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1.
Viruses ; 15(5)2023 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-37243241

RESUMO

The coronavirus infectious disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has been spreading rapidly worldwide, creating a pandemic. This article describes the evaluation of the antiviral activity of nordihydroguaiaretic acid (NDGA), a molecule found in Creosote bush (Larrea tridentata) leaves, against SARS-CoV-2 in vitro. A 35 µM concentration of NDGA was not toxic to Vero cells and exhibited a remarkable inhibitory effect on the SARS-CoV-2 cytopathic effect, viral plaque formation, RNA replication, and expression of the SARS-CoV-2 spike glycoprotein. The 50% effective concentration for NDGA was as low as 16.97 µM. Our results show that NDGA could be a promising therapeutic candidate against SARS-CoV-2.


Assuntos
COVID-19 , SARS-CoV-2 , Animais , Chlorocebus aethiops , Masoprocol/farmacologia , Masoprocol/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Células Vero
2.
Sensors (Basel) ; 22(7)2022 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-35408257

RESUMO

In this study, we demonstrate that Raman microscopy combined with computational analysis is a useful approach to discriminating accurately between brain tumor bio-specimens and to identifying structural changes in glioblastoma (GBM) bio-signatures after nordihydroguaiaretic acid (NDGA) administration. NDGA phenolic lignan was selected as a potential therapeutic agent because of its reported beneficial effects in alleviating and inhibiting the formation of multi-organ malignant tumors. The current analysis of NDGA's impact on GBM human cells demonstrates a reduction in the quantity of altered protein content and of reactive oxygen species (ROS)-damaged phenylalanine; results that correlate with the ROS scavenger and anti-oxidant properties of NDGA. A novel outcome presented here is the use of phenylalanine as a biomarker for differentiating between samples and assessing drug efficacy. Treatment with a low NDGA dose shows a decline in abnormal lipid-protein metabolism, which is inferred by the formation of lipid droplets and a decrease in altered protein content. A very high dose results in cell structural and membrane damage that favors transformed protein overexpression. The information gained through this work is of substantial value for understanding NDGA's beneficial as well as detrimental bio-effects as a potential therapeutic drug for brain cancer.


Assuntos
Glioblastoma , Antioxidantes , Glioblastoma/tratamento farmacológico , Humanos , Masoprocol/farmacologia , Masoprocol/uso terapêutico , Fenilalanina , Espécies Reativas de Oxigênio
3.
Eur J Pharmacol ; 919: 174777, 2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-35085517

RESUMO

Acute lung injury (ALI) is a continuum of pulmonary changes caused by various lung insults. Previously, we synthesized a series of nordihydroguaiaretic acid analogs; of these, compound 3a exhibited excellent antioxidant capacity in a murine model of middle cerebral artery occlusion. However, it remains unclear whether compound 3a can modulate lipopolysaccharide (LPS)-induced ALI. ALI was induced via tracheal LPS administration, and the pathological changes were assessed. The level of inflammation was verified by immunofluorescence and immunohistochemical analyses. Apoptosis was measured by terminal deoxynucleotidyl transferase dUTP nick-end labeling assays and Western blotting. Changes in the levels of mitogen-activated protein kinase (MAPK)/nuclear factor-κB (NF-κB) pathway proteins were assessed by immunofluorescence assays and Western blotting. In vitro, RAW 264.7 cells were treated with compound 3a prior to LPS challenge, and the intracellular level of inflammation was assessed by quantitative PCR (qPCR). Relevant proteins were detected via immunofluorescence assays and Western blotting. Mice developed extensive lung inflammation by 24 h after LPS challenge. Histological examination revealed signs typical of ALI. Preadministration of compound 3a markedly ameliorated the histopathological changes and reduced fluid exudation into the alveolar space. Compound 3a also greatly reduced the levels of inflammation and apoptosis both in vivo and in vitro. Moreover, compound 3a markedly reduced phosphorylation of MAPK/NF-κB pathway-related proteins and p65 translocation, consistent with the in vitro observations. In summary, administration of compound 3a prior to LPS suppressed ALI via inhibition of the MAPK/NF-κB pathway.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Masoprocol/farmacologia , Substâncias Protetoras/farmacologia , Animais , Apoptose/efeitos dos fármacos , Inflamação/metabolismo , Lipopolissacarídeos , Masculino , Masoprocol/química , Masoprocol/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Substâncias Protetoras/química , Substâncias Protetoras/uso terapêutico , Células RAW 264.7/efeitos dos fármacos
4.
Can J Physiol Pharmacol ; 100(2): 134-141, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34559972

