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Propylparaben (PrP) and dichloropropylparaben (diClPrP) are found in soil worldwide, mainly due to the incorporation of urban sludge in crop soils and the use of non-raw wastewater for irrigation. Studies on the adverse effects of PrP on plants are incipient and not found for diClPrP. PrP and diClPrP were evaluated at concentrations 4, 40, and 400 µg/L for their phytotoxic potential to seeds of Allium cepa (onion), Cucumis sativus (cucumber), Lycopersicum sculentum (tomato), and Lactuca sativa (lettuce), and cytotoxic, genotoxic potential, and for generating oxygen-reactive substances in root meristems of A. cepa bulbs. PrP and diClPrP caused a significant reduction in seed root elongation in all four species. In A. cepa bulb roots, PrP and diClPrP resulted in a high prophase index; in addition, PrP at 400 µg/L and diClPrP at the three concentrations significantly decreased cell proliferation and caused alterations in a significant number of cells. Furthermore, diClPrP concentrations induced the development of hooked roots in onion bulbs. The two chemical compounds caused significant changes in the modulation of catalase, ascorbate peroxidase, and guaiacol peroxidase, disarming the root meristems against hydroxyl radicals and superoxides. Therefore, PrP and diClPrP were phytotoxic and cytogenotoxic to the species tested, proving dangerous to plants.
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Cebolas , Parabenos , Parabenos/toxicidade , Cebolas/efeitos dos fármacos , Poluentes do Solo/toxicidade , Lactuca/efeitos dos fármacos , Raízes de Plantas/efeitos dos fármacos , Cucumis sativus/efeitos dos fármacosRESUMO
Safer analgesic drugs remain a hard challenge because of cardiovascular and/or gastrointestinal toxicity, mainly. So, this study evaluated in vivo the antiproliferative actions of a fraction with casearins (FC) from Casearia sylvestris leaves against human colorectal carcinomas and antihyperalgesic effects on inflammatory- or opiate-based pain relief and oncologic pain in Sarcoma 180 (S180)-bearing mice. Moreover, docking investigations evaluated the binding among Casearin X and NMDA(N-methyl-D-aspartate)-type glutamate receptors. HCT-116 colorectal carcinoma-xenografted mice were treated with FC for 15 days. Antinociceptive assays included chemically induced algesia and investigated mechanisms by pharmacological blockade. Intraplantar region S180-bearing animals received a single dose of FC and were examined for mechanical allodynia and behavior alterations. AutoDock Vina determined molecular interactions among Cas X and NMDA receptor subunits. FC reduced tumor growth at i.p. (5 and 10 mg/kg) and oral (25 mg/kg/day) doses (31.12-39.27%). FC reduced abdominal pain, as confirmed by formalin and glutamate protocols, whose antinociception activity was blocked by naloxone and L-NAME (neurogenic phase) and naloxone, atropine, and flumazenil (inflammatory phase). Meanwhile, glibenclamide potentiated the FC analgesic effects. FC increased the paw withdrawal threshold without producing changes in exploratory parameters or motor coordination. Cas X generated a more stable complex with active sites of the NMDA receptor GluN2B subunits. FC is a promising antitumor agent against colorectal carcinomas, has peripheral analgesic effects by desensitizing secondary afferent neurons, and inhibits glutamate release from presynaptic neurons and/or their action on cognate receptors. These findings emphasize the use of clerodane diterpenes against cancer-related pain conditions.
