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1.
J Ethnopharmacol ; 296: 115429, 2022 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-35659916

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Larrea divaricata Cav. (Zygophyllaceae) (jarilla) is a native plant of South America widely distributed across Argentina and used in popular medicine to treat diabetes and hypercholesterolemia by the Diaguita-Calchaquí, Amaichas, and Quilmes indigenous communities and by non-indigenous population (criollos) of Calamuchita, in the province of Córdoba, Argentina. L. divaricata has also proved to have anti-inflammatory properties. However, the antidiabetic effects and the nutritional properties of the aqueous extract (AE) of this plant remain to be scientifically determined. AIM OF THE STUDY: The aim of the present work was to evaluate the capacity of an aqueous extract of L. divaricata (AE) and its main compound nordihydroguaiaretic acid (NDGA) to modulate the glucose, cholesterol, triglycerides and oxidative stress levels in STZ-induced diabetes in mice. The general objective of the present work was to search for extracts that can be used as adjuvant therapy in for diabetes. The suitability of the extract to be used as a dietary supplement was also assessed by determining the proximate amount of fibre, lipids, proteins, and minerals. MATERIALS AND METHODS: Diabetes was induced in mice by administration of streptozotocin (STZ). AE and NDGA were administered by the oral route. The animals' glycaemia was periodically monitored in blood samples obtained from the tail vein. The glucose dehydrogenase method was used. The effect of the AE on cholesterol, triglycerides, oxidative stress, lipid peroxidation and reduced glutathione (GSH) levels were determined in plasma samples by spectrophotometric assays. RESULTS: In STZ-treated mice, AE significantly decreased glucose (33%, ****p < 0.0001) and cholesterol levels (32%, **p < 0.01). AE and NDGA decreased lipid peroxidation (30% and 38%, respectively, ****p < 0.0001), and increased GSH levels (20%, **p < 0.01). The effects of AE on glucose and lipid levels could not be ascribed to NDGA; however, this compound was involved in the extract antioxidant effects. The overall effects of AE were probably related to its antioxidant activity and to the anti-hyperglycaemic effect mainly mediated by flavonoids, fibre (carbohydrates) and mineral elements such as potassium, calcium, magnesium, and zinc. The AE protein content also confers the extract nutritional properties. CONCLUSIONS: These results support the hypothesis that AE could be used as a therapeutic adjuvant or as a nutritional supplement to control glucose levels and lipid metabolism in metabolic syndrome-associated diseases. Moreover, these results scientifically reinforce the popular use of the plant.


Assuntos
Diabetes Mellitus Experimental , Larrea , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Glucose , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Masoprocol/farmacologia , Camundongos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Estreptozocina , Triglicerídeos , Água
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.
Analyst ; 147(4): 661-670, 2022 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-35060574

RESUMO

The concept of a reversible polymer displacement sensor mechanism for electrochemical glucose monitoring is demonstrated. A pyrene-derivatised boronic acid chemo-receptor for glucose is adsorbed onto a graphene foam electrode. Spontaneous oxidative polymerisation of nordihydroguaiaretic acid (NHG) onto the graphene foam electrode leads to a redox active film (poly-NHG) covalently attached to the boronic acid receptors. Oxidation of poly-NHG frees the boronic acid receptors to interact with glucose from the solution phase, which is detected due to competitive binding when reduced poly-NHG re-binds to the boronic acid functional groups. The sensor shows the anticipated boronic acid selectivity of fructose > glucose. The ratio of charges under the voltammetric peaks for poly-NHG unbound and bound is employed for glucose sensing with an approximately linear analytical range from 1 to 50 mM glucose in aqueous pH 7 buffer. The new methodology is shown to give apparent saccharide - boronic acid binding constants and to work in human serum. Therefore, in the future it could be developed further for glucose monitoring.


