RESUMO
Obesity is intimately related to a chronic inflammatory state, with augmentation of macrophage infiltration and pro-inflammatory cytokine secretion in white adipose tissue (WAT) and mitochondrial dysfunction in skeletal muscle. The specific aim of this study is to evaluate effects of tartary buckwheat extract (TB) on obesity-induced adipose tissue inflammation and muscle peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α/sirtulin 1 (SIRT1) pathway in rats fed a high-fat diet. Sprague-Dawley rats were divided into four groups and fed either a normal diet (NOR), 45% high-fat diet (HF), HF + low dose of TB (TB-L; 5 g/kg diet), or HF + high dose of TB (TB-H; 10 g/kg diet) for 13 weeks. TB significantly reduced adipose tissue mass with decreased adipogenic gene expression of PPAR-γ and aP2. Serum nitric oxide levels and adipose tissue macrophage M1 polarization gene markers, such as iNOS, CD11c, and Arg1, and pro-inflammatory gene expression, including TNF-α, IL-6, and MCP-1, were remarkably downregulated in the TB-L and TB-H groups. Moreover, TB supplementation increased gene expression of PGC-1α and SIRT1, involved in muscle biogenesis and function. These results suggested that TB might attenuate obesity-induced inflammation and mitochondrial dysfunction by modulating adipose tissue inflammation and the muscle PGC-1α/SIRT1 pathway.
Assuntos
Tecido Adiposo/metabolismo , Fagopyrum , Inflamação/prevenção & controle , Músculo Esquelético/metabolismo , Obesidade/complicações , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Sirtuína 1/metabolismo , Animais , Citocinas/metabolismo , Dieta Hiperlipídica , Regulação para Baixo , Inflamação/etiologia , Inflamação/metabolismo , Macrófagos/metabolismo , Masculino , Óxido Nítrico/sangue , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Ratos Sprague-DawleyRESUMO
Due to poor water solubility and high susceptibility to chemical degradation, the applications of quercetin have been limited. This study investigated the effects of pH on the formation of quercetin-loaded nanoemulsion (NQ) and compared the hypocholesterolemic activity between quercetin and NQ to utilize the quercetin as functional food ingredient. NQ particle size exhibited a range of 207â»289 nm with polydispersity index range (<0.47). The encapsulation efficiency increased stepwise from 56 to 92% as the pH increased from 4.0 to 9.0. Good stability of NQ was achieved in the pH range of 6.5â»9.0 during 3-month storage at 21 and 37 °C. NQ displayed higher efficacy in reducing serum and hepatic cholesterol levels and increasing the release of bile acid into feces in rats fed high-cholesterol diet, compared to quercetin alone. NQ upregulated hepatic gene expression involved in bile acid synthesis and cholesterol efflux, such as cholesterol 7 alpha-hydroxylase (CYP7A1), liver X receptor alpha (LXRα), ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette sub-family G member 1 (ABCG1). These results suggest at least partial involvement of hepatic bile acid synthesis and fecal cholesterol excretion in nanoemulsion quercetin-mediated beneficial effect on lipid abnormalities.
Assuntos
Colesterol na Dieta/administração & dosagem , Hipercolesterolemia/tratamento farmacológico , Nanoestruturas , Quercetina/uso terapêutico , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Emulsões/química , Masculino , Quercetina/química , Distribuição Aleatória , Ratos , Ratos Sprague-DawleyRESUMO
Longevity in medicine can be defined as a long life without mental or physical deficits. This can be prevented by Alzheimer's disease (AD). Current conventional AD treatments only alleviate the symptoms without reversing AD progression. Recent studies demonstrated that Panax ginseng extract improves AD symptoms in patients with AD, and the two main components of ginseng might contribute to AD amelioration. Ginsenosides show various AD-related neuroprotective effects. Gintonin is a newly identified ginseng constituent that contains lysophosphatidic acids and attenuates AD-related brain neuropathies. Ginsenosides decrease amyloid ß-protein (Aß) formation by inhibiting ß- and γ-secretase activity or by activating the nonamyloidogenic pathway, inhibit acetylcholinesterase activity and Aß-induced neurotoxicity, and decrease Aß-induced production of reactive oxygen species and neuroinflammatory reactions. Oral administration of ginsenosides increases the expression levels of enzymes involved in acetylcholine synthesis in the brain and alleviates Aß-induced cholinergic deficits in AD models. Similarly, gintonin inhibits Aß-induced neurotoxicity and activates the nonamyloidogenic pathway to reduce Aß formation and to increase acetylcholine and choline acetyltransferase expression in the brain through lysophosphatidic acid receptors. Oral administration of gintonin attenuates brain amyloid plaque deposits, boosting hippocampal cholinergic systems and neurogenesis, thereby ameliorating learning and memory impairments. It also improves cognitive functions in patients with AD. Ginsenosides and gintonin attenuate AD-related neuropathology through multiple routes. This review focuses research demonstrating that ginseng constituents could be a candidate as an adjuvant for AD treatment. However, clinical investigations including efficacy and tolerability analyses may be necessary for the clinical acceptance of ginseng components in combination with conventional AD drugs.
RESUMO
Ginger is a plant whose rhizome is used as a spice or folk medicine. We aimed to investigate the effect of ginger root extract on obesity and inflammation in rats fed a high-fat diet. Sprague-Dawley rats were divided into three groups and fed either a 45% high-fat diet (HF), HF + hot-water extract of ginger (WEG; 8 g/kg diet), or HF + high-hydrostatic pressure extract of ginger (HPG; 8 g/kg diet) for 10 weeks. The HPG group had lower body weight and white adipose tissue (WAT) mass compared to the HF group. Serum and hepatic lipid levels of HPG group were lower, while fecal lipid excretion of the HPG group was higher than that of the HF group. In the WAT of the WEG and HPG groups, mRNA levels of adipogenic genes were lower than those of the HF group. Moreover, HPG group had lower mRNA levels of pro-inflammatory cytokines than did the HF group. MicroRNA (miR)-21 expression was down-regulated by both WEG and HPG. Additionally, miR-132 expression was down-regulated by HPG. The adenosine monophosphate-activated protein kinase (AMPK) activity of HPG group was greater than that of the HF group. HPG may have beneficial effects on obesity and inflammation, partially mediated by regulation of miR-21/132 expression and AMPK activation in WAT.
Assuntos
Tecido Adiposo Branco/metabolismo , MicroRNAs/metabolismo , Extratos Vegetais/uso terapêutico , Proteínas Quinases/metabolismo , Zingiber officinale , Quinases Proteína-Quinases Ativadas por AMP , Animais , Regulação para Baixo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Extratos Vegetais/química , Proteínas Quinases/genética , Ratos Sprague-DawleyRESUMO
Stress contributes to physiological changes such as weight loss and hormonal imbalances. The aim of the present study was to investigate antistress effects of high hydrostatic pressure extract of ginger (HPG) in immobilization-stressed rats. Male Sprague-Dawley rats (n = 24) were divided into three groups as follows: control (C), immobilization stress (2 h daily, for 2 weeks) (S), and immobilization stress (2 h daily, for 2 weeks) plus oral administration of HPG (150 mg/kg body weight/day) (S+G). Immobilization stress reduced the body weight gain and thymus weight by 50.2% and 31.3%, respectively, compared to the control group. The levels of serum aspartate transaminase, alanine transaminase, and corticosterone were significantly higher in the stress group, compared to the control group. Moreover, immobilization stress elevated the mRNA levels of tyrosine hydroxylase (Th), dopamine beta-hydroxylase (Dbh), and cytochrome P450 side-chain cleavage (P450scc), which are related to catecholamine and corticosterone synthesis in the adrenal gland. HPG administration also increased the body weight gain and thymus weight by 12.7% and 16.6%, respectively, compared to the stress group. Furthermore, the mRNA levels of Th, Dbh, phenylethanolamine-N-methyltransferase, and P450scc were elevated by the HPG treatment when compared to the stress group. These results suggest that HPG would have antistress effects partially via the reversal of stress-induced physiological changes and suppression of mRNA expression of genes related to corticosterone and catecholamine synthetic enzymes.
Assuntos
Extratos Vegetais/administração & dosagem , Estresse Fisiológico/efeitos dos fármacos , Zingiber officinale/química , Animais , Catecolaminas/metabolismo , Corticosterona/metabolismo , Dopamina beta-Hidroxilase/genética , Dopamina beta-Hidroxilase/metabolismo , Humanos , Pressão Hidrostática , Masculino , Feniletanolamina N-Metiltransferase/genética , Feniletanolamina N-Metiltransferase/metabolismo , Extratos Vegetais/isolamento & purificação , Ratos , Ratos Sprague-Dawley , Estresse Fisiológico/genética , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Tartary buckwheat (Fagopyrum tataricum) has been established globally as a nutritionally important food item, particularly owing to high levels of bioactive compounds such as rutin. This study investigated the effect of tartary buckwheat extracts (TBEs) on adipogenesis and inflammatory response in 3T3-L1 cells. TBEs inhibited lipid accumulation, triglyceride content, and glycerol-3-phosphate dehydrogenase (GPDH) activity during adipocyte differentiation of 3T3 L1 cells. The mRNA levels of genes involved in fatty acid synthesis, such as peroxisome proliferator-activated receptor-γ (PPAR-γ), CCAAT/enhancer binding protein-α (CEBP-α), adipocyte protein 2 (aP2), acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and stearoylcoenzyme A desaturase-1 (SCD-1), were suppressed by TBEs. They also reduced the mRNA levels of inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), monocyte chemoattractant protein 1 (MCP-1), and inducible nitric oxide synthase (iNOS). In addition, TBEs were decreased nitric oxide (NO) production. These results suggest that TBEs may inhibit adipogenesis and inflammatory response; therefore, they seem to be beneficial as a food ingredient to prevent obesity-associated inflammation.
Assuntos
Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Fagopyrum/química , Obesidade/tratamento farmacológico , Extratos Vegetais/farmacologia , Rutina , Células 3T3-L1 , Acetil-CoA Carboxilase/metabolismo , Adipócitos/citologia , Adipócitos/metabolismo , Animais , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Diferenciação Celular , Ácido Graxo Sintases/metabolismo , Glicerolfosfato Desidrogenase/metabolismo , Inflamação/metabolismo , Interleucina-6/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos , Óxido Nítrico/biossíntese , Obesidade/complicações , Obesidade/metabolismo , PPAR gama/metabolismo , Rutina/administração & dosagem , Rutina/química , Rutina/farmacologia , Rutina/uso terapêutico , Triglicerídeos/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
In this study, we attempted to develop a multimodality approach using chemotherapeutic agent mitomycin C, biologic agent tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo-2L), and mild hyperthermia to treat colon cancer. For this study, human colon cancer LS174T, LS180, HCT116 and CX-1 cells were infected with secretory TRAIL-armed adenovirus (Ad.TRAIL) and treated with chemotherapeutic agent mitomycin C and hyperthermia. The combinatorial treatment caused a synergistic induction of apoptosis which was mediated through an increase in caspase activation. The combinational treatment promoted the JNK-Bcl-xL-Bak pathway which transmitted the synergistic effect through the mitochondria-dependent apoptotic pathway. JNK signaling led to Bcl-xL phosphorylation at serine 62, dissociation of Bak from Bcl-xL, oligomerization of Bak, alteration of mitochondrial membrane potential, and subsequent cytochrome c release. Overexpression of dominant-negative mutant of Bcl-xL (S62A), but not dominant-positive mutant of Bcl-xL (S62D), suppressed the synergistic death effect. Interestingly, Beclin-1 was dissociated from Bcl-xL and overexpression of dominant-negative mutant of Bcl-xL (S62A), but not dominant-positive mutant of Bcl-xL (S62D), suppressed dissociation of Beclin-1 from Bcl-xL. A combinatorial treatment of mitomycin C, Ad.TRAIL and hyperthermia induced Beclin-1 cleavage, but the Beclin-1 cleavage was abolished in Beclin-1 double mutant (D133A/D146A) knock-in HCT116 cells, suppressing the apoptosis induced by the combination therapy. We believe that this study supports the application of the multimodality approach to colon cancer therapy.
Assuntos
Adenoviridae/genética , Antibióticos Antineoplásicos/farmacologia , Proteínas Reguladoras de Apoptose/metabolismo , Apoptose , Neoplasias do Colo/patologia , Hipertermia Induzida , Proteínas de Membrana/metabolismo , Mitomicina/farmacologia , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Proteína bcl-X/metabolismo , Proteína Beclina-1 , Linhagem Celular Tumoral , Neoplasias do Colo/metabolismo , Citocromos c/metabolismo , Vetores Genéticos , Humanos , MAP Quinase Quinase 4/metabolismo , Mitocôndrias/metabolismo , Multimerização Proteica , Ligante Indutor de Apoptose Relacionado a TNF/genética , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismoRESUMO
Colorectal cancer is the third leading cause of cancer-related mortality in the world--the main cause of death from colorectal cancer is hepatic metastases, which can be treated with isolated hepatic perfusion (IHP). Searching for the most clinically relevant approaches for treating colorectal metastatic disease by isolated hepatic perfusion (IHP), we developed the application of oxaliplatin concomitantly with hyperthermia and humanized death receptor 4 (DR4) antibody mapatumumab (Mapa), and investigated the molecular mechanisms of this multimodality treatment in human colon cancer cell lines CX-1 and HCT116 as well as human colon cancer stem cells Tu-12, Tu-21 and Tu-22. We showed here, in this study, that the synergistic effect of the multimodality treatment-induced apoptosis was caspase dependent and activated death signaling via both the extrinsic apoptotic pathway and the intrinsic pathway. Death signaling was activated by c-Jun N-terminal kinase (JNK) signaling which led to Bcl-xL phosphorylation at serine 62, decreasing the anti-apoptotic activity of Bcl-xL, which contributed to the intrinsic pathway. The downregulation of cellular FLICE inhibitory protein long isoform (c-FLIPL) in the extrinsic pathway was accomplished through ubiquitination at lysine residue (K) 195 and protein synthesis inhibition. Overexpression of c-FLIPL mutant (K195R) and Bcl-xL mutant (S62A) completely abrogated the synergistic effect. The successful outcome of this study supports the application of multimodality strategy to patients with colorectal hepatic metastases who fail to respond to standard chemoradiotherapy that predominantly targets the mitochondrial apoptotic pathway.
Assuntos
Anticorpos Monoclonais/farmacologia , Apoptose , Neoplasias do Colo/metabolismo , Neoplasias do Colo/terapia , Hipertermia Induzida , Compostos Organoplatínicos/farmacologia , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Sinergismo Farmacológico , Humanos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Metástase Neoplásica , Compostos Organoplatínicos/agonistas , OxaliplatinaRESUMO
Colorectal cancer is the third leading cause of cancer-related mortality in the world. The main cause of death because of colorectal cancer is hepatic metastases, which can be treated using isolated hepatic perfusion (IHP), allowing treatment of colorectal metastasis with various methods. In this study, we present a novel potent multimodality strategy comprising humanized death receptor 4 (DR4) antibody mapatumumab in combination with oxaliplatin and hyperthermia to treat human colon cancer cells. Oxaliplatin and hyperthermia sensitized colon cancer cells to mapatumumab in the mitochondrial-dependent apoptotic pathway and increased reactive oxygen species (ROS) production, leading to Bcl-xL phosphorylation at serine 62 in a c-jun-NH2-kinase (JNK)-dependent manner. Overexpression of Bcl-xL reduced the efficacy of the multimodality treatment, whereas phosphorylation of Bcl-xL decreased its antiapoptotic activity. The multimodality treatment dissociated Bcl-xL from Bax, allowing Bax oligomerization to induce cytochrome c release from mitochondria. In addition, the multimodality treatment significantly inhibited colorectal cancer xenografts' tumor growth. The successful outcome of this study will support the application of multimodality strategy to colorectal hepatic metastases.
Assuntos
Anticorpos Monoclonais/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias do Colo/terapia , Hipertermia Induzida/métodos , Compostos Organoplatínicos/farmacologia , Proteína bcl-X/metabolismo , Animais , Anticorpos Monoclonais Humanizados , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Terapia Combinada , Citocromos c/metabolismo , Sinergismo Farmacológico , Células HCT116 , Humanos , MAP Quinase Quinase 4/metabolismo , Masculino , Camundongos , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Oxaliplatina , Fosforilação/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Proteína X Associada a bcl-2/metabolismoRESUMO
Colorectal cancer is the third leading cause of cancer-related mortality in the world; death usually results from uncontrolled metastatic disease. Previously, we developed a novel strategy of TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) in combination with hyperthermia to treat hepatic colorectal metastases. However, previous studies suggest a potential hepatocyte cytotoxicity with TRAIL. Unlike TRAIL, anti-human TRAIL receptor antibody induces apoptosis without hepatocyte toxicity. In this study, we evaluated the anti-tumor efficacy of humanized anti-death receptor 4 (DR4) antibody mapatumumab (Mapa) by comparing it with TRAIL in combination with hyperthermia. TRAIL, which binds to both DR4 and death receptor 5 (DR5), was approximately tenfold more effective than Mapa in inducing apoptosis. However, hyperthermia enhances apoptosis induced by either agent. We observed that the synergistic effect was mediated through elevation of reactive oxygen species, c-Jun N-terminal kinase activation, Bax oligomerization, and translocalization to the mitochondria, loss of mitochondrial membrane potential, release of cytochrome c to cytosol, activation of caspases, and increase in poly(ADP-ribose) polymerase cleavage. We believe that the successful outcome of this study will support the application of Mapa in combination with hyperthermia to colorectal hepatic metastases.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Ligante Indutor de Apoptose Relacionado a TNF/administração & dosagem , Anticorpos Monoclonais Humanizados , Apoptose , Proteínas Reguladoras de Apoptose/deficiência , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Terapia Combinada , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Hipertermia Induzida , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Mitocôndrias/metabolismo , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Proteína X Associada a bcl-2/deficiência , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismoRESUMO
The aim of this study was to investigate the effect of garlic constituent diallyl trisulfide (DATS) on the cell-death signaling pathway in a human breast cell line (MDA-MB-231). We observed that DATS (10-100 µM) treatment resulted in dose- and time-dependent cytotoxicity. Treatment of MDA-MB-231 cells with a cytotoxicity inducing concentration of DATS (50-80 µM) resulted in an increase in the intracellular level of reactive oxygen species (ROS). Data from assay with MitoSOX(TM) Red reagent suggest that mitochondria are the main source of ROS generation during DATS treatment. DATS-induced oxidative stress was detected through glutaredoxin (GRX), a redox-sensing molecule, and subsequently GRX was dissociated from apoptosis signal-regulating kinase 1 (ASK1). Dissociation of GRX from ASK1 resulted in the activation of ASK1. ASK1 activated a downstream signal transduction JNK (c-Jun N-terminal kinase)-Bim pathway. SP600125, a JNK inhibitor, inhibited DATS-induced Bim phosphorylation and protected cells from DATS-induced cytotoxicity. Our results indicate that the cytotoxicity caused by DATS is mediated by the generation of ROS and subsequent activation of the ASK1-JNK-Bim signal transduction pathway in human breast carcinoma MDA-MB-231 cells.