RESUMO
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.
Assuntos
Antineoplásicos , Chalconas , Neoplasias , Animais , Camundongos , Humanos , Preparações Farmacêuticas , Chalconas/farmacologia , Chalconas/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Morte Celular , Autofagia , Linhagem Celular Tumoral , Células MCF-7 , ApoptoseRESUMO
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.
Assuntos
Vinho , Ratos , Animais , Acetilglucosaminidase , Sistema Enzimático do Citocromo P-450/metabolismo , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Polissacarídeos/farmacologiaRESUMO
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.
Assuntos
Carcinoma , Fator A de Crescimento do Endotélio Vascular , Animais , Camundongos , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Quinase 1 de Adesão Focal/metabolismo , Integrina beta1/metabolismo , Invasividade Neoplásica , Adesão CelularRESUMO
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.
Assuntos
Antineoplásicos , Neoplasias da Mama , Neoplasias Mamárias Animais , Vinho , Camundongos , Feminino , Humanos , Animais , Metotrexato/farmacologia , Metotrexato/uso terapêutico , Metotrexato/análise , Vinho/análise , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Oligossacarídeos/farmacologia , Oligossacarídeos/uso terapêutico , Oligossacarídeos/análise , Neoplasias da Mama/tratamento farmacológicoRESUMO
Resumo Objetivo Analisar a evolução clínica de um paciente acometido pela Doença de Alzheimer (DA) e discutir as repercussões de um diagnóstico precoce. Método Estudo de caso instrumental do tipo qualitativo e de caráter descritivo que se desenvolveu em três etapas: 1) seleção e delimitação do caso; 2) coleta dos dados em campo; e 3) organização e redação do relatório. Este estudo baseia-se na análise da evolução clínica descrita em prontuário de um paciente com diagnóstico de DA, atendido e acompanhado pelo Centro de Atenção Psicossocial (CAPS), por um período de 10 anos, na região do Alto Vale do Rio do Peixe. Resultados Estudo realizado com a paciente M.R., sexo feminino, 71 anos, casada e do lar, com ensino fundamental incompleto, portadora de DA e hipotireoidismo, a qual iniciou seu acompanhamento no CAPS II em 10 de setembro de 2012. Paciente submetida ao Miniexame do Estado Mental (MEEM), tendo como resultado no primeiro teste 14 pontos, abaixo do ponto de corte para o nível de escolaridade da paciente. Posteriormente, em 2018, registraram-se 10 pontos no MEEM, e em 2020 possuiu pontuação igual a 11, já em tratamento medicamentoso para DA: Memantina 10mg 2x/dia e Donepezila 5mg 1x/dia. Conclusão O diagnóstico precoce da DA é de extrema importância para tratamento adequado a fim de retardar a progressão da doença. No entanto, afecções mentais, tal como a depressão, constituem-se como barreiras na análise clínica inicial dos pacientes e ainda em certos casos apresenta-se como pródromo para a DA.
Abstract Objective To analyze the clinical evolution of a patient affected by Alzheimer's disease and discuss the repercussions of an early diagnosis. Method Instrumental case study of qualitative and descriptive type that was developed in three stages: 1) selection and delimitation of the case; 2) collection of data in the field; and 3) organization and writing of the report. This study is based on the analysis of the clinical evolution described in the medical records of a patient diagnosed with Alzheimer's disease, treated and followed-up by the Center for Psychosocial Care (CAPS), for a period of 10 years, in the Alto Vale do Rio do Peixe region. Results This study was conducted with the patient M.R., female, 71 years old, married, housewife, with incomplete elementary education, carrier of AD and hypothyroidism, who started her follow-up at CAPS II on September 10, 2012. Patient submitted to the Mini Mental State Examination (MMSE), with a result of 14 points in the first test, below the cut-off point for the patient's level of education. Later, in 2018, she scored 10 points on the MMSE, and in 2020 she scored 11, already under medication treatment for AD: memantine 10mg 2x/day and donepezilla 5mg 1x/day. Conclusion Early diagnosis of AD is extremely important for appropriate treatment to slow the progression of the disease. However, mental disorders such as depression are barriers in the initial clinical analysis of patients and in some cases presents itself as a prodrome for AD.
Assuntos
Humanos , Feminino , Idoso , Idoso , Disfunção Cognitiva , Serviços de Saúde Mental , Qualidade de Vida , Transtornos Neurocognitivos/tratamento farmacológicoRESUMO
Baccharis trimera is a native medicinal plant from South America popularly known as "carqueja". Its infusion is traditionally ingested for the treatment and prevention of hepatic disorders. Up to now, only the crude aqueous extract or hydroethanolic fractions, containing the secondary metabolites, have been studied and correlated with their biological action on the liver. Here we report that an inulin type fructan is present in the B. trimera infusion and contributes to the hepatoprotective effect of the species. In vitro, inulin at 300 µg/mL, was able to scavenger 97% of the DPPH radicals. In vivo experiments showed that it protected the liver against CCl4-induced injuries. The administration of inulin at low dose of 1 mg/kg significantly reduced the blood levels of ALT, AST and ALP, reduced the lipid peroxidation and increased the catalase activity and the levels of reduced glutathione in the liver of CCl4-treated mice. Moreover, the administration of inulin at 100 mg/kg increased GSH levels in the liver of Naïve mice. No signs of toxicity were observed. Thus, inulin present in B. trimera infusion protects the liver from the oxidative stress caused by CCl4 administration and can corroborate with the hepatoprotective effects presented by the species infusion.
Assuntos
Baccharis , Animais , Fígado , Camundongos , Extratos Vegetais/farmacologia , Polissacarídeos/farmacologia , América do SulRESUMO
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.
RESUMO
Salvia lachnostachys is an herbaceous plant with anti-inflammatory, analgesic and cytotoxic properties. This study investigated the antitumor effect of an ethanolic extract of Salvia lachnostachys leaves (EES) in a solid Ehrlich carcinoma model. Ehrlich cells were inoculated subcutaneously in the right pelvic member (2 × 106 cells) in female Swiss mice. The animals were treated with vehicle (10 mL kg-1, p.o.), EES (30 and 100 mg kg-1, p.o.), or methotrexate (2.5 mg kg-1, i.p.) for 21 days (early treatment) or 14 days (late treatment) after tumor inoculation, or 10 days before tumor inoculation and continued for 21 days after tumor inoculation (chemopreventive treatment). The acute toxicity test was performed according OECD guidelines Late treatment with EES had no antitumor effect. Early treatment with 100 mg kg-1 EES prevented tumor development, increased tumor necrosis factor-α (TNF-α) levels and decreased tumor superoxide dismutase (SOD) activity, interleukin-10 (IL-10) levels and Cyclin D1 expression, and tumor cell necrosis was observed. Chemopreventive treatment with EES for 10 and 31 days prevented tumor development in the same manner. EES treatment for 31 days decreased hepatic and tumor SOD activity, tumor IL-10 levels and Cyclin D1 expression, and increased tumor reduced glutathione, N-acetylglucosaminidase, reactive oxygen species, lipid peroxidation, TNF-α levels and Nrf2 expression. No toxicity was observed in the acute toxicity assay. In conclusion, EES had an antitumor effect by inhibiting Cyclin D1 expression and increasing inflammation with early and chemopreventive treatment. Modulation of the antioxidant system also contribute for the antitumor effects of EES.
Assuntos
Anticarcinógenos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Extratos Vegetais/farmacologia , Salvia/química , Animais , Anticarcinógenos/química , Antineoplásicos Fitogênicos/química , Carcinoma de Ehrlich/genética , Carcinoma de Ehrlich/metabolismo , Quimioprevenção , Cromatografia Líquida de Alta Pressão , Ciclina D1/genética , Ciclina D1/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Camundongos , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química , Folhas de Planta/química , Espécies Reativas de Oxigênio/metabolismoRESUMO
INTRODUCTION AND OBJECTIVES: Acute liver injury is a current health problem with few effective treatments. The present study investigated the hepatoprotective and curative potential of the glucagon-like peptide-1 analog liraglutide against carbon tetrachloride (CCl4)-induced hepatotoxicity. MATERIALS AND METHODS: Male Swiss mice were subjected to two protocols. The first protocol (Pretreatment) consisted of intraperitoneal (i.p.) treatment with liraglutide (0.057 and 0.118mgkg-1) or vehicle (distilled water) once daily for 7 days. On days 6 and 7, the animals were challenged with 2% CCl4 (5mgkg-1, i.p.). The second protocol (Late treatment) began with an injection of 5% CCl4 (5mgkg-1, i.p.) and subsequent treatment with liraglutide (0.057mgkg-1) or vehicle (distilled water) for 1 day. In both protocols, 24h after the last administration, blood and bile were collected from anesthetized animals, followed by euthanasia and liver collection. Plasma and bile underwent biochemical analyses, and histological, oxidative stress, and metabolic parameters were evaluated in the liver. RESULTS: Both liraglutide treatment protocols attenuated hepatotoxicity that was induced by CCl4, decreasing plasma levels of hepatic enzymes, stimulating the hepatic antioxidant system, and decreasing centrilobular necrosis, hepatic glycogen, and lipid accumulation. CCl4 tended to reduce bile lipid excretion, but liraglutide did not influence this parameter. CONCLUSIONS: The present results demonstrated the hepatoprotective and therapeutic effects of liraglutide, which may be attributable to a decrease in liver oxidative stress and the preservation of metabolism. Liraglutide may have potential as a complementary therapy for acute liver injury.
Assuntos
Tetracloreto de Carbono/toxicidade , Incretinas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Liraglutida/farmacologia , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Alanina Transaminase/efeitos dos fármacos , Alanina Transaminase/metabolismo , Fosfatase Alcalina/efeitos dos fármacos , Fosfatase Alcalina/metabolismo , Animais , Aspartato Aminotransferases/efeitos dos fármacos , Aspartato Aminotransferases/metabolismo , Ácidos e Sais Biliares/metabolismo , Catalase/efeitos dos fármacos , Catalase/metabolismo , Doença Hepática Induzida por Substâncias e Drogas , Glutationa Transferase/efeitos dos fármacos , Glutationa Transferase/metabolismo , Glicogênio/metabolismo , Ácido Láctico/metabolismo , Fígado/metabolismo , Fígado/patologia , Camundongos , Ácido Pirúvico/metabolismo , Superóxido Dismutase/efeitos dos fármacos , Superóxido Dismutase/metabolismoRESUMO
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.