groups (n = 10) according to bleaching varnish (PL, PolaLuminate; VS, VivaStyle Paint On Plus; CA, Cavex Bite&White whitening pen and; AW AlignerWhite) and time (10 and 30 min), and a control group (no bleaching). The penetration of HP was evaluated by UV–Vis spectroscopy. To evaluate the color change (ΔEab, ΔE00, ΔWID) a digital spectrophotometer was used (α = 0.05). Results: The AW group in 10 min and the control group showed similar and lower HP penetration in the pulp chamber when compared to the other groups (p = 0.003). Increasing the application time to 30 minutes elevated the amount of HP inside the pulp chamber for all groups (p = 0.003), except for PL (p > 0.05). When applied for 30 min all bleaching varnishes showed higher color change (ΔWID) when compared to 10 min (p = 0.04). Conclusions: For all bleaching varnishes evaluated, PolaLuminate applied for 30 min showed lower penetration into the pulp chamber and higher bleaching effects. Clinical Significance: The use of bleaching varnishes seems promising for teeth bleaching, but it varies according to user product and protocol. [ABSTRACT FROM AUTHOR]

Propolis is a resinous substance collected by bees (Apis mellifera). It is used for its biological properties. This natural product is available as a safe therapeutic option. Herein, we report the antiviral effects of brown propolis extract from Mexico and green and red propolis extracts from Brazil, as well as their phenolic compounds (quercetin, caffeic acid, and rutin) in preventing infection of MRC-5 cells by HCoV-229E. Normal human fibroblast lung cells (MRC-5) were used to determine the cytotoxicity of the compounds. All samples studied showed antiviral activity. Green and brown propolis extracts, and quercetin exhibited the best EC50 values with values of 19.080, 11.240, and 77.208 µg/mL against HCoV-229E, respectively, and with TC50 of 62.19, 29.192, and 298 µg/mL on MRC-5 cells, respectively. These results are the first in vitro study of the effects of propolis on HCoV-229E and provide the basis for the development of natural formulations against other coronavirus strains. [ABSTRACT FROM AUTHOR]

Epidemiologic studies suggest an inverse correlation between coffee consumption and the occurrence of neurodegenerative diseases, but the role of caffeine and roasting degree are still matter of debate. The objective of this work was to evaluate the effects of caffeinated (light, medium, and dark roast) and decaffeinated instant coffee samples in acetylcholinesterase (AchE) inhibition and antioxidant assays, as well as in animal models of Parkinson's disease. Caffeinated coffees inhibited the AchE in much smaller concentrations than decaffeinated coffee. All coffee samples showed antioxidant capacity without relation with the caffeine content. Blockade in the haloperidol-induced catalepsy was observed with caffeinated coffee, but not in the decaffeinated sample. The medium-roast coffee reduced the number of rotations of rats after methamphetamine administration on the 6-hydroxydopamine unilateral lesion of the medial forebrain bundle. However, the coffee treatment did not avoid the loss of dopaminergic neurons on substantia nigra pars compact and only the smallest dose of coffee was able to avoid the decrease of dopamine levels in the lesioned side of the striatum. Altogether, these results suggest that coffee exerts moderate pro-cholinergic and pro-dopaminergic effects and caffeine seems to be the main factor responsible for these effects. [ABSTRACT FROM AUTHOR]

Salvia lachnostachys Benth is native to Brazil and has anti-inflammatory, anti-arthritic, cytotoxic, antitumor, and antihyperalgesic activities. The population, including pregnant women, consume this plant to treat pain, inflammation, flu, spasms, insomnia, and depression, mainly. There are no safety reports on the use of this plant during pregnancy. The present study aimed to evaluate the effects of S. lachnostachys ethanolic extract (EESl) on reproductive performance, embryofetal development, and DNA integrity of pregnant female mice. Pregnant females were randomly divided into three experimental groups (n = 10): The Control group was treated with a vehicle, and treatment groups were administered with EESl at 100 and 1000 mg/kg, respectively. Treatment occurred by gavage throughout the gestational period until day 18. Afterward, reproductive performance, embryofetal development, and DNA integrity parameters were evaluated. The results indicated that EESl did not alter any reproductive performance parameters. However, it changed embryofetal outcome through reduced placental weight (EESl 100 mg/kg), decreased fetal weight (EESl 100 and 1000 mg/kg), and increased frequency of small for gestational age fetuses (EESl 1000 mg/kg). In addition, EES1 increased the frequency of external, visceral, and skeletal malformations. Because of the above, it is considered that EESl is not maternotoxic, does not alter reproductive performance, but does alter embryofetal development. Its use in the gestational period is not indicated due to its teratogenic potential. [ABSTRACT FROM AUTHOR]

H. pectinata (L.) Poit, popularly known as " sambacaitá " or " canudinho ", is a plant endemic to north-eastern Brazil. Its aerial parts, leaves and flowers have traditionally been used to treat gastrointestinal disorders, rhinopharyngitis, nasal congestion, bacterial and fungal infections, fever, colic, inflammation, and pain. The aim of this review was to provide information on the botanical characteristics, ethnomedicinal uses, phytochemistry and biological-pharmacological activities of H. pectinata. This systematic review followed the Cochrane Handbook Collaboration and the PRISMA guidelines. The review question was what are the biological-pharmacological activities of H. pectinata presented in non-clinical studies. The search for articles was conducted in the Medline (via PubMed), Embase, Web of Science, Scopus, Virtual Health Library, SciELO, Google Scholar and the Brazilian Digital Library of Theses and Dissertations databases. Two reviewers independently selected the studies that met the inclusion criteria, extracted the data, and assessed the risk of bias of the included studies. 39 articles were included in this review, of which 19 reported in vitro experiments, 16 in vivo studies and 4 in vivo and in vitro experiments. H. pectinata is a plant widely used in folk medicine in north-eastern Brazil for the treatment of various ailments, such as respiratory diseases, gastrointestinal disorders, bacterial and fungal infections, and general inflammation. Supporting its popular use, several in vitro and in vivo pharmacological investigations of the essential oil and extract of H. pectinata have demonstrated their anti-inflammatory, antinociceptive, antioxidant, antidepressant, anticancer, hepatoregenerative, healing, and antimicrobial activities. H. pectinata has been reported to contain 75 bioactive constituents, comprising 9 flavonoids, 54 terpenes, and 12 other compounds. H. pectinata is a plant commonly used in traditional medicine. Phytochemically, it contains several bioactive constituents, including terpenes and flavonoids, and has been shown to have antinociceptive, anti-inflammatory, antimicrobial and antitumour activity, as well as hepatorregenerative and healing effects, and low toxicity. [Display omitted] • H. pectinata is widely used in traditional medicine in north-eastern Brazil. • Preparations of H. pectinata are rich in alkaloids, monoterpenes, and flavonoids. • H. pectinata exhibits diverse biological activities. • H. pectinata does not present toxicity. [ABSTRACT FROM AUTHOR]

Snakebite envenomation (SBE) is the world's most lethal neglected tropical disease. Bothrops jararaca is the species that causes the greatest number of SBEs in the South and Southeastern of Brazil. The main symptoms are local (inflammation, edema, hemorrhage, and myonecrosis) and systemic (hemorrhage, hemostatic alterations with consumptive coagulopathy, and death) effects. Species of the genus Siparuna , Siparunaceae, are used in folk and traditional medicine to treat SBE. However, limited information is available concerning Brazilian Siparuna species against SBE. To investigate the correlation between the compounds present in the extracts of five Siparuna species as potential agents against proteolytic activity, plasma coagulation, and phospholipase A 2 (PLA 2) activity caused by B. jararaca venom, using data obtained by UHPLC-MS/MS, biological activity, and multivariate statistics. The ethanol extracts from leaves of S. ficoides , S. decipiens , S. glycycarpa , S. reginae, and S. cymosa were fractionated by liquid-liquid extraction using different solvents of increasing polarity (hexane, dichloromethane, ethyl acetate, and n -butanol), affording their respective extracts, totaling 25 samples that were assayed through in vitro plasma coagulation and proteolytic activity assays. Moreover, the extracts were analyzed by UHPLC-MS/MS, using electrospray ionization (ESI) and atmospheric-pressure chemical ionization (APCI) in negative and positive ionization modes. The data was processed in MZmine v. 2.53 and evaluated by multivariate statistical tests (PLS) using the software UnscramblerX v. 10.4. These data were also used to build molecular networks (GNPS), and some ions of interest could be annotated using the library of molecules on the GNPS platform. A total of 19 extracts inhibited B. jararaca -induced plasma coagulation, with emphasis on S. cymosa and S. reginae (800 s). The inhibition of the proteolytic activity was also promising, ranging from 16% (S. glycycarpa) to 99% (S. cymosa, S. decipiens, and S. reginae). In addition, most extracts from S. cymosa and S. reginae inhibited 70–90% of PLA 2 activity. Based on data from positive mode APCI analyses, it was possible to obtain a statistic model with reliable predictive capacity which exhibited an average R2 of 0.95 and a Q2 of 0.88, indicating a robust fit. This process revealed five ions, identified as the alkaloids: coclaurine (1), stepholidine (2) O -methylisopiline (3), nornantenine (4) and laurolitsine (5). This is the first study to evidence the potential antivenom of alkaloids from Siparuna species. Altogether, our results give support to the popular use of Siparuna extracts in SBE accidents, suggesting their potential as an alternative or complementary strategy against envenoming by B. jararaca venom. The predicted ions in the chemometric analysis for the assayed activities can also be correlated with the blocking activity and encourage the continuation of this study for possible isolation and testing of individual compounds on the used models. [Display omitted] • Siparuna spp. are used in folk medicine to counter snakebite envenomation in tropics. • Siparuna extracts inhibited B. jararaca snake venom proteolytic activity (30–96%). • Siparuna extracts inhibit B. jararaca venom-induced plasma coagulation (75–800s). • Siparuna extracts can inhibit up to 90% of PLA 2 of B. jararaca activity. • Five alkaloids in the PLSr model are candidates with potential antivenom activity. [ABSTRACT FROM AUTHOR]