RESUMO

Fingolimod (FTY720) inhibits Ca2+-permeable, Mg2+-sensitive channels called transient receptor potential melastatin 7 (TRPM7), but its effects on Ca2+ paradox (CP) - induced myocardial damage has not been evaluated. We studied the effect of FTY720 on CP-induced myocardial damage and used other TRPM7 channel inhibitors nordihydroguaiaretic acid (NDGA) and Mg2+ to test if any effect of FTY720 was via TRPM7 inhibition. Langendorff-perfused Wistar rat hearts were treated with FTY720 or NDGA and subjected to a CP protocol consisting of Ca2+ depletion followed by Ca2+ repletion. Hearts of rats pre-treated with MgSO4 were also subjected to CP. Hemodynamic parameters were measured using an intraventricular balloon, and myocardial infarct size was quantified using triphenyltetrazolium chloride stain. TRPM7 proteins in ventricular tissue were detected using immunoblot analysis. FTY720, but not NDGA, decreased CP-induced infarct size. Both FTY720 and NDGA minimized the CP-induced elevation of left ventricular end-diastolic pressure, but only FTY720 ultimately improved ventricular developed pressure. Mg2+ pre-treatment had no effect on CP-induced infarct size, nor hemodynamic parameters during CP, nor the level of TRPM7 protein expression in ventricular tissue. Overall, FTY720 attenuated CP-induced myocardial damage, with potential therapeutic implications on Ca2+-mediated cardiotoxicity; however, the cardioprotective mechanism of FTY720 seems to be unrelated to TRPM7 channel modulation.


Assuntos
Cálcio/efeitos adversos , Cálcio/metabolismo , Cardiotônicos , Cloridrato de Fingolimode/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Animais , Cloridrato de Fingolimode/uso terapêutico , Técnicas In Vitro , Magnésio/metabolismo , Masculino , Masoprocol/farmacologia , Masoprocol/uso terapêutico , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Ratos Wistar , Canais de Cátion TRPM/antagonistas & inibidores , Canais de Cátion TRPM/metabolismo
5.
Molecules ; 25(1)2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31906391

RESUMO

Lignans are widely produced by various plant species; they are a class of natural products that share structural similarity. They usually contain a core scaffold that is formed by two or more phenylpropanoid units. Lignans possess diverse pharmacological properties, including their antiviral activities that have been reported in recent years. This review discusses the distribution of lignans in nature according to their structural classification, and it provides a comprehensive summary of their antiviral activities. Among them, two types of antiviral lignans-podophyllotoxin and bicyclol, which are used to treat venereal warts and chronic hepatitis B (CHB) in clinical, serve as examples of using lignans for antivirals-are discussed in some detail. Prospects of lignans in antiviral drug discovery are also discussed.


Assuntos
Antivirais/farmacologia , Antivirais/uso terapêutico , Lignanas/química , Plantas/química , Podofilotoxina/química , Antivirais/química , Benzodioxóis/química , Benzodioxóis/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/uso terapêutico , Desenvolvimento de Medicamentos , Furanos/química , Furanos/farmacologia , Lignanas/farmacologia , Masoprocol/análogos & derivados , Masoprocol/química , Masoprocol/farmacologia , Masoprocol/uso terapêutico , Podofilotoxina/farmacologia , Podofilotoxina/uso terapêutico
6.
Curr Cancer Drug Targets ; 20(2): 86-103, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31642411

RESUMO

Nordihydroguaiaretic acid (NDGA) is a plant lignan obtained from creosote bush, Larrea tridentata and is known to possess antioxidant, anticancer activities and is used in traditional medicine in North America and Mexico. However, its prolonged consumption leads to liver damage and kidney dysfunction. Despite its toxicity and side effects, there is little awareness to forbid its consumption and its use in the treatment of medical ailments has continued over the years. Several reports discuss its therapeutic efficiency and its medical applications have tremendously been on the rise to date. There has been a recent surge of interest in the chemical synthesis of NDGA derivatives for therapeutic applications. NDGA derivatives have been developed as better alternatives to NDGA. Although several NDGA derivatives have been chemically synthesized as evidenced by recent literature, there is a paucity of information on their therapeutic efficacies. This review is to highlight the medicinal applications of NDGA, its toxicity evaluations and discuss the chemical derivatives of NDGA synthesized and studied so far and suggest to continue research interests in the development of NDGA analogs for therapeutic applications. We suggest that NDGA derivatives should be investigated more in terms of chemical synthesis with preferred conformational structures and exploit their biological potentials with future insights to explore in this direction to design and develop structurally modified NDGA derivatives for potential pharmacological properties.


