Regulatory Peptides最新文献

The aim of the present study was an investigation of mechanisms mediating selective effect of vasotocin analogues on water, sodium, and potassium excretion. We tested vasotocin analogues: Mpa¹-vasotocin (dAVT), Mpa¹-Arg⁴-vasotocin (dAAVT) and Mpa¹-DArg⁸-vasotocin (dDAVT). The effects on water, sodium, and potassium transport were evaluated in experiments using normal and water-loaded Wistar rats. It was shown that all tested peptides exerted antidiuretic activity. Vasotocin and dAVT induced natriuresis and kaliuresis in rats. V_1a agonist (Phe²-Ile³-Orn⁸-vasopressin) reproduced the renal effects of dAVT on sodium and potassium excretion but not on water reabsorption. dAAVT, dDAVT and V₂ agonist (desmopressin) induced kaliuresis without any effect on sodium excretion. Natriuresis was associated with increase in cGMP excretion, whereas kaliuresis was correlated with rise of cAMP excretion. V_1a antagonist (Pmp¹-Tyr(Me)²-vasopressin) significantly reduced the dAVT-stimulated natriuresis and did not influence on urinary potassium excretion. V₂ antagonist (Pmp¹-DIle²-Ile⁴-vasopressin) significantly reduced the dAVT- and dAAVT-induced kaliuresis. It is assumed that effects of the nonapeptides on sodium and potassium transport are independent of their antidiuretic activity and mediated by different subtypes of V receptors (the V_1a or V_1a-like receptor for natriuretic effect and V₂ or V₂-like one for kaliuretic). In accordance to the data obtained, there is a possibility of selective regulation of renal water reabsorption and urinary sodium and potassium excretion with involvement of neurohypophysial hormones.

Background

The classic chromogranin–secretogranin (granin) proteins are produced in the myocardium and throughout the neuroendocrine system, but while chromogranin (Cg) A and B levels are high in the adrenal medulla, secretogranin (Sg) II production is higher in the pituitary gland. Whether these differences may influence the response to physical activity is not known.

Methods

We measured circulating granin proteins during (1) a short-term maximal bicycle exercise stress test and (2) a 7 day military ranger course of continuous physical activity and sleep and energy deprivation.

Results

In 9 healthy subjects performing the exercise stress test (7 male, age 45 ± 5 y [mean ± SEM], duration 10.13 ± 1.14 min), CgB levels increased from before to immediately after the test: 1.20 ± 0.12 vs. 1.45 ± 0.09 nmol/L, p = 0.013. Metabolic equivalents, representing an index of performed work, were closely associated with the change (∆) in CgB levels during stress testing and explained 74% of the variability in _∆CgB levels (p = 0.004). CgA and SgII levels were not increased after exercise stress testing. In the second cohort of 8 male subjects (age 25 ± 1 y) participating in the ranger course, CgB levels increased from day 1 and were significantly elevated on days 5 and 7. CgA also increased gradually with levels significantly elevated on day 7, while SgII was markedly increased on day 5 whereas levels on days 3 and 7 were unchanged compared to baseline levels.

Conclusion

We demonstrate a heterogeneous response to short- and long-term physical activities among circulating granin proteins with the most potent effect on CgB levels.

The sensory neuropeptide, α-calcitonin gene-related peptide (α-CGRP) is protective against hypertension-induced heart damage and cardiac ischemia/reperfusion injury. To determine whether this neuropeptide is also cardioprotective in heart failure, this study examined whether the absence of α-CGRP exacerbated the adverse cardiac remodeling, dysfunction and mortality in pressure overload heart failure induced by transverse aortic constriction (TAC). Male α-CGRP knockout (KO) and wild type (WT) mice had TAC or sham surgery at day 0 and were studied on days 3, 14, 21, and 28. The survival rate of TAC α-CGRP KO mice was lower than the TAC WT mice over the duration of the protocol. Left ventricular α-CGRP content in TAC WT mice was higher at days 3, 14, and 21 than sham WT mice. Echocardiography demonstrated greater adverse cardiac remodeling and dysfunction in the TAC α-CGRP KO compared to the TAC WT mice. The lung/body weight ratios and left ventricular masses were higher in TAC α-CGRP KO compared to the TAC WT mice. While there was increased cardiac fibrosis in the TAC WT mice compared to shams, the TAC α-CGRP KO mice had markedly increased fibrosis above that of the TAC WT mice. TAC WT mice had greater cardiac inflammation, cell death, and adaptive angiogenesis compared to sham mice. Importantly, the TAC α-CGRP KO mice had greater inflammation, cell death, and attenuation of angiogenesis compared to TAC WT hearts. Thus, α-CGRP plays a significant protective role in TAC-induced heart failure which may be mediated by decreased inflammation, cell death, and fibrosis.