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Gamma-terpinene (γ-TPN) is a cyclohexane monoterpene isolated from plant essential oils, such as tea tree (Melaleuca alternifolia), oregano (Origanum vulgare), rosemary (Rosmarinus officinalis L.), thyme (Thymus vulgaris Marchand), and eucalyptus (Eucalyptus sp.). Terpenes are widely studied molecules pharmacologically active on the cardiovascular system, hemostasis, and antioxidant actions. Herein, it was investigated the cytotoxic and antiplatelet activity of γ-TPN using different non-clinical laboratory models. For in silico evaluation, the PreADMET, SwissADME, and SwissTargetPrediction softwares were used. Molecular docking was performed using the AutoDockVina and BIOVIA Discovery Studio databases. The cytotoxicity of γ-TPN was analyzed by the MTT assay upon normal murine endothelial SVEC4-10 and fibroblast L-929 cells. Platelet aggregation was evaluated with platelet-rich (PRP) and platelet-poor (PPP) plasma from spontaneously hypertensive rats (SHR), in addition to SVEC4-10 cells pre-incubated with γ-TPN (50, 100, and 200 µM) for 24 h. SHR animals were pre-treated by gavage with γ-TPN for 7 days and divided into four groups (negative control, 25, 50, and 100 mg/kg). Blood samples were collected to measure nitrite using the Griess reagent. Gamma-TPN proved to be quite lipid-soluble (Log P = +4.50), with a qualified profile of similarity to the drug, good bioavailability, and adequate pharmacokinetics. It exhibited affinity mainly for the P2Y12 receptor (6.450 ± 0.232 Kcal/mol), moderate cytotoxicity for L-929 (CC50 = 333.3 µM) and SVEC 4-10 (CC50 = 366.7 µM) cells. The presence of γ-TPN in SVEC 4-10 cells was also able to reduce platelet aggregation by 51.57 and 44.20% at lower concentrations (50 and 100 µM, respectively). Then, γ-TPN has good affinity with purinergic receptors and an effect on the reversal of platelet aggregation and oxidative stress, being promising and safe for therapeutic targets and subsequent studies on the control of thromboembolic diseases.
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Tithonia diversifolia is a perennial bushy plant found in South America with significant ethnopharmacological importance as an antimalarial, antidiabetic, antibacterial, and anticancer agent. The aim of the present study was to determine the cytotoxicity of the ethanolic extract from leaves of T. diversifolia (TdE) on human cancer cell lines (HCT-116, SNB-19, NCIH-460 and MCF-7), as well as the mechanism of action involved in cell death and cellular modulation of oxidative stress. The TdE exhibited significant activity with IC50 values ranging from 7.12 to 38.41 µg/ml, with HCT-116 being the most sensitive cell line. Subsequent experiments were conducted with HCT-116 cell line. TdE decreased the number of viable cells, followed by induction of apoptotic events, increase in mitochondrial membrane permeabilization, and enhanced G2/M phase of the cell cycle. Pro-oxidative effects including elevated acidic vesicular organelle formation, lipid peroxidation, and nitric oxide by-products, as well as reduced levels of intracellular glutathione and reactive oxygen species production were also observed following incubation with TdE, which may lead to DNA damage followed by apoptotic cell death. These results demonstrate the potential of TdE ethanolic leaf extraction for biological activity and enhance the importance of continuing to study natural sources of plants for the development of anticancer agents.
