The living record of
peptide science.

[Reduced thymulin production during occupational exposure to lead].

G Ital Med Lav Ergon

L Santarelli, L Di Lorenzo, M Valentino +8 more

Thymulin is a thymic hormone that being activated by binding a zinc ion promotes differentiation and several functions of T lymphocytes. It has been demonstrated only in experimental animals that metallic lead (Pb) is able to cause adverse effects on thymocyte number and function. The objective of this study is to evaluate the plasmatic level of active thymulin of 58 male workers being exposed for more than one year to low lead doses with respect to 59 male never exposed workers. All these were subjected to anamnesis collection, medical examination and determination of blood lead (PbB), plasmatic lead (PbPl), plasmatic thymulin, urinary lead (PbU) and urinary zinc (ZnU) levels. The mean plasma concentration of active thymulin was significantly lower in lead exposed than in non exposed workers. Active thymulin was also significantly and negatively correlated to PbB, PbPl and PbU level and resulted to be significantly and negatively influenced by PbB. Lead exposed workers had slightly higher zinc concentration in urine than non exposed workers, increasing ZnU levels by class of PbB. It is the first time that a toxic effect of lead on plasmatic active thymulin levels is demonstrated in humans, particularly in occupationally exposed workers. This study opens perspectives for further research that would both confirm the results and verify the mechanisms of action of lead on thymulin either direct or indirect and the possible role of zinc.

Muscle regeneration through myostatin inhibition.

Curr Opin Rheumatol

Kathryn R Wagner

Myostatin is an endogenous, negative regulator of muscle growth. Selective inhibition of myostatin may have broad clinical utility by improving regeneration in diverse and burdensome muscle disorders. An understanding of this potential is relevant because inhibitors of myostatin have recently entered clinical trials.

[Comparative study of the long-term behavioral effects of noopept and piracetam in adult male rats and female rats in postnatal period].

Eksp Klin Farmakol

T A Voronina, L S Guzevatykh, S S Trofimov

Adult male and female rats were treated with the peptide nootrope drug noopept (daily dose, 0.1 mg/kg) and piracetam (200 mg/kg). In the period from 8th to 20th day, both drugs (cognitive enhancers) suppressed the horizontal and vertical activity and the anxiety in test animals as compared to the control group treated with 0.9 % aqueous NaCl solution. Early postnatal injections of the nootropes influenced neither the morphology development nor the behavior of adult female rats in the plus maze, extrapolational escape, passive avoidance, and pain sensitivity threshold tests. Animals in the "intact" group (having received neither drugs not physiological solution, that is, developing in a poor sensor environment), showed less pronounced habituation in the open field test as compared to the control and drug treated groups.

[Effect of new synthetic anxiolytic selank on gastric wall blood flow and mesenteryc lymphatic vessels contractility in anesthetized rats].

Ross Fiziol Zh Im I M Sechenova

T S Pavlov, L Ts Sanzhieva, G E Samonina +2 more

The influence of a new heptapeptide Selank on microcirculation in anesthetized white rats was investigated. Selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro) is a new synthetic anxiolytic which exerts obvious antiulcerogenic action and promotes healing of experimental ulcers. Action of the peptide on gastric blood flow in the stomach by using the method ofhydrogenic clearance and Selank action on mesenteric lymphatic contractility by microscopical observation in situ, were studied. Selank fail to influence basal gastric blood flow but it can normalize blood flow reduced by indomethacin. The study of dose-depended of Selank effect on lymphatic vessels contractility showed that its low concentration (10(-12)--10(-14) M) enhanced amplitude and increase frequency of lymphatic vessel contractions which indicates an enhancement of lymphatic flow. The high doses of peptide (10(-6)--10(-10) M) also augmented the contraction amplitude but decreased its frequency. The maintenance of adequate blood flow and lymphatic vessel contractility can be one of the mechanisms of the Selank antiulcerogenic properties.

Chromatographic separation and mass spectrometric identification of positional isomers of polyethylene glycol-modified growth hormone-releasing factor (1-29).

