Regulatory Peptides最新文献

Objective

The aim of this study was to investigate the effects of carnosine on the bioenergetic profile of cultured cortical astrocytes under normal and ischemic conditions.

Methods

The Seahorse Bioscience XF96 Extracellular Flux Analyzer was used to measure the oxygen consumption rates (OCRs) and extracellular acidification rates (ECARs) of cultured cortical astrocytes treated with and without carnosine under normal and ischemic conditions.

Results

Under the normal growth condition, the basal OCRs and ECARs of astrocytes were 21.72 ± 1.59 pmol/min/μg protein and 3.95 ± 0.28 mpH/min/μg protein respectively. Mitochondrial respiration accounted for ~ 80% of the total cellular respiration and 85% of this coupled to ATP synthesis. Carnosine significantly reduced basal OCRs and ECARs and ATP-linked respiration, but it strikingly increased the spare respiratory capacity of astrocytes. The cellular ATP level in carnosine-treated astrocytes was reduced to ~ 42% of the control. However, under the ischemic condition, carnosine upregulated the mitochondrial respiratory and cellular ATP content of astrocytes exposed to 8 h of oxygen–glucose deprivation (OGD) followed by 24 h of recovery under the normal growth condition.

Conclusions

Carnosine may be an endogenous regulator of astrocyte energy metabolism and a clinically safe therapeutic agent for promoting brain energy metabolism recovery after ischemia/reperfusion injury.

The stomach produces acid, which may play an important role in the regulation of bone homeostasis. The aim of this study was to reveal signaling pathways in the gastric mucosa that involve the acid secretion and possibly the bone metabolism in CCK₁ and/or CCK₂ receptor knockout (KO) mice. Gastric acid secretion was impaired and the ECL cell signaling pathway was inhibited in CCK₂ receptor KO mice but not in CCK₁ receptor KO mice. However, in CCK_1 + 2 receptor double KO mice the acid secretion in response to pylorus ligation-induced vagal stimulation and the ECL cell pathway were partially normalized, which was associated with an up-regulated pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 receptor (PAC1). The basal part of the gastric mucosa expressed parathyroid hormone-like hormone (PTHLH) in a subpopulation of likely ECL cells (and possibly other cells) and vitamin D3 1α hydroxylase probably in trefoil peptide2-immunoreactive cells. In conclusion, mice lacking CCK receptors exhibited a functional shift from the gastrin-CCK pathways to the neuronal pathway in control of the ECL cells and eventually the acid secretion. Taking the present data together with previous findings, we suggest a possible link between gastric PTHLH and vitamin D and bone metabolism.

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.