Warfarin is the most widely used anticoagulant in the world, but it has several limitations including its narrow therapeutic range, need for dose adjustment and high potential for interactions. The simultaneous use of other drugs or even medicinal plants and certain foods could interfere with its therapeutic activity. In this context, this study aims to investigate the in vitro anticoagulant potential and phytochemical constitution of 17 plants selected from a previous clinical cross-sectional study (2014), that investigated the habits of plant utilization among patients taking warfarin. Ethanol extracts and essential oils were evaluated, in vitro, as to their effect in the prothrombin time (PT) and activated partial thromboplastin time (aPTT) tests. Four species that presented aPTT >50 s were selected for phytochemical evaluation. Thirteen of the 17 plants selected demonstrated a significant anticoagulant effect in at least one of the evaluated parameters. Citrus sinensis (PT=14.75 and aPTT=53.15), Mentha crispa (aPTT=51.25), Mikania laevigata (PT=14.90 and aPTT=52.10), and Nasturtium officinale (aPTT=50.55) showed greater anticoagulant potential compared to normal plasma pool (PT=12.25 and aPTT=37.73). Chemical profiles of these four species were obtained, and certain compounds were identified: rosmarinic acid from M. crispa and isoorientin from N. officinale. Thus, the results of this study could be a useful indicator for clinical practice towards the possibility of interaction between these plants and anticoagulants, although further clinical research is needed taking into consideration the limitations of in vitro studies. These findings also suggest that further research into the action of these plants could be of real clinical value in identifying potential alternative anticoagulant therapies. [ABSTRACT FROM AUTHOR]

The species Jatropha gossypiifolia, popularly known as "pinhão-roxo", is distributed throughout Brazil, is commonly employed for topical or oral administration in treating wounds, inflammations, and snake bites. Given the significant impact of snakebites on public health and the limitations of antivenom, coupled with the diverse molecular composition of this plant species, investigating its healing and antidermonecrotic capacities is relevant. This study aimed to develop a topical nanoemulsion incorporating the hydroethanolic extract of J. gossypiifolia leaves, to evaluate its therapeutic potential, particularly in terms of its efficacy in wound healing and inhibition of dermonecrosis induced by B. erythromelas venom (BeV). The extract of J. gossypiifolia (JgE) leaves was obtained by maceration and remaceration. The phytochemical analysis was conducted and J. gossypiifolia nanoemulsion (JgNe) was obtained, characterized and assessed for stability. The cytotoxicity was determined in normal cells (erythrocytes and 3T3) using hemolytic assay and cell viability assay using crystal violet staining. The antioxidant activity was evaluated by the reduction of ABTS and DPPH radicals. The evaluation of wound healing was conducted in vivo following treatment with JgNe, wherein the percentage of wound closure and inflammatory mediators. The skin irritation test was assessed in vivo by applying JgNe directly to the animal's skin. In vitro , the antivenom capacity was evaluated through enzymatic inhibition assays (phospholipase A 2 and hyaluronidase) of BeV. Additionally, the in vivo antidermonecrotic activity of JgNe was evaluated by measuring the reduction of the dermonecrotic halo. The HPLC-DAD analysis identified flavonoids, specifically vitexin, luteolin derivatives and apigenin derivatives. In addition, 95.08 ± 5.46 mg of gallic acid/g of extract and 137.92 ± 0.99 mg quercetin/g extract, was quantified. JgNe maintained stability over a 4-week period. Moreover, JgE and JgNe demonstrated no cytotoxicity in human erythrocytes and murine fibroblasts at tested concentrations (32.25–250 μg/mL). Additionally, exhibited significant antioxidant activity by reducing ABTS and DPPH radicals. The treatment with JgNe did not induce skin irritation and accelerated wound healing, with significant wound closure observed from 5th day and reduction in nitrite levels, myeloperoxidase activity, and cytokine. Both JgE and JgNe demonstrated in vitro inhibition of the phospholipase and hyaluronidase enzymes of BeV. Moreover, JgNe exhibited antidermonecrotic activity by reducing the dermonecrotic halo caused by BeV after 24 h. JgNe and JgE exhibited no cytotoxicity at the tested concentrations. Additionally, our findings demonstrate that JgNe has the ability to accelerate wound closure and reduce dermonecrosis caused by BeV, indicating to be promising formulation for complementary therapy to antivenom treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

Cordiera myrciifolia is an abundant species in Northeast Brazil that presents metabolites of biological/therapeutic interest. From this perspective, the present study aimed to investigate the chemical constituents and evaluate the in vitro antimicrobial activity of hexane (HECM) and ethanolic (EECM) extracts of C. myrciifolia leaves. The extracts were analyzed by chromatographic techniques (GC and UPLC) coupled with mass spectrometry. The antimicrobial activity of the extracts and the extracts combined with conventional drugs was evaluated by microdilution. The in vitro effect of the treatments on Candida 's morphological transition was verified through cultivation in humid chambers. In HECM, 11 constituents including fatty acids, and triterpenes, including phytosterols, alkanes, tocols, and primary alcohols were identified. Triterpenes represented >40% of the identified constituents, with Lupeol being the most representative. In EECM, 13 constituents were identified, of which eight belonged to the class of flavonoids. High antibacterial activity of HECM was detected against Escherichia coli and Staphylococcus aureus , with Minimum Inhibitory Concentrations of 8 and 16 μg/mL, respectively. The combined activity was more effective when combined with Norfloxacin and Imipenem. In anti- Candida activity, the IC 50 of the extracts ranged from 36.6 to 129.1 μg/mL. There was potentiating effect when associated with Fluconazole. Both extracts inhibited the filamentous growth of C. tropicalis at a concentration of 512 μg/mL. C. myrciifolia extracts prove to be candidates for the development of new therapeutic formulations to treat bacterial and fungal infections. [Display omitted] • The hexane extract of Cordiera myrciifolia (HECM) has antibacterial effect. • The ethanolic extract (EECM) potentiates the action of Norfloxacin and Imipenem. • HECM and EECM showed antifungal activity against Candida. • HECM shows lupeol as major compound and EECM contains a large number of flavonoids. [ABSTRACT FROM AUTHOR]

In Brazil, latex from Euphorbia umbellata (African milk tree) has been increasingly used in folk medicine to treat several types of cancer, including melanoma. The effect of lyophilized latex (LL), its hydroethanolic extract (E80), triterpene (F-TRI)- and diterpene (F-DIT)-enriched fractions, along with six isolated phorbol esters from LL and phorbol 12-myristate 13-acetate (PMA) on J774A.1, THP-1, SK-MEL-28, and B16-F10 cell line viability were evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method. The compounds were identified by 2D-NMR and HRESIMS. The effect of the LL, extract and fractions on cell viability was also assessed through a resazurin reduction assay. At 100 μg/ml, LL, and its fractions moderately inhibited J774A.1 (37.5–59.5%) and THP-1 (12.6–43.6%) metabolism. LL (IC 50 70 μg/ml) and F-TRI (IC 50 68 μg/ml) were barely more effective against B16-F10 cells, and only F-TRI exerted an inhibitory effect on SK-MEL-28 cells (IC 50 66–75 μg/ml). The samples did not effectively inhibit THP-1 growth (IC 50 69–87 μg/ml, assessed by MTT). B16-F10 was susceptible to PMA (IC 50 53 μM) and two 12-phenylacetate esters (IC 50 56–60 μM), while SK-MEL-28 growth was inhibited (IC 50 58 μM) by one of these kinds of esters with an additional 4β-deoxy structure. Synagrantol A (IC 50 39 μM) was as effective as PMA (IC 50 47 μM) in inhibiting J774A.1 growth in a dose-dependent manner. Furthermore, an in silico study with target receptors indicated a high interaction of the compounds with the PKC proteins. These results provide useful knowledge on the effect of tigliane-type diterpenes on tumor cell from the perspective of medicinal chemistry. [Display omitted] [ABSTRACT FROM AUTHOR]

