RESUMEN
Chagas Disease (CD) affects around eight million people worldwide. It is considered a neglected disease that presents few treatment options with efficacy only in the acute phase. Nanoparticles have many positive qualities for treating parasite infections and may be effectively and widely employed in clinical medicine. This research aimed to evaluate the nanoencapsulated benznidazole treatment in animals experimentally infected with Trypanosoma cruzi. To analyze the treatment efficacy, we evaluated survival during thirty days, parasitemia, genotoxicity, and heart and liver histopathology. Thirty-five female Swiss mice were organized into seven groups characterizing a dose curve: A - Negative control (uninfected animals), B - Positive control (infected animals), C - Benznidazole (BNZ) 100 mg/kg (infected animals), D - 5 mg/kg Benznidazole nanocapsules (NBNZ) (infected animals), E - 10 mg/kg Benznidazole nanocapsules (infected animals), F - 15 mg/kg Benznidazole nanocapsules (infected animals), G - 20 mg/kg Benznidazole nanocapsules (infected animals). The animals were infected with the Y strain of T. cruzi intraperitoneally. The treatment was administered for eight days by oral gavage. It was possible to observe that the treatment with the highest NBNZ dose presented efficacy similar to the standard benznidazole drug. The 20 mg/kg NBNZ dose was able to reduce parasitemia, increase survival, and drastically reduce heart and liver tissue damage compared to the 100 mg/kg BNZ dose. Moreover, it showed a lower DNA damage index than the BNZ treatment. In conclusion, the nanoencapsulation of BNZ promotes an improvement in parasite proliferation control with a five times smaller dose relative to the standard dose of free BNZ, thus demonstrating to be a potential innovative therapy for CD.
Asunto(s)
Enfermedad de Chagas , Nanocápsulas , Nitroimidazoles , Tripanocidas , Trypanosoma cruzi , Ratones , Animales , Femenino , Parasitemia/tratamiento farmacológico , Parasitemia/parasitología , Tripanocidas/farmacología , Tripanocidas/uso terapéutico , Enfermedad de Chagas/parasitología , Nitroimidazoles/farmacología , Nitroimidazoles/uso terapéuticoRESUMEN
The effects of Toxoplasma gondii during embryonic development have not been explored despite the predilection of this parasite for neurons and glial cells. Here, we investigated the activation of the purinergic system and proinflammatory responses during congenital infection by T. gondii. Moreover, neuroprotective and neuromodulatory properties of resveratrol (RSV), a polyphenolic natural compound, were studied in infected neuronal progenitor cells (NPCs). For this study, NPCs were isolated from the telencephalon of infected mouse embryos and subjected to neurosphere culture in the presence of EGF and FGF2. ATP hydrolysis and adenosine deamination by adenosine deaminase activity were altered in conditions of T. gondii infection. P2X7 and adenosine A2A receptor expression rates were augmented in infected NPCs together with an increase of proinflammatory (INF-γ and TNF-α) and anti-inflammatory (IL-10) cytokine gene expression. Our results confirm that RSV counteracted T. gondii-promoted effects on enzymes hydrolyzing extracellular nucleotides and nucleosides and also upregulated P2X7 and A2A receptor expression and activity, modulating INF-γ, TNF-α, and IL-10 cytokine production, which plays an integral role in the immune response against T. gondii.
Asunto(s)
Antioxidantes/farmacología , Células-Madre Neurales , Receptor de Adenosina A2A/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Resveratrol/farmacología , Toxoplasmosis/metabolismo , Animales , Femenino , Ratones , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/inmunología , Células-Madre Neurales/microbiología , Embarazo , Efectos Tardíos de la Exposición Prenatal/microbiología , Purinas/metabolismo , Receptor de Adenosina A2A/inmunología , Receptores Purinérgicos P2X7/inmunología , Toxoplasmosis/inmunologíaRESUMEN
The mammalian target of rapamycin (mTOR) and mitogen-activated protein kinases (MAPKs) pathways are frequently upregulated in cancer. Some authors have reported that some antioxidant molecules could be potential inhibitors of these pathways. Therefore, we investigated the in vitro antitumor effect of guaraná by inhibiting the AKT/mTOR/S6K and MAPKs pathways. Colorectal and breast cancer cell lineages, HT-29 and MCF-7 cells, respectively, were exposed to different guaraná concentrations (0.1, 1, 10, and 100 µg/mL) as well as its main bioactive molecule, caffeine, in proportional concentrations to those found in the extract. Western blot, clonogenic assay, and growth curve were performed. Moreover, we investigated the potential cytotoxic effect of guaraná in normal cells. The results revealed that guaraná and caffeine inhibited some MAPKs proteins (p-p38 and p-HSP27) in MCF-7 cells. However, they did not affect this pathway in HT-29 cells. Furthermore, guaraná inhibited mTORC1 (p-S6K) and mTORC2 (p-AKT) in MCF-7 cells, but only mTORC1 in HT-29 cells. Caffeine only inhibited the mTOR pathway in MCF-7 cells. Guaraná decreased the colony formation and cell growth in MCF-7 and HT-29 cells. Guaraná did not affect normal cells. In conclusion, guaraná could be an important agent in antitumor pharmacologic therapies by inhibiting the mTOR and MAPKs pathways.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Paullinia/química , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Cafeína/farmacología , Línea Celular Tumoral , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Femenino , Células HT29 , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Células MCF-7 , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Quinasas S6 Ribosómicas/metabolismo , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Environmental contamination by pharmaceuticals from industrial waste and anthropogenic activities poses adverse health effects on non-target organisms. We evaluated the neurobehavioral and biochemical responses accompanying exposure to ecological relevant concentrations of atenolol (0, 0.1, 1.0, and 10 µg/L) for seven uninterrupted days in adult zebrafish (Danio rerio). Atenolol-exposed fish exhibited anxiety-like behavior, characterized by significant bottom-dwelling with marked reduction in vertical exploration. Atenolol-exposed fish exhibited marked increase in the duration and frequency of aggressive events without altering their preference for conspecifics. Biochemical data using brain samples indicated that atenolol disrupted antioxidant enzyme activities and induced oxidative stress. Exposure to atenolol markedly decreased ATP and AMP hydrolysis without affecting ADP hydrolysis and acetylcholinesterase (AChE) activity. Atenolol significantly upregulated tryptophan hydroxylase 1 (tph1) mRNA expression but downregulated brain-derived neurotrophic factor (bdnf) mRNA. Collectively, waterborne atenolol elicits aggressive and anxiety-like responses in adult zebrafish, accompanied by oxidative stress, reduced nucleotide hydrolysis, altered tph1 and bdnf mRNA expression, which may impact the survival and health of fish in aquatic environment.
Asunto(s)
Atenolol , Conducta Animal , Estrés Oxidativo , Contaminantes Químicos del Agua , Pez Cebra , Animales , Atenolol/farmacología , Contaminantes Químicos del Agua/toxicidad , Estrés Oxidativo/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Triptófano Hidroxilasa/metabolismo , Triptófano Hidroxilasa/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismoRESUMEN
The present study investigated the neuroprotective effect of taurine against the deleterious effects of chronic-recurrent neuroinflammation induced by LPS in the cerebellum of rats. Adult male Wistar rats were treated with taurine for 28 days. Taurine was administered at a dose of 30 or 100 mg/kg, by gavage. On days 7, 14, 21, and 28, the animals received LPS (250 µg/kg) intraperitoneally. The vehicle used was saline. The animals were divided into six groups: vehicle, taurine 30 mg/kg, taurine 100 mg/kg, LPS, LPS plus taurine 30 mg/kg, and LPS plus taurine 100 mg/kg. On day 29, the animals were euthanized, and the cerebellum was removed and prepared for immunofluorescence analysis using antibodies of GFAP, NeuN, CD11b, and cleaved caspase-3. LPS group showed a reduction in the immunoreactivity of GFAP in the arbor vitae and medullary center and of NeuN in the granular layer of the cerebellar cortex. LPS increased the immunoreactivity of CD11b in the arbor vitae and in the medullary center. Taurine protected against these effects induced by LPS in immunoreactivity of GFAP, NeuN, and CD11b, with the 100 mg/kg dose being the most effective. LPS induced an increase in the number of positive cleaved caspase-3 cells in the Purkinje cell layers, granular layer, arbor vitae, and medullary center. Taurine showed its antiapoptotic activity by reducing the cleaved caspase-3 cells in relation to the LPS group. Here, a potential neuroprotective role of taurine can be seen since this amino acid was effective in protecting the cerebellum of rats against cell death and changes in glial and neuronal cells in the face of chronic-recurrent neuroinflammation.
Asunto(s)
Cerebelo/efectos de los fármacos , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Taurina/farmacología , Animales , Apoptosis/efectos de los fármacos , Apoptosis/inmunología , Caspasa 3/análisis , Caspasa 3/metabolismo , Cerebelo/inmunología , Cerebelo/patología , Enfermedad Crónica , Modelos Animales de Enfermedad , Humanos , Lipopolisacáridos/administración & dosificación , Lipopolisacáridos/inmunología , Masculino , Microglía/efectos de los fármacos , Microglía/inmunología , Microglía/patología , Enfermedades Neuroinflamatorias/inmunología , Neuronas/efectos de los fármacos , Neuronas/inmunología , Neuronas/patología , Fármacos Neuroprotectores/uso terapéutico , Ratas , Ratas Wistar , Recurrencia , Taurina/uso terapéuticoRESUMEN
BACKGROUND: Açaí (Euterpe oleracea Mart), a Brazilian fruit, is considered a "superfruit" due its energetic properties and bioactive compounds. The açai's anti-inflammatory effects could attenuate the undesirable metabolic and pro-inflammatory side effects triggered by some antipsychotic drugs, such as Olanzapine (OLZ). It is possible to infer that açai supplement could potentially minimize the adverse effects of OLZ. Aim. This study tested the potential in vitro effects of açai hydroalcoholic extract on the inflammatory activation of the RAW 264.7 macrophage line triggered by OLZ antipsychotic drugs. METHODS: An in vitro protocol was performed using commercial RAW 264.7 macrophages, cultured under sterile conditions at 37°C with 5% CO2 saturation. Initially, a pharmacological curve was defined to determine the concentration of Olanzapine to be used. After this, the cells were supplemented with different concentrations of hydroalcoholic extract of açaí, which had been previously chemically characterized. After 24 and 72 hours of treatment, oxidative and inflammatory tests were performed. Therefore, the aim of this study was to verify whether the hydroalcoholic extract of açaí can modulate the oxy-inflammatory response of olanzapine in vitro. RESULTS: From a preliminary analysis, the açai extract at 5 mg/mL presented higher activity against inflammation triggered by OLZ (0.03 µg/mL). At this concentration, açai was able to reduce several oxidative and inflammatory markers triggered by OLZ (0.03 µg/mL) exposure, such as nitric oxide (NO), reactive oxygen species (ROS), and pro-inflammatory cytokine levels (IL-1b, IL-6, TNF-a, IFN-g) caused by OLZ (0.03 µg/mL). Moreover, açaí reverted the levels of anti-inflammatory cytokine IL-10 that had been dropped by OLZ exposure to their pre-exposure treatments. CONCLUSIONS: The results suggest that açai extract could be useful in attenuating the peripheral inflammatory states triggered by OLZ. Additional pre-clinical and clinical investigations could be useful in testing therapeutic açai extract supplements.
Asunto(s)
Antiinflamatorios/uso terapéutico , Antipsicóticos/efectos adversos , Euterpe/química , Inflamación/prevención & control , Olanzapina/efectos adversos , Fitoterapia , Extractos Vegetales/uso terapéutico , Animales , Antocianinas/análisis , Antocianinas/farmacología , Antocianinas/uso terapéutico , Antiinflamatorios/análisis , Antiinflamatorios/farmacología , Antioxidantes/análisis , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Citocinas/metabolismo , Suplementos Dietéticos , Frutas/química , Inflamación/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/química , Extractos Vegetales/farmacología , Células RAW 264.7 , Especies Reactivas de Oxígeno/metabolismo , alfa-Tocoferol/análisis , alfa-Tocoferol/farmacología , alfa-Tocoferol/uso terapéuticoRESUMEN
Neurodegenerative diseases are associated with chronic inflammatory states. There is evidence to support the design of novel supplements based on guarana (G) (Paullinia cupana), selenium (S), and L-carnitine (C), the use of which, potentially attenuates neuro oxi-inflammatory conditions. Therefore, this study analyzed the cytotoxic and redox effects of GSC on human leucocytes, the inflammatory activation of microglia BV-2 cells, and effect on mortality, oxidative metabolism, and the immune modulation of red earthworms (Eisenia fetida). The GSC concentrations tested in cell culture were in the range of 0.04-2.1 mg/mL. All the GSC-supplemented samples tested, reverted H2O2 oxidation in DNA molecules, suggesting its genoprotective potential. GSC did not induce mortality in leucocyte cultures. On the contrary, a reduction in the levels of oxidation of lipids, proteins, and cell apoptosis was observed, via downregulation of caspase 3 and 8 genes. GSC showed a dual effect on microglia, decreasing the cellular proliferation at lower concentrations (<0.24 mg/mL) and increasing the cellular proliferation mainly at concentrations > 1.0 mg/mL. GSC did not have a toxic effect on red earthworms, but induced an increase in amoebocyte cells and in brown body formation, indicating immune response activation. The results suggest that GSC could be safe for human consumption.
Asunto(s)
Carnitina/farmacología , Eimeria/efectos de los fármacos , Paullinia , Selenio/farmacología , Carnitina/química , Ciclo Celular , Línea Celular , Supervivencia Celular/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Humanos , Peroxidación de Lípido , Microglía , Oxidación-Reducción , Selenio/químicaRESUMEN
The ubiquitous presence of aluminum in the environment leads to a high likelihood of human exposure. Neurotoxicity of the trivalent cationic form of this metal (Al3+) occurs in the central nervous system via accumulation of Al in cells of neural origin, including neural progenitor cells (NPCs). NPCs play a key role in the development and regeneration of the brain throughout life; therefore, this metal may contribute to neuropathological conditions. Here, we evaluated the effects of different Al3+ concentrations (0-50⯵M) on the purinergic system of NPCs isolated from embryonic telencephalons, cultured as neurospheres. Al3+ adhered to the cell surface of neurospheres reducing extracellular ATP release, as well as ATP, ADP, and AMP hydrolysis by NTPDase and 5'-nucleotidase, respectively. In addition, impaired nucleotide release by Al3+ reduced P2Y1 and adenosine A2A receptors expression in differentiated neurospheres. These receptors are crucial for NPC proliferation during brain development and self-repair against external stimuli, such as metal exposure. Thus, Al3+ represents an environmental agent linked to neurodegeneration through alterations in the ATP-signalling pathway, proving to be a potential mechanism associated with NPC proliferation and brain degeneration.
Asunto(s)
Aluminio/toxicidad , 5'-Nucleotidasa , Adenosina Trifosfato/metabolismo , Aluminio/metabolismo , Animales , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Sistema Nervioso Central/metabolismo , Proteínas Ligadas a GPI , Humanos , Transducción de Señal/efectos de los fármacos , Células Madre , Pruebas de ToxicidadRESUMEN
Aging accelerates neurodegeneration, while natural and safe neuroprotective agents, such as Uncaria tomentosa, may help to overcome this problem. This study assessed the effects of U. tomentosa extract treatment on the aging process in the brain of Wistar rats. The spatial memory and learning, acetylcholinesterase (AChE) activity, and DNA damage were assessed. Animals of 14 months were tested with different doses of U. tomentosa (5 mg/kg, 15 mg/kg, and 30 mg/kg) and with different durations of treatment (one month and one year). In the Morris Water Maze (MWM), the escape latency was significantly (p < 0.0001) shorter in rats that received 5 mg/kg, 15 mg/kg, and 30 mg/kg of U. tomentosa for both one month and one year of treatment. There was a significant difference in time spent at the platform zone (p < 0.05) of the middle-aged rats treated with U. tomentosa extract for one year when compared to the control rats. The cortex and hippocampus of rats treated with U. tomentosa for one year showed significant (p > 0.05) reduction in AChE activity. DNA damage index on cortex was significantly lower (p < 0.05) in animals treated with 30 mg/kg of U. tomentosa for one month while all the tested doses demonstrated significant (p < 0.001) reductions in DNA damage index in animals treated for one year. In conclusion, U. tomentosa may represent a source of phytochemicals that could enhance memory activity, repair DNA damage, and alter AChE activity, thereby providing neuroprotection during the aging process.