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Antineoplásicos , Tithonia , Humanos , Extratos Vegetais/farmacologia , Células HCT116 , Estresse Oxidativo , Apoptose , Espécies Reativas de Oxigênio/metabolismo , Etanol , Antineoplásicos/farmacologia , Folhas de PlantaRESUMO
Bufadienolides are digitalis-like aglycones mainly found in skin secretions of toads. Among their biological properties, the mechanisms of antiproliferative action on tumor cells remain unclear for many compounds, including against leukemia cells. Herein, it was evaluated the mechanisms involved in the antiproliferative and genotoxic actions of hellebrigenin on tumor cell lines and in silico capacity to inhibit the human topoisomerase IIa enzyme. Firstly, its cytotoxic action was investigated by colorimetric assays in human tumor and peripheral blood mononuclear cells (PBMC). Next, biochemical and morphological studies were detailed by light microscopy (trypan blue dye exclusion), immunocytochemistry (BrdU uptake), flow cytometry and DNA/chromosomal damages (Cometa and aberrations). Finally, computational modelling was used to search for topoisomerase inhibition. Hellebrigenin reduced proliferation, BrdU incorporation, viability, and membrane integrity of HL-60 leukemia cells. Additionally, it increased G2/M arrest, internucleosomal DNA fragmentation, mitochondrial depolarization, and phosphatidylserine externalization in a concentration-dependent manner. In contrast to doxorubicin, hellebrigenin did not cause DNA strand breaks in HL-60 cell line and lymphocytes, and it interacts with ATPase domain residues of human topoisomerase IIa, generating a complex of hydrophobic and van der Waals interactions and hydrogen bonds. So, hellebrigenin presented potent anti-leukemic activity at concentrations as low as 0.06 µM, a value comparable to the clinical anticancer agent doxorubicin, and caused biochemical changes suggestive of apoptosis without genotoxic/clastogenic-related action, but it probably triggers catalytic inhibition of topoisomerase II. These findings also emphasize toad steroid toxins as promising lead antineoplasic compounds with relatively low cytotoxic action on human normal cells.
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Antineoplásicos , Bufanolídeos , Leucemia , Humanos , Leucócitos Mononucleares , Bromodesoxiuridina/farmacologia , Dano ao DNA , Antineoplásicos/farmacologia , Bufanolídeos/química , Células HL-60 , Apoptose , DNA/farmacologia , Doxorrubicina/farmacologiaRESUMO
Introdução: a própolis é uma composição resinosa produzida por abelhas e utilizada em suas colmeias contra microrganismos. Existem diversos tipos desse composto, sendo o de coloração vermelha o último espécime relatado na literatura. Assim, dentre suas aplicabilidades, a atividade antifúngica da própolis vermelha tem sido explorada com vistas a ampliar sua ação terapêutica. Objetivo: explorar estudos acerca da ação antifúngica da própolis vermelha, identificando suas potencialidades e desafios. Metodologia: foi realizada uma revisão integrativa nas bases de dados bibliográficos MEDLINE (via PubMed), SciELO e Google Acadêmico, complementada por uma diligência nas bases de ensaios clínicos ReBEC e Clinical Trials. Em seguida todos os estudos selecionados foram explorados para obtenção do cenário atual sobre o tema. Resultados: foram incluídos 08 estudos, sendo 01 deles um ensaio clínico. Os estudos comprovam a ação antifúngica da própolis vermelha, principalmente contra Candida spp. e Paracoccidioides brasiliensis, e evidenciam a maior potência fungicida deste composto em detrimento de outros tipos de própolis. Conclusão: a ação antifúngica da própolis vermelha mostra-se uma potencialidade em diversos estudos. Entretanto, o volume de pesquisas científicas relativas a esse tema é insuficiente e a complexidade desse composto configura-se como um desafio à sua aplicabilidade.
Introduction: propolis is a resinous composition produced by compounds and used in their hives against microorganisms. There are several types of this compound, the red one is the last specimen reported in the literature. Thus, among its applicability, the antifungal activity of red propolis has been explored as a path to expand its therapeutic action. Objective: to explore studies about the antifungal action of red propolis, identifying its potentialities and challenges. Methodology: Na integrative review was carried out in the bibliographic databases MEDLINE (via PubMed), SciELO and Google Scholar, complemented by a diligence in ReBEC and Clinical Trials databases. Then, all selected studies were explorers to obtain the current scenario on the subject. Results: 08 studies were included, which 01 of them was a clinical trial. Studies prove the antifungal action of red propolis, mainly against Candida spp. and Paracoccidioides brasiliensis, and show the greater fungicidal power of this compound compared to other types of propolis. Conclusion: the antifungal action of red propolis shows potential in several studies. However, the volume of scientific research on this theme is insufficient and the complexity of this compound represents a challenge to its applicability.
