RESUMEN
Melanoma is the most aggressive type of skin cancer. Brain metastasis is the worst scenario in metastatic melanoma and the treatment options for these patients are limited. Temozolomide (TMZ) is a chemotherapy agent used to treat primary central nervous system tumors. Our objective was to develop chitosan-coated nanoemulsion containing temozolomide (CNE-TMZ) for nasal route administration to melanoma brain metastasis treatment. A preclinical model of metastatic brain melanoma was standardized, and the efficiency of the developed formulation was further determined in vitro and in vivo. The nanoemulsion was done by spontaneous emulsification method and the formulation was characterized by size, pH, polydispersity index, and zeta potential. Culture assessments to determine cell viability were done in the A375 human melanoma cell line. To determine the safety of formulation, healthy C57/BL6 mice were treated with a nanoemulsion without TMZ. The model in vivo used B16-F10 cells implanted by stereotaxic surgery in C57/BL6 mice brains. The results demonstrate that the preclinical model used showed to be useful to analyze the efficiency of new candidate drugs to treat melanoma brain metastasis. The chitosan-coated nanoemulsions with TMZ showed the expected physicochemical characteristics and demonstrated safety and efficacy, reducing around 70% the tumor size compared to control mice, and presenting a tendency in mitotic index reduction, becoming an interesting approach to treat melanoma brain metastasis.
Asunto(s)
Neoplasias Encefálicas , Quitosano , Melanoma , Humanos , Animales , Ratones , Temozolomida/farmacología , Temozolomida/uso terapéutico , Dacarbazina/farmacología , Dacarbazina/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/patología , Melanoma/secundario , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/secundario , Línea Celular TumoralRESUMEN
Glioblastoma (GB) is the most aggressive type of brain tumor with heterogeneity, strong invasive ability, and high resistance to therapy due to immunosuppressive mechanisms. CD73 is an overexpressed enzyme in GB that acts via two main mechanisms: (1) CD73 acts as an adhesion protein independent of the enzymatic activity or (2) via the catalyses of AMP to adenosine (ADO) generating a strong modulatory molecule that induces alterations in the tumor cells and in the tumor microenvironment cells (TME). Taken together, CD73 is receiving attention during the last years and studies demonstrated its dual potential benefit as a target to GB therapy. Here, we review the roles of CD73 and P1 receptors (ADO receptors) in GB, the impact of CD73 in the immune interactions between tumor and other immune cells, the proposed therapeutic strategies based on CD73 regulation, and discuss the gap in knowledge and further directions to bring this approach from preclinical to clinical use.
Asunto(s)
5'-Nucleotidasa , Neoplasias Encefálicas , Glioblastoma , Humanos , Adenosina/metabolismo , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/metabolismo , Glioblastoma/terapia , Inmunosupresores , Transducción de Señal , Microambiente TumoralRESUMEN
Glioblastoma (GB) is the worst and most common primary brain tumor. Temozolomide (TMZ), an alkylating agent, is widely used for treating primary and recurrent high-grade gliomas. However, at least 50% of TMZ treated patients do not respond to TMZ and the development of chemoresistance is a major problem. Here, we designed a lipid nanoemulsion containing a thermoresponsive polymer (poloxamer 407) aiming to improve TMZ release into the brain via nasal delivery. Increasing amounts of poloxamer 407 were added to preformed nanoemulsions (250 nm-range) obtained by spontaneous emulsification. The influence of the polymer concentration (from 2.5% to 12.5%) and temperature on viscosity was clearly evidenced. Such effect was also noticed on the mucoadhesiveness of formulations, as well as TMZ release rate and retention/permeation through nasal porcine mucosa using Franz-type diffusion cells. From these results, a formulation containing 10% of poloxamer (NTMZ-P10) was selected for further experiments by nasal route. A significantly higher TMZ amount was observed in the brain of rats from NTMZ-P10 in comparison with controls. Finally, our results show that formulation reduced significantly tumor growth by three-fold: 103.88 ± 43.67 mm3 (for NTMZ-P10) and 303.28 ± 95.27 mm3 (control). Overall, these results suggest the potential of the thermoresponsive formulation, administered by the non-invasive nasal route, as a future effective glioblastoma treatment.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Ratas , Animales , Porcinos , Temozolomida/uso terapéutico , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Administración Intranasal , Poloxámero/uso terapéutico , Línea Celular Tumoral , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Antineoplásicos Alquilantes/uso terapéuticoRESUMEN