J Chromatogr A

Yu Seok Youn, Dong Hee Na, Sun Dong Yoo +2 more

A one-step chromatographic method capable of separating all isomers of polyethylene glycol (PEG)-growth hormone-releasing factor (GRF) (1-29) conjugates was developed. The unmodified GRF (1-29) and seven different isomers of PEG-GRF (1-29) conjugates were separated by using a simple reversed-phase HPLC method depending on the differences of hydrophobicity due to the number and site of PEG attachment. The PEGylation sites of all isomers of PEG-GRF (1-29) conjugates were identified by determining the molecular masses of the Lys-C digested fragments with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. This study is a first report for the separation of all PEG-conjugate isomers and would be useful for further studies to find the promising conjugate by evaluating biological activity and stability of each isomer.

A new property of the synthetic anxiolytic Selank and its derivatives.

Dokl Biol Sci

T S Pavlov, G E Samonina, L A Andreeva +2 more

Growth factors and muscle ageing.

Exp Gerontol

Geoffrey Goldspink, Stephen D R Harridge

Loss of muscle mass (sarcopenia) is one of the main problems associated with ageing as it has major health care as well as socioeconomic implications. The growth hormone (GH)/IGF-I axis is regarded as an important regulator of muscle mass. However, it is now appreciated that other tissues in addition to the liver express IGF-I and that there are local as well as systemic forms of IGF-I which have different functions. At least two different kinds of IGF-I that are expressed by skeletal muscle are derived from the IGF-I gene by alternative splicing, one of which is expressed in response to physical activity which has now been called 'mechano growth factor' (MGF). The other is similar to the systemic or liver type (IGF-IEa) and is important as the provider of mature IGF-I required for upregulating protein synthesis. MGF differs from systemic IGF-IEa in that it has a different peptide sequence which is responsible for replenishing the satellite (stem) cells in skeletal muscle. The ability to produce MGF declines with age, and this is commensurate with the decline in circulating GH levels. GH treatment up regulates the level of IGF-I gene expression in older people and when combined with resistance exercise more is spliced towards MGF and hence should improve the ability of muscle to respond to physical activity. The possibility of ameliorating sarcopenia using MGF is discussed.

Mechanical signals and IGF-I gene splicing in vitro in relation to development of skeletal muscle.

J Cell Physiol

Umber Cheema, Robert Brown, Vivek Mudera +3 more

It has been shown that the insulin-like growth factor (IGF-I) gene is spliced in response to mechanical signals producing forms of IGF-I which have different actions. In order to study how mechanical signals influence this gene splicing in developing muscle, C2C12 cells were grown in three-dimensional (3D) culture and subjected to different regimens of mechanical strain. IGF-IEa which initiates the fusion of myoblasts to form myotubes was found to be constitutively expressed in myoblasts and myotubes (held under endogenous tension) and its expression upregulated by a single ramp stretch of 1-h duration but reduced by repeated cyclical stretch. In contrast, mechano growth factor (MGF), which is involved in the proliferation of mononucleated myoblasts that are required for secondary myotube formation and to establish the muscle satellite (stem) cell pool, showed no significant constitutive expression in static cultures, but was upregulated by a single ramp stretch and by cycling loading. The latter types of force simulate those generated in myoblasts by the first contractions of myotubes. These data indicate the importance of seeking to understand the physiological signals that determine the ratios of splice variants of some growth factor/tissue factor genes in the early stages of development of skeletal muscle.

Age-related loss of skeletal muscle function; impairment of gene expression.

J Musculoskelet Neuronal Interact

G Goldspink

Mechano Growth Factor (MGF) is derived from the insulin-like growth factor (IGF-I) but its sequence differs from the systemic IGF-I produced by the liver. MGF is expressed by mechanically overloaded muscle and is involved in tissue repair and adaptation. It is expressed as a pulse following muscle damage and involved in the activation of muscle satellite (stem) cells. These donate nuclei to the muscle fibers that are required for repair and for the hypertrophy processes which may have similar regulatory mechanisms. Muscles in the elderly are unable to upregulate MGF in response to exercise. This is also true in certain diseases and this helps to explain muscle loss in those conditions. There is evidence that MGF is a local tissue repair factor as well as a growth factor and that it has an important role in damage limitation and inducing repair in other post-mitotic tissues. As there is no cell replacement in these tissues there has to be an effective local cellular repair mechanism. With advancing years this seems to become deficient and there is an increased chance that the damaged cells will undergo cell death leading to progressive loss of tissue function.

[Ghrelin-related drugs: clinical perspectives].

Nihon Rinsho

Akira Shimatsu

Thymulin and the neuroendocrine system.

