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1.
Front Pharmacol ; 10: 1154, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31680950

RESUMO

Obesity is constantly rising into a major health threat worldwide. Activation of brown-like transdifferentiation of white adipocytes (browning) has been proposed as a promising molecular target for obesity treatment. In this study, we investigated the effect of ginsenoside Rb1 (Rb1), a saponin derived from Panax ginseng Meyer, on browning. We used 3T3-L1 murine adipocytes and leptin receptor mutated db/db mice. The lipid accumulation, AMP-activated protein kinase alpha (AMPKα)-related pathways, lipolytic and thermogenic factors were measured after Rb treatment in 3T3-L1 adipocytes. Body weight change and lipolysis-thermogenesis factors were investigated in Rb1-treated db/db mice. Beta 3 adrenergic receptor activation (ß3AR) changes were measured in Rb1-treated 3T3-L1 cells with or without ß3AR inhibitor L748337 co-treatment. As a result, Rb1 treatment decreased lipid droplet size in 3T3-L1 adipocytes. Rb1 also induced phosphorylations of AMPKα pathway and sirtuins. Moreover, lipases and thermogenic factors such as uncoupling protein 1 were increased by Rb1 treatment. Through these results, we could expect that the non-shivering thermogenesis program can be induced by Rb1. In db/db mice, 6-week injection of Rb1 resulted in decreased inguinal white adipose tissue (iWAT) weight associated with shrunken lipid droplets and increased lipolysis and thermogenesis. The thermogenic effect of Rb1 was possibly due to ß3AR, as L748337 pre-treatment abolished the effect of Rb1. In conclusion, we suggest Rb1 as a potential lipolytic and thermogenic therapeutic agent which can be used for obesity treatment.

4.
Front Pharmacol ; 9: 773, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30061836

RESUMO

Benign prostate hyperplasia (BPH) is a common disease in elderly men, characterized by proliferated prostate and urinary tract symptoms. The hormonal cascade starting by the action of 5-alpha-reductase (5AR) is known to be one of the pathways responsible for the pathogenesis of BPH. Present investigation evaluated the capacity of berberine (BBR), a nature-derived compound abundant in Coptis japonica, in testosterone-induced BPH rats. Experimental BPH was induced by inguinal injection with testosterone propionate (TP) for 4 weeks. BBR or finasteride, a 5AR inhibitor as positive control, was treated for 4 weeks during BPH. BPH induced by TP evoked weight gaining and histological changes of prostate and BBR treatment improved all the detrimental effects not only weight reduction and histological changes but also suppression of prostate-specific antigen (PSA), which is elevated during BPH. Additionally, BBR suppressed TP-associated increase of 5AR, androgen receptor (AR) and steroid coactivator-1 (SRC-1), the key factors in the pathogenesis of BPH. To evaluate the underlying molecular mechanisms responsible for beneficial effects of BBR, we investigated whether these effects were associated with the mitogen-activated protein kinase pathway. BPH induced by TP showed increased phosphorylation of extracellular signal-regulated kinase (ERK), whereas this was suppressed by BBR treatment. On the other hand, c-jun-N-terminal kinase (JNK) and p38 mitogen-activated protein kinase was not changed in BPH rats. In in vitro study using RWPE-1 cells, a human prostate epithelial cell line. TP increased cell proliferation and BPH-related key factors such as PSA, AR, and 5AR in RWPE-1 cells, and those factors were significantly decreased in the presence of BBR. Furthermore, these proliferative effects in RWPE-1cells were attenuated by treatment with U0126, an ERK inhibitor, confirming BBR can relieve overgrowth of prostate via ERK-dependent signaling. The cotreatment of U0126 and BBR did not affect the change of 5AR nor proliferation compared with U0126 alone, suggesting that the effect of BBR was dependent on the action of ERK. In conclusion, this study shows that BBR can be used as a therapeutic agent for BPH by controlling hyperplasia of prostate through suppression of ERK mechanism.

6.
FASEB J ; 32(3): 1388-1402, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29141998

RESUMO

Energy expenditure is a target gaining recent interest for obesity treatment. The antiobesity effect of vanillic acid (VA), a well-known flavoring agent, was investigated in vivo and in vitro. High-fat diet (HFD)-induced obese mice and genetically obese db/db mice showed significantly decreased body weights after VA administration. Two major adipogenic markers, peroxisome proliferator activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), were reduced while the key factor of energy metabolism, AMPKα, was increased in the white adipose tissue and liver tissue of VA-treated mice. Furthermore, VA inhibited lipid accumulation and reduced hepatotoxic/inflammatory markers in liver tissues of mice and HepG2 hepatocytes. VA treatment also decreased differentiation of 3T3-L1 adipocytes by regulating adipogenic factors including PPARγ and C/EBPα. AMPKα small interfering RNA was used to examine whether AMPK was associated with the actions of VA. In AMPKα-nulled 3T3-L1 cells, the inhibitory action of VA on PPARγ and C/EBPα was attenuated. Furthermore, in brown adipose tissues of mice and primary cultured brown adipocytes, VA increased mitochondria- and thermogenesis-related factors such as uncoupling protein 1 and PPARγ-coactivator 1-α. Taken together, our results suggest that VA has potential as an AMPKα- and thermogenesis-activating antiobesity agent.-Jung, Y., Park, J., Kim, H.-L., Sim, J.-E., Youn, D.-H., Kang, J., Lim, S., Jeong, M.-Y., Yang, W. M., Lee, S.-G., Ahn, K. S., Um, J.-Y. Vanillic acid attenuates obesity via activation of the AMPK pathway and thermogenic factors in vivo and in vitro.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adipogenia/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Obesidade/tratamento farmacológico , Termogênese/efeitos dos fármacos , Ácido Vanílico/farmacologia , Células 3T3-L1 , Tecido Adiposo Marrom/patologia , Animais , Proteínas Estimuladoras de Ligação a CCAAT , Ativação Enzimática/efeitos dos fármacos , Masculino , Camundongos , Obesidade/metabolismo , Obesidade/patologia , PPAR gama/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo
7.
Eur J Pharmacol ; 820: 235-244, 2018 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-29269018

RESUMO

Flaxseeds are used to treat metabolic diseases such as type 2 diabetes, fatty liver, hyperlipidemia and obesity. Secoisolariciresinol diglucoside (SDG) is a main substance of lignan which belongs to the phytoestrogen family and exists abundantly in flaxseeds. In this study, SDG reduced the body weight and size of adipose tissue, and decreased protein expressions of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT-enhancer-binding protein α (C/EBPα) in the high fat diet-fed-induced obese mice model. In the vitro study, we examined the anti-adipogenic effect of SDG during differentiation of 3T3-L1 cells into adipocytes. 3T3-L1 preadipocytes were differentiated and treated with various concentrations of SDG. Oil Red O staining was done to measure the quantity of lipid contents. As a result, SDG reduced lipid accumulation and decreased the expressions of adipogenic-related genes such as adipocyte fatty-acid-binding protein 2, adiponectin, and resistin. SDG also decreased the mRNA and protein levels of PPARγ and C/EBPα. Furthermore, phosphorylation levels of AMP-activated protein kinase α (AMPK α) and its upstream activator, liver kinase B1, were significantly increased by SDG in 3T3-L1 cells. These results suggest that SDG inhibits adipogenesis by activating AMPKα, suggesting it could be an attractive therapeutic candidate for the treatment of obesity.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adipogenia/efeitos dos fármacos , Butileno Glicóis/farmacologia , Glucosídeos/farmacologia , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Animais , Butileno Glicóis/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Glucosídeos/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/induzido quimicamente , Obesidade/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos
8.
Oncotarget ; 8(50): 87194-87208, 2017 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-29152074

RESUMO

Benign prostatic hyperplasia (BPH) is a common disease in the male population, especially in elderly men. Vanillic acid (VA), a dihydroxybenzoic derivative used as a flavoring agent, is reported to have an anti-inflammatory effect. However, there are no reports of its effects on BPH to date. BPH was induced with a pre-4-week treatment of daily subcutaneous injections of testosterone propionate (TP), and the normal control group received injections of ethanol with corn oil instead. Six weeks of further injections were done with (a) ethanol with corn oil, (b) TP only, (c) TP + finasteride, and (d) TP + VA. Finasteride was used as a positive control group. VA had protective effects on the TP-induced BPH. In the VA treatment group, the prostate weight was reduced, and the histological changes including the epithelial thickness and lumen area were restored like in the normal control group. Furthermore, in the VA treatment group, two proliferation related factors, high molecular weight cytokeratin 34ßE12 and α smooth muscle actin, were significantly down-regulated compared to the TP-induced BPH group. The expressions of dihydrotestosterone and 5α-reductase, the most crucial factors in BPH development, were suppressed by VA treatment. Expressions of the androgen receptor, estrogen receptor α and steroid receptor coactivator 1 were also significantly inhibited by VA compared to the TP-induced BPH group. In addition, we established an in vitro model for BPH by treating a normal human prostatic epithelial cell line RWPE-1 with TP. VA successfully inhibited proliferation and BPH-related factors in a concentration-dependent manner in this newly established model. These results suggest a new and potential pharmaceutical therapy of VA in the treatment of BPH.

9.
Front Pharmacol ; 8: 654, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29033835

RESUMO

Brown adipocytes dissipate energy as heat and hence have an important therapeutic capacity for obesity. Development of brown-like adipocytes (also called beige) is also another attractive target for obesity treatment. Here, we investigated the effect of farnesol, an isoprenoid, on adipogenesis in adipocytes and on the browning of white adipose tissue (WAT) as well as on the weight gain of high-fat diet (HFD)-induced obese mice. Farnesol inhibited adipogenesis and the related key regulators including peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein α through the up-regulation of AMP-activated protein kinase in 3T3-L1 murine adipocytes and human adipose tissue-derived mesenchymal stem cells (hAMSCs). Farnesol markedly increased the expression of uncoupling protein 1 and PPARγ coactivator 1 α in differentiated hAMSCs. In addition, farnesol limited the weight gain in HFD obese mice and induced the development of beige adipocytes in both inguinal and epididymal WAT. These results suggest that farnesol could be a potential therapeutic agent for obesity treatment.

10.
Metabolism ; 73: 85-99, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28732574

RESUMO

OBJECTIVE: Brown adipose tissue (BAT) activation has been identified as a possible target to treat obesity and to protect against metabolic diseases by increasing energy consumption. We explored whether albiflorin (AF), a natural compound, could contribute to lowering the high risk of obesity with BAT and primary brown preadipocytes in vivo and in vitro. MATERIALS/METHODS: Human adipose tissue-derived mesenchymal stem cells (hAMSCs) were cultured with adipogenic differentiation media with or without AF. Male C57BL/6J mice (n=5 per group) were fed a high-fat diet (HFD) for six weeks with or without AF. Brown preadipocytes from the interscapular BAT of mice were cultured with or without AF. RESULTS: In white adipogenic differentiation of hAMSCs, AF treatment significantly reduced the formation of lipid droplets and the expression of adipogenesis-related genes. In HFD-induced obese C57BL/6J mice, AF treatment significantly reduced body weight gain as well as the weights of the white adipose tissue, liver and spleen. Furthermore, AF induced the expression of genes involved in thermogenic function in BAT. In primary brown adipocytes, AF effectively stimulated the expressions of thermogenic genes and markedly up-regulated the AMP-activated protein kinase (AMPK) signaling pathway. Pretreatment with phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 nullified the induction of the thermogenic genes by AF in primary brown adipocytes. Moreover, AF activated beige cell marker genes induced by the pharmacological activation of peroxisome proliferator-activated receptor γ in hAMSCs. CONCLUSION: This study shows that AF prevents the development of obesity in hAMSCs and mice fed an HFD and that it is also capable of stimulating the differentiation of brown adipocytes through the modulation of thermogenic genes by AMPK and PI3K/AKT.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Células-Tronco Mesenquimais/citologia , Obesidade/tratamento farmacológico , Proteína Oncogênica v-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Termogênese/genética , Adipócitos Marrons/efeitos dos fármacos , Tecido Adiposo/citologia , Tecido Adiposo Branco/efeitos dos fármacos , Animais , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Diferenciação Celular , Células Cultivadas , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ativação Transcricional
11.
Angle Orthod ; 78(2): 234-40, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18251617

RESUMO

OBJECTIVE: To determine the variation in the insertion torque of orthodontic miniscrews according to the screw length, diameter, and shape. MATERIALS AND METHODS: The maximum insertion torque (MIT) was measured using a torque tester at a constant speed of 3 rotations per minute. Cylindrical and taper type of miniscrews (Biomaterials Korea Inc, Seoul, Korea) with different lengths, diameters, and pitches were tested. RESULTS: The results showed that the insertion torque significantly increased with increasing screw length (P < .01). In particular, there was a significant increase in torque with increasing screw length and diameter (P < .01). An analysis of the serial insertion torque of miniscrews revealed the cylindrical type screw to have much higher insertion torque at the incomplete screw thread, while the taper type screw showed a much higher insertion torque at the final inclination part of the screw thread. The insertion torque was affected by the outer diameter, length, and shape in that order. CONCLUSIONS: An increase in screw diameter can efficiently reinforce the initial stability of the miniscrew, but the proximity of the root at the implanted site should be considered.


Assuntos
Parafusos Ósseos , Implantação Dentária Endo-Óssea , Procedimentos de Ancoragem Ortodôntica/instrumentação , Desenho de Aparelho Ortodôntico , Análise do Estresse Dentário , Miniaturização , Análise de Regressão , Torque
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