Colorectal cancer (CRC) is among the most common cancers and exhibits a high fatality rate. Gut inflammation is related to CRC, with loss of homeostasis in immune cell activities. The cells of the innate and adaptive immune system, including macrophages, neutrophils, mast cells, and lymphocytes, are present in most solid tumors. Purinergic signaling allows for communication between immune cells within the tumor microenvironment (TME) and can alter the TME to promote tumor progression. This system is regulated by the availability of extracellular purines to activate purinoceptors (P1 and P2) and is tightly controlled by ectonucleotidases (E-NPP, CD73/CD39, ADA) and kinases, which interact with and modify nucleotides and nucleosides availability. In this review, we compiled articles detailing the relationship of the purinergic system with CRC progression. We found that increased expression of CD73 leads to the suppression of effector immune cell functions and tumor progression in CRC. The P1 family purinoceptors A1, A2A, and A2B were positively associated with tumor progression, but A2B resulted in increased cancer cell apoptosis. The P2 family purinoceptors P2X5, P2X7, P2Y2, P2Y6, and P2Y12 were factors primarily associated with promoting CRC progression. In summary, CD39/CD73 axis and the purinergic receptors exhibit diagnostic and prognostic value and have potential as therapeutic targets in CRC.
RESUMEN
Many studies have shown that mesenchymal stromal cells (MSCs) and their secreted factors may modulate the biology of tumor cells. However, how these interactions happen in vivo remains unclear. In the present study, we investigated the effects of rat adipose-derived stromal cells (ADSCs) and their conditioned medium (ADSC-CM) in glioma tumor growth and malignancy in vivo. Our results showed that when we co-injected C6 cells plus ADSCs into the rat brains, the tumors generated were larger and the animals exhibited shorter survival, when compared with tumors of the animals that received only C6 cells or C6 cells pre-treated with ADSC-CM. We further showed that the animals that received C6 plus ADSC did not present enhanced expression of CD73 (a gene highly expressed in ADSCs), indicating that the tumor volume observed in these animals was not a mere consequence of the higher density of cells administered in this group. Finally, we showed that the animals that received C6 + ADSC presented tumors with larger necrosis areas and greater infiltration of immune cells. These results indicate that the immunoregulatory properties of ADSCs and its contribution to tumor stroma can support tumor growth leading to larger zones of necrosis, recruitment of immune cells, thus facilitating tumor progression. Our data provide new insights into the way by which ADSCs and tumor cells interact and highlight the importance of understanding the fate and roles of MSCs in tumor sites in vivo, as well as their intricate crosstalk with cancer cells.
Asunto(s)
Glioblastoma , Tejido Adiposo/metabolismo , Animales , Medios de Cultivo Condicionados/metabolismo , Medios de Cultivo Condicionados/farmacología , Glioblastoma/genética , Glioblastoma/terapia , Necrosis , Ratas , Células del Estroma/metabolismoRESUMEN
Inflammation causes severe dysregulation of organ functions, via the development of oxidative stress and inflammation damage. Polyphenol compounds found in green tea (GTE), including the most important component epigallocatechin-3-gallate (EGCG), have a great therapeutic potential. Here, protective properties of GTE and EGCG against lipopolysaccharide (LPS)-induced inflammation are explored. To this end, the effects of GTE and EGCG were studied on LPS challenged macrophages. Mice received GTE (250 mg/kg/d/p.o) or EGCG (25 mg/kg/d/i.p.) for 7 d, before the inflammation shock was provoked with a single intraperitoneal injection of LPS. The frequencies of lymphocytes CD4+, CD8+, NK1-1+ and CD4+CD25highFOXP3+ (Treg), macrophages CD11b+F480+, monocytes CD11b+Ly6Clow/high, neutrophils CD11b+Ly6G+, MDSCs CD11b+Gr-1high, M2/N2-like phenotype CD206+ and M1-like phenotype CD86+ in spleen, bone marrow and peripheral blood were determined. In vitro studies revealed that GTE and EGCG significantly attenuated LPS-induced CD80 expression and increased the CD163 expression, showing a potential to reduce the macrophage inflammatory phenotype. In vivo, GTE and EGCG inhibited the inflammation, mainly by reducing M1-macrophages and increasing Treg cells in the bone marrow. In addition, GTE and EGCG increase M2-macrophages, N2-neutrophils and Tregs in the spleen and blood and block the migration of monocytes from the bone marrow to the peripheral blood. These findings indicate that EGCG and GTE prevent LPS-induced inflammatory damage contributing to restoring the immune system homeostasis.
