Amburana cearensis seed extract stimulates astrocyte glutamate homeostatic mechanisms in hippocampal brain slices and protects oligodendrocytes against ischemia.

BACKGROUND: Stroke is a leading cause of death and disability worldwide. A major factor in brain damage following ischemia is excitotoxicity caused by elevated levels of the neurotransmitter glutamate. In the brain, glutamate homeostasis is a primary function of astrocytes. Amburana cearensis has long been used in folk medicine and seed extract obtained with dichloromethane (EDAC) have previously been shown to exhibit cytoprotective activity in vitro. The aim of the present study was to analyse the activity of EDAC in hippocampal brain slices. METHODS: We prepared a dichloromethane extract (EDAC) from A. cearensis seeds and characterized the chemical constituents by 1H and 13C-NMR. Hippocampal slices from P6-8 or P90 Wistar rats were used for cell viability assay or glutamate uptake test. Hippocampal slices from P10-12 transgenic mice SOX10-EGFP and GFAP-EGFP and immunofluorescence for GS, GLAST and GLT1 were used to study oligodendrocytes and astrocytes. RESULTS: Astrocytes play a critical role in glutamate homeostasis and we provide immunohistochemical evidence that in excitotoxicity EDAC increased expression of glutamate transporters and glutamine synthetase, which is essential for detoxifying glutamate. Next, we directly examined astrocytes using transgenic mice in which glial fibrillary acidic protein (GFAP) drives expression of enhanced green fluorescence protein (EGFP) and show that glutamate excitotoxicity caused a decrease in GFAP-EGFP and that EDAC protected against this loss. This was examined further in the oxygen-glucose deprivation (OGD) model of ischemia, where EDAC caused an increase in astrocytic process branching, resulting in an increase in GFAP-EGFP. Using SOX10-EGFP reporter mice, we show that the acute response of oligodendrocytes to OGD in hippocampal slices is a marked loss of their processes and EDAC protected oligodendrocytes against this damage. CONCLUSION: This study provides evidence that EDAC is cytoprotective against ischemia and glutamate excitotoxicity by modulating astrocyte responses and stimulating their glutamate homeostatic mechanisms.

Bromelain supplementation and inflammatory markers: A systematic review of clinical trials.

BACKGROUND AND AIMS: The inflammatory process is a response mechanism to any stressor agent. Emerging novel therapeutic options derived mainly from natural products such as bromelain have been used to reduce the significant side effects of available anti-inflammatory drugs. Bromelain is an enzyme complex derived from Ananas comosus, known for its anti-inflammatory potential and good tolerance. Therefore, the aim was to assess whether bromelain supplementation exerts anti-inflammatory effects in adults. METHODS: The systematic review was registered in PROSPERO (n° CRD42020221395), and the search was performed in MEDLINE, Scopus, Web of Science, and Cochrane Library. The terms used in the search were: "bromelains", "bromelain", "randomized clinical trial", and "clinical trial". Eligibility criteria were: randomized clinical trials with participants aged 18 years or over, of both sexes, who received supplementation with bromelain alone or in combination with other oral compounds, with an evaluation of inflammatory parameters as primary and secondary outcomes, published in English, Portuguese or Spanish. RESULTS: 1375 studies were retrieved, of which 269 were duplicates. Seven (7) randomized controlled trials were eligible for the systematic review. In most studies, supplementation with bromelain, isolated or in combined therapy, reduced inflammatory parameters. Regarding the reduction of inflammatory parameters among studies with associated bromelain, two presented reduction of inflammatory parameters, while in the evaluation of bromelain treated alone, two studies also showed reduction. In relation to doses supplemented, the studies with associated bromelain ranged from 99.9 to 1200 mg/day and the supplementation time ranged from 3 to 16 weeks. Moreover, the inflammatory parameters evaluated were: IL-12, PGE-2, COX-2, IL-6, IL-8, TNF-α, IL-1ß, IL-10, CRP, NFγ B1, PPAR-α, TNF, TRAF, MCP-1 and adiponectin. In studies with isolated bromelain supplementation, it ranged from 200 to 1050 mg/day for 1 week to 16 weeks. Markers associated with inflammation varied between studies, including IL-2, IL-5, IL-6, IL-8, IL-10, IL-13, IFNγ and MCP-1, PGE-2, CRP and fibrinogen. Eleven (11) participants experienced side effects, and two discontinued treatment in the studies. The reported adverse effects were mainly gastrointestinal but well tolerated. CONCLUSION: The general effect of bromelain supplementation on inflammation is inconsistent because of population heterogeneity, doses used, treatment duration, and parameters evaluated. The observed effects are punctual and isolated, and further standardization is needed to establish doses, supplementation time, and which type of inflammatory condition is indicated.

Toxicogenetic profile of the monoterpene alpha-terpineol on normal and tumor eukaryotic cells.

Alpha-terpineol is a monoterpene alcohol found in essential oils from medicinal plants with some well-known pharmacological activities and widely used in cosmetics. However, the toxicological effects and additional pharmacological activities need to be clarified. Thus, the study evaluated the toxic, cytotoxic, genotoxic, hemolytic, and oxidative potential of alpha-terpineol in non-clinical bioassays. Different concentrations of alpha-terpineol were used in bioassays, including MTT (50, 100, 200, and 400 µg/mL), Artemia salina (6.25-400 µg/mL), Allium cepa (10, 50, and 100 µg/mL), comet assay (100, 200, and 500 µg/mL), cytokinesis-block micronucleus (100, 250, and 500 µg/mL), confocal microscopy for apoptosis quantification (100 and 500 µg/mL), hemolysis and Saccharomyces cerevisiae central disk test (10, 35, and 75 µg/mL). For the MTT test, alpha-terpineol was more cytotoxic on melanoma murine B16-F10 cells rather than macrophages. For A. salina test, alpha-terpineol showed LC50 of 68.29 and 76.36 µg/mL for 24 h and 48 h of exposure time, respectively. Meanwhile, alpha-terpineol was also cytotoxic to meristematic cells, which revealed inhibition of cellular division and mutagenic action by formation of bridges and delayed anaphases. The compound increased damage index and frequency of damage corroborated by the presence of micronuclei, bridges and nuclear buds at 500 µg/mL, but it caused neither hemolysis, oxidative damage on the S. cerevisiae nor cell death in normal fibroblasts. The findings indicate alpha-terpineol has cytotoxic potential by cytogenetic and molecular mechanisms associated with apoptosis and probable target effects against melanoma cells.

Consumption and supplementation of vitamin E in breast cancer risk, treatment, and outcomes: A systematic review with meta-analysis.

BACKGROUND: Robust evidence have shown diet or dietary components in playing a direct role on cancer chemoprevention such as breast cancer (BC), and also prevention against cancer therapy side effects. In this context, vitamin E isoforms have been associated with tumor suppression pathways, mainly related to proliferation, invasion, metastasis, tumor metabolism and chemoresistance. OBJECTIVE: Therefore, we performed a systematic review with meta-analysis to assess the effects of vitamin E consumption and/or supplementation on breast cancer risk, treatment, and outcomes. METHODS: The studies were selected in the electronic databases PubMed, Science Direct, Scopus and Web of Science. RESULTS: A total of 22 articles were selected, which nine manuscripts we perform the meta-analysis. The summary effect estimate did not indicate any significant association between consumption versus non-consumption of total vitamin E and breast cancer risk. After assessing the effects of vitamin E supplementation on breast cancer risk, only two had data for comparison and vitamin E supplementation presented no impact on breast cancer risk. However, the summary effect estimate from the included studies indicated that vitamin E consumption was inversely associated with breast cancer recurrence in the control group. There are no significant results regarding dietary or supplemental vitamin E intake and BC risk reduction. CONCLUSION: Finally, regarding recurrence, survival, and mortality, the results indicated that vitamin E consumption was inversely associated with breast cancer recurrence, although no association was found for breast cancer mortality.

Toxic profile of marinobufagin from poisonous Amazon toads and antitumoral effects on human colorectal carcinomas.

ETHNOPHARMACOLOGICAL RELEVANCE: South Americans natives have extensively used the toad "kururu" to reduce/treat skin infections, cutaneous lesions and sores. They release secretions rich in bufadienolides, polyhydroxy steroids with well-documented cardiotonic and antiproliferative actions, but in vivo antitumoral evaluations in mammals are rare, and toxicological safety has been left in second place. AIMS OF THE STUDY: This investigation used in silico, in vitro and in vivo tools to evaluate acute and subacute toxic effects of marinobufagin and the anticancer action in tumor-bearing mice models. MATERIALS AND METHODS: Initially, in silico toxic predictions were performed, followed by in vitro assays using human and murine normal and tumor lines. Next, acute and subacute studies on mice investigated the behavior, hematological and intestinal transit profile and antitumoral activity of marinobufagin in sarcoma 180- and HCT-116 colorectal carcinoma-transplanted mice for 7 and 15 days, respectively. Ex vivo and in vivo cytogenetic assays in Sarcoma 180 and bone marrow cells and histopathological examinations were also executed. RESULTS: In silico studies revealed ecotoxicological effects on crustaceans (Daphnia sp.), fishes (Pimephales promelas and Oryzias latipes), and algae. A 24-h marinobufagin-induced acute toxicity included signals of central activity, mainly (vocal frenzy, absence of body tonus, increased ventilation, ataxia, and equilibrium loss), and convulsions and death at 10 mg/kg. The bufadienolide presented effective in vitro cytotoxic action on human lines of colorectal carcinomas in a similar way to ouabain and tumor reduction in marinobufagin-treated SCID-bearing HCT-116 heterotopic xenografts. Animals under subacute nonlethal doses exhibited a decrease in creatinine clearance with normal levels of blood urea, probably as a result of a marinobufagin-induced renal perfusion fall. Nevertheless, only minor morphological side effects were identified in kidneys, livers, hearts and lungs. CONCLUSIONS: Marinobufagin has in vitro and in vivo anticancer action on colorectal carcinoma and mild and reversible alterations in key metabolic organs without direct chemotherapy-induced gastrointestinal effects at subacute exposure, but it causes acute ataxia, equilibrium loss, convulsions and death at higher acute exposure.