Assuntos
Masoprocol/farmacologia , Animais , Humanos , Interações Hidrofóbicas e Hidrofílicas , Masoprocol/síntese química , Masoprocol/uso terapêutico , Masoprocol/toxicidade , Conformação Molecular
7.
Lipids Health Dis ; 18(1): 43, 2019 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-30736810

RESUMO

BACKGROUND: Diabetic encephalopathy is a chronic complications of diabetes mellitus that affects the central nervous system. We evaluated the effect of ω3 and ω6 polyunsaturated fatty acids (PUFAs) supplementation plus the antioxidant agent nordihydroguaiaretic acid (NDGA) on the etiopathology of diabetic encephalopathy in eSS rats, a spontaneous model of type 2 diabetes. METHODS: One hundred twenty spontaneous diabetic eSS male rats and 38 non-diabetic Wistar, used as healthy control, received monthly by intraperitoneal route, ω3 or ω6 PUFA (6.25 mg/kg) alone or plus NDGA (1.19 mg/kg) for 12 months. Diabetic rats had a worse performance in behavioural Hole-Board test. Histopathological analysis confirmed lesions in diabetic rats brain tissues. We also detected low expression of synaptophysin, a protein linked to release of neurotransmitters, by immunohistochemically techniques in eSS rats brain. Biochemical and histopathological studies of brain were performed at 12th month. Biochemical analysis showed altered parameters related to metabolism. High levels of markers of oxidative stress and inflammation were detected in plasma and brain tissues. Data were analysed by ANOVA test and paired t test was used by comparison of measurements of the same parameter at different times. RESULTS: The data obtained in this work showed that behavioural, biochemical and morphological alterations observed in eSS rats are compatible with previously reported indices in diabetic encephalopathy and are associated with increased glucolipotoxicity, chronic low-grade inflammation and oxidative stress burden. Experimental treatments assayed modulated the values of studied parameters. CONCLUSIONS: The treatments tested with ω3 or ω3 plus NDGA showed improvement in the values of the studied parameters in eSS diabetic rats. These observations may form the basis to help in prevent and manage the diabetic encephalopathy.


Assuntos
Encefalopatias/etiologia , Neuropatias Diabéticas/prevenção & controle , Ácidos Graxos Ômega-3/uso terapêutico , Masoprocol/uso terapêutico , Animais , Glicemia/análise , Encéfalo/patologia , Encefalopatias/patologia , Encefalopatias/prevenção & controle , Neuropatias Diabéticas/patologia , Suplementos Nutricionais , Modelos Animais de Doenças , Teste de Tolerância a Glucose , Hipocampo/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar
9.
Respir Physiol Neurobiol ; 234: 26-31, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27595978

RESUMO

Therapeutic natural products and medicinal herbs has gained popularity. The anti-antigenic action of the plant alkaloid nordihydroguaiaretic acid (NDGA) was studied in ovalbumin (OA)-sensitized guinea pigs. In one series of experiments conscious, non-sedated guinea pigs were challenged with OA aerosol. Specific airway resistance (SRAW) was monitored using a two-chambered whole-body plethysmograph. OA aerosol increased SRAW above that produced by vehicle administration. Prior NDGA administration by a 1min 0.9% aerosol (w/vol) attenuated the increase in SRAW resulting from OA challenge. In the anesthetized guinea pig pretreated with indomethacin, pyrilamine and propranolol, intravenous OA injection increased intra-tracheal pressure above vehicle injection. Intravenous NDGA administration (5mg/kg) reduced the intra-tracheal pressure increases. In a third series of experiments plasma leukotriene C4 was measured by radio-immunoassay in 3 groups challenged with OA aerosol: vehicle-treated OA-sensitized, OA-sensitized receiving NDGA and vehicle treated guinea pigs. NDGA pretreatment reduced plasma LTC4 in response to OA challenge in OA sensitized guinea pigs. This study demonstrates that NDGA is an effective antigenic agent when given by aerosol or intravenous injection in either conscious or anesthetized guinea pigs, respectively. The mechanism of action of NDGA is presumed primarily be due to the blockage of 5-lipoxygenase and therefore the synthesis of leukotrienes.


