Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 121
Filtrar
Mais filtros

Bases de dados
País/Região como assunto
Tipo de documento
Intervalo de ano de publicação
1.
Mol Cell ; 81(18): 3820-3832.e7, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34233158

RESUMO

A metabolic imbalance between lipid synthesis and degradation can lead to hepatic lipid accumulation, a characteristic of patients with non-alcoholic fatty liver disease (NAFLD). Here, we report that high-fat-diet-induced sterol regulatory element-binding protein (SREBP)-1c, a key transcription factor that regulates lipid biosynthesis, impairs autophagic lipid catabolism via altered H2S signaling. SREBP-1c reduced cystathionine gamma-lyase (CSE) via miR-216a, which in turn decreased hepatic H2S levels and sulfhydration-dependent activation of Unc-51-like autophagy-activating kinase 1 (ULK1). Furthermore, Cys951Ser mutation of ULK1 decreased autolysosome formation and promoted hepatic lipid accumulation in mice, suggesting that the loss of ULK1 sulfhydration was directly associated with the pathogenesis of NAFLD. Moreover, silencing of CSE in SREBP-1c knockout mice increased liver triglycerides, confirming the connection between CSE, autophagy, and SREBP-1c. Overall, our results uncover a 2-fold mechanism for SREBP-1c-driven hepatic lipid accumulation through reciprocal activation and inhibition of hepatic lipid biosynthesis and degradation, respectively.


Assuntos
Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Fígado Gorduroso/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Animais , Autofagia , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/fisiologia , Linhagem Celular Tumoral , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/fisiopatologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Metabolismo dos Lipídeos/fisiologia , Lipídeos/fisiologia , Lipogênese , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/metabolismo , Transdução de Sinais/fisiologia , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/fisiologia , Triglicerídeos/metabolismo
2.
Mol Cell ; 57(2): 207-18, 2015 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-25533187

RESUMO

mTORC1 plays a key role in autophagy as a negative regulator. The currently known targets of mTORC1 in the autophagy pathway mainly function at early stages of autophagosome formation. Here, we identify that mTORC1 inhibits later stages of autophagy by phosphorylating UVRAG. Under nutrient-enriched conditions, mTORC1 binds and phosphorylates UVRAG. The phosphorylation positively regulates the association of UVRAG with RUBICON, thereby enhancing the antagonizing effect of RUBICON on UVRAG-mediated autophagosome maturation. Upon dephosphorylation, UVRAG is released from RUBICON to interact with the HOPS complex, a component for the late endosome and lysosome fusion machinery, and enhances autophagosome and endosome maturation. Consequently, the dephosphorylation of UVRAG facilitates the lysosomal degradation of epidermal growth factor receptor (EGFR), reduces EGFR signaling, and suppresses cancer cell proliferation and tumor growth. These results demonstrate that mTORC1 engages in late stages of autophagy and endosome maturation, defining a broader range of mTORC1 functions in the membrane-associated processes.


Assuntos
Endossomos/enzimologia , Complexos Multiproteicos/fisiologia , Fagossomos/enzimologia , Processamento de Proteína Pós-Traducional , Serina-Treonina Quinases TOR/fisiologia , Proteínas Supressoras de Tumor/metabolismo , Sequência de Aminoácidos , Animais , Proteínas Relacionadas à Autofagia , Proliferação de Células , Classe III de Fosfatidilinositol 3-Quinases/metabolismo , Células HCT116 , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos Nus , Transplante de Neoplasias , Fosforilação , Proteínas rab de Ligação ao GTP/metabolismo , proteínas de unión al GTP Rab7
3.
Nutr Res Rev ; : 1-10, 2023 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-37469212

RESUMO

Age is a risk factor for numerous diseases. Although the development of modern medicine has greatly extended the human lifespan, the duration of relatively healthy old age, or 'healthspan', has not increased. Targeting the detrimental processes that can occur before the onset of age-related diseases can greatly improve health and lifespan. Healthspan is significantly affected by what, when and how much one eats. Dietary restriction, including calorie restriction, fasting or fasting-mimicking diets, to extend both lifespan and healthspan has recently attracted much attention. However, direct scientific evidence that consuming specific foods extends the lifespan and healthspan seems lacking. Here, we synthesized the results of recent studies on the lifespan and healthspan extension properties of foods and their phytochemicals in various organisms to confirm how far the scientific research on the effect of food on the lifespan has reached.

4.
FASEB J ; 34(6): 8068-8081, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32293073

RESUMO

Dietary habits can alter the skeletal muscle performance and mass, and Undaria pinnatifida extracts are considered a potent candidate for improving the muscle mass and function. Therefore, in this study, we aimed to assess the effect of U pinnatifida extracts on exercise endurance and skeletal muscle mass. C57BL/6 mice were fed a 0.25% U pinnatifida extract-containing diet for 8 weeks. U pinnatifida extract-fed mice showed increased running distance, total running time, and extensor digitorum longus and gastrocnemius muscle weights. U pinnatifida extract supplementation upregulated the expression of myocyte enhancer factor 2C, oxidative muscle fiber markers such as myosin heavy chain 1 (MHC1), and oxidative biomarkers in the gastrocnemius muscles. Compared to the controls, U pinnatifida extract-fed mice showed larger mitochondria and increased gene and protein expression of molecules involved in mitochondrial biogenesis and oxidative phosphorylation, including nuclear respiratory factor 2 and mitochondrial transcription factor A. U pinnatifida extract supplementation also increased the mRNA expression of angiogenesis markers, including VEGFa, VEGFb, FGF1, angiopoietin 1, and angiopoietin 2, in the gastrocnemius muscles. Importantly, U pinnatifida extracts upregulated the estrogen-related receptor γ and peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α)/AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) networks, which are partially increased by fucoxanthin, hesperetin, and caffeic acid treatments. Collectively, U pinnatifida extracts enhance mitochondrial biogenesis, increase oxidative muscle fiber, and promote angiogenesis in skeletal muscles, resulting in improved exercise capacity and skeletal muscle mass. These effects are attributable to fucoxanthin, hesperetin, and caffeic acid, bioactive components of U pinnatifida extracts.


Assuntos
Músculo Esquelético/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Condicionamento Físico Animal/fisiologia , Resistência Física/efeitos dos fármacos , Extratos Vegetais/farmacologia , Undaria/química , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Biomarcadores/metabolismo , Linhagem Celular , Proteínas de Ligação a DNA/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Músculo Esquelético/metabolismo , Doenças Musculares/tratamento farmacológico , Doenças Musculares/metabolismo , Biogênese de Organelas , Fosforilação Oxidativa/efeitos dos fármacos , Sirtuína 1/metabolismo , Fatores de Transcrição/metabolismo
5.
Biochem Biophys Res Commun ; 524(3): 744-749, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32035621

RESUMO

Endoplasmic reticulum (ER) stress and autophagy are regulated by shared signaling pathways, and their dysfunction is directly related to pathological conditions. This study investigated the function of the unc-51 like autophagy activating kinase 1 (ULK1)-autophagy related 13 (ATG13) complex in ER stress conditions through a knockout (KO) approach. Unlike other autophagy genes, KO of ULK1 or ATG13 attenuated ER stress and promoted mammalian target of rapamycin complex 1 (mTORC1) activation. Compared with wild type (WT) cells, ULK1 and ATG13 KO cells displayed increased viability, while beclin 1, ATG14, and ULK1/2 KO cells did not. Tunicamycin treatment upregulated the expression of ER stress markers (DNA damage inducible transcript 3, heat shock protein family A (Hsp70) member 5, and phosphorylated eukaryotic translation initiation factor 2 alpha kinase 3, eukaryotic translation initiation factor 2 subunit alpha, and endoplasmic reticulum to nucleus signaling 1); however, these were decreased in ULK1 and ATG13 KO cells. Insulin treatment upregulates the phosphorylation of ribosomal protein S6 kinase B1 (RPS6KB1) and AKT serine/threonine kinase 1 (AKT1), which was suppressed by tunicamycin. Notably, ATG13 and ULK1 deficiency ameliorated tunicamycin-induced insulin resistance, with enhanced RPS6KB1 and AKT1 phosphorylation in KO cells compared to WT cells. Although ULK1 and ATG13 are necessary for autophagy induction after tunicamycin-induced ER stress, autophagy does not seem to directly affect tunicamycin-induced cell death, ER stress, or insulin resistance. Our results indicate that loss of the ULK1-ATG13 complex attenuates ER stress and cell death and increases mTORC1 signaling.


Assuntos
Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Proteínas Relacionadas à Autofagia/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Tunicamicina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Estresse do Retículo Endoplasmático , Células HCT116 , Humanos , Insulina/farmacologia , Camundongos
6.
FASEB J ; 33(3): 3252-3263, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30376359

RESUMO

The consumption of soybeans is known to have beneficial effects on osteoporosis in postmenopausal women. However, the effects of soybean fermentation on the bioavailability and the antiosteoporotic effect have not yet been elucidated. To address this question, we fed ovariectomized C57BL/6J mice with a 5% nonfermented raw soybean (RS)- or fermented soybean (FS)-supplemented diet. After 18 wk of treatment, microcomputed tomography showed that FSs significantly increased bone mineral density compared with RSs. This was because of the up-regulation of bone morphogenic protein 2 (Bmp2) and its downstream target osteopontin in bone tissues. We analyzed isoflavone metabolite profiles in the sera of RS- or FS-fed mice and observed that the levels of 19 isoflavone metabolites were significantly increased in the sera of FS-fed mice. Among these metabolites, we observed that both dihydrodaidzein (DHD) and 6-hydroxydaidzein (6-HD) increased osteogenesis via Bmp2 signaling pathway in MC3T3-E1 cells and reduced receptor activator of nuclear factor κ-B ligand-induced osteoclastogenesis in RAW264.7 cells through the inhibition of NF-κB activation and MAPK phosphorylation. These data suggest that improved bioavailability of FSs resulted from the production of active metabolites such as DHD and 6-HD after consumption. DHD and 6-HD can be used as potential therapeutics for the amelioration of osteoporotic bone loss.-Kim, J.-S., Lee, H., Nirmala, F. S., Jung, C. H., Kim, M. J., Jang, Y.-J., Ha, T. Y., Ahn, J. Dihydrodaidzein and 6-hydroxydaidzein mediate the fermentation-induced increase of anti-osteoporotic effect of soybeans in ovariectomized mice.


Assuntos
Glycine max/metabolismo , Isoflavonas/metabolismo , Osteoporose/dietoterapia , Células 3T3 , Animais , Disponibilidade Biológica , Proteína Morfogenética Óssea 2/metabolismo , Modelos Animais de Doenças , Feminino , Fermentação , Alimentos Fermentados , Alimento Funcional , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Osteoclastos/metabolismo , Osteogênese , Osteoporose/metabolismo , Ovariectomia , Células RAW 264.7 , Transdução de Sinais , Via de Sinalização Wnt
7.
Int J Mol Sci ; 21(8)2020 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-32316567

RESUMO

As obesity promotes ectopic fat accumulation in skeletal muscle, resulting in impaired skeletal muscle and mitochondria function, it is associated with skeletal muscle loss and dysfunction. This study investigated whether Chrysanthemi zawadskii var. latilobum (CZH) protected mice against obesity-induced skeletal muscle atrophy and the underlying molecular mechanisms. High-fat diet (HFD)-induced obese mice were orally administered either distilled water, low-dose CZH (125 mg/kg), or high-dose CZH (250 mg/kg) for 8 w. CZH reduced obesity-induced increases in inflammatory cytokines levels and skeletal muscle atrophy, which is induced by expression of atrophic genes such as muscle RING-finger protein 1 and muscle atrophy F-box. CZH also improved muscle function according to treadmill running results and increased the muscle fiber size in skeletal muscle. Furthermore, CZH upregulated mRNA and protein levels of protein arginine methyltransferases (PRMT)1 and PRMT7, which subsequently attenuated mitochondrial dysfunction in the skeletal muscle of obese mice. We also observed that CZH significantly decreased PRMT6 mRNA and protein expression, which resulted in decreased muscle atrophy. These results suggest that CZH ameliorated obesity-induced skeletal muscle atrophy in mice via regulation of PRMTs in skeletal muscle.


Assuntos
Chrysanthemum/química , Dieta Hiperlipídica/efeitos adversos , Músculo Esquelético/patologia , Atrofia Muscular/tratamento farmacológico , Obesidade/complicações , Extratos Vegetais/administração & dosagem , Proteína-Arginina N-Metiltransferases/metabolismo , Administração Oral , Animais , Citocinas/metabolismo , Masculino , Camundongos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Cadeias Pesadas de Miosina/metabolismo , Obesidade/induzido quimicamente , Obesidade/metabolismo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Proteína-Arginina N-Metiltransferases/genética , Regulação para Cima/efeitos dos fármacos
8.
Biochem Biophys Res Commun ; 513(3): 553-559, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-30981498

RESUMO

Recent studies suggest an alternative pathway of lipid breakdown called lipophagy, which delivers lipid droplets (LDs) to lysosomes for degradation of LDs. However, molecular mechanisms regulating lipophagy are still largely unknown. In this study, we evaluated the effect of oleic acid (OA) on lipophagy in cells. We found that OA treatment results in accumulation of p62 and LC3-II proteins and reduces red fluorescence in cells stably expressing mCherry-GFP-LC3. In addition, OA inhibits the co-localization of LC3 with LAMP1 under serum-deprived condition, suggesting that OA blocks autophagosome-lysosome fusion. In the cells with ATG5 or ULK1 gene deletion, LDs did not increase upon OA treatment more than in wild type cells. However, cell starvation following OA removal resulted in reduced lipid accumulation by lipophagy and recovery of autophagy flux, suggesting that the specific condition of OA treatment and cell starvation are important for lipophagy flux activity.


Assuntos
Autofagia/efeitos dos fármacos , Lipólise/efeitos dos fármacos , Lisossomos/efeitos dos fármacos , Ácido Oleico/farmacologia , Animais , Autofagossomos/efeitos dos fármacos , Autofagossomos/metabolismo , Linhagem Celular , Células Hep G2 , Humanos , Gotículas Lipídicas/metabolismo , Lisossomos/metabolismo , Camundongos
9.
Mol Cell ; 43(4): 572-85, 2011 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-21855797

RESUMO

Autophagy, the primary recycling pathway of cells, plays a critical role in mitochondrial quality control under normal growth conditions and in the response to cellular stress. The Hsp90-Cdc37 chaperone complex coordinately regulates the activity of select kinases to orchestrate many facets of the stress response. Although both maintain mitochondrial integrity, the relationship between Hsp90-Cdc37 and autophagy has not been well characterized. Ulk1, one of the mammalian homologs of yeast Atg1, is a serine-threonine kinase required for mitophagy. Here we show that the interaction between Ulk1 and Hsp90-Cdc37 stabilizes and activates Ulk1, which in turn is required for the phosphorylation and release of Atg13 from Ulk1, and for the recruitment of Atg13 to damaged mitochondria. Hsp90-Cdc37, Ulk1, and Atg13 phosphorylation are all required for efficient mitochondrial clearance. These findings establish a direct pathway that integrates Ulk1- and Atg13-directed mitophagy with the stress response coordinated by Hsp90 and Cdc37.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Autofagia/fisiologia , Proteínas de Ciclo Celular/fisiologia , Chaperoninas/fisiologia , Proteínas de Choque Térmico HSP90/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Mitocôndrias/metabolismo , Proteínas Serina-Treonina Quinases/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteína Homóloga à Proteína-1 Relacionada à Autofagia , Proteínas Relacionadas à Autofagia , Proteínas de Ciclo Celular/metabolismo , Diferenciação Celular , Linhagem Celular , Chaperoninas/metabolismo , Células Eritroides/citologia , Células Eritroides/metabolismo , Células HEK293 , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Células K562 , Camundongos , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Estabilidade Proteica , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/fisiologia
10.
Planta Med ; 85(3): 210-216, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30199902

RESUMO

2,6-Dimethoxy-1,4-benzoquinone is a natural phytochemical present in fermented wheat germ. It has been reported to exhibit anti-inflammatory, antitumor, and antibacterial activities. However, the anti-adipogenic effects of 2,6-dimethoxy-1,4-benzoquinone and the mechanisms responsible have not previously been elucidated. Such findings may have ramifications for the treatment of obesity. 2,6-Dimethoxy-1,4-benzoquinone (5 and 7.5 µM) significantly reduced the expression of various adipogenic transcription factors, including peroxisome proliferator-activated receptor-γ and CCAAT/enhancer binding protein α as well as adipocyte protein 2 and fatty acid synthase. 2,6-Dimethoxy-1,4-benzoquinone upregulated AMP-dependent protein kinase phosphorylation and inhibited the mature form of sterol regulatory element-binding protein 1c. Notably, 2,6-dimethoxy-1,4-benzoquinone attenuated mammalian target of rapamycin complex 1 activity in 3T3-L1 and mouse embryonic fibroblast cells. These findings highlight a potential role for 2,6-dimethoxy-1,4-benzoquinone in the suppression of adipogenesis. Further studies to determine the anti-obesity effects of 2,6-dimethoxy-1,4-benzoquinone in animal models appear warranted.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adipócitos/efeitos dos fármacos , Benzoquinonas/farmacologia , Diferenciação Celular/efeitos dos fármacos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Transdução de Sinais/genética , Células 3T3-L1 , Adipócitos/metabolismo , Adipócitos/fisiologia , Animais , Camundongos , Camundongos Knockout , Transdução de Sinais/efeitos dos fármacos
11.
Muscle Nerve ; 58(2): 314-318, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29572868

RESUMO

INTRODUCTION: Apigenin (AP) has been reported to elicit anti-inflammatory effects. In this study, we investigated the effect of AP on sciatic nerve denervation-induced muscle atrophy. METHODS: Sciatic nerve-denervated mice were fed a 0.1% AP-containing diet for 2 weeks. Muscle weight and cross-sectional area (CSA), and the expression of atrophic genes and inflammatory cytokines in the gastrocnemius were analyzed. RESULTS: Denervation significantly induced muscle atrophy. However, values for muscle weight and CSA were greater in the denervated muscle of the AP mice than the controls. AP suppressed the expression of MuRF1, but upregulated both myosin heavy chain (MHC) and MHC type IIb. AP also significantly suppressed expression of tumor necrosis-alpha in the gastrocnemius and soleus muscles, and interleukin-6 expression in the soleus muscle. DISCUSSION: AP appears to inhibit denervation-induced muscle atrophy, which may be due in part to its inhibitory effect on inflammatory processes within muscle. Muscle Nerve 58: 314-318, 2018.


Assuntos
Apigenina/uso terapêutico , Atrofia Muscular/etiologia , Atrofia Muscular/prevenção & controle , Nervo Isquiático , Anatomia Transversal , Animais , Denervação , Expressão Gênica/efeitos dos fármacos , Interleucina-6/biossíntese , Interleucina-6/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Musculares/biossíntese , Proteínas Musculares/genética , Atrofia Muscular/genética , Cadeias Pesadas de Miosina/biossíntese , Cadeias Pesadas de Miosina/genética , Tamanho do Órgão , Proteínas com Motivo Tripartido/biossíntese , Proteínas com Motivo Tripartido/genética , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossíntese , Ubiquitina-Proteína Ligases/biossíntese , Ubiquitina-Proteína Ligases/genética
12.
Biosci Biotechnol Biochem ; 82(7): 1197-1206, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29557265

RESUMO

Mitochondrial dysfunction is associated with insulin resistance. Although chicoric acid (CA) is known to have beneficial effects on insulin sensitivity, the involvement of mitochondrial function has not been elucidated yet. Here, we investigated the effect of CA on insulin resistance and mitochondrial dysfunction. In palmitate-induced insulin-resistant C2C12 myotubes, CA improved impaired glucose uptake and insulin signaling pathways, along with enhanced mitochondrial membrane potential and oxygen consumption. CA treatment in diet-induced obese mice ameliorated glucose tolerance and increased insulin sensitivity. CA treatment also recovered the dysregulated expression of glucose metabolism-related genes in the high-fat-fed mice. CA significantly increased the mitochondrial DNA content, citrate synthase, and ATP content, as well as the expression of genes related to mitochondrial biogenesis and oxidative phosphorylation in the liver and skeletal muscle in high-fat- fed obese mice. These findings suggested that CA attenuates insulin resistance and promotes insulin sensitivity by enhancing mitochondrial function.


Assuntos
Ácidos Cafeicos/farmacologia , Resistência à Insulina , Mitocôndrias Musculares/efeitos dos fármacos , Succinatos/farmacologia , Animais , Western Blotting , Linhagem Celular , Dieta Hiperlipídica , Ácidos Graxos não Esterificados/metabolismo , Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Mitocôndrias Musculares/fisiologia , Músculo Esquelético/citologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Fosforilação Oxidativa
13.
J Cell Mol Med ; 20(5): 909-19, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26861188

RESUMO

A number of natural phytochemicals have anti-photoaging properties that appear to be mediated through the inhibition of matrix metalloproteinase-1 (MMP-1) expression, but their direct target molecule(s) and mechanism(s) remain unclear. We investigated the effect of naringenin, a major flavonoid found in citrus, on UVB-induced MMP-1 expression and identified its direct target. The HaCaT human skin keratinocyte cell line and 3-dimensional (3-D) human skin equivalent cultures were treated or not treated with naringenin for 1 hr before exposure to UVB. The mechanism and target(s) of naringenin were analysed by kinase assay and multiplex molecular assays. Dorsal skins of hairless mice were exposed to UVB 3 times per week, with a dose of irradiation that was increased weekly by 1 minimal erythema dose (MED; 45 mJ/cm(2)) to 4 MED over 15 weeks. Wrinkle formation, water loss and water content were then assessed. Naringenin suppressed UVB-induced MMP-1 expression and AP-1 activity, and strongly suppressed UVB-induced phosphorylation of Fos-related antigen (FRA)-1 at Ser265. Importantly, UVB irradiation-induced FRA1 protein stability was reduced by treatment with naringenin, as well as with a mitogen-activated protein kinase (MEK) inhibitor. Naringenin significantly suppressed UVB-induced extracellular signal-regulated kinase 2 (ERK2) activity and subsequently attenuated UVB-induced phosphorylation of p90(RSK) by competitively binding with ATP. Constitutively active MEK (CA-MEK) increased FRA1 phosphorylation and expression and also induced MMP-1 expression, whereas dominant-negative ERK2 (DN-ERK2) had opposite effects. U0126, a MEK inhibitor, also decreased FRA1 phosphorylation and expression as well as MMP-1 expression. The photoaging data obtained from mice clearly demonstrated that naringenin significantly inhibited UVB-induced wrinkle formation, trans-epidermal water loss and MMP-13 expression. Naringenin exerts potent anti-photoaging effects by suppressing ERK2 activity and decreasing FRA1 stability, followed by down-regulation of AP-1 transactivation and MMP-1 expression.


Assuntos
Flavanonas/farmacologia , Queratinócitos/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Envelhecimento da Pele/efeitos dos fármacos , Protetores Solares/farmacologia , Raios Ultravioleta/efeitos adversos , Animais , Butadienos/farmacologia , Técnicas de Cultura de Células , Linhagem Celular , Feminino , Regulação da Expressão Gênica , Genes Reporter , Humanos , Queratinócitos/citologia , Queratinócitos/metabolismo , Queratinócitos/efeitos da radiação , Luciferases/genética , Luciferases/metabolismo , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Camundongos , Camundongos Pelados , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Nitrilas/farmacologia , Fosforilação/efeitos dos fármacos , Fosforilação/efeitos da radiação , Proteínas Proto-Oncogênicas c-fos/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Quinases S6 Ribossômicas 90-kDa/antagonistas & inibidores , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Envelhecimento da Pele/genética , Envelhecimento da Pele/patologia , Fator de Transcrição AP-1/antagonistas & inibidores , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo , Água/metabolismo
14.
Biochem Biophys Res Commun ; 469(3): 748-52, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26692476

RESUMO

Dysfunction of pancreatic ß-cell is a major determinant for the development of type 2 diabetes. Because of the stimulated insulin secretion in metabolic syndrome, endoplasmic reticulum (ER) stress plays a central mediator for ß-cell failure. In this study, we investigated whether an antioxidant phenolic compound, tyrosol protects against ß-cell dysfunction associated with ER stress. To address this issue, we exposed pancreatic ß cells, NIT-1 to tunicamycin with tyrosol. We found tyrosol diminished tunicamycin-induced cell death in a dose-dependent manner. We also detected tyrosol decreased the expressions of apoptosis-related markers. Exposure to tunicamycin evoked UPR response and co-treatment of tyrosol led to reduction of ER stress. These effects of tyrosol were mediated by the phosphorylation of JNK. Moreover, we confirmed supplement of tyrosol ameliorated ß-cell loss induced by high fat feeding. Taken together, our study provides a molecular basis for signaling transduction of protective effect of tyrosol against ER stress-induced ß-cell death. Therefore, we suggest tyrosol could be a potential therapeutic candidate for amelioration of type 2 diabetes.


Assuntos
Apoptose/fisiologia , Estresse do Retículo Endoplasmático/fisiologia , Células Secretoras de Insulina/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Álcool Feniletílico/análogos & derivados , Extratos Vegetais/administração & dosagem , Polifenóis/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Relação Dose-Resposta a Droga , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Álcool Feniletílico/administração & dosagem
15.
Molecules ; 21(1): E128, 2016 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-26805800

RESUMO

Tyrosol is considered a potential antioxidant; however, little is known regarding the pharmacokinetics of its metabolites. To study the pharmacokinetics of tyrosol-derived metabolites after oral administration of a single dose of tyrosol, we attempted to identify tyrosol metabolites in rat plasma by using ultra-performance liquid chromatography and quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Two tyrosol metabolites (M1 and M2) were detected in the plasma. M1 was identified as tyrosol-4-sulfate (T4S) with an [M - H](-) ion at m/z 217. While M2 showed an [M - H](-) ion at m/z 151.0, its metabolite was not identified. Pharmacokinetic analysis of T4S and M2 showed rapid uptake after oral administration of tyrosol within 1 h. The metabolites were rapidly distributed in most organs and tissues and eliminated within 4 h. The greatest T4S deposition by tissue weight was observed in the liver, followed by the kidney and spleen, while M2 was most concentrated in the kidney followed by the liver and spleen. These findings indicate that T4S and M2 were distributed mainly in tissues with an abundant blood supply and were rapidly excreted in urine.


Assuntos
Antioxidantes/farmacocinética , Álcool Feniletílico/análogos & derivados , Administração Oral , Animais , Antioxidantes/administração & dosagem , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida , Masculino , Álcool Feniletílico/administração & dosagem , Álcool Feniletílico/farmacocinética , Ratos , Espectrometria de Massas em Tandem , Distribuição Tecidual
16.
Biochem Biophys Res Commun ; 467(4): 941-7, 2015 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-26471303

RESUMO

Shikonin is a naturally occurring naphthoquinone pigment and a major constituent present in Lithospermum erythrorhizon. Since microRNAs (miRNAs) are one of the key post-transcriptional regulators of adipogenesis, their manipulation represents a potential new strategy to inhibit adipogenesis. Our aim was to investigate shikonin-dependent inhibition of adipogenesis with an emphasis on miRNA-related processes. Mir-34a increased during induced adipogenesis, and this was suppressed in the presence of shikonin. mRNA expression of FKBP1B, a suggested target of mir-34a according to bioinformatics studies, decreased during adipogenesis, but was recovered by shikonin treatment, which reversely correlated with mir-34a expression. A mir-34a inhibitor suppressed MDI-induced adipogenesis by blocking PPARγ and C/EBPα expression, while suppression of mir-34a recovered MDI-induced down-regulation of FKBP1B expression. A mir-34a mimic decreased FKBP1B mRNA expression in 3T3-L1 preadipocytes. We also observed that mir-34a bound directly to the 3'-untranslated region of FKBP1B. Finally, FKBP1B overexpression attenuated MDI-induced adipogenesis, PPARγ, and C/EBPα expression. These results suggest that mir-34a regulates adipogenesis by targeting FKBP1B expression. Our findings reveal that shikonin prevents adipogenesis by blocking the mir-34a-FKBP1B pathway which represents a promising potential target for preventing obesity.


Assuntos
Adipócitos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , MicroRNAs/fisiologia , Naftoquinonas/farmacologia , Proteínas de Ligação a Tacrolimo/fisiologia , Células 3T3-L1 , Adipócitos/citologia , Adipogenia/fisiologia , Animais , Camundongos , MicroRNAs/antagonistas & inibidores , Proteínas de Ligação a Tacrolimo/genética
17.
Biochem Biophys Res Commun ; 458(3): 462-469, 2015 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-25660457

RESUMO

The endoplasmic reticulum (ER) stress induces hepatic steatosis and inflammation in the liver. Although melatonin ameliorates ER stress-target genes, it remains unknown whether melatonin protects against hepatic steatosis as well as inflammation through regulation of miRNA. MicroRNAs have been identified as pivotal regulators in the field of gene regulation and their dysfunctions are a common feature in a variety of metabolic diseases. Especially, among miRNAs, miR-23a has been shown to regulate ER stress. Herein, we investigated the crucial roles of melatonin in hepatic steatosis and inflammation in vivo. Tunicamycin challenge caused increase of hepatic triglyceride and intracellular calcium levels through activation of ER stress, whereas these phenomena were partially disrupted by melatonin. We also demonstrated that expression of miR-23a stimulated with tunicamycin was rescued by melatonin treatment, resulting in reduced ER stress in primary hepatocytes. Overall, these results suggest a new function of melatonin that is involved in ameliorating ER stress-induced hepatic steatosis and inflammation by attenuating miR-23a. Melatonin may be useful as a pharmacological agent to protect against hepatic metabolic diseases due to its ability to regulate expression of miR-23a.


Assuntos
Antioxidantes/uso terapêutico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/genética , Melatonina/uso terapêutico , MicroRNAs/genética , Animais , Antioxidantes/metabolismo , Linhagem Celular , Células Cultivadas , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Melatonina/metabolismo , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismo , Tunicamicina
18.
Toxicol Appl Pharmacol ; 279(3): 253-265, 2014 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-25034532

RESUMO

Glioblastoma multiforme (GBM) is the most lethal and aggressive astrocytoma of primary brain tumors in adults. Although there are many clinical trials to induce the cell death of glioblastoma cells, most glioblastoma cells have been reported to be resistant to TRAIL-induced apoptosis. Here, we showed that gingerol as a major component of ginger can induce TRAIL-mediated apoptosis of glioblastoma. Gingerol increased death receptor (DR) 5 levels in a p53-dependent manner. Furthermore, gingerol decreased the expression level of anti-apoptotic proteins (survivin, c-FLIP, Bcl-2, and XIAP) and increased pro-apoptotic protein, Bax and truncate Bid, by generating reactive oxygen species (ROS). We also found that the sensitizing effects of gingerol in TRAIL-induced cell death were blocked by scavenging ROS or overexpressing anti-apoptotic protein (Bcl-2). Therefore, we showed the functions of gingerol as a sensitizing agent to induce cell death of TRAIL-resistant glioblastoma cells. This study gives rise to the possibility of applying gingerol as an anti-tumor agent that can be used for the purpose of combination treatment with TRAIL in TRAIL-resistant glioblastoma tumor therapy.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Catecóis/farmacologia , Álcoois Graxos/farmacologia , Glioblastoma/patologia , Ligante Indutor de Apoptose Relacionado a TNF/toxicidade , Proteínas Reguladoras de Apoptose/metabolismo , Astrócitos/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular Tumoral , Humanos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Interferente Pequeno/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/biossíntese
19.
Molecules ; 19(10): 16013-23, 2014 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-25299819

RESUMO

We evaluated whether intake of an ethanolic extract of Taheebo (TBE) from Tabebuia avellanedae protects against body weight increase and fat accumulation in mice with high-fat diet (HFD)-induced obesity. Four-week old male C57BL/6 mice were fed a HFD (25% fat, w/w) for 11 weeks. The diet of control (HFD) mice was supplemented with vehicle (0.5% sodium carboxymethyl cellulose by gavage); the diet of experimental (TBE) mice was supplemented with TBE (150 mg/kg body weight/day by gavage). Mice administered TBE had significantly reduced body weight gain, fat accumulation in the liver, and fat pad weight, compared to HFD mice. Reduced hypertrophy of fat cells was also observed in TBE mice. Mice administered TBE also showed significantly lower serum levels of triglycerides, insulin, and leptin. Lipid profiles and levels of mRNAs and proteins related to lipid metabolism were determined in liver and white adipose tissue of the mice. Expression of mRNA and proteins related to lipogenesis were decreased in TBE-administered mice compared to mice fed HFD alone. These results suggest that TBE inhibits obesity and fat accumulation by regulation of gene expression related to lipid metabolism in HFD-induced obesity in mice.


Assuntos
Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Extratos Vegetais/farmacologia , Adipogenia/efeitos dos fármacos , Adipogenia/genética , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Modelos Animais de Doenças , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Masculino , Camundongos
20.
Antioxid Redox Signal ; 40(1-3): 122-144, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37917113

RESUMO

Significance: Hydrogen sulfide (H2S) is a recently recognized gasotransmitter involved in physiological and pathological conditions in mammals. It protects organs from oxidative stress, inflammation, hypertension, and cell death. With abundant expression of H2S-production enzymes, the liver is closely linked to H2S signaling. Recent Advances: Hepatic H2S comes from various sources, including gut microbiota, exogenous sulfur salts, and endogenous production. Recent studies highlight the importance of hepatic H2S in liver diseases such as nonalcoholic fatty liver disease (NAFLD), liver injury, and cancer, particularly at advanced stages. Endogenous H2S production deficiency is associated with severe liver disease, while exogenous H2S donors protect against liver dysfunction. Critical Issues: However, the roles of H2S in NAFLD, liver injury, and liver cancer are still debated, and its effects depend on donor type, dosage, treatment duration, and cell type, suggesting a multifaceted role. This review aimed to critically evaluate H2S production, metabolism, mode of action, and roles in liver function and disease. Future Direction: Understanding H2S's precise roles and mechanisms in liver health will advance potential therapeutic applications in preclinical and clinical research. Targeting H2S-producing enzymes and exogenous H2S sources, alone or in combination with other drugs, could be explored. Quantifying endogenous H2S levels may aid in diagnosing and managing liver diseases. Antioxid. Redox Signal. 40, 122-144.


Assuntos
Sulfeto de Hidrogênio , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Animais , Humanos , Sulfeto de Hidrogênio/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Inflamação/tratamento farmacológico , Mamíferos/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA