Search

The oil of Carapa guianensis showed leishmanicidal activity, with its activity being related to limonoids, but fatty acids are the major constituents of this oil. The present study evaluated the physicochemical, pharmacokinetic, and toxicity profiles of limonoids and fatty acids already identified in the species. Based on these results, 2 limonoids (methyl angosinlate, 6-OH-methyl angosinlate) and 2 fatty acids (arachidic acid; myristic acid) were selected for the prediction of possible targets and molecular docking. Included in this study were: Gedunin, 6α-acetoxygedunin, Methyl angosenlato, 7-deacetoxy-7-oxogedunin, Andirobin, 6-hydroxy-angolensate methyl, 17β-hydroxyazadiradione, 1,2-dihydro-3β-hydroxy-7-deacetoxy-7-oxogedunin, xyllocensin k, 11beta-Hydroxygedunin, 6α,11-11β-diacetoxygedunin, Oleic Acid, Palmitic Acid, Stearic Acid, Arachidic Acid, Myristic Acid, Palmitoleic Acid, Linoleic Acid, Linolenic Acid, and Beenic Acid. Regarding physicochemical aspects, fatty acids violated LogP, and only limonoid 11 violated Lipinski's rule. A common pharmacokinetic aspect was that all molecules were well absorbed in the intestine and inhibited CYP. All compounds showed toxicity in some model, with fatty acids being mutagenic and carcinogenic, and limonoids not being mutagenic and carcinogenic at least for rats. In in vivo models, fatty acids were less toxic. Molecular dockings were performed on COX-2 steroids (15 and 16) and hypoxia-inducible factor 1 alpha for limonoids (3,6), with this target being essential for the intracellular development of leishmania. Limonoids 3 and 6 appear to be promising as leishmanicidal agents, and fatty acids are promising as wound healers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 de Barros, Araujo da Costa, Farias, de Albuquerque, Marinho, Campos, Marinho and Dolabela.)

Oxidative stress is involved in the pathogenesis of malaria, causing anemia, respiratory complications, and cerebral malaria. To mitigate oxidative stress, we investigated the effect of nutritional supplementation whit lycopene (LYC) on the evolution of parasitemia and survival rate in mice infected with Plasmodium berghei ANKA (Pb), comparing to the effects promoted by N-acetylcysteine (NAC). Therefore, 175 mice were randomly distributed into 4 groups; Sham: untreated and uninfected animals; Pb: animals infected with Pb; LYC+Pb: animals treated with LYC and infected with Pb; NAC+Pb: animals treated with NAC and infected with Pb. The animals were followed for 12 days after infection, and survival and parasitemia rates were evaluated. There was a 40.1% increase in parasitemia in the animals of the Pb group on the 12th day, and a survival rate of 45%. LYC supplementation slowed the development of parasitemia to 19% and promoted a significative increase in the survival rate of 80% on the 12th day after infection, compared to the Pb group, effects superior to those promoted by NAC, providing strong evidence of the beneficial effect of LYC on in vivo malaria and stressing the importance of antioxidant supplementation in the treatment of this disease.

Objective: To investigate the effectiveness of linezolid and vancomycin for the treatment of nosocomial infections in children under 12 years old., Data Sources: This is a systematic review in which five randomized clinical trials about the effectiveness of linezolid and vancomycin, involving a total of 429 children with nosocomial infections, were evaluated. They were searched in scientific databases: PubMed, Bvs, and SciELO., Summary of Findings: The main nosocomial infections that affected children were bacteremia, skin, and soft tissue infections followed by nosocomial pneumonia. Most infections were caused by Gram-positive bacteria, which all studies showed infections caused by Staphylococcus aureus, with methicillin-resistant S. aureus (MRSA) and methicillin-resistant coagulase-negative staphylococci strains being isolated. Both linezolid and vancomycin showed high therapeutic efficacy against different types of nosocomial infections, ranging from 84.4% to 94% for linezolid and 76.9% to 90% for vancomycin. Patients receiving linezolid had lower rates of rash and red man syndrome compared to those receiving vancomycin. However, despite the adverse reactions, antimicrobials can be safely administered to children to treat nosocomial infections caused by resistant Gram-positive bacteria., Conclusion: Both linezolid and vancomycin showed good efficacy in the treatment of bacterial infections caused by resistant Gram-positive bacteria in hospitalized children. However, linezolid stands out regarding its pharmacological safety. Importantly, to strengthen this conclusion, further clinical trials are needed to provide additional evidence., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2023 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.)

Ipê is a plant of the Bignoniaceae family. Among the compounds extracted from this tree, lapachol is notable because its structural modification allows the production of β-lapachone, which has anticancer properties. The objective of this work was to test this hypothesis at a cellular level in vitro and assess its potential safety for use. The following tests were performed: MTT cell viability assay, apoptotic index determination, comet assay, and micronucleus test. The results showed that β-lapachone had a high cytotoxic capacity for all cell lines tested: ACP02 (gastric adenocarcinoma cells), MCF7 (breast carcinoma cells), HCT116 (colon cancer cells) and HEPG2 (hepatocellular carcinoma cells). Regarding genotoxicity, the exposure of cells to sublethal doses of β-lapachone induced DNA damage (assessed by the comet assay) and nuclear abnormalities, such as nucleoplasmic bridges and nuclear buds (assessed by the micronucleus test). All tested cell lines responded similarly to β-lapachone, except for ACP02 cells, which were relatively resistant to the cytotoxic effects of the compound in the MTT test. Our results collectively indicate that although β-lapachone showed antiproliferative activity against cancer cell lines, it also caused harmful effects in these cells, suggesting that the use of β-lapachone in treating cancer should be carried out with caution.

