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1.
Biochemistry (Mosc) ; 85(7): 833-837, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33040727

RESUMO

Nrf2 is a key transcription factor responsible for antioxidant defense in many tissues and cells, including alveolar epithelium, endothelium, and macrophages. Furthermore, Nrf2 functions as a transcriptional repressor that inhibits expression of the inflammatory cytokines in macrophages. Critically ill patients with COVID-19 infection often present signs of high oxidative stress and systemic inflammation - the leading causes of mortality. This article suggests rationale for the use of Nrf2 inducers to prevent development of an excessive inflammatory response in COVID-19 patients.


Assuntos
Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Terapia de Alvo Molecular/métodos , Fator 2 Relacionado a NF-E2/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/metabolismo , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Catequina/análogos & derivados , Catequina/farmacologia , Catequina/uso terapêutico , Infecções por Coronavirus/virologia , Fumarato de Dimetilo/farmacologia , Fumarato de Dimetilo/uso terapêutico , Feminino , Humanos , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Inflamação/metabolismo , Isotiocianatos/farmacologia , Isotiocianatos/uso terapêutico , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Pandemias , Pneumonia Viral/virologia , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Síndrome do Desconforto Respiratório do Adulto/metabolismo , Síndrome do Desconforto Respiratório do Adulto/virologia , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Tiossulfatos/farmacologia , Tiossulfatos/uso terapêutico
2.
Mutat Res ; 854-855: 503201, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32660825

RESUMO

Oxidative stress is a critical factor in the pathogenesis of several gastrointestinal diseases. Sulforaphane (SFN), a bioactive compound found in cruciferous vegetables, activates the redox-sensitive nuclear erythroid 2-related factor 2 (NRF2). In addition to its protective role, SFN exerts cytotoxic effects on cancer cells. However, there is a lack of information concerning the toxicity of SFN in normal cells. We investigated the effects of SFN on cell viability, antioxidant defenses, and gene expression in human stomach mucosa cells (MNP01). SFN reduced ROS formation and protected the cells against induced oxidative stress but high concentrations increased apoptosis. An intermediate SFN concentration (8 µM) was chosen for RNA sequencing studies. We observed upregulation of genes of the NRF2 (antioxidant) pathway, the DNA damage response, and apoptosis signaling; whereas SFN downregulated cell cycle and DNA repair pathway genes. SFN may be cytoprotective at low concentrations and cytotoxic at high concentrations.


Assuntos
Apoptose/efeitos dos fármacos , Isotiocianatos/farmacologia , Membrana Mucosa/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estômago/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos , Anticarcinógenos/farmacologia , Antioxidantes/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Membrana Mucosa/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Oxirredução/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
3.
Plant Dis ; 104(10): 2688-2695, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32729797

RESUMO

This study evaluated the potential of horseradish (Armoracia rusticana) oil (ARO) and eight isothiocyanates (propyl ITC [ProITC], isopropyl ITC [IsoproITC], n-butyl ITC [n-BuITC], 3-butenyl ITC [3-BeITC], phenyl ITC [PhITC], benzyl ITC [BzITC], 2-phenylethyl ITC [PhEITC], and allyl ITC [AITC]) as preservatives and antifungal agents for postharvest tomato disease control. Results showed that ARO and eight ITCs demonstrated antifungal activities against Botrytis cinerea, Alternaria alternata, Rhizopus stolonifer, and Geotrichum candidum, which can cause the decay of mature green tomato during storage. Allyl-ITC (AITC) had the lowest EC50 values of mycelia growth suppression, with 0.18, 0.44, 0.29, and 0.43 µg/ml air for B. cinerea, A. alternata, R. stolonifer, and G. candidum, respectively. ARO, 2-PhEITC, BzITC, and AITC exhibited better efficacy as preservatives of mature green tomato than other ITCs on the basis of some parameters, such as low decay rate, slow reduction in weight loss, slight change in hardness, slow decrease in acidity, and total soluble solid content of treated tomatoes. GC-MS revealed that 2-PhEITC (77.78%) and AITC (15.87%) were the major components of ARO. These results can be used as a basis to develop preservative products composed of ITCs.


Assuntos
Armoracia , Lycopersicon esculentum , Isotiocianatos/farmacologia , Extratos Vegetais
4.
Phytomedicine ; 75: 153238, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32507349

RESUMO

BACKGROUND: The NLRP3 inflammasome formation and following cytokine secretion is a crucial step in innate immune responses. Internal and external factors may trigger inflammasome activation and result in inflammatory cytokine secretion. Inflammasome formation and activity play critical roles in several disease pathologies such as cardiovascular, metabolic, renal, digestive, and CNS diseases. Underlying pathways are not yet clear, but phytochemicals as alternative therapies have been extensively used for suppression of inflammatory responses. PURPOSE: In this review, we aimed to summarize in vivo and in vitro effects on NLRP3 inflammasome activation of selected phytochemicals. METHOD: Three phytochemicals; Sulforaphane, Curcumin, and Resveratrol were selected, and studies were reviewed to clarify their intracellular signaling mechanism in NLRP3 inflammasome activity. PubMed and Scopus databases are used for the search. For sulforaphane, 8 articles, for curcumin, 25 articles, and for resveratrol, 41 articles were included in the review. CONCLUSION: In vitro and in vivo studies pointed out that the selected phytochemicals have inhibitory properties on NLRP3 inflammasome activity. However, neither the mechanism is clear, nor the study designs and doses are standardized.


