Discovery of a new reproductive hormone in teleosts: pituitary adenylate cyclase-activating polypeptide-related peptide (PRP)

Pituitary adenylate cyclase-activating polypeptide (PACAP)-related peptide (PRP) is a peptide encoded with PACAP in the same precursor protein. Non-mammalian PRPs were previously termed growth hormone-releasing hormone (GHRH)-like peptide, and was regarded as the mammalian GHRH homologue in non-mammalian vertebrates until the discovery of authentic GHRH genes in teleosts and amphibians. Although a highly specific receptor for PRP, which is lost in mammals, is present in non-mammals, a clear function of PRP in vertebrates remains unknown. Using goldfish as a model, here we show the expression of PRP and its cognate receptor in the brain-pituitary-gonadal (BPG) axis, thus suggesting a function of goldfish (gf) PRP in regulating reproduction. We found that gfPRP controls the expression of reproductive hormones in the brain, pituitary and ovary. Goldfish PRP exerts stimulatory effects on the expression of salmon gonadotropin-releasing hormone (sGnRH) in the brain, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in pituitary primary culture cells, but inhibits the expression of LH in the ovary. Using the same technique, we showed that gfPRP did not alter the mRNA level of growth hormone in the pituitary primary culture. In summary, we have discovered the first function of vertebrate PRP in regulating reproduction, which provides a new research direction in studying the neuroendocrine control of reproduction not only in teleosts, but also in other non-mammalian vertebrates.     

How main-chains of proteins explore the free-energy landscape in native states

Understanding how a single native protein diffuses on its free-energy landscape is essential to understand protein kinetics and function. The dynamics of a protein is complex, with multiple relaxation times reflecting a hierarchical free-energy landscape. Using all-atom molecular dynamics simulations of an α/β protein (crambin) and a β-sheet polypeptide (BS2) in their “native” states, we demonstrate that the mean-square displacement of dihedral angles, defined by 4 successive C^α atoms, increases as a power law of time, t^α, with an exponent α between 0.08 and 0.39 (α = 1 corresponds to Brownian diffusion), at 300 K. Residues with low exponents are located mainly in well-defined secondary elements and adopt 1 conformational substate. Residues with high exponents are found in loops/turns and chain ends and exist in multiple conformational substates, i.e., they move on multiple-minima free-energy profiles.     

Gut hormones and appetite control

Many peptides are synthesized and released from the gastrointestinal tract. Although their roles in the regulation of gastrointestinal function have been known for some time, it is now evident that they also physiologically influence eating behavior. Our understanding of how neurohormonal gut-brain signaling regulates energy homeostasis has advanced significantly in recent years. Ghrelin is an orexigenic peptide produced by the stomach, which appears to act as a meal initiator. Satiety signals derived from the intestine and pancreas include peptide YY, pancreatic polypeptide, glucagon-like peptide 1, oxyntomodulin, and cholecystokinin. Recent research suggests that gut hormones can be manipulated to regulate energy balance in humans, and that obese subjects retain sensitivity to the actions of gut hormones. Gut hormone-based therapies may thus provide an effective and well-tolerated treatment for obesity.     

P物质、血管活性肠肽和乙酰胆碱能神经在大鼠肠道内的分布及其关系

应用乙酰胆碱酯酶(AChE)组织化学和PAP免疫组织化学方法,比较观察P物质(SP)、血管活性肠肽(VIP)和AChE三种阳性神经元在大鼠十二指肠、空肠、回肠、结肠和直肠内的分布特征及其相互关系。结果显示:SP、VIP、AChE阳性神经神经元和纤维均分布于肠壁各层,从十二指肠、空肠到回肠逐渐增多,但从结肠到直肠则逐渐减少;AChE阳性神经元或纤维在肠壁各层最丰富,其中VIP以粘膜层和粘膜下神经丛较丰富,SP以肠肌丛较丰富;三者的分布密度为AChE>VIP>SP。AChE、SP和VIP阳性神经元胞体及神经纤维在不同肠段的分布密度有明显差异(P<0.05),提示可能与不同肠段肠动力调节功能有关。     

肠促胰素的胰腺外作用研究进展

肠促胰素是经食物刺激后由肠道细胞分泌入血、能够刺激胰岛素分泌的一类激素.人体中,胰升糖素样肽1(GLP-1)和糖依赖性胰岛素释放肽((GIP)发挥肠促胰素效应.本文简要介绍肠促胰素的胰腺作用,重点回顾其胰腺外生理作用,以全面评价肠促胰素类药物的临床应用前景.

Abstract：

Incretin is defined as an intestinal hormone released in response to nutrient ingestion, which potentiates the glucose-induced insulin response. In human body, the incretin's effect is mainly induced by two peptide hormones, glucagon-like peptide-I (GLP-I)and glucose-dependent insulinotropic polypeptide (GIP). In order to fully evaluate the clinical advantages of novel agents based on incretin, this review introduces the islet actions of incretin in brief, and mainly focuses on the extra-islet effect of incretin.     

Accumulation of insoluble protein and aging

It is proposed that biological aging mainly depends on a deleterious accumulation of insoluble inert protein that has escaped physiological proteolytic degradation. Intracellularly, a three-dimensional network of polypeptide chains may exclude macromolecular structures and organelles from part of the cytosolic water. In this way vital intracellular transport mechanisms may be obstructed, providing a rationale to several observations linked to aging. This revised version was published online in July 2006 with corrections to the Cover Date.     

Islet amyloid polypeptide (amylin) and insulin are differentially expressed in chronic diabetes induced by streptozotocin in rats

Summary Islet amyloid polypeptide (IAPP) is over-expressed relative to insulin under several experimental conditions relevant to diabetes mellitus, including the immediate phase (7 days) following induction of streptozotocin diabetes. In the present study, IAPP and insulin gene expression were examined in chronic streptozotocin diabetes (3 weeks) in rats. Quantitative in situ hybridization, determining grain areas and optical densities of mRNA labelling, revealed that IAPP and insulin expression were reduced at the islet level at both low and high streptozotocin doses, partly due to reduced beta-cell mass. In contrast, the cellular levels of IAPP mRNA were either increased or unaffected at the low and high streptozotocin doses, respectively, whereas those of insulin mRNA were unaffected or reduced. When dexamethasone was administered to rats given the low streptozotocin dose, IAPP expression was increased, whereas that of insulin was markedly reduced. Immunocytochemistry revealed that IAPP predominantly occurred in insulin cells and to a lesser extent in somatostatin cells at all treatments examined. Our findings demonstrate that IAPP and insulin gene expression are differentially regulated; the over-expression of IAPP relative to insulin is augmented when the beta-cell insult is aggravated, in our experiments represented by massive beta-cell destruction (high streptozotocin dose) or a combination of moderate beta-cell damage and peripheral insulin resistance (low streptozotocin dose and dexamethasone). An over-expression of IAPP relative to insulin may therefore be involved in diabetes pathogenesis, contributing to its metabolic perturbations, possibly through the capacity of IAPP to restrain insulin release and action and to form islet amyloid.Abbreviations IAPP Islet amyloid polypeptide - IR immunoreactive - NIDDM non-insulin-dependent diabetes mellitus - OD optical density - FITC fluorescein isothiocyanate - TRITC tetramethyl rhodamine isothiocyanate - AMCA 7-amino-4-methyl coumarin-3-acetic acid     

Substance P,vasoactive intestinal polypeptide,and gastrin catabolism in canine liver and kidney

No reports have described the catabolic mechanism of substance Pin vivo. We studied the effects of hepatic or renal transit on substance P, vasoactive intestinal polypeptide, and gastrin in anesthetized dogs. It was found that the liver plays a more important role in vasoactive intestinal polypeptide catabolism than the kidney and the kidney is more important in gastrin catabolism than the liver. Substance P was more rapidly degraded than the other two peptides in both organs. The transrenal substance P loss measured byC-terminal antiserum differed from that measured byN-terminal antiserum, although there was no difference in the liver. This suggested that there were different patterns of cleavage of substance P between the liver and the kidney, and that itsC terminal was degraded more strongly than itsN terminal in the kidney.     

Effect of synthetic prostaglandin E1 analog (ornoprostil) on gastric emptying and pancreatic polypeptide release after solid-meal ingestion in man

The effect of orally administered ornoprostil, 17S,20-dimethyl-6-oxoprostaglandin E₁ methyl ester, on gastric emptying and on pancreatic polypeptide (PP) release after solid meal ingestion, was investigated in man. A radionuclide technique was used to measure gastric emptying of eight healthy volunteers. In addition, four parameters [SI (starting index): the lag time in the start of emptying;K value: the emptying rate;T1/2: the half emptying time; 120 min RR: the percent retention at 120 min] were determined for evaluation. Also, the PP response was analyzed according to two parameters: IPPR_SI, the integrated PP response for periods up to SI, and IPPR₁₂₀, the integrated PP response for 120 min. The results demonstrated that 5 g of orally administered ornoprostil significantly reduced the gastric emptying rate of solid meal (T1/2 and 120 min RR,P<0.05). However, ornoprostil affected neither the basal PP concentrations nor the cephalic phase of PP secretion which was determined as IPPR_SI. This thus suggests that ornoprostil affects the gastric motor function without interfering with the vagal-cholinergic pathway to the stomach.