Introduction: Leishmaniasis is caused by protozoa of the genus Leishmania , classified as tegumentary and visceral. The disease treatment is still a serious problem, due to the toxic effects of available drugs, the costly treatment and reports of parasitic resistance, making the search for therapeutic alternatives urgent. This study assessed the in vitro anti-leishmanial potential of the extract, fractions, and isoeleutherin from Eleutherine plicata , as well as the in silico interactions of isoeleutherin and its analogs with Trypanothione Reductase (TR), in addition to predicting pharmacokinetic parameters. Methods: From the ethanolic extract of E. plicata (EEEp) the dichloromethane fraction (FDEp) was obtained, and isoeleutherin isolated. All samples were tested against promastigotes, and parasite viability was evaluated. Isoeleutherin analogues were selected based on similarity in databases (ZINK and eMolecules) to verify the impact on structural change. Results and Discussion: The extract and its fractions were not active against the promastigote form (IC 50 > 200 μg/mL), while isoeleutherin was active (IC 50 = 25 μg/mL). All analogues have high intestinal absorption (HIA), cell permeability was moderate in Caco2 and low to moderate in MDCK. Structural changes interfered with plasma protein binding and blood-brain barrier permeability. Regarding metabolism, all molecules appear to be CYP3A4 metabolized and inhibited 2-3 CYPs. Molecular docking and molecular dynamics assessed the interactions between the most stable configurations of isoeleutherin, analogue compound 17, and quinacrine (control drug). Molecular dynamics simulations demonstrated stability and favorable interactions with TR. In summary, fractionation contributed to antileishmanial activity and isoleutherin seems to be promising. Structural alterations did not contribute to improve pharmacokinetic aspects and analogue 17 proved to be more promising than isoeleutherin, presenting better stabilization in TR., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Albuquerque, Veiga, Silveira, Campos, Costa, Brito, Melo, Percario, Molfetta and Dolabela.)

As life expectancy increases, the number of people affected by cancer is increasing. The available drugs still cause several adverse reactions, and it is important to look for less toxic drugs that act on resistant cancers. The present study evaluated the antitumor potential of acetogenins. Through a literature review, 44 acetogenins isolated from Annona muricata were selected and subjected to in silico studies to predict the physicochemical properties, pharmacokinetics (Preadmet and Admet lab), toxicity (Preadmet and Protox II) and molecular docking in caspase 3 (DockThor). For muricatacin, a literature review was carried out for antitumor activity and cytotoxicity. Only muricatacin met all physicochemical criteria, while all compounds showed high cutaneous and intestinal absorption (HIA), moderate permeability in Madin-Darby canine kidney and Caco2 cells, strongly bound plasma proteins, freely crossed the blood-brain barrier, inhibited CYP2C19, CYP2C9 and CYP3A4 and have an affinity for CYP3A4, being metabolized by it, an undesirable characteristic for antitumor drugs. All compounds were toxic in at least one model, while compound 28 was not carcinogenic in rats and mice. Compounds 13, 14, 15, 16, 17 and 28 were selected for molecular docking into Caspase 3. Docking showed hydrophobic interactions, hydrogen and covalent bonds performed to maintain the stability of caspase 3, and cis-uvariamicin IV stood out more through the energies and chemical bonds of this parameter. The chloroform fraction from the methanolic extract of the seeds showed activity against triple-negative breast cancer, both in vitro and in vivo , and only muricatacin has studies in which the antitumor activity was evaluated in vitro and showed to be very promising. In summary, muricatacin and cis-uvariamicin IV appear to be very promising as antitumors, especially cis-uvariamicin IV., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Fallon Adido, Silva Chagas, Ferreira, Carmo Bastos and Dolabela.)

From Eleutherine plicata , naphthoquinones, isoeleutherine, and eleutherol were isolated, and previous studies have reported the antioxidant activity of these metabolites. The present work evaluated the role of oxidative changes in mice infected with Plasmodium berghei and treated with E. plicata extract, fraction, and isolated compounds, as well as to verify possible oxidative changes induced by these treatments. E. plicata extracts were prepared from powder from the bulbs, which were submitted to maceration with ethanol, yielding the extract (EEEp), which was fractionated under reflux, and the dichloromethane fraction (FDMEp) was submitted for further fractionation, leading to the isolation of isoeleutherine, eleutherine, and eleutherol. The antimalarial activity was examined using the suppressive test, evaluating the following parameters of oxidative stress: trolox equivalent antioxidant capacity (TEAC), thiobarbituric acid reactive substances (TBARS), and reduced glutathione (GSH). Furthermore, the molecular docking of naphthoquinones, eleutherol, eleutherine, and isoeleutherine interactions with antioxidant defense enzymes was investigated, which was favorable for the formation of the receptor-ligand complex, according to the re-rank score values. Eleutherine and isoeleutherine are the ones with the lowest binding energy for catalase (CAT), glutathione reductase (GR), and glutathione peroxidase (GPx1), showing themselves as possible targets of these molecules in the involvement of redox balance. Data from the present study showed that treatments with E. plicata stimulated an increase in antioxidant capacity and a reduction in oxidative stress in mice infected with P. berghei , with naphthoquinones being responsible for reducing oxidative changes and disease severity.

The alkaloids isolated from Zanthoxylum rhoifolium have demonstrated great pharmacological potential; however, the toxic profiles of these extracts and fractions are still not well elucidated. This study evaluated the toxicity of the ethanol extract (EEZR) and neutral (FNZR) and alkaloid (FAZR) fractions. Chemical characterization was performed by chromatographic methods: thin-layer chromatography (TLC) and high-performance liquid chromatography coupled with diode array detection (HPLC-DAD). The cytotoxicity of the samples was evaluated in human hepatocellular carcinoma (HepG2) cells using the cell viability method (MTT) and mutagenicity by the Allium cepa assay (ACA). Alkaloids isolated from the species were selected for toxicity prediction using preADMET and PROTOX. The molecular docking of the topoisomerase II protein (TOPOII) was used to investigate the mechanism of cell damage. In the EEZR, FNZR, and FAZR, the presence of alkaloids was detected in TCL and HPLC-DAD analyses. These samples showed a 50% inhibitory concentration (IC 50 ) greater than 400 μg/mL in HepG2 cells. In ACA, time- and concentration-dependent changes were observed, with a significant reduction in the mitotic index and an increase in chromosomal aberrations for all samples. Nuclear sprouts and a micronucleus of the positive control (PC) were observed at 10 µg/mL and in the FAZR at 30 µg/mL; a chromosomal bridge in FNZR was observed at 105 µg/mL, CP at a concentration of 40 µg/mL, and nuclear bud and mitotic abnormalities in the EEZR were observed at 170 µg/mL. The alkaloids with a benzophenanthridine were selected for the in silico study, as structural alterations demonstrated certain toxic effects. Molecular docking with topo II demonstrated that all alkaloids bind to the protein. In summary, the fractionation of Z. rhoifolium did not interfere with toxicity; it seems that alkaloids with a benzophenanthridine nucleus may be involved in this toxicity.

Gastric cancer is among the major causes of death from neoplasia leading causes of death worldwide, with high incidence rates and problems related to its treatment. Here, we outline how Geissospermum sericeum exerts antitumor activity on the ACP02 cell line (human gastric adenocarcinoma) and the mechanism of cell death. The ethanol extract and fractions, neutral fraction and alkaloid fraction, were characterized by thin-layer chromatography and HPLC-DAD, yielding an alkaloid (geissoschizoline N4-methylchlorine) identified by NMR. The cytotoxicity activity of the samples (ethanol extract, neutral fraction, alkaloid fraction, and geissoschizoline N4-methylchlorine) in HepG2 and VERO cells was determined by MTT. The ACP02 cell line was used to assess the anticancer potential. Cell death was quantified with the fluorescent dyes Hoechst 33342, propidium iodide, and fluorescein diacetate. The geissoschizoline N4-methylchlorine was evaluated in silico against caspase 3 and 8. In the antitumor evaluation, there was observed a more significant inhibitory effect of the alkaloid fraction (IC50 18.29 µg/mL) and the geissoschizoline N4-methylchlorine (IC 50 12.06 µg/mL). However, geissoschizoline N4-methylchlorine showed lower cytotoxicity in the VERO (CC 50 476.0 µg/mL) and HepG2 (CC 50 503.5 µg/mL) cell lines, with high selectivity against ACP02 cells (SI 39.47 and 41.75, respectively). The alkaloid fraction showed more significant apoptosis and necrosis in 24 h and 48 h, with increased necrosis in higher concentrations and increased exposure time. For the alkaloid, apoptosis and necrosis were concentration- and time-dependent, with a lower necrosis rate. Molecular modeling studies demonstrated that geissoschizoline N4-methylchlorine could occupy the active site of caspases 3 and 8 energetically favorably. The results showed that fractionation contributed to the activity with pronounced selectivity for ACP02 cells, and geissoschizoline N4-methylchlor is a promising candidate for caspase inhibitors of apoptosis in gastric cancer. Thus, this study provides a scientific basis for the biological functions of Geissospermum sericeum , as well as demonstrates the potential of the geissoschizoline N4-methylchlorine in the treatment of gastric cancer.

Docosahexaenoic acid (DHA), also known as omega-3 ( n -3) polyunsaturated fatty acid (PUFA), is a natural compound that has demonstrated pharmacological activity against several malignant neoplasms. Available cancer treatments cause side effects, affect healthy cells, reduce the quality of life of patients and may cause resistance to antineoplastics. For these reasons, the search for new therapies is continuous. This narrative review aimed to compile information on in vitro experiments that study the cytotoxic effect of DHA or molecules derived from DHA in tumor and nontumor cells. This was performed to highlight the potential of DHA as a strategy for cancer therapy and to gather information, which will help researchers plan experimental designs and develop research to discover effective therapies against cancer. In addition, studies were presented that demonstrate the dose of DHA that can treat patients with cancer. Thus, a search was conducted for articles on the SCOPUS and Web of Science platforms, published until 2022, that analyzed the action of DHA against breast, lung, colorectal, prostate, stomach and liver cancers. Cytotoxic effects were observed in tumor and nontumor cell lines, and these results varied with the type of cell line studied, drug concentration, incubation time and treatment combination, i.e., with DHA alone, combined with other drugs and with molecules derived from DHA. In patients with cancer, in all analyzed studies, DHA intake was associated with eicosapentaenoic acid (EPA) and/or proteins to aid chemotherapy, and with this procedure, tumor reduction, chemotherapy tolerance and muscle mass gain were obtained. This work contributes to the community by demonstrating the possible applicability of DHA in the pharmaceutical area of oncological therapies.

Men who have sex with men who suffer stigmatization and discrimination become more fragile in facing life's problems, such as the search for treatment in health services. In the present study, the social aspects related to discrimination and violence among men who have sex with men in Belém, Pará, are evaluated. Data were obtained by applying the respondent-driven sampling method to recruit 349 participants aged 18 years or older and who reported having had at least one sexual relationship with a man in the last 12 months. Data were collected from June to December 2016 in a semi-structured interview. Five seeds were initially recruited who applied RDS. The vast majority were between 18 and 35 years old, had completed elementary school but not high school, and were of mixed race. Almost a third lived in peripheral neighborhoods and were employed/self-employed. Additionally, most participants reported having suffered aggression/discrimination, more often in religious contexts, with family or in health services. The findings reported here may contribute to the development of public policies aimed at this population and indicate the need for new strategies to combat sexually transmitted infections, stigma, and discrimination suffered by this population.

This study evaluated the genotoxicity of Ethanol Extract (EEEp), Dichloromethane Fraction (FDCMEp) and isoeleutherin isolated from Eleutherine plicata , using the micronucleus test and the impact of structural alterations on toxicity and molecular docking (topoisomerase II and DNA complex). The extract was obtained by maceration and fractionation in a chromatography column. The genotoxicity was evaluated by the micronucleus test in human hepatoma cells (HepG2). Isoeleutherin was the starting molecule in the search for analogues by structural similarity, using the ZINC and e-Molecules databases. Isoeleutherin and analogues were subjected to in silico toxicity prediction, and compounds free of toxicological risks (CP13, CP14, CP17 and isoeleutherin) were selected for molecular docking in Topoisomerase II (PDB: 1ZXM). In the micronucleus test, isoeleutherin was less genotoxic. Among the 22 isoeleutherin analogues there were variations in the toxicity profile. Molecular docking studies showed that the compounds have good complementarity in the active site with important hydrogens bonds. Therefore, the structural changes of isoeleutherin led to the obtaining of a molecule with a lower mutagenic potential, and the CP13 can be considered a prototype compound for the development of new molecules with pharmacological potential.

Cancer is a multifactorial organic dysfunction for which great efforts are being devoted in searching for new treatments and therapeutic adjuvants. Annona muricata is a fruit that has promising activity against several types of cancer, as it contains acetogenins, the metabolite group associated with this action. Thus, the objective of this study was to evaluate, in experimental models, the toxic behavior of an extract and fraction rich in acetogenins from A. muricata seeds and study the acetogenin, Annonacin, in silico. Phytochemical characterization was made by thin layer chromatography, spectroscopy in the infrared region and nuclear magnetic resonance. Toxicity was evaluated by tests of Allium cepa and Artemia salina , and in silico studies using the SwissDock servers DockThor, PharmMapper, ADMETLab, PreADME, Osiris and ProTox. The extract and fraction showed genotoxic activity against meristematic cells of A. cepa , reducing the mitotic index; however, the extract produced great deleterious effects on the system, even causing cell necrosis. In A. Saline, the extract was more toxic than the fraction, but both samples were considered toxic. Annonacin was effectively linked to complex I, and presented different activities regarding toxicity. Thus, the results of this study are promising, highlighting the anticancer potential of acetogenins.

Malaria is an infectious disease and a serious public health problem in the world, with 3.3 billion people in endemic areas in 100 countries and about 200 million new cases each year, resulting in almost 1 million deaths in 2018. Although studies look for strategies to eradicate malaria, it is necessary to know more about its pathophysiology to understand the underlying mechanisms involved, particularly the redox balance, to guarantee success in combating this disease. In this review, we addressed the involvement of oxidative stress in malaria and the potential benefits of antioxidant supplementation as an adjuvant antimalarial therapy.

This study evaluated the morphological changes caused by fractions and subfractions, obtained from barks of Aspidosperna nitidum, against L. (L.) amazonensis promastigotes. The ethanolic extract (EE) obtained through the maceration of trunk barks was subjected to an acid-base partition, resulting the neutral (FN) and the alkaloid (FA) fractions, and fractionation under reflux, yielded hexane (FrHEX), dichloromethane (FrDCL), ethyl acetate (FrACoET), and methanol (FrMEOH) fractions. The FA was fractionated and three subfractions (SF5-6, SF8, and SF9) were obtained and analyzed by HPLC-DAD and 1 H NMR. The antipromastigote activity of all samples was evaluated by MTT, after that, scanning electron microscopy (SEM) and transmission electron microscopy (TEM) for the active fractions were performed. Chromatographic analyzes suggest the presence of alkaloids in EE, FN, FA, and FrDCL. The fractionation of FA led to the isolation of the indole alkaloid dihydrocorynantheol (SF8 fractions). The SF5-6, dihydrocorynantheol and SF-9 samples were active against promastigotes, while FrDCL was moderately active. The SEM analysis revealed cell rounding and changes in the flagellum of the parasites. In the TEM analysis, the treated promastigotes showed changes in flagellar pocket and kinetoplast, and presence of lipid inclusions. These results suggest that alkaloids isolated from A. nitidum are promising as leishmanicidal., (© 2022. The Author(s).)

This study investigated the acute and subacute toxicity of the ethanolic extract (EE) and alkaloid fraction (FA) from A. nitidum. The EE was obtained from trunk bark with ethanol, FA was obtained from the fractionation of EE. To test the acute toxicity, mice were divided into four groups, and the negative controls received water or aqueous solution of dimethyl sulfoxide, whereas the others received EE or FA (2000 mg/kg, orally, single dose). The same controls were used in the subacute trial. However, the animals were treated for 28 days, and the dose used was 1000 mg/kg per day of EE and FA. Daily clinical evaluations of the animals were performed. At the end of the experiment, hematological, biochemical, and histopathological assessments (liver, lung, heart, and kidney) were performed. In the acute and subacute toxicity studies, mice treated with EE and FA did not show any clinical changes, there were no changes in weight gain, hematological and biochemical parameters compared to the control groups (p > 0.05). In the histopathological examination, there was no abnormality in the organs of the treated animals. Therefore, EE and FA did not produce toxic effects in mice after acute and subacute treatment., (© 2021. The Author(s).)

Eleutherine plicata has been shown to be a promising medicinal plant, and its activity has been associated with naphthoquinones. The present study aimed at evaluating the cytotoxicity, genotoxicity, and oral toxicity of the ethanol extract (EEEp), dichloromethane fraction (FDMEp) of E. plicata , and isoeleutherin. For the cytotoxicity evaluation, the viability test (MTT) was used. Genotoxicity was accessed through the Comet assay (alkaline version), acute and subacute oral toxicities were also evaluated. The antioxidant capacity of the samples in the wells where the cells were treated with E. plicata was evaluated. Furthermore, the participation of caspase-8 in the possible mechanism of action of isoeleutherin, eleutherin, and eleutherol was also investigated through a docking study. FDMEp and isoeleutherin were cytotoxic, with higher rates of DNA fragmentation observed for FDMEp and isoeleutherin, and all samples displayed higher antioxidant potential than the control. In the acute oral toxicity test, EEEp, FDMEp, and isoeleutherin did not cause significant clinical changes. In the subacute toxicity assay, EEEp and FDMEp also did not cause clinical, hematological, or biochemical changes. The three compounds bound similarly to caspase-8. Despite the results of cytotoxicity, in vitro studies demonstrated that the use of EEEp appears to be safe and cell death may involve its binding to caspase-8., (© 2021 Published by Elsevier B.V.)

The present study aimed to evaluate the effects of dexamethasone on the redox status, parasitemia evolution, and survival rate of Plasmodium berghei-infected mice. Two-hundred and twenty-five mice were infected with Plasmodium berghei and subjected to stimulation or inhibition of NO synthesis. The stimulation of NO synthesis was performed through the administration of L-arginine, while its inhibition was made by the administration of dexamethasone. Inducible NO synthase (iNOS) inhibition by dexamethasone promoted an increase in the survival rate of P. berghei-infected mice, and the data suggested the participation of oxidative stress in the brain as a result of plasmodial infection, as well as the inhibition of brain NO synthesis, which promoted the survival rate of almost 90% of the animals until the 15th day of infection, with possible direct interference of ischemia and reperfusion syndrome, as seen by increased levels of uric acid. Inhibition of brain iNOS by dexamethasone caused a decrease in parasitemia and increased the survival rate of infected animals, suggesting that NO synthesis may stimulate a series of compensatory redox effects that, if overstimulated, may be responsible for the onset of severe forms of malaria.

Parkinson's disease (PD) occurs in approximately 1% of the population over 65 years of age and has become increasingly more common with advances in age. The number of individuals older than 60 years has been increasing in modern societies, as well as life expectancy in developing countries; therefore, PD may pose an impact on the economic, social, and health structures of these countries. Oxidative stress is highlighted as an important factor in the genesis of PD, involving several enzymes and signaling molecules in the underlying mechanisms of the disease. This review presents updated data on the involvement of oxidative stress in the disease, as well as the use of antioxidant supplements in its therapy., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Sandro Percário et al.)

Background: Cerebral malaria is the most severe form of infection with Plasmodium falciparum characterized by a highly inflammatory response. This systematic review aimed to investigate the association between TNF-α levels and cerebral malaria., Methods: This review followed the Preferred Reporting of Systematic Review and Meta-analyses (PRISMA) guidelines. The search was performed at PubMed, LILACS, Scopus, Web of Science, The Cochrane Library, OpenGrey and Google Scholar. We have included studies of P. falciparum-infected humans with or without cerebral malaria and TNF-α dosage level. All studies were evaluated using a risk of bias tool and the GRADE approach., Results: Our results have identified 2338 studies, and 8 articles were eligible according to this systematic review inclusion criteria. Among the eight articles, five have evaluated TNF- α plasma dosage, while two have evaluated at the blood and one at the brain (post-Morten). Among them, only five studies showed higher TNF-α levels in the cerebral malaria group compared to the severe malaria group. Methodological problems were identified regarding sample size, randomization and blindness, but no risk of bias was detected., Conclusion: Although the results suggested that that TNF-α level is associated with cerebral malaria, the evidence is inconsistent and imprecise. More observational studies evaluating the average TNF-alpha are needed.

Chemotherapy is limited in the treatment of leishmaniasis due to the toxic effects of drugs, low efficacy of alternative treatments, and resistance of the parasite. This work assesses the in vitro activity of flavopereirine on promastigote cultures of Leishmania amazonensis . In addition, an in silico evaluation of the physicochemical characteristics of this alkaloid is performed. The extract and fractions were characterized by thin-layer chromatography and HPLC-DAD, yielding an alkaloid identified by NMR. The antileishmanial activity and cytotoxicity were assayed by cell viability test (MTT). The theoretical molecular properties were calculated on the Molinspiration website. The fractionation made it possible to isolate a beta-carboline alkaloid (flavopereirine) in the alkaloid fraction. Moreover, it led to obtaining a fraction with greater antileishmanial activity, since flavopereirine is very active. Regarding the exposure time, a greater inhibitory effect of flavopereirine was observed at 24 h and 72 h (IC 50 of 0.23 and 0.15 μg/mL, respectively). The extract, fractions, and flavopereirine presented low toxicity, with high selectivity for the alkaloid. Furthermore, flavopereirine showed no violation of Lipinski's rule of five, showing even better results than the known inhibitor of oligopeptidase B, antipain, with three violations. Flavopereirine also interacted with residue Tyr-499 of oligopeptidase B during the molecular dynamics simulations, giving a few insights of a possible favorable mechanism of interaction and a possible inhibitory pathway. Flavopereirine proved to be a promising molecule for its antileishmanial activity., Competing Interests: The authors declare no conflict of interest.

This study aimed to evaluate the leishmanicidal activity of ethanol extract, fractions, and isolated substance from Handroanthus serratifolius against Leishmania amazonensis . Furthermore, this activity was related to cytotoxicity, and the selectivity index was determined. The ethanol extract was obtained by maceration of the stem powder, and the extract was subjected to fractionation on chromatographic column. The lapachol was obtained by acid base extraction followed by purification in chromatographic column. The antipromastigote activity and cytotoxicity tests were carried out by the cell viability method (MTT). Modified THP-1 cells were infected with L. amazonensis promastigotes and treated for 24 h with different concentrations of the extract, fractions, and lapachol. The ethanol extract, dichloromethane, and ethyl acetate fractions were not active against promastigotes (IC 50 > 200  μ g/mL) or cytotoxic (CC 50 > 500  μ g/mL), and the selectivity index (SI) was greater than 2.5. The ethyl acetate fraction was active only in promastigotes; it is not cytotoxic (CC 50 > 500  μ g/mL, SI > 5). The lapachol was selectively active only against amastigote (IS > 2.5, CC 50 > 500  μ g/mL). In summary, lapachol and ethyl acetate fraction are promising against amastigote and promastigote forms, respectively., Competing Interests: The authors declare that there is no conflict of interests.

The present study describes the use of the traditional species Copaifera for treating wounds, such as ulcers scarring and antileishmanial wounds. It also relates phytochemical studies, evaluation of the leishmanicidal activity, and toxicity. The species of Copaifera with a higher incidence in the Amazon region are Copaifera officinalis , Copaifera reticulata , Copaifera multijuga Hayne. The copaiba oil is used in the Amazon's traditional medicine, especially as anti-inflammatory ingredient, in ulcers healing, and in scarring and for leishmaniasis. Chemical studies have shown that these oils contain diterpenes and sesquiterpenes. The copaiba oil and terpenes isolated have antiparasitic activity, more promising in the amastigote form of L. amazonensis . This activity is probably related to changes in the cell membrane and mitochondria. The oil showed low cytotoxicity and genotoxicity. Furthermore, it may interfere with immune response to infection and also has a healing effect. In summary, the copaiba oil is promising as leishmanicidal agent., Competing Interests: The authors declare that there are no competing interests.

Background: Different species of Croton are used in traditional Amazonian medicine. Among the popular uses are treatment of bacterial diseases, poorly healing wounds and fevers., Objective: This study evaluated the antileishmanial, antiplasmodial and antimicrobial activities of the extracts and diterpenes of Croton palanostigma Klotzsch (Euphorbiaceae)., Materials and Methods: Leaves and bark were extracted with dichloromethane and methanol. The bark dichloromethane extract (BDE) was chromatographed on a column, obtaining cordatin and aparisthman. The extracts and diterpenes were assayed thought agar disk diffusion method and their bactericidal or fungicidal effects were evaluated by minimum bactericidal or fungicidal concentration. The antiplasmodial activity was evaluated after 24 and 72 h of exposition. The antileishmanial activity was performed on promastigotes forms of Leishmania amazonensis., Results: The bark methanol extract (BME) and cordatin were not active against any microbial strains tested; BDE and leaves methanol extract (LME) were positive for Pseudomonas aeruginosa and aparisthman was positive for Candida albicans. In the determination of the minimum bactericidal concentration, neither of them were active in the highest concentration tested. The extracts and diterpenes were inactive in Plasmodium falciparum, except the LME in 72 h. Any extract was shown to be active in promastigote forms of L. amazonensis., Conclusion: These results indicate that the BDE and LME did not inhibit the bacterial growth, then they probably had bacteriostatic effect. LME presented activity in P. falciparum.

Background: Several species of the genus Aspidosperma (Apocynaceae) are used for the treatment of human malaria in Brazil and other meso- and South American countries., Methods: Ethanol extract from Aspidosperma parvifolium trunk bark was submitted to acid-base extractions leading to alkaloid and neutral fractions. The alkaloid fraction was chromatographed over a silica gel column. Ethanol extract, fractions and uleine were analysed by HPLC-DAD, UPLC-ESI-MS/MS and HPLC-ESI-MicroTOF-MS. The anti-malarial activity was assayed against resistant and sensitive chloroquine Plasmodium falciparum strains by microscopic, [(3)H]-hypoxanthine incorporation and HRPII techniques. Cytotoxicity (CC50) was evaluated against Vero and HepG2 cell lines by the MTT technique; selectivity indexes (SI = CC50/IC50) were calculated., Results: The major peak in the HPLC-DAD chromatograms of the ethanol extract, alkaloid and neutral fractions suggested the presence of uleine that was isolated from the alkaloid fraction by column chromatography and was characterized by spectroscopic methods. A total of 15 alkaloids, besides uleine, were identified in the alkaloid fraction by UPLC-DAD-ESI-MS/MS and HPLC-ESI-MicroTOF-MS. The ethanol extract from Aspidosperma parvifolium and the neutral fraction were moderately active against P. falciparum strains. The alkaloid fraction and uleine disclosed high anti-malarial activity against chloroquine-resistant P. falciparum strain (IC50 < 1 µg/mL). The ethanol extract, neutral fraction and uleine showed low cytotoxicity against Vero and HepG2 cell lines (CC50 > 300 µg/mL). The alkaloid fraction showed moderate cytotoxicity to HepG2 cell line (CC50 = 74.4 µg/mL). High SI values (>10) were determined for all samples., Conclusion: Ethanol extract from Aspidosperma parvifolium trunk bark afforded uleine that is the major constituent of the alkaloid fraction and disclosed a good in vitro anti-malarial activity. Moreover, 15 other indole alkaloids have been identified along with uleine.

Background: Different species of Croton are used in traditional Amazonian medicine. Among the popular uses are treatment of bacterial diseases, poorly healing wounds and fevers., Objective: This study evaluated the antileishmanial, antiplasmodial and antimicrobial activities of the extracts and diterpenes of Croton palanostigma Klotzsch (Euphorbiaceae)., Materials and Methods: Leaves and bark were extracted with dichloromethane and methanol. The bark dichloromethane extract (BDE) was chromatographed on a column, obtaining cordatin and aparisthman. The extracts and diterpenes were assayed thought agar disk diffusion method and their bactericidal or fungicidal effects were evaluated by minimum bactericidal or fungicidal concentration. The antiplasmodial activity was evaluated after 24 and 72 h of exposition. The antileishmanial activity was performed on promastigotes forms of Leishmania amazonensis., Results: The bark methanol extract (BME) and cordatin were not active against any microbial strains tested; BDE and leaves methanol extract (LME) were positive for Pseudomonas aeruginosa and aparisthman was positive for Candida albicans. In the determination of the minimum bactericidal concentration, neither of them were active in the highest concentration tested. The extracts and diterpenes were inactive in Plasmodium falciparum, except the LME in 72 h. Any extract was shown to be active in promastigote forms of L. amazonensis., Conclusion: These results indicate that the BDE and LME did not inhibit the bacterial growth, then they probably had bacteriostatic effect. LME presented activity in P. falciparum.

The risk of chronic diseases such as Alzheimer's disease is growing as a result of the continuous increasing average life span of the world population, a syndrome characterized by the presence of intraneural neurofibrillary tangles and senile plaques composed mainly by beta-amyloid protein, changes that may cause a number of progressive disorders in the elderly, causing, in its most advanced stage, difficulty in performing normal daily activities, among other manifestations. Therefore, it is important to understand the underlying pathogenic mechanisms of this syndrome. Nevertheless, despite intensive effort to access the physiopathological pathways of the disease, it remains poorly understood. In that context, some hypotheses have arisen, including the recent oxidative stress hypothesis, theory supported by the involvement of oxidative stress in aging, and the vulnerability of neurons to oxidative attack. In the present revision, oxidative changes and redox mechanisms in Alzheimer's disease will be further stressed, as well as the grounds for antioxidant supplementation as adjuvant therapy for the disease will be addressed.

Background: Malaria infection can cause high oxidative stress, which could lead to the development of severe forms of malaria, such as pulmonary malaria. In recent years, the role of reactive oxygen species in the pathogenesis of the disease has been discussed, as well as the potential benefit of antioxidants supplementation. The aim of this study was to investigate the effects of N-acetyl cysteine (NAC) or mushroom Agaricus sylvaticus supplementation on the pulmonary oxidative changes in an experimental model of malaria caused by Plasmodium berghei strain ANKA., Methods: Swiss male mice were infected with P. berghei and treated with NAC or AS. Samples of lung tissue and whole blood were collected after one, three, five, seven or ten days of infection for the assessment of thiobarbituric acid reactive substances (TBARS), trolox equivalent antioxidant capacity (TEAC), nitrites and nitrates (NN) and to assess the degree of parasitaemia., Results: Although parasitaemia increased progressively with the evolution of the disease in all infected groups, there was a significant decrease from the seventh to the tenth day of infection in both antioxidant-supplemented groups. Results showed significant higher levels of TEAC in both supplemented groups, the highest occurring in the group supplemented with A. sylvaticus. In parallel, TBARS showed similar levels among all groups, while levels of NN were higher in animals supplemented with NAC in relation to the positive control groups and A. sylvaticus, whose levels were similar to the negative control group., Conclusion: Oxidative stress arising from plasmodial infection was attenuated by supplementation of both antioxidants, but A. sylvaticus proved to be more effective and has the potential to become an important tool in the adjuvant therapy of malaria.

Background: Plasmodium falciparum has become resistant to some of the available drugs. Several plant species are used for the treatment of malaria, such as Himatanthus articulatus in parts of Brazil. The present paper reports the phyto-chemistry, the anti-plasmodial and anti-malarial activity, as well as the toxicity of H. articulatus., Methods: Ethanol and dichloromethane extracts were obtained from the powder of stem barks of H. articulatus and later fractionated and analysed. The anti-plasmodial activity was assessed against a chloroquine resistant strain P. falciparum (W2) in vitro, whilst in vivo anti-malarial activity against Plasmodium berghei (ANKA strain) was tested in mice, evaluating the role of oxidative stress (total antioxidant capacity--TEAC; lipid peroxidation--TBARS, and nitrites and nitrates--NN). In addition, cytotoxicity was evaluated using the HepG2 A16 cell-line. The acute oral and sub-chronic toxicity of the ethanol extract were evaluated in both male and female mice., Results: Plumieride was isolated from the ethyl acetate fraction of ethanol extract, Only the dichloromethane extract was active against clone W2. Nevertheless, both extracts reduced parasitaemia in P. berghei-infected mice. Besides, a significant reduction in pulmonary and cerebral levels of NN (nitrites and nitrates) was found, as well as in pulmonary TBARS, indicating a reduced oxidative damage to these organs. The ethanol extract showed low cytotoxicity to HepG2 A16 cells in the concentrations used. No significant changes were observed in the in vivo toxicity studies., Conclusions: The ethanol extract of H. articulatus proved to be promising as anti-malarial medicine and showed low toxicity.

Background: The involvement of free radicals and oxidative stress in HIV infection has been extensively studied, and the benefits of antioxidant supplementation in animal studies have been demonstrated. However, few studies have demonstrated a benefit in clinical studies., Objective: To verify the effects of dietary supplementation with Agaricus sylvaticus, a mushroom rich in antioxidants, on the oxidative profile of children born with HIV undergoing antiretroviral therapy., Design: The sample included 24 children (both boys and girls) between two and eight years of age, of whom 10 were HIV positive and received supplementation with Agaricus sylvaticus for a three-month period, and 14 were HIV negative and received no supplementation. At the beginning and conclusion of the study, thiobarbituric acid-reactive substances (TBARS), nitrite and nitrate (NN), Trolox equivalent antioxidant capacity, and the antioxidant capacity of inhibition of diphenyl-picrilhidrazil (DPPH) free radicals were analyzed., Results: Before supplementation, significantly higher values of TBARS and NN, but decreased values of DPPH, were observed in infected subjects when compared with HIV-negative subjects. After supplementation, a reduction of TBARS and NN values and an increase in DPPH and Trolox equivalent antioxidant capacity values were observed in HIV-positive subjects., Conclusions: The results of the present study suggest the involvement of oxidative stress in HIV infection, with the participation of NN synthesis. Additionally, supplementation reversed oxidative alterations and improved antioxidant defense in infected individuals, and may become a complementary strategy in the treatment of these patients.

Several plant species belonging to the genus Aspidosperma are traditionally used in Brazil and other Meso- and South American countries for the treatment of malaria and fevers. These traditional uses were motivation for this review. A literature survey completed for this review has identified scientific bibliographical references to the use of 24 Aspidosperma species to treat malaria/fevers and to 19 species that have had their extracts and/or alkaloids evaluated, with good results, for in vitro and/or in vivo antimalarial activity. Indole alkaloids are typical constituents of Aspidosperma species. However, only 20 out of more than 200 known indole alkaloids isolated from this genus have been assayed for antimalarial activity. These data support the potential of Aspidosperma species as sources of antimalarials and the importance of research aimed at validating their use in the treatment of human malaria., (Georg Thieme Verlag KG Stuttgart · New York.)

Malaria is a significant public health problem in more than 100 countries and causes an estimated 200 million new infections every year. Despite the significant effort to eradicate this dangerous disease, lack of complete knowledge of its physiopathology compromises the success in this enterprise. In this paper we review oxidative stress mechanisms involved in the disease and discuss the potential benefits of antioxidant supplementation as an adjuvant antimalarial strategy.

Ethnomedicinal informations point to some Aspidosperma species (Apocynaceae) as antimalarial plants in Brazil and have motivated the evaluation of six species which were collected in the state of Minas Gerais: A. cylindrocarpon Müll. Arg., A. parvifolium A. DC., A. olivaceum Müll. Arg., A. ramiflorum Müll. Arg., A. spruceanum Benth. ex Müll. Arg. and A. tomentosum Mart.. A total of 23 extracts of different plant parts in different solvents were assayed in vitro against chloroquine-resistant (W2) and chloroquine-sensitive (3D7) strains of Plasmodium falciparum. All the extracts were shown to be active with IC50 values in the range of 5.0 ± 0 2.8 µg/mL to 65.0 ± 4.2 µg/mL. TLC profile of the extracts revealed the presence of alkaloids in the six species assayed. These results seem to confirm the popular use of Aspidosperma species to treat human malaria in Brazil and seem point to alkaloids as the putative active compounds of the assayed species.

Ethnopharmacological Relevance: From seeds of Carapa guianensis the Amazon native people extracts the andiroba oil, which is traditionally used as febrifuge, anti-malarial, insecticidal and repellant. The non-saponifiable fraction separated from the oil is rich in limonoids, which assigns its pharmacological effects., Materials and Methods: The andiroba oil and its limonoid-rich fraction were submitted to in vitro antiplasmodial bioassay using W(2) and Dd(2) strains of Plasmodium falciparum. The acute toxicity of andiroba oil was evaluated. The limonoid-rich fraction was subjected to fractionation and identified its major constituents., Results: Andiroba oil and its limonoid-rich fraction inhibited the growth of W(2) clone in 100%, between 24 and 72 h, at concentrations of 8.2 μg/mL and 3.1 μg/mL, respectively. Under the same conditions, the parasitaemia of Dd(2) clone provoked by the andiroba oil showed inhibition of 31% (IC(50) >82 μg/mL) with a time-dependent relationship of 24h and inhibition of 88% (IC(50) 8.4 μg/mL) after 72 h, while for the limonoid-rich fraction the inhibition of Dd(2) clone was 56% (IC(50) 2.8μg/mL) at 24h and 82% (IC(50) 0.4 μg/mL) after 72 h. Andiroba oil in acute toxicity test with a fixed dose (LD(50) >2000 mg/kg) was not toxic The limonoids identified in the oil were gedunin, 6α-acetoxygedunin, 7-deacetoxy-7-oxogedunin, 7-deacetylgedunin, 1,2-dihydro-3β-hydroxy-7-deacetoxy-7-oxogedunin and andirobin. Gedunin and derivatives has been reputed as anti-malarials., Conclusion: The results support the traditional use of andiroba oil as antiplasmodial, which additionally proved not to be toxic in bioassays conducted with mice., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Malaria remains one of the most serious world health problem and the major cause of mortality and morbidity in the endemic regions. Brazil is among the 30 high-burden countries and most of the cases occur in the Legal Amazonian Region. New chemotherapeutical agents are needed for the treatment of malaria. Many plant species are used in traditional medicines of malarious countries and a relatively few number of these have been investigated for evaluation of their antimalarial effect. Still lower is the number of those that have had the active natural compounds isolated and the toxicity determined. This area is, then, of great research interest. discovery project of antimalarial natural products from plants traditionally used to treat malaria must include in vitro and in vivo assays as well as bioguided isolation of active compounds. The final products would be antimalarial chemical entities, potential new drugs or templates for new drugs development, and/or standardized antimalarial extracts which are required for pre-clinical and clinical studies when the aim is the development of effective and safe phythomedicines. This review discusses these two approaches, presents briefly the screening methodologies for evaluation of antimalarial activity and focuses the activity of alkaloids belonging to different structural classes as well as its importance as new antimalarial drugs or leads and chemical markers for phytomedicines.

Esenbeckia febrifuga (Rutaceae) is a plant traditionally used to treat malaria in the Brazilian Amazon region. Ethanol extract of stems displayed a good antiplasmodial activity against Plasmodium falciparum strains W-2 (IC(50) 15.5+/-0.71 microg/ml) and 3 D7 (IC(50) 21.0+/-1.4 microg/ml). Two coumarins (bergaptene 1 and isopimpinellin 2), five alkaloids (flindersiamine 3, kokusaginine 4, skimmiamine 5, gamma-fagarine 6 and 1-hydroxy-3-methoxy-N-methylacridone, 7), besides a limonoid (rutaevine 8), have been isolated for the first time from this species. Antiplasmodial activity of compounds 3, 5-8 has been evaluated in vitro against P. falciparum strains (W-2 and 3D7) and the furoquinolines 5 and 6 were the most potent displaying IC(50) values <50 microg/ml; flindersiamine (3) showed a weak activity while alkaloid 7 and rutaevine (8) were inactive (IC(50)>100 microg/ml).

Macfadyena unguis-cati (L.) has been widely used in folk medicine as an anti-inflammatory, antimalarial and antivenereal. The purpose of this study was to chemically characterize the main plant components, and to evaluate the biological properties of some of the fractions derived from leaves (MACb) and liana (MACa) of this plant. Chemical characterization allowed the identification of the compounds corymboside, vicenin-2, quercitrin, chlorogenic acid, isochlorogenic acid, lupeol, beta-sitosterol, beta-sitosterylglucoside, allantoin and lapachol. The biological screening of fractions and/or purified substances derived from fractions revealed antitumoral and antitrypanosomal activities in fractions MACa/lapachol and MACb/MACb21, respectively. The anti-lipoxygenase and anti-cyclooxygenase effect seen in fractions MACa and MACb showed a partial correlation with the anti-inflammatory property attributed to this plant.

We examined the radioprotective effect of aminothiol 2-N-propylamine-cyclo-hexanethiol (20-PRA) on a human leukemic cell line (K562) following various radiation doses (5, 7.5 and 20 Gy) using a source of 60Co gamma-rays. At 5 Gy and 1 nM 20-PRA, a substantial protective effect (58%) was seen 24 h after irradiation, followed by a decrease at 48 h (11%). At the high radiation dose (20 Gy) a low protective effect was also seen (35%). In addition, the antitumorigenic potential of 10 nM 20-PRA was shown by the inhibition of crown gall formation induced by Agrobacterium tumefaciens. The radioprotective potency of 20-PRA is 10(5)-10(6) times higher than that of the aminothiol WR-1065 (N-(2-mercaptoethyl)-1,3-diaminopropane) whose protective effect is in the 0.1 to 1.0 mM range.