Asunto(s)
Catequina/análogos & derivados , Inflamación/inmunología , Inflamación/terapia , Linfocitos/inmunología , Macrófagos/inmunología , Té , Animales , Catequina/farmacología , Humanos , Lipopolisacáridos/inmunología , Activación de Macrófagos , Masculino , Ratones , Ratones Endogámicos BALB C , Células Mieloides/inmunología , Sustancias ProtectorasRESUMEN
Lipopolysaccharide (LPS) is the major component of the outer membrane of Gram-negative bacteria and is usually administrated to establish models of inflammation. Artesunate (ART), a water-soluble artemisinin derivative, displays multiple pharmacological actions against tumors, viral infections, and inflammation, and has been used as a therapeutic weapon against malaria. In this study, our aim was to evaluate whether ART pretreatment is capable of preventing inflammation induced by LPS. BALB/c mice were treated with 100 mg/kg of ART i.p. for 7 days followed by a single dose of LPS. ART pretreatment led to an improvement in clinical score, prevented alterations in biochemical markers, and reestablished the platelet counts. Flow cytometry analysis showed that ART protected the inflammation mainly by reducing the percentage of M1 macrophages while increasing M2 macrophages and a reestablishment of classical monocytes in the BM. In the spleen, ART pretreatment increased N2 neutrophils, myeloid-derived suppressor cells (MDSC), and regulatory T cells, the latter was also increased in peripheral blood. In addition, a marked decrease in inflammatory cytokines and chemokines was observed in the ART treated group. Our data suggest that ART prevents inflammation, reducing tissue damage and restoring homeostasis.
Asunto(s)
Antiinflamatorios/farmacología , Artesunato/farmacología , Inflamación/prevención & control , Células Mieloides/efectos de los fármacos , Linfocitos T Reguladores/efectos de los fármacos , Animales , Quimiocinas/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Humanos , Inflamación/inducido químicamente , Inflamación/inmunología , Inflamación/metabolismo , Lipopolisacáridos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Ratones Endogámicos BALB C , Células Mieloides/inmunología , Células Mieloides/metabolismo , Células Supresoras de Origen Mieloide/efectos de los fármacos , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/metabolismo , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Neutrófilos/metabolismo , Fenotipo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismoRESUMEN
Monocytes are components of the tumor microenvironment related to cancer progression and immune escape. Therapeutic strategies for reprogramming monocytes from a tumor-supporting phenotype towards a tumoricidal phenotype are of great interest. Artesunate (ART) may be an interesting option for cancer treatment; however, the role of ART in regulating the inflammatory tumor microenvironment has not yet been investigated. Our aim is to evaluate the immunomodulatory potential of ART in vitro in human primary monocytes. ART treatment induced an increase in inflammatory monocytes (CD14highCD16-) with HLA-DR high expression and MCP-1/IL-1ß release. On the other hand, ART treatment reduced CD206 and CD163 expression, and abolished the monocyte population known as non-classical and intermediate. Leukemia cells in contact with monocytes programmed with ART presented enhanced in vitro apoptosis suggesting that monocytes acquired the ability to kill leukemic cells. ART induced changes in the monocyte phenotype were mediated by JAK2/STAT3 downregulation. The induction of immunosuppressive environment is an important step for cancer progression. ART showed an immunomodulatory activity, leading immune cells to an antitumor phenotype and could be a candidate for immunotherapy in cancer patients.