Peptides

Rodolfo G Goya, Oscar A Brown, Jean-Marie Pléau +1 more

Thymulin is a thymic hormone exclusively produced by the thymic epithelial cells. It consists of a nonapeptide component coupled to the ion zinc, which confers biological activity to this molecule. After its discovery in the early 1970, thymulin was characterized as a thymic hormone involved in several aspects of intra- and extrathymic T-cell differentiation. Subsequently, it was demonstrated that thymulin production and secretion is strongly influenced by the neuroendocrine system. Conversely, an emerging core of information points to thymulin as a hypophysotropic peptide. Here we review the evidence supporting the hypothesis that thymulin is an important player in the hypophyso-thymic axis.

Hexarelin modulates the expression of growth hormone secretagogue receptor type 1a mRNA at hypothalamic and pituitary sites.

Neuroendocrinology

Elena Bresciani, Ralf Nass, Antonio Torsello +5 more

Ghrelin and the synthetic growth hormone secretagogues (GHSs) activate a G-protein-coupled receptor (GHS-R) originally cloned from the pituitary, but which is also expressed in the hypothalamus, in other areas of the brain and in numerous peripheral tissues. Several studies have shown that growth hormone (GH)-releasing hormone (GHRH) is necessary for GHSs to exert maximal GH release in vivo. The exact mechanism of this synergism is not clear. Previous data suggest that GHSs can affect pituitary GHS-R mRNA expression; however, it is unknown whether this effect is age dependent and whether hypothalamic GHS-Rs are also affected. In this study, we tested whether (a) the synthetic GHS hexarelin regulates mRNA expression of its own receptor at the pituitary and/or hypothalamus and whether this effect is age dependent, and (b) whether short-term treatment with GHRH or, conversely, passive immunization against GHRH affects pituitary GHS-R1a mRNA expression in infant (10 days old) and young adult rats. GHS-R1a mRNA expression was measured with competitive reverse transcriptase-polymerase chain reaction. Hexarelin treatment significantly increased pituitary and hypothalamic GHS-R1a mRNA levels in normal infant rats, but not in normal young adult rats. In addition, hexarelin administration also stimulated pituitary GHS-R1a mRNA in infant as well as in young adult rats passively immunized against GHRH. GHRH treatment significantly enhanced pituitary GHS-R1a mRNA expression in GHRH-deprived young adult rats, though it did not affect the basal levels of GHS-R1a mRNA in normal infant and adult rats. These data further support the hypothesis that GHRH can affect GHS-R1a expression and that hexarelin upregulates the expression of its own receptor at the pituitary as well as the hypothalamus in an age-dependent fashion.

Urocortins: take them to heart.

Curr Med Chem Cardiovasc Hematol Agents

Tiziano Scarabelli, Richard Knight

The urocortins, together with corticotropin releasing hormone (CRH), have a long evolutionary pedigree. In the brain, CRH largely mediates anxiogenic effects associated with the stress response, while the urocortins are concerned with adaptive and coping behaviour. The urocortins, in particular, are also expressed in peripheral sites, including the heart. Here, they may play an autocrine/paracrine role, since CRH-R2 receptor subtypes, which preferentially bind the urocortins, are also expressed in the heart. Endogenous cardiac urocortin expression is enhanced by ischaemia/reperfusion injury in vitro, and addition of exogenous urocortins reduces cell death caused by ischaemia/reperfusion in vitro, ex vivo and in vivo. In the isolated perfused heart, urocortin improves haemodynamic recovery, and partially prevents the reduction in high energy phosphates following ischaemia/reperfusion. Urocortin-mediated cardioprotection involves several mechanisms, including increased expression of Kir6.1 K(ATP) channels and HSP90, although other as yet poorly understood mechanisms have also been implicated. Moreover, there is early data suggesting that urocortin has beneficial haemodynamic effects in an ovine model of heart failure, and further studies of the value of both endogenous and exogenous urocortins in the compromised heart are clearly needed. In man, there is suggestive, though indirect, data, that urocortin may also provide an endogenous myocyte salvage mechanism against iatrogenic ischaemia/reperfusion injury associated with bypass surgery. These experimental studies suggest that assessment of the clinical use of urocortins as direct and/or cardioplegic therapies in ischaemia/reperfusion, and maybe heart failure, should be actively pursued.

Neonatal quinpirole treatment impairs Morris water task performance in early postweanling rats: relationship to increases in corticosterone and decreases in neurotrophic factors.

Biol Psychiatry

Russell W Brown, Timothy J Flanigan, Kimberly N Thompson +3 more

Past studies from this laboratory have shown that quinpirole administration from postnatal day (P) 1-21 produces persistent supersensitization of the dopamine D2 receptor that persists throughout the animal's lifetime.

Elucidation of the effect of brain cortex tetrapeptide Cortagen on gene expression in mouse heart by microarray.

Neuro Endocrinol Lett

Sergey V Anisimov, Vladimir Kh Khavinson, Vladimir N Anisimov

Aging is associated with significant alterations in gene expression in numerous organs and tissues. Anti-aging therapy with peptide bioregulators holds much promise for the correction of age-associated changes, making a screening for their molecular targets in tissues an important question of modern gerontology. The synthetic tetrapeptide Cortagen (Ala-Glu-Asp-Pro) was obtained by directed synthesis based on amino acid analysis of natural brain cortex peptide preparation Cortexin. In humans, Cortagen demonstrated a pronounced therapeutic effect upon the structural and functional posttraumatic recovery of peripheral nerve tissue. Importantly, other effects were also observed in cardiovascular and cerebrovascular parameters.

Corticotrophin releasing factor-induced synaptic plasticity in the amygdala translates stress into emotional disorders.

J Neurosci

Donald G Rainnie, Richard Bergeron, Tammy J Sajdyk +3 more

The amygdala is involved in the associative processes for both appetitive and aversive emotions, and its function is modulated by stress hormones. The neuropeptide corticotrophin releasing factor (CRF) is released during stress and has been linked to many stress-related behavioral, autonomic, and endocrine responses. In the present study, nonanxiety-inducing doses of a potent CRF type 1 and 2 receptor agonist, urocortin (Ucn), was infused locally into the basolateral amygdala (BLA) of rats. After 5 daily injections of Ucn, the animals developed anxiety-like responses in behavioral tests. Intravenous administration of the anxiogenic agent sodium lactate elicited robust increases in blood pressure, respiratory rate, and heart rate. Furthermore, in the absence of any additional Ucn treatment, these behavioral and autonomic responses persisted for >30 d. Whole-cell patch-clamp recordings from BLA neurons of these hyper-reactive animals revealed a pronounced reduction in both spontaneous and stimulation-evoked IPSPs, leading to a hyperexcitability of the BLA network. This Ucn-induced plasticity appears to be dependent on NMDA receptor and subsequent calcium-calmodulin-dependent protein kinase II (CaMKII) activation, because it is blocked by pretreatment with NMDA receptor antagonists and by coadministration of CaMKII inhibitors. Our results show for the first time a stress peptide-induced behavioral syndrome that can be correlated with cellular mechanisms of neural plasticity, a novel mechanism that may explain the etiological role of stress in several chronic psychiatric and medical disorders.

Melanocortin 4 receptor-mediated hyperphagia and activation of neuropeptide Y expression in the dorsomedial hypothalamus during lactation.

J Neurosci

Peilin Chen, Sarah M Williams, Kevin L Grove +1 more

In several hyperphagic models, including lactation, in which hypothalamic melanocortin signaling is reduced, a novel expression of NPY mRNA in the dorsomedial hypothalamus (DMH) has been observed, suggesting that melanocortin signaling and the induced NPY in the DMH may constitute unique neurocircuitry in mediating energy balance. Using lactating rats as a model, the present study first showed that in the DMH abundant alpha-MSH and agouti-related protein fibers are in close apposition to NPY-positive cells. However, no NPY and MC4R (a melanocortin receptor) double-labeled neurons were observed. These data suggested that melanocortin input may synapse on presynaptic terminals that then synapse on DMH NPY cells. To study the function of DMH MC4Rs in energy balance, an MC3/4R-selective agonist, melanotan II (MTII), was injected bilaterally into the DMH. MTII injection significantly suppressed feeding induced by 24 hr fasting or suckling-induced hyperphagia. Furthermore, MTII treatment greatly attenuated suckling-induced NPY expression in the DMH. MTII treatment also stimulated uncoupling protein 1 activity in the brown adipose tissue of suckling female rats, indicative of increased sympathetic outflow. In summary, the present study demonstrated that the melanocortin system in the DMH not only plays an important role in inducing NPY expression in the DMH of lactating rats but also in regulating energy homeostasis, at least in part, by modulating appetite and energy expenditure.

Neurotensin, schizophrenia, and antipsychotic drug action.

Int Rev Neurobiol

Becky Kinkead, Charles B Nemeroff

The search for the underlying pathophysiology of schizophrenia has been an active avenue of investigation since the disease was first recognized more than 100 years ago. Although a great deal of the research has been driven by the known pharmacology of effective antipsychotic drugs, i.e., overactivity of the dopamine system, recent advances in neurobiology provide evidence that reduced synaptic connectivity/neurotransmission may play a substantial role in this disorder. One neuropeptide long posited to play a role in the biology of schizophrenia is neurotensin (NT). Central nervous system administration of NT has been shown to produce a wide variety of effects. Because of its close association with the dopamine (DA) system, the role of the NT system in clinical disorders hypothesized to involve DA circuits such as schizophrenia, Parkinson's disease, and drug abuse has been closely scrutinized. In addition, NT neurotransmission has been implicated in regulation of the stress response, stress-induced gastric ulcers, temperature regulation, food consumption, and analgesia. NT also acts as a growth factor in a variety of human cancer cell lines derived from lung, colon, prostate, and pancreas. This review first provides a background of the NT system. Second, data indicating that NT may mediate the effects of antipsychotic drugs are summarized. Third, data implicating NT in the pathophysiology of schizophrenia are described. Finally, evidence suggesting the use of NTergic compounds as novel antipsychotic drugs are presented.

Selank and short peptides of the tuftsin family in the regulation of adaptive behavior in stress.

Neurosci Behav Physiol

M M Kozlovskaya, I I Kozlovskii, E A Val'dman +1 more

White laboratory male rats, inbred male C57BL/6 and Balb/c mice, and male Wistar rats, all previously divided on the basis of the type of emotional reactivity, were used to compare the effects of ten peptide compounds of the tuftsin family and Selank on the behavioral manifestations of emotional stress created by a conflict situation. Peptides were shown to have positive emotional effects and antistress actions. Individual physiologically significant effects were seen, due to the molecular structures of the study peptides and/or their degradation fragments. The results demonstrate the potential for the synthesis of peptide compounds with predictable directions of pharmacological actions and safe for wide use.

Growth hormone secretagogues modulate the electrical and contractile properties of rat skeletal muscle through a ghrelin-specific receptor.

Br J Pharmacol

Sabata Pierno, Annamaria De Luca, Jean-François Desaphy +7 more

(1) Growth hormone secretagogues (GHS) exhibit potent growth hormone (GH)-releasing activity through the activation of a pituitary receptor. Here, we consider the possibility that GHS can target a specific receptor in rat skeletal muscle and have a role in the control of muscle function. (2) By means of the intracellular microelectrode technique, we found that in vitro application of hexarelin and L-163,255 dose dependently reduced resting chloride (gCl) and potassium (gK) conductances in rat skeletal muscle. These effects were prevented by the GHS-receptor antagonist [D-Lys-3]-GHRP-6, and by either phospholipase C or protein kinase C (PKC) inhibitors. Ghrelin, a natural ligand of GHS receptors, also induced a reduction of muscle gCl and gK, which was antagonised by [D-Lys-3]-GHRP-6. (3) Both GHS shifted the mechanical threshold for the contraction of muscle fibres towards more negative voltages. Accordingly, by means of FURA-2 fluorescent measurements, we demonstrated that L-163,255 induced a resting [Ca(2+)](i) increase, which was reversible and not blocked by nifedipine or removal of external Ca(2+). (4) Ageing is a condition characterised by a deficit of GH secretion, which in turn modifies the electrical and contractile properties of skeletal muscle. In contrast to GH, chronic treatment of aged rats with hexarelin or L-163,255 failed to restore the electrical and contractile muscle properties. Moreover, the two GHS applied in vitro were able to antagonise the beneficial effect on gCl and gK obtained through chronic treatment of aged animals with GH. (5) Thus, skeletal muscle expresses a specific GHS receptor able to decrease gCl and gK through a PKC-mediated intracellular pathway. This peripheral action may account for the lack of restoration of skeletal muscle function in long-term GHS-treated aged animals.