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Secoisolariciresinol diglucoside (SDG) is the main phytoestrogen component of flaxseed known as an antioxidant. Current study focused on the effect of SDG in white adipose tissue (WAT) browning. Browning of WAT is considered as a promising treatment strategy for metabolic diseases. To demonstrate the effect of SDG as an inducer of browning, brown adipocyte markers were investigated in inguinal WAT (iWAT) of high fat diet-fed obese mice and genetically obese db/db mice after SDG administration. SDG increased thermogenic factors such as uncoupling protein 1, peroxisome proliferator-activated receptor gamma coactivator 1 alpha and PR domain containing 16 in iWAT and brown adipose tissue (BAT) of mice. Similar results were shown in beige-induced 3T3-L1 adipocytes and primary cultured brown adipocytes. Furthermore, SDG increased factors of mitochondrial biogenesis and activation. We also observed SDG-induced alteration of AMP-activated protein kinase α (AMPKα). As AMPKα is closely related in the regulation of adipogenesis and thermogenesis, we then evaluated the effect of SDG in AMPKα-inhibited conditions. Genetic or chemical inhibition of AMPKα demonstrated that the role of SDG on browning and thermogenesis was dependent on AMPKα signaling. In conclusion, our data suggest SDG as a potential candidate for improvement of obesity and other metabolic disorders.
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Proteínas Quinasas Activadas por AMP/efectos de los fármacos , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Blanco/efectos de los fármacos , Butileno Glicoles/farmacología , Glucósidos/farmacología , Fitoestrógenos/farmacología , Transducción de Señal/efectos de los fármacos , Termogénesis/efectos de los fármacos , Células 3T3-L1 , Adipocitos Marrones/efectos de los fármacos , Animales , Dieta Alta en Grasa , Prueba de Tolerancia a la Glucosa , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Biogénesis de OrganelosRESUMEN
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.
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Proteínas Quinasas Activadas por AMP/metabolismo , Adipogénesis/efectos de los fármacos , Tejido Adiposo Pardo/metabolismo , Obesidad/tratamiento farmacológico , Termogénesis/efectos de los fármacos , Ácido Vanílico/farmacología , Células 3T3-L1 , Tejido Adiposo Pardo/patología , Animales , Proteínas Potenciadoras de Unión a CCAAT , Activación Enzimática/efectos de los fármacos , Masculino , Ratones , Obesidad/metabolismo , Obesidad/patología , PPAR gamma/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismoRESUMEN
Although arctigenin (ARC) has been reported to have some pharmacological effects such as anti-inflammation, anti-cancer, and antioxidant, there have been no reports on the anti-obesity effect of ARC. The aim of this study is to investigate whether ARC has an anti-obesity effect and mediates the AMP-activated protein kinase (AMPK) pathway. We investigated the anti-adipogenic effect of ARC using 3T3-L1 pre-adipocytes and human adipose tissue-derived mesenchymal stem cells (hAMSCs). In high-fat diet (HFD)-induced obese mice, whether ARC can inhibit weight gain was investigated. We found that ARC reduced weight gain, fat pad weight, and triglycerides in HFD-induced obese mice. ARC also inhibited the expression of peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding protein alpha (C/EBPα) in in vitro and in vivo. Furthermore, ARC induced the AMPK activation resulting in down-modulation of adipogenesis-related factors including PPARγ, C/EBPα, fatty acid synthase, adipocyte fatty acid-binding protein, and lipoprotein lipase. This study demonstrates that ARC can reduce key adipogenic factors by activating the AMPK in vitro and in vivo and suggests a therapeutic implication of ARC for obesity treatment. J. Cell. Biochem. 117: 2067-2077, 2016. © 2016 Wiley Periodicals, Inc.
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Proteínas Quinasas Activadas por AMP/metabolismo , Adipocitos/metabolismo , Adipogénesis/efectos de los fármacos , Grasas de la Dieta/efectos adversos , Furanos/farmacología , Lignanos/farmacología , Obesidad , Pérdida de Peso/efectos de los fármacos , Células 3T3-L1 , Animales , Grasas de la Dieta/farmacología , Activación Enzimática/efectos de los fármacos , Humanos , Masculino , Células Madre Mesenquimatosas/metabolismo , Ratones , Obesidad/inducido químicamente , Obesidad/tratamiento farmacológico , Obesidad/metabolismoRESUMEN
Reconstruction of the lateral malleolus or calcaneus region is challenging because of poor vascularity, minimal presence of soft tissue, and difficulties with flap positioning during and after the operation. In many cases, local flaps are limited in terms of size, durability, and vascularity. Free tissue transfer can be useful for complicated wounds. We report here on the results of the reconstruction in this region using free thoracodorsal artery perforator flaps. Between October 2010 and October 2013, 16 cases of lateral malleolus or calcaneus defects were reconstructed using free thoracodorsal artery perforator flaps. The defects varied from 2 × 5 cm(2) to 12 × 16 cm(2), and the flaps from 3 × 5 cm(2) to 10 × 15 cm(2). Two cases were reconstructed using chimeric-pattern flaps. Only the superficial adipose layers were harvested for all the flaps, without further thinning or debulking process. Five cases with complications occurred, including three cases of partial necrosis of the flap and two cases of venous congestion caused by thrombosis and compression of the venous pedicle, and one flap was totally lost. The mean follow-up duration was 11.8 months. All the patients were able to wear shoes. All but one were able to walk. The thoracodorsal artery perforator flap can be made super-thin, allowing patients to wear shoes, and it can be harvested in a chimeric-pattern for complex defects. Therefore, it may represent a viable alternative choice for the reconstruction of the lateral malleolus and calcaneus region.
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Traumatismos del Tobillo/cirugía , Traumatismos de los Pies/cirugía , Colgajos Tisulares Libres/trasplante , Colgajo Perforante/trasplante , Procedimientos de Cirugía Plástica/métodos , Tórax/irrigación sanguínea , Adolescente , Adulto , Anciano , Tobillo/cirugía , Femenino , Estudios de Seguimiento , Colgajos Tisulares Libres/irrigación sanguínea , Talón/cirugía , Humanos , Masculino , Persona de Mediana Edad , Colgajo Perforante/irrigación sanguínea , Adulto JovenRESUMEN
Diclazepam, a designer benzodiazepine, is a lesser-known novel anxiolytic substance and a structural analog of diazepam. Although several case studies have reported the adverse effects of diclazepam, their potential impacts remain unknown. Therefore, this study aimed to determine the effects of diclazepam in rodents using drug discrimination, locomotor activity, self-administration (SA), and conditioned place preference (CPP) tests. Sprague-Dawley rats (male, 8 weeks old, weighing 220-450 g, n = 12 per group) and C57BL/6 mice (male, 7 weeks old, weighing 20-25 g, n = 7-8 per group) were administered alprazolam, morphine, and diclazepam. Diclazepam fully elicited alprazolam-appropriate dose-dependent lever responses (>80 %) similar to those of alprazolam. In rats administered 0.5 mg/kg of morphine, a partial substitution (80 %-20 %) was observed. Mice receiving intraperitoneal injections of diclazepam (0.05, 0.2, and 2 mg/kg) showed decreased locomotor activity. In the SA experiment, mice that self-administered intravenous diclazepam (2 µg/kg/infusion) showed significantly higher infusion and active lever responses compared to the vehicle group. No statistically significant rewarding effects of diclazepam at the doses of 0.2 and 2 mg/kg evaluated using the CPP paradigm were found. In conclusion, diclazepam has reinforcing effects and shares the interoceptive effects of alprazolam. Therefore, legal restrictions on the use of diclazepam should be carefully considered.
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Alprazolam , Benzodiazepinas , Roedores , Ratas , Ratones , Masculino , Animales , Alprazolam/farmacología , Ratas Sprague-Dawley , Ratones Endogámicos C57BL , Diazepam/farmacología , Morfina/farmacología , Relación Dosis-Respuesta a DrogaRESUMEN
An N-protected methylenedioxymethamphetamine (MDMA), N-tert-butoxycarbonyl-3,4-methylenedioxymethamphetamine (t-BOC-3,4-MDMA), contains tert-butoxycarbonyl and can remain undetected in the illicit drug market. It is a new type of precursor substance that is not a chemical intermediate and can be converted into a controlled substance, MDMA, by deprotection of the N-tert-butoxycarbonyl group. Categorization of this chemical into a precursor or psychotropic substance is an issue because it is an unprecedented precursor that could have misuse potential. Although MDMA causes rewarding and reinforcing effect through dopaminergic transmission, the misuse potential of t-BOC-3,4-MDMA has not yet been characterized. Here, we aim to evaluate the misuse potential of t-BOC-3,4-MDMA. The response to the drug at a dose of 5 mg/kg was determined by a climbing test, and its rewarding and reinforcing properties were assessed through conditioned place preference and self-administration tests. In the conditioned place preference test, intraperitoneal administration of t-BOC-3,4-MDMA (5 mg/kg) significantly altered place preference in mice. In the self-administration models, t-BOC-3,4-MDMA induced drug-taking behavior at the dose of 0.5 mg/kg/infusion (intravenous) during 2 hr sessions under fixed-ratio schedules in mice. In addition, microdialysis experiments verified that t-BOC-3,4-MDMA impacted the dopamine levels of the brain (striatum) of rats. These experimental results indicate that t-BOC-3,4-MDMA has a potential for misuse. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
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The drug 25H-NBOMe is a new psychoactive substance (NPS). The use of these substances is likely to pose a threat to public health because they elicit effects similar to those of known psychoactive substances with similar chemical structures. However, data regarding the abuse potential of 25H-NBOMe are lacking. Here, we evaluated the abuse liability of 25H-NBOMe in rodents. The rewarding and reinforcing effects were evaluated through conditioned place preference (CPP) and self-administration (SA) tests after administration of 25H-NBOMe. To investigate the effects of 25H-NBOMe on the central nervous system, we determined the changes in dopamine levels by in vivo microdialysis. In the locomotor activity test, 25H-NBOme significantly increased locomotor activity in mice. In the place conditioning test, the 25H-NBOMe (0.1 and 0.5 mg/kg) groups showed a significantly increase in CPP in mice. In the SA test, the 25H-NBOMe (0.01 mg/kg) administered group showed a significant increased number of infusions and active lever presses. In microdialysis, the 25H-NBOMe (10 mg/kg) administered group was significantly increased in rats.
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RATIONALE: Methamnetamine (MNA; PAL-1046) is a new psychoactive substance that acts as a full biogenic amine transporter (BAT) substrate. BAT substrates promote neurotransmitter release from the nerve terminal and can be abused as stimulants. However, scientific information on the abuse potential of methamnetamine is lacking. OBJECTIVE: We evaluated the abuse liability of methamnetamine. METHODS: The effective dose range of methamnetamine was determined using a climbing behavior test. The rewarding effect and reinforcing effect of the test compound were evaluated in mice by conditioned place preference (CPP) testing and self-administration (SA) testing at the selected doses. Dopamine level changes were analyzed using synaptosomes and in vivo microdialysis to investigate the effects of methamnetamine on the central nervous system. Drug discrimination experiments were used to examine the potential similarity of the interoceptive effects of methamnetamine and cocaine. RESULTS: A significant response was observed in the climbing behavior test with 10 and 40 mg/kg intraperitoneally administered methamnetamine. In the CPP test, mice intraperitoneally administered methamnetamine (10 and 20 mg/kg) showed a significant preference for the drug-paired compartment. In the SA test, mice that intravenously received 1 mg/kg/infusion showed significant active-lever responses. Dopamine was significantly increased in synaptosomes and in in vivo microdialysis tests. Furthermore, methamnetamine showed cross-generalization with cocaine in a dose-dependent manner. CONCLUSIONS: Methamnetamine exhibits interceptive stimulus properties similar to those of cocaine and induces rewarding and reinforcing effects, suggesting its dependence liability potential.
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Condicionamiento Clásico/efectos de los fármacos , Psicotrópicos/administración & dosificación , Refuerzo en Psicología , Recompensa , Trastornos Relacionados con Sustancias/psicología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Condicionamiento Clásico/fisiología , Dopamina/metabolismo , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos C57BL , Ratas , Ratas Sprague-Dawley , Roedores , AutoadministraciónRESUMEN
Benign prostatic hyperplasia (BPH) is a common disease in elderly men which can be characterized by an abnormal enlargement of the prostate associated with lower urinary symptoms. Current medications available for BPH treatment display several adverse effects; thus, the search for effective treatments with less side effects is still ongoing. In this study, we investigated the effect of Aconiti Lateralis Radix Preparata (dried root of Aconitum carmichaelii Debx.; AL), which is an herb used to treat extremely cold symptoms in traditional Korean medicine, on BPH using a testosterone propionate- (TP-) induced BPH rat model. Eight-week inguinal injection of TP induced BPH in rats, the prostate of which was displaying an abnormal proliferation. The pathological proliferation of the prostate was ameliorated by AL treatment of 4 weeks. Pathohistological changes in the prostate including epithelial thickness and lumen area were restored in AL-treated rats. Furthermore, 5α-reductase (5AR) and androgen receptor (AR), the two main factors in the pathogenesis of BPH, were decreased. In addition, the ratio of BAX and Bcl-2, an indicator of apoptosis, was increased by AL as well. Similar results were observed in AL-treated LNCaP prostate cancer cells. AL treatment suppressed the expression of the 5AR-AR axis and increased the ratio of BAX and Bcl-2. Apoptosis in the testis is considered a crucial side effect of finasteride, a 5AR inhibitor used to treat BPH. Our results showed that AL treatment did not display such effects, while finasteride treatment resulted in loss of spermatogenic cells within the prostate. Overall, these results suggest AL as a potentially safe nature-derived therapeutic agent for BPH treatment.
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Atopic dermatitis (AD) is an inflammatory disease of the skin, resulting from an immune dysfunction, that often occurs as a comorbidity of obesity. This investigation evaluated the capacity of Taeumjowi-tang (TJT), a Korean herbal formulation from the Sasang medical tradition to influence prognostic features of AD and obesity in a mouse model. Here, obesity and AD were induced by a high-fat diet (HFD) and 1-fluoro-2,4-dinitrobenzene (DNFB). Following an 8-week HFD regimen and 4 weeks of DNFB administration, the comorbid (CO) group manifested increased body weight and AD-like lesions, as compared to normal control (NC) mice, while TJT administration diminished these symptoms of obesity and AD. Specifically, TJT treatment reduced epidermal thickness and eosinophil/mast cell infiltration, along with reduction in immunoglobulin E, interleukin (IL)-4, IL-6, and tumor necrosis factor-alpha (TNF-α). It was additionally demonstrated that TJT suppresses HFD/DNFB-associated increase of the inflammation-related nuclear factor-kappa beta (NF-κB) and mitogen activated protein kinase. Moreover, significantly increased levels of hypoxia inducible factor-1 alpha (HIF-1α) protein was observed in CO group versus controls, an increase significantly down-regulated by TJT-treatment. These outcomes suggest that TJT may prove useful in clinical management of obesity-AD comorbidity treatment, an effect that may be due to regulation of HIF-1α expression.
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[This corrects the article DOI: 10.18632/oncotarget.19909.].
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[This corrects the article DOI: 10.3389/fphar.2018.00773.].
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Obesity has become a major health threat in developed countries. However, current medications for obesity are limited because of their adverse effects. Interest in natural products for the treatment of obesity is thus rapidly growing. Korean medicine is characterized by the wide use of herbal formulas. However, the combination rule of herbal formulas in Korean medicine lacks experimental evidence. According to Shennong's Classic of Materia Medica, the earliest book of herbal medicine, Bupleuri Radix (BR) and Scutellariae Radix (SR) possess the Sangsoo relationship, which means they have synergistic features when used together. Therefore these two are frequently used together in prescriptions such as Sosiho-Tang. In this study, we used the network pharmacological method to predict the interaction between these two herbs and then investigated the effects of BR, SR, and their combination on obesity in 3T3-L1 adipocytes. BR, SR, and BR-SR mixture significantly decreased lipid accumulation and the expressions of two major adipogenic factors, peroxisome proliferator-activated receptor-gamma (PPARγ) and CCAAT/enhancer-binding protein-alpha (C/EBPα), and their downstream genes, Adipoq, aP2, and Lipin1 in 3T3-L1 cells. In addition, the BR-SR mixture had synergistic effects compared with BR or SR on inhibition of adipogenic-gene expressions. BR and SR also inhibited the protein expressions of PPARγ and C/EBPα. Furthermore, the two extracts successfully activated AMP-activated protein kinase alpha (AMPK α), the key regulator of energy metabolism. When compared to those of BR or SR, the BR-SR mixture showed higher inhibition rates of PPARγ and C/EBPα, along with higher activation rate of AMPK. These results indicate a new potential antiobese pharmacotherapy and also provide scientific evidence supporting the usage of herbal combinations instead of mixtures in Korean medicine.
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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.
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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.
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Proteínas Quinasas Activadas por AMP/metabolismo , Adipogénesis/efectos de los fármacos , Butileno Glicoles/farmacología , Glucósidos/farmacología , Células 3T3-L1 , Adipocitos/citología , Adipocitos/efectos de los fármacos , Animales , Butileno Glicoles/uso terapéutico , Supervivencia Celular/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Glucósidos/uso terapéutico , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/inducido químicamente , Obesidad/tratamiento farmacológico , Transducción de Señal/efectos de los fármacosRESUMEN
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.
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Benign prostatic hyperplasia (BPH) is one of the most common chronic diseases in male population, of which incidence increases gradually with age. In this study, we investigated the effect of chrysophanic acid (CA) on BPH. BPH was induced by a 4-week injection of testosterone propionate (TP). Four weeks of further injection with vehicle, TP, TP + CA, TP + finasteride was carried on. In the CA treatment group, the prostate weight was reduced and the TP-induced histological changes were restored as the normal control group. CA treatment suppressed the TP-elevated prostate specific antigen (PSA) expression. In addition, 5α-reductase, a crucial factor in BPH development, was suppressed to the normal level close to the control group by CA treatment. The elevated expressions of androgen receptor (AR), estrogen receptor α and steroid receptor coactivator 1 by TP administration were also inhibited in the CA group when compared to the TP-induced BPH group. Then we evaluated the changes in three major factors of the mitogen-activated protein kinase chain during prostatic hyperplasia; extracellular signal-regulated kinase (ERK), c-Jun-N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38). While ERK was elevated in the process of BPH, JNK and p38 was not changed. This up-regulated ERK was also reduced as normal by CA treatment. Further in vitro studies with RWPE-1 cells confirmed TP-induced proliferation and elevated AR, PSA and p-ERK were all reduced by CA treatment. Overall, these results suggest a potential pharmaceutical feature of CA in the treatment of BPH.
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3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/metabolismo , Inhibidores de 5-alfa-Reductasa/farmacología , Antraquinonas/farmacología , Proliferación Celular/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Próstata/efectos de los fármacos , Hiperplasia Prostática/prevención & control , Propionato de Testosterona , Animales , Línea Celular , Modelos Animales de Enfermedad , Regulación hacia Abajo , Receptor alfa de Estrógeno/metabolismo , Finasterida/farmacología , Masculino , Coactivador 1 de Receptor Nuclear/metabolismo , Tamaño de los Órganos , Fosforilación , Próstata/enzimología , Próstata/patología , Antígeno Prostático Específico/metabolismo , Hiperplasia Prostática/inducido químicamente , Hiperplasia Prostática/enzimología , Hiperplasia Prostática/patología , Ratas Sprague-Dawley , Receptores Androgénicos/metabolismo , Transducción de Señal/efectos de los fármacos , Factores de TiempoRESUMEN
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.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Hidrocarburos Aromáticos con Puentes/farmacología , Células Madre Mesenquimatosas/citología , Obesidad/tratamiento farmacológico , Proteína Oncogénica v-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Termogénesis/genética , Adipocitos Marrones/efectos de los fármacos , Tejido Adiposo/citología , Tejido Adiposo Blanco/efectos de los fármacos , Animales , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Diferenciación Celular , Células Cultivadas , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Activación TranscripcionalRESUMEN
BACKGROUND: The prevalence of allergic inflammatory diseases such as atopic dermatitis (AD), asthma, and allergic rhinitis worldwide has increased and complete recovery is difficult. Korean Red Ginseng, which is the heat-processed root of Panax ginseng Meyer, is widely and frequently used as a traditional medicine in East Asia. In this study, we investigated whether Korean Red Ginseng water extract (RGE) regulates the expression of proinflammatory cytokines and chemokines via the mitogen-activated protein kinases (MAPKs)/nuclear factor kappa B (NF-κB) pathway in allergic inflammation. METHODS: Compound 48/80-induced anaphylactic shock and 1-fluoro-2,4-dinitrobenzene (DNFB)-induced AD-like skin lesion mice models were used to investigate the antiallergic effects of RGE. Human keratinocytes (HaCaT cells) and human mast cells (HMC-1) were also used to clarify the effects of RGE on the expression of proinflammatory cytokines and chemokines. RESULTS: Anaphylactic shock and DNFB-induced AD-like skin lesions were attenuated by RGE administration through reduction of serum immunoglobulin E (IgE) and interleukin (IL)-6 levels in mouse models. RGE also reduced the production of proinflammatory cytokines including IL-1ß, IL-6, and IL-8, and expression of chemokines such as IL-8, thymus and activation-regulated chemokine (TARC), and macrophage-derived chemokine (MDC) in HaCaT cells. Additionally, RGE decreased the release of tumor necrosis factor-α (TNF-α), IL-1ß, IL-6, and IL-8 as well as expressions of chemokines including macrophage inflammatory protein (MIP)-1α, MIP-1ß, regulated on activation, normal T cell expressed and secreted (RANTES), monocyte chemoattractant protein (MCP)-1, and IL-8 in HMC-1 cells. Furthermore, our data demonstrated that these inhibitory effects occurred through blockage of the MAPK and NF-κB pathway. CONCLUSION: RGE may be a useful therapeutic agent for the treatment of allergic inflammatory diseases such as AD-like dermatitis.
RESUMEN
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.