Regulatory Peptides最新文献

Background

Ghrelin and obestatin are important appetite- and energy-regulating peptides, secreted by the stomach. These gut peptides and thyroid hormones are involved in metabolism regulation. Although subclinical thyroidism is common, to date, very few studies have been reported about gut hormones in thyroid dysfunction, and their results are controversial. The purpose of this study was to investigate ghrelin and obestatin in patients with subclinical hypo- and hyperthyroidism. Moreover, is association between thyroid hormones and gut peptides able to suggest new regulatory relation between the HPT axis and gut?

Materials and methods

The study group included 70 subclinical hypo- and hyperthyroid subjects (in equal groups) and 35 healthy euthyroid controls. Serum values of ghrelin, obestatin, free T3, free T4, thyroid-stimulating hormone and the ratio of ghrelin to obestatin were measured in all participants.

Results

Ghrelin and obestatin both decreased in subclinical hypothyroid subjects (320 ± 81 ng/l and 44.3 ± 11.7 ng/l, respectively) compared to the control group (487 ± 110 ng/l and 58.5 ± 10.3 ng/l, respectively). On the other hand, ghrelin and obestatin both increased in subclinical hyperthyroid subjects (750 ± 289 ng/l and 71.1 ± 27.3 ng/l, respectively) compared to the control group. In addition, ghrelin and obestatin showed strong correlations with TSH, FT3 and FT4.

Conclusion

This study shows that gut hormones are significantly associated with thyroid hormones. Thus, there may be a cross talk between the HPT axis and gut. We would like to consider new regulatory relation for description of the found data.

The aim of this work was to investigate whether the expression of leptin receptors (OBR) in the hypothalamic–pituitary (HP) axis is regulated by the orexigenic neuropeptide Y (NPY) during ovulation. To this end, we performed in vitro assays, using cultures of both hypothalamic and anterior pituitary explants from immature rats primed with gonadotropins to induce ovulation. In hypothalamic explants, protein expression of both the long and short OBR isoforms was increased by the presence of NPY at 100–500 ng/ml and at 300–500 ng/ml, respectively. Similarly, in pituitary explants, protein expression of the long isoform was increased between 30 and 300 ng/ml while that of the short isoform was increased only at 300 ng/ml. When both tissues were incubated with NPY and BIBP3226, a specific antagonist of the NPY Y1 receptor subtype, the NPY-induced protein expression was totally reversed by the antagonist at almost every concentration assayed. However, this antagonist was not always capable of blocking the increase caused by the presence of NPY at transcript level. In conclusion, our results indicate that NPY is able to regulate the expression of both the long and the short isoforms of OBR in the HP axis, at least in part, through the NPY Y1 receptor. These results reinforce the fact that NPY and its NPY Y1 receptor play a critical role in reproduction by modulating leptin sensitivity.

The aim of this study was to investigate the neurotrophic effects of the mystixin-7 mini-peptide (MTX, a synthetic corticotrophin-releasing-factor-like peptide-like peptide) using a slice-based system. The technique on-line monitoring of electrophysiological parameters (excitatory glutamatergic AMPAR-, NMDAR-dependent and inhibitory GABA_B-ergic postsynaptic mechanisms) in the olfactory cortex slices of the rat brain exposed to varied amounts of MTX was used. MTX in a dose-dependent manner inhibited both the AMPAR- and NMDAR-mediated postsynaptic processes. The peptide caused depression of inhibitory GABA_B-ergic processes only at low doses of MTX (10, 25, 50 mg/mL) while at higher doses (100, 250 mg/mL) it enhanced them. These effects of MTX were reversible. AMPA-dependent (but not NMDA-mediated mechanisms) and inhibitory processes were restored after washing.

Triple reperfusion of slices with MTX (100 mg/mL) accelerated the inhibitory processes and induced NMDAR desensitization. MTX evoked the long-term depression on θ burst stimulation of the slices. This study did not only lead to the conclusion that the functions of the MTX mini-peptide is not limited to anti-inflammatory effects, but also is included modifications of excitatory glutamatergic AMPAR-, NMDAR-dependent and inhibitory GABA_B-ergic postsynaptic mechanisms.

The neurohypophyseal hormones oxytocin (OT) and vasopressin (VP) are involved in behavioral, autonomic and neuroendocrine functions. Both peptides are synthesized in magnocellular neurons of paraventricular and supraoptic nuclei at hypothalamic level whose axons terminate in the neurohypophysis (NH), from where OT and VP are released into the systemic circulation. NH contains abundant nitric oxide (NO) synthase suggesting that NO plays a role in the release of these neuropeptides. The endocannabinoid system is present in magnocellular neurons of the hypothalamic neurohypophyseal system, and we have previously demonstrated that endocannabinoids modulate OT secretion at hypothalamic level.

In the present work, we investigated the in vitro effect of the endocannabinoid anandamide (AEA) on OT and VP release from NH of untreated adult male rats and the involvement of NO in this action.

Our results showed that AEA decreased OT and VP secretion from NH. AEA action was mediated by NO, since the inhibition of NO synthesis completely blocked this inhibitory effect. We found that cannabinoid receptor type 2 (CB₂) and transient receptor potential cation channel subfamily V member 1 (TRPV1) are involved in the inhibitory effect of AEA because AM630 and capsazepine, CB₂ and TRPV1 antagonists respectively, but not AM251, a CB₁ antagonist, blocked AEA effect at neurohypophyseal level.

These findings revealed an interaction between endocannabinoid, nitric oxide and oxytocin/vasopressin systems that could be involved in the modulation of homeostatic, behavioral and reproductive processes.

L6 skeletal muscle cells overexpressed ICAM-1 when treated with H₂O₂. Maximum effect was observed at 200 μM H₂O₂. Des-aspartate-angiotensin I (DAA-I) concentration-dependently attenuated the overexpression. Maximum attenuation occurred at 10^− 10 M DAA-I. H₂O₂ activated NFκB and its translocation into the nucleus of L6 muscle cells suggesting that NFκB mediates the H₂O₂-induced overexpression of ICAM-1. DAA-I inhibited the activation and translocation of NFκB. H₂O₂ is a major oxidant formed during skeletal muscle contraction and is implicated in oxidative stress and skeletal muscle damage in excessive unaccustomed exercise. The data show that DAA-I has antioxidant action, and its action was further investigated in the soleus muscle of mice subjected to 240 min of eccentric exercise on a rodent treadmill. The eccentric exercise induced superoxide formation and overexpression of ICAM-1 in the soleus muscle of the mice at 3 days post exercise. DAA-I (0.2 nmole/kg/day) administered orally on day 1 (pre-exercise) and 2 days post-exercise attenuated both the ROS formation and ICAM-1 overexpression. Earlier studies show that DAA-I acts as an agonist on the angiotensin AT₁ receptor and elicits responses opposing those of angiotensin II. The present and earlier findings support the recent suggestion that angiotensin II is involved in skeletal muscle damage, and curtailment of its actions via ACE inhibitors and losartan protects and improves skeletal muscle damage. These findings open up new avenues for treatment and management of skeletal muscle damage via the interventions of the renin angiotensin system.

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder. In a previous study the total number of endocrine cells in the rectum of IBS patients, as detected by chromogranin A, did not differ from that of healthy controls. While the total endocrine cell content of the rectum appears to be unchanged in IBS patients, changes in particular endocrine cells cannot be excluded. This study was undertaken, therefore, to investigate the cell density of different rectal endocrine cell types in (IBS) patients. Fifty patients with IBS (41 females and 9 males) were included in the study. Thirty patients had diarrhoea (IBS-D) and 20 had constipation (IBS-C) as the predominant symptom. Twenty-seven subjects were included as controls (19 females and 8 males). Rectal biopsy specimens were immunostained using the avidin–biotin-complex method for serotonin, peptide YY (PYY), pancreatic polypeptide (PP), and oxyntomodulin and somatostatin cells. The cell densities were quantified by computerised image analysis. The serotonin cell density did not differ significantly, although a type II statistical error cannot be excluded, due to the small size of the sample. The densities of PYY and Oxyntomodulin cells were significantly lower and that of somatostatin were significantly higher in IBS patients than controls. These abnormalities were observed in both IBS-D and IBS-C patients. The abnormalities in the endocrine cells observed in this study in the rectum differed considerably from those seen in the colon of IBS patients. This indicates that caution in using the rectum to represent the large intestine in these patients. These abnormalities could be primary (genetic) or secondary to changes in the gut hormones found in other segments of the gut and/or other pathological processes. Although the-cause-and effect relationship of the abnormalities found in rectal endocrine cells is difficult to elucidate, they might contribute to the symptoms associated with IBS. The densities of PYY and somatostatin cells are potential biomarkers with good sensitivity and specificity for the diagnosis of IBS.

Aim

Orexin A and orexin B (hypocretins) are neuropeptides synthesized mainly by neurons located in the lateral hypothalamus and projections throughout the brain. They are agonists at both the orexin 1 and orexin 2 G protein-coupled receptors. They have been related to arousal, sleep and feeding, autonomic and neuroendocrine functions. Their role in the brain control of gonadotropins secretion was postulated in rodents and humans. Previously, we demonstrated the participation of the orexinergic system in attaining successful reproduction in in vivo studies.

Methods

We studied in vitro the effects of both neuropeptides, in the presence or absence of selective antagonists, on the mRNA expression of orexin 1 and orexin 2 receptors in anterior pituitary cells of proestrous rats, as well as the direct effects on FSH and LH secretion.

Results

Both orexin A and orexin B increased FSH and LH secretion; these effects were suppressed by the orexin 1 receptor blocking agent SB-334867 and the orexin 2 receptor antagonists JNJ-10397049. Orexin A and orexin B decreased OX1 receptor mRNA expression and this effect was modified only when both blocking agents were present. Neither orexin A nor the blocking drugs by themselves modified OX2 receptor mRNA expression. Orexin B treatment increased the mRNA expression of OX2 receptor. The effect was abolished only by the OX2 receptor antagonist.

Conclusion

In an in vitro model, we demonstrated a direct effect of orexins on gonadotropins release and orexins receptors expression, underlining the hypothesis that orexins participate in the brain control of pituitary functions.

Regular exercise is generally recommended for the treatment of obesity and type 2 diabetes. Exercise reduces body weight, improves glycemic control and cardiovascular (CV) function. This study was designed to determine the impact of voluntary wheel running on the cardiac oxytocin (OT)–natriuretic peptide (NP) system and plasma CV risk factors in the ob/ob mouse, a model of insulin resistance coupled with severe obesity. Five-week-old male ob/ob mice and non-obese heterozygote control littermates were assigned to either a sedentary or running group. Voluntary running was performed using a wheel system for a period of 8 weeks. Compared to non-obese mice, daily running activity expressed in kilometers, was significantly lower in ob/ob mice. In these mice, voluntary running improved body weight, but exacerbated CV markers, including plasma glucose and triglyceride levels. OT receptor gene expression was decreased in hearts of ob/ob mice compared to non-obese mice, and no improvement in the expression of this receptor was observed after voluntary running. Hearts from ob/ob mice also expressed lower BNP mRNA, whereas no differences in A- and C-type NP were observed between non-obese and ob/ob mice. After voluntary running, a downregulation in the expression of all three NPs coupled with increased apoptosis was observed in ob/ob hearts. Our results show that voluntary exercise running activity was decreased in the ob/ob mouse. Surprisingly, this was associated with a worsening of common CV plasma markers, reduced expression of peptides linked to the cardioprotective OT–NP system, and increased expression of cardiac apoptotic markers.

Background

The enteroendocrine hormone glucagon like peptide-2 (GLP-2) and its ligands are under development as therapeutic agents for a variety of intestinal pathologies. A number of these conditions occur in neonates and infants, and thus a detailed understanding of the effects of GLP-2 during the phase of rapid growth during infancy is required to guide the development of therapeutic applications. We studied the effects of GLP-2 in the neonatal pig to determine the potential effects of exogenous administration.

Methods

Two day old newborn domestic piglets were treated with GLP-2 (1–33) at 40 μg/kg/day or control drug vehicle (saline), by subcutaneous injection, given in two doses per day, (n = 6/group) for 42 days. Animals were weaned normally, over days 21–25. In the fifth week of life, they underwent neuro-developmental testing, and a pharmacokinetic study. On day 42, they were euthanized, and a complete necropsy performed, with histological assessment of tissues from all major organs.

Results

GLP-2 treatment was well tolerated, one control animal died from unrelated causes. There were no effects of GLP-2 on weight gain, feed intake, or behavior. In the treated animals, GLP-2 levels were significantly elevated at 2400 ± 600 pM while at necropsy, organ weights and histology were not affected except in the intestine, where the villus height in the small intestine and the crypt depth, throughout the small intestine and colon, were increased. Similarly, the rate of crypt cell proliferation (Ki-67 staining) was increased in the GLP-2 treated animals and the rate of apoptosis (Caspase-3) was decreased, the depth of the microvilli was increased and the expression of the mRNA for the GLP-2 receptor was decreased throughout the small and large intestine.

Conclusions

In these growing animals, exogenous GLP-2 at pharmacologic doses was well tolerated, with effects confined to the gastrointestinal tract.