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This study investigated the antitumoral, anti-inflammatory and oxidative effects of polysaccharides from tucum (Bactris setosa, TUC) using the Ehrlich carcinoma as a tumor model. Additionally, the glycogen content, cytochrome P levels, and gluconeogenesis from lactate were assessed in the liver of healthy animals. Tumor-bearing female mice were orally treated with 50 and 100 mg.kg-1 of TUC or vehicle, once a day, or with 1.5 mg.kg-1 methotrexate via i.p., every 3 days, along 21 days. Both doses of TUC reduced the tumor weight and volume. In the tumor tissue, it decreased GSH and IL-1ß levels, and increased LPO, NAG, NO and TNF-α levels. The tumor histology showed necrosis and leukocytes infiltration. The metabolic effects of TUC were investigated by measurement of total cytochrome P (CYP) and glycogen in tumor-bearing mice, and by ex vivo liver perfusion on non-bearing tumor male mice, using lactate as gluconeogenic precursor. Metabolically, the hepatic glucose and pyruvate productions, oxygen uptake, and the total CYP concentration were not modified by TUC. Thus, tucum-do-cerrado polysaccharides have antitumor effects through the modulation of oxidative stress and inflammation, without impairing glucose production from lactate in the liver, the main organ responsible for the metabolism of organic and xenobiotic compounds.
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Although TRPV1 receptors play an essential role in the adverse effects on the airways following captopril treatment, there is no available evidence of their involvement in treatment regimens involving repeated doses of captopril. Comparing the difference in these two treatment regimens is essential since captopril is a continuous-use medication. Thus, this study explored the role of the transient receptor potential vanilloid 1 (TRPV1) in the effects of captopril on rat airways using two treatment regimens. Airway resistance, bronchoalveolar lavage (BAL), and histological and immunohistochemical analyses were conducted in rats administered with single or repeated doses of captopril. This study showed that the hyperresponsiveness to bradykinin and capsaicin in captopril-treated rats was acute. Treatment with the selective B2 antagonist, HOE140 reduced bradykinin hyperresponsiveness and abolished capsaicin exacerbation in single-dose captopril-treated rats. Likewise, degeneration of TRPV1-positive neurones also reduced hyperresponsiveness to bradykinin. Single-dose captopril treatment increased leukocyte infiltration in the BAL when compared with the vehicle and this increase was reduced by TRPV1-positive neurone degeneration. However, when compared with the vehicle treatment, animals treated with repeated doses of captopril showed an increase in leukocyte influx as early as 1 h after the last captopril treatment, but this effect disappeared after 24 h. Additionally, an increase in TRPV1 expression occurred only in animals who received repeated captopril doses and the degeneration of TRPV1-positive neurones attenuated TRPV1 upregulation. In conclusion, these data strongly indicate that a treatment regimen involving multiple doses of captopril not only enhances sensitisation but also upregulates TRPV1 expression. Consequently, targeting TRPV1 could serve as a promising strategy to reduce the negative impact of captopril on the airways.
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Breast cancer is a high-magnitude public health problem, continually challenging physicians and scientists worldwide in the field of drug therapy. 4-nitrochalcone (4NC) is a phenolic compound that has promising antitumor activity in vitro, but its application in breast cancer treatment is still poorly explored. This study aimed to evaluate the action of 4NC in vitro and in vivo breast cancer models. The cytotoxic potential of 4NC was tested towards MCF-7 and MDA-MD-231 breast cancer cells, with a lower impact in the non-tumor lineage HB4a. For in vivo studies, solid Ehrlich carcinoma (SEC) was used, a syngeneic mouse model with non-nuclear estrogen and progesterone positivity, characterized by immunohistochemistry. Daily oral administration of 4NC (25 mg kg-1) for 21 days led to a consistent reduction in tumor growth compared to the vehicle group. No signs of toxicity evaluated by hematological, biochemical, histological, and oxidative stress parameters were observed in mice, and the DL50 was >2000 mg kg-1. The effectors Raptor and S6K1 showed decreased activation, with a consequent reduction in protein synthesis; concomitantly, there was an increase in LC3-II levels, but the protective autophagic response was not completed, with the maintenance of p62 levels and cell death. These results open new possibilities for the use of 4NC as a tumor cell metabolism modulating agent.
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Antineoplásicos , Chalconas , Neoplasias , Animales , Ratones , Humanos , Preparaciones Farmacéuticas , Chalconas/farmacología , Chalconas/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Muerte Celular , Autofagia , Línea Celular Tumoral , Células MCF-7 , ApoptosisRESUMEN
Breast cancer is one of the most common types of cancer in the world and current therapeutic strategies present severe drawbacks. l-carvone (CRV), a monoterpene found in Mentha spicata (spearmint), has been reported to have potent anti-inflammatory activity. Here, we examined the role of CRV in breast cancer cell adhesion, migration and invasion in vitro and how this component could suppress the growth of Ehrlich carcinoma-bearing mice. In vivo, treatment with CRV significantly decreased tumor growth, increased tumor necrosis area, and reduced the expression of VEGF and HIF-1α in Ehrlich carcinoma-bearing mice. Furthermore, the anticancer efficacy of CRV was similar to currently used chemotherapy (Methotrexate), and the combination of CRV with MTX potentiated the chemotherapy effects. Further mechanistic investigation in vitro revealed that CRV modulates the interaction of breast cancer cells with the extracellular matrix (ECM) by disrupting focal adhesion, which was shown by scanning electron microscopy (SEM) and immunofluorescence. Moreover, CRV caused a decrease in ß1-integrin expression and inhibited focal adhesion kinase (FAK) activation. FAK is one of the most important downstream activators of several metastatic processes, including MMP-2 mediated invasion and HIF-1α/VEGF angiogenesis stimulus, both of which were found to be reduced in MDA-MB-231 cells exposed to CRV. Our results provide new insight about targeting ß1-integrin/FAK signaling pathway with CRV, which could be a new potential agent in the treatment of breast cancer.
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Carcinoma , Factor A de Crecimiento Endotelial Vascular , Animales , Ratones , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Línea Celular Tumoral , Movimiento Celular , Quinasa 1 de Adhesión Focal/metabolismo , Integrina beta1/metabolismo , Invasividad Neoplásica , Adhesión CelularRESUMEN
The soluble fraction of polysaccharides from cabernet franc red wine (SFP) previously showed antitumoral effects by modulating the immune system. The present study tested the hypothesis that the SFP can regulate CYPs in vitro in HepG2 cells and in vivo in Walker-256 tumor-bearing rats. The SFP was used in the following protocols: (i) solid tumor, (ii) liquid tumor, and (iii) chemopreventive solid tumor. The SFP reduced solid tumor growth in both solid tumor protocols but did not inhibit liquid tumor development. The SFP reduced total CYP levels in the solid and liquid tumor protocols and reduced the gene expression of Cyp1a1 and Cyp2e1 in rats and CYP1A2 in HepG2 cells. An increase of N-acetylglucosaminidase activity was observed in all SFP-treated rats, and TNF-α levels increased in the solid tumor protocol in the vehicle, SFP, and vincristine (positive control) groups. The chemopreventive solid tumor protocol did not modify CYP levels in the liver or intestine or N-acetylglucosaminidase and myeloperoxidase activity in the liver. The in vitro digestion and nuclear magnetic resonance analyses suggested that SFP was minimally modified in the gastrointestinal system. In conclusion, SFP inhibited CYPs both in vivo and in vitro, likely as a result of its immunoinflammatory actions.
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Vino , Ratas , Animales , Acetilglucosaminidasa , Sistema Enzimático del Citocromo P-450/metabolismo , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Polisacáridos/farmacologíaRESUMEN
The present study characterized oligosaccharide compounds (Oligo) in Cabernet Franc red wine and investigated its antineoplastic effects against mammary tumor cells in vivo and in vitro, isolated or in combination with chemotherapy. The Oligo fraction was characterized by nuclear magnetic resonance spectroscopy and mass spectrometry. The complex mixture of Oligo showed high amounts of oligoxyloglucuronans, oligorhamnogalacturonans, oligoarabinogalactans, and oligoglucans, such as trehalose and isomaltotriose. To investigate the antineoplastic effects of Oligo, Female Swiss mice were subcutaneously inoculated with Ehrlich tumor cells and then received vehicle (distilled water, p.o.), Oligo solution (9, 35, or 70 mg/kg, p.o.), or methotrexate (1.5 mg/kg, i.p.). The treatments were administered in a conventional (21-d) or chemopreventive (42-d) protocol. Oligo reduced the growth of Ehrlich tumors in both protocols and increased the effectiveness of methotrexate in controlling tumor growth. Oligo did not reduce the viability of MCF-7, MDA-MB-231, MDA-MB-436, and HB4a human breast cells that were cultured for 48 h, showing no cytotoxicity. Overall, Oligo exerted an in vivo antineoplastic effect and modulated immune blood cells, dependent on treatment time, and was not directly cytotoxic to tumor cells. Thus, Oligo may indirectly regulate tumor cell development and may be a promising drug for cancer therapy in combination with methotrexate.
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Antineoplásicos , Neoplasias de la Mama , Neoplasias Mamarias Animales , Vino , Ratones , Femenino , Humanos , Animales , Metotrexato/farmacología , Metotrexato/uso terapéutico , Metotrexato/análisis , Vino/análisis , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Oligosacáridos/farmacología , Oligosacáridos/uso terapéutico , Oligosacáridos/análisis , Neoplasias de la Mama/tratamiento farmacológicoRESUMEN
Background and Objective: Breast cancer is the most prevalent cancer worldwide, responsible for a large number of deaths, especially among women. Therapeutic options for breast cancer include surgery, radiotherapy, chemotherapy, hormone therapy, and immunotherapy, but further studies of the pathogenesis of this disease and new treatments are still needed. In vitro and in vivo cancer models are important research tools. Murine Ehrlich tumors are one of these models, especially for hormone-positive breast cancer. The present narrative review discusses characteristics of the Ehrlich tumor model, laboratory manipulations of Ehrlich cells (ECs), and applications in pharmacological, pathological, and translational studies. Methods: This review was based on scientific articles, books, and theses on Ehrlich tumors. We searched the PubMed, SciELO, Google Scholar, Google, and Clarivate databases. Key Content and Findings: Hormone-positive ECs produce solid Ehrlich carcinoma (SEC) and ascitic Ehrlich carcinoma (AEC), with different features and applications. The presence of SEC or AEC induces systemic and immunological alterations that are similar to cancer in humans, what makes this model applicable to different studies in the cancer field. Conclusions: Ehrlich tumors are a relevant tool for improving our understanding of the pathogenesis of breast cancer and investigating the tumor microenvironment, side effects of therapies, and new treatment options. Despite some limitations, such as the absence of an invasive phenotype to produce metastasis, both SEC and AEC are relevant in preclinical and translational studies of breast cancer.
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The enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) is a critical engine that supports glucose catabolism. PFKFB3 produces the signaling molecule fructose-2,6-biphosphate (F2,6BP), which activates the second gatekeeper in glycolysis, 6-phosphofructo-1-kinase (PFK-1), and favors the Warburg phenotype. Transcriptional and post-transcriptional processes regulate the abundance and phosphorylation of PFKFB3 in cells, and its activation has been implicated in the progression of several types of cancer. PFKFB3 is important for sustaining glycolysis in the tumorigenesis environment even under unfavorable conditions, thereby promoting metabolic reprogramming, cell proliferation, DNA repair, and drug resistance. Despite its heterogeneous phenotype, breast cancer has unique characteristics that drive the constitutive and inducible expression of PFKFB3 in this opportunistic glycolytic shift. This enzyme is a point of convergence of multiple exogenous and endogenous growth-promoting and oncogenic signaling pathways, especially kinase cascades. The present review summarizes advances in in vitro and in vivo therapy studies that focus on PFKFB3 and the interplay between hormone receptor status and the underlying essential signal transduction system in breast cancer metabolic remodeling.
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Neoplasias de la Mama , Fosfofructoquinasa-2 , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Femenino , Glucólisis , Humanos , Fosfofructoquinasa-2/genética , Fosfofructoquinasa-2/metabolismo , Fosforilación , Transducción de SeñalRESUMEN
This study aims to report the detection of N. caninum DNA in a newborn lamb (1) with neurological signs and congenital neosporosis and in a stillborn lamb (2), both born from the same ewe in a herd of Southern Brazil. The lambs were born during different pregnancies of a Suffolk ewe seropositive to N. caninum and seronegative to T. gondii. Histopathological lesions were observed only in the central nervous system of the lambs. The newborn lamb (1) showed mild and focal gliosis in the frontal lobe. In the hippocampal region of the stillborn lamb (2), lymphoplasmacytic perivascular cuffs and N. caninum cysts were observed in the cytoplasm of neurons and confirmed by IHC. PCR was performed using brain samples to detect the protozoa N. caninum and Toxoplasma gondii. The infection with N. caninum was confirmed in the newborn lamb (1) by PCR and in the stillborn lamb (2) by histopathology, immunohistochemistry, and PCR tests.
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Coccidiosis , Transmisión Vertical de Enfermedad Infecciosa/veterinaria , Neospora , Enfermedades de las Ovejas , Ovinos/parasitología , Animales , Brasil/epidemiología , Coccidiosis/epidemiología , Coccidiosis/transmisión , Coccidiosis/veterinaria , Femenino , Neospora/aislamiento & purificación , Embarazo , Enfermedades de las Ovejas/epidemiología , Enfermedades de las Ovejas/parasitología , Enfermedades de las Ovejas/transmisiónRESUMEN
This study investigated the antineoplastic effects and toxicity of long-term treatment with polysaccharides from sweet green pepper (Capsicum annuum [CAP]), and concomitant treatment with CAP + methotrexate (MTX) on mammary tumor cells in vivo and in vitro. Ehrlich tumor cells were subcutaneously inoculated in female Swiss mice. The long-term treatment (31 days) with CAP (100 mg kg-1, p.o.) reduced the tumor growth and did not induce toxicity. The combined treatment protocol of 100 mg kg-1 CAP (p.o.) + 1 mg kg-1 MTX (i.p.) for 21 days inhibited the tumor growth in 95%, higher than the inhibition induced by MTX alone (1.0 or 2.5 mg kg-1, i.p.). In tumors, both CAP and CAP + MTX decreased the gene expression of Vegf, vessel area, and IL-4 and IL-10 levels, and increased IL-6 levels and the degree of necrosis. Treatment with CAP + MTX also increased TNF-α levels in tumors. Additionally, CAP + MTX treatment reduced the viability of human MDA-MB-231 and MDA-MB-436 mammary tumor cells in culture. In fact, CAP exerted antineoplastic effects in vivo and in vitro against mammary tumor cells, possibly by modulating inflammation and angiogenesis. CAP may be a promising adjunct chemotherapy with lower toxicity.
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The present study evaluated the effects of acute treatment with silymarin, an extract that is obtained from Silybum marianum, on angiogenesis, oxidative stress, and inflammation in normoglycemic and diabetic mice. Diabetes was induced by streptozotocin (80 mg/kg, intraperitoneal) in male Swiss mice, 6 weeks of age. A polyether-polyurethane sponge was surgically implanted in the back of the mice as a model of healing in both diabetic and normoglycemic animals that were treated with oral silymarin or water for 10 days. The pancreas, liver, kidneys, blood, and sponges were collected and analyzed. Diabetes led to impairments of antioxidant defenses, reflected by a reduction of pancreatic superoxide dismutase and hepatic and renal catalase and an increase in pancreatic lipoperoxidation. An inflammatory process was observed in diabetic mice, reflected by an increase in pancreatic tumor necrosis factor α (TNF-α) and the infiltration of inflammatory cells in islets. The number of vessels was lower in the implanted sponges in diabetic mice. Silymarin treatment attenuated this damage, restoring antioxidant enzymes and reducing pancreatic TNF-α and inflammatory infiltration. However, silymarin treatment did not restore angiogenesis or glycemia. In conclusion, treatment with silymarin red uced oxidative stress and inflammation that were induced in the model of streptozotocin-induced diabetes in several organs, without apparent toxicity. Silymarin may be a promising drug for controlling diabetic complications.
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Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/patología , Neovascularización Fisiológica/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Silimarina/uso terapéutico , Animales , Vasos Sanguíneos/efectos de los fármacos , Vasos Sanguíneos/patología , Peso Corporal/efectos de los fármacos , Colágeno/metabolismo , Diabetes Mellitus Experimental/sangre , Depuradores de Radicales Libres/farmacología , Hiperglucemia/sangre , Hiperglucemia/complicaciones , Inflamación/patología , Riñón/efectos de los fármacos , Riñón/patología , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Páncreas/efectos de los fármacos , Páncreas/metabolismo , Páncreas/patología , Silimarina/farmacologíaRESUMEN
The present study investigated the antineoplastic effects of pectic polysaccharides that were extracted from green sweet pepper (Capsicum annuum [CAP]) in the Ehrlich carcinoma in mice and in human mammary tumor lineages. After the subcutaneous inoculation of 2 × 106 Ehrlich tumor cells, Female Swiss mice received 50, 100, or 150 mg/kg CAP or vehicle orally once daily or methotrexate (2.5 mg/kg, i.p., every 5 days) for 21 days. CAP dose-dependently reduced Ehrlich tumor growth. It also reduced the viability of MCF-7, MDA-MB-231, and MDA-MB-436 human mammary cell lineages. Treatment with CAP reduced the gene expression of vascular endothelial growth factor in vivo and in vitro, reduced vessel areas of the tumors, and induced necrosis in Ehrlich solid tumors. CAP treatment significantly increased Interleukin-6 in tumors. The antineoplastic effect of CAP appears to depend on the regulation of inflammation and angiogenesis. Further studies are encouraged to better understand the CAP potential for the treatment of breast tumors.
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Antineoplásicos Fitogénicos , Neoplasias de la Mama/tratamiento farmacológico , Capsicum/química , Carcinoma de Ehrlich/tratamiento farmacológico , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Pectinas , Animales , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Carcinoma de Ehrlich/metabolismo , Carcinoma de Ehrlich/patología , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Células MCF-7 , Neoplasias Mamarias Experimentales/metabolismo , Ratones , Pectinas/química , Pectinas/aislamiento & purificación , Pectinas/farmacologíaRESUMEN
The present study evaluated the in vivo antitumor effects and toxicity of a new Ru(II) compound, cis-(Ru[phen]2[ImH]2)2+ (also called RuphenImH [RuC]), against Walker-256 carcinosarcoma in rats. After subcutaneous inoculation of Walker-256 cells in the right pelvic limb, male Wistar rats received 5 or 10mgkg-1 RuC orally or intraperitoneally (i.p.) every 3 days for 13 days. A positive control group (2mgkg-1 cisplatin) and negative control group (vehicle) were also used. Tumor progression was checked daily. After treatment, tumor weight, plasma biochemistry, hematology, oxidative stress, histology, and tumor cell respiration were evaluated. RuC was effective against tumors when administered i.p. but not orally. The highest i.p. dose of RuC (10mgkg-1) significantly reduced tumor volume and weight, induced oxidative stress in tumor tissue, reduced the respiration of tumor cells, and induced necrosis but did not induce apoptosis in the tumor. No clinical signs of toxicity or death were observed in tumor-bearing or healthy rats that were treated with RuC. These results suggest that RuC has antitumor activity through the modulation of oxidative stress and impairment of oxidative phosphorylation, thus promoting Walker-256 cell death without causing systemic toxicity. These effects make RuC a promising anticancer drug for clinical evaluation.
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Antineoplásicos/farmacología , Carcinoma 256 de Walker/tratamiento farmacológico , Complejos de Coordinación/farmacología , Regulación Neoplásica de la Expresión Génica , Especies Reactivas de Oxígeno/agonistas , Rutenio/farmacología , Animales , Antineoplásicos/síntesis química , Carcinoma 256 de Walker/genética , Carcinoma 256 de Walker/metabolismo , Carcinoma 256 de Walker/patología , Caspasa 3/genética , Caspasa 3/metabolismo , Respiración de la Célula/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Evaluación Preclínica de Medicamentos , Inyecciones Subcutáneas , Masculino , Necrosis/inducido químicamente , Necrosis/genética , Necrosis/metabolismo , Estrés Oxidativo/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Rutenio/química , Carga Tumoral/efectos de los fármacos , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismoRESUMEN
INTRODUCTION: The incidence of canine leptospirosis in Brazil needs to be assessed. METHODS: The same dogs in southern Brazil were sampled over two years to determine the prevalence, incidence and association of canine leptospirosis with various risk factors. RESULTS: In 2009, the prevalence was 33 (14.4%) of 228 dogs, with a predominance of serovar Canicola (33.4%). In 2010, 90 dogs were re-evaluated (the remaining dogs were lost to deaths, address changes and donations), and the prevalence was found to be 35 (38.9%) of 90, with the predominant serovar being Icterohaemorrhagiae (51.4%). Moreover, the incidence was 26 of 90 (28.9%), and the disease was statistically associated with age (2009) and street access (2010). CONCLUSIONS: Our findings revealed instability in the dog population and age to be relevant risk factors for canine leptospirosis.