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Caffeine and creatine are ingredients in the most popular dietary supplements consumed by soccer players. However, some products may not contain the disclosed amounts of the ingredients listed on the label, compromising the safe usage and the effectiveness of these supplements. Therefore, the aim of this study was to evaluate the content of caffeine and creatine in dietary supplements consumed by Brazilian soccer players. The results obtained were compared with the caffeine content listed on the product label. Two batches of the supplement brands consumed by > 50% of the players were considered for analysis. The quantification of caffeine and creatine in the supplements was determined by a high-performance liquid chromatography system with UV detector. Nine supplements of caffeine and 7 supplements of creatine met the inclusion criteria for analysis. Eight brands of caffeine and five brands of creatine showed significantly different values (p < .05) as compared with the values stated on the label. There were no significant differences between the two batches of supplements analyzed, except for one caffeine supplement. It can be concluded that caffeine and creatine dietary supplements consumed by Brazilian soccer players present inaccurate values listed on the label, although most presented no difference among batches. To ensure consumer safety and product efficacy, accurate information on caffeine and creatine content should be provided on all dietary supplement labels. [ABSTRACT FROM AUTHOR]

In recent years, certain Lactobacillus sp. have emerged in health care as an alternative therapy for various diseases. Based on this, this study is aimed at evaluating in vitro the potential probiotics of five lactobacilli strains isolated from pulp of cupuaçu fruit fermentation against Gardnerella vaginalis and Neisseria gonorrhoeae. Our lactobacilli strains were classified as safe for use in humans, and they were tolerant to heat and pH. Our strains were biofilm producers, while hydrophobicity and autoaggregation varied from 13% to 86% and 13% to 25%, respectively. The coaggregation of lactobacilli used in this study with G. vaginalis and N. gonorrhoeae ranged from 15% to 36% and 32% to 52%, respectively. Antimicrobial activity was present in all tested Lactobacillus strains against both pathogens, and the growth of pathogens in coculture was reduced by the presence of our lactobacilli. Also, all tested lactobacilli reduced the pH of the culture, even in incubation with pathogens after 24 hours. The cell-free culture supernatants (CFCS) of all five lactobacilli demonstrated activity against the two pathogens with a halo presence and CFCS characterization assay together with gas chromatography revealed that lactic acid was the most abundant organic acid in the samples (50% to 62%). Our results demonstrated that the organic acid production profile is strain-specific. This study revealed that cupuaçu is a promising source of microorganisms with probiotic properties against genital pathogens. We demonstrated by in vitro tests that our Lactobacillus strains have probiotic properties. However, the absence of in vivo tests is a limitation of our work due to the need to evaluate the interaction of our lactobacilli with pathogens in the vaginal mucosa. We believe that these findings may be useful in developing a product containing our lactobacilli and their supernatants in order to support with vaginal health. [ABSTRACT FROM AUTHOR]

The Asteraceae family is widely known for its therapeutic, aromatic, and nutritional properties. Chaptalia nutans (C. nutans), a member of the family, is widely used in folk medicine in southern Brazil. In this study, we aim to assess compounds present in root extracts of C. nutans, and evaluate their antioxidant capacity and toxicity. To determine the chemical composition of the extract, was performed through Liquid Chromatography coupled with Mass Spectroscopy. Antioxidant capacity, toxicity (Artemia salina biosassay), cytotoxicity, genotoxicity (Allium cepa test), and neurotoxicity (Drosophila melanogaster model) were evaluated. A large number of bioactive phytoconstituents were determined to be present, such as alkaloids, coumarins, flavonoids, terpenes, and especially phenolic compounds, which may explain the antioxidant capacity of the extract. Extracts had the capacity to protect cells from protein and lipid damage, and inhibit the formation of oxygen radicals. The A. salina bioassay revealed that extracts were only slightly toxic. In A. cepa, cells exposed to 1.5 mg/mL extract were protected against chromosomal damage caused by glyphosate, and had mitotic index values that were reduced by 49%. A concentration of 10 mg/mL extract did not kill flies, and when coadministered with paraquat (PQ) (52.5%) produced a mortality rate of only 18.75%. These findings indicated that the extract had the potential to protect against PQ-induced neurotoxicity. Taken together, these data reveal for the first time that the root extract of C. nutans is a rich source of natural antioxidants. The extract may be useful in the food and pharmaceutical industries. [ABSTRACT FROM AUTHOR]

Purpose: To characterize the surface of implants from Brazilian companies by light interferometry and evaluate the level of control of the surface treatment process. Materials and Methods: Oral implants from the five largest Brazilian companies were evaluated topographically. The surfaces of the implants were analyzed on the tops, valleys, and flanks of the threads, totaling nine measurements for each unit. The implants and results were separated in groups by their types of surface treatment and compared with wellknown international implants used as references. Results: The implants examined presented a mean height deviation of less than 1 μm, which was considered minimally rough, except for the SIN-SW implant (1.01 μm) and the Vulcano Actives design (1.26 μm). The surface enlargement values varied considerably in relation to the reference implant, with lower values noted in the group of implants subjected to sandblasting and acid-etching and with higher values obtained in the group treated by acid-etching and anodizing. There were statistically significant differences between batches of implants from all companies assessed, indicative of a substantial variance in implant topography from one batch to another. Conclusions: The low values of roughness found in the measurements and the differences between the values of the batches suggest that these companies should consider improving their surface treatments to achieve more uniform roughness. [ABSTRACT FROM AUTHOR]

The objective of this in vitro study was to evaluate the influence of remineralizing agents on the surface roughness of eroded tooth enamel. Forty incisive bovines were selected and sectioned to obtain specimens of 4mm X 4mm, resulting in a surface area of 16,00mm², with a thickness of 2.50mm. The specimens were immersed in lemon juice, twice a day, over 5 days, and randomly divided into the following 4 groups: G1 = No treatment; G2 = 1.23% APF; G3 = Fluoride Varnish 5% and G4 = Regenerated. The surface roughness of the specimens was analyzed by means of confocal laser scanning microscopy. The obtained data were submitted to ANOVA after attend the homogeneity (Levene´s) and normality tests (Kolmogorov-Smirnov). All tests were statistically significant at 5% (α=0.05). The results showed that there was no statistically significant difference on the enamel roughness surface area between groups in the experimental region and the founded values were higher at the experimental when compared to the control region, however, without differences between the groups in each region. It was concluded that the remineralizing agents were not able to reduce the surface roughness of the studied groups. [ABSTRACT FROM AUTHOR]

Sincoraea mucugensis (Wand. & A.A. Conc.) LOUZADA & WAND, an endangered bromeliad, is confined to the central region of the Chapada Diamantina, in the municipality of Mucugê, Brazil. From various researches, it is evident that for the propagation of this species, the in vitro technique is a feasible option. However, due to the low multiplication rates reported in various papers, this study aimed to establish a micropropagation protocol of direct organogenesis for S. mucugensis. First, the inoculation of the stem explants was done in MS ½ culture medium which contained different levels of BAP (0.00; 6.66; 8.88; 11.10; 13.20 µM) and NAA (0.00; 2.60; 5.20 µM). These shoots were then subjected to a couple of distinct rooting periods (of 30- and 60-day duration) using activated charcoal; finally, these microplants were transferred to a greenhouse for acclimatization, and covered with transparent plastic cups, as a water loss prevention test method. All the data were submitted to the analysis of variance (ANOVA), and the means were subjected to regression analysis or compared using the Tukey test. The findings revealed that the S. mucugensis stem explants raised in the NAA-rich medium (6.42 to 7.43 shoots/explants) showed high multiplication rates; the shoot rooting was done for 30 days using activated charcoal with the medium. Acclimatization, which was performed by directly exposing the microplants to the ex vitro environment, showed 95% survival rate. [ABSTRACT FROM AUTHOR]