Introducción: el propóleo es una composición resinosa producida por las abejas y utilizada en sus colmenas contra los microorganismos. Existen varios tipos de este compuesto, siendo el rojo el último ejemplar reportado en la literatura. Así, entre sus posibilidades de aplicación, se ha explorado la actividad antifúngica del propóleo rojo con vistas a ampliar su acción terapéutica. Objetivo: explorar estudios sobre la acción antifúngica del propóleo rojo, identificando sus potencialidades y desafíos. Metodología: Se realizó una revisión en las bases de datos bibliográficas MEDLINE (vía PubMed), SciELO y Google Scholar, complementada con una diligencia en las bases de datos de ensayos clínicos ReBEC y Clinical Trials. Luego se exploraron todos los estudios seleccionados para obtener el escenario actual sobre el tema. Resultados: Se incluyeron 08 estudios, 01 de los cuales fue un ensayo clínico. Los estudios demuestran la acción antifúngica del propóleo rojo, principalmente contra Candida spp. y Paracoccidioides brasiliensis, y muestran el mayor poder fungicida de este compuesto en detrimento de otros tipos de propóleos. Conclusión: la acción antifúngica del propóleo rojo muestra potencial en varios estudios. Sin embargo, el volumen de investigación científica sobre este tema es insuficiente y la complejidad de este compuesto representa un desafío para su aplicabilidad.
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Própole/uso terapêutico , Antifúngicos/uso terapêutico , Paracoccidioides/efeitos dos fármacos , Candida/efeitos dos fármacos , Anti-Infecciosos/uso terapêuticoRESUMO
(1) Background: Riparin-A presents several pharmacological activities already elucidated, such as antimicrobial modulator, antileishmania, anxiolytic, anti-inflammatory, antinociceptive, and antioxidant. Even with important bioactive effects, the applicability of Riparin-A is limited due to its low solubility in water, impairing its dissolution in biological fluids. Thus, the objective of this study was to develop a nanohybrid based on Riparin-A and Laponite to obtain a better dissolution profile and evaluate its cytotoxic potential. (2) Methods: The formation of a hybrid system was highlighted by X-ray powder diffraction, infrared spectroscopy, and thermal analysis. Solubility, dissolution, and cytotoxicity studies were performed; (3) Results: An increase in the solubility and aqueous dissolution rate of Riparin-A was observed in the presence of clay. Diffractometric analysis of the hybrid system suggests the amorphization of Riparin-A, and thermal analyses indicated attenuation of decomposition and melting of the Riparin-A after interaction with clay. Furthermore, the nanosystem did not exhibit cytotoxic activity on normal and tumorigenic lines. (4) Conclusions: These results are promising for the development of the Riparin-A/Laponite nanosystem for therapeutic purposes, suggesting an increase in the range of possible routes of administration and bioavailability of this bioactive compound.
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Buthionine sulfoximine (BSO) is a synthetic amino acid that blocks the biosynthesis of reduced glutathione (GSH), an endogenous antioxidant cellular component present in tumor cells. GSH levels have been associated with tumor cell resistance to chemotherapeutic drugs and platinum compounds. Consequently, by depleting GSH, BSO enhances the cytotoxicity of chemotherapeutic agents in drug-resistant tumors. Therefore, the aim of this study was to conduct a systematic review with meta-analysis of preclinical studies utilizing BSO in cancer treatments. The systematic search was carried out using the following databases: PubMed, Web of Science, Scopus, and EMBASE up until March 20, 2023, in order to collect preclinical studies that evaluated BSO, alone or in association, as a strategy for antineoplastic therapy. One hundred nine investigations were found to assess the cytotoxic potential of BSO alone or in combination with other compounds. Twenty-one of these met the criteria for performing the meta-analysis. The evidence gathered indicated that BSO alone exhibits cytotoxic activity. However, this compound is generally used in combination with other antineoplastic strategies, mainly chemotherapy ones, to improve cytotoxicity to carcinogenic cells and treatment efficacy. Finally, this review provides important considerations regarding BSO use in cancer treatment conditions, which might optimize future studies as a potential adjuvant antineoplastic therapeutic tool.
