Regulatory Peptides最新文献

Ghrelin is a novel growth hormone-releasing peptide, which has been shown to exert beneficial effects on cardiac function and ventricular remodeling. The present study aimed to investigate the expression of ghrelin and the growth hormone (GH) secretagogue receptor 1a (GHSR-1a), and the association with cardiac remodeling in rats with myocardial infarction (MI). Twenty-four hours after ligation of the anterior descending artery (LAD), adult male Sprague–Dawley rats were randomized to 3 d, 7 d and 28 d group. Sham animals underwent thoracotomy and pericardiotomy, but not LAD ligation. Expression of both ghrelin and GHSR-1a was assessed by means of immunohistochemistry and real-time PCR. Plasma ghrelin levels were measured by ELISA kit. In addition, cardiac remodeling was assessed by echocardiographic and hemodynamic measurements. Plasma and cardiac expression of ghrelin decreased on days 3, 7 and 28 compared with the sham group (P < 0.05). In contrast the GHSR-1a mRNA levels increased during the same days (P < 0.05). Decreased positive immunoreaction for ghrelin and increased positive GHSR-1a were also observed in the infarcted heart. Interestingly, plasma ghrelin correlated negatively with left ventricular end-diastolic pressure (r = − 0.59, P = 0.002) and left ventricular end-diastolic dimension (r = − 0.73, P < 0.01). The ghrelin system may play an important role regulating cardiac remodeling after MI and present as a potential significant target for pharmacological modulation and treating cardiac remodeling.

In humans, alcoholism is associated with a decrease in basal ACTH and cortisol levels, and blunted pituitary ACTH responses to administered corticotropin-releasing hormone (CRH) during active drinking and after long-term abstinence. Preclinical studies indicate that a persistent decrease in pituitary activation after chronic exposure to ethanol is due to a direct effect of ethanol on the corticotrope of the anterior pituitary. The present studies were undertaken to determine if ethanol has effects on proopiomelanocortin (POMC) gene transcription activity in mouse anterior pituitary corticotrope tumor cell AtT20. We measured the levels of the POMC primary nuclear RNA transcript (PT), processing intermediate, and mature mRNA in the nucleus and the levels of the POMC mRNA in the cytoplasm after treatment of AtT20 cells with 5–15 mM concentrations of ethanol. After 15 mM ethanol for 60 to 120 min, the POMC PT levels were significantly decreased. This decreased POMC gene transcription activity was coupled with a significant reduction of the POMC cytoplasmic mRNA levels. After ethanol for 4 h, however, both the decreases were no longer observed. After 8 h, a decrease in the ACTH secretion in the medium was found. We further investigated if CRH or glutamate modulates the effects of ethanol on the POMC gene transcription activity. CRH at 10 nM after 60 min increased the POMC PT levels, and 15 mM ethanol attenuated the effect of CRH on the nuclear transcription activity. Glutamate receptor proteins, including NMDA receptor subtype NR1 (but not NR2A or NR2B) and GluR2, were identified by Western immunoblot analysis in AtT20 cells, with similar sizes to those in mouse hypothalamus. The inhibitory effect of 60 min ethanol at 5 to 15 mM on the POMC PT levels was attenuated by 50 μM L-glutamate. Together, our data showed that: (1) ethanol treatment in intoxicate doses significantly inhibited POMC gene transcription activity in a dose- and time-dependent manner in AtT20 cells, and (2) the POMC gene transcription activity in response to CRH or glutamate was altered by ethanol. Our results suggest that ethanol has an inhibitory effect on the POMC gene transcription activity in the anterior pituitary corticotrope, which may contribute to the persistent decrease in pituitary activation after chronic ethanol exposure.

Glucagon-like peptide-1 (GLP-1) is a novel treatment modality for type 2 diabetes mellitus. However, GLP-1 has been suggested as a therapeutic target for Alzheimer's disease (AD). In rodent studies, GLP-1 reduces amyloid beta (Aβ) and facilitates synaptic plasticity. Therefore, in the present study, we investigated how GLP-1 facilitates synaptic plasticity and reduces the Aβ in vivo. Exendin-4, a GLP-1 receptor agonist that can cross the blood brain barrier, was subcutaneously administered to adult mice. We then extracted the total and the plasma membrane proteins from the mouse neocortex. Exendin-4 significantly increased the phosphorylation level of cAMP response element-binding protein (CREB). Consistently, the expression level of brain-derived neurotrophic factor (BDNF), a transcriptional target of CREB, was increased. Furthermore, exendin-4 increased the membrane protein level of the AMPA receptor GluR1 subunit and postsynaptic density protein-95 (PSD-95), whereas GluR2 was unaffected. These exendin-4-dependent increases in membrane GluR1, total PSD-95 and BDNF were abrogated by pretreatment with temozolomide (TMZ), a DNA-alkylating agent, indicating that these alterations were dependent on exendin-4-induced transcriptional activity. In addition, we found that exendin-4 increased the level of the α-C terminal fragment (α-CTF) of amyloid precursor protein (APP). Furthermore, protein levels of both mature and immature ADAM10, the α-secretase of APP in the plasma membrane, were increased, whereas the total mature and immature ADAM10 levels were unchanged. These exendin-4-dependent increases in α-CTF and ADAM10 were not affected by TMZ. These findings suggested that GLP-1 facilitates the GluR1 membrane insertion through CREB activation and increases α-secretase activity through ADAM10 membrane trafficking. Upregulation of GluR1 and ADAM10 at the plasma membrane were also observed in mice with intracerebroventricular administration of Aβ oligomer, indicating that a part of benefit of exendin-4 against AD may depend on the GluR1 and ADAM10 membrane trafficking.

Objective

Adropin is a recently identified bioactive protein that is important for energy homeostasis and maintaining insulin sensitivity. We sought to detect serum adropin levels in acute myocardial infarction (AMI) patients.

Methods

We enrolled 138 AMI patients, 114 stable angina pectoris (SAP) patients and 75 controls. Adropin levels were measured by enzyme-linked immunosorbent assay (ELISA).

Results

Serum adropin levels were significantly lower in patients with AMI compared with SAP patients or controls (P < 0.01). Multivariate logistic regression demonstrated that lower adropin was the independent predictor for the presence of AMI in coronary artery disease (CAD) patients (P < 0.01). Serum adropin levels were negatively associated with body mass index (BMI) (P < 0.01) and triglyceride levels (P < 0.05) in AMI patients.

Conclusion

Decreased serum adropin levels are associated with the presence of AMI in CAD patients. These results revealed that adropin might represent as a novel biomarker for predicting AMI onset in CAD patients.

Dipeptidyl peptidase 4 (DPP-4) inhibitors are current drugs for the treatment of type 2 diabetes (T2D) based on their main property to enhance endogenous glucagon-like peptide-1 (GLP-1) levels, thus increasing insulin secretion. However, the mechanism of action of DPP-4 inhibition in extra pancreatic tissues has been poorly investigated and it might occur differently from that induced by GLP-1R agonists.

Increased adult neurogenesis by GLP-1R agonists has been suggested to play a role in functional recovery in animal models of brain disorders. We recently showed that the DPP-4 inhibitor linagliptin reduces brain damage after stroke in normal and type 2 diabetic (T2D) mice. The aim of this study was to determine whether linagliptin impacts stroke-induced neurogenesis.

T2D was induced by 25 weeks of high-fat diet. Linagliptin treatment was carried out for 7 weeks. Standard diet fed-mice were used as controls. Stroke was induced by middle cerebral artery occlusion 4 weeks into the linagliptin treatment. Neural stem cell (NSC) proliferation/neuroblast formation and striatal neurogenesis/gliogenesis were assessed 3 weeks after stroke. The effect of linagliptin on NSC viability was also determined in vitro.

The results show that linagliptin enhances NSC proliferation in T2D mice but not in normal mice. Linagliptin did not increase NSC number in vitro indicating that the effect of linagliptin on NSC proliferation in T2D is indirect. Neurogenesis and gliogenesis were not affected.

In conclusion, we found no correlation between acute neuroprotection (occurring in both T2D and normal mice) and increased NSC proliferation (occurring only in T2D mice). However, our results show that linagliptin evokes a differential response on NSC proliferation after stroke in normal and T2D mice suggesting that DPP-4 inhibition effect in the CNS might go beyond the well known increase of GLP-1.

Aim of the study

The gastrointestinal peptide hormone ghrelin (Ghr) was discovered in 1999 as the endogenous ligand for the growth hormone secretagogue receptor (GHSR-1a). It is a pleiotropic peptide that modulates a wide spectrum of biological activities, such as growth hormone (GH) release, feeding stimulation, adiposity and cardiovascular actions. The presence of Ghr mRNA in the iris and ciliary body (CB) epithelium was recently demonstrated in animal models, where a possible myorelaxing effect on the iris muscles has been suggested. Based on these observations, the aim of our study was to investigate the Ghr and GHSR-1a expression and localization in the normal human eye.

Material

Five different ciliary body/iris samples from normal eyes were subjected to Western blot analysis. Immunohistochemical detection was performed on three enucleated eyes. Twenty aqueous humor (AqH) samples obtained from patients submitted to cataract surgery were analyzed with an ELISA for the presence of Ghr.

Results

Ghr and GHSR-1a were co-expressed by the pigmented epithelium (PE) of the CB, by the retinal pigmented epithelium (RPE) and by the anterior limiting layer (ALL) of the iris. No reaction was detected at the subepithelial level in the ciliary or pupillae smooth muscle cells. The AqH samples were positive for the presence of Ghr.

Conclusion

This study provides the first evidence that Ghr and GHSR-1a are expressed in the human eye by specific cells. The understanding of the functional role of Ghr at the human eye level needs more efforts and investigation, but a hypothetical action on the GH retinal synthesis and/or on the circadian clock system could be suggested.