RESUMO
Being endocrine signaling molecules that regulate lipid metabolism and affect energy balance, bile acids are potential drug candidates for non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) could improve NASH accompanied by significant side effects. Therefore, it is worthwhile to develop safer and more effective bile acid analogs. In this study, a new bile acid analog A17 was synthesized and its potential anti-NASH effects were assessed in vitro and in vivo. The impact of A17 on steatosis was investigated in the rat primary hepatocytes challenged with oleic acid. It was found that A17 alleviated lipid accumulation by reducing fatty acid (FA) uptake and promoting FA oxidation. The reduction of FA uptake came from inhibiting fatty acid translocase (Cd36) expression. The promotion of FA oxidation came from stimulating the phosphorylation of adenosine monophosphate (AMP)-activated protein kinase alpha (AMPKα). In addition, A17 reduced lipopolysaccharide-induced inflammation in Raw264.7 cells by activating Takeda G protein-coupled receptor 5 (TGR5). In in vivo study, male Golden Syrian hamsters were fed with high fat (HF) diet and then treated with 50 mg/kg/d A17 for 6 weeks. A17 lowered the lipid profiles and liver enzyme levels in serum and improved liver pathological conditions with less side effects compared with OCA. Further studies confirmed that the molecular mechanisms of A17 in vivo were similar to those in vitro. In conclusion, a novel bile acid analog A17 was identified to ameliorate NASH in HF-fed hamsters. The potential mechanisms could be contributed to reducing FA uptake, stimulating FA oxidation and relieving inflammation.
Assuntos
Ácidos e Sais Biliares/farmacologia , Dieta Hiperlipídica/efeitos adversos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Animais , Antígenos CD36/genética , Antígenos CD36/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Cricetinae , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Hepatócitos/metabolismo , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares/metabolismoRESUMO
2-Desoxy-4-epi-puchellin (PCL) is a sesquiterpene-lactone, which naturally occurs in many traditional Chinese medicinal plants, and has antitumor and anti-inflammatory activities. In this work, a series of 13-amino derivatives of PCL were synthesized through Michael addition reaction. Inhibition of IL-6-induced STAT3 signaling pathway and in vitro cytotoxicity of these compounds were evaluated, and their effect on the cell cycle was also studied. The methyl hydroxyethylamine derivatives showed higher potency than PCL, which could induce significant mitotic arrest via G2/M arrest in HCT116 cancer cells, indicating that these derivatives have the potential to be developed into anti-colon cancer drugs.
Assuntos
Aminas/farmacologia , Antineoplásicos/farmacologia , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Lactonas/farmacologia , Sesquiterpenos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Aminas/síntese química , Aminas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Células HCT116 , Humanos , Lactonas/síntese química , Lactonas/química , Estrutura Molecular , Fator de Transcrição STAT3/metabolismo , Sesquiterpenos/síntese química , Sesquiterpenos/química , Relação Estrutura-AtividadeRESUMO
We investigated the function and molecular mechanisms of 2-desoxy-4ß-propylcarbamate-pulchellin (P-13), a sesquiterpene lactone derivative of 2-desoxy-4-epi-pulchellin from the traditional Chinese medicinal herb Carpesium abrotanoides L, in regulating STAT3 signaling and cancer cell growth. We found that P-13 inhibited the IL-6-induced, as well as the constitutive, STAT3 activation in a dose and time-dependent manner. In vitro kinase activity analyses demonstrated that P-13 directly inhibited JAK2 kinase activity. The inhibitory effects of P-13 on JAK2/STAT3 signaling could be blocked by reducing agents dithiothreitol (DTT) or glutathione (GSH), indicating an involvement of the thiol-reactive α-ß unsaturated carbonyl group in P-13. Further analyses with mass spectrograph, as well as molecular docking, revealed that P-13 covalently bound with the C452 in the SH2 domain of JAK2. Furthermore, P-13 inhibited growth and induced death of many cancer cell lines, particularly those expressing constitutively activated STAT3. It also inhibited in vivo growth of human cancer cell xenografts. Taken together, these findings revealed P-13 as a novel covalent inhibitor of JAK2, uncovered a new mechanism to inhibit JAK2, and provided a promising anti-cancer drug candidate.