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Antineoplásicos , Neoplasias , Humanos , Butionina Sulfoximina/farmacologia , Butionina Sulfoximina/uso terapêutico , Metionina Sulfoximina/uso terapêutico , Metionina Sulfoximina/toxicidade , Resistencia a Medicamentos Antineoplásicos , Neoplasias/tratamento farmacológico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêuticoRESUMO
Cordia oncocalyx Allemão is an endemic economically underexploited plant from Brazilian semi-arid region. Herein, we carried out a well-defined bibliographic review about the pharmacological activities of oncocalyxones from C. oncocalyx and mechanisms responsible for the biomedical properties. MeSH terms were used in the scientific databases for a narrative exploration. Technological development and bioproducts were also examined. Cordia oncocalyx is a deciduous tree of sexual reproduction rich in terpenoid quinones. Among them, oncocalyxone A, a 1,4-benzoquinone, the main compound from heartwood ethanol extracts, revealed anti-inflammatory and anti-edematogenic actions induced by carrageenan and dextran and antinociceptive potential in mice provoked by acetic acid and formalin. Oncocalyxone A inhibits platelet aggregation via activation of the soluble guanylate cyclase enzyme and blocks glycation processes. In addition to the antimicrobial effects against protozoa, fungi and bacteria and relaxation of smooth muscles, oncocalyxone A reduces mean blood pressure and glycemia in diabetic rats, decreases glomerular filtration parameters and tubular transport of electrolytes, and presents in vitro antimitotic and cytotoxic action upon different types of cancers, including resistant lung carcinoma lines. It has low oral acute toxicity (LD50 > 2000 mg/kg) and activates cellular apoptosis through the production of free radicals and interactions with DNA. However, no patents were found, which also emphasizes that Brazil, as the cradle of the main articles on C. oncocalyx, is wasting time and money. Moreover, slight systemic deleterious effects in mammals stimulate the use of oncocalyxone A and related compounds as lead constituents of safer drugs against chronic diseases.
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Cordia , Diabetes Mellitus Experimental , Ratos , Camundongos , Animais , Cordia/química , Estrutura Molecular , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Doença Crônica , MamíferosRESUMO
Phytol (Pyt), a diterpenoid, possesses many important bioactivities. This study evaluates the anticancer effects of Pyt on sarcoma 180 (S-180) and human leukemia (HL-60) cell lines. For this purpose, cells were treated with Pyt (4.72, 7.08, or 14.16 µM) and a cell viability assay was performed. Additionally, the alkaline comet assay and micronucleus test with cytokinesis were also performed using doxorubicin (6 µM) and hydrogen peroxide (10 mM) as positive controls and stressors, respectively. Results revealed that Pyt significantly reduced the viability and rate of division in S-180 and HL-60 cells with IC50 values of 18.98 ± 3.79 and 1.17 ± 0.34 µM, respectively. Pyt at 14.16 µM exerted aneugenic and/or clastogenic effects in S-180 and HL-60 cells, where the number of micronuclei and other nuclear abnormalities (e.g., nucleoplasmic bridges and nuclear buds) were frequently observed. Moreover, Pyt at all concentrations induced apoptosis and showed necrosis at 14.16 µM, suggesting its anticancer effects on the tested cancer cell lines. Taken together, Pyt showed promising anticancer effects, possibly through inducing apoptosis and necrosis mechanisms, and it exerted aneugenic and/or clastogenic effects on the S-180 and HL-60 cell lines.
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Sarcoma 180 , Sarcoma , Animais , Humanos , Células HL-60 , Fitol/farmacologia , Apoptose , Necrose , Testes para MicronúcleosRESUMO
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.
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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.
