The living record of
peptide science.

[Cortexin. Molecular mechanisms and targets of neuroprotective activity].

Zh Nevrol Psikhiatr Im S S Korsakova

O A Gomazkov

Neurotrophic drug cortexin, a lyophilized extraction of animal cortex, comprises neuropeptides, amino acids and trace elements. The nucleoprotein complexes of the cerebral cortex can also retain elements of chromatin with DNA fragments. All of these components of cortexin have a specific range of "targets" for the specific correction of the molecular and cellular processes at various stages of the pathological process. A modern concept of neurosignaling considers the associated processes - from the synaptic level to the epigenetic patterns of neuron nucleus, in which an important place belongs to corrective peptide molecules. Peptide components of cortexin derived from the animal brain, which interact with cellular and molecular "targets", provide a new view on mechanisms of neuroprotection.

[THE INFLUENCE OF DELTA SLEEP-INDUCING PEPTIDE ON FUNCTIONAL STATE OF RATS HEPATOCYTES IN FOOT-SHOCK STRESS].

Ross Fiziol Zh Im I M Sechenova

A E Belykh, I I Bobyntsev, A A Kryukov +1 more

The effect of delta sleep-inducing peptide (DSIP) intraperitoneal injection in the doses of 40, 120, 360, and 1080 mcg/kg b. w. on lipid peroxidation and functional hepatocyte state in Wistar male rats subjected to acute and chronic electrical foot-shock stress was investigated. It was observed that 120 mcg/kg peptide normalized the elevation of malondialdehyde (MDA) level in the liver homogenate caused by acute foot-shock stress and also significantly decreased catalase activity in all investigated doses. In serum the injection of DSIP up to 40 mcg/kg increased aminotransferase activity. Peptide in all doses provided the normalization of protein synthetic hepatocyte function, increased catalase and superoxide dismutase activity in chronic stress. In addition malondialdehyde content in the liver homogenate was significantly decreased in the dose of 40 mcg/kg and in other cases it was significantly increased against the background of the common antioxidative activity reduction. The stress-induced increase in serum alanine aminotransferase activity was normalized by peptide administration in the doses of 120, 360, and 1080 mcg/kg.

[Optimization of the treatment of anxiety disorders with selank].

Zh Nevrol Psikhiatr Im S S Korsakova

V E Medvedev, O N Tereshchenko, N V Kost +5 more

To compare the efficacy and tolerability of monotherapy with phenazepam to complex treatment with the peptide preparation selank and phenazepam in patients with anxiety disorders.

Somatostatin system: molecular mechanisms regulating anterior pituitary hormones.

J Mol Endocrinol

Tamar Eigler, Anat Ben-Shlomo

The somatostatin (SRIF) system, which includes the SRIF ligand and receptors, regulates anterior pituitary gland function, mainly inhibiting hormone secretion and to some extent pituitary tumor cell growth. SRIF-14 via its cognate G-protein-coupled receptors (subtypes 1-5) activates multiple cellular signaling pathways including adenylate cyclase/cAMP, MAPK, ion channel-dependent pathways, and others. In addition, recent data have suggested SRIF-independent constitutive SRIF receptor activity responsible for GH and ACTH inhibition in vitro. This review summarizes current knowledge on ligand-dependent and independent SRIF receptor molecular and functional effects on hormone-secreting cells in the anterior pituitary gland.

Enhanced memory consolidation in mice lacking the circadian modulators Sharp1 and -2 caused by elevated Igf2 signaling in the cortex.

Proc Natl Acad Sci U S A

Ali Shahmoradi, Konstantin Radyushkin, Moritz J Rossner

The bHLH transcription factors SHARP1 and SHARP2 are partially redundant modulators of the circadian system. SHARP1/DEC2 has been shown to control sleep length in humans and sleep architecture is also altered in double mutant mice (S1/2(-/-)). Because of the importance of sleep for memory consolidation, we investigated the role of SHARP1 and SHARP2 in cognitive processing. S1/2(-/-) mice show enhanced cortex (Cx)-dependent remote fear memory formation as well as improved reversal learning, but do not display alterations in hippocampus (Hi)-dependent recent fear memory formation. SHARP1 and SHARP2 single null mutants do not display any cognitive phenotype supporting functional redundancy of both factors. Molecular and biochemical analyses revealed elevated insulin-related growth factor 2 (IGF2) signaling and increased phosphorylation of MAPK and S6 in the Cx but not the Hi of S1/2(-/-) mice. No changes were detected in single mutants. Moreover, adeno-associated virus type 2-mediated IGF2 overexpression in the anterior cingulate cortex enhanced remote fear memory formation and the analysis of forebrain-specific double null mutants of the Insulin and IGF1 receptors revealed their essential function for memory formation. Impaired fear memory formation in aged S1/2(-/-) mice indicates that elevated IGF2 signaling in the long term, however, has a negative impact on cognitive processing. In summary, we conclude that the bHLH transcription factors SHARP1 and SHARP2 are involved in cognitive processing by controlling Igf2 expression and associated signaling cascades. Our analyses provide evidence that the control of sleep and memory consolidation may share common molecular mechanisms.