Supplemental digital content is available in the text. Objective: The aim of this study was to analyze the effects of low-intensity pulsed ultrasound therapy under different pulse regimes on cultures of semiconfluent L929 fibroblasts, evaluating cell viability, anatomical structural alterations, modulation of vascular endothelial growth factor, interleukin 6, collagen type 1 alpha 1, collagen type 1 alpha 2, and fibroblast growth factor 7, as well as the amount of inflammatory mediators interleukin 2, interleukin 4, interleukin 6, interferon γ, tumor necrosis factor, interleukin 17A, and interleukin 10 at 24, 48, and 72 hrs. Design: The design was experimental study. Methods: The treatments consisted of 0.2 W/cm2 doses at a frequency of 1 MHz, with a pulse rate of 10% and 20%. Viability was assessed by the MTT assay (3-(4,5-dimethylthiazole)-2,5-diphenyltetrazolium bromide), gene expression by real-time quantitative polymerase chain reaction, and cytokine quantification by flow cytometry. Results: At 48 hrs, ultrasound enhanced cell viability and affected interleukin 6 cytokine production, vascular endothelial growth factor, interleukin 6, type 1 alpha 1 and alpha 2 collagens, and fibroblast growth factor 7 gene modulation. Conclusions: Low-intensity pulsed ultrasound therapy had a biostimulatory effect on semiconfluent in vitro L929 fibroblast cells, where the group with a dose of 0.2 W/cm2-10% (G2) presented higher responses, in all the analyzed aspects, toward the dose pulsed to 20%, confirming its therapeutic properties related to the initial phases of tissue healing. [ABSTRACT FROM AUTHOR]

Toxoplasma gondii, the agent of toxoplasmosis, is an intracellular parasite that can infect a wide range of vertebrate hosts. Toxoplasmosis causes severe damage to immunocompromised hosts and its treatment is mainly based on the combination of pyrimethamine and sulfadiazine, which causes relevant side effects primarily observed in AIDS patients, including bone marrow suppression and hematological toxicity (pyrimethamine) and/or hypersensitivity and allergic skin reactions (sulfadiazine). Thus, it is important to investigate new compounds against T. gondii, particularly those that may act on bradyzoites, which are present in cysts during the chronic disease phase. We propose an in vitro model to simultaneously study new candidate compounds against the two main causative stages of Toxoplasma infection in humans, using the EGS-DC strain that was modified from a type I/III strain (EGS), isolated from a case of human congenital toxoplasmosis in Brazil and engineered to express markers for both stages of development. One feature of this strain is that it presents tachyzoite and bradyzoite in the same culture system and in the same host cell under normal culture conditions. Additionally, this strain presents stage-specific fluorescent protein expression, allowing for easy identification of both stages, thus making this strain useful in different studies. HFF cells were infected and after 4 and 7 days post infection the cells were treated with 10 μM of pyrimethamine or atovaquone, for 48 or 72 h. We used high-throughput screening to quantify the extent of parasite infection. Despite a reduction in tachyzoite infection caused by both treatments, the atovaquone treatment reduced the bradyzoite infection while the pyrimethamine one increased it. Ultrastructural analysis showed that after treatment with both drugs, parasites displayed altered mitochondria. Fluorescence microscopy of cells labeled with MitoTracker CMXRos showed that the cysts present inside the cells lost their mitochondrial membrane potential. Our results indicate that this experimental model is adequate to simultaneously analyze new active compounds against tachyzoite and bradyzoite forms. [ABSTRACT FROM AUTHOR]

Eugenia uniflora Linn, popularly known as 'pitanga', is a native plant endemic to Brazil that belongs to the Myrtaceae family. Its traditional use (leaves infusion) has been reported for the treatment of different diseases, including hypertension, inflammation, and as a diuretic agent. Considering the snakebite problem and the rich molecule repertoire of this herbal species, studies that evaluate its antiophidic potential are relevant for a broad social impact. This approach aims to evaluate the anti-inflammatory and antiophidic potential in vitro and in vivo of the extract (aqueous) and a fraction (ethyl acetate) of E. uniflora leaves against Bothrops leucurus and Bothrops brazili venoms. Extract and fraction from E. uniflora leaves were obtained by turbo-extraction and partitioning. The cytotoxicity was assayed on normal cell lines (Vero E6 and 3T3) using the 3-methyl-[4-5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide method. The anti-inflammatory activity of the aqueous extract was analyzed in vivo in the zymosan-induced air pouch model, and the leukocytes migration and other molecular inflammatory mediators quantified (myeloperoxidase, total protein, pro-inflammatory cytokine, malondialdehyde, and glutathione). In vitro, the antiophidic effect was evaluated by the ability of the E. uniflora extract and fraction to inhibit the enzymatic action (proteolytic, phospholipase A 2, and hyaluronidase) of B. leucurus and B. brazili venoms. In addition, the antiophidic action in vivo was investigated after treatment with E. uniflora extract and fraction (50, 100, and 200 mg/kg) in the B. leucurus venom-induced paw edema with an evaluation of the antiedematogenic effect and quantification of myeloperoxidase (MPO) and pro-inflammatory cytokine levels. The E. uniflora leaves extract (7.8–125 mg/mL) revealed no toxicity in cell culture, but reduced MTT by 47% at the highest concentration (250 mg/mL) in Vero E6 cells. In contrast, the E. uniflora fraction (7.8–250 mg/mL) showed no cytotoxicity for both cell lines. In the air pouch model, E. uniflora leaves extract demonstrated anti-inflammatory activity, reducing cell migration, MPO activity, protein, malondialdehyde, and proinflammatory cytokines, and increased glutathione levels. Evaluating the antiophidic action in vitro , E. uniflora extract and fraction inhibited the proteolytic, phospholipase, and hyaluronidase effects of B. leucurus and B. brazili venoms at low concentrations. In addition, the extract and fraction also demonstrated in vivo antiophidic activity by reducing edema in the first 0.5 h after treatment, besides reducing MPO and pro-inflammatory cytokines levels. E. uniflora leaves extract showed cytotoxicity only at the highest concentration while the fraction revealed no toxic effect in vitro. This approach showed for the first time that the aqueous extract and ethyl acetate fraction of E. uniflora leaves has similar antiophidic action in vitro and in vivo , with antiedematogenic and anti-inflammatory effects and the ability to inhibit the enzymatic action of B. leucurus and B. brazili venoms. Therefore, this study points to the presence of bioactive components in the leaves of E. uniflora useful for the treatment of inflammatory disorders and ophidian accidents, expanding the therapeutic potential of this herbal species. [Display omitted] • Aqueous extract from E. uniflora leaves showed anti-inflammatory action. • E. uniflora leaves reduced the enzymatic action of bothropic venom in vitro. • Extract and fraction from E. uniflora leaves revealed antivenom effect in vivo. • Extract and fraction from E. uniflora leaves showed similar antiedematogenic action. [ABSTRACT FROM AUTHOR]

Summary: The latex from Euphorbia tirucalli is used in Brazil as a folk medicine for several diseases, including cancer. Recently, we showed a cytotoxic activity of E. tirucalli euphol in a wide range of cancer cell lines. Moreover, we showed that euphol inhibits proliferation, motility and colony formation in pancreatic cancer cells, induces autophagy and sensitizes glioblastoma cells to temozolomide cytotoxicity. Herein, we report in vitro activity of three semi-synthetic ingenol compounds derived from E. tirucalli, IngA (ingenol-3-trans-cinnamate), IngB (ingenol-3-hexanoate) and IngC (ingenol-3-dodecanoate), against a large panel of human cancer cell lines. Antineoplastic effects of the three semi-synthetic compounds were assessed using MTS assays on 70 cancer cell lines from a wide array of solid tumors. Additionally, their antitumor potential was compared with known compounds of the same class, namely ingenol-3-angelate (Picato®) and ingenol 3,20-dibenzoate and in combination with standard chemotherapeutic agents. We observed that IngA, B, and C exhibited dose-dependent cytotoxic effects. Amongst the semi-synthetic compounds, IngC displayed the best activity across the tumor cell lines. In comparison with ingenol-3-angelate and ingenol 3,20-dibenzoate, IngC showed a mean of 6.6 and 3.6-fold higher efficacy, respectively, against esophageal cancer cell lines. Besides, IngC sensitized esophageal cancer cells to paclitaxel treatment. In conclusion, the semi-synthetic ingenol compounds, in particular, IngC, demonstrated a potent antitumor activity on all cancer cell lines evaluated. Although the underlying mechanisms of action of IngC are not elucidated, our results provide insights for further studies suggesting IngC as a putative therapy for cancer treatment. [ABSTRACT FROM AUTHOR]