Assuntos
Curcumina/farmacologia , Inflamassomos/efeitos dos fármacos , Isotiocianatos/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Compostos Fitoquímicos/uso terapêutico , Resveratrol/farmacologia , Animais , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Doenças do Sistema Nervoso Central/tratamento farmacológico , Doenças do Sistema Nervoso Central/metabolismo , Humanos , Inflamassomos/antagonistas & inibidores , Inflamassomos/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Transdução de Sinais/efeitos dos fármacos
5.
PLoS One ; 15(6): e0234484, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32511271

RESUMO

Inflammation plays a crucial role in the defense response of the innate immune system against pathogen infection. In this study, we selected 4 compounds for their potential or proven anti-inflammatory and/or anti-microbial properties to test on our in vitro model of bacteria-infected THP-1-derived macrophages. We first compared the capacity of sulforaphane (SFN), wogonin (WG), oltipraz (OTZ), and dimethyl fumarate (DMF) to induce the nuclear factor erythroid 2-related factor 2 (Nrf2), a key regulator of the antioxidant, anti-inflammatory response pathways. Next, we performed a comparative evaluation of the antioxidant and anti-inflammatory efficacies of the 4 selected compounds. THP-1-derived macrophages and LPS-stimulated macrophages were treated with each compound and expression levels of genes coding for inflammatory cytokines IL-1ß, IL-6, and TNF-α were quantified by RT-qPCR. Moreover, expression levels of genes coding for M1 (IL-23, CCR7, IL-1ß, IL-6, and TNF-α) and M2 (PPARγ, MRC1, CCL22, and IL-10) markers were determined in classically-activated M1 macrophages treated with each compound. Finally, the effects of each compound on the intracellular bacterial survival of gram-negative E. coli and gram-positive S. aureus in THP-1-derived macrophages and PBMC-derived macrophages were examined. Our data confirmed the anti-inflammatory and antioxidant effects of SFN, WG, and DMF on LPS-stimulated THP-1-derived macrophages. In addition, SFN or WG treatment of classically-activated THP-1-derived macrophages reduced expression levels of M1 marker genes, while SFN or DMF treatment upregulated the M2 marker gene MRC1. This decrease in expression of M1 marker genes may be correlated with the decrease in intracellular S. aureus load in SFN- or DMF-treated macrophages. Interestingly, an increase in intracellular survival of E. coli in SFN-treated THP-1-derived macrophages that was not observed in PBMC-derived macrophages. Conversely, OTZ exhibited pro-oxidant and proinflammatory properties, and affected intracellular survival of E. coli in THP-1-derived macrophages. Altogether, we provide new potential therapeutic alternatives in treating inflammation and bacterial infection.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Infecções por Escherichia coli/tratamento farmacológico , Inflamação/tratamento farmacológico , Ativação de Macrófagos/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/imunologia , Estresse Oxidativo/efeitos dos fármacos , Infecções Estafilocócicas/tratamento farmacológico , Fumarato de Dimetilo/farmacologia , Escherichia coli/efeitos dos fármacos , Infecções por Escherichia coli/imunologia , Flavanonas/farmacologia , Humanos , Inflamação/imunologia , Isotiocianatos/farmacologia , Leucócitos Mononucleares , Ativação de Macrófagos/imunologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Estresse Oxidativo/imunologia , Pirazinas/farmacologia , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/efeitos dos fármacos , Células THP-1
6.
Food Chem ; 328: 127102, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-32512468

RESUMO

Sprouting process enhances plant bioactive compounds. Broccoli (Brassica oleracea L) sprouts are well known for their high levels of glucosinolates (GLs), amino acids, and antioxidants, which offer outstanding biological activities with positive impacts on plant metabolism. Elevated CO2 (eCO2, 620 ppm) was applied for 9 days to further improve nutritive and health-promoting values of three cultivars of broccoli sprouts i.e., Southern star, Prominence and Monotop. eCO2 improved sprouts growth and induced GLs accumulation e.g., glucoraphanin, possibly through amino acids production e.g., high methionine and tryptophan. There were increases in myrosinase activity, which stimulated GLs hydrolysis to yield health-promoting sulforaphane. Interestingly, low levels of ineffective sulforaphane nitrile were detected and positively correlated with reduced epithiospecifier protein after eCO2 treatment. High glucoraphanin and sulforaphane levels in eCO2 treated sprouts improved the anticarcinogenic and anti-inflammatory properties of their extracts. In conclusion, eCO2 treatment enriches broccoli sprouts with health-promoting metabolites and bioactivities.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Brassica/metabolismo , Dióxido de Carbono/metabolismo , Glucosinolatos/metabolismo , Aminoácidos/metabolismo , Anti-Inflamatórios/farmacologia , Brassica/química , Brassica/crescimento & desenvolvimento , Linhagem Celular , Glucosinolatos/farmacologia , Humanos , Imidoésteres/metabolismo , Imidoésteres/farmacologia , Isotiocianatos/metabolismo , Isotiocianatos/farmacologia , Extratos Vegetais/farmacologia
7.
Life Sci ; 255: 117823, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32445760

