RESUMO
The protective effects of ruscogenin on nonalcoholic steatohepatitis in hamsters fed a high-fat diet were investigated. Ruscogenin (0.3, 1.0, or 3.0 mg/kg/day) was orally administered by gavage once daily for eight weeks. A high-fat diet induced increases in plasma levels of total cholesterol, triglycerides, and free fatty acids, while the degree of insulin resistance was lowered by ruscogenin. High-fat diet-induced hepatic steatosis and necroinflammation were improved by ruscogenin. Gene expression of inflammatory cytokines and activity of nuclear transcription factor-κB were also increased in the high-fat diet group, which were attenuted by ruscogenin. Ruscogenin decreased hepatic mRNA levels of sterol regulatory element-binding protein-1c and its lipogenic target genes. The hepatic mRNA expression of peroxisome proliferator-activated receptor α, together with its target genes responsible for fatty acid ß-oxidation were upregulated by ruscogenin. In conclusion, these findings suggest that ruscogenin may attenuate high-fat diet-induced steatohepatitis through anti-inflammatory mechanisms, reducing hepatic lipogenic gene expression, and upregulating proteins in the fatty acid oxidation process.
Assuntos
Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Substâncias Protetoras/farmacologia , Espirostanos/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Cricetinae , Citocinas/genética , Citocinas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Oxirredução/efeitos dos fármacos , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/química , Espirostanos/administração & dosagem , Espirostanos/química , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Triglicerídeos/metabolismoRESUMO
The aim of the study was to investigate the protective effects of ruscogenin, a major steroid sapogenin in Ophiopogon japonicus, on experimental models of nonalcoholic steatohepatitis. HepG2 cells were exposed to 300 µmol/l palmitic acid (PA) for 24 h with the preincubation of ruscogenin for another 24 h. Ruscogenin (10.0 µmol/l) had inhibitory effects on PA-induced triglyceride accumulation and inflammatory markers in HepG2 cells. Male golden hamsters were randomly divided into five groups fed a normal diet, a high-fat diet (HFD), or a HFD supplemented with ruscogenin (0.3, 1.0, or 3.0 mg/kg/day) by gavage once daily for 8 weeks. Ruscogenin alleviated dyslipidemia, liver steatosis, and necroinflammation and reversed plasma markers of metabolic syndrome in HFD-fed hamsters. Hepatic mRNA levels involved in fatty acid oxidation were increased in ruscogenin-treated HFD-fed hamsters. Conversely, ruscogenin decreased expression of genes involved in hepatic lipogenesis. Gene expression of inflammatory cytokines, chemoattractive mediator, nuclear transcription factor-(NF-) κB, and α-smooth muscle actin were increased in the HFD group, which were attenuated by ruscogenin. Ruscogenin may attenuate HFD-induced steatohepatitis through downregulation of NF-κB-mediated inflammatory responses, reducing hepatic lipogenic gene expression, and upregulating proteins in ß-oxidation pathway.
Assuntos
Inflamação/tratamento farmacológico , Lipogênese/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Espirostanos/administração & dosagem , Animais , Cricetinae , Dieta Hiperlipídica , Regulação da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Inflamação/genética , Inflamação/patologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipogênese/genética , Masculino , Mesocricetus , Redes e Vias Metabólicas/efeitos dos fármacos , NF-kappa B/biossíntese , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , RNA Mensageiro/biossíntese , Fator de Necrose Tumoral alfa/biossínteseRESUMO
BACKGROUND: The polysaccharides from Liriopes Radix (PSLR) has been indicated to ameliorate insulin signaling transduction and glucose metabolism. We aimed to investigate whether PSLR exerts an ameliorative effect on renal damage in diabetes induced by streptozotocin. METHODS: Diabetes was induced with STZ (60 mg/kg) by intraperitoneal injection in rats. Two weeks after STZ injection, rats in the treatment group were orally dosed with PSLR (200 and 300 mg/kg/day for 8 weeks. The normal rats were chosen as nondiabetic control group. Changes in renal function-related parameters in plasma and urine were analyzed at the end of the study. Kidneys were isolated for pathology histology, immunohistochemistry, and Western blot analyses. RESULTS: Diabetic rats exhibited renal dysfunction, as evidenced by reduced creatinine clearance, blood urea nitrogen and proteinuria, along with marked elevation in the ratio of kidney weight to body weight. All of these abnormalities were significantly reversed by PSLR. The histological examinations revealed amelioration of diabetes-induced glomerular pathological changes following treatment with PSLR. The less protein expressions of renal nephrin and podocin in diabetic rats were increased following treatment with PSLR. PSLR reduced the accumulation of ED-1-expressing macrophages in renal tissue of diabetic rats. PSLR almost completely abolished T cells infiltration and attenuated the expression of proinflammatory cytokines. PSLR treatments not only reduced the degradation of inhibitory kappa B kinase, but also downregulated the protein expression of nuclear factor kappa B (NF-κB) and p38 mitogen-activated protein kinase (MAPK) in diabetic kidney. CONCLUSIONS: The results suggest that the renal protective effects of PSLR occur through improved glycemic control and renal structural changes, which are involved in the inhibition of NF-κB and p-38 MAPK mediated inflammation.
Assuntos
Nefropatias Diabéticas/prevenção & controle , Liliaceae/química , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/metabolismo , Polissacarídeos/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Inflamação/metabolismo , Insulina/metabolismo , Rim/efeitos dos fármacos , Masculino , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Raízes de Plantas/química , Polissacarídeos/isolamento & purificação , Polissacarídeos/uso terapêutico , Ratos , Ratos Wistar , Transdução de Sinais , EstreptozocinaRESUMO
We investigated the effects of zerumbone, a natural cyclic sesquiterpene of Zingiber zerumbet Smith, on high-fat diet (HFD)-induced hyperlipidemic hamsters. After being fed HFD for 2 weeks, Syrian golden hamsters were dosed orally with zerumbone (25, 50, and 100 mg/kg) once daily for 8 weeks. Decreased plasma levels of TC, TG and LDL-C, as well as the concentrations of hepatic lipids, with a simultaneous increase in fecal lipids were found. The ratios of LDL-C/HDL-C and TC/HDL-C were elevated by zerumbone. Zerumbone exhibited the ability to decreased hepatic mRNA levels of fatty acid synthase, malic enzyme, sterol-regulatory element binding protein and 3-hydroxy-3-methyl-glutaryl-CoA reductase reductase. The hepatic mRNA expression of peroxisome proliferator-activated receptor α, together with its target gene carnitine palmitoyl transferase and acyl-CoA oxidase were also upregulated by zerumbone. Zerumbone is effective to improve dyslipidemia by modulating the genes expression involving in the lipolytic and lipogenic pathways of lipids metabolism.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Hiperlipidemias/tratamento farmacológico , Sesquiterpenos/farmacologia , Zingiberaceae/química , Animais , Peso Corporal/efeitos dos fármacos , Carnitina O-Palmitoiltransferase/genética , Modelos Animais de Doenças , Ingestão de Alimentos/efeitos dos fármacos , Fezes , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperlipidemias/induzido quimicamente , Lipase/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Lipídeos/sangue , Lipólise/efeitos dos fármacos , Lipólise/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Mesocricetus , Sesquiterpenos/química , Proteína de Ligação a Elemento Regulador de Esterol 1/genéticaRESUMO
BACKGROUND: Ruscogenin is a major steroid sapogenin in the traditional Chinese herb Ophiopogon japonicus that have multiple bioactivities. Recent studies have demonstrated that ruscogenin is involved in down-regulation of intercellular adhesion molecule-1 (ICAM-1) and nuclear factor-κB (NF-κB) activation in anti-inflammatory pathways. We hypothesized that ruscogenin protects against diabetic nephropathy (DN) by inhibiting NF-κB-mediated inflammatory pathway. To test this hypothesis, the present study was to examine the effects of ruscogenin in rats with streptozotocin (STZ)-induced DN. METHODS: Diabetes was induced with STZ (60 mg/kg) by intraperitoneal injection in rats. Two weeks after STZ injection, rats in the treatment group were orally dosed with 0.3, 1.0 or 3.0 mg/kg ruscogenin for 8 weeks. The normal rats were chosen as nondiabetic control group. The rats were sacrificed 10 weeks after induction of diabetes. Changes in renal function-related parameters in plasma and urine were analyzed at the end of the study. Kidneys were isolated for pathology histology, immunohistochemistry, and Western blot analyses. RESULTS: Ruscogenin administration did not lower the levels of plasma glucose and glycosylated hemoglobin in STZ-diabetic rats. Diabetic rats exhibited renal dysfunction, as evidenced by reduced creatinine clearance, blood urea nitrogen and proteinuria, along with marked elevation in the ratio of kidney weight to body weight, that were reversed by ruscogenin. Ruscogenin treatment was found to markedly improve histological architecture in the diabetic kidney. Renal NF-κB activity, as wells as protein expression and infiltration of macrophages were increased in diabetic kidneys, accompanied by an increase in protein content of intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 in kidney tissues. All of the above abnormalities were reversed by ruscogenin treatment, which also decreased the expression of transforming growth factor-ß1 and fibronectin in the diabetic kidneys. CONCLUSIONS: Our data demonstrated that ruscogenin suppressed the inflammation and ameliorated the structural and functional abnormalities of the diabetic kidney in rats might be associated with inhibition of NF-κB mediated inflammatory genes expression.
Assuntos
Anti-Inflamatórios/farmacologia , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/tratamento farmacológico , Rim/efeitos dos fármacos , Ophiopogon/química , Fitoterapia , Espirostanos/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Quimiocina CCL2/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Regulação para Baixo , Fibronectinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Rim/metabolismo , Masculino , NF-kappa B/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Ratos , Transdução de Sinais , Espirostanos/uso terapêutico , Fator de Crescimento Transformador beta1/metabolismoRESUMO
The tuberous root of Liriope spicata var. prolifera (TRLS; Liliaceae family) is valued for the ability to promote glucose homeostasis, and it may therefore be utilized as an adjuvant therapy in the control of diabetic complications. The aim of the present study was to examine the effects of an aqueous ethanol extract from TRLS (TRLS-ext) (100 or 200 mg kg(-1) per day for eight weeks) on rats with streptozotocin-induced diabetic nephropathy (DN). Renal dysfunction in diabetic rats was ameliorated by TRLS-ext as evidenced by reduced creatinine clearance, as well as increased blood urea nitrogen and proteinuria. Treatment with TRLS-ext was found to markedly improve histological architecture in the diabetic kidney. Hyperglycemia induced degradation of inhibitory kappa B and reduced nuclear factor kappa B activation, leading to increased infiltration of macrophages and increased levels of proinflammatory cytokines, including interleukin-1 and tumor necrosis factor- α . All of the above abnormalities were reversed by TRLS-ext treatment, which also decreased the expression of intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and fibronectin in the diabetic kidneys. These findings provide a perspective on the renoprotective effects of TRLS-ext in DN.
RESUMO
The aim of this study was to examine the effects of Cassia tora seeds on high-fat diet (HFD)-induced hepatic steatosis, and elucidate the molecular mechanisms behind its effects. After being fed a HFD for two weeks, rats were orally dosed with Cassia seed ethanol extract (CSEE) (100, 200, or 300mg/kg) once daily for 8weeks. CSEE induced dose-dependent reductions in plasma lipid levels, as well as decreased the over hepatic lipid accumulation. Furthermore, CSEE treatment improved HFD-induced hepatic histological lesions. CSEE enhanced the phosphorylation of AMP-activated protein kinase (AMPK) and its primary downstream targeting enzyme, acetyl-CoA carboxylase, up-regulated the gene expression of carnitine palmitoyl transferase 1, and down-regulated sterol regulatory element binding protein 1 and fatty acid synthase protein levels in the livers of HFD-fed rats. AMPK inhibition by compound C retarded CSEE-induced reduction in triglyceride accumulation in HepG2 cells stimulated by insulin. Our findings suggest that CSEE may regulate hepatic lipid homeostasis related with an AMPK-dependent signaling pathway. Targeting AMPK activation with CSEE may represent a promising approach for the prevention and treatment of obesity-related non-alcoholic fatty liver disease.
Assuntos
Cassia/química , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/tratamento farmacológico , Extratos Vegetais/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Acetil-CoA Carboxilase/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/patologia , Células Hep G2/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Lipídeos/sangue , Masculino , Hepatopatia Gordurosa não Alcoólica , Obesidade/complicações , Fosforilação/efeitos dos fármacos , Ratos , Ratos Wistar , Sementes/química , Triglicerídeos/sangueRESUMO
Natural herbal medications may be one answer to the worldwide epidemic of obesity. This study examines the effects of Cassia seed ethanol extract (CSEE) upon lipid accumulation in white adipose tissue (WAT). CSEE exhibited a significant concentration-dependent decrease in the intracellular accumulation of trigycerides in 3T3-L1 adipocytes. After being fed a high-fat diet (HFD) for 2 weeks, rats were fed CSEE (100, 200 or 300 mg/kg) once daily for 8 weeks. CSEE caused dose-related reductions in body weight gain (as well as plasma lipid levels and epididymal WAT sizes in HFD-fed rats). CSEE enhanced the phosphorylation of AMP-activated protein kinase (AMPK) and its primary downstream targeting enzyme, acetyl-CoA carboxylase, up-regulated gene expression of carnitine palmitoyl transferase 1, and down-regulated sterol regulatory element-binding protein 1 and fatty acid synthase protein levels in epididymal WAT of HFD-fed rats. CSEE could attenuate lipid accumulation in WAT via AMPK signaling pathway activation.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Tecido Adiposo Branco/metabolismo , Fármacos Antiobesidade/administração & dosagem , Cassia/química , Metabolismo dos Lipídeos/efeitos dos fármacos , Obesidade/tratamento farmacológico , Obesidade/enzimologia , Extratos Vegetais/administração & dosagem , Células 3T3-L1 , Proteínas Quinases Ativadas por AMP/genética , Tecido Adiposo Branco/efeitos dos fármacos , Animais , Regulação para Baixo/efeitos dos fármacos , Humanos , Masculino , Camundongos , Obesidade/genética , Obesidade/metabolismo , Ratos Wistar , SementesRESUMO
Emodin is an active herbal component traditionally used in China for treating a variety of diseases. The aim of this study was to examine the effect of emodin on the reducing lipid accumulation in white adipose tissue of high-fat diet-fed rats, and on the regulation of the expression of the genes involved in lipid metabolism to elucidate the mechanisms. After being fed a high-fat diet for two weeks, rats were dosed orally with emodin (20, 40, 80 mg/kg/day) or pioglitazone (20 mg/kg/day), once daily for eight weeks. Changes in body weight, feeding pattern, serum lipids, coronary artery risk index, and atherogenic index were investigated. Subcutaneous white adipose tissues were isolated for pathology histology and Western blot analyses. Changes of triglyceride accumulation in differentiated 3 T3-L1 adipocytes were also investigated. Emodin exhibited a significant concentration-dependent decrease in the intracellular accumulation of triglyceride in 3 T3-L1 adipocytes. Emodin (80 mg/kg/day) displayed similar characteristics to pioglitazone (20 mg/kg/day) in reducing body weight gain and plasma lipid levels as well as the coronary artery risk and atherogenic indices of high-fat diet-fed rats. Emodin also caused dose related reductions in epididymal white adipose tissue sizes in high-fat diet-fed rats. Emodin and pioglitazone enhanced the phosphorylation of AMP-activated protein kinase and its primary downstream targeting enzyme, acetyl-CoA carboxylase, upregulated gene expression of carnitine palmitoyl transferase 1, and downregulated sterol regulatory element binding protein 1 and fatty acid synthase protein levels in the epididymal white adipose tissue of high-fat diet-fed rats. Our findings suggest that emodin could attenuate lipid accumulation in white adipose tissue through AMP-activated protein kinase activation.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/enzimologia , Dieta Hiperlipídica/efeitos adversos , Emodina/farmacologia , Obesidade/tratamento farmacológico , Células 3T3-L1 , Proteínas Quinases Ativadas por AMP/genética , Adipócitos Brancos/efeitos dos fármacos , Adipócitos Brancos/enzimologia , Adipócitos Brancos/patologia , Tecido Adiposo Branco/patologia , Animais , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/farmacologia , Western Blotting , Peso Corporal/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Dieta Aterogênica/efeitos adversos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Emodina/administração & dosagem , Comportamento Alimentar/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica , Metabolismo dos Lipídeos , Masculino , Camundongos , Obesidade/induzido quimicamente , Obesidade/genética , Obesidade/metabolismo , Fosforilação , Pioglitazona , Preparações de Plantas/farmacologia , Ratos , Ratos Wistar , Rheum/química , Índice de Gravidade de Doença , Tiazolidinedionas/administração & dosagem , Triglicerídeos/sangueRESUMO
The aim of this study was to investigate the antiobesity and antihyperlipidaemic effects of emodin on high-fat diet (HFD)-induced obese rats, and on the regulation of the expression of the genes involved in lipid metabolism to elucidate the mechanisms. After being fed HFD for two weeks, Wistar rats were dosed orally with emodin (40 and 80 mg kg(-1)) or pioglitazone (20 mg kg(-1)), once daily for eight weeks. Emodin (80 mg kg(-1) per day) displayed similar characteristics to pioglitazone (20 mg kg(-1) per day) in reducing body weight gain, plasma lipid levels as well as coronary artery risk index and atherogenic index of HFD-fed rats. Emodin also caused dose related reductions in the hepatic triglyceride and cholesterol contents and lowered hepatic lipid droplets accumulation in HFD-fed rats. Emodin and pioglitazone enhanced the phosphorylation of AMP-activated protein kinase (AMPK) and its primary downstream targeting enzyme, acetyl-CoA carboxylase, up-regulated gene expression of carnitine palmitoyl transferase 1, and down-regulated sterol regulatory element binding protein 1 and fatty acid synthase protein levels in hepatocytes of HFD-fed rats. Our findings suggest emodin could attenuate lipid accumulation by decreasing lipogenesis and increasing mitochondrial fatty acid ß-oxidation mediated by activation of the AMPK signaling pathway.
RESUMO
The aim of this study was to investigate the antiobesity and antihyperlipidemic effects of vinegar-baked Radix Bupleuri (VBRB) on high-fat diet- (HFD-) induced obese rats. After being fed HFD for two weeks, rats were dosed orally with VBRB or fenofibrate, once daily for further twelve weeks. VBRB (1.0 g kg(-1) per day) produced effects similar to fenofibrate (100 mg kg(-1)) in reducing body weight (BW) gain, visceral fat-pad weights, plasma lipid levels, as well as hepatic TG and cholesterol content of HFD-fed rats. VBRB also lowered hepatic lipid droplet accumulation and the size of epididymal adipocytes in HFD-fed rats. VBRB and fenofibrate reversed the HFD-induced downregulation of hepatic peroxisome proliferator-activated receptor (PPAR)α. HFD-induced reductions in the hepatic levels of acyl-CoA oxidase (ACO) and cytochrome P450 isoform 4A1 (CYP4A1) proteins were reversed by VBRB and fenofibrate. The elevated expression of hepatic sterol regulatory element binding proteins (SREBPs) in HFD-fed rats was lowered by VBRB and fenofibrate. The results of this study show that VBRB suppresses BW gain and body fat accumulation by increasing fatty acid oxidation, an effect which is likely mediated via upregulation of PPARα and downregulation of SREBP expression in the liver of HFD-fed rats.