The role of urocortins in the cardiovascular system.

J Physiol Pharmacol

J Walczewska, A Dzieza-Grudnik, O Siga +1 more

Urocortins (Ucn) 1, 2 and 3 are a group of endogenous peptide hormones belonging to the corticotropin-releasing hormone (CRH) family of peptides. The presence of urocortins has been detected in the central nervous system as well as in peripheral tissues. They play an important role in a stress response (with respect to its duration, intensity and restoration of homeostasis). They also act as regulatory factors of the cardiovascular, gastrointestinal, reproductive and immune systems. Urocortins act by binding to G-protein-coupled receptors (GPCR). The "central" effects of urocortins are mediated mainly by activation of CRH receptor 1 (CRH-R1), and the "peripheral" effects by activation of CRH-R2. Ucn2 and Ucn3 are selective CRH-R2 agonists and have much higher binding affinity to this receptor than CRH and Ucn1. Recent studies have shown that urocortins exert various biological effects in the cardiovascular system, such as vasodilation, positive inotropic and lusitropic effects, as well as cardioprotection against ischemia-reperfusion injury. They also suppress the renin-angiotensin system and may have an impact on the sympathetic nervous system. Urocortins and CRH-R2 may be a potential therapeutic target in coronary heart disease, congestive heart failure and hypertension. This review summarizes the data published to date on the role of urocortins in the cardiovascular system.

Intrinsically disordered cytoplasmic domains of two cytokine receptors mediate conserved interactions with membranes.

Biochem J

Gitte W Haxholm, Louise F Nikolajsen, Johan G Olsen +7 more

Class 1 cytokine receptors regulate essential biological processes through complex intracellular signalling networks. However, the structural platform for understanding their functions is currently incomplete as structure-function studies of the intracellular domains (ICDs) are critically lacking. The present study provides the first comprehensive structural characterization of any cytokine receptor ICD and demonstrates that the human prolactin (PRL) receptor (PRLR) and growth hormone receptor (GHR) ICDs are intrinsically disordered throughout their entire lengths. We show that they interact specifically with hallmark lipids of the inner plasma membrane leaflet through conserved motifs resembling immuno receptor tyrosine-based activation motifs (ITAMs). However, contrary to the observations made for ITAMs, lipid association of the PRLR and GHR ICDs was shown to be unaccompanied by changes in transient secondary structure and independent of tyrosine phosphorylation. The results of the present study provide a new structural platform for studying class 1 cytokine receptors and may implicate the membrane as an active component regulating intracellular signalling.

[EFFECT OF SYNTHETIC PEPTIDES ON AGING OF PATIENTS WITH CHRONIC POLYMORBIDITY AND ORGANIC BRAIN SYNDROME OF THE CENTRAL NERVOUS SYSTEM IN REMISSION].

Adv Gerontol

V N Meshchaninov, E L Tkachenko, S V Zharkov +2 more

We've estimated the cellular and metabolic part of geroprophylactic effects of short synthetic tripeptides vesugen and pinealon for correction of the biological age. 32 people (18 men, 12 women) aged 41-83 years with polymorbidity and the organic brain syndrome in remission participated in the study. The preparations of "Pinealon" and "Vesugen" have had the significant anabolic effect. They have improved the activity of the Central nervous system and other vital organs, which slows the rate of aging by biological age indicators. Vesugen has demonstrated more visible geroprophylactic effect than Pinealon. At the same time we've found the prooxidant activity through chemiluminescence. Decrease of markers CD34+ positive hematopoietic polypotent cells in blood has shown significant inhibition of hemopoiesis. Apparently, the cells have not been involved in the adaptive reactions. Pinealon and Vesugen haven't affected the degree of chromatin condensation, so they are safe on nuclear genetic level. This property should be studied in future. In geriatric practice, we recommend to apply the peptides Pinealon and Vesugen as geroprotectors anabolic neuroprotective and no antioxidant type for reducing the rate of aging in patients with the organic brain syndrome vascular and/or traumatic genesis.

A phase 1/2a follistatin gene therapy trial for becker muscular dystrophy.

