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1.
Nutrients ; 11(5)2019 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-31130604

RESUMO

Flaxseed is a rich source of the omega-3 fatty acid, alpha linolenic acid, the lignan secoisolariciresinol diglucoside and fiber. These compounds provide bioactivity of value to the health of animals and humans through their anti-inflammatory action, anti-oxidative capacity and lipid modulating properties. The characteristics of ingesting flaxseed or its bioactive components are discussed in this article. The benefits of administering flaxseed or the individual bioactive components on health and disease are also discussed in this review. Specifically, the current evidence on the benefits or limitations of dietary flaxseed in a variety of cardiovascular diseases, cancer, gastro-intestinal health and brain development and function, as well as hormonal status in menopausal women, are comprehensive topics for discussion.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Dieta , Linho/química , Metabolismo dos Lipídeos/efeitos dos fármacos , Sementes/química , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Butileno Glicóis/farmacologia , Butileno Glicóis/uso terapêutico , Doenças Cardiovasculares/terapia , Fibras na Dieta/farmacologia , Fibras na Dieta/uso terapêutico , Suplementos Nutricionais , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-3/uso terapêutico , Feminino , Alimento Funcional , Gastroenteropatias/terapia , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Hormônios/metabolismo , Humanos , Lignanas/farmacologia , Lignanas/uso terapêutico , Neoplasias/terapia , Ácido alfa-Linoleico/farmacologia , Ácido alfa-Linoleico/uso terapêutico
2.
J Mol Cell Cardiol ; 127: 232-245, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30611795

RESUMO

Sepsis is the overwhelming systemic immune response to infection, which can result in multiple organ dysfunction and septic shock. Myocardial dysfunction during sepsis is associated with advanced disease and significantly increased in-hospital mortality. Our group has shown that energetic failure and excess reactive oxygen species (ROS) generation constitute major components of myocardial dysfunction in sepsis. Because ROS production is central to cellular metabolic health, we tested if the synthetic anti-oxidant lignan secoisolariciresinol diglucoside (SDG; LGM2605) would alleviate septic cardiac dysfunction and investigated the underlying mechanism. Using the cecal ligation and puncture (CLP) mouse model of peritonitis-induced sepsis, we observed impairment of cardiac function beginning at 4 h post-CLP surgery. Treatment of mice with LGM2605 (100 mg/kg body weight, i.p.) 6 h post-CLP surgery reduced cardiac ROS accumulation and restored cardiac function. Assessment of mitochondrial respiration (Seahorse XF) in primary cardiomyocytes obtained from adult C57BL/6 mice that had undergone CLP and treatment with LGM2605 showed restored basal and maximal respiration, as well as preserved oxygen consumption rate (OCR) associated with spare capacity. Further analyses aiming to identify the cellular mechanisms that may account for improved cardiac function showed that LGM2605 restored mitochondria abundance, increased mitochondrial calcium uptake and preserved mitochondrial membrane potential. In addition to protecting against cardiac dysfunction, daily treatment with LGM2605 and antibiotic ertapenem (70 mg/kg) protected against CLP-associated mortality and reversed hypothermia when compared against mice receiving ertapenem and saline. Therefore, treatment of septic mice with LGM2605 emerges as a novel pharmacological approach that reduces cardiac ROS accumulation, protects cardiac mitochondrial function, alleviates cardiac dysfunction, and improves survival.


Assuntos
Butileno Glicóis/síntese química , Butileno Glicóis/uso terapêutico , Cardiomiopatias/complicações , Cardiomiopatias/tratamento farmacológico , Glucosídeos/síntese química , Glucosídeos/uso terapêutico , Mitocôndrias Cardíacas/metabolismo , Miócitos Cardíacos/metabolismo , Sepse/complicações , Sepse/tratamento farmacológico , Animais , Antioxidantes/metabolismo , Autofagia/efeitos dos fármacos , Biomarcadores/metabolismo , Butileno Glicóis/química , Butileno Glicóis/farmacologia , Cálcio/metabolismo , Cardiomiopatias/genética , Cardiomiopatias/fisiopatologia , Ceco/patologia , Linhagem Celular , Citocinas/sangue , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Glucosídeos/química , Glucosídeos/farmacologia , Humanos , Mediadores da Inflamação/metabolismo , Ligadura , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Mitocôndrias Cardíacas/efeitos dos fármacos , Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , NF-kappa B/metabolismo , Biogênese de Organelas , Estresse Oxidativo/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Punções , Sepse/genética , Sepse/fisiopatologia
3.
Diving Hyperb Med ; 48(4): 235-240, 2018 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-30517956

RESUMO

BACKGROUND: Recent studies indicated that ketone ester R,S-1,3-butanediol acetoacetate diester (BD-AcAc2) may be effective in preventing central nervous system oxygen toxicity (CNS-OT) and concomitant acute lung injury, a serious medical problem to be faced when breathing hyperbaric oxygen (HBO). This study aimed to further investigate the protective effects of BD-AcAc2 against CNS-OT and concomitant acute lung injury (ALI) in mice. METHODS: Mice were treated with BD-AcAc2 in peanut oil vehicle (2.5, 5.0 or 10.0 g·kg⁻² body weight) by gavage 20 minutes before 600 kPa HBO exposure. Control mice received the vehicle only. Seizure latency was recorded. Malondialdehyde content in brain and lung tissues, total protein level in bronchoalveolar lavage fluid (BLF) and lung water content were measured 60 minutes after the hyperbaric exposure. Histopathology of lung tissue was undertaken. RESULTS: Compared with the vehicle alone, BD-AcAc2 prolonged seizure latency in a dose-dependent manner (P < 0.01). The HBO-induced increase in brain malondialdehyde, BLF protein and lung water were significantly reduced by BD-AcAc2 (P < 0.01). CONCLUSION: Oral administration of the ketone ester BD-AcAc2 significantly protected against CNS-OT and concomitant ALI. Alleviation of oxidative stress may be one underlying mechanism providing this effect.