Abstract Ethnopharmacological relevance Aspidosperma excelsum Benth. (Apocynaceae), a native tree in the Brazilian Amazonia, is traditionally used to treat various diseases, including malaria. Aim of study To investigate the chemical constitution, antiplasmodial activity and cytotoxicity of samples obtained from A. excelsum trunk bark by different procedures aiming to evaluate their potential as an antimalarial phytomedicine. Materials and methods A hydroethanolic extract and alkaloid extracts were prepared and assayed for antiplasmodial activity and cytotoxicity against chloroquine-resistant Plasmodium falciparum (W2 strain) and HepG2 cells, respectively. Taking into account the known occurrence and antimalarial activity of Aspidosperma monoterpene indole alkaloids (MIA), acid-base extractions were carried out and the fractions were assayed for antiplasmodial activity and cytotoxicity. All the samples were analysed by hyphenated chromatographic techniques, such as UPLC-DAD-ESI-MS/MS and HRMS (HPLC-MS MicroTOF), comparing their chemical composition to the literature data. Results The hydroethanolic extract disclosed a moderate in vitro activity against chloroquine-resistant Plasmodium falciparum (W2 strain) with IC 50 23.68 ± 3.08 µg/mL), low cytotoxicity to HepG2 cells (> 250 µg/mL) and good SI (> 10.56). A total of 20 known monoterpene indole alkaloids were identified, seven of which are here firstly described for A. excelsum. Known highly active alkaloids, namely demethylaspidospermine, aspidocarpine, and ochrolifuanine are present in active alkaloid fractions and might contribute to their observed antiplasmodial effect. An alkaloid fraction (Ae-Alk2), obtained directly from trunk bark by extraction with dil. aqueous HCl, pointed out for its activity (IC 50 8.75±2.26 µg/mL, CC 50 185.14±1.97 µg/mL, SI 21.16) and should be highlighted as the most promising out of the assayed samples. Conclusion The present results represent a preliminary support to the alleged antimalarial use of A. excelsum trunk bark and allowed to highlight alkaloid fractions as promising phytomedicines. Graphical abstract fx1 [ABSTRACT FROM AUTHOR]

Abstract Ethnopharmacological relevance Terminalia argentea Mart. (Combretaceae), known mainly as "capitão", is a native tree, not endemic, that occurs in the Amazon, Caatinga, Cerrado and Atlantic Forest in Brazil. Leaf infusion is popularly mentioned by riverine communities that inhabit the microregion of Northern Araguaia (Mato Grosso, Brazil) for the treatment of gastric ulcer, bronchitis and haemorrhage. Considering the wide medicinal use, lack of studies that evaluate the safety of use and the scarcity of phytochemical studies of T. argentea leaves, this work was carried out with the objective of evaluating the toxicity of the hydroethanolic extract of the leaves of T. argentea Mart. (HETa) in experimental models in vivo and in vitro , as well as to advance the phytochemical analysis of HETa. Materials and methods HETa was prepared by macerating the leaf powder in hydroethanolic solution. Phytochemical characterisation was carried out by thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC) and mass spectrometry through direct flow infusion coupled with electrospray ionization and ion-trap analyzer (DFI-ESI-IT-MS analyses) The contents of phenols, flavonoids and phytosterols were analysed by colorimetric methods. Cytotoxicity was assessed by the Alamar blue assay on Chinese hamster ovary epithelial cells (CHO-K1) and human gastric adenocarcinoma cells (AGS). In vitro genotoxicity of HETa (10, 30 or 100 μg/mL) was assessed by micronucleus (MN) and comet tests using CHO-K1 cells. The acute toxicity assessment was performed by oral administration of HETa in single dose Swiss mice (males and females) up to 2000 mg/kg and sub-chronic toxicity by daily oral administration of HETa (50, 200 and 800 mg/kg) in Wistar rats for 30 days. The parameters related to the clinical and toxicological observations were determined every 6 days and at the end of the treatment the blood was collected for biochemical and haematological analysis, and some organs were removed for macroscopic and histopathological analysis. Results Preliminary phytochemistry and TLC analysis of HETa revealed the presence of phenolic compounds (18.8%), flavonoids (10.8%), saponins, tannins and phytosterols (19%). The HPLC data revealed the presence of gallic acid, rutin, ellagic acid, catechin, quercetin and kaempferol. In the analysis by DFI-ESI-IT-MS, the presence of gallic acid, rutin, ellagic acid and quercetin was confirmed and identified caffeic acid, quinic acid, galloylmucic acid, quercetin xyloside, quercetin rhamnoside, quercetin glucoside, caffeoyl ellagic acid, quercetin galloyl xyloside, terminalin, quercetin galloyl glucose, corilagin, quercetin digalloyl xyloside, quercetin digalloyl glucoside, punicalin and punicalagin. HETa showed no cytotoxic effect on CHO-K1 and AGS cells. In the MN assay, HETa increased the number of MNs and nuclear buds (NBUDs) in binucleate cells at the three concentrations tested and the nucleoplasmic bridges (NPBs) number at 30 μg/mL. In the comet test, HETa (10 and 100 μg/mL) alone showed a genotoxic effect on CHO-K1 cells. In pre-treatment, HETa at all concentrations tested prevented DNA damage induced by H 2 O 2. In co-treatment with H 2 O 2 , HETa showed genotoxic effects at the three concentrations, and post-treatment DNA damage in exposed CHO-K1 cells to H 2 O 2 was repaired in 22.5% with 10 μg/mL HETa. In the acute toxicity test, the HETa did not cause death in the mice, being verified only by piloerection and reversible in 2 h in males and in 4 days in females. No macroscopic changes were observed in the analysed organs. In the sub-chronic toxicity test, the HETa did not cause death in the rats after 30 days and the few changes were: absolute (103/mm3) and relative (%) values of basophils increased by 477.8% and 423% (p < 0.001), respectively, with 50 mg/kg; reduction in feed intake (23.6%, p < 0.01) only on day 18; total cholesterol concentration (13.1%, p < 0.05) and relative heart weight (13.2% %, p < 0.05) at a dose of 800 mg/kg. These effects were not dose-dependent nor followed by clinical signs and symptoms of intoxication, nor of macroscopic and histopathological changes in the organs of animals treated with HETa. Conclusions The results demonstrated that HETa had no cytotoxic in vitro effects for CHO-K1 and AGS cells. In in vitro genotoxicity assays, the HETa induced different responses, according to concentration and experimental condition. In the MN test the HETa presented genotoxic potential by increasing the number of MNs, NBUDs and NPBs. In the comet assay, HETa was genotoxic by itself and in the co-treatment protocol with H 2 O 2. In pre-treatment or post-treatment protocols with H 2 O 2 , HETa presented an antigenotoxic effect by preventing or repairing, respectively, the genotoxicity induced by H 2 O 2. In the in vivo models, HETa was shown to be relatively safe after acute administration in mice [no-observed-adverse effect level (NOAEL) of 2000 mg/kg] and sub-chronic in rats (NOAEL of 800 mg/kg), confirming the riverine information that it is non-toxic in the dosage used. Phytochemical analysis of HETa revealed the presence of phenolic compounds, flavonoids, saponins, tannins and phytosterols. Among the flavonoids and tannins, we highlight gallic acid, rutin, ellagic acid, quercetin, caffeic acid, quinic acid, corilagin, punicalin and punicalagin. Thus, it can be stated that HETa has a good safety margin for therapeutic use. Graphical abstract fx1 [ABSTRACT FROM AUTHOR]

In Brazil, there are species of snakes that become involved in accidents and cause serious health problems to the inhabitants, highlighting the genus Bothrops for being responsible for approximately 90% of accidents reported annually. In the northern region of the country, this genus is responsible for the largest number of accidents, especially among rural dwellers. These populations invest in alternative treatments for with the purpose of improving the symptoms caused by snakebites. The species Mauritia flexuosa L. f., known as buriti, is traditionally used for the treatment of envenomation by snakes. This study aimed to evaluate the antiophidic potential of the oil of Mauritia flexuosa L. f. for Bothrops moojeni H. venom, confronting cultural and scientific knowledge. The physicochemical properties were determined, and the components present in the oil, extracted from fruit pulp, were analyzed by Gas Chromatography Coupled with Mass Spectrometry. The in vitro inhibitory capacity of the oil for phospholipase, metalloprotease and serine protease activities was investigated. In the in vivo studies, male Swiss mice were used to evaluate the effect of oil on lethality and toxicity, and hemorrhagic, myotoxic and edematogenic activities were assessed. GC‒MS analysis identification of 90.95% of the constituents of the oil, with the main components being 9-eicosenoic acid, (Z)- (34.54%), n-hexadecanoic acid (25.55%) and (E)-9-octadecenoic acid ethyl ester (12.43%). For the substrates, the outcomes indicate that the oil inhibited the activity of the main classes of toxins present in Bothrops moojeni H. venom (VBm) at the highest dose tested (0.5 μL), with inhibition of 84% for the hydrolysis of the selective substrate for serine protease and inhibition of 60% for the hydrolysis of substrates for PLA 2 and metalloproteases. The antiophidic activity in vivo was evaluated with two concentrations of the oil: 1.5 mg, the dosage the population, diluted in mineral oil to a volume of 1 tablespoon and 15 mg, administered by gavage 30 min before poisoning and at time zero (concomitant to poisoning), and both concentrations administered by gavage in combination with topical use at time zero. The bleeding time in the group treated with oil at a concentration of 15 mg administered at time zero was significantly lower than that in the control group (p < 0.05). However, a greater inhibition of bleeding time was observed when local application was combined with the gavage treatment at both concentrations tested at time zero (p < 0.05). In the myotoxicity test, oil was efficient in reducing the myotoxic effects induced by the venom at the two concentrations tested, with gavage administration at time zero and gavage plus topical administration at time zero (p < 0.05). The data obtained show that the oil is safe to use at the concentrations studied and contains fatty acids that may collaborate for cellular-level repair of the injuries caused by Bm poisoning. The in vitro and in vivo experiments showed that oil inhibits the main proteolytic enzymes present in the venom and that it has important activities to control the local effects caused by bothropic venom. [Display omitted] • Buriti oil is popularly used for treating snakebites in northern Brazil. • In vitro, buriti oil inhibited the major classes of toxins in Bothrops moojeni venom. • Per se, the Buriti oil shows no toxicity in vivo • Buriti oil was efficient in reducing the myotoxic, but not edematous effects induced by the venom. • It shows a promising effect for complementary treatment of local lesions induced by Bothrops venom. [ABSTRACT FROM AUTHOR]