α-tocopherol as a selective modulator of toxicogenic damage induced by antineoplastic agents cyclophosphamide and doxorubicin.

The aim of this study was to determine the oxidative/antioxidative effects, modulatory and selective potential of α-tocopherol (vitamin E) on antineoplastic drug-induced toxicogenetic damage. The toxicity, cytotoxicity and genotoxicity induced by antineoplastic agents cyclophosphamide (CPA) and doxorubicin (DOX) was examined utilizing as models Saccharomyces cerevisiae, Allium cepa, Artemia salina and human peripheral blood mononuclear cells (PBMCs) in the presence of α-tocopherol. For these tests, concentrations of α- tocopherol 100 IU/ml (67mg/ml), CPA 20 µg/ml, DOX 2 µg/ml were used. The selectivity of α-tocopherol was assessed by the MTT test using human mammary gland non-tumor (MCF10A) and tumor (MCF-7) cell lines. Data showed cytoplasmic and mitochondrial oxidative damage induced by CPA or DOX was significantly diminished by α-tocopherol in S. cerevisiae. In addition, the toxic effects on A. salina and cytotoxic and mutagenic effects on A. cepa were significantly reduced by α-tocopherol. In PBMCs, α-tocopherol alone did not markedly affect these cells, and when treated in conjunction with CPA or DOX, α-tocopherol reduced the toxicogenetic effects noted after antineoplastic drug administration as evidenced by decreased chromosomal alterations and lowered cell death rate. In human mammary gland non-tumor and tumor cell lines, α-tocopherol produced selective cytotoxicity with 2-fold higher effect in tumor cells. Evidence indicates that vitamin E (1) produced anti-cytotoxic and anti-mutagenic effects against CPA and DOX (2) increased higher selectivity toward tumor cells, and (3) presented chemoprotective activity in PBMCs.

Chemopreventive and anti-tumor potential of vitamin E in preclinical breast cancer studies: A systematic review.

BACKGROUND: Vitamin E has been investigated for its antitumor potential, including the ability to change cancer gene pathways as well as promote antioxidant and pro-oxidant activity. OBJECTIVE: Therefore, this systematic review aimed to evaluate antitumor and chemopreventive activity of different vitamin E isoforms (tocopherols and tocotrienols) through in vitro and in vivo studies. METHOD: The systematic review was registered in PROSPERO (No. CRD4202126207) and the search was carried out in four electronic databases (PubMed, Science Direct, Scopus and Web of Science) in June 2021 by three independent reviewers. The search equation used was: "Supplementation" AND ("Vitamin E" OR Tocopherol OR Tocotrienol) AND "breast cancer" AND (chemotherapy OR therapy OR prevention). In vitro studies and animal models of breast cancer supplemented with tocopherol or tocotrienol vitamers, alone or in combination, were included. RESULTS: The results revealed 8546 relevant studies that were initially identified in our search. After analysis, a total of 12 studies were eligible for this systematic review. All studies included animal models, and 5 of them also performed in vitro experiments on cancer cell lines. The studies performed supplementation with tocopherols, mixtures (tocopherols and tocotrienols) and synthetic vitamin E forms. There was an significant association of estradiol, dendritic cells and pterostilbene in combined therapy with vitamin E. Vitamin E delayed tumor development, reduced tumor size, proliferation, viability, expression of anti-apoptotic and cell proliferation genes, and upregulated pro-apoptotic genes, tumor suppressor genes and increased immune response. The effects on oxidative stress markers and antioxidant activity were conflicting among studies. Only one study with synthetic vitamin E reported cardiotoxicity, but it did not show vitamin E genotoxicity. CONCLUSION: In conclusion, vitamin E isoforms, isolated or associated, showed antitumor and chemopreventive activity. However, due to studies heterogeneity, there is a need for further analysis to establish dose, form, supplementation time and breast cancer stage.

Oxylipin status, before and after LC n-3 PUFA supplementation, has little relationship with skeletal muscle biology in older adults at risk of sarcopenia.