Asunto(s)
Antineoplásicos/farmacología , Artesunato/farmacología , Factores Inmunológicos/farmacología , Leucemia/tratamiento farmacológico , Monocitos/efectos de los fármacos , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Células Cultivadas , Quimiocina CCL2/inmunología , Humanos , Inmunoterapia , Interleucina-1beta/inmunología , Leucemia/inmunología , Monocitos/inmunología , Escape del Tumor/efectos de los fármacosRESUMEN
Diphenyl diselenide [(PhSe)2] is a pleiotropic pharmacological agent, but it has low aqueous solubility. The nanoencapsulation of (PhSe)2 allowed the preparation of an aqueous formulation as well as potentiated its in vitro antitumor effect and the effectiveness in a preclinical model of glioblastoma when administered by the intragastric route. Thus, aiming at maximizing the therapeutic potential of (PhSe)2, the present study designed a pegylated-formulation intending to intravenous administration of the (PhSe)2 as a new approach for glioma therapy. The poly(Æ-caprolactone) nanocapsules containing (PhSe)2 were physically coated with polyethyleneglycol (PEG) using the preformed polymer interfacial deposition technique and evaluated through physicochemical, morphological, spectroscopic, and thermal characteristics. Hemocompatibility was determined by the in vitro hemolysis test and cytotoxicity assays were performed in astrocytes and glioma C6 cells (10-100 µM). The pegylated-nanocapsules had an average diameter of 218 ± 25 nm, polydispersity index of 0.164 ± 0.046, zeta potential of - 8.1 ± 1.6 mV, pH 6.0 ± 0.09, (PhSe)2 content of 102.00 ± 3.57%, and encapsulation efficiency around 98%. Besides, the (PhSe)2 pegylated-nanocapsules were spherical, presented absence of chemical interaction among the constituents, and showed higher thermal stability than the non-encapsulated materials. PEG-coated nanocapsules did not cause hemolytic effect while formulations without PEG induced a hemolysis rate above 10%. Moreover, pegylated-nanocapsules had superior in vitro antiglioma effect in comparison to free compound (IC50: 24.10 µM and 74.83 µM, respectively). Therefore, the (PhSe)2-loaded pegylated-nanocapsule suspensions can be considered a hemocompatible formulation for the glioma treatment by the intravenous route.
Asunto(s)
Antineoplásicos/administración & dosificación , Derivados del Benceno/administración & dosificación , Materiales Biocompatibles , Glioma/tratamiento farmacológico , Nanocápsulas/química , Compuestos de Organoselenio/administración & dosificación , Polietilenglicoles/química , Animales , Antineoplásicos/química , Astrocitos/efectos de los fármacos , Derivados del Benceno/química , Compuestos de Organoselenio/química , SolubilidadRESUMEN
BACKGROUND: Glioblastoma is one of the most immunosuppressive human tumors. Emerging data suggest that glioblastoma-derived exosomes (GBex) reprogram the tumor microenvironment into a tumor-promoting milieu by mechanisms that not yet understood. METHODS: Exosomes were isolated from supernatants of glioblastoma cell lines by size exclusion chromatography. The GBex endosomal origin, size, protein cargos, and ex vivo effects on immune cell functions were determined. GBex were injected intravenously into mice to evaluate their ability to in vivo modulate normal immune cell subsets. RESULTS: GBex carried immunosuppressive proteins, including FasL, TRAIL, CTLA-4, CD39, and CD73, but contained few immunostimulatory proteins. GBex co-incubated with primary human immune cells induced simultaneous activation of multiple molecular pathways. In CD8+ T cells, GBex suppressed TNF-α and INF-γ release and mediated apoptosis. GBex suppressed natural killer (NK) and CD4+ T-cell activation. GBex activated the NF-κB pathway in macrophages and promoted their differentiation into M2 cells. Inhibition of the NF-κB pathway in macrophages reversed the GBex-mediated effects. GBex-driven reprogramming of macrophages involved the release of soluble factors that promoted tumor proliferation in vitro. In mice injected with GBex, the frequency of splenic CD8+ T cells, NK cells, and M1-like macrophages was reduced, while that of naïve and M2-like macrophages increased (P < .05). CONCLUSIONS: GBex reprogrammed functions of all types of immune cells in vitro and altered their frequency in vivo. By creating and sustaining a highly immunosuppressive environment, GBex play a key role in promoting tumor progression.
RESUMEN
Rosmarinic acid (RA) is a natural polyphenolic compound with a well-documented neuroprotective effect mainly associated with its anti-inflammatory and antioxidant activities. Recently, our research group developed and optimized chitosan-coated RA nanoemulsions (RA CNE) intended to be used for nasal delivery as a new potential neuroprotective therapy. In this sense, the present study aimed to evaluate the protective and/or therapeutic potential of RA CNE in inflammation/oxidative stress induced by LPS (1 µg mL-1) in rat astrocyte primary cultures. In summary, pre-treatment with RA CNE before exposure to LPS (protective protocol) reduced significantly the LPS-induced alterations in astrocyte cell viability, proliferation, and cell death by necrosis, which was not observed in therapeutic protocol. RA CNE protective protocol also enhanced anti-oxidative status by ~ 50% by decreasing oxygen reactive species production and nitric oxide levels and preventing total thiol content decrease. Finally, our results demonstrate the protective effect of RA CNE in migratory activation and GFAP expression of reactive astrocytes. Overall, our findings indicate for the first time the RA CNE glioprotective potential, associated with an increase in cell viability and proliferation, a preventive effect on cellular death by necrosis, migratory ability and hypertrophic reactive astrocytes, and the reparation of astrocyte redox state.