Assuntos
Anafilaxia/tratamento farmacológico , Inibidores de Lipoxigenase/uso terapêutico , Masoprocol/uso terapêutico , Aerossóis , Resistência das Vias Respiratórias/efeitos dos fármacos , Análise de Variância , Anafilaxia/induzido quimicamente , Animais , Broncoconstrição/efeitos dos fármacos , Modelos Animais de Doenças , Esquema de Medicação , Cobaias , Leucotrieno C4/metabolismo , Masculino , Ovalbumina/toxicidade , Pletismografia , Análise de Regressão
10.
J Drug Target ; 24(8): 703-8, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26811100

RESUMO

BACKGROUND: Synthesized dl-Nordihydroguaiaretic acid (dl-NGDA or "Nordy") can inhibit the growth of malignant human tumors, especially the tumor angiogenesis. However, its liposoluble nature limits its in vivo efficacy in the hydrosoluble circulation of human. PURPOSE: We tried to use the ultrasonic microbubble as the carrier and the ultrasound-induced destruction for the targeted release of Nordy and evaluate its in vitro and in vivo anti-tumor effect. METHODS: Nordy-loaded lipid microbubbles were prepared by mechanical vibration. Effects of ultrasound-induced Nordy-loaded microbubbles destruction on proliferation of human umbilical vein endothelial cells (HUVECs), tumor derived endothelial cells (Td-ECs), and rabbit transplanted VX2 tumor models were evaluated. RESULTS: The ultrasound-induced Nordy-loaded microbubbles destruction inhibited the proliferations of HUVECs and Td-ECs in vitro, and inhibited the tumor growth and the microvasculature in vivo. Its efficacy was higher than those of Nordy used only and Nordy with ultrasound exposure. CONCLUSION: Ultrasonic microbubbles can be used as the carrier of Nordy and achieve its targeted release with improved anti-tumor efficacy in the condition of ultrasound-induced microbubbles destruction.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Masoprocol/administração & dosagem , Microbolhas , Fonoforese/métodos , Ondas Ultrassônicas , Inibidores da Angiogênese/uso terapêutico , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Masoprocol/uso terapêutico , Neoplasias Experimentais/irrigação sanguínea , Neoplasias Experimentais/tratamento farmacológico , Coelhos
11.
Int Immunopharmacol ; 28(1): 634-42, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26247680

RESUMO

Cisplatin is a widely used antineoplastic drug, but its clinical usefulness is limited due to dose dependent nephrotoxicity. Nordihydroguaiaretic acid (NDGA) is a natural compound with broad pharmacological properties like antioxidant, anti-inflammatory and anticancer activity. The present study was undertaken to evaluate the possible beneficial effects of NDGA on cisplatin induced nephrotoxicity as well as its anticancer activity in rats bearing DMBA induced mammary tumors. The effect of NDGA on cisplatin induced nephrotoxicity was evaluated by checking serum nephrotoxicity markers, antioxidant enzymes and inflammatory markers level and kidney histopathology. NDGA induced amelioration of cisplatin nephrotoxicity was clearly visible from significant reductions in serum blood urea nitrogen (86.51 g/dl) and creatinine (5.30 g/dl) levels and significant improvement in body weight change (-10.34 g) and kidney weight (728 mg/kg). The protective effect of NDGA against cisplatin induced nephrotoxicity in the rats was further confirmed by significant restoration of antioxidant enzymes like SOD (86.28% inhibition), inflammatory markers like TNF-α (34.6 pg/ml) and histopathological examination. Moreover, our results showed that NDGA potentiated anti-breast cancer activity of cisplatin through an increment in the expression of antioxidant enzymes like SOD (85.35% inhibition) in breast cancer tissue. These results indicated that NDGA potentiated the anti-breast cancer activity of cisplatin, which was clearly evident from the tumor volume and % tumor inhibition in breast cancer rats. The current study demonstrated that NDGA may modify the therapeutic effect of cisplatin in DMBA induced breast cancer in female Sprague-Dawley rats.


Assuntos
Antineoplásicos/efeitos adversos , Antioxidantes/uso terapêutico , Cisplatino/efeitos adversos , Nefropatias/prevenção & controle , Neoplasias Mamárias Experimentais/tratamento farmacológico , Masoprocol/uso terapêutico , 9,10-Dimetil-1,2-benzantraceno/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Antioxidantes/administração & dosagem , Nitrogênio da Ureia Sanguínea , Catalase/metabolismo , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Creatinina/sangue , Feminino , Rim/efeitos dos fármacos , Rim/patologia , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Nefropatias/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/patologia , Masoprocol/administração & dosagem , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo , Carga Tumoral/efeitos dos fármacos
12.
Am J Physiol Lung Cell Mol Physiol ; 309(5): L449-62, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26092993