Leptin has been shown to modulate gastrointestinal functions including nutrient absorption, growth, and inflammation and to display complex effects on gut motility. Leptin receptors have also been identified within the enteric nervous system (ENS), which plays a crucial role in digestive functions. Although leptin has recently been shown to activate neurons in the ENS, the precise mechanisms involved are so far unknown. Therefore, the aim of the present study was to determine the effects of leptin on rat proximal colon smooth muscle and enteric neuron activities. The effects of exogenous leptin on tone and on responses to transmural nerve stimulation (TNS) of isolated circular smooth muscle of proximal colon in rats were investigated using an organ bath technique. The effects of a physiological concentration (0.1 μM) of leptin were also studied on tone and TNS-induced relaxation in the presence of atropine, hexamethonium, L-N^G-nitroarginine methyl ester (L-NAME) and capsazepine. Leptin caused a slight but significant decrease in tone, TNS-induced relaxation and contraction in a concentration-dependent manner in colonic preparations. Cholinergic antagonists abolished the effects of 0.1 μM leptin on TNS-induced relaxation. This concentration of leptin had no further effect on relaxation in the presence of L-NAME. In the presence of capsazepine, leptin had no further effect either on tone or relaxation compared to the drug alone. In conclusion, leptin modulates the activity of enteric inhibitory and excitatory neurons in proximal colon. These effects may be mediated through nitrergic neurons. Intrinsic primary afferent neurons may be involved.

Objective

Thymosin β4, a member of a large family of thymic proteins, plays an important role in the process of articular cartilage degeneration which is a common cause of osteoarthritis (OA). This study aims to determine thymosin β4 levels in the serum and synovial fluid (SF) of patients with knee OA and analyze the correlation of thymosin β4 levels with the radiographic severity of OA.

Methods

This study consisted of 216 patients with knee OA and 152 healthy controls. OA progression was classified based on Kellgren–Lawrence by evaluating x-ray changes observed in anteroposterior knee radiography. Thymosin β4 levels in the serum and SF were measured by enzyme-linked immunosorbent assay method.

Results

The knee OA patients had higher levels of serum thymosin β4 than the healthy controls. Knee OA patients with KL grade 4 showed significantly elevated thymosin β4 levels in the serum and SF compared with those with KL grades 2 and 3. Knee OA patients with KL grade 3 had significantly higher SF levels of thymosin β4 than those with KL grade 2. Thymosin β4 levels in the serum and SF of knee OA patients were significantly correlated with disease severity according to KL grading criteria.

Conclusion

The thymosin β4 levels in the serum and SF may serve as effective biomarkers for the severity of OA.

Objective

Nonylphenol (NP) is an estrogenic-like compound which can induce vitellogenin synthesis in males and immature teleostean species. Known as an endocrine disruptor, it has been reported to affect endocrine glands; however, little is known about its effects on thyroid function. The present study aimed to evaluate whether exposure to NP alters the structure and function of the thyroid gland of rats and/or the underlying mechanisms.

Methods

Rats were gavaged with NP (40, 80 and 200 mg/kg/d) for 15 days. Serum levels of thyroid-stimulating hormone were determined by radioimmunoassay. Ultramicroscopic structure of follicular cells was examined by a transmission electron microscope. Histopathology was conducted with hematoxylin-eosin (HE) staining.

Results

We found that NP exposure induced a decrease in serum levels of free tetraiodothyronine (FT) 3 and FT4 while it induced an increase in serum levels of thyroid-stimulating hormone (TSH) in a dose-dependent manner. There was a negative correlation between different doses of NP with serum levels of FT3 and FT4 (FT4 r = − 0.932; FT3 r = − 0.926) and a positive correlation with serum levels of TSH (r = 0.967). Histological and morphometric study in the NP-exposed group revealed dilation of endoplasmic reticulum into cystic in thyroid follicular cells. Mitochondrion was damaged in the 80 and 200 mg/kg/d groups.

Conclusions

Exposure to NP may lead to thyroid dysfunction. It may be a potential contributor to thyroid disruption.

Recently, neuropeptide Y (NPY) and Y1 receptor (Y1R) were found to be expressed and synthesized in adipose tissue. This study aimed to compare NPY and Y1R mRNA expressions in subcutaneous and visceral fat tissues as well as serum NPY in normal weight and obese humans and their correlations with clinical parameters and peripheral metabolic factors. We demonstrated that NPY mRNA expression was higher in obese than in normal weight humans (p < 0.05) in both subcutaneous and visceral adipose tissues and was significantly greater in visceral when compared with subcutaneous fat in overall (p < 0.01), obese (p < 0.05) and normal weight humans (p < 0.05). Y1R mRNA expression was higher in obese than normal weight subjects in visceral (p < 0.01) but not in subcutaneous adipose tissue and was statistically greater in subcutaneous when compared to visceral adipose tissue in obese (p < 0.05) and overall subjects (p < 0.05). Serum NPY was higher in obese than normal weight groups (p < 0.05). Obese subjects showed significantly greater levels of systolic blood pressure (SBP) (p < 0.01), diastolic blood pressure (DBP) (p < 0.05), plasma insulin (p < 0.05), and HOMA-IR (p < 0.05) when compared with normal weight subjects. Additionally, Y1R mRNA expression in visceral adipose tissue was positively correlated with body weight (R = 0.586), BMI (R = 0.611), waist (R = 0.474) and hip (R = 0.483) circumferences, insulin levels (R = 0.539), and HOMA-IR (R = 0.480). As the result, Y1R expression in visceral adipose tissue might be an indicator of increased risk of metabolic syndrome. Further studies about blocking specific Y1R may propose strategies for risk reduction in metabolic syndrome and prevention or treatment of obesity.

This study aimed to investigate the effect of combination of felodipine + puerarin on ACE2–Ang (1–7)–Mas axis, and to explore the protective effect of the combination against kidney in renovascular hypertensive rats. Goldblatt rats were randomly divided into 5 groups as follows: 4 groups which were treated with felodipine (Felo), puerarin (Pue), Felo + Pue, and Felo + captopril (Cap), respectively, and a control group of animals that were administrated with distilled water. Contents of Ang II and Ang (1–7) in renal tissues were determined by ELISA kit. The mRNA expression of ACE2/Mas and ACE/AT₁ in kidneys was analyzed by RT-PCR. After 8 weeks of treatment, compared with Goldblatt group, Felo + Pue reduced SBP, DBP and HR (p < 0.01 or p < 0.05), ameliorated renal interstitial fibrosis, decreased the level of Ang II and increased that of Ang (1–7), upregulated mRNA expression of ACE2 and Mas, decreased that of ACE and AT₁, and downregulated protein expression of TGF-β₁ in kidneys (p < 0.01). Compared with Felo group, Felo + Pue decreased DBP and HR more markedly, attenuated fibrosis, decreased Ang II levels and increased those of Ang (1–7), upregulated mRNA expression of ACE2 in bilateral kidneys and that of Mas in ischemic kidney, downregulated that of ACE in bilateral kidneys and that of AT₁ in ischemic kidney, and decreased expression of TGF-β₁ protein significantly. In a word, a combination of Felo + Pue has a more efficient therapeutic effect on DBP and HR, and contributes to a better protection against renal interstitial fibrosis.

Whether leptin targets the hypothalamic serotonergic system to inhibit food intake is not established. We examined the effect of a short-term i.c.v. leptin treatment on serotonin microdialysate levels in rat lateral hypothalamus. Adipose tissue gene expression was also evaluated.

Male rats received four daily injections of leptin (5 μg) or vehicle (with pair-feeding to leptin-induced intake) and a fifth injection during collection of LH microdialysates. We found that serotonin and 5-HIAA levels were not affected by the leptin pre-treatment, as basal levels were similar between the leptin and the pair-fed group. These levels remained unaltered after the acute leptin injection.

For gene expression studies, rats were pre-treated with five daily injections of either leptin (5 μg) or vehicle (with either pair-feeding or ad libitum intake). mRNA levels of resistin, adiponectin, lipoprotein lipase, and PPAR-gamma were unaltered by either leptin or pair-feeding. Leptin gene expression was significantly reduced by leptin but not by pair-feeding, in both the retroperitoneal (− 74%) and the epididymal (− 99%) depots while no differences were observed in the subcutaneous depot.

The observations confirmed the absence of an acute stimulatory effect of central leptin on serotonin release in the lateral hypothalamus and showed that the pre-treatment with leptin failed to modify this pattern. This indicates that components of the serotonergic system are probably not directly affected by leptin. Additionally, the central effect of leptin was able to downregulate its own adipose tissue gene expression in a depot-specific manner while other adipokine genes were not affected.

Both galanin (Gal) and calcitonin gene-related peptide (CGRP) are sensory neuropeptides which expressed in dorsal root ganglion (DRG) neurons and are involved in nociceptive processing. Capsaicin (CAP) influences nociceptive processing via influencing the expression of sensory neuropeptides in primary sensory neurons. However, little is known about the alterations of Gal and CGRP expression at the same condition stimulated by CAP. In the present study, primary cultured DRG neurons were used to determine the different responses of Gal and CGRP to CAP stimulation. DRG neurons were cultured for 48 hours and then exposed to CAP (2 μmol/L), capsazepine (CPZ) (2 μmol/L) plus CAP (2 μmol/L), or extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor PD98059 (10 μmol/L) plus CAP (2 μmol/L) for an additional 24 hours. The DRG neurons were continuously exposed to culture media as a control. After that, the levels of Gal mRNA and CGRP mRNA of DRG neurons were determined using real time-PCR analysis. Gal and CGRP expression in situ was detected by an immunofluorescent labeling technique. The levels of phosphorylated-ERK1/2 (pERK1/2) protein were detected using a Western blot assay. The results showed that CAP evoked increases of Gal and its mRNA and decreases of CGRP and its mRNA in DRG neurons. Administration of either CPZ or PD98059 blocked the effects of CAP. These data indicate that Gal and CGRP shared different responses to CAP stimulation. Gal and CGRP may have different effects in nociceptive processing during neurogenic inflammation.