Mol Ther

Jerry R Mendell, Zarife Sahenk, Vinod Malik +17 more

Becker muscular dystrophy (BMD) is a variant of dystrophin deficiency resulting from DMD gene mutations. Phenotype is variable with loss of ambulation in late teenage or late mid-life years. There is currently no treatment for this condition. In this BMD proof-of-principle clinical trial, a potent myostatin antagonist, follistatin (FS), was used to inhibit the myostatin pathway. Extensive preclinical studies, using adeno-associated virus (AAV) to deliver follistatin, demonstrated an increase in strength. For this trial, we used the alternatively spliced FS344 to avoid potential binding to off target sites. AAV1.CMV.FS344 was delivered to six BMD patients by direct bilateral intramuscular quadriceps injections. Cohort 1 included three subjects receiving 3 × 10(11) vg/kg/leg. The distance walked on the 6MWT was the primary outcome measure. Patients 01 and 02 improved 58 meters (m) and 125 m, respectively. Patient 03 showed no change. In Cohort 2, Patients 05 and 06 received 6 × 10(11) vg/kg/leg with improved 6MWT by 108 m and 29 m, whereas, Patient 04 showed no improvement. No adverse effects were encountered. Histological changes corroborated benefit showing reduced endomysial fibrosis, reduced central nucleation, more normal fiber size distribution with muscle hypertrophy, especially at high dose. The results are encouraging for treatment of dystrophin-deficient muscle diseases.

Reg IV is differently expressed in enteroendocrine cells of human small intestine and colon.

Regul Pept

Kukka Heiskala, Leif C Andersson

Reg IV is a 17 kD secreted C-type lectin physiologically found in selected enteroendocrine cells (EEC). It is thought be involved in the regulation of normal and pathological intestinal and/or neuroendocrine differentiation and proliferation but its ultimate functional role(s) is still unclear. We used immunostaining and compared the cellular expression of Reg IV with a panel of neuroendocrine markers in human GI-tract tissue samples. Reg IV showed cellular co-distribution with serotonin and chromogranin A in all parts of GI-tract. Co-localization of Reg IV with somatostatin was seen in colon and with substance P in ileum. Subpopulations of cells expressing Reg IV overlapped with EECs containing GLP-1, GLP-2, secretin, PYY, and ghrelin, depending on the anatomical localization of the samples. The results further underscore the high degree of diversity among EECs and suggest that Reg IV may be involved in the finetuning of functions exerted by the neuroendocrine cells in the GI-tract.

Selective innervation of NK1 receptor-lacking lamina I spinoparabrachial neurons by presumed nonpeptidergic Aδ nociceptors in the rat.

Pain

Najma Baseer, Abdullah S Al-Baloushi, Masahiko Watanabe +2 more

Fine myelinated (Aδ) nociceptors are responsible for fast, well-localised pain, but relatively little is known about their postsynaptic targets in the spinal cord, and therefore about their roles in the neuronal circuits that process nociceptive information. Here we show that transganglionically transported cholera toxin B subunit (CTb) labels a distinct set of afferents in lamina I that are likely to correspond to Aδ nociceptors, and that most of these lack neuropeptides. The vast majority of lamina I projection neurons can be retrogradely labelled from the lateral parabrachial area, and these can be divided into 2 major groups based on expression of the neurokinin 1 receptor (NK1r). We show that CTb-labelled afferents form contacts on 43% of the spinoparabrachial lamina I neurons that lack the NK1r, but on a significantly smaller proportion (26%) of those that express the receptor. We also confirm with electron microscopy that these contacts are associated with synapses. Among the spinoparabrachial neurons that received contacts from CTb-labelled axons, contact density was considerably higher on NK1r-lacking cells than on those with the NK1r. By comparing the density of CTb contacts with those from other types of glutamatergic bouton, we estimate that nonpeptidergic Aδ nociceptors may provide over half of the excitatory synapses on some NK1r-lacking spinoparabrachial cells. These results provide further evidence that synaptic inputs to dorsal horn projection neurons are organised in a specific way. Taken together with previous studies, they suggest that both NK1r(+) and NK1r-lacking lamina I projection neurons are directly innervated by Aδ nociceptive afferents.

Identification and characterization by LC-UV-MS/MS of melanotan II skin-tanning products sold illegally on the Internet.