Assuntos
Grafite , Glicemia , Automonitorização da Glicemia , Ácidos Borônicos , Glucose , Humanos , Masoprocol , Polímeros
4.
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
5.
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
6.
Braz. J. Pharm. Sci. (Online) ; 58: e19517, 2022. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1383995

RESUMO

Nordihydroguaiaretic acid (NDGA) is a natural product obtained by the alkaline extraction of dried plants of Larrea tridentata species. Due to the biological properties presented, such as antioxidant, anti-inflammatory, antiviral and cytotoxic capacity, this compound is being increasingly studied. In this review, it was evaluated the benefits of NDGA against different animal models. Besides that, it was found that this compound has antitumor activity similar to its synthetic derivative terameprocol in prostate tumors. The hypoglycemic effect may be evidenced by the inhibition of sugar uptake by NDGA; in obesity, studies have observed that NDGA presented a positive regulatory effect for Peroxisome proliferator-activated receptors (PPAR-α) involved in the oxidation of hepatic fatty acids and reduced the expression of lipogenic genes. Regarding its antioxidant potential, its mechanism is related to the ability to in vitro scavenging reactive substances. Although there are several studies demonstrating the benefits of using NDGA, there are also reports of its toxicity, mainly of liver damage and nephrotoxicity


Assuntos
Masoprocol/análise , Fenômenos Químicos , Antivirais/farmacologia , Plantas/classificação , Produtos Biológicos/análise , Técnicas In Vitro/métodos , Modelos Animais , Toxicidade , Hipoglicemiantes/farmacologia , Neoplasias , Antioxidantes/farmacologia
7.
J Pharm Biomed Anal ; 209: 114525, 2022 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-34906921

RESUMO

The global transcription inhibitor terameprocol is being evaluated clinically as an oral formulation to treat high-grade glioma. A sensitive, reliable method was developed to quantitate terameprocol using LC-MS/MS to perform detailed pharmacokinetic studies. Sample preparation involved protein precipitation using acetonitrile. Separation of terameprocol and the internal standard, Sorafenib-methyl-d3, was achieved with a Zorbax XDB C18 column (2.1 × 50 mm, 3.5 µm) and gradient elution over a 2-minute total analytical run time. A SCIEX 4500 or SCIEX 5500 triple quadrupole mass spectrometer operated in positive electrospray ionization mode was used for terameprocol detection. The assay range of 5-1000 ng/mL was demonstrated to be accurate (92.7-107.4%) and precise (CV ≤ 11.3%). A sample diluted 1:10 (v/v) was accurately quantitated. Terameprocol in plasma has been proven stable for at least 20 months when stored at -70 °C. The method was applied to the measurement of total plasma concentrations of terameprocol in a patient with a high-grade glioma receiving a 300 mg oral dose.


Assuntos
Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Humanos , Masoprocol/análogos & derivados , Reprodutibilidade dos Testes
8.
Molecules ; 26(23)2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34885681

RESUMO

In this study, the antioxidant and antiradical properties of some phyto lignans (nordihydroguaiaretic acid, secoisolariciresinol, secoisolariciresinol diglycoside, and α-(-)-conidendrin) and mammalian lignans (enterodiol and enterolactone) were examined by different antioxidant assays. For this purpose, radical scavenging activities of phyto and mammalian lignans were realized by 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) radical (ABTS•+) scavenging assay and 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) scavenging assay. Additionally, the reducing ability of phyto and mammalian lignans were evaluated by cupric ions (Cu2+) reducing (CUPRAC) ability, and ferric ions (Fe3+) and [Fe3+-(TPTZ)2]3+ complex reducing (FRAP) abilities. Also, half maximal inhibitory concentration (IC50) values were determined and reported for DPPH• and ABTS•+ scavenging influences of all of the lignan molecules. The absorbances of the lignans were found in the range of 0.150-2.320 for Fe3+ reducing, in the range of 0.040-2.090 for Cu2+ reducing, and in the range of 0.360-1.810 for the FRAP assay. On the other hand, the IC50 values of phyto and mammalian lignans were determined in the ranges of 6.601-932.167 µg/mL for DPPH• scavenging and 13.007-27.829 µg/mL for ABTS•+ scavenging. In all of the used bioanalytical methods, phyto lignans, as secondary metabolites in plants, demonstrated considerably higher antioxidant activity compared to that of mammalian lignans. In addition, it was observed that enterodiol and enterolactone exhibited relatively weaker antioxidant activities when compared to phyto lignans or standard antioxidants, including butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), Trolox, and α-tocopherol.