Assuntos
Acetoacetatos/uso terapêutico , Lesão Pulmonar Aguda , Encéfalo/efeitos dos fármacos , Butileno Glicóis/uso terapêutico , Oxigenação Hiperbárica , Acetoacetatos/farmacologia , Lesão Pulmonar Aguda/tratamento farmacológico , Animais , Oxigenação Hiperbárica/efeitos adversos , Camundongos , Oxigênio , Ratos Sprague-Dawley , Convulsões/tratamento farmacológico
4.
Eur J Pharmacol ; 820: 235-244, 2018 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-29269018

RESUMO

Flaxseeds are used to treat metabolic diseases such as type 2 diabetes, fatty liver, hyperlipidemia and obesity. Secoisolariciresinol diglucoside (SDG) is a main substance of lignan which belongs to the phytoestrogen family and exists abundantly in flaxseeds. In this study, SDG reduced the body weight and size of adipose tissue, and decreased protein expressions of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT-enhancer-binding protein α (C/EBPα) in the high fat diet-fed-induced obese mice model. In the vitro study, we examined the anti-adipogenic effect of SDG during differentiation of 3T3-L1 cells into adipocytes. 3T3-L1 preadipocytes were differentiated and treated with various concentrations of SDG. Oil Red O staining was done to measure the quantity of lipid contents. As a result, SDG reduced lipid accumulation and decreased the expressions of adipogenic-related genes such as adipocyte fatty-acid-binding protein 2, adiponectin, and resistin. SDG also decreased the mRNA and protein levels of PPARγ and C/EBPα. Furthermore, phosphorylation levels of AMP-activated protein kinase α (AMPK α) and its upstream activator, liver kinase B1, were significantly increased by SDG in 3T3-L1 cells. These results suggest that SDG inhibits adipogenesis by activating AMPKα, suggesting it could be an attractive therapeutic candidate for the treatment of obesity.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adipogenia/efeitos dos fármacos , Butileno Glicóis/farmacologia , Glucosídeos/farmacologia , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Animais , Butileno Glicóis/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Glucosídeos/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/induzido quimicamente , Obesidade/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos
5.
Int J Mol Sci ; 18(12)2017 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-29186841

RESUMO

Radiation therapy for the treatment of thoracic malignancies has improved significantly by directing of the proton beam in higher doses on the targeted tumor while normal tissues around the tumor receive much lower doses. Nevertheless, exposure of normal tissues to protons is known to pose a substantial risk in long-term survivors, as confirmed by our work in space-relevant exposures of murine lungs to proton radiation. Thus, radioprotective strategies are being sought. We established that LGM2605 is a potent protector from radiation-induced lung toxicity and aimed in the current study to extend the initial findings of space-relevant, proton radiation-associated late lung damage in mice by looking at acute changes in human lung. We used an ex vivo model of organ culture where tissue slices of donor living human lung were kept in culture and exposed to proton radiation. We exposed donor human lung precision-cut lung sections (huPCLS), pretreated with LGM2605, to 4 Gy proton radiation and evaluated them 30 min and 24 h later for gene expression changes relevant to inflammation, oxidative stress, and cell cycle arrest, and determined radiation-induced senescence, inflammation, and oxidative tissue damage. We identified an LGM2605-mediated reduction of proton radiation-induced cellular senescence and associated cell cycle changes, an associated proinflammatory phenotype, and associated oxidative tissue damage. This is a first report on the effects of proton radiation and of the radioprotective properties of LGM2605 on human lung.


Assuntos
Anti-Inflamatórios/uso terapêutico , Butileno Glicóis/uso terapêutico , Glucosídeos/uso terapêutico , Prótons/efeitos adversos , Pneumonite por Radiação/prevenção & controle , Protetores contra Radiação/uso terapêutico , Anti-Inflamatórios/farmacologia , Butileno Glicóis/farmacologia , Pontos de Checagem do Ciclo Celular , Senescência Celular , Glucosídeos/farmacologia , Humanos , Pulmão/efeitos dos fármacos , Pulmão/efeitos da radiação , Estresse Oxidativo , Pneumonite por Radiação/tratamento farmacológico , Pneumonite por Radiação/etiologia , Protetores contra Radiação/farmacologia
6.
Oxid Med Cell Longev ; 2017: 7395238, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29075366

RESUMO

BACKGROUND: The interaction of asbestos with macrophages drives two key processes that are linked to malignancy: (1) the generation of reactive oxygen species (ROS)/reactive nitrogen species (RNS) and (2) the activation of an inflammation cascade that drives acute and chronic inflammation, with the NLRP3 inflammasome playing a key role. Synthetic secoisolariciresinol diglucoside (SDG), LGM2605, is a nontoxic lignan with anti-inflammatory and antioxidant properties and was evaluated for protection from asbestos in murine peritoneal macrophages (MF). METHODS: MFs were exposed to crocidolite asbestos ± LGM2605 given 4 hours prior to exposure and evaluated at various times for NLRP3 expression, secretion of inflammasome-activated cytokines (IL-1ß and IL-18), proinflammatory cytokines (IL-6, TNFα, and HMGB1), NF-κB activation, and levels of total nitrates/nitrites. RESULTS: Asbestos induces a significant (p < 0.0001) increase in the NLRP3 subunit, release of proinflammatory cytokines, NLRP3-activated cytokines, NF-κB, and levels of nitrates/nitrites. LGM2605 significantly reduced NLRP3 ranging from 40 to 81%, IL-1ß by 89-96%, and TNFα by 67-78%, as well as activated NF-κB by 48-49% while decreasing levels of nitrates/nitrites by 85-93%. CONCLUSIONS: LGM2605 reduced asbestos-induced NLRP3 expression, proinflammatory cytokine release, NF-κB activation, and nitrosative stress in MFs supporting its possible use in preventing the asbestos-induced inflammatory cascade leading to malignancy.