RESUMO

AIMS: Skeletal muscle diseases have become to be the most common complication in patients with type 2 diabetic mellitus (T2DM). However, the effective therapies against skeletal muscle diseases are not yet available. Sulforaphane (SFN) is an organic isothiocyanate found in cruciferous plants. Our aim was to explore whether SFN could attenuate the skeletal muscle diseases in spontaneous type 2 diabetic db/db mice. MATERIALS AND METHODS: The db/m and littermate db/db mice were treated with SFN or dimethyl sulfoxide. The grip strength of mice was measured by a grasping forcing machine. The electron transmission microscopy was used to perform the skeletal muscle. The western blot was used to detect the nuclear factor E2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) signal pathway related proteins, and inflammatory and apoptotic associated proteins. The mRNA levels of anti-inflammatory and anti-oxidative relative genes were detected by RT-QPCR. KEY FINDINGS: We found that SFN could significantly increase the grip strength of the db/db mice. The lean mass and gastrocnemius mass were increased in the db/db mice after administration with SFN. Additionally, the db/db mice restored the skeletal muscle fiber organization after SFN treatment. Mechanistically, SFN could activate the Nrf2/HO-1 signal pathway, and downregulate the expression of inflammatory and apoptotic associated proteins. Furthermore, SFN could also regulate the mRNA levels of anti-inflammatory and anti-oxidative related genes. SIGNIFICANCE: Our results demonstrated that SFN can protect against skeletal muscle diseases in db/db type 2 diabetic mice and provide a potential drug to prevent skeletal muscle dysfunction in T2DM patients.


Assuntos
Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/complicações , Isotiocianatos/farmacologia , Músculo Esquelético/efeitos dos fármacos , Doenças Musculares/prevenção & controle , Animais , Antioxidantes/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Heme Oxigenase-1/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Músculo Esquelético/patologia , Doenças Musculares/etiologia , Fator 2 Relacionado a NF-E2/metabolismo , RNA Mensageiro/metabolismo
8.
Artigo em Inglês | MEDLINE | ID: mdl-32233794

RESUMO

Transient receptor potential ankyrin-1 (TRPA1) is a ligand-gated cation channel that responds to endogenous and exogenous irritants. TRPA1 is expressed on multiple cell types throughout the lungs, but previous studies have primarily focused on TRPA1 stimulation of airway sensory nerves. We sought to understand the integrated physiological airway response to TRPA1 stimulation. The TRPA1 agonists allyl isothiocyanate (AITC) and cinnamaldehyde (CINN) were tested in sedated, mechanically ventilated guinea pigs in vivo. Reproducible bronchoconstrictions were induced by electrical stimulation of the vagus nerves. Animals were then treated with intravenous AITC or CINN. AITC and CINN were also tested on isolated guinea pig and mouse tracheas and postmortem human trachealis muscle strips in an organ bath. Tissues were contracted with methacholine, histamine, or potassium chloride and then treated with AITC or CINN. Some airways were pretreated with TRPA1 antagonists, the cyclooxygenase inhibitor indomethacin, the EP2 receptor antagonist PF 04418948, or tetrodotoxin. AITC and CINN blocked vagally mediated bronchoconstriction in guinea pigs. Pretreatment with indomethacin completely abolished the airway response to TRPA1 agonists. Similarly, AITC and CINN dose-dependently relaxed precontracted guinea pig, mouse, and human airways in the organ bath. AITC- and CINN-induced airway relaxation required TRPA1, prostaglandins, and PGE2 receptor activation. TRPA1-induced airway relaxation did not require epithelium or tetrodotoxin-sensitive nerves. Finally, AITC blocked airway hyperreactivity in two animal models of allergic asthma. These data demonstrate that stimulation of TRPA1 causes bronchodilation of intact airways and suggest that the TRPA1 pathway is a potential pharmacological target for bronchodilation.


Assuntos
Dinoprostona/metabolismo , Músculo Liso/metabolismo , Canal de Cátion TRPA1/genética , Traqueia/metabolismo , Acroleína/análogos & derivados , Acroleína/farmacologia , Animais , Broncoconstrição/efeitos dos fármacos , Estimulação Elétrica , Regulação da Expressão Gênica , Cobaias , Histamina/farmacologia , Humanos , Indometacina/farmacologia , Isotiocianatos/farmacologia , Masculino , Cloreto de Metacolina/farmacologia , Camundongos , Músculo Liso/efeitos dos fármacos , Técnicas de Cultura de Órgãos , Cloreto de Potássio/farmacologia , Prostaglandina-Endoperóxido Sintases/genética , Prostaglandina-Endoperóxido Sintases/metabolismo , Respiração Artificial , Transdução de Sinais , Canal de Cátion TRPA1/agonistas , Canal de Cátion TRPA1/antagonistas & inibidores , Canal de Cátion TRPA1/metabolismo , Tetrodotoxina/farmacologia , Traqueia/efeitos dos fármacos , Nervo Vago/fisiologia
9.
Microbiol Immunol ; 64(6): 416-423, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32190917

RESUMO

Papillomatous digital dermatitis (PDD) is a foot disease causing lameness in dairy cattle. It is regarded as a polymicrobial infection, although its etiology is not fully understood. PDD is treated by the topical or systemic administration of antibiotics such as lincomycin (LCM); however, the milk of the cows cannot be marketed during the treatment and withdrawal period due to the residual antibiotics in milk. Allyl isothiocyanate (AITC), an extract of Wasabia japonica (known as wasabi or Japanese horseradish) widely employed as a food additive, can be used as an alternative antimicrobial agent that overcomes this problem. We previously showed that AITC is as effective as LCM in PDD treatment. Here, using the samples obtained in the previous clinical study, we analyzed changes in the bacterial population in the PDD-associated microbiota after AITC treatment and compared those with that following LCM treatment by 16S ribosomal RNA (rRNA)-based amplicon analysis. Both treatments induced major changes in the bacterial population, and Treponema species, which have been regarded as the major causative agents of PDD, were efficiently eliminated by both agents. However, the AITC-treated samples exhibited higher diversity compared with pretreatment samples, but this trend was not observed for LCM treatment, probably reflecting different antibacterial activities of the two agents. Importantly, this analysis detected population changes before morphological changes in PDD lesions (clinical signs of healing) became evident, indicating that 16S rRNA-based amplicon analysis represents an efficient strategy for analyzing and monitoring the treatment efficiency of PDD as well as other polymicrobial diseases.


Assuntos
Antibacterianos , Doenças dos Bovinos/tratamento farmacológico , Coinfecção/tratamento farmacológico , Dermatite Digital/tratamento farmacológico , Isotiocianatos , RNA-Seq/métodos , Treponema , Administração Tópica , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Bovinos , Feminino , Isotiocianatos/farmacologia , Isotiocianatos/uso terapêutico , Lactação , Leite/química , RNA Ribossômico 16S/genética , Treponema/efeitos dos fármacos , Treponema/genética , Wasabia/metabolismo
10.
Arch Biochem Biophys ; 686: 108329, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32151565

RESUMO

In the body, alcohol dehydrogenase rapidly converts ethanol to its toxic metabolite, acetaldehyde, which is further metabolized to non-toxic acetic acid by aldehyde dehydrogenase (ALDH). 6-(methylsulfinyl)hexyl isothiocyanate (6-MSITC), a major bioactive compound in Wasabi (Wasabia japonica) has various physiological effects such as anti-oxidative, anti-inflammatory and anti-cancer effects. However, the effect of 6-MSITC on alcohol metabolism has not been studied. In this study, we investigated the effects of 6-MSITC on hepatic ALDH activity and protein expression both in vitro and in vivo. 6-MSITC inhibited ethanol- and acetaldehyde-induced cytotoxicity. Treatment with 6-MSITC to HepG2 cells enhanced ALDH activity through the induction of mitochondrial ALDH2 expression, but not cytosolic ALDH1A1. Knockdown of Nrf2 canceled the 6-MSITC-induced ALDH2 expression, indicating that Nrf2 regulated ALDH2 expression. Moreover, 6-MSITC increased the nuclear translocation of Nrf2 and the expression levels of HO-1 and SOD2, Nrf2-regulated phase II drug-metabolizing enzymes. Oral administration of 6-MSITC increased the mitochondrial ALDH2 activity and its expression in the liver of C57BL/6J mice. These results suggested that 6-MSITC is possible to protect acetaldehyde toxicity in hepatocytes by induction of mitochondrial ALDH2 expression through Nrf2/ARE pathway.


Assuntos
Acetaldeído/metabolismo , Aldeído-Desidrogenase Mitocondrial/metabolismo , Antineoplásicos/farmacologia , Hepatócitos/metabolismo , Isotiocianatos/farmacologia , Acetaldeído/toxicidade , Alanina Transaminase/metabolismo , Álcool Desidrogenase/metabolismo , Aldeído-Desidrogenase Mitocondrial/genética , Animais , Aspartato Aminotransferases/metabolismo , Etanol/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Heme Oxigenase-1/metabolismo , Células Hep G2 , Humanos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , Fosforilação , Superóxido Dismutase/metabolismo
11.
Curr Med Sci ; 40(1): 55-62, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32166665

RESUMO

The present study aimed to explore the molecular mechanisms underlying the increase of nicotinamide adenine dinucleotide phosphate:quinine oxidoreductase 1 (NQO1) and γ-glutamylcysteine synthetase (γ-GCS) in brain tissues after intracerebral hemorrhage (ICH). The microglial cells obtained from newborn rats were cultured and then randomly divided into the normal control group (NC group), model control group (MC group), rosiglitazone (RSG) intervention group (RSG group), retinoic-acid intervention group (RSG+RA group), and sulforaphane group (RSG+SF group). The expression levels of NQO1, γ-GCS, and nuclear factor E2-related factor 2 (Nrf2) were measured by real-time polymerase chain reaction (RT-PCR) and Western blotting, respectively. The results showed that the levels of NQO1, γ-GCS and Nrf2 were significantly increased in the MC group and the RSG group as compared with those in the NC group (P<0.01). They were found to be markedly decreased in the RSG+RA group and increased in the RSG+SF group when compared with those in the MC group or the RSG group (P<0.01). The RSG+SF group displayed the highest levels of NQO1, γ-GCS, and Nrf2 among the five groups. In conclusion, a medium dose of RSG increased the anti-oxidative ability of thrombin-activated microglia by increasing the expression of NQO1 and γ-GCS. The molecular mechanisms underlying the increase of NQO1 and γ-GCS in thrombin-activated microglia may be associated with the activation of Nrf2.


Assuntos
Hemorragia Cerebral/genética , Glutamato-Cisteína Ligase/genética , Microglia/citologia , NAD(P)H Desidrogenase (Quinona)/genética , Fator 2 Relacionado a NF-E2/genética , PPAR gama/genética , Trombina/farmacologia , Animais , Animais Recém-Nascidos , Células Cultivadas , Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/metabolismo , Modelos Animais de Doenças , Feminino , Glutamato-Cisteína Ligase/metabolismo , Isotiocianatos/administração & dosagem , Isotiocianatos/farmacologia , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , PPAR gama/metabolismo , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Rosiglitazona/administração & dosagem , Rosiglitazona/farmacologia , Tretinoína/administração & dosagem , Tretinoína/farmacologia
12.
Cell Physiol Biochem ; 54(1): 142-159, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32028545

RESUMO

BACKGROUND/AIMS: It is well established that oxidative stress and inflammation are common pathogenic features of retinal degenerative diseases. ITH12674 is a novel compound that induces the transcription factor Nrf2; in so doing, the molecule exhibits anti-inflammatory, and antioxidant properties, and affords neuroprotection in rat cortical neurons subjected to oxidative stress. We here tested the hypothesis that ITH12674 could slow the retinal degeneration that causes blindness in rd10 mice, a model of retinitis pigmentosa. METHODS: Animals were intraperitoneally treated with 1 or 10 mg/Kg ITH12674 or placebo from P16 to P30. At P30, retinal functionality and visual acuity were analyzed by electroretinography and optomotor test. By immunohistochemistry we quantified the photoreceptor rows and analyzed their morphology and connectivity. Oxidative stress and inflammatory state was studied by Western blot, and microglia reactivity was monitored by flow cytometry. The blood-brain barrier permeation of ITH12674 was evaluated using a PAMPA-BBB assay. RESULTS: In rd10 mice treated with 10 mg/Kg of the compound, the following changes were observed (with respect to placebo): (i) a decrease of vision loss with higher scotopic a- and b-waves; (ii) increased visual acuity; (iii) preservation of cone photoreceptors morphology, as well as their synaptic connectivity; (iv) reduced expression of TNF-α and NF-κB; (v) increased expression of p38 MAPK and Atg12-Atg5 complex; and (vi) decreased CD11c, MHC class II and CD169 positive cell populations. CONCLUSION: These data support the view that a Nrf2 inducer compound may arise as a new therapeutic strategy to combat retinal neurodegeneration. At present, we are chemically optimising compound ITH12674 with the focus on improving its neuroprotective potential in retinal neurodegenerative diseases.


Assuntos
Isotiocianatos/uso terapêutico , Melatonina/análogos & derivados , Fator 2 Relacionado a NF-E2/agonistas , Retinite Pigmentosa/tratamento farmacológico , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Modelos Animais de Doenças , Eletrorretinografia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Isotiocianatos/química , Isotiocianatos/farmacologia , Masculino , Melatonina/química , Melatonina/farmacologia , Melatonina/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , Células Fotorreceptoras/efeitos dos fármacos , Células Fotorreceptoras/patologia , Retina/efeitos dos fármacos , Retina/metabolismo , Retinite Pigmentosa/metabolismo , Retinite Pigmentosa/patologia , Fator de Necrose Tumoral alfa/metabolismo , Acuidade Visual/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
13.
Artigo em Inglês | MEDLINE | ID: mdl-32108526

RESUMO

Right ventricular (RV) dysfunction is the main determinant of mortality in patients with pulmonary arterial hypertension (PAH) and while inflammation is pathogenic in PAH, there is limited information on the role of RV inflammation in PAH. Sulforaphane (SFN), a potent Nrf2 activator, has significant anti-inflammatory effects and facilitates cardiac protection in preclinical diabetic models. Therefore, we hypothesized that SFN might play a comparable role in reducing RV and pulmonary inflammation and injury in a murine PAH model. We induced PAH using SU5416 and 10% hypoxia (SuHx) for 4 wk in male mice randomized to SFN at a daily dose of 0.5 mg/kg 5 days per week for 4 wk or to vehicle control. Transthoracic echocardiography was performed to characterize chamber-specific ventricular function during PAH induction. At 4 wk, we measured RV pressure and relevant measures of histology and protein and gene expression. SuHx induced progressive RV, but not LV, diastolic and systolic dysfunction, and RV and pulmonary remodeling, fibrosis, and inflammation. SFN prevented SuHx-induced RV dysfunction and remodeling, reduced RV inflammation and fibrosis, upregulated Nrf2 expression and its downstream gene NQO1, and reduced the inflammatory mediator leucine-rich repeat and pyrin domain-containing 3 (NLRP3). SFN also reduced SuHx-induced pulmonary vascular remodeling, inflammation, and fibrosis. SFN alone had no effect on the heart or lungs. Thus, SuHx-induced RV and pulmonary dysfunction, inflammation, and fibrosis can be attenuated or prevented by SFN, supporting the rationale for further studies to investigate SFN and the role of Nrf2 and NLRP3 pathways in preclinical and clinical PAH studies.NEW & NOTEWORTHY Pulmonary arterial hypertension (PAH) in this murine model (SU5416 + hypoxia) is associated with early changes in right ventricular (RV) diastolic and systolic function. RV and lung injury in the SU5416 + hypoxia model are associated with markers for fibrosis, inflammation, and oxidative stress. Sulforaphane (SFN) alone for 4 wk has no effect on the murine heart or lungs. Sulforaphane (SFN) attenuates or prevents the RV and lung injury in the SUF5416 + hypoxia model of PAH, suggesting that Nrf2 may be a candidate target for strategies to prevent or reverse PAH.


Assuntos
Anti-Inflamatórios/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Isotiocianatos/uso terapêutico , Artéria Pulmonar/efeitos dos fármacos , Remodelação Vascular , Disfunção Ventricular Direita/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Hipertensão Pulmonar/complicações , Isotiocianatos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Artéria Pulmonar/patologia , Disfunção Ventricular Direita/etiologia , Disfunção Ventricular Direita/prevenção & controle
14.
PLoS One ; 15(1): e0227484, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31923212

RESUMO

Nosema ceranae is a microsporidian parasite that causes nosemosis in the honey bee (Apis mellifera). As alternatives to the antibiotic fumagillin, ten nutraceuticals (oregano oil, thymol, carvacrol, trans-cinnmaldehyde, tetrahydrocurcumin, sulforaphane, naringenin, embelin, allyl sulfide, hydroxytyrosol) and two immuno-stimulatory compounds (chitosan, poly I:C) were examined for controlling N. ceranae infections. Caged bees were inoculated with N. ceranae spores, and treatments were administered in sugar syrup. Only two compounds did not significantly reduce N. ceranae spore counts compared to the infected positive control, but the most effective were sulforaphane from cruciferous vegetables, carvacrol from oregano oil, and naringenin from citrus fruit. When tested at several concentrations, the highest sulforaphane concentration reduced spore counts by 100%, but also caused 100% bee mortality. For carvacrol, the maximum reduction in spore counts was 57% with an intermediate concentration and the maximum bee mortality was 23% with the highest concentration. For naringenin, the maximum reduction in spore counts was 64% with the highest concentration, and the maximum bee mortality was only 15% with an intermediate concentration. In the longevity experiment, naringenin-fed bees lived as long as Nosema-free control bees, both of which lived significantly longer than infected positive control bees. While its antimicrobial properties may be promising, reducing sulforaphane toxicity to bees is necessary before it can be considered as a candidate for controlling N. ceranae. Although further work on formulation is needed with naringenin, its effect on extending longevity in infected bees may give it an additional value as a potential additive for bee feed in honey bee colonies.


Assuntos
Abelhas/microbiologia , Suplementos Nutricionais/análise , Nosema/fisiologia , Animais , Abelhas/efeitos dos fármacos , Abelhas/metabolismo , Cicloexanos/farmacologia , Cimenos/farmacologia , Ácidos Graxos Insaturados/farmacologia , Flavanonas/farmacologia , Isotiocianatos/farmacologia , Longevidade/efeitos dos fármacos , Nosema/efeitos dos fármacos , Sesquiterpenos/farmacologia , Esporos Fúngicos/fisiologia
15.
PLoS One ; 15(1): e0223814, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31910217

RESUMO

INTRODUCTION: Chimeric antigen receptor (CAR) T-cells have been recently developed and are producing impressive outcomes in patients with hematologic malignancies. However, there is no standardized method for cell trafficking and in vivo CAR T-cell monitoring. We assessed the feasibility of real-time in vivo 89Zr-p-Isothiocyanatobenzyl-desferrioxamine (Df-Bz-NCS, DFO) labeled CAR T-cell trafficking using positron emission tomography (PET). RESULTS: The 89Zr-DFO radiolabeling efficiency of Jurkat/CAR and human peripheral blood mononuclear cells (hPBMC)/CAR T-cells was 70%-79%, and cell radiolabeling activity was 98.1-103.6 kBq/106 cells. Cell viability after radiolabeling was >95%. Cell proliferation was not significantly different during the early period after radiolabeling, compared with unlabeled cells; however, the proliferative capacity decreased over time (day 7 after labeling). IL-2 or IFN-γ secretion was not significantly different between unlabeled and labeled CAR T-cells. PET/magnetic resonance imaging in the xenograft model showed that most of the 89Zr-DFO-labeled Jurkat/CAR T-cells were distributed in the lung (24.4% ± 3.4%ID) and liver (22.9% ± 5.6%ID) by one hour after injection. The cells gradually migrated from the lung to the liver and spleen by day 1, and remained stable in these sites until day 7 (on day 7: lung 3.9% ± 0.3%ID, liver 36.4% ± 2.7%ID, spleen 1.4% ± 0.3%ID). No significant accumulation of labeled cells was identified in tumors. A similar pattern was observed in ex vivo biodistributions on day 7 (lung 3.0% ± 1.0%ID, liver 19.8% ± 2.2%ID, spleen 2.3% ± 1.7%ID). 89Zr-DFO-labeled hPBMC/CAR T-cells showed a similar distribution, compared with Jurkat/CAR T-cells, on serial PET images. CAR T cell distribution was cross-confirmed by flow cytometry, Alu polymerase chain reaction, and immunohistochemistry. CONCLUSION: Real-time in vivo cell trafficking is feasible using PET imaging of 89Zr-DFO-labeled CAR T-cells. This can be used to investigate cellular kinetics, initial in vivo biodistribution, and safety profiles in future CAR T-cell development.


Assuntos
Desferroxamina/análogos & derivados , Isotiocianatos/farmacologia , Radioisótopos/farmacologia , Receptores de Antígenos de Linfócitos T/isolamento & purificação , Receptores de Antígenos Quiméricos/isolamento & purificação , Zircônio/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desferroxamina/farmacologia , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/patologia , Humanos , Imunoconjugados/farmacologia , Marcação por Isótopo , Células Jurkat , Leucócitos Mononucleares/química , Leucócitos Mononucleares/efeitos dos fármacos , Tomografia por Emissão de Pósitrons , Radioisótopos/química , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/uso terapêutico , Receptores de Antígenos Quiméricos/química , Receptores de Antígenos Quiméricos/uso terapêutico , Linfócitos T/química , Linfócitos T/imunologia , Distribuição Tecidual
16.
Life Sci ; 243: 117291, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31927049

RESUMO

AIMS: Chronic obstructive pulmonary disease (COPD) is a disease with high morbidity and mortality worldwide, which can cause serious social and economic burdens. Allyl isothiocyanate (AITC) is one of the most common natural isothiocyanates and has been shown to have anti-inflammatory and antioxidant biological activities. The purpose of this study was to investigate whether AITC regulated Multidrug resistance-associated protein 1 (MRP1), reactive oxide species (ROS) and reduced glutathione (GSH) levels via Nrf2 and Notch1 signaling pathways to treat COPD and whether there was an interaction between these two pathways. MAIN METHODS: Lung function indexes and histopathological changes in mice were determined by lung function instrument and HE staining, respectively. The protein expression was analyzed using immunohistochemistry and Western blotting. The mRNA expression was measured by RT-PCR in human bronchial epithelial cell line 16HBE. The contents of ROS, GSH and GSSG were detected by kits in 16HBE cells. KEY FINDINGS: The protein expression of Notch1, Hes1, MRP1, Nrf2, and HO-1 in lung tissues of WT mice and untransfected cells were significantly down-regulated in COPD, then significantly ameliorated in treatment groups. The protein expression of MRP1, Notch1 and Hes1 in lung tissues of Nrf2-/- mice were markedly reduced. There was a significant reduction in expression of Nrf2, HO-1 and MRP1 in si-Notch1 transfected cells. Pretreatment with AITC markedly improved oxidative stress and GSH-redox disorder in COPD. SIGNIFICANCE: Our study demonstrates that there is a potential interaction between Nrf2 and Notch1 signaling pathways during treatment of COPD.


Assuntos
Isotiocianatos/uso terapêutico , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Receptor Notch1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Animais , Isotiocianatos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/genética , Oxirredução , Doença Pulmonar Obstrutiva Crônica/metabolismo , Fatores de Transcrição HES-1/metabolismo
17.
J Agric Food Chem ; 68(5): 1226-1236, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31922739

RESUMO

As a substitute for methyl bromide, effects of allyl isothiocyanate (AITC) on nontarget microorganisms in soil are poorly understood. This study measured the half-life of AITC in the soil as well as its effects on the soil substrate-induced respiration (SIR) and on communities of soil bacteria and fungi. The results showed that AITC had a short half-life and a short-term inhibition of SIR; high-throughput sequencing analysis showed that AITC had less effect on bacterial than fungal communities. Fumigation reduced the diversity of soil bacteria temporarily, but stimulated the diversity of soil fungi in the long-term and significantly changed the structure of the fungal community. Following AITC fumigation there were significant increases in the relative abundance of probiotics such as Sphingomonas, Streptomyces, Hypocreales, Acremonium, Aspergillus, and Pseudallescheria that help to control plant diseases. Our study provided useful information for assessing the ecological safety of AITC.


Assuntos
Bactérias/efeitos dos fármacos , Fungos/efeitos dos fármacos , Isotiocianatos/farmacologia , Microbiologia do Solo , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Biodiversidade , Fumigação , Fungos/classificação , Fungos/genética , Fungos/isolamento & purificação , Isotiocianatos/química , Lycopersicon esculentum/crescimento & desenvolvimento , Solo/química
18.
Mol Cell Biol ; 40(6)2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-31932477

RESUMO

Nrf2 (NF-E2-related-factor 2) is a stress-responsive transcription factor that protects cells against oxidative stresses. To clarify whether Nrf2 prevents Alzheimer's disease (AD), AD model AppNL-G-F/NL-G-F knock-in (AppNLGF ) mice were studied in combination with genetic Nrf2 induction model Keap1FA/FA mice. While AppNLGF mice displayed shorter latency to escape than wild-type mice in the passive-avoidance task, the impairment was improved in AppNLGF ::Keap1FA/FA mice. Matrix-assisted laser desorption ionization-mass spectrometry imaging revealed that reduced glutathione levels were elevated by Nrf2 induction in AppNLGF ::Keap1FA/FA mouse brains compared to AppNLGF mouse brains. Genetic Nrf2 induction in AppNLGF mice markedly suppressed the elevation of the oxidative stress marker 8-OHdG and Iba1-positive microglial cell number. We also determined the plasmalogen-phosphatidylethanolamine (PlsPE) level as an AD biomarker. PlsPE containing polyunsaturated fatty acids was decreased in the AppNLGF mouse brain, but Nrf2 induction attenuated this decline. To evaluate whether pharmacological induction of Nrf2 elicits beneficial effects for AD treatment, we tested the natural compound 6-MSITC [6-(methylsulfinyl)hexyl isothiocyanate]. Administration of 6-MSITC improved the impaired cognition of AppNLGF mice in the passive-avoidance task. These results demonstrate that the induction of Nrf2 ameliorates cognitive impairment in the AD model mouse by suppressing oxidative stress and neuroinflammation, suggesting that Nrf2 is an important therapeutic target of AD.


Assuntos
Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/fisiologia , Peptídeos beta-Amiloides/metabolismo , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Proteínas de Ligação ao Cálcio/metabolismo , Cognição/efeitos dos fármacos , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Glutationa/sangue , Inflamação/patologia , Isotiocianatos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas dos Microfilamentos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fosfatidiletanolaminas/metabolismo , Placa Amiloide/genética , Placa Amiloide/patologia , Plasmalogênios/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
19.
Phytother Res ; 34(4): 721-728, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31972874

RESUMO

Effective management and treatment of cancer depend on developing novel antitumor drugs with the capability of targeting various molecular pathways. Identification and subsequent targeting of these pathways are of importance in cancer therapy. MicroRNAs (miRNAs) are small noncoding RNA molecules responsible for post-transcriptional regulation of genes. Notably, miRNAs participate in a number of biological processes such as proliferation, apoptosis, differentiation, and cell cycle regulation. So, any impairment in the expression and function of miRNAs is associated with development of disorders, particularly cancer. Naturally occurring nutraceutical compounds have attracted much attention due to their great antitumor activity. Among them, sulforaphane isolated from Brassica oleracea (broccoli) is of interest due to its therapeutic and biological activities such as antidiabetic, antioxidant, anti-inflammatory, hepatoprotection, and cardiprotection. Sulforaphane has demonstrated great antitumor activity and is able to significantly inhibit proliferation, viability, migration, malignancy, and epithelial-to-mesenchymal transition of cancer cells. These antitumor effects have widely been investigated, and it appears that there is a need for a precise review to demonstrate the molecular pathway that sulforaphane follows to exert its antitumor activity. At the present review, we focus on the modulatory impact of sulforaphane on miRNAs and exhibit that how various miRNAs in different cancers are regulated by sulforaphane.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Isotiocianatos/farmacologia , MicroRNAs/fisiologia , Neoplasias/tratamento farmacológico , Neoplasias/genética , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Brassica/química , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Isotiocianatos/isolamento & purificação , MicroRNAs/metabolismo , Neoplasias/patologia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico
20.
Life Sci ; 241: 117061, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31794774

RESUMO

The consumption of cruciferous vegetables rich in isothiocyanates has long been associated with a reduced risk of various types of cancer. 4-(methylthio)butyl isothiocyanate also called erucin is an isothiocyanate present in appreciable quantity in the seeds of Eruca sativa Mill. plant. Although the literature has revealed its protective effects via inducing phase II enzymes and inhibiting carcinogen activating phase I enzymes, recent studies also suggest that, it inhibits the proliferation of cancer cells by altering the telomerase activity, dynamics of microtubules, expression of histone deacetylases, and other molecular pathways. With this in mind, the emphasis has been made to review the molecular targets involved in cancer prevention by 4-(methylthio)butyl isothiocyanate.


Assuntos
Anticarcinógenos/farmacologia , Antineoplásicos/farmacologia , Isotiocianatos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Humanos , Telomerase/metabolismo , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
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