Assuntos
Antioxidantes/química , Sequestradores de Radicais Livres/química , Lignanas/química , Peroxidação de Lipídeos/efeitos dos fármacos , Compostos Fitoquímicos/química , Animais , Antioxidantes/farmacologia , Benzotiazóis/química , Benzotiazóis/farmacologia , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacologia , Hidroxianisol Butilado/química , Hidroxitolueno Butilado/química , Butileno Glicóis/química , Cromanos/química , Cobre/química , Sequestradores de Radicais Livres/farmacologia , Íons/química , Ferro/química , Lignanas/farmacologia , Mamíferos , Masoprocol/química , Compostos Fitoquímicos/farmacologia , Picratos/síntese química , Picratos/farmacologia , Ácidos Sulfônicos/química , Ácidos Sulfônicos/farmacologia , Tetra-Hidronaftalenos/química
9.
Molecules ; 26(23)2021 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-34885809

RESUMO

Medulloblastoma is a common malignant brain tumor in the pediatric age. The current therapeutics present serious collateral effects. Polyphenols α-mangostin and nordihydroguaiaretic acid (NDGA) exert potent antitumoral activity in different cancer models, although their antitumoral effects have not been described in medulloblastoma cells yet. This study aimed to examine the proapoptotic effects of these polyphenols on human medulloblastoma cells. Medulloblastoma cell line Daoy was incubated with increasing concentrations of α-mangostin or NDGA for 24 h. The cell viability was analyzed using crystal violet and trypan blue dyes. Determination of the glutathione (GSH)/glutathione disulfide (GSSG) ratio and levels of carbonylated proteins was performed to evaluate the oxidative stress. Cell cycle progression and induction of cell death by fluorochrome-couple and TUNEL assays were evaluated using flow cytometry assays. Individual treatments with α-mangostin or NDGA decreased the viability of Daoy cells in a dose-dependent manner, inducing G2/M and S-G2/M cell cycle arrest, respectively. Both polyphenols induced cell death and increased oxidative stress. Very interestingly, α-mangostin showed more potent effects than NDGA. Our results indicate that α-mangostin and NDGA exert important cytostatic and cytotoxic effects in the Daoy cell line. These data highlight the potential usefulness of these compounds as an alternative strategy in medulloblastoma treatment.


Assuntos
Apoptose , Pontos de Checagem do Ciclo Celular , Neoplasias Cerebelares/patologia , Masoprocol/farmacologia , Meduloblastoma/patologia , Estresse Oxidativo , Polifenóis/farmacologia , Xantonas/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Modelos Biológicos , Estresse Oxidativo/efeitos dos fármacos
10.
Artigo em Inglês | MEDLINE | ID: mdl-34303171

RESUMO

Cytoplasmic availability of leukocyte lipid bodies is controlled by a highly regulated cycle of opposing biogenesis- and catabolism-related events. While leukocyte biogenic machinery is well-characterized, lipid body catabolic mechanisms are yet mostly unknown. Here, we demonstrated that nordihydroguaiaretic acid (NDGA) very rapidly decreases the numbers of pre-formed lipid bodies within lipid body-enriched cytoplasm of mouse leukocytes - macrophages, neutrophils and eosinophils. NDGA mechanisms driving leukocyte lipid body disappearance were not related to loss of cell viability, 5-lipoxygenase inhibition, ATP autocrine/paracrine activity, or biogenesis inhibition. Proteasomal-dependent breakdown of lipid bodies appears to control NDGA-driven leukocyte lipid body reduction, since it was Bortezomib-sensitive in macrophages, neutrophils and eosinophils. Our findings unveil an acute NDGA-triggered lipid body catabolic event - a novel experimental model for the still neglected research area on leukocyte lipid body catabolism, additionally favoring further insights on proteasomal contribution to lipid body breakdown.


Assuntos
Leucócitos/efeitos dos fármacos , Gotículas Lipídicas/efeitos dos fármacos , Inibidores de Lipoxigenase/farmacologia , Masoprocol/farmacologia , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Animais , Eosinófilos/efeitos dos fármacos , Eosinófilos/metabolismo , Leucócitos/metabolismo , Gotículas Lipídicas/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo
11.
Molecules ; 26(7)2021 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-33916785

RESUMO

Nordihydroguaiaretic acid (NDGA) is a major lignan metabolite found in Larrea spp., which are widely used in South America to treat various diseases. In breast tissue, estradiol is metabolized to the catechol estrogens such as 4-hydroxyestradiol (4-OHE2), which have been proposed to be cancer initiators potentially involved in mammary carcinogenesis. Catechol-O-methyltransferase (COMT) catalyzes the O-methylation of catechol estrogens to their less toxic methoxy derivatives, such as 4-O-methylestradiol (4-MeOE2). The present study investigated the novel biological activities of NDGA in relation to COMT and the effects of COMT inhibition by NDGA on 4-OHE2-induced cyto- and genotoxicity in MCF-7 human breast cancer cells. Two methoxylated metabolites of NDGA, 3-O-methylNDGA (3-MNDGA) and 4-O-methyl NDGA (4-MNDGA), were identified in the reaction mixture containing human recombinant COMT, NDGA, and cofactors. Km values for the COMT-catalyzed metabolism of NDGA were 2.6 µM and 2.2 µM for 3-MNDGA and 4-MNDGA, respectively. The COMT-catalyzed methylation of 4-OHE2 was inhibited by NDGA at an IC50 of 22.4 µM in a mixed-type mode of inhibition by double reciprocal plot analysis. Molecular docking studies predicted that NDGA would adopt a stable conformation at the COMT active site, mainly owing to the hydrogen bond network. NDGA is likely both a substrate for and an inhibitor of COMT. Comet and apurinic/apyrimidinic site quantitation assays, cell death, and apoptosis in MCF-7 cells showed that NDGA decreased COMT-mediated formation of 4-MeOE2 and increased 4-OHE2-induced DNA damage and cytotoxicity. Thus, NDGA has the potential to reduce COMT activity in mammary tissues and prevent the inactivation of mutagenic estradiol metabolites, thereby increasing catechol estrogen-induced genotoxicities.


Assuntos
Inibidores de Catecol O-Metiltransferase/química , Inibidores de Catecol O-Metiltransferase/farmacologia , Catecol O-Metiltransferase/metabolismo , Estrogênios de Catecol/metabolismo , Masoprocol/metabolismo , Masoprocol/farmacologia , Mutagênicos/toxicidade , Sítios de Ligação , Morte Celular/efeitos dos fármacos , Dano ao DNA , Estrogênios de Catecol/química , Estrogênios de Catecol/farmacologia , Humanos , Células MCF-7 , Masoprocol/química , Metilação , Simulação de Acoplamento Molecular , Proteínas Recombinantes/metabolismo , Especificidade por Substrato/efeitos dos fármacos
12.
Antiviral Res ; 187: 104976, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33444704

RESUMO

The genus Orthobunyavirus are a group of viruses within arbovirus, with a zoonotic cycle, some of which could lead to human infection. A characteristic of these viruses is their lack of antiviral treatment or vaccine for its prevention. The objective of this work was to study the in vitro antiviral activity of nordihydroguaiaretic acid (NDGA), the most important active compound of Larrea divaricata Cav. (Zigophyllaceae), against Fort Sherman virus (FSV) as a model of Orthobunyavirus genus. At the same time, the effect of NDGA as a lipolytic agent on the cell cycle of this viral model was assessed. The method of reducing plaque forming units on LLC-MK2 cells was used to detect the action of NDGA on CbaAr426 and SFCrEq231 isolates of FSV. NDGA did not show virucidal effect, but it had antiviral activity with a similar inhibition in both isolates, which was dose dependent. It was established that the NDGA has a better inhibition 1-h post-internalization (p.i.), showing a different behavior in each isolate, which was dependent upon the time p.i. Since virus multiplication is dependent on host cell lipid metabolism, the antiviral effect of NDGA has been previously related to its ability to disturb the lipid metabolism, probably by interfering with the 5-lipoxigenase (5-LOX) and the sterol regulatory element-binding proteins (SREBP) pathway. We determined by using caffeic acid, a 5-LOX inhibitor, that the inhibition of this enzyme negatively affected the FSV replication; and by means of resveratrol, a SREBP1 inhibitor, it was showed that the negative regulation of this pathway only had action on the SFCrEq231 reduction. In addition, it was proved that the NDGA acts intracellularly, since it showed the ability to incorporate into LLC-MK2 cells. The information provided in this work converts the NDGA into a compound with antiviral activity in vitro against FSV (Orthobunyavirus), which can be subjected to structural modifications in the future to improve the activity.


Assuntos
Metabolismo dos Lipídeos/efeitos dos fármacos , Masoprocol/farmacologia , Orthobunyavirus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/farmacologia , Araquidonato 5-Lipoxigenase/metabolismo , Relação Dose-Resposta a Droga , Haplorrinos , Viabilidade Microbiana , Orthobunyavirus/fisiologia , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Fatores de Tempo
13.
PLoS One ; 15(8): e0237613, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32790786

RESUMO

BACKGROUND: Nordihydroguaiaretic acid (NDGA) is a plant extract that has been shown to act as a free radical scavenger and pluripotent inhibitor of pro-inflammatory cytokines, two major cellular processes involved in the pathophysiology of sepsis. We investigated whether NDGA would improve markers of organ injury as well as survival in a rodent model of sepsis. METHODS: Abdominal sepsis was induced by cecal ligation and double puncture (CLP) in male Sprague-Dawley rats. NDGA was administered either at the time of injury (pre-) or 6 hours later (post-treatment). A sham surgery group and a vehicle only group were also followed as controls. Blood and lung tissue were collected 24 h after CLP. Lung tissue was used for histopathologic analysis and to measure pulmonary edema. Arterial oxygenation was measured directly to generate PaO2/FiO2, and markers of renal injury (blood urea nitrogen), liver injury (alanine aminotransferase), and tissue hypoxia (lactate) were measured. In a separate set of animals consisting of the same treatment groups, animals were followed for up to 36 hours for survival. RESULTS: NDGA pre-treatment resulted in improved oxygenation, less lung edema, lower lactate, lower BUN, and reduced histologic lung injury. NDGA post-treatment resulted in less lung edema, lower lactate, lower BUN, and less histologic lung injury, but did not significantly change oxygenation. None of the NDGA treatment groups statistically affected ALT or creatinine. NDGA pre-treatment showed improved survival compared with control CLP animals at 36 hours, while post-treatment did not. CONCLUSIONS: NDGA represents a novel pleiotropic anti-inflammatory agent with potential clinical utility for modulation of organ injury secondary to sepsis.


Assuntos
Antioxidantes/farmacologia , Ceco/cirurgia , Ligadura/efeitos adversos , Pneumopatias/tratamento farmacológico , Masoprocol/farmacologia , Punções/efeitos adversos , Sepse/cirurgia , Animais , Pneumopatias/etiologia , Pneumopatias/patologia , Masculino , Ratos , Ratos Sprague-Dawley
14.
J Plant Physiol ; 251: 153192, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32554070

RESUMO

Fig fruit is well-known for its attractive flavor, color, and nutritional and medicinal value. Anthocyanin contributes to the fruit's color and constitutes a high percentage of the total antioxidant content of the fig fruit. We quantified the major anthocyanins and characterized the expression levels of anthocyanin-biosynthesis and transcription factor genes in fruit treated on-tree with exogenous abscisic acid (ABA) or ethephon, or the ABA inhibitors nordihydroguaiaretic acid (NDGA) or fluridone. The major anthocyanins cyanidin 3-O-glucoside and cyanidin 3-O-rutinoside were found in significantly higher quantities in exogenous ABA- and ethephon-treated fruit, with early dark purple color compared to the controls. On the other hand, NDGA- and fluridone-treated fruit had significantly lower amounts of anthocyanins, with less purple color coverage than controls. Expression levels of the anthocyanin-biosynthesis genes FcPAL, FcCHS2, FcCHI, FcF3H, FcDFR, FcANS, FcUFGT and Fc3RT were upregulated by exogenous ABA and ethephon treatment, and downregulated by NDGA and fluridone treatment. The MYB-bHLH-WD40 complex-related genes of ripe fig fruit were identified. In particular, FcMYB113 was strongly upregulated by exogenous ABA and ethephon, and strongly downregulated by NDGA and fluridone. In addition, moderate upregulation of FcGL3 and FcWD40 was observed with exogenous ABA and ethephon treatment, and moderate downregulation in NDGA- and fluridone-treated fruit. These results indicate that ABA can initiate anthocyanin biosynthesis, which ultimately improves the color and nutritional value of fig fruit, enhancing their attractiveness to consumers.


Assuntos
Antocianinas/metabolismo , Ficus/fisiologia , Frutas/fisiologia , Pigmentação/efeitos dos fármacos , Reguladores de Crescimento de Plantas , Ácido Abscísico/antagonistas & inibidores , Ácido Abscísico/farmacologia , Cor , Ficus/crescimento & desenvolvimento , Frutas/crescimento & desenvolvimento , Masoprocol/farmacologia , Compostos Organofosforados/farmacologia , Reguladores de Crescimento de Plantas/antagonistas & inibidores , Reguladores de Crescimento de Plantas/farmacologia , Piridonas/farmacologia
15.
Nat Chem Biol ; 16(7): 783-790, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32393899

RESUMO

Leukotrienes (LT) are lipid mediators of the inflammatory response that are linked to asthma and atherosclerosis. LT biosynthesis is initiated by 5-lipoxygenase (5-LOX) with the assistance of the substrate-binding 5-LOX-activating protein at the nuclear membrane. Here, we contrast the structural and functional consequences of the binding of two natural product inhibitors of 5-LOX. The redox-type inhibitor nordihydroguaiaretic acid (NDGA) is lodged in the 5-LOX active site, now fully exposed by disordering of the helix that caps it in the apo-enzyme. In contrast, the allosteric inhibitor 3-acetyl-11-keto-beta-boswellic acid (AKBA) from frankincense wedges between the membrane-binding and catalytic domains of 5-LOX, some 30 Å from the catalytic iron. While enzyme inhibition by NDGA is robust, AKBA promotes a shift in the regiospecificity, evident in human embryonic kidney 293 cells and in primary immune cells expressing 5-LOX. Our results suggest a new approach to isoform-specific 5-LOX inhibitor development through exploitation of an allosteric site in 5-LOX.


Assuntos
Araquidonato 5-Lipoxigenase/química , Produtos Biológicos/química , Inibidores de Lipoxigenase/química , Masoprocol/química , Triterpenos/química , Sítio Alostérico , Araquidonato 5-Lipoxigenase/genética , Araquidonato 5-Lipoxigenase/metabolismo , Produtos Biológicos/metabolismo , Domínio Catalítico , Clonagem Molecular , Cristalografia por Raios X , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Humanos , Ácidos Hidroxieicosatetraenoicos/química , Ácidos Hidroxieicosatetraenoicos/metabolismo , Leucotrieno B4/química , Leucotrieno B4/metabolismo , Inibidores de Lipoxigenase/metabolismo , Masoprocol/metabolismo , Modelos Moleculares , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Especificidade por Substrato , Triterpenos/metabolismo
16.
J Nanobiotechnology ; 18(1): 74, 2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32410712

RESUMO

BACKGROUND: Nordihydroguaiaretic acid (NDGA) is a plant lignan obtained from creosote bush, known to possess anti-oxidant, anti-cancer and anti-viral activities and is being used in traditional medicine. However, toxicity studies indicated liver and kidney damage despite its immense medicinal properties. There has been a recent increase of curiosity in the chemical synthesis of NDGA derivatives for therapeutic applications. NDGA derivatives have been developed as better alternatives to NDGA and for targeted delivery to the site of tissue by chemical derivatives. In this regard, an analog of NDGA, Acetyl NDGA (Ac-NDGA), has been synthesized based on a previous procedure and formulated as a nanostructured complex with Polycaprolactone/Polyethylene glycol polymer matrices, by o/w solvent evaporation method. RESULTS: The drug-incorporated polymeric nanospheres exhibited a drug load of 10.0 ± 0.5 µg drug per mg of nanospheres in acetonitrile solvent with 49.95 ± 10% encapsulation efficiency and 33-41% drug loading capacity with different batches of nanospheres preparation. The in vitro drug release characteristics indicated 82 ± 0.25% drug release at 6 h in methanol. Further, the nanospheres have been characterized extensively to evaluate their suitability for therapeutic delivery. CONCLUSIONS: The present studies indicate a new and efficient formulation of the nanostructured AcNDGA with good therapeutic potential.


Assuntos
Antioxidantes , Masoprocol , Nanoestruturas/química , Polímeros/química , Antioxidantes/química , Antioxidantes/farmacocinética , Antioxidantes/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Masoprocol/química , Masoprocol/farmacocinética , Masoprocol/farmacologia , Teste de Materiais , Tamanho da Partícula
17.
Respir Physiol Neurobiol ; 278: 103441, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32339697

RESUMO

We previously reported that intracerebroventricularly (ICV) injected arachidonic acid (AA) could produce pressor and bradycardic responses on the cardiovascular system and hyperventilation effect on the respiratory system by activating cyclooxygenase (COX). We also demonstrated that centrally injected AA-induced cardiovascular and respiratory responses were mediated by COX-metabolites, such as thromboxane A2 (TXA2), prostaglandin (PG) D, PGE, and PGF2α. Brain tissue is also able to express the lipoxygenase (LOX) enzyme and LOX-induced AA-metabolites. The current study was designed to investigate the possible mediation of the central LOX pathway in AA-induced cardiorespiratory effects in anesthetized rats. Central pretreatment with different doses of a non-selective LOX inhibitor, nordihydroguaiaretic acid (NDGA) (500 and 1000 µg; ICV) partially blocked the AA (0.5 µmol; ICV)-evoked pressor and bradycardic cardiovascular responses in male anesthetized Sprague Dawley rats. Pretreatment with different doses of NDGA (500 and 1000 µg; ICV) also reduced AA-induced hyperventilation responses, with an increase in tidal volume, respiratory rate and minute ventilation, in the rats. Moreover, AA-induced increasing pO2 and decreasing pCO2 responses were diminished by central NDGA pretreatment. In summary, our findings show that the central LOX pathway might mediate, at least in part, centrally administered AA-evoked cardiorespiratory and blood gases responses.


Assuntos
Ácido Araquidônico/farmacologia , Pressão Arterial/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Lipoxigenase/fisiologia , Taxa Respiratória/efeitos dos fármacos , Volume de Ventilação Pulmonar/efeitos dos fármacos , Animais , Gasometria , Dióxido de Carbono/sangue , Injeções Intraventriculares , Inibidores de Lipoxigenase/farmacologia , Masoprocol/farmacologia , Oxigênio/sangue , Pressão Parcial , Ratos
18.
Mar Drugs ; 18(4)2020 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-32272633

RESUMO

Several biochemical mechanisms, including the arachidonic acid cascade and activation of nicotinic acetylcholine receptors (nAChRs), are involved in increased tumor survival. Combined application of inhibitors acting on these two pathways may result in a more pronounced antitumor effect. Here, we show that baicalein (selective 12-lipoxygenase inhibitor), nordihydroguaiaretic acid (non-selective lipoxygenase inhibitor), and indomethacin (non-selective cyclooxygenase inhibitor) are cytotoxic to Ehrlich carcinoma cells in vitro. Marine snail α-conotoxins PnIA, RgIA and ArIB11L16D, blockers of α3ß2/α6ß2, α9α10 and α7 nAChR subtypes, respectively, as well as α-cobratoxin, a blocker of α7 and muscle subtype nAChRs, exhibit low cytotoxicity, but enhance the antitumor effect of baicalein 1.4-fold after 24 h and that of nordihydroguaiaretic acid 1.8-3.9-fold after 48 h of cell cultivation. α-Conotoxin MII, a blocker of α6-containing and α3ß2 nAChR subtypes, increases the cytotoxic effect of indomethacin 1.9-fold after 48 h of cultivation. In vivo, baicalein, α-conotoxins MII and PnIA inhibit Ehrlich carcinoma growth and increase mouse survival; these effects are greatly enhanced by the combined application of α-conotoxin MII with indomethacin or conotoxin PnIA with baicalein. Thus, we show, for the first time, antitumor synergism of α-conotoxins and arachidonic acid cascade inhibitors.


Assuntos
Carcinoma de Ehrlich/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacos , Conotoxinas/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Inibidores de Lipoxigenase/farmacologia , Antagonistas Nicotínicos/farmacologia , Animais , Ácido Araquidônico/antagonistas & inibidores , Carcinoma/tratamento farmacológico , Proteínas Neurotóxicas de Elapídeos/farmacologia , Sinergismo Farmacológico , Flavanonas/farmacologia , Indometacina/farmacologia , Masoprocol/farmacologia , Camundongos , Receptores Nicotínicos
19.
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
20.
Physiol Res ; 69(1): 49-59, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-31852209

RESUMO

Autologous and allogenic human pericardia used as biomaterials for cardiovascular surgery are traditionally crosslinked with glutaraldehyde. In this work, we have evaluated the resistivity to collagenase digestion and the cytotoxicity of human pericardium crosslinked with various concentrations of glutaraldehyde in comparison with pericardium crosslinked by genipin, nordihydroguaiaretic acid, tannic acid, and in comparison with unmodified pericardium. Crosslinking retained the wavy-like morphology of native pericardium visualized by second harmonic generation microscopy. The collagenase digestion products were analyzed using SDS-PAGE, capillary electrophoresis, and a hydroxyproline assay. Glutaraldehyde and genipin crosslinking protected the native pericardium efficiently against digestion with collagenase III. Only low protection was provided by the other crosslinking agents. The cytotoxicity of crosslinked pericardium was evaluated using xCELLigence by monitoring the viability of porcine valve interstitial cells cultured in eluates from crosslinked pericardium. The highest cell index, reflecting both the number and the shape of the monitored cells was observed in eluates from genipin. Crosslinking pericardium grafts with genipin therefore seems to be a promising alternative procedure to the traditional crosslinking with glutaraldehyde, because it provides similarly high protection against degradation with collagenase, without cytotoxic effects.


Assuntos
Reagentes de Ligações Cruzadas , Pericárdio/química , Transplantes/química , Materiais Biocompatíveis , Glutaral , Humanos , Iridoides , Masoprocol , Taninos
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