Assuntos
Asbestos/efeitos adversos , Butileno Glicóis/uso terapêutico , Glucosídeos/uso terapêutico , Inflamassomos/efeitos adversos , Macrófagos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Butileno Glicóis/farmacologia , Glucosídeos/farmacologia , Camundongos
7.
J Med Assoc Thai ; 100(1): 70-7, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29911772

RESUMO

Background: 5% minoxidil solution is approved for the treatment of male androgenetic alopecia (AGA). However, there have been occasional reports of adverse events that were caused mostly by propylene glycol sensitivity. As an alternative treatment, Siriraj hair team developed a proprietary preparation referred to as "minoxidil milky lotion" that uses butylene glycol as a substitute for propylene glycol. Objective: To compare the efficacy and safety of 5% minoxidil solution with 5% minoxidil milky lotion in the treatment of male AGA. Materials and Method: Twenty males with AGA were recruited for this prospective randomized study. Subjects were randomly treated with 5% minoxidil solution or 5% minoxidil milky lotion. Clinical outcomes and adverse events were recorded at 8, 16, and 24 weeks. Results: The mean age of subjects was 43.5±12.5 years (range, 26-65 years). Percentage increase in hair density at 8 weeks after receiving 5% minoxidil solution and 5% minoxidil milky lotion was 8.8% and 37.4%, respectively (p = 0.01). However, there was no statistically significant difference between the two preparations at the 16 and 24 week visits. Mild irritation was reported in 1 case in the 5% minoxidil milky lotion group. Study limitation: Small sample size. Conclusion: Both formulations were found to be effective and safe in the treatment of male AGA. 5% minoxidil milky lotion may be an alternative treatment in propylene glycol-sensitive patients, with efficacy that is comparable to that of 5% minoxidil solution.


Assuntos
Alopecia/tratamento farmacológico , Minoxidil/uso terapêutico , Administração Tópica , Adulto , Idoso , Butileno Glicóis/administração & dosagem , Butileno Glicóis/efeitos adversos , Butileno Glicóis/uso terapêutico , Emolientes/administração & dosagem , Emolientes/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Minoxidil/administração & dosagem , Minoxidil/efeitos adversos , Estudos Prospectivos , Resultado do Tratamento , Vasodilatadores/administração & dosagem , Vasodilatadores/efeitos adversos , Vasodilatadores/uso terapêutico
8.
Appl Physiol Nutr Metab ; 41(12): 1303-1310, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27849354

RESUMO

Secoisolariciresinol diglucoside (SDG), a lignan extracted from flaxseed, has been shown to suppress benign prostatic hyperplasia (BPH). However, little is known about the mechanistic basis for its anti-BPH activity. The present study showed that enterolactone (ENL), the mammalian metabolite of SDG, shared the similar binding site of G1 on a new type of membranous estrogen receptor, G-protein-coupled estrogen eceptor 1 (GPER), by docking simulations method. ENL and G1 (the specific agonist of GPER) inhibited the proliferation of human prostate stromal cell line WPMY-1 as shown by MTT assay and arrested cell cycle at the G0/G1 phase, which was displayed by propidium iodide staining following flow cytometer examination. Silencing GPER by short interfering RNA attenuated the inhibitory effect of ENL on WPMY-1 cells. The therapeutic potential of SDG in the treatment of BPH was confirmed in a testosterone propionate-induced BPH rat model. SDG significantly reduced the enlargement of the rat prostate and the number of papillary projections of prostatic alveolus and thickness of the pseudostratified epithelial and stromal cells when comparing with the model group. Mechanistic studies showed that SDG and ENL increased the expression of GPER both in vitro and in vivo. Furthermore, ENL-induced cell cycle arrest may be mediated by the activation of GPER/ERK pathway and subsequent upregulation of p53 and p21 and downregulation of cyclin D1. This work, in tandem with previous studies, will enhance our knowledge regarding the mechanism(s) of dietary phytochemicals on BPH prevention and ultimately expand the scope of adopting alternative approaches in BPH treatment.


Assuntos
4-Butirolactona/análogos & derivados , Antineoplásicos Fitogênicos/metabolismo , Butileno Glicóis/metabolismo , Linho/química , Glucosídeos/metabolismo , Lignanas/metabolismo , Modelos Moleculares , Hiperplasia Prostática/metabolismo , Receptores Acoplados a Proteínas-G/agonistas , 4-Butirolactona/química , 4-Butirolactona/metabolismo , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/uso terapêutico , Sítios de Ligação , Butileno Glicóis/química , Butileno Glicóis/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , Suplementos Nutricionais , Regulação Neoplásica da Expressão Gênica , Glucosídeos/química , Glucosídeos/uso terapêutico , Glicosídeos/química , Glicosídeos/metabolismo , Glicosídeos/uso terapêutico , Humanos , Lignanas/química , Lignanas/uso terapêutico , Masculino , Simulação de Acoplamento Molecular , Proteínas de Neoplasias/agonistas , Proteínas de Neoplasias/química , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Próstata/metabolismo , Próstata/patologia , Hiperplasia Prostática/dietoterapia , Hiperplasia Prostática/patologia , Interferência de RNA , Distribuição Aleatória , Ratos , Ratos Wistar , Receptores Estrogênicos/química , Receptores Estrogênicos/genética , Receptores Estrogênicos/metabolismo , Receptores Acoplados a Proteínas-G/química , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Sementes/química
9.
Biomed Pharmacother ; 83: 733-739, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27470575