RESUMO

Pulmonary arterial hypertension (PAH) is a disease characterized by thickening of pulmonary artery walls, elevated pulmonary vascular resistance, pulmonary vascular thrombotic lesions, and right heart failure. Recent studies suggest that 15-lipoxygenase (15-LO)/15-hydroxyeicosatetraenoic acid (15-HETE) play an important role in PAH, acting on arterial walls. Here, we show evidence for the action of the 15-LO/15-HETE signaling in the pulmonary vascular thrombotic lesions in the experimental PAH models. Platelet deposition was augmented in rats exposed to hypoxia and Sugen 5416, which were both prevented by nordihydroguaiaretic acid (NDGA), a 15-LO inhibitor. Chronic hypoxic resulted in the platelet deposition specifically in pulmonary vasculature, which was reversed by 15-LO inhibitor. The 15-LO pathway mediated in the endothelial dysfunction induced by hypoxia in vivo. Meanwhile, 15-HETE positively regulated the generation of IL-6 and monocyte chemoattractant protein-1 (MCP-1). The coagulation and platelet activation induced by hypoxia were reversed by 15-LO inhibitor NDGA or the MCP-1 inhibitor synthesis inhibitor bindarit in rats. The 15-LO/15-HETE signaling promoted the coagulation and platelet activation, which was suppressed by MCP-1 inhibition. These results therefore suggest that 15-LO/15-HETE signaling plays a role in platelet activation and pulmonary vascular thrombosis in PAH, involving MCP-1.


Assuntos
Araquidonato 15-Lipoxigenase/metabolismo , Ácidos Hidroxieicosatetraenoicos/metabolismo , Hipertensão Pulmonar/patologia , Trombose/metabolismo , Resistência Vascular/fisiologia , Animais , Araquidonato 15-Lipoxigenase/genética , Plaquetas/patologia , Células Cultivadas , Quimiocina CCL2/antagonistas & inibidores , Citocinas/metabolismo , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Hipóxia/sangue , Hipóxia/patologia , Indazóis/uso terapêutico , Inibidores de Lipoxigenase/uso terapêutico , Masculino , Masoprocol/uso terapêutico , Ativação Plaquetária/efeitos dos fármacos , Propionatos/uso terapêutico , Artéria Pulmonar/patologia , Interferência de RNA , RNA Interferente Pequeno , Distribuição Aleatória , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Trombose/tratamento farmacológico , Trombose/etiologia , Resistência Vascular/efeitos dos fármacos
13.
Chem Biol Interact ; 233: 106-14, 2015 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-25770929

RESUMO

Drug and chemically-induced immunosuppression has been implicated as a confounding factor for cancer development. Management of cancer in such situation is often a challenging task. We tested the efficacy of nordihydroguiaretic acid (NDGA) against immunosuppressant tacrolimus-induced augmentation of mouse skin tumorigenesis. It was observed that topical administration of tacrolimus significantly accelerated the tumor promotion events in dimethylbenz(a)anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA) promoted two-stage mouse skin carcinogenesis, which were accompanied by reduced CD4(+)/CD8(+) ratio of lymph nodes and serum IL-2 level. NDGA pre-treatment before each TPA application reduced the tumor incidence, its multiplicity and volume together with improvement in histopathological alterations and decrease in proliferating cell nuclear antigen (PCNA) labeling index (LI). However, NDGA had no significant influence on the immunosuppressive effect of tacrolimus. The present study demonstrates chemopreventive effect of NDGA in normal as well as in the condition of immunosuppression. Thus, NDGA has the potential to inhibit or delay the onset of tumor development during immunosuppressive regimen.


Assuntos
Anticarcinógenos/uso terapêutico , Imunossupressores/efeitos adversos , Masoprocol/uso terapêutico , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/prevenção & controle , Pele/efeitos dos fármacos , Tacrolimo/efeitos adversos , Animais , Carcinogênese/induzido quimicamente , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Feminino , Camundongos , Pele/patologia , Neoplasias Cutâneas/patologia
14.
Phytomedicine ; 20(10): 775-9, 2013 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-23643094

RESUMO

It has been shown that the pretreatment with nordihydroguaiaretic acid (NDGA), a lignan with direct and indirect antioxidant properties, protects against the ischemia-reperfusion (I/R)-induced renal oxidant damage. Although it has been shown that NDGA induces Nrf2 nuclear translocation in renal epithelial LLC-PK1 cells in culture, it is unknown if NDGA may induce Nrf2 translocation in vivo. In this work was explored if NDGA is able to induce in vivo Nrf2 nuclear translocation in kidneys of rats submitted to uni-nephrectomy (U-NX) or I/R injury. Four groups of male Wistar rats were used: U-NX, NDGA, I/R, and I/R+NDGA. NDGA was injected i.p. (10mg/kg/day) starting 48 h before I/R. Kidney samples were obtained at 3 h of reperfusion after to measure Nrf2 translocation. Additional groups of rats were studied at 24 h of reperfusion to measure histological damage and apoptosis. NDGA was able to induce Nrf2 translocation in vivo in kidneys of rats submitted to both U-NX and I/R injury and to protect against renal histological damage and apoptosis. It is concluded that the pretreatment of NDGA is able to induce in vivo nuclear Nrf2 translocation in kidney of rats suggesting that this may be involved in the renoprotection against I/R.


Assuntos
Injúria Renal Aguda/prevenção & controle , Apoptose/efeitos dos fármacos , Masoprocol/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Sinais de Localização Nuclear/biossíntese , Traumatismo por Reperfusão/prevenção & controle , Injúria Renal Aguda/patologia , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Masculino , Masoprocol/uso terapêutico , Ratos , Ratos Wistar , Traumatismo por Reperfusão/patologia
15.
Brain Res ; 1516: 83-92, 2013 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-23603407

RESUMO

After spinal cord injury (SCI), a series of complex pathophysiological processes follows the initial injury. Because inflammation plays a key role in this secondary pathology damage, anti-inflammatory drug treatment may reduce secondary damage and protect neurons after SCI. Though nordihydroguaiaretic acid (NDGA) can inhibit inflammatory responses, its potential roles in neuroprotection and anti- inflammation in an SCI model have not been studied. In this study, we investigated the anti-inflammatory effects of NDGA in SCI. First, histopathological alterations were evaluated with hematoxylin/eosin (HE) and Nissl staining, showing an increased number of neurons after NDGA administration. Additionally, the extent of secondary damage was assessed by TUNEL assay and measurement of astrocyte proliferation. The data showed that the numbers of apoptotic cells and the proliferative extent of astrocytes were significantly decreased by the use of NDGA. The anti-inflammatory effect of NDGA was evaluated by measuring myeloperoxidase (MPO) levels as an indicator of neutrophil activity, macrophage/microglia numbers, and expression of inflammatory cytokines including IL-1ß and TNF-α. NDGA treatment significantly decreased the MPO level and the number of macrophages/microglia. In addition, NDGA also suppressed the expression of IL-1ß and TNF-α after SCI. These data suggest that anti-inflammatory action by NDGA can reduce secondary damage after SCI.


Assuntos
Anti-Inflamatórios/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/etiologia , Masoprocol/uso terapêutico , Traumatismos da Medula Espinal/complicações , Animais , Astrócitos/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Marcação In Situ das Extremidades Cortadas , Inflamação/patologia , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Peroxidase/metabolismo , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
16.
Invest New Drugs ; 31(4): 858-70, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23299390

RESUMO

Glioblastoma (GBM), one of the most malignant human neoplasias, responds poorly to current treatment modalities, with temozolomide (TMZ) being the drug most frequently used for its treatment. Tetra-O-methyl Nordihydroguaiaretic Acid (M4N) is a global transcriptional repressor of genes dependent on the Sp1 transcription factor, such as Survivin and Cdk1. In the present study we evaluated the gene expression of Survivin, its spliced variants and Cdk1 in GBM samples and cell lines. Moreover, we investigated the effects of M4N combined or not with TMZ and/or radiation on GBM primary cultures and cell lines. qRT-PCR assays were performed to determine the Survivin-spliced variants and Cdk1 gene mRNA expression in GBM tumor samples and cell lines. Cell proliferation was measured by XTT assay and cell cycle and apoptosis were determined by flow cytometry. Drug combination analyses using different schedules of administration (simultaneous and sequential) were performed on GBM cell lines and primary cultures based on the Chou-Talalay method. For clonogenic survival, doses of 2, 4, and 6 Gy of gamma radiation. were used. All Survivin-spliced variants and the Cdk1 gene were expressed in GBM samples (n = 16) and cell lines (n = 6), except the Survivin-2B variant that was only expressed in GBM cell lines. M4N treatment down regulated the expression of Cdk1, Survivin and the Survivin-ΔEx3 variant, while the Survivin-2B variant was up-regulated. M4N decreased the cell proliferation separately and synergistically with TMZ, and enhanced the effects of radiation, mainly when associated with TMZ. M4N also induced apoptotic cell death, decreased the mitotic index and arrested the cell cycle mainly in the G2/M phase. Our results suggest a potential clinical application of M4N in combination with TMZ and radiation for GB treatment.


Assuntos
Apoptose/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Proteínas Inibidoras de Apoptose/genética , Masoprocol/análogos & derivados , Fator de Transcrição Sp1/metabolismo , Transcrição Gênica/efeitos dos fármacos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos da radiação , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/radioterapia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Dacarbazina/análogos & derivados , Dacarbazina/farmacologia , Dacarbazina/uso terapêutico , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Concentração Inibidora 50 , Masculino , Masoprocol/farmacologia , Masoprocol/uso terapêutico , Índice Mitótico , Splicing de RNA/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Radiossensibilizantes/farmacologia , Radiossensibilizantes/uso terapêutico , Survivina , Temozolomida
17.
Am J Physiol Gastrointest Liver Physiol ; 304(1): G72-86, 2013 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-23104557

RESUMO

Creosote bush-derived nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, possesses antioxidant properties and functions as a potent antihyperlipidemic agent in rodent models. Here, we examined the effect of chronic NDGA treatment of ob/ob mice on plasma dyslipidemia, hepatic steatosis, and changes in hepatic gene expression. Feeding ob/ob mice a chow diet supplemented with either low (0.83 g/kg diet) or high-dose (2.5 g/kg diet) NDGA for 16 wk significantly improved plasma triglyceride (TG), inflammatory chemokine levels, hyperinsulinemia, insulin sensitivity, and glucose intolerance. NDGA treatment caused a marked reduction in liver weight and TG content, while enhancing rates of fatty acid oxidation. Microarray analysis of hepatic gene expression demonstrated that NDGA treatment altered genes for lipid metabolism, with genes involved in fatty acid catabolism most significantly increased. NDGA upregulated the mRNA and nuclear protein levels of peroxisome proliferator-activated receptor α (PPARα), and the activated (phosphorylated) form of AMP-activated kinase. NDGA increased PPARα promoter activity in AML12 hepatocytes and also prevented the fatty acid suppression of PPARα expression. In contrast, PPARα siRNA abrogated the stimulatory effect of NDGA on fatty acid catabolism. Likewise, no stimulatory effect of NDGA on hepatic fatty acid oxidation was observed in the livers of PPARα-deficient mice, but the ability of NDGA to reverse fatty liver conditions was unaffected. In conclusion, the beneficial actions of NDGA on dyslipidemia and hepatic steatosis in ob/ob mice are exerted primarily through enhanced fatty acid oxidation via PPARα-dependent pathways. However, PPARα-independent pathways also contribute to NDGA's action to ameliorate hepatic steatosis.


Assuntos
Hipolipemiantes/uso terapêutico , Transtornos do Metabolismo dos Lipídeos/tratamento farmacológico , Inibidores de Lipoxigenase/uso terapêutico , Fígado/metabolismo , Masoprocol/uso terapêutico , PPAR alfa/fisiologia , Adipocinas/metabolismo , Animais , Dieta , Estresse do Retículo Endoplasmático/fisiologia , Endorribonucleases/metabolismo , Ácidos Graxos/metabolismo , Fígado Gorduroso/tratamento farmacológico , Teste de Tolerância a Glucose , Leptina/deficiência , Metabolismo dos Lipídeos/genética , Lipoproteínas VLDL/metabolismo , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Análise em Microsséries , Família Multigênica , Proteínas Serina-Treonina Quinases/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/efeitos dos fármacos , Triglicerídeos/biossíntese
18.
Amyloid ; 19 Suppl 1: 39-42, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22620965

RESUMO

Several natural polyphenols have been reported to act on different amyloidogenic proteins inhibiting amyloid formation therefore we decided to test their effect on transthyretin (TTR) amyloid formation. We found that epigallocatechin-3-gallate (EGCG), curcumin and nordihydroguaiaretic acid (NDGA) bind to TTR and modulate its amyloidogenicity, in vitro, although through different mechanisms of action. Based on these in vitro studies, we decided to test EGCG in vivo using mice models for familial amyloidotic polyneuropathy (FAP). Therefore, we performed a subchronic administration of EGCG to mice, for 6 weeks. Next, we assessed the effects of EGCG treatment by immunohistochemistry (IHC) and western blot analysis of mice tissues. The results obtained demonstrate that EGCG inhibits TTR aggregates deposition in about 50% along the gastrointestinal (GI) tract and peripheral nervous system (PNS) and lowered the levels of several FAP associated biomarkers. Furthermore, treatment of old FAP mice with EGCG resulted not only in the decrease of nonfibrillar TTR deposition but also in the disaggregation of congophilic amyloid deposits. The dual effect as inhibitor of aggregation and as disruptor of amyloid together with its low toxicity indicates that EGCG presents a therapeutic application in FAP.


Assuntos
Neuropatias Amiloides Familiares/tratamento farmacológico , Neuropatias Amiloides Familiares/metabolismo , Polifenóis/uso terapêutico , Pré-Albumina/metabolismo , Animais , Western Blotting , Catequina/análogos & derivados , Catequina/uso terapêutico , Curcumina/uso terapêutico , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/metabolismo , Imuno-Histoquímica , Masoprocol/uso terapêutico , Camundongos , Sistema Nervoso Periférico/efeitos dos fármacos , Sistema Nervoso Periférico/metabolismo
19.
J Diet Suppl ; 9(1): 1-8, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22432798

RESUMO

Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons and the aggression of alpha Synuclein (αS) in the brain. Drosophila mutants and transgenes have provided a platform to understand the mechanistic insight associated with the degenerative diseases. A number of polyphenols have been reported to inhibit the αS aggregation resulting in the possible prevention of PD. The involvement of free radicals in mediating the neuronal death in PD has also been implicated. In the present study, the effect of Nordihydroguaiaretic acid (NDGA) was studied on the climbing ability of the PD model Drosophila expressing normal human alpha synuclein (h-αS) in the neurons. These flies exhibit locomotor dysfunction as the age progresses. NDGA at final concentration of 0.01, 0.1, 0.5, and 1µl/ml was supplemented with the diet and the flies were allowed to feed for the 24 days. NDGA at 0.01 µl/ml did not showed any significant delay in the loss of climbing ability of PD model flies. However, NDGA doses at 0.1, 0.5, and 1.0 µl/ml showed a dose dependent significant (p < .05) delay in the loss of climbing ability of PD model flies as compared to the untreated PD flies. The results suggest that the NDGA is potent in delaying the climbing disability of PD model flies and also supports the utility of this model in studying PD symptoms.


Assuntos
Suplementos Nutricionais , Locomoção/efeitos dos fármacos , Masoprocol/uso terapêutico , Doença de Parkinson/prevenção & controle , Fitoterapia , Extratos Vegetais/uso terapêutico , alfa-Sinucleína/antagonistas & inibidores , Animais , Animais Geneticamente Modificados , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Relação Dose-Resposta a Droga , Proteínas de Drosophila/antagonistas & inibidores , Drosophila melanogaster , Radicais Livres/metabolismo , Humanos , Masoprocol/farmacologia , Mutação , Doença de Parkinson/metabolismo , Extratos Vegetais/farmacologia
20.
Brain Res ; 1445: 73-81, 2012 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-22325100

RESUMO

Nordihydroguaiaretic acid (NDGA) is a powerful antioxidant and/or lipoxygenase (LOX) inhibitor which is isolated from Larrea tridentate. NDGA has been shown to have neuroprotective effects both in vitro and in vivo experiments. However, little is known regarding NDGA's protective mechanism in ischemia/reperfusion (I/R) injury. We therefore investigated the potential protective effects of NDGA and explored the underlying mechanisms. Oxygen-glucose deprivation (OGD) was performed in cultured rat cortical neurons for 60min. The effect of NDGA on OGD induced cell death and apoptosis was examined at 24h after reperfusion. Western blot was used to analyze the expression of p-c-jun and p-JNK. Exogenous 5-, 12-, 15-hydroxyeicosatetraenoic acid (HETE) was added respectively to the cells to investigate the contribution of the products of LOX to the c-Jun N-terminal protein kinase (JNK) pathway. Rats were injected intraperitoneally with NDGA before being subjected to middle cerebral artery occlusion (MCAO). At 24h after reperfusion, neurological deficit, brain infarct volume and the expression of p-c-jun and p-JNK were measured. The results showed that NDGA increased cell viability and inhibited apoptosis after OGD in neurons. NDGA suppressed the expression of p-c-jun and p-JNK in cortical neurons, whereas exogenous 12-, 15-HETE attenuated this effect. NDGA improved neurological deficit, reduced infarct volumes, and downregulated the overexpression of p-c-jun and p-JNK after MCAO and reperfusion. In conclusion, these results suggest that NDGA's protective effect against I/R injury is mediated by the suppression of JNK pathway. This effect is probably due to its 12/15-LOX inhibitor property.


Assuntos
Infarto da Artéria Cerebral Média , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masoprocol/uso terapêutico , Doenças do Sistema Nervoso/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , Animais , Infarto Encefálico/etiologia , Infarto Encefálico/prevenção & controle , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Córtex Cerebral/citologia , Modelos Animais de Doenças , Embrião de Mamíferos , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/deficiência , Ácidos Hidroxieicosatetraenoicos/farmacologia , Hipóxia/tratamento farmacológico , Marcação In Situ das Extremidades Cortadas , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/metabolismo , MAP Quinase Quinase 4/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Doenças do Sistema Nervoso/etiologia , Exame Neurológico , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Proteínas Proto-Oncogênicas c-jun/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo
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