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Neoplasias Colorretais , Venenos , Sarcoma 180 , Humanos , Animais , Camundongos , Camundongos SCID , Bufonidae , Neoplasias Colorretais/tratamento farmacológico , Ataxia , MamíferosRESUMO
The aim of this review was to (i) acknowledge structural advantages of natural products (NPs) for designing therapeutic drugs; (ii) emphasize how wildlife conservation is socially and economically necessary for scientific and commercial progress in Brazilian regions; and (iii) show how decisions by governmental regulations exert damaging effects on safeguarding of biodiversity. Natural products (NPs) from animals (e.g.: bufadienolides as marinobufagin), plants (diterpenes: casearin X and paclitaxel; triterpenes: betulinic acid) and microorganisms (depsipeptides: geodiamolides; antraciclines: doxorubicin) are the main source of oral drugs and have innate advantages for enteral and parenteral drug design, synthesis and combinational chemistry using novel techniques, including green chemistry. NPs possess high chemical diversity, binding flexibility to biological targets, chiral centers, aliphatic systems, hydrogen-bond acceptors and donors, and/or heteroatoms, and broad-spectrum pharmacological properties, including against malign disorders. Nonetheless, all Brazilian biomes and connected ecosystems have been systemically threatened since 2019 by the following fire, deforestation, monocultures, cattle raising, mining and/or oil spills mainly as consequence of financial cuts in key institutions which oversee environmental stability for terrestrial and marine Brazilian fauna and flora. Nevertheless, natural chemical entities, broad traditional knowledge on agrobiodiversity, fishing, fire management, and pioneering processes of economic interest play a vital role for "Science of Biodiversity," which arises as business bioeconomy opportunities to convert Brazil into a self-sufficient country for production of pharmaceutical supplies, cosmeticsand foods. Hence, Brazil needs sustainable development projects supported by government and scientific input if one wishes to use the chemical and biological biodiversity to treat individuals and improve the quality of life.
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Produtos Biológicos , Ecossistema , Animais , Bovinos , Brasil , Qualidade de Vida , Biodiversidade , Desenvolvimento de Medicamentos , Conservação dos Recursos Naturais/métodosRESUMO
Flavorings used in cookies, electronic cigarettes, popcorn, and breads contain approximately 30 chemical compounds, which makes it difficult to determine and correlate signs and symptoms of acute, subacute or chronic toxicity. The aim of this study was to characterize a butter flavoring chemically and subsequently examine the in vitro and in vivo toxicological profile using cellular techniques, invertebrates, and lab mammals. For the first time, the ethyl butanoate was found as the main compound of a butter flavoring (97.75%) and 24 h-toxicity assay employing Artemia salina larvae revealed a linear effect and LC50 value of 14.7 (13.7-15.7) mg/ml (R2 = 0.9448). Previous reports about higher oral doses of ethyl butanoate were not found. Observational screening with doses between 150-1000 mg/kg by gavage displayed increased amount of defecation, palpebral ptosis, and grip strength reduction, predominantly at higher doses. The flavoring also produced clinical signs of toxicity and diazepam-like behavioral changes in mice, including loss of motor coordination, muscle relaxation, increase of locomotor activity and intestinal motility, and induction of diarrhea, with deaths occurring after 48 h exposure. This substance fits into category 3 of the Globally Harmonized System. Data demonstrated that butter flavoring altered the emotional state in Swiss mice and disrupted intestinal motility, which may be a result of neurochemical changes or direct lesions in the central/peripheral nervous systems.
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Sistemas Eletrônicos de Liberação de Nicotina , Camundongos , Animais , Manteiga , Aromatizantes/toxicidade , MamíferosRESUMO
Abstract We critically analyzed clinical trials performed with chloroquine (CQ) and hydroxychloroquine (HCQ) with or without macrolides during the first wave of COVID-19 and discussed the design and limitations of peer-reviewed studies from January to July 2020. Seventeen studies were eligible for the discussion. CQ and HCQ did not demonstrate clinical advantages that justified their inclusion in therapeutic regimens of free prescription for treatment or prophylactic purposes, as suggested by health authorities, including in Brazil, during the first wave. Around August 2020, robust data had already indicated that pharmacological effects of CQ, HCQ and macrolides as anti-SARS-CoV-2 molecules were limited to in vitro conditions and largely based on retrospective trials with low quality and weak internal validity, which made evidence superficial for decision-making. Up to that point, most randomized and nonrandomized clinical trials did not reveal beneficial effects of CQ or HCQ with or without macrolides to reduce lethality, rate of intubation, days of hospitalization, respiratory support/mechanical ventilation requirements, duration, type and number of symptoms, and death and were unsuccessful in increasing virus elimination and/or days alive in hospitalized or ambulatory patients with COVID-19. In addition, many studies have demonstrated that side effects are more common in CQ-or HCQ-treated patients.
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Macrolídeos/análise , Pandemias/classificação , COVID-19/patologia , Antimaláricos/análise , Comorbidade , Ensaios Clínicos como Assunto/instrumentação , Coronavirus/efeitos dos fármacos , Aminoquinolinas/agonistas , HospitalizaçãoRESUMO
Breast cancer (BC) diagnosis has been associated with significant risk factors, including family history, late menopause, obesity, poor eating habits, and alcoholism. Despite the advances in the last decades regarding cancer treatment, some obstacles still hinder the effectiveness of therapy. For example, chemotherapy resistance is common in locally advanced or metastatic cancer, reducing treatment options and contributing to mortality. In this review, we provide an overview of BC metabolic changes, including the impact of restrictive diets associated with chemoresistance, the therapeutic potential of the diet on tumor progression, pathways related to metabolic health in oncology, and perspectives on the future in the area of oncological nutrition.
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Neoplasias da Mama , Neoplasias da Mama/tratamento farmacológico , Reprogramação Celular , Dieta , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , ObesidadeRESUMO
Research background: Commercialization of Mauritia flexuosa (buriti) fruits in Brazil is at an early stage. Herein, we evaluate the nutritional value of pulp, peel and endocarp samples from buriti fruits, perform macroscopic and microscopic evaluations and analyze their physicochemical properties. Experimental approach: Size and mass, pH, sugar and protein contents, soluble/insoluble fiber, total titratable acidity and energy value of the samples were analyzed. Mineral profiling was performed by energy dispersive X-ray fluorescence spectrometry, and fatty acids and phytosterols were determined by gas chromatography-mass spectrometry. Samples were also submitted to differential scanning calorimetry coupled to a thermal analyzer, and microstructure, morphology, surface and viscosity were evaluated by scanning electron microscopy (SEM) and X-ray diffraction (XRD) with copper radiation. Rheological behavior was also studied. Results and conclusions: Lyophilized pulp had higher nutritional content of minerals, proteins, carbohydrates and energy than in natura pulp. Lyophilized pulp and its by-products showed suitable yields (>17.31%) and low a w, and potassium, manganese and monounsaturated fatty acid contents. Peels showed elevated amounts of saturated and polyunsaturated fatty acids and phytosterols (ß-sitosterol and stigmasterol), and endothermic behavior. The reductions of calcium, magnesium and manganese ranging from 18.5 to 22.7% were observed following the lyophilization. Drying processes generated semi-crystalline powders. Both peels and endocarp contained higher amounts of insoluble fiber and lower contents of sugars. Similar results were obtained by microscopic morphological analysis, differential scanning calorimetry and XRD analysis. Pulp and endocarp exhibited pseudoplastic non-Newtonian behavior, and flow behavior index values were lower than 1, while peels presented dilatant behaviour. Thus, physicochemical and nutritional characterization of pulp and by-products, such as peels and endocarp, are essential to support scientific research and exploration of new sustainable products. Novelty and scientific contribution: Processing and conservation techniques, like lyophilization, maintain the good quality of nutritional contents and bioactive compounds of buriti whole fruits, and can be used to extend their shelf life, preserve alimentary characteristics and provide wider purposes and availability. Such parameters may generate income and food security for local and regional communities.
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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 DPPHâ¢. 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.
Assuntos
Antimitóticos , Stevia , Animais , Antioxidantes/farmacologia , Mamíferos , Camundongos , Componentes Aéreos da Planta , Extratos Vegetais/farmacologia , ToxicogenéticaRESUMO
The present work aimed to characterize the exopolysaccharide obtained from water kefir grains (EPSwk), a symbiotic association of probiotic microorganisms. New findings of the technological, mechanical, and biological properties of the sample were studied. The EPSwk polymer presented an Mw of 6.35 × 105 Da. The biopolymer also showed microcrystalline structure and characteristic thermal stability with maximum thermal degradation at 250 °C. The analysis of the monosaccharides of the EPSwk by gas chromatography demonstrated that the material is composed of glucose units (98 mol%). Additionally, EPSwk exhibited excellent emulsifying properties, film-forming ability, a low photodegradation rate (3.8%), and good mucoadhesive properties (adhesion Fmax of 1.065 N). EPSwk presented cytocompatibility and antibacterial activity against Escherichia coli and Staphylococcus aureus. The results of this study expand the potential application of the exopolysaccharide from water kefir as a potential clean-label raw material for pharmaceutical, biomedical, and cosmetic applications.
Assuntos
Kefir , Probióticos , Antibacterianos , Biopolímeros , Escherichia coli , Kefir/microbiologia , ÁguaRESUMO
The indiscriminate consumption of antimalarials against coronavirus disease-2019 emphasizes the longstanding clinical weapons of medicines. In this work, we conducted a review on the antitumor mechanisms of aminoquinolines, focusing on the responses and differences of tumor histological tissues and toxicity related to pharmacokinetics. This well-defined analysis shows similar mechanistic forms triggered by aminoquinolines in different histological tumor tissues and under coexposure conditions, although different pharmacological potencies also occur. These molecules are lysosomotropic amines that increase the antiproliferative action of chemotherapeutic agents, mainly by cell cycle arrest, histone acetylation, physiological changes in tyrosine kinase metabolism, inhibition of PI3K/Akt/mTOR pathways, cyclin D1, E2F1, angiogenesis, ribosome biogenesis, triggering of ATM-ATR/p53/p21 signaling, apoptosis, and presentation of tumor peptides. Their chemo/radiotherapy sensitization effects may be an adjuvant option against solid tumors, since 4-aminoquinolines induce lysosomal-mediated programmed cytotoxicity of cancer cells and accumulation of key markers, predominantly, LAMP1, p62/SQSTM1, LC3 members, GAPDH, beclin-1/Atg6, α-synuclein, and granules of lipofuscin. Adverse effects are dose-dependent, though most common with chloroquine, hydroxychloroquine, amodiaquine, and other aminoquinolines are gastrointestinal changes, blurred vision ventricular arrhythmias, cardiac arrest, QTc prolongation, severe hypoglycemia with loss of consciousness, and retinopathy, and they are more common with chloroquine than with hydroxychloroquine and amodiaquine due to pharmacokinetic features. Additionally, psychological/neurological effects were also detected during acute or chronic use, but aminoquinolines do not cross the placenta easily and low quantity is found in breast milk despite their long mean residence times, which depends on the coexistence of hepatic diseases (cancer-related or not), first pass metabolism, and comedications. The low cost and availability on the world market have converted aminoquinolines into "star drugs" for pharmaceutical repurposing, but a continuous pharmacovigilance is necessary because these antimalarials have multiple modes of action/unwanted targets, relatively narrow therapeutic windows, recurrent adverse effects, and related poisoning self-treatment. Therefore, their use must obey strict rules, ethical and medical prescriptions, and clinical and laboratory monitoring.