Abstract Two new iridoids (1–2) and a new decomposition product of valepotriates (3), together with fifteen known compounds (4–18) were isolated from the roots and rhizomes of Valeriana polystachya Smith, a native species from the Pampa Biome. Their structures were elucidated by means of NMR spectroscopy, mass spectrometry and optical rotation. The structures of 3 and 18 were further confirmed by single crystal X-ray diffraction analysis. In the group of the isolated compounds, 6β-hydroxysitostenone, hydroxymaltol and isovillosol were isolated from the Valeriana genus for the first time. The extracts and isolated compounds were evaluated for their in vitro activities against acetylcholinesterase (AChE) and prolyloligopeptidase (POP). Compounds 7 , 9 and 11 showed weak inhibitory activity against AChE, while 3 and 5 displayed exceptional POP inhibitory activity, with IC 50 values of 5.3 ± 0.07 and 7.9 ± 0.4 μM, respectively. Graphical abstract Unlabelled Image Highlights • Iridoids from Valeriana polystachya Smith. • Valeriana polystachya Smith and prolyl oligopeptidase inhibition. • Valeriana polystachya Smith enzymatic inhibition. [ABSTRACT FROM AUTHOR]

Baccharis retusa, a medicinal Brazilian plant from Asteraceae, has been used in Brazilian folk medicine to treatment of several illnesses, including parasitic diseases. Bioactivity-guided fractionation of the n-hexane extract from the aerial parts of B. retusa resulted in the isolation and characterization of three active related diterpenes: ent -15β-senecioyl-oxy-kaur-16-en-19-oic acid ( 1 ), ent -kaur-16-en-19-oic ( 2 ) and ent -16-oxo-17-nor-kauran-19-oic ( 3 ) acids. The structures of isolated compounds were defined by spectroscopic analysis, including NMR and HRESIMS. Antitrypanosomal activity of 1–3 was performed against cell-derived trypomastigotes using the colorimetric resazurin assay. The obtained results demonstrated that isolated compounds displayed a reduced toxicity against NCTC cells and were effective against the trypomastigote forms of T. cruzi with IC 50 values of 3.8 μM ( 1 ), 75.3 μM ( 2 ) and 44.2 μM ( 3 ). Additionally, compound 3 displayed activity against amastigote forms of T. cruzi with IC 50 of 83.2 μM. Compound 1 displayed the highest selectivity index (SI) when considered the trypomastigote forms, and its effect in the plasma membrane of parasite was evaluated using the fluorescent probe SYTOX Green. A considerable permeabilization (57%) in the membrane of the parasite was observed when compared to the untreated trypomastigotes. These data demonstrate, for the first time, the antitrypanosomal activity and mechanism of action of 1 and related compounds 2 and 3 , obtained from aerial parts of B. retusa . [ABSTRACT FROM AUTHOR]

Pharmacology relevance Baccharis trinervis (Lam, Persoon) leaves are used in the traditional medicine for the treatment of high fevers, edema, inflammation, sores and muscle cramps, snakebites and as antiseptic. Aim of the study To investigate the cytotoxic, genotoxic, and mutagenic effects of extracts and fractions of B. trinervis from Brazil and Colombia in Chinese Hamster Ovary (CHO) cells, and to examine the mutagenic activity in Salmonella typhimurium . Material and methods Aqueous extracts (AE) of aerial parts of B. trinervis from Brazil (B) and Colombia (C) were fractioned in ethyl acetate fraction (EAF), butanol extract (BF), and aqueous residue fraction (ARF). Qualitative chemical screening and determination of total flavonoid content were made. Identification of chemical constituents was performed by High Performance Liquid Chromatography (HPLC) and High Resolution Mass Spectrometry (HRMS). For the in vitro tests, CHO cells were treated for 3 h with extracts and fractions. The cytotoxic activity was evaluated by clonal survival and 3-(4.5-dimethylthiazole-2-yl)−2.5-biphenyl tetrazolium bromide reduction assay (MTT). Genotoxic and mutagenic effects were evaluated by the alkaline comet assay and Cytokinesis-blockage micronucleus test (CBMN), respectively. Additionally, Salmonella /microsome assay was carried out to determinate the mutagenic effects in EAF from Brazil and Colombia. Results Phytochemical analyses indicated the presence of saponins and flavonoids. AE and EAF were the samples with the highest quantity of total flavonoids. HPLC showed the presence of luteolin only in AEC, and caffeic acid, ellagic acid, rosmarinic acid, and rutin were identified in AEB and AEC (AEC>AEB). The HRMS in positive mode of EAFB and EAFC showed presence of two carboxylic acids, coumarin, and two terpenoids. In addition, were identified one terpenoid and two carboxylic acids in AE, BF and ARF of B. trinervis from both countries in negative mode. Dose-dependent cytotoxic effects were observed in CHO cells treated with B. trinervis extracts and fractions by using clonal survival and MTT at concentrations higher than 0.05 mg/mL. All the extracts and fractions induced DNA strand breaks in CHO cells with dose-dependent response, mostly EAFB and EAFC. The EAF from Brazil and Colombia showed mutagenic effect at 0.5 mg/mL, while the other fractions did not show a significant difference in relation to the control. No mutagenic effects were found in EAF from both countries by the Salmonella /microsome assay. Conclusions Cytotoxic and genotoxic effects were demonstrated in all extracts and fractions used, although only EAF showed mutagenic effects by CBMN, but not by Salmonella /microsome assay. Our results suggest that flavonoids, phenylpropanoids, coumarins, and diterpenes may be responsible for the cytotoxic, genotoxic and mutagenic effects observed. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Jatropha species (Euphorbiaceae) are largely used in traditional medicine to treat different pathologies in Africa, Asia and Latin America. In Northeastern Brazilian folk medicine, several Jatropha species, such as Jatropha gossypiifolia L. and Jatropha mollissima (Pohl) Baill., are indistinctly used to treat snakebites. Aim of the study To compare two of the Brazilian most used Jatropha species for snakebites ( J. gossypiifolia and J. mollissima ), in relation to their ability to inhibit local edematogenic activity of Bothrops erythromelas snake venom in mice, their in vitro antibacterial activity and phytochemical profile. Material and methods Aqueous leaf extracts of J. gossypiifolia (AEJg) and J. mollissima (AEJm) were prepared by decoction. AEJg and AEJm were compared chemically, by thin layer chromatography (TLC) and high-performance liquid chromatography with diode array detection (HPLC-DAD) analysis. They were also pharmacologically compared, using the mouse model of paw edema induced by Bothrops erythromelas snake venom (BeV), and in vitro by broth microdilution and agar dilution antimicrobial tests. Results Flavonoids were detected as the major compounds in both extracts. However, AEJg and AEJm showed quantitatively different chemical profiles by HPLC-DAD. AEJg presented fewer peaks of flavonoids than AEJm, however, when the intensity of peaks were analyzed, these compounds were at high concentration in AEJg, even using the same concentration of both extracts. Differences were also observed in the biological activity of the two extracts. While no difference was observed when the extracts were administered by oral route ( P > 0.05), by the intraperitoneal route AEJg presented anti-edematogenic activity significantly ( P < 0.001) higher than AEJm. In antimicrobial assays, only AEJg presented antibacterial activity against Staphylococcus epidermidis, Staphylococcus aureus and Bacillus cereus . Conclusions Although used indistinctly by folk medicine, our results suggested that AEJg is more active than AEJm in relation to its antiedematogenic and antibacterial activities. Significant differences were observed in their phytochemical profiles, especially a higher content of C -glycosylated flavonoids in the most active species, which could justify the different biological effects observed. These findings strengthen the potentiality of J. gossypiifolia species for use as complementary treatment for local effects induced by Bothrops venoms and could be helpful for distinction of the species and control quality assessment of future herbal medicines based on Jatropha plants. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Copaifera malmei Harms (Fabaceae), known mainly as óleo-mirim, is a native and endemic plant found in the states of Mato Grosso and Goiás of Brazil. The plant's leaves infusion is popularly used by riverine communities of the northern Araguaia microregion, Mato Grosso, Brazil, for the treatment of gastric ulcers and inflammatory diseases of the respiratory tract. The gastric antiulcer activity of the standardized leaves infusion extract of Copaifera malmei (SIECm) in rodents has been reported. The objective of this study was to advance the investigation of the safety profile of SIECm by evaluating the genotoxicity and subchronic toxicity using in vitro and in vivo experimental models. Materials and methods SIECm was prepared by infusion, by incubating the powdered dried leaves material in boiled water for 15 min. In vitro genotoxicity of SIECm (10, 30 or 100 μg/mL) was assessed by micronucleus and comet tests using Chinese hamster ovary (CHO-k1) epithelial cells. The evaluation of subchronic toxicity profile was performed by daily oral administration of SIECm (100, 400 or 1000 mg/kg) to Wistar rats for 30 days. Clinical observations of toxicological related parameters were done every 6 days. After the treatment period, blood was collected for hematological and biochemical analysis, and some organs were removed for macroscopic and histopathological analysis. Results In the micronucleus assay, SIECm demonstrated anti-mutagenic activity. In the comet assay, SIECm presented anti-genotoxic effect preventing DNA damage at all the three concentrations tested with pre-treatment, while the same effect was only observed in the co-treatment at the lowest concentration. Post-treatment with SIECm increased the genetic damage induced by hydrogen peroxide (H 2 O 2 ) at the highest concentration. In the subchronic toxicity test, few changes were observed, such as increase in feed consumption in the group of animals treated with 100 mg/kg of the SIECm, which reversed after 6 days. There were no macroscopic, histological and relative weights changes in the organs of animals treated with SIECm. No toxicologically relevant changes were observed in the hematological analysis. Subchronic administration of SIECm reduced levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in animals treated with 100 mg/kg and serum triglyceride levels at 400 and 1000 mg/kg. However, the hematological and biochemical changes observed are within the physiological ranges for this animal species. Conclusion The results demonstrate that SIECm is not genotoxic, and does not present toxicity when used orally for up to 30 days. In addition, it showed protection to the genetic damage induced by H 2 O 2. The SIECm therefore has a high safety margin for therapeutic use. [ABSTRACT FROM AUTHOR]

Background. Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America and affects 10 million people worldwide. Approximately 12 000 deaths attributable to Chagas disease occur annually due to chronic Chagas disease cardiomyopathy (CCC), an inflammatory cardiomyopathy presenting with heart failure and arrythmia; 30% of infected subjects develop CCC years after infection. Genetic mechanisms play a role in differential progression to CCC, but little is known about the role of epigenetic modifications in pathological gene expression patterns in CCC patients' myocardium. DNA methylation is the most common modification in the mammalian genome. Methods. We investigated the impact of genome-wide cardiac DNA methylation on global gene expression in myocardial samples from end-stage CCC patients, compared to control samples from organ donors. Results. In total, 4720 genes were differentially methylated between CCC patients and controls, of which 399 were also differentially expressed. Several of them were related to heart function or to the immune response and had methylation sites in their promoter region. Reporter gene and in silico transcription factor binding analyses indicated promoter methylation modified expression of key genes. Among those, we found potassium channel genes KCNA4 and KCNIP4, involved in electrical conduction and arrythmia, SMOC2, involved in matrix remodeling, as well as enkephalin and RUNX3, potentially involved in the increased T-helper 1 cytokine-mediated inflammatory damage in heart. Conclusions. Results support that DNA methylation plays a role in the regulation of expression of pathogenically relevant genes in CCC myocardium, and identify novel potential disease pathways and therapeutic targets in CCC. [ABSTRACT FROM AUTHOR]

In tropical America, principally in Northeastern Brazil, the leaf extract of Anacardium occidentale is traditionally used for treatment of different diseases. However, chemical and biological properties and activities of Anacardium occidentale are poorly investigated and known. Here, we evaluated the antioxidant and anti-inflammatory activities “in vitro” of leaf extract from Anacardium occidentale. Our results show that leaf extract exhibits antioxidant activity when used to treat RAW 264.7 macrophage cells. Antioxidant effects were observed by decrease in oxidative damage in macrophage cells treated with 0.5 µg/mL and 5 µg/mL of leaf extract. Moreover, leaf extract reversed oxidative damage and inflammatory parameters induced in LPS-stimulated RAW 264.7 macrophage cells. Leaf extract at 0.5 µg/mL and 5 µg/mL was able to inhibit release of TNF-α and IL-1β in LPS-stimulated cells. Taken together, our results indicate antioxidant and anti-inflammatory effects of leaf extract from Anacardium occidentale and reveal the positive effects that intake of these products can mediate in biological system. [ABSTRACT FROM AUTHOR]

Ethnopharmacological importance The hemiparasitic species Psittacanthus plagiophyllus Eichl. (Loranthaceae), also known as erva de passarinho , is used in folk medicine in the Santarém region in the state of Pará, Brazil, to treat gastritis and a variety of inflammatory disorders. In view of the lack of pharmacological studies on this species in the literature and the fact that it is used constantly by the local population, this study sought to standardize the extract of the leaves of P. plagiophyllus (AEPp) and to assess its anti-inflammatory potential in in vivo tests. Material and methods Quality control and standardization of AEPp were performed following the 5th edition of the Brazilian Pharmacopeia. To assess the in vivo anti-inflammatory activity of AEPp, the carrageenan-induced and dextran-induced rat paw edema models were initially used. To investigate the effect of AEPp on carrageenan-induced leukocyte recruitment and exudate production, the air pouch inflammation model was used. In addition, the antioxidant activity of AEPp was assessed in vitro by the DPPH radical scavenging method. Results The chromatographic profile of AEPp indicated the presence of flavonoids, coumarins and hydrolyzable and condensed tannins. Measurement of phenolics revealed the following percentages in the extract: 12.62±0.18% total phenolics, 5.39±0.01% total tannins, 12.54±0.24% hydrolyzable tannins, 8.37±0.32% condensed tannins and 1.23±0.02% total flavonoids. In 500 and 1000 mg/kg doses (p.o.) AEPp had significant edema-inhibiting activity ( p <0.01) in both the models used, suggesting that the extract may act in vascular and cell events in the inflammatory response and exert an inhibitory effect on mediators responsible for edema. In all the doses tested [250, 500 and 1000 mg/kg (p.o.)], AEPp inhibited total leukocyte and neutrophil migration and reduced the amount of exudate in the air pouch in a dose-dependent manner. Both effects were statistically significant ( p <0.01). The extract also reduced the DPPH radical (maximum reduction 93.13±1.71% at a concentration of 75 µg/mL), indicating that it has antioxidant activity. AEPp, therefore, exhibited considerable in vivo anti-inflammatory activity and in vitro antioxidant activity. This may be due to its high phenolics content. Conclusion These findings provide evidence to support the use of P. plagiophyllus in folk medicine to treat inflammatory disorders. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance The stem bark of Dilodendron bipinnatum Radlk. (Sapindaceae), a tree native to Pantanal of Mato Grosso, Brazil, popularly known as “mulher-pobre” (poor woman), has been historically used by the locals, after decoction and maceration, for the treatment of inflammatory conditions. We have recently shown that these preparations indeed possess anti-inflammatory properties, which are mediated by the inhibition of cell migration and the modulation of Th1 and Th2 cytokines. The NO pathway was not affected. Aim of the present study The aim of the present study was to further investigate the mechanisms responsible for the anti-inflammatory properties of the hydroethanolic extract of the stem bark of Dilodendron bipinnatum (HE Db ). Materials and methods HEDb was obtained by maceration of the stem bark of D. bipinnatum as previously described. The corresponding effects on a macrophage-like cell line, RAW 264.7, were investigated. The apoptosis of RAW 264.7 upon treatment with LPS, HEDb and N-acetyl- L -cysteine (NAC) was assessed by flow cytometry, using an Annexin V-PE kit. The production of inflammatory cytokines (TNF-α, IL-1β and IL-10) and PGE 2 were evaluated by ELISA, after cell challenge with LPS. The intracellular redox state and changes in mitochondrial membrane potential were also assessed by flow cytometry, using DCFH-DA and JC-1 as probes. The protein expression levels of MAPK p-p38, p-ERK, p-JNK, MKP-1 and COX-2 were analysed by western blotting. Nuclear translocation of NF-қB was assessed by immunofluorescence microscopy. The quantified results are presented as a nuclear:cytoplasmic ratio. Results LPS, HEDb and NAC did not appear to decrease the number of viable cells in comparison to control treatment. HEDb attenuated the production of pro-inflammatory cytokines (IL-1β and TNF-α) and PGE 2 induced by LPS but did not affect IL-10. The production of ROS was also inhibited by HEDb (1, 5 or 20 µg/mL), even at the lowest concentration; at 20 µg/mL, HEDb was more effective than NAC, which was used as a positive control (74.1% and 66.2% inhibition of LPS's effect, respectively). LPS induced an increase in ΔΨm (19.2%, p<0.001), while HEDb inhibited the change in ΔΨm (7.7% at 20 µg/mL, p<0.001). The results of western blotting showed that HEDb inhibited the expression of MAPK p-p38, p-JNK and COX-2, while the expression of MKP-1 was increased. p-ERK was not affected. LPS promoted the nuclear translocation of NF-қB p65 (67%, p<0.01) in RAW 264.7 cells, in comparison to baseline (33%). Pre-treatment with HEDb inhibited this translocation of NF-κB p65 (58% at 20 µg/mL, p<0.001). Conclusion: HEDb has a potent anti-inflammatory activity and acts on multiple targets and biological pathways of potential therapeutic relevance. [ABSTRACT FROM AUTHOR]