Drug Test Anal

Torben Breindahl, Michael Evans-Brown, Peter Hindersson +4 more

New methods were developed and validated to determine the identity, contents, and purity of samples of melanotan II, a synthetic melanocortin receptor agonist, sold in vials as injectable skin-tanning products that were purchased from three online shops. Methods were based on liquid chromatography with ultra-violet detection (LC-UV) at wavelength 218 nm, and tandem mass spectrometric detection (MS/MS) after collision-induced fragmentation of the double charged [M+2H](2+) precursor ion (m/z 513). Identification of melanotan II was verified by correct chromatographic retention time, and relative abundance ratios of five qualifying fragment ions. LC-UV was used to quantify melanotan II as well as impurities. Method validation was performed with reference to guidelines for assessing active substances in authorized medicinal products to reach acceptable accuracy and precision. Vials from two shops contained unknown impurities ranging from 4.1 to 5.9%; impurities from one shop were below the quantification limit. The total amount of melanotan II in vials ranged between 4.32 and 8.84 mg, although each shop claimed that vials contained 10 mg melanotan II. A broad range of drugs used for enhancement purposes can be obtained from the illicit market. However, users of these drugs may be exposed to a range of potential harms, as shown in this study, given that these products are manufactured, distributed and supplied from an illicit market.

Traditional Chinese medicine formulas for irritable bowel syndrome: from ancient wisdoms to scientific understandings.

Am J Chin Med

Hai-Tao Xiao, Linda Zhong, Siu-Wai Tsang +2 more

Traditional Chinese Medicine (TCM) serves as the most common alternative therapeutic approach for Western medicine and benefits IBS patients globally. Due to the lack of scientific evidence in the past, TCM formulas were not internationally well recognized as promising IBS remedies. In this review, firstly, we present the etiology and therapy of IBS in terms of traditional Chinese medical theory. Secondly, we summarize the clinical randomized controlled trials (RCTs) of TCM formulas for IBS patients that are available in the literature (from 1998 to September 2013), in which 14 RCTs conducted of high quality were discussed in detail. Of the 14 selected trials, 12 of those concluded that TCM formulas provided superior improvement in the global symptoms of IBS patients over the placebo or conventional medicines. As well, all 14 RCTs suggested that TCM formulas have good safety and tolerability. Last but not least, we explore the pharmacological mechanisms of the anti-IBS TCM formulas available in the literature (from 1994 to September, 2013). Collectively, in combating IBS symptoms, most TCM formulas exert multi-targeting actions including the regulation of neurotransmitters and hormones in the enteric nervous system (ENS), modulation of smooth muscle motility in the gastrointestinal (GI) tract, modulation of the hypothalamic-pituitary-adrenal (HPA) axis, attenuation of intestinal inflammation and restoration of intestinal flora, etc. In conclusion, TCM formulas appear to be promising for IBS treatment. This review provides a useful reference for the public in furthering a better understanding and acceptance of TCM formulas as IBS remedies.

Serelaxin: a novel therapy for acute heart failure with a range of hemodynamic and non-hemodynamic actions.

Am J Cardiovasc Drugs

Javier Díez

Acute heart failure (AHF) is characterized by high morbidity and mortality and high costs. Although the treatment of AHF has not changed substantially in recent decades, it is becoming clear that treatment strategies for AHF need to address both the immediate hemodynamic abnormalities giving rise to congestion as well as prevent organ damage that can influence long-term prognosis. Serelaxin, the recombinant form of human relaxin-2, a naturally occurring peptide hormone, has been found to significantly improve symptoms and signs of AHF, prevent in-hospital worsening heart failure, as well as significantly improve 180-day cardiovascular and all-cause mortality after a 48-h infusion commenced within 16 h of presentation (RELAX-AHF study). Available data suggest that the clinical benefits may be attributable to a potential combination of multiple actions of serelaxin, including improving systemic, cardiac, and renal hemodynamics, and protecting cells and organs from damage via anti-inflammatory, anti-cell death, anti-fibrotic, anti-hypertrophic, and pro-angiogenic effects. This manuscript describes the short- and long-term effects of serelaxin in AHF patients, analyzing how these effects can be explained by taking into account the range of hemodynamic and non-hemodynamic actions of serelaxin. In addition, this paper also addresses several aspects related to the role of serelaxin in the therapy of AHF that remain to be clarified and warrant further investigation.

[Using deltalicin for the treatment of patients with diabetic retinopathy].

Eksp Klin Farmakol

N V Kresiun, L S Godlevskiĭ

The characteristics of visual evoked potential (VEP) have been investigated in a group of 15 healthy volunteers (aged 31.7 ± 3.6 years) and 30 insulin-dependent patients (aged 32.1 ± 4.0 years) with diabetes mellitus, among which 15 patients suffered from diabetic retinopathy and 15 patients had no retinopathy. