RESUMO
Obesity has now surpassed malnutrition and infectious diseases as the most significant contributor to health problems worldwide. In particular, obesity is associated with several metabolic disorders, including hyperlipidemia, hepatic steatosis, and subfertility. Genipin (GNP), the aglycone of geniposide, is isolated from the extract of the traditional Chinese medicine Gardenia jasminoides Ellis and has been used in traditional oriental medicine against several inflammation-driven diseases. However, the effect and molecular mechanism of GNP on obesity-associated dyslipidemia and sperm dysfunction still need to be explored. In this study, we detect the effects of GNP on hyperlipidemia, hepatic lipid accumulation and sperm function using a high-fat diet (HFD)-induced obese mouse model. We find that obese mice treated with GNP show an improvement in body weight, serum triglyceride levels, serum hormone levels, serum inflammatory cytokines, hepatic steatosis and sperm function. At the molecular level, HFD/GNP diversely regulates the expression of miR-132 in a tissue-specific manner. miR-132 further targets and regulates the expression of SREBP-1c in liver cells, as well as the expressions of SREBP-1c and StAR in Leydig cells in the testis, thus modifying lipogenesis and steroidogenesis, respectively. Collectively, our data demonstrate that GNP shows a broad effect on the improvement of HFD-induced metabolic disorder and sperm dysfunction in male mice by tissue-specific regulation of miR-132. Our findings reveal the function GNP in ameliorating hepatic lipid metabolism and sperm function and suggest that this compound is a versatile drug to treat metabolic disorders.
Assuntos
Fígado Gorduroso , Hiperlipidemias , Doenças Metabólicas , MicroRNAs , Masculino , Animais , Camundongos , Metabolismo dos Lipídeos , Camundongos Obesos , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Sêmen/metabolismo , Fígado/metabolismo , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/metabolismo , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Hiperlipidemias/metabolismo , Dieta Hiperlipídica/efeitos adversos , Doenças Metabólicas/metabolismo , MicroRNAs/metabolismo , Espermatozoides/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Hyperlipidemia is a chronic disorder which plays an important role in the development of cardiovascular diseases, type 2 diabetes, atherosclerosis, hypertension, and nonalcoholic fatty liver disease. Genipin (GNP) is a metabolite from genipioside, which is an active component of the traditional Chinese medicine Gardenia jasminoides Ellis, and has been recognized as a beneficial compound against metabolic disorders. However, whether it can correct overnutrition-induced dyslipidemia is still unknown. In this study, the effects of GNP on attenuating hyperlipidemia and hepatic lipid accumulation were investigated using normal and obese mice induced with a high-fat diet (HFD) and primary hepatocytes treated with free fatty acids. We also sought to identify potential targets of GNP to mediate its effects in the liver. We found that obese mice treated with GNP showed a decrease in the body weight, serum lipid levels, as well as hepatic lipid accumulation. Besides, GNP regulated hepatic expression levels of lipid metabolic genes, which are important in maintaining systemic lipid homeostasis. At the molecular level, GNP increased the expression levels of miR-142a-5p, which bound to 3' untranslated region of Srebp-1c, an important regulator of lipogenesis, which thus led to the inhibition of lipogenesis. Collectively, our data demonstrated that GNP effectively antagonized HFD-induced hyperlipidemia and hepatic lipid accumulation in mice. Such effects were achieved by regulating miR-142a-5p/SREBP-1c axis.
Assuntos
Hiperlipidemias/tratamento farmacológico , Iridoides/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipotrópicos/uso terapêutico , Fígado/efeitos dos fármacos , MicroRNAs/agonistas , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/farmacologia , Fármacos Antiobesidade/uso terapêutico , Células Cultivadas , Biologia Computacional , Dieta Hiperlipídica/efeitos adversos , Relação Dose-Resposta a Droga , Ácidos Graxos não Esterificados/efeitos adversos , Ácidos Graxos não Esterificados/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Genes Reporter/efeitos dos fármacos , Hiperlipidemias/etiologia , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Resistência à Insulina , Iridoides/administração & dosagem , Iridoides/farmacologia , Lipotrópicos/administração & dosagem , Lipotrópicos/farmacologia , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/tratamento farmacológico , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia , Distribuição Aleatória , Proteína de Ligação a Elemento Regulador de Esterol 1/agonistas , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismoRESUMO
Vascular smooth muscle cell (VSMC) proliferation is a key event in the development of instent restenosis. Evodiamine is an indole alkaloid extracted from the Chinese medicine, evodia, and has been shown to inhibit tumor cell proliferation and protect the cardiovascular system. However, whether evodiamine affects VSMC proliferation remains to be elucidated. Therefore, the present study examined the effects and the mechanisms of action of evodiamine on the proliferation of rat VSMCs. The cells were treated with evodiamine alone or in combination with plateletderived growth factorBB (PDGFBB) stimulation. It was found that evodiamine inhibited PDGFBBinduced VSMC proliferation in a dosedependent manner, without inducing cell death. Evodiamine also retarded cell cycle progression, evidenced by the suppression of the expression of cell cyclepromoting cyclin proteins and cyclindependent kinases. In addition, evodiamine attenuated the PDGFBBinduced phosphorylation of mitogenactivated protein kinases p38 and extracellular signalregulated kinases 1/2, however, it had no effect on the phosphorylation of Akt. Evodiamine also inhibited the increase of reactive oxygen species generation and upregulated the mRNA expression levels of genes encoding antioxidant enzymes. These findings provide important insights into the mechanisms underlying the vasoprotective actions of evodiamine and suggest that it may be a useful therapeutic agent for the treatment of vascular occlusive disease.
Assuntos
Proliferação de Células/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Quinazolinas/administração & dosagem , Animais , Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Evodia/química , Regulação da Expressão Gênica/efeitos dos fármacos , Medicina Tradicional Chinesa , Músculo Liso Vascular/crescimento & desenvolvimento , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-sis/administração & dosagem , Proteínas Proto-Oncogênicas c-sis/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Doenças Vasculares/tratamento farmacológico , Doenças Vasculares/genética , Doenças Vasculares/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/biossíntese , Proteínas Quinases p38 Ativadas por Mitógeno/genéticaRESUMO
The causative agent of tremor disease (TD) in the Chinese mitten crab Eriocheir sinensis has been shown to be a member of the genus Spiroplasma. In the present study, a susceptibility test indicated that oxytetracycline (OTC) has both a high degree of efficacy in the inhibition of Spiroplasma and a broad range of safe concentrations. Treatment experiments showed that the best concentration of OTC for use against TD was 40 mg OTC kg(-1) crab weight. Acute toxicity experiments demonstrated that the 24 and 48 h median lethal dosages (LD50) of OTC for this species of crab were 366 and 340 mg OTC kg(-1) crab body weight, respectively, while the safe concentration was 82.5 mg OTC kg(-1) crab weight. We suggest that OTC has potential as a highly effective inhibitor of Spiroplasma pathogens in aquatic animals and has been proven to be a potent, safe and low cost cure for TD. This represents a novel use of OTC in the therapeutic treatment of an aquacultural disease caused by a Spiroplasma pathogen.