Asunto(s)
Astrocitos/patología , Quitosano/química , Cinamatos/farmacología , Depsidos/farmacología , Inflamación/patología , Nanopartículas/química , Neuroglía/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Animales , Animales Recién Nacidos , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Cinamatos/química , Depsidos/química , Emulsiones , Proteína Ácida Fibrilar de la Glía/metabolismo , Lipopolisacáridos , Neuroglía/metabolismo , Fármacos Neuroprotectores/química , Ratas Wistar , Ácido RosmarínicoRESUMEN
The aim of this study was to further evaluate the antitumoral effect of (PhSe)2-loaded polymeric nanocapsules (NC (PhSe)2) against a resistant melanoma cell line (SK-Mel-103) and develop a xanthan gum-based hydrogel intending the NC (PhSe)2 cutaneous application. For the in vitro evaluation, cells were incubated with free (PhSe)2 or NC (PhSe)2 (0.7-200 µM) and after 48 h the MTT assay, propidium iodide uptake (necrosis marker) and nitrite levels were assessed. The hydrogels were developed by thickening of the NC (PhSe)2 suspension or (PhSe)2 solution with xanthan gum and characterized in terms of average diameter, polydispersity index, pH, drug content, spreadability, rheological profiles and in vitro permeation in human skin. The results showed that NC (PhSe)2 provided a superior antitumoral effect in comparison to free (PhSe)2 (IC50 value of 47.43 µM and 65.05 µM, respectively) and increased the nitrite content. Both compound forms induced propidium iodide uptake, suggesting a necrosis-related pathway could be involved in the cytotoxic action of (PhSe)2. All hydrogels showed pH values around 7, drug content close to the theoretical values (5 mg/g) and mean diameter in the nanometric range. Besides, formulations were classified as non-Newtonian flow with pseudoplastic behavior and suitable spreadability factor. Skin permeation studies revealed that the compound content was higher for the nano-based hydrogel in the dermis layer, demonstrating its superior permeation, achieved by the compound encapsulation. It is the first report on an adequate formulation development for cutaneous application of NC (PhSe)2 that could be used as an adjuvant treatment in melanoma therapy.
Asunto(s)
Antineoplásicos/farmacología , Derivados del Benceno/farmacología , Hidrogeles/química , Hidrogeles/farmacología , Melanoma Experimental/tratamiento farmacológico , Nanocápsulas/química , Compuestos de Organoselenio/farmacología , Polisacáridos Bacterianos/química , Animales , Antineoplásicos/química , Derivados del Benceno/química , Línea Celular , Humanos , Ratones , Compuestos de Organoselenio/química , Permeabilidad/efectos de los fármacos , Polímeros/químicaRESUMEN
BACKGROUND: Gliomas are the most aggressive malignant tumors of the central nervous system. The diphenyl diselenide [(PhSe)2] is an organoselenium compound that has multiple pharmacological properties. Previous reports showed that (PhSe)2 nanoencapsulation potentiates its in vitro antitumoral action and reduces its toxicity. OBJECTIVE: In this sense, the current study was designed to further evaluate the (PhSe)2 antitumoral effect by a set of in vitro techniques using a glioma cell line as well as by an animal model of gliobastoma. METHODS: For the in vitro tests, the cell viability, propidium iodide uptake and nitrite levels of rat glioma C6 cells were determined after incubation with free (PhSe)2 or (PhSe)2-loaded nanocapsules (NC). The glioblastoma model was induced by implantation of C6 glioma cells in the right striatum of rats. Following, animals were submitted to a repeated intragastric administration treatment with (PhSe)2 or NC (PhSe)2 (1â¯mg/kg/day for 15 days) to assess the possible antitumor effect. MAIN FINDINGS: Both compound forms decreased the C6 glioma cells viability without causing any effect in astrocytes cells (healthy control). Importantly, the NC (PhSe)2 had superior cytotoxic effect than its free form and increased the nitrite content. Independent of the (PhSe)2 forms, the intragastric treatment reduced brain tumor size and caused neither alteration in the plasma renal and hepatic markers of function nor in the parameters of oxidative balance in brain, liver and kidneys. PRINCIPAL CONCLUSIONS: The (PhSe)2 nanoencapsulation improved its cytotoxic effect against C6 glioma cells and both compound forms attenuated the tumor development.
Asunto(s)
Antineoplásicos/farmacología , Derivados del Benceno/farmacología , Modelos Animales de Enfermedad , Glioblastoma/tratamiento farmacológico , Nanocápsulas/química , Compuestos de Organoselenio/farmacología , Animales , Antineoplásicos/química , Astrocitos/efectos de los fármacos , Derivados del Benceno/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Ensayos de Selección de Medicamentos Antitumorales , Glioblastoma/patología , Masculino , Nitritos/análisis , Compuestos de Organoselenio/química , Ratas , Ratas WistarRESUMEN
Among gliomas types, glioblastoma is considered the most malignant and the worst form of primary brain tumor. It is characterized by high infiltration rate and great angiogenic capacity. The presence of an inflammatory microenvironment contributes to chemo/radioresistance, resulting in poor prognosis for patients. Recent data show that thiazolidinones have a wide range of pharmacological properties, including anti-inflammatory and antiglioma activities. Nanocapsules of biodegradable polymers become an alternative to cancer treatment since they provide targeted drug delivery and could overcome blood-brain barrier. Therefore, here we investigated the in vitro antiglioma activity and the potential in vivo toxicity of 2- (2-methoxyphenyl) -3- ((piperidin-1-yl) ethyl) thiazolidin-4-one-loaded polymeric nanocapsules (4L-N). Nanocapsules were prepared and characterized in terms of particle size, polydispersity index, zeta potential, pH, molecule content and encapsulation efficiency. Treatment with 4L-N selectively decreased human U138MG and rat C6 cell lines viability and proliferation, being even more efficient than the free-form molecule (4L). In addition, 4L-N did not promote toxicity to primary astrocytes. We further demonstrated that the treatment with sub-therapeutic dose of 4L-N did not alter weight, neither resulted in mortality, toxicity or peripheral damage to Wistar rats. Finally, 4L as well as 4L-N did not alter makers of oxidative damage, such as TBARS levels and total sulfhydryl content, and did not change antioxidant enzymes SOD and CAT activity in liver and brain of treated rats. Taken together, these data indicate that the nanoencapsulation of 4L has potentiated its antiglioma effect and does not cause in vivo toxicity.
Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Nanocápsulas/química , Piperidinas/toxicidad , Piperidinas/uso terapéutico , Polímeros/química , Tiazolidinas/toxicidad , Tiazolidinas/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Astrocitos/patología , Biomarcadores de Tumor/sangre , Encéfalo/efectos de los fármacos , Encéfalo/patología , Neoplasias Encefálicas/sangre , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Liberación de Fármacos , Glioma/sangre , Glioma/patología , Humanos , Luz , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Estrés Oxidativo/efectos de los fármacos , Piperidinas/síntesis química , Piperidinas/química , Polímeros/síntesis química , Ratas Wistar , Tiazolidinas/síntesis química , Tiazolidinas/química , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Pruebas de Toxicidad , Pérdida de Peso/efectos de los fármacosRESUMEN
Anthocyanins (ANT) are polyphenolic flavonoids with antioxidant and neuroprotective properties. This study evaluated the effect of ANT treatment on cognitive performance and neurochemical parameters in an experimental model of sporadic dementia of Alzheimer's type (SDAT). Adult male rats were divided into four groups: control (1 ml/kg saline, once daily, by gavage), ANT (200 mg/kg, once daily, by gavage), streptozotocin (STZ, 3 mg/kg) and STZ plus ANT. STZ was administered via bilateral intracerebroventricular (ICV) injection (5 µl). ANT were administered after ICV injection for 25 days. Cognitive deficits (short-term memory and spatial memory), oxidative stress parameters, and acetylcholinesterase (AChE) and Na+-K+-ATPase activity in the cerebral cortex and hippocampus were evaluated. ANT treatment protected against the worsening of memory in STZ-induced SDAT. STZ promoted an increase in AChE and Na+-K+-ATPase total and isoform activity in both structures; ANT restored this change. STZ administration induced an increase in lipid peroxidation and decrease in the level of antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), in the cerebral cortex; ANT significantly attenuated these effects. In the hippocampus, an increase in reactive oxygen species (ROS), nitrite and lipid peroxidation levels, and SOD activity and a decrease in CAT and GPx activity were seen after STZ injection. ANT protected against the changes in ROS and antioxidant enzyme levels. In conclusion, the present study showed that treatment with ANT attenuated memory deficits, protected against oxidative damage in the brain, and restored AChE and ion pump activity in an STZ-induced SDAT in rats.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Antocianinas/farmacología , Bombas Iónicas/metabolismo , Trastornos de la Memoria/tratamiento farmacológico , Estrés Oxidativo , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/inducido químicamente , Animales , Antioxidantes/uso terapéutico , Encéfalo/metabolismo , Catalasa/metabolismo , Corteza Cerebral/metabolismo , Cognición , Modelos Animales de Enfermedad , Glutatión Peroxidasa/metabolismo , Hipocampo/metabolismo , Infusiones Intraventriculares , Peroxidación de Lípido , Masculino , Aprendizaje por Laberinto , Memoria/efectos de los fármacos , Trastornos de la Memoria/inducido químicamente , Fármacos Neuroprotectores/uso terapéutico , Ratas , Ratas Wistar , Estreptozocina/efectos adversos , Compuestos de Sulfhidrilo , Superóxido Dismutasa/metabolismoRESUMEN
Altered astrocytic function is a contributing factor to the development of neurological diseases and neurodegeneration. Berry fruits exert neuroprotective effects by modulating pathways involved in inflammation, neurotransmission, and oxidative stress. The aim of this study was to examine the effects of the lingonberry extract on cellular viability and oxidative stress in astrocytes exposed to lipopolysaccharide (LPS). In the reversal protocol, primary astrocytic cultures were first exposed to 1 µg/mL LPS for 3 h and subsequently treated with lingonberry extract (10, 30, 50, and 100 µg/mL) for 24 and 48 h. In the prevention protocol, exposure to the lingonberry extract was performed before treatment with LPS. In both reversal and prevention protocols, the lingonberry extracts, from 10 to 100 µg/mL, attenuated LPS-induced increase in reactive oxygen species (around 55 and 45%, respectively, P < 0.01), nitrite levels (around 50 and 45%, respectively, P < 0.05), and acetylcholinesterase activity (around 45 and 60%, respectively, P < 0.05) in astrocytic cultures at 24 and 48 h. Also, in both reversal and prevention protocols, the lingonberry extract also prevented and reversed the LPS-induced decreased cellular viability (around 45 and 90%, respectively, P < 0.05), thiol content (around 55 and 70%, respectively, P < 0.05), and superoxide dismutase activity (around 50 and 145%, respectively, P < 0.05), in astrocytes at both 24 and 48 h. Our findings suggested that the lingonberry extract exerted a glioprotective effect through an anti-oxidative mechanism against LPS-induced astrocytic damage.
Asunto(s)
Acetilcolinesterasa/metabolismo , Astrocitos/metabolismo , Lipopolisacáridos/farmacología , Neuroglía/metabolismo , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacología , Vaccinium vitis-Idaea/química , Animales , Animales Recién Nacidos , Antioxidantes/metabolismo , Astrocitos/efectos de los fármacos , Astrocitos/enzimología , Biomarcadores/metabolismo , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Neuroglía/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Compuestos de Sulfhidrilo/metabolismoRESUMEN
High plasma levels of methionine (Met) and its metabolites such as methionine sulfoxide (MetO) may occur in several genetic abnormalities. Patients with hypermethioninemia can present neurological dysfunction; however, the neurotoxicity mechanisms induced by these amino acids remain unknown. The aim of the present work was to study the effects of Met and/or MetO on oxidative stress, genotoxicity, cytotoxicity and to evaluate whether the cell death mechanism is mediated by apoptosis in the cerebral cortex of young rats. Forty-eight Wistar rats were divided into groups: saline, Met 0.4 g/Kg, MetO 0.1 g/Kg and Met 0.4 g/Kg + MetO 0.1 g/Kg, and were euthanized 1 and 3 h after subcutaneous injection. Results showed that TBARS levels were enhanced by MetO and Met+MetO 1 h and 3 h after treatment. ROS was increased at 3 h by Met, MetO and Met+MetO. SOD activity was increased in the Met group, while CAT was reduced in all experimental groups 1 h and 3 h after treatment. GPx activity was enhanced 1 h after treatment by Met, MetO and Met+MetO, however it was reduced in the same experimental groups 3 h after administration of amino acids. Caspase-3, caspase-9 and DNA damage was increased and cell viability was reduced by Met, MetO and Met+MetO at 3 h. Also, Met, MetO and Met+MetO, after 3 h, enhanced early and late apoptosis cells. Mitochondrial electrochemical potential was decreased by MetO and Met+MetO 1 h and 3 h after treatment. These findings help understand the mechanisms involved in neurotoxicity induced by hypermethioninemia.
Asunto(s)
Apoptosis/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Metionina/análogos & derivados , Metionina/toxicidad , Animales , Caspasas/metabolismo , Catalasa/metabolismo , Muerte Celular/efectos de los fármacos , Corteza Cerebral/citología , Corteza Cerebral/metabolismo , Daño del ADN/efectos de los fármacos , Masculino , Mutágenos/toxicidad , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa-1/metabolismo , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
This study aimed to develop poly(ε-caprolactone) nanocapsules loaded with indole-3-cabinol (I3C) using rose hip oil (RHO) or medium chain triglycerides (MCT) as oil core. In vitro radical scavenging activity (DPPH method), hemolysis, and antitumor effects on breast (MCF-7) and glioma (C6) cells were conducted. Preformulation evaluations revealed that RHO is suitable to prepare the nanocapsules considering the log P determination and dissolution/swelling experiments of polymer films. The nanocapsules were prepared and presented adequate physicochemical characteristics as mean size around 250nm, polydispersity index values <0.2, zeta potential negative values and I3C encapsulation efficiency around 42%, without any influence of the oil core (RHO or MCT) on these parameters. However, the photodegradation study demonstrated that RHO nanocapsules showed less degree of I3C degradation in comparison to MCT nanocapsules. The in vitro release profile showed that both nanocapsule suspensions demonstrated an initial burst effect followed by a prolonged I3C release. In addition, the formulations were considered hemocompatibles at 10µg/mL and showed an enhanced radical scavenging activity in comparison to free I3C. Moreover, nanocapsules prepared with RHO increased about two times the antitumor effect of I3C on MCF-7 and C6 cells without significant reduction of astrocyte cell viability. In conclusion, nanocapsule formulations developed in this study might be considered promising for cancer treatment.
Asunto(s)
Antineoplásicos/química , Depuradores de Radicales Libres/química , Indoles/química , Nanocápsulas/química , Aceites Volátiles/química , Rosa/química , Antineoplásicos/toxicidad , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Humanos , Células MCF-7 , Ensayo de Materiales , Nanocápsulas/toxicidad , Fotólisis/efectos de los fármacos , Rosa/metabolismo , Solubilidad , Rayos UltravioletaRESUMEN
The present study assessed the biological potential of fourteen 1,3-thiazolidin-4-ones evaluating the antiglioma effect through decreasing of cell viability of glioblastoma multiform cells. The new compounds were efficient synthesized through multicomponent or multicomponent one-pot procedures in moderate to good yields (22-86%) from two arenealdehydes (4-(methylthio)benzaldehyde and 4-(methylsulfonyl)benzaldehyde), seven amines (aromatic and aliphatic) and mercaptoacetic acid. The compounds were identified and characterized by GC/MS and NMR, five of them by HRMS. Six thiazolidinones showed significant effect of decreasing cell viability compared to standard drug TMZ at 100 µM in 72 h in C6 cell line by MTT assay. The compounds 5b, 5e, 5g and 6e showed the best results in the screening at 100 µM and were analyzed at different concentrations (5, 25, 50, 100 and 250 µM). Compounds 5b and 5e showed statistical difference at 5 µM, 6e at 25 µM and 5g at 50 µM in 72 h of treatment. The cytotoxicity study in primary astrocytes cells was evaluated and none of fourteen compounds showed toxicity at 100 µM, eight of them were not cytotoxic at 250 µM, both in 72 h. In addition, the propidium iodide assay demonstrated that the compounds might induce cell death by necrosis. In conclusion, this work reports at least four compounds (5b, 5e, 5g and 6e) with potential anti-tumor effect against glioblastoma multiform cell presenting activity at low concentrations and safe profile of cytotoxicity.