RESUMEN
Asthma is a common chronic respiratory disease, which causes inflammation and airway stenosis, leading to dyspnea, wheezing and chest tightness. Using transgelin-2 as a target, we virtually screened the lead compound glycyrrhizin from the self-built database of anti-asthma compounds by molecular docking technology, and found that it had anti-inflammatory, anti-oxidative and anti-asthma pharmacological effects. Then, molecular dynamics simulations were used to confirm the stability of the glycyrrhizin-transgelin-2 complex from a dynamic perspective, and the hydrophilic domains of glycyrrhizin was found to have the effect of targeting transgelin-2. Due to the self-assembly properties of glycyrrhizin, we explored the formation process and mechanism of the self-assembly system using self-assembly simulations, and found that hydrogen bonding and hydrophobic interactions were the main driving forces. Because of the synergistic effect of glycyrrhizin and salbutamol in improving asthma, we revealed the mechanism through simulation, and believed that salbutamol adhered to the surface of the glycyrrhizin nano-drug delivery system through hydrogen bonding and hydrophobic interactions, using the targeting effect of the hydrophilic domains of glycyrrhizin to reach the pathological parts and play a synergistic anti-asthmatic role. Finally, we used network pharmacology to predict the molecular mechanisms of glycyrrhizin against asthma, which indicated the direction for its clinical transformation.
RESUMEN
BACKGROUND The (pro)renin receptor ((P)RR) was reported to be expressed in various tissues including the pancreas, and handle region peptide (HRP) is believed to block the function of (P)RR. This study aimed to investigate the effect of HRP on the glucose tolerance status and ß-cell function of female rats, neonatally treated with sodium L-glutamate (MSG) and to compare with the previously reported HRP effect on male rats. MATERIAL AND METHODS Female MSG rats aged 8 weeks were divided into MSG control group and HRP treated group and the normal SD rats served as control. The MSG rats were treated with HRP by osmotic minipumps with dose of 1 mg/kg per day for total 28 days. Glucose tolerance status was evaluated at the end of the study. Islets α-cell and ß-cell were marked with insulin antibody and glucagon antibody respectively. The proliferation of islet cells and expression of subunit of NADPH oxidase P22phox were marked by PCNA and P22phox antibody. Picrosirius red staining was performed for evaluating fibrosis of islets. RESULTS HRP improved the glucose status tolerance with decreasing α-cell mass, islets PCNA-positive cells, expression of P22phox and picrosirius red stained areas, and increasing ß-cell mass in female MSG rats. The indexes with obviously interacted effect of sexes and HRP for the MSG rats were the AUC of blood glucose concentration (P<0.01), α-cell mass (P<0.05), proliferation of islet cells (P<0.01) and area of picrosirius red staining (P<0.01). CONCLUSIONS HRP improved the glucose tolerance status in the females although it was previously reported to worsen the glucose tolerance in male MSG rats. Different levels of sex hormones may partly account for the disparate effects observed for HRP in different sexes.
Asunto(s)
Glucemia/fisiología , Células Secretoras de Insulina/fisiología , Oligopéptidos/metabolismo , Oligopéptidos/farmacología , Caracteres Sexuales , Análisis de Varianza , Animales , Proliferación Celular/efectos de los fármacos , Femenino , Células Secretoras de Glucagón/efectos de los fármacos , Células Secretoras de Glucagón/fisiología , Prueba de Tolerancia a la Glucosa , Inmunohistoquímica , Células Secretoras de Insulina/efectos de los fármacos , Masculino , NADPH Oxidasas/metabolismo , Antígeno Nuclear de Célula en Proliferación/metabolismo , Ratas , Glutamato de Sodio/farmacologíaRESUMEN
Handle region peptide (HRP), which was recognized as a blocker of (pro)renin receptor ((P)RR), may block the function of (P)RR. The aim of this study was to investigate the effect of HRP with a large dose of 1 mg/kg/d on glucose status in the rats treated neonatally with monosodium L-glutamate (MSG). At the age of 8 weeks, the MSG rats were randomly divided into MSG control group, HRP treated group with minipump (MSG-HRP group), losartan treated group (MSG-L group), and HRP and losartan cotreated group (MSG-HRP-L group) and fed with high-fat diet for 4 weeks. Losartan but not HRP increased the levels of insulin releasing and ameliorate glucose status although both losartan and HRP improved insulin sensitivity. On the one hand, both losartan and HRP decreased levels of pancreatic local Ang-II and NADPH oxidase activity as well as its subunits P(22phox). On the other hand, losartan but not HRP decreased α -cell mass and number of PCNA-positive cells located periphery of the islets and decreased picrosirius red stained area in islets. HRP ameliorating insulin resistance but not ß -cell functions leads to hyperglycemia in the end in male MSG rats, and the dual characters of HRP may partly account for the phenomenon.