RESUMO

BACKGROUND: There is increased risk of colon cancer in both men and women having diabetes. The objective of the study was to evaluate the role of Secoisolariciresinol diglucoside rich extract(SRE) of L.usissatisimum(flaxseed) in colon cancer associated with type 2 diabetes mellitus. MATERIAL AND METHODS: Diabetes was induced by administering high fat diet with low dose streptozotocin model. After 6 weeks, diabetes was confirmed and 1,2 dimethylhydrazine(25mg/kg, sc) weekly administration was from 6th to 18th weeks. Rats were treated with the SRE(500mg/kg) orally from 6th to 24th week. After 24 weeks, various biochemical and enzymatic parameters were estimated. Animals were sacrificed and colon tissue was separated and subjected to analysis of histopathological, PCNA studies and mRNA expression of CDK4. RESULTS: Disease control rats depicted hyperglycaemia, hyperinsulinaemia, elevated pro-inflammatory cytokines and cancer biomarker levels, and marked presence of proliferating cells. Treatment with SRE controlled hyperglycaemia, hyperinsulinaemia, reduced pro-inflammatory cytokines and cancer biomarker levels, and decreased no. of proliferating cells. We found that disease control rats depicted over expression of CDK4 mRNA levels which were reduced by SRE treatment. CONCLUSIONS: SRE of L. usitatissimum exhibited chemopreventive effect in colon cancer associated with type 2 diabetes mellitus which might be mediated through inhibition of CDK4.


Assuntos
Butileno Glicóis/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/prevenção & controle , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Diabetes Mellitus Tipo 2/tratamento farmacológico , Linho/química , Glucosídeos/uso terapêutico , Extratos Vegetais/uso terapêutico , Animais , Biomarcadores Tumorais/metabolismo , Butileno Glicóis/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/enzimologia , Neoplasias do Colo/patologia , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Teste de Tolerância a Glucose , Glucosídeos/farmacologia , Hiperglicemia/complicações , Hiperglicemia/tratamento farmacológico , Hiperglicemia/patologia , Mediadores da Inflamação/metabolismo , Masculino , Compostos Fitoquímicos/análise , Extratos Vegetais/farmacologia , Antígeno Nuclear de Célula em Proliferação/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley
10.
Eur J Pharmacol ; 767: 183-92, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26494631

RESUMO

Peripheral painful neuropathy is one of the most common complications in diabetes and necessitates improved treatment. Secoisolariciresinol diglycoside (SDG), a predominant lignan in flaxseed, has been shown in our previous studies to exert antidepressant-like effect. As antidepressant drugs are clinically used to treat chronic neuropathic pain, this work aimed to investigate the potential analgesic efficacy of SDG against diabetic neuropathic pain in a mouse model of type 1 diabetes. We subjected mice to diabetes by a single intraperitoneal (i.p.) injection of streptozotocin (STZ, 200 mg/kg), and Hargreaves test or von Frey test was used to assess thermal hyperalgesia or mechanical allodynia, respectively. Chronic instead of acute SDG treatment (3, 10 or 30 mg/kg, p.o., twice per day for three weeks) ameliorated thermal hyperalgesia and mechanical allodynia in diabetic mice, and these analgesic actions persisted about three days when SDG treatment was terminated. Although chronic treatment of SDG to diabetic mice did not impact on the symptom of hyperglycemia, it greatly attenuated excessive oxidative stress in sciatic nerve and spinal cord tissues, and partially counteracted the condition of weight decrease. Furthermore, the analgesic actions of SDG were abolished by co-treatment with the reactive oxygen species donor tert-butyl hydroperoxide (t-BOOH), but potentiated by the reactive oxygen species scavenger phenyl-N-tert-butylnitrone (PBN). These findings indicate that chronic SDG treatment can correct neuropathic hyperalgesia and allodynia in mice with type 1 diabetes. Mechanistically, the analgesic actions of SDG in diabetic mice may be associated with its antioxidant activity.


Assuntos
Analgésicos/uso terapêutico , Antioxidantes/metabolismo , Butileno Glicóis/uso terapêutico , Diabetes Mellitus Tipo 1/complicações , Neuropatias Diabéticas/tratamento farmacológico , Linho/química , Lignanas/uso terapêutico , Analgésicos/farmacologia , Animais , Butileno Glicóis/antagonistas & inibidores , Butileno Glicóis/farmacologia , Óxidos N-Cíclicos/farmacologia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Neuropatias Diabéticas/induzido quimicamente , Neuropatias Diabéticas/complicações , Neuropatias Diabéticas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Glicosídeos/antagonistas & inibidores , Glicosídeos/farmacologia , Glicosídeos/uso terapêutico , Hiperalgesia/complicações , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Lignanas/antagonistas & inibidores , Lignanas/farmacologia , Masculino , Camundongos , Neuralgia/complicações , Neuralgia/tratamento farmacológico , Nervo Isquiático/metabolismo , Medula Espinal/metabolismo , terc-Butil Hidroperóxido/farmacologia
11.
J Surg Res ; 197(2): 436-46, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25990692

RESUMO

BACKGROUND: Collagen-rich extracellular matrix from land-based mammalian tissues is increasingly used in regenerative medicine. However, its uses are associated with risk of disease transfer and may carry an ethnocultural stigma. In the present study, collagen-rich acellular swim bladder matrix (ASBM) from Rohu fish was prepared using sodium deoxycholate and crosslinked with 1,4-butanediol diglycidyl ether (BDDGE). Wound healing potential of ASBM and ASBM-BDDGE was compared in full-thickness skin wounds in rabbits. MATERIALS AND METHODS: Four full-thickness skin wounds (20 × 20 mm(2) each) were created on the dorsum of 18 rabbits and randomly divided into three equal groups. Wounds were left open, repaired with ASBM and ASBM-BDDGE in groups sham (I), ASBM (II), and ASBM-BDDGE (III), respectively. Planimetry, contracture, immunologic, and histologic observations were carried out to evaluate wound healing. RESULTS: Significantly (P < 0.05) lesser wound contraction was observed in ASBM (II) and ASBM-BDDGE (III) groups compared with sham (I) group. Total immunoglobulin G response in rabbit sera was decreased significantly (P < 0.05) in the ASBM-BDDGE (III) group compared with ASBM (II) group by enzyme-linked immunosorbent assay. Stimulation index of peripheral blood lymphocytes was decreased significantly (P < 0.05) in the ASBM-BDDGE (III) group compared with ASBM (II) group by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Histologically, improved epithelialization, neovascularization, fibroplasia, and best arranged collagen fibers were observed in ASBM (II) and ASBM-BDDGE (III) groups as early as on postimplantation day 21. CONCLUSIONS: Findings of this study indicate that BDDGE crosslinked ASBM derived from Rohu fish has potential for the clinical applications. Furthermore, it is expected that their clinical applications will not be limited by ethnocultural stigma.


Assuntos
Sacos Aéreos , Butileno Glicóis/uso terapêutico , Matriz Extracelular/transplante , Regeneração Tecidual Guiada/métodos , Pele/lesões , Cicatrização , Animais , Butileno Glicóis/farmacologia , Reagentes para Ligações Cruzadas , Cyprinidae , Feminino , Masculino , Coelhos , Distribuição Aleatória , Pele/efeitos dos fármacos , Pele/patologia , Cicatrização/efeitos dos fármacos
12.
J Med Food ; 18(2): 233-40, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25546379

RESUMO

This exploratory study was designed to assess the effectiveness of a lignan-rich extract of flaxseed hulls (LinumLife EXTRA(®)) in alleviating symptoms in subjects with benign prostatic hyperplasia (BPH) compared with placebo. Two dosages of extract were compared against placebo in a double-blinded, randomized, parallel, multicenter study. Newly diagnosed cases of BPH in patients aged 45-75 years with an American Urological Association Symptom Index (AUASI) score of ≥13 were included. Study treatment consisted of 500 or 1000 mg of extract containing 100 mg (low-dose active [LDA] group, n=26) or 200 mg (high-dose active [HDA] group, n=26) of secoisolariciresinol diglucoside (SDG), respectively. The placebo (P) group (n=28) received matching maltodextrin capsules. Sixty subjects (LDA [n=19], HDA [n=20], and P [n=21]) completed the study as per the protocol requirements. Change in the AUASI score within a period of 8 weeks, from baseline to end of treatment, was assessed. Significant improvement of obstructive symptoms and management of irritable BPH symptoms was achieved in all groups after treatment. Due to a strong placebo effect, there was no statistical difference between the groups that were treated with flaxseed hull extract as compared with the placebo group. Treatment with flaxseed hull extract did not lead to adverse effects compared with placebo. Supplementation with flaxseed hull extract was found to be safe and well-tolerated and may have improved the quality of life of individuals with BPH. The significant placebo effect as well as the number of subjects per treatment group and the relative short duration of the study may explain the lack of statistical significance between groups.


Assuntos
Butileno Glicóis/uso terapêutico , Linho/química , Glucosídeos/uso terapêutico , Fitoterapia , Extratos Vegetais/uso terapêutico , Hiperplasia Prostática/tratamento farmacológico , Sementes/química , Idoso , Método Duplo-Cego , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Efeito Placebo , Polissacarídeos/uso terapêutico , Hiperplasia Prostática/sangue , Qualidade de Vida , Resultado do Tratamento
13.
J Physiol Biochem ; 70(4): 961-9, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25316298

RESUMO

Due to substantial morbidity and high complication rate of diabetes mellitus, which is considered as the third killer in the world, a search for the effective blockade of the progression of diabetic nephropathy (DN) remains a therapeutic challenge. Alternative antidiabetic drugs from natural plants are highly demanded nowadays. The aim of this study was to investigate the renoprotective effect of secoisolariciresinol diglucoside (SDG) on DN induced in rats. Diabetes was induced in male Sprague-Dawley rats by a high-fat diet (HFD) and an intraperitoneal 35 mg/kg streptozotocin (STZ) injection. Rats were divided into four groups: normal control rats, diabetic control rats, diabetic rats treated with SDG at 10 mg/kg/day for 4 weeks, and diabetic rats treated with SDG at 20 mg/kg/day for 4 weeks. At the end of the treatment, blood and renal tissue samples were collected for biochemical examination. The results revealed that SDG treatment significantly increased insulin level and decreased blood glucose, fructosamine, creatinine, and blood urea nitrogen levels in diabetic rats. Also, SDG significantly increased renal reduced glutathione, superoxide dismutase and decreased malondialdehyde and nitric oxide levels. In addition, SDG downregulated the renal nuclear factor kappa-B (NF-κB), tumor necrosis factor (TNF)-α, and inducible nitric oxide synthase (iNOS) and upregulated renal survivin and B-cell lymphoma-2 (Bcl-2) expressions when compared with untreated diabetic control rats. This study demonstrated, for the first time, the renoprotective effects of SDG in HFD/STZ-induced DN in rats through correction of hyperglycemia; attenuation of oxidative/nitrosative stress markers; downregulation of renal expressions of inflammatory markers NF-κB, TNF-α, and iNOS; along with upregulation of renal expressions of antiapoptotic markers survivin and Bcl-2.


Assuntos
Butileno Glicóis/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Glucosídeos/uso terapêutico , Hipoglicemiantes/uso terapêutico , Animais , Apoptose , Butileno Glicóis/farmacologia , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/etiologia , Avaliação Pré-Clínica de Medicamentos , Glucosídeos/farmacologia , Hipoglicemiantes/farmacologia , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos Sprague-Dawley , Estreptozocina , Survivina , Fator de Necrose Tumoral alfa/metabolismo
14.
Anim Reprod Sci ; 148(3-4): 145-52, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24957968

RESUMO

Pre-partum feeding of 1,3-butanediol to sows has been shown to improve the metabolic status and survival rate of neonatal pigs. To evaluate the efficacy of short-term, pre-partum feeding of 1,3-butanediol on pig and sow productivity on a large scale and low concentration was the focus of the research. The secondary objective was to determine if pre-partum feeding of 1,3-butanediol had any effect on survival rate and weight gain of lesser body weight pigs, sow body weight and subsequent sow reproductive performance. In a large commercial unit, 2537 sows were fed one of two pre-partum diets (0% or 4.55% 1,3-butanediol) on Day 108±3 of pregnancy. 1,3-butanediol provided 8% of the total metabolizable energy. Pigs born live in those litters were equalized by cross-fostering among sows receiving the same pre-partum diet. Pigs were weaned from the sows at 16±3 days post-partum and return of sows to estrus and conception rates were determined. Pre-partum feeding of 1,3-butanediol reduced (P=0.01) pre-weaning pig mortalities from 1.44 to 1.24 pigs per litter. The reduction in pig mortality was independent of length of 1,3-butanediol feeding (4 to 11 days). In a subset of 750 litters, four lesser birth-weight pigs from each litter were tagged and monitored to determine the effect of 1,3-butanediol on survival rates and pre-weaning weight gain of pigs with the greatest mortality risk. 1,3-butanediol reduced (P=0.01) pre-weaning mortality of these low birth weight pigs by 5.27%. Based on these data, short-term pre-partum feeding of 1,3-butanediol effectively improves pre-weaning pig productivity at a lower concentration than previously reported.


Assuntos
Animais Recém-Nascidos/fisiologia , Butileno Glicóis/uso terapêutico , Viabilidade Fetal/efeitos dos fármacos , Fenômenos Fisiológicos da Nutrição Pré-Natal , Suínos , Fenômenos Fisiológicos da Nutrição Animal , Animais , Relação Dose-Resposta a Droga , Feminino , Tamanho da Ninhada de Vivíparos , Nascimento Vivo/veterinária , Gravidez , Resultado do Tratamento , Ganho de Peso/efeitos dos fármacos
15.
Am J Physiol Regul Integr Comp Physiol ; 304(10): R829-36, 2013 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-23552496

RESUMO

Central nervous system oxygen toxicity (CNS-OT) seizures occur with little or no warning, and no effective mitigation strategy has been identified. Ketogenic diets (KD) elevate blood ketones and have successfully treated drug-resistant epilepsy. We hypothesized that a ketone ester given orally as R,S-1,3-butanediol acetoacetate diester (BD-AcAc(2)) would delay CNS-OT seizures in rats breathing hyperbaric oxygen (HBO(2)). Adult male rats (n = 60) were implanted with radiotelemetry units to measure electroencephalogram (EEG). One week postsurgery, rats were administered a single oral dose of BD-AcAc(2), 1,3-butanediol (BD), or water 30 min before being placed into a hyperbaric chamber and pressurized to 5 atmospheres absolute (ATA) O2. Latency to seizure (LS) was measured from the time maximum pressure was reached until the onset of increased EEG activity and tonic-clonic contractions. Blood was drawn at room pressure from an arterial catheter in an additional 18 animals that were administered the same compounds, and levels of glucose, pH, Po(2), Pco(2), ß-hydroxybutyrate (BHB), acetoacetate (AcAc), and acetone were analyzed. BD-AcAc(2) caused a rapid (30 min) and sustained (>4 h) elevation of BHB (>3 mM) and AcAc (>3 mM), which exceeded values reported with a KD or starvation. BD-AcAc(2) increased LS by 574 ± 116% compared with control (water) and was due to the effect of AcAc and acetone but not BHB. BD produced ketosis in rats by elevating BHB (>5 mM), but AcAc and acetone remained low or undetectable. BD did not increase LS. In conclusion, acute oral administration of BD-AcAc(2) produced sustained ketosis and significantly delayed CNS-OT seizures by elevating AcAc and acetone.


Assuntos
Acetoacetatos/uso terapêutico , Encéfalo/efeitos dos fármacos , Butileno Glicóis/uso terapêutico , Cetose/induzido quimicamente , Oxigênio , Convulsões/tratamento farmacológico , Acetoacetatos/farmacologia , Animais , Glicemia , Encéfalo/fisiopatologia , Butileno Glicóis/farmacologia , Eletroencefalografia , Masculino , Ratos , Ratos Sprague-Dawley , Convulsões/fisiopatologia , Telemetria
16.
J Nat Med ; 67(1): 222-7, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22476613

RESUMO

Secoisolariciresinol (SECO) is a natural lignan-type phytoestrogen constituent mainly found in flaxseed. It can be metabolized in vivo to mammalian lignans of enterodiol and enterolactone, which have been proven to be effective in relieving menopausal syndrome. Depression is one of the most common symptoms of menopausal syndrome, and is currently treated with estrogen replacement and antidepressant therapy. However, due to the serious side-effects of such agents, there are urgent needs for safer and more tolerable treatments. In this paper, using two classical depression models, the forced swimming test and the tail suspension test, we report the antidepressant effect of SECO on ovariectomized (OVX) mice by intragastric administration for 14 consecutive days at doses of 5, 10 and 20 mg/kg. The results showed that SECO (10 mg/kg) treatment could significantly reduce the duration of immobility of OVX mice in these two models compared with the control group (OVX mice + vehicle), which was similar to the positive control imipramine. In addition, SECO treatment could substantially increase brain monoamine (norepinephrine and dopamine) levels in OVX mice. The present studies showed that SECO can reverse depressive-like behavior and exhibit monoamine-enhancing effects.


Assuntos
Antidepressivos/uso terapêutico , Butileno Glicóis/uso terapêutico , Linho/química , Lignanas/uso terapêutico , Fitoestrógenos/uso terapêutico , Animais , Antidepressivos/química , Comportamento Animal/efeitos dos fármacos , Butileno Glicóis/química , Depressão/tratamento farmacológico , Feminino , Lignanas/química , Camundongos , Ovariectomia , Fitoestrógenos/química
17.
Phytomedicine ; 20(3-4): 237-45, 2013 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-23271000

RESUMO

Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycaemia. Its complications such as neuropathy, cardiopathy, nephropathy, and micro and macro vascular diseases are believed to be due to the increase in oxidative stress and decrease in the level of antioxidants. The aim of this study was to determine the antihyperglycemic activity of synthetic Secoisolariciresinol diglucoside (SDG) in streptozotocin (STZ)-induced diabetic rats. The synthetic SDG in a single-dose (20 mg/kg b.w.) two-day study showed dose-dependent reduction in glucose levels with maximum effect of 64.62% at 48 h post drug treatment (p<0.05), which is comparable to that of the standard drug tolbutamide (20 mg/kg b.w.). In a multi-dose fourteen-day study, lower doses of SDG (5 and 10 mg/kg b.w.) exhibited moderate reduction in glucose levels, lipid profile, restoration of antioxidant enzymes and improvement of the insulin and c-peptide levels which shows the regeneration of ß-cell which secretes insulin. Altered levels of lipids and enzymatic antioxidants were also restored by the SDG to the considerable levels in diabetic rats. Results of the present investigation suggest that diabetes is associated with an increase in oxidative stress as shown by increase in serum malondialdehyde (MDA), decreased levels of catalase (CAT), superoxide dismutase (SOD), and glutathione (GSH). Also, diabetes is associated with an increase in serum total cholesterol as well as triglycerides levels and decrease in insulin and c-peptide levels. SDG is effective in retarding the development of diabetic complications. We propose that synthetic SDG exerts anti hyperglycemic effect by preventing the liver from peroxidation damage through inhibition of ROS level mediated increased level of enzymatic and non-enzymatic antioxidants. And, also maintaining tissue function which results in improving the sensitivity and response of target cells in STZ-induced diabetic rats to insulin.


Assuntos
Butileno Glicóis/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Glucosídeos/uso terapêutico , Hipoglicemiantes/uso terapêutico , Animais , Antioxidantes/metabolismo , Glicemia/efeitos dos fármacos , Butileno Glicóis/síntese química , Butileno Glicóis/farmacologia , Peptídeo C/sangue , Diabetes Mellitus Experimental/sangue , Avaliação Pré-Clínica de Medicamentos , Linho/química , Glucosídeos/síntese química , Glucosídeos/farmacologia , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Insulina/sangue , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Pâncreas/efeitos dos fármacos , Pâncreas/enzimologia , Fitoterapia , Ratos , Ratos Wistar
18.
J Med Food ; 15(9): 840-5, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22925074

RESUMO

The objective of this study was to evaluate the efficacy of flaxseed meal and flaxseed extract in reducing climacteric symptoms of menopausal women. Ninety menopausal women were randomly distributed into three study groups: group I received 1 g per day of flaxseed extract containing at least 100 mg of secoisolariciresinol diglucoside (SDG), group II received 90 g per day of flaxseed meal containing at least 270 mg of SDG, and group III received 1 g per day of collagen (placebo group). Subjects were assessed for menopausal symptoms by the Kupperman index at the beginning and at the end of the 6 months of treatment. Subjects were also assessed for endometrial thickness and vaginal cytology. The Kupperman index values at the beginning and end of the treatments were analyzed using the paired t-test. Both the flaxseed extract (P=.007) and the flaxseed meal (P=.005) were effective in reducing the menopausal symptoms when compared with the placebo control (P=.082). Alternatively, the changes in Kupperman index were also computed and submitted to analysis of variance. In this case, no significant differences were found (P=.084) although the data indicate a decreasing tendency for the Kupperman index by both the flaxseed extract and the flaxseed meal groups. Neither the flaxseed extract nor the flaxseed meal exerted clinically important estrogenic effects on the vaginal epithelium or endometrium as revealed by the absence of changes in the blood levels of follicle stimulating hormone and estradiol, as well as in the endometrial thickness, and vaginal epithelial maturation value. No serious adverse events related to the treatments were reported. Although the results of the present study do not allow an unequivocal conclusion about the action of flaxseed on the menopausal symptoms, they suggest that it could be premature to conclude that no such action exists. Clearly the matter still deserves further experimental attention.


Assuntos
Suplementos Nutricionais , Linho/química , Fogachos/prevenção & controle , Menopausa , Extratos Vegetais/uso terapêutico , Sementes/química , Idoso , Brasil , Butileno Glicóis/administração & dosagem , Butileno Glicóis/efeitos adversos , Butileno Glicóis/análise , Butileno Glicóis/uso terapêutico , Suplementos Nutricionais/efeitos adversos , Endométrio/diagnóstico por imagem , Endométrio/patologia , Células Epiteliais/diagnóstico por imagem , Células Epiteliais/patologia , Estradiol/sangue , Feminino , Linho/efeitos adversos , Hormônio Foliculoestimulante Humano/sangue , Glucosídeos/administração & dosagem , Glucosídeos/efeitos adversos , Glucosídeos/análise , Glucosídeos/uso terapêutico , Fogachos/fisiopatologia , Humanos , Hipertrofia , Menopausa/sangue , Pessoa de Meia-Idade , Fitoestrógenos/administração & dosagem , Fitoestrógenos/efeitos adversos , Fitoestrógenos/análise , Fitoestrógenos/uso terapêutico , Extratos Vegetais/efeitos adversos , Extratos Vegetais/química , Sementes/efeitos adversos , Índice de Gravidade de Doença , Ultrassonografia , Vagina/diagnóstico por imagem , Vagina/patologia
19.
Fitoterapia ; 83(5): 941-6, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22542959

RESUMO

The potential effects of secoisolariciresinol diglucoside lignan-enriched flaxseed powder (LEFP) on bodyweight, visceral fat, lipid profile, adipokines, and blood pressure were investigated using rats, divided into four groups (n=8); a normal control diet (NC), a normal control diet with 0.02% LEFP (NCL), a high-fat and high-fructose diet (HFD), or a high-fat and high-fructose diet with 0.02% LEFP (HFDL). Liver, heart, kidney, adipose tissues, and blood were collected following 12-weeks on the diets. The average body weight of the HFD group was significantly higher than those of the NC, NCL, and the HFDL groups (P<0.05). Also, the average weights of kidneys from the HFD and HFDL groups was higher than those of the NC and NCL groups (P<0.05), although not significantly different in the weights of livers and hearts. The visceral fat weight was significantly higher in rats in the HFD group, but notably reduced in the HFDL fed rats (P<0.05). Accordingly, plasma leptin increased significantly in rats fed the HFD diet, higher than rats fed the HFDL diet. Also, the rats in the HFDL group showed improved lipid profile, compared to the rats in the HFD group (P<0.05). Furthermore, a significant reduction in blood pressure was observed in the rats of the HFDL group compared to the HFD group (P<0.05). These data suggest that the LEFP supplementation may provide beneficial effects such as the reduction of bodyweight and fat accumulation, the lipid profile improvement, and blood pressure control.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Butileno Glicóis/uso terapêutico , Dieta Hiperlipídica/efeitos adversos , Linho , Glucosídeos/uso terapêutico , Gordura Intra-Abdominal/efeitos dos fármacos , Lipídeos/sangue , Sementes , Animais , Butileno Glicóis/farmacologia , Gorduras na Dieta/administração & dosagem , Sacarose na Dieta/administração & dosagem , Alimentos Fortificados , Frutose/efeitos adversos , Glucosídeos/farmacologia , Coração/efeitos dos fármacos , Rim/efeitos dos fármacos , Leptina/sangue , Fígado/efeitos dos fármacos , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
20.
Nutr Cancer ; 62(4): 533-42, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20432175

RESUMO

Flaxseed (FS), an oilseed containing high amounts of the phytoestrogen lignan, secoisolariciresinol diglucoside (SDG), and n-3 fatty acid, alpha-linolenic acid-rich oil (FO), has been shown to inhibit the growth of established human breast tumors (MCF-7) in ovariectomized (OVX) athymic mice. However, the major FS component responsible for this effect and the mechanism(s) of its action are unclear. Hence, this study determined, in a 2 x 2 factorial design, the effect of SDG and FO, alone or in combination, on the growth of established human estrogen receptor positive (ER+) breast tumors and the potential mechanism(s) of its action. OVX mice with established ER+ human breast tumors (MCF-7) were treated for 8 wk with basal diet (BD, control) or BD supplemented with SDG (1 g/kg), FO (38.5 g/kg), or SDG + FO. All treatments reduced the tumor growth, but SDG had the greatest effect primarily through reducing tumor cell proliferation rather than increasing apoptosis. SDG had a main effect in the reduction of PS2, BCL2, and IGF-1R mRNA expression, whereas FO had a main effect only in PAKT reduction. SDG alone also lowered the ERalpha, ERbeta, EGFR, BCL2 mRNA, and PMAPK protein, indicating that its effect involves the modulation of the ER- and growth factor receptor-mediated signaling pathways.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Butileno Glicóis/farmacologia , Butileno Glicóis/uso terapêutico , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Óleo de Semente do Linho/farmacocinética , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Óleo de Semente do Linho/uso terapêutico , Camundongos , Camundongos Nus , Fitoestrógenos/farmacologia , Fitoestrógenos/uso terapêutico , Fitoterapia , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , RNA Mensageiro/metabolismo , Receptores Estrogênicos/genética , Receptores Estrogênicos/metabolismo , Receptores de Fatores de Crescimento/genética , Receptores de Fatores de Crescimento/metabolismo , Fatores de Tempo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
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