INTRODUCTION: Oxylipins form endogenously via the oxygenation of long-chain polyunsaturated fatty acids (LC PUFA). Several oxylipins are highly bioactive molecules and are believed to be key mediators of LC PUFA metabolism in the body. However, little is known in relation to whether oxylipins mediate alterations in skeletal muscle mass and function. The objective of this study was to determine if a relationship exists between the oxylipin profile and skeletal muscle biology in healthy older adults at risk of sarcopenia and determine if this changes in response to LC n-3 PUFA supplementation. MATERIALS AND METHODS: This exploratory study investigated the baseline correlations between LC n-3, n-6 and n-9 PUFA-derived oxylipins and markers of muscle biology. For this, the concentration of 79 free (i.e., non-esterified) oxylipins was quantified in human plasma by liquid chromatography-mass spectrometry (LC-MS) and retrospectively correlated to phenotypic outcomes obtained pre-intervention from the NUTRIMAL study (n = 49). After examining the baseline relationship, the potential effect of supplementation (LC n-3 PUFA or an isoenergetic control made of high-oleic sunflower and corn oil) was evaluated by correlating the change in oxylipins concentration and the change in markers of skeletal muscle biology. The relationship between oxylipins pre- and post-intervention and their parent PUFA were also examined. RESULTS: At baseline, the hydroxy product of mead acid (n-9 PUFA), 5-HETrE, was negatively correlated to the phenotypic parameters appendicular lean mass index (ALMI) (p = 0.003, r=-0.41), skeletal muscle mass index (SMMI) (p = 0.001, r=-0.46), handgrip strength (HGS) (p<0.001, r = 0.48) and isometric knee extension (p<0.001, r=-0.48). Likewise, LC n-6 PUFA hydroxy­PUFA were negatively correlated to HGS (i.e., 12-HETrE, p = 0.002, r=-0.42, and 5- and 11-HETE, p = 0.006, r=-0.47 and p<0.001, r=-0.50 respectively), single leg stand time (i.e., 12-HETrE, p = 0.006, r=-0.39 and 16-HETE, p = 0.002, r=-0.43), and five-time-sit-to-stand test (FTST) performance (16-HETE, p = 0.006, r = 0.39), and positively correlated to gait speed (i.e., 12-HETrE, p = 0.007, r = 0.38 and 16-HETE, p = 0.006, r = 0.39). LC n-3 PUFA supplementation increased eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) derived oxylipins and reduced n-6 PUFA derived oxylipins. Parameters of skeletal muscle mass and strength were not significantly altered in either LC n-3 PUFA or placebo groups. Changes in plasma oxylipins concentrations were closely related to changes in their parent PUFA, assessed in the erythrocyte membrane, but were not associated with any changes in skeletal muscle parameters. DISCUSSION AND CONCLUSION: At baseline, the status n-9 (5-HETrE) and n-6 PUFA derivates [12-HETrE, and 5-, 11- and 16-HETE], but not n-3 PUFA derived oxylipins, were associated with poor skeletal muscle health parameters (i.e., mass and strength). However, these correlations were no longer present when correlating relative changes from pre to post timepoints. An independent cohort validation is needed to explore baseline correlations further. Further research is warranted to assess other biological mechanisms by which LC n-3 PUFA might affect muscle biology.

RELATIONSHIP BETWEEN SELENIUM NUTRITIONAL STATUS AND MARKERS OF LOW-GRADE CHRONIC INFLAMMATION IN OBESE WOMEN.

Low-grade chronic inflammation is one of the main disorders that characterize adipose tissue dysfunction in obesity and is an important element in the pathogenesis of several comorbidities. In this context, selenium is an essential micronutrient that exerts important anti-inflammatory functions, and the role of selenium in controlling inflammation associated with obesity is not well defined. Thus, this study aimed to evaluate the relationship between markers of the nutritional status of selenium and low-grade chronic inflammation in obese women. This cross-sectional study included 81 women aged between 18 and 50 years, who were divided into two groups according to body mass index (BMI): the obesity group (n = 38) and normal weight group (n = 43). Selenium intake was assessed by 3-day diet records. The plasma, erythrocyte, and urinary selenium concentrations were determined using inductively coupled plasma optical emission spectrometry. The analysis of serum cytokines interleukin (IL)-8, IL-1ß, IL-6, IL-10, and tumor necrosis factor alpha (TNFα) was performed using flow cytometry. The results of this study revealed that the obese women had higher dietary intake of selenium than eutrophic women. However, obese participants showed decreased selenium concentrations in plasma and erythrocytes, in parallel with increased concentrations of selenium in the urine. Regarding the inflammatory parameters, obese women exhibited higher concentrations of IL-6 and lower concentrations of the cytokines IL-8, IL-1ß, and TNFα than eutrophic women. In the binary logistic regression analysis, erythrocyte selenium was considered an independent predictor of the serum concentrations of cytokine IL-8 in obese women, reflecting the anti-inflammatory action of this micronutrient.

Antimitotic and toxicogenetic action of Stevia urticifolia aerial parts on proliferating vegetal and mammalian cells: in vitro and in vivo traditional and replacement methods.

Stevia urticifolia Thunb. is an underexploited herb possessing bioactive flavonoids, saponins, and terpenoids. The aim of this study was to examine the antiproliferative and toxicogenetic properties of the ethyl acetate extract from Stevia urticifolia aerial parts (EtAcSur) upon Artemia salina, erythrocytes, Allium cepa and sarcoma 180 cells and fibroblasts, as well as in vivo studies on mice to determine systemic, macroscopic, and behavioral alterations and bone marrow chromosomal damage. The assessment using A. salina larvae and mouse blood cells revealed LC50 and EC50 values of 68.9 and 113.6 µg/ml, respectively. Root growth and mitosis were inhibited by EtAcSur, and chromosomal aberrations were detected only at 100 µg/ml. EtAcSur exhibited potent concentration-dependent viability reduction of S180 and L-929 cells and antioxidant capacity employing ABTS• and DPPH•. No previous in vivo studies were performed before with the EtAcSur. Signals of acute toxicity were not observed at 300 mg/kg. Physiological and toxicological investigations at 25 and 50 mg/mg/day i.p. for 8 days did not markedly change body or organ relative weights, nor patterns of spontaneous locomotor and exploratory activities. In contrast, clastogenic effects on bone marrow were found at 50 mg/mg/day. EtAcSur was found to (1) produce toxicity in microcrustaceans, (2) capacity as free radical scavenger, (3) antimitotic, cytotoxic and clastogenic activties upon vegetal and mammalian cells, and (4) lethality on both tumor and normal murine cells indistinctly. In vivo damage systemic effects were not remarkable and clinical signals of toxicity were not observed, suggesting the significant pharmacological potential of S. urticifolia for the development of antineoplastic agents.Abbreviations: ABTS: 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid); DMSO: dimethylsulfoxide; DPPH: 1,1-diphenyl-2-picrylhydrazyl; EC50: effective concentration 50%; EtAcSur: ethyl acetate extract from Stevia urticifolia aerial parts; Hb, hemoglobin; IC50: inhibitory concentration 50%; LC50,: lethal concentration 50%; MI: mitotic index; RBC, red blood cells; Trolox: 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid.

Activities and Molecular Mechanisms of Diterpenes, Diterpenoids, and Their Derivatives in Rheumatoid Arthritis.

Diterpenes and their derivatives have many biological activities, including anti-inflammatory and immunomodulatory effects. To date, several diterpenes, diterpenoids, and their laboratory-derived products have been demonstrated for antiarthritic activities. This study summarizes the literature about diterpenes and their derivatives acting against rheumatoid arthritis (RA) depending on the database reports until 31 August 2021. For this, we have conducted an extensive search in databases such as PubMed, Science Direct, Google Scholar, and Clinicaltrials.gov using specific relevant keywords. The search yielded 2708 published records, among which 48 have been included in this study. The findings offer several potential diterpenes and their derivatives as anti-RA in various test models. Among the diterpenes and their derivatives, andrographolide, triptolide, and tanshinone IIA have been found to exhibit anti-RA activity through diverse pathways. In addition, some important derivatives of triptolide and tanshinone IIA have also been shown to have anti-RA effects. Overall, findings suggest that these substances could reduce arthritis score, downregulate oxidative, proinflammatory, and inflammatory biomarkers, modulate various arthritis pathways, and improve joint destruction and clinical arthritic conditions, signs, symptoms, and physical functions in humans and numerous experimental animals, mainly through cytokine and chemokine as well as several physiological protein interaction pathways. Taken all together, diterpenes, diterpenoids, and their derivatives may be promising tools for RA management.

Reações adversas do montelucaste no tratamento da asma pediátrica: uma revisão integrativa da literatura / Adverse reactions of montelukast in the treatment of pediatric asthma: an integrative literature review / Reacciones adversas de montelukast en el tratamiento del asma pediátrico: una revisión integrativa de la literatura

Buscou-se analisar as reações adversas do montelucaste quando prescrito para o tratamento da asma pediátrica. Revisão integrativa da literatura utilizando as bases de dados: U.S. National Library of Medicine (PubMed), Biblioteca Virtual da Saúde (BVS), SCOPUS e Business Source Complete (EBSCO), empregando os descritores: "asthma", "pediatric", "montelukast" e "adverse effects", unidos pelo booleano "AND''. Incluíram-se artigos na íntegra; publicados nos últimos 5 anos; redigidos em português, inglês ou espanhol; pesquisados em humanos e com uma relação com o nosso objetivo. Excluíram-se os que se enquadravam em nossos critérios de exclusão.Foram identificados 53 artigos, dos quais 11 compuseram a amostra final desta revisão. A exposição ao montelucaste foi associada a uma chance 2 vezes maior de reações neuropsiquiátricas em um dos artigos analisados, porém os estudos ainda não forneceram uma explicação fisiopatológica em comum. Reações neuropsiquiátricas foram as de maior prevalência, representando mais de 90% da amostra.

We analyzed the adverse reactions of montelukast when prescribed for the treatment of pediatric asthma. This is an integrative literature review using the databases: U.S. National Library of Medicine (PubMed), Virtual Health Library (BVS), SCOPUS and Business Source Complete (EBSCO), using the descriptors: "asthma", "pediatric", "montelukast" and "adverse effects", connected by the Boolean " AND''. Articles in full were included, published in the last 5 years, written in Portuguese, English or Spanish, researched in humans and related to our objective. Those that met our exclusion criteria were excluded. Fifty-three articles were identified, of which 11 comprised the final sample of this review. Exposure to montelukast was associated with a 2-fold greater chance of neuropsychiatric reactions in one of the articles analyzed, but the studies have not yet provided a common pathophysiological explanation. Neuropsychiatric reactions were the most prevalent, representing more than 90% of the sample.

Se intentó analizar las reacciones adversas de montelukast cuando se prescribe para el tratamiento del asma pediátrica. Revisión integrativa de la literatura usando las bases de datos: U.S. National Library of Medicine (PubMed), Virtual Health Library (BVS), SCOPUS y Business Source Complete (EBSCO), utilizando los descriptores: "asma", "pediátrico", "montelukast" y "efectos adversos", unidos por el booleano " Y". Se incluyeron artículos completos, publicados en los últimos 5 años, escritos en portugués, inglés o español, investigados en humanos y relacionados con nuestro objetivo. Se excluyeron aquellos que cumplieron con nuestros criterios de exclusión. Se identificaron cincuenta y tres artículos, de los cuales 11 constituyeron la muestra final de esta revisión. La exposición a montelukast se asoció con una probabilidad 2 veces mayor e reacciones neurosiquiátricas en uno de los artículos analizados, pero los estudios aún no han proporcionado una explicación fisiopatológica común. Las reacciones neurosiquiátricas fueron las más prevalentes, representando más del 90% de la muestra

Cytogenotoxic evaluation of the acetonitrile extract, citrinin and dicitrinin-A from Penicillium citrinum.

Endophytic fungi are promising sources of bioactive substances; however, their secondary metabolites are toxic to plants, animals, and humans. This study aimed toevaluate the toxic, cytotoxic, mutagenic and oxidant/antioxidant activities of acetonitrile extract (AEPc), citrinin (CIT) and dicitrinin-A (DIC-A) of Penicillium citrinum. For this, the test substances at 0.5; 1.0; 1.5 and 2 µg/mLwere exposed for 24 and 48 h in Artemia salina, and 48 h in Allium cepa test systems. The oxidant/antioxidant test was evaluated in pre-, co- and post-treatment with the stressor hydrogen peroxide (H2O2) in Saccharomyces cerevisiae. The results suggest that the AEPc, CIT and DIC-A at 0.5; 1.0; 1.5 and 2 µg/mL showed toxicity in A. saline, with LC50 (24 h) of 2.03 µg/mL, 1.71 µg/mL and 2.29 µg/mL, and LC50 (48 h) of 0.51 µg/mL, 0.54 µg/mL and 0.54 µg/mL, respectively.In A. cepa, the test substances also exerted cytotoxic and mutagenic effects. The AEPc, CIT and DIC-A at lower concentrations modulated the damage induced by H2O2 in the proficient and mutant strains of S. cerevisiae for cytoplasmic and mitochondrial superoxide dismutase. Moreover, the AEPc at 2 µg/mL and CIT at the two highest concentrations did not affect the H2O2-induced DNA damage in the test strains. In conclusion, AEPc, CIT and DIC-A of P. citrinum may exert their toxic, cytotoxic and mutagenic effects in the test systems possibly through oxidative stress induction pathway.

Chemotherapeutic and Safety Profile of a Fraction from Mimosa caesalpiniifolia Stem Bark.

Mimosa caesalpiniifolia (Fabaceae) is used by Brazilian people to treat hypertension, bronchitis, and skin infections. Herein, we evaluated the antiproliferative action of the dichloromethane fraction from M. caesalpiniifolia (DFMC) stem bark on murine tumor cells and the in vivo toxicogenetic profile. Initially, the cytotoxic activity of DFMC on primary cultures of Sarcoma 180 (S180) cells by Alamar Blue, trypan, and cytokinesis block micronucleus (CBMN) assays was assessed after 72 h of exposure, followed by the treatment of S180-bearing Swiss mice for 7 days, physiological investigations, and DNA/chromosomal damage. DFMC and betulinic acid revealed similar in vitro antiproliferative action on S180 cells and induced a reduction in viable cells, induced a reduction in viable cells and caused the emergence of bridges, buds, and morphological features of apoptosis and necrosis. S180-transplanted mice treated with DFMC (50 and 100 mg/kg/day), a betulinic acid-rich dichloromethane, showed for the first time in vivo tumor growth reduction (64.8 and 80.0%) and poorer peri- and intratumor quantities of vessels. Such antiproliferative action was associated with detectible side effects (loss of weight, reduction of spleen, lymphocytopenia, and neutrophilia and increasing of GOT and micronucleus in bone marrow), but preclinical general anticancer properties of the DFMC were not threatened by toxicological effects, and these biomedical discoveries validate the ethnopharmacological reputation of Mimosa species as emerging phytotherapy sources of lead molecules.

Olaparib-mediated enhancement of 5-fluorouracil cytotoxicity in mismatch repair deficient colorectal cancer cells.

BACKGROUND: The advances in colorectal cancer (CRC) treatment include the identification of deficiencies in Mismatch Repair (MMR) pathway to predict the benefit of adjuvant 5-fluorouracil (5-FU) and oxaliplatin for stage II CRC and immunotherapy. Defective MMR contributes to chemoresistance in CRC. A growing body of evidence supports the role of Poly-(ADP-ribose) polymerase (PARP) inhibitors, such as Olaparib, in the treatment of different subsets of cancer beyond the tumors with homologous recombination deficiencies. In this work we evaluated the effect of Olaparib on 5-FU cytotoxicity in MMR-deficient and proficient CRC cells and the mechanisms involved. METHODS: Human colon cancer cell lines, proficient (HT29) and deficient (HCT116) in MMR, were treated with 5-FU and Olaparib. Cytotoxicity was assessed by MTT and clonogenic assays, apoptosis induction and cell cycle progression by flow cytometry, DNA damage by comet assay. Adhesion and transwell migration assays were also performed. RESULTS: Our results showed enhancement of the 5-FU citotoxicity by Olaparib in MMR-deficient HCT116 colon cancer cells. Moreover, the combined treatment with Olaparib and 5-FU induced G2/M arrest, apoptosis and polyploidy in these cells. In MMR proficient HT29 cells, the Olaparib alone reduced clonogenic survival, induced DNA damage accumulation and decreased the adhesion and migration capacities. CONCLUSION: Our results suggest benefits of Olaparib inclusion in CRC treatment, as combination with 5-FU for MMR deficient CRC and as monotherapy for MMR proficient CRC. Thus, combined therapy with Olaparib could be a strategy to overcome 5-FU chemotherapeutic resistance in MMR-deficient CRC.

Citrinin against breast cancer: A cytogenotoxicological study.

Breast cancer is one of the most lethal types of cancer and a leading cause of mortality among Women worldwide. Citrinin (CIT), a polyketide extracted from the fungus Penicillium citrinum, exhibits a wide range of biological activities such as antibacterial, antifungal, and cytotoxic effects. The aim of the current study was to evaluate the antitumoral effects of CIT against 7,12-dimethylbenzanthracene (DMBA)-induced mammary carcinoma in Swiss mice For this, CIT, DMBA and the standard cyclophosphamide (CPA) induced behavioral changes in experimental animals, and these changes were screened by using the rota rod and open field tests. Additionally, hematological, biochemical, immuno-histochemical, and histopathological analyses were carried out. Results suggest that CIT did not alter behavioral, hematological, and biochemical parameters in mice. DMBA induced invasive mammary carcinoma and showed genotoxic effects in the breasts, bone marrow, lymphocytes, and hepatic cells. It also caused mutagenic effects in the formation of micronuclei, bridges, shoots, and binucleate cells in bone marrow and liver. CIT and CPA genotoxic effects were observed after 3 weeks of therapy, where CIT exhibited a repair capacity and induced significant apoptotic damage in mouse lymphocytes. In conclusion, CIT showed antitumoral effects in Swiss mice, possibly through induction of apoptosis.

Non-clinical toxicity of (+)-limonene epoxide and its physio-pharmacological properties on neurological disorders.

The compound (+)-limonene epoxide has antioxidant, anxiolytic, and antihelminthic properties. However, investigations to determine its long-term exposure were not performed. We investigated the systemic toxicological profile after chronic exposure as well as the antidepressant and antiepileptic potentialities of (+)-limonene epoxide on mice. Initially, we evaluated acute toxicity on Artemia salina nauplii and cytotoxicity on mice erythrocytes and peripheral blood mononuclear cells (PBMC). Aftterwards, mice were chronically treated for 120 days by gavage with (+)-limonene epoxide (25, 50, and 75 mg/kg/day) and this exposure was assessed by pathophysiological measurements. For antidepressant and anticonvulsivant analysis, we performed the forced swimming and tail suspension protocols and pentylenetetrazol- and picrotoxin-induced seizures, respectively. (+)-Limonene epoxide showed a LC50 value of 318.7 µg/mL on A. salina shrimps, caused lysis of red blood cells at higher concentrations only but did not show cytotoxicity on PMBC, which suggests pharmacological safety if plasma concentrations do not exceed 100 µg/mL. Macroscopic, hematological, clinical chemistry, and nutritional changes were not detected, though focal areas of hepatic necrosis, inflammatory infiltrate, and karyolysis have been detected at 75 mg/kg/day. The compound inhibited the developing of pentylenetetrazol- and picrotoxin-induced seizures, decreased deaths, and reduced immobility times, mainly at 75 mg/kg. So, it reversed reserpine effects, suggesting antidepressant effects should be linked to serotonergic and/or adrenergic transmission. It is feasible that (+)-limonene epoxide plays a benzodiazepine-like anticonvulsive action and may be also recommended as an antidote for poisonings caused by central depressants.

Amburana cearensis: Pharmacological and Neuroprotective Effects of Its Compounds.

Amburana cearensis A.C. Smith is an endemic tree from Northeastern Brazil used in folk medicine as teas, decocts and syrups for the treatment of various respiratory and inflammatory diseases, since therapeutic properties have been attributed to compounds from its stem bark and seeds. Numerous pharmacological properties of semi-purified extracts and isolated compounds from A. cearensis have been described in several biological systems, ranging from antimicrobial to anti-inflammatory effects. Some of these activities are attributed to coumarins and phenolic compounds, the major compounds present in A. cearensis seed extracts. Multiple lines of research demonstrate these compounds reduce oxidative stress, inflammation and neuronal death induced by glutamate excitotoxicity, events central to most neuropathologies, including Alzheimer's disease (AD) and Parkinson's Disease (PD). This review focuses on the botanical aspects, folk medicine use, biological effects and pharmacological activities of A. cearensis compounds and their potential as novel non-toxic drugs for the treatment of neurodegenerative diseases.

Antitumoral effects of [6]-gingerol [(S)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-3-decanone] in sarcoma 180 cells through cytogenetic mechanisms.

BACKGROUND: [6]-Gingerol [(S)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-3-decanone] is a phenolic substance reported for several ethnopharmacological usage by virtue of its antioxidant, antiemetic, anti-inflammatory and anticancer properties. This study assessed the antitumoral effects of [6]-Gingerol in primary cells of Sarcoma 180 as well as in peripheral blood lymphocytes of mice. METHODS: The effect of [6]-Gingerol was assessed by applying cytogenetic biomarkers as indicative of genotoxicity, mutagenicity and apoptosis. Ascitic liquid cells were treated with [6]-Gingerol at concentrations of 21.33, 42.66 and 85.33 µM and subjected to the cytotoxicity assays using Trypan blue test and the comet assay, as well as the cytokinesis-block micronucleus assay. Doxorubicin (6 µM) and hydrogen peroxide (85.33 µM) were used as positive controls. RESULTS: [6]-Gingerol, especially at concentrations of 42.66 and 85.33 µM, showed notable cytotoxicity in Sarcoma 180 cells by reducing cell viability and cell division rates via induction of apoptosis. Genotoxicity at the concentrations used was punctuated by the increase in the index and frequency of DNA damage in tested groups. [6]-Gingerol, at all concentrations tested, did not induce significant aneugenic and/or clastogenic effects. It did, however, induced other nuclear abnormalities, such as nucleoplasmic bridges, nuclear buds and apoptosis. The genotoxic effects observed in the cotreatment with H2O2 (challenge assay) employing neoplastic and healthy cells, indicated that [6]-Gingerol may induce oxidative stress. CONCLUSIONS: Observations suggest that [6]-Gingerol may be a candidate for pharmaceutical antitumoral formulations due to its cytotoxicity and to mechanisms associated with genetic instability generated by nuclear alterations especially by apoptosis.

Anti-Cancer Effects of Asiatic Acid, a Triterpene from Centilla asiatica L: A Review.

BACKGROUND: Centilla asiatica L is a medicinal herb that has been widely used in folk medicine to treat various diseases. Asiatic Acid (AA), a triterpene and a known component of this herb, has been shown to display important biological activities, including anti-inflammatory, antibacterial, antidiabetic and antihyperlipidemic, neuroprotective, anxiolytic and antidepressant, hepatoprotective, pancreas protective, and cardio- protective. OBJECTIVE: This review focuses on AA's anti-cancer effects on the basis of published literature found in a number of databases such as PubMed and Science Direct. Emphasis has been given to the mechanisms of action of its anti-cancer effect. METHODS: A literature survey was conducted using known databases such as PubMed and Science Direct using the keywords 'Asiatic acid', pairing with 'cancer', 'tumor', 'anti-cancer effect', 'cytotoxic effect', 'anti-tumor activity', 'cell line', 'animal cancer', and 'human cancer'. RESULTS: Findings suggest that AA exerts anti-cancer effects in several test systems through various pathways, including oxidative/antioxidant, anti-inflammatory, cytotoxicity, apoptotic cell death, necrosis, anti-angiogenesis, inhibition of proliferation and cell migration, and chemoprevention. CONCLUSION: AA may be an effective plant-based cancer chemotherapeutic agent and a promising lead for the development of potent anticancer drugs.