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1.
Aging Male ; 22(2): 129-140, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29925283

RESUMO

Testosterone is the predominant gonadal androgen in men. Low testosterone levels are found to be associated with an increased in metabolic risk and systematic inflammation. Since adipose tissue is a source of inflammatory cytokines, testosterone may regulate inflammation by acting on adipose tissue. This review aimed to explore the role of testosterone in inflammation and its mechanism of action. Both animal studies and human studies showed that (1) testosterone deficiency was associated with an increase in pro-inflammatory cytokines; (2) testosterone substitution reduced pro-inflammatory cytokines. The suppression of inflammation by testosterone were observed in patients with coronary artery disease, prostate cancer and diabetes mellitus through the increase in anti-inflammatory cytokines (IL-10) and the decrease in pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α). Despite these, some studies also reported a non-significant relationship. In conclusion, testosterone may possess anti-inflammatory properties but its magnitude is debatable. More evidence is needed to validate the use of testosterone as a marker and in the management of chronic inflammatory diseases.


Assuntos
Inflamação/sangue , Testosterona/sangue , Tecido Adiposo/metabolismo , Idoso , Animais , Biomarcadores/sangue , Humanos , Inflamação/fisiopatologia , Interleucina-10/sangue , Interleucina-1beta/sangue , Interleucina-6/sangue , Masculino , Síndrome Metabólica/sangue , Testosterona/farmacologia , Fator de Necrose Tumoral alfa/sangue
2.
BMC Complement Altern Med ; 14: 72, 2014 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-24559113

RESUMO

BACKGROUND: Nuclear factor-erythroid 2 p45 related factor 2 (Nrf2) is a primary transcription factor, protecting cells from oxidative stress by regulating a number of antioxidants and phase II detoxifying enzymes. Dietary components such as sulforaphane in broccoli and quercetin in onions have been shown to be inducers of Nrf2. Piper betle (PB) grows well in tropical climate and the leaves are used in a number of traditional remedies for the treatment of stomach ailments and infections among Asians. The aim of this study was to elucidate the effect of Piper betle (PB) leaves extract in Nrf2 signaling pathway by using 2 types of cells; mouse embryonic fibroblasts (MEFs) derived from wild-type (WT) and Nrf2 knockout (N0) mice. METHODS: WT and N0 cells were treated with 5 and 10 µg/ml of PB for 10 and 12-h for the determination of nuclear translocation of Nrf2 protein. Luciferase reporter gene activity was performed to evaluate the antioxidant response element (ARE)-induction by PB. Real-time PCR and Western blot were conducted on both WT and N0 cells after PB treatment for the determination of antioxidant enzymes [superoxide dismutase (SOD1) and heme-oxygenase (HO-1)], phase I oxidoreductase enzymes [ NAD(P)H: quinone oxidoreductase (NQO1)] and phase II detoxifying enzyme [glutathione S-transferase (GST)]. RESULTS: Nuclear translocation of Nrf2 by PB in WT cells was better after 10 h incubation compared to 12 h. Real time PCR and Western blot analysis showed increased expressions of Nrf2, NQO1 and GSTA1 genes with corresponding increases in glutathione, NQO1 and HO-1 proteins in WT cells. Reporter gene ARE was stimulated by PB as shown by ARE/luciferase assay. Interestingly, PB induced SOD1 gene and protein expressions in N0 cells but not in WT cells. CONCLUSION: The results of this study confirmed that PB activated Nrf2-ARE signaling pathway which subsequently induced some phase I oxidoreductase, phase II detoxifying and antioxidant genes expression via ARE reporter gene involved in the Nrf2 pathway with the exception of SOD1 which may not be dependent on this pathway.


Assuntos
Elementos de Resposta Antioxidante , Antioxidantes/metabolismo , Inativação Metabólica/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Piper betle , Extratos Vegetais/farmacologia , Animais , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Expressão Gênica/efeitos dos fármacos , Glutationa/metabolismo , Glutationa Transferase/metabolismo , Desintoxicação Metabólica Fase I/genética , Desintoxicação Metabólica Fase II/genética , Camundongos , NAD(P)H Desidrogenase (Quinona)/metabolismo , Transdução de Sinais
3.
Drug Des Devel Ther ; 14: 969-976, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32184566

RESUMO

PURPOSE: Annatto-derived tocotrienol (AnTT) has been shown to improve bone formation in animal models of osteoporosis and promote differentiation of pre-osteoblastic cells. However, the mechanism of action of AnTT in achieving these effects is unclear. This study aims to investigate the mechanism of action of AnTT on MC3T3-E1 pre-osteoblasts via the mevalonate pathway. METHODS: Murine pre-osteoblastic cells, MC3T3-E1, were cultured with the density of 1 × 104 cells/mL and treated with 4 concentrations of AnTT (0.001-1 µg/mL). Expression of HMG-CoA reductase (HMGR) gene was carried out using qPCR after treatment with AnTT for 21 days. RhoA activation and bone morphogenetic protein-2 (BMP-2) were measured using immunoassay after 9 and 15 days of AnTT treatment. Lovastatin was used as the positive control. Mineralized nodules were detected using Von Kossa staining after 21 days of AnTT treatment. RESULTS: The results showed that HMGR was up-regulated in the lovastatin group on day 9 and 21 compared to the control. Lovastatin also inhibited RhoA activation (day 9 and 15) and increased BMP-2 protein (day 15). On the other hand, AnTT at 0.001 µg/mL (day 3) and 0.1 µg/mL (day 21) significantly down-regulated HMGR gene expression compared to the control. On day 21, HMGR gene expression was significantly reduced in all groups compared to day 15. AnTT at 0.1 µg/mL significantly decreased RhoA activation on day 9 compared to the control. AnTT at 1 µg/mL significantly increased BMP-2 protein on day 15 compared to the control (P<0.05). Mineralized calcium nodules were more abundant in AnTT treated groups compared to the control on day 21. CONCLUSION: AnTT suppresses the mevalonate pathway by downregulating HMGR gene expression and inhibiting RhoA activation, leading to increased BMP-2 protein in MC3T3-E1 cells. This explains the stimulating effects of AnTT on osteoblast mineralization.


Assuntos
Proteína Morfogenética Óssea 2/genética , Carotenoides/farmacologia , Hidroximetilglutaril-CoA Redutases/genética , Extratos Vegetais/farmacologia , Tocotrienóis/farmacologia , Proteína rhoA de Ligação ao GTP/antagonistas & inibidores , Células 3T3 , Animais , Bixaceae , Proteína Morfogenética Óssea 2/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Hidroximetilglutaril-CoA Redutases/metabolismo , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade , Proteína rhoA de Ligação ao GTP/metabolismo
4.
Drug Des Devel Ther ; 12: 1715-1726, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29942115

RESUMO

PURPOSE: Annatto-derived tocotrienol (AnTT) has been shown to improve bone formation in animal models of osteoporosis. However, detailed studies of the effects of AnTT on preosteoblastic cells were limited. This study was conducted to investigate the osteogenic effect of AnTT on preosteoblast MC3T3-E1 cells in a time-dependent manner. MATERIALS AND METHODS: Murine MC3T3-E1 preosteoblastic cells were cultured in the different concentrations of AnTT (0.001-1 µg/mL) up to 24 days. Expression of osteoblastic differentiation markers was measured by qPCR (osterix [OSX], collagen 1 alpha 1 [COL1α1], alkaline phosphatase [ALP], and osteocalcin [OCN]) and by fluorometric assay for ALP activity. Detection of collagen and mineralized nodules was done via Direct Red staining and Alizarin Red staining, respectively. RESULTS: The results showed that osteoblastic differentiation-related genes, such as OSX, COL1α1, ALP, and OCN, were significantly increased in the AnTT-treated groups compared to the vehicle group in a time-dependent manner (P<0.05). Type 1 collagen level was increased from day 3 to day 15 in the AnTT-treated groups, while ALP activity was increased from day 9 to day 21 in the AnTT-treated groups (P<0.05). Enhanced mineralization was observed in the AnTT-treated groups via increasing Alizarin Red staining from day 3 to day 21 (P<0.05). CONCLUSION: Our results suggest that AnTT enhances the osteogenic activity by promoting the bone formation-related genes and proteins in a temporal and sequential manner.


Assuntos
Bixaceae , Osteoblastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos , Tocotrienóis/farmacologia , Células 3T3 , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Animais , Bixaceae/química , Proliferação de Células/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Cadeia alfa 1 do Colágeno Tipo I , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Osteoblastos/metabolismo , Osteocalcina/genética , Osteocalcina/metabolismo , Osteogênese/genética , Fitoterapia , Plantas Medicinais , Sementes , Fator de Transcrição Sp7/genética , Fator de Transcrição Sp7/metabolismo , Células-Tronco/metabolismo , Fatores de Tempo , Tocotrienóis/isolamento & purificação
5.
J Nutrigenet Nutrigenomics ; 9(5-6): 243-253, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28002828

RESUMO

BACKGROUND/AIMS: The objective of this study was to elucidate the underlying antioxidant mechanism of aqueous extract of Piper betle (PB) in aging rats. The nuclear factor erythroid 2-related factor 2 (Nrf2)/ARE pathway involving phase II detoxifying and antioxidant enzymes plays an important role in the antioxidant system by reducing electrophiles and reactive oxygen species through induction of phase II enzymes and proteins. METHODS: Genes and proteins of phase II detoxifying antioxidant enzymes were analyzed by QuantiGenePlex 2.0 Assay and Western blot analysis. RESULTS: PB significantly induced genes and proteins of phase II and antioxidant enzymes, NAD(P)H quinone oxidoreductase 1, and catalase in aging mice (p < 0.05). The expression of these enzymes were stimulated via translocation of Nrf2 into the nucleus, indicating the involvement of ARE, a cis-acting motif located in the promoter region of nearly all phase II genes. CONCLUSIONS: PB was testified for the first time to induce cytoprotective genes through the Nrf2/ARE signaling pathway, thus unraveling the antioxidant mechanism of PB during the aging process.


Assuntos
Envelhecimento , Elementos de Resposta Antioxidante/efeitos dos fármacos , Citoproteção , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Piper betle/química , Extratos Vegetais/farmacologia , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Envelhecimento/metabolismo , Animais , Elementos de Resposta Antioxidante/genética , Elementos de Resposta Antioxidante/fisiologia , Antioxidantes/farmacologia , Citoproteção/efeitos dos fármacos , Citoproteção/genética , Masculino , Desintoxicação Metabólica Fase II/genética , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/genética , Extratos Vegetais/química , Proteínas/efeitos dos fármacos , Proteínas/genética , Proteínas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
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