Ethnopharmacological importance The effectiveness of aqueous extract of Bellucia dichotoma Cogn. (Melastomataceae) specimems collected in Santarém, PA, against some biological activities of Bothrops atrox venom (BaV) has been scientifically proven. Here, we analyzed the components and assessed the anti-snakebite potential of aqueous extracts of bark of B. dichotoma collected in Manaus, AM, (AEBd-MAO) and Santarém, PA, (AEBd-STM), both in Brazil. Materials and methods The phytochemical profiles of the aqueous extracts were identified using thin layer chromatography (TLC), and the concentrations of phenolics were determined by colorimetric assay. The inhibitory potential of the extracts was tested against the phospholipase A 2 , coagulant and gelatinolytic activities of BaV in vitro and its defibrinating and edema-inducing activities in vivo. Interaction between BaV and the extracts was investigated using SDS-Page electrophoresis and Western blotting. Extract cytotoxicity and antioxidant potential were assessed using the human fibroblast cell line MRC-5 and the DPPH assay in cell culture, respectively. Results While there was no difference between the phytochemical profiles of the extracts, AEBd-MAO had higher concentrations of total phenolics, total tannins and hydrolysable tannins. The extracts inhibited 100% of the phospholipase and coagulant activity of BaV when pre-incubated. Without pre-incubation, however, there was no reduction in phospholipase activity, although significant inhibition of coagulant activity was observed. In the doses used in folk medicine, without pre-incubation, both extracts inhibited 100% of the coagulant activity of BaV. In vivo, the extracts were unable to inhibit the defibrinating activity of the venom but were effective in inhibiting its edema-inducing activity. In the profiles of the extracts pre-incubated with BaV, not all the protein bands revealed by SDS-PAGE and Western blot were observed. Both extracts had a high antioxidant potential and neither had a cytotoxic effect. Conclusion Although the concentrations of phenolics in each extract were different, the anti-snakebite potential was similar for the concentrations of extract tested. Our findings are of importance for the quality control of this raw material, which, once tested in accordance with Brazilian National Health Surveillance Agency recommendations, may be suitable for use as a phytomedicine to complement treatment of the local effects induced by Bothrops venoms. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Vismia guianensis (Aubl.) Pers. is traditionally used in North and Northeast of Brazil for the treatment of dermatomycoses. Since the strategy associating immunomodulators with antifungal drugs seems to be promissory to improve the treatment efficacy in fungal infections, we aimed to investigate the antifungal activity of V. guianensis ethanolic extract of leaves (VGL) and bark (VGB) against Sporothrix schenckii ATCC 16345 and their antinflammatory activities. Material and methods The extracts were analyzed by HPLC-DAD-IT MS/MS for in situ identification of major compounds. Antifungal activity was evaluated in vitro (microdilution test) and in vivo using a murine model of S. schenckii infection. The production of TNF-α, IFN-γ, IL-4, IL-10 and IL-12 by measured by ELISA, as well as measured the production and inhibition of the NO after treatment with the plant extracts or itraconazole (ITR). Results Two O-glucosyl-flavonoids and 16 prenylated benzophenone derivatives already described for Vismia were detected. Both VGL and VGB showed significant antifungal activity either in in vitro assay of microdilution (MIC=3.9 µg/mL) and in vivo model of infection with reduction of S. schenckii load in spleen. It was also observed a predominance of reduction in the production of NO and the proinflammatory cytokines evaluated except TNFα, but with stimulation of IL-10, as evidence of a potential anti-inflammatory effect associated. Conclusion The results showed that both VGL and VGB have a significant antifungal against S. schenckii and an anti-inflammatory activity. These results can support the use of these extracts for alternative treatment of sporotrichosis. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance 3β,6β,16β-Trihydroxylup-20(29)-ene (TTHL) is a triterpene isolated from the flowers of Combretum leprosum, a plant used in folk medicine in the north of Brazil for the treatment of skin disorders. Aim of the study In the present study, TTHL was evaluated as a potential topical anti-inflammatory and anti-proliferative agent through in vivo and in vitro models. Material and methods Anti-inflammmatory and anti-proliferative effects of TTHL were assessed using Swiss mice in acute and chronic models of skin inflammation induced by 12- O -tetradecanoylphorbol-acetate (TPA) application. Anti-proliferative activity was proved through in vitro experiments with the HaCaT human keratinocyte cell line. Results Treatment with TTHL inhibited inflammatory parameters such as oedema formation and cellular infiltration in acute and chronic models. In the chronic model, TTHL also inhibited epidermal hyperproliferation, as evidenced by reduction of epidermis thickness and proliferating cell nuclear antigen expression. The anti-proliferative effect was confirmed by the capability of TTHL in reducing the proliferation and inducing cell apoptosis of HaCaT cells. Suggesting a mechanism of action, TTHL showed activation of corticosteroid receptors, but without the induction of corticosteroid-related cutaneous side effects. Conclusion Our results demonstrate consistent anti-inflammatory and anti-proliferative activity and assign TTHL as a valuable tool in the development of a new treatment for skin inflammatory and proliferative diseases, such as psoriasis. [ABSTRACT FROM AUTHOR]

Bothrops jararaca (BJ) and Bothrops erythromelas (BE) are viper snakes found in South-Southeast and Northeast regions of Brazil, respectively. Snake venoms are bioactive neurotoxic substances synthesized and stored by venom glands, with different physiological and pharmacological effects, recently suggesting a possible preference for targets in cancer cells; however, mechanisms of snakes have been little studied. Here, we investigated the mechanism responsible for snake crude venoms toxicity in cultured cervical cancer cells SiHa and HeLa. We show that BJ and BE snake crude venoms exert cytotoxic effects to these cells. The percentage of apoptotic cells and cell cycle analysis and cell proliferation were assessed by flow cytometry and MTT assay. Detection of mitochondrial membrane potential (Rhodamine-123), nuclei morphological change, and DNA fragmentation were examined by staining with DAPI. The results showed that both the BJ and BE venoms were capable of inhibiting tumor cell proliferation, promoting cytotoxicity and death by apoptosis of target SiHa and HeLa cells when treated with BJ and BE venoms. Furthermore, data revealed that both BJ venoms in SiHa cell promoted nuclear condensation, fragmentation, and formation of apoptotic bodies by DAPI assay, mitochondrial damage by Rhodamine-123, and cell cycle block in the G1-G0 phase. BJ and BE venoms present anticancer potential, suggesting that both Bothrops venoms could be used as prototypes for the development of new therapies. [ABSTRACT FROM AUTHOR]

Ethnopharmacology relevance Stachytarpheta cayennensis is a plant that is traditionally used to treat tegumentary leishmaniasis and as an anti-inflammatory agent. Aim of the study This study aimed to evaluate the action of S. cayennensis extracts on the Leishmania ( Leishmania ) amazonensis arginase enzyme. Materials and methods: S. cayennensis was collected from the Brazilian Amazon region. Aqueous extracts were fractionated with n -butanol. The leishmanicidal effects of the n -butanolic fraction (BUF) were evaluated in L . ( L .) amazonensis promastigotes and amastigotes. BUF was tested against recombinant arginase from both L . ( L .) amazonensis and macrophage arginase. Promastigote cultures and infected macrophage cultures were supplemented with L-ornithine to verify arginase inhibition. NMR analysis was used to identify the major components of BUF. Results BUF showed an EC 50 of 51 and 32 µg/mL against promastigotes and amastigotes of L . ( L .) amazonensis , respectively. BUF contains a mixture of verbascoside and isoverbascoside (7:3 ratio) and is a potent L . ( L .) amazonensis arginase inhibitor (IC 50 =1.2 µg/mL), while macrophage arginase was weakly inhibited (IC 50 >1000 µg/mL). The inhibition of arginase by BUF in promastigotes and amastigotes could be demonstrated by culture media supplementation with L-ornithine, a product of the hydrolysis of L-arginine by arginase. Conclusions Leishmanicidal effects of the S. cayennensis BUF fraction on L . ( L .) amazonensis are associated with selective parasite arginase inhibition. [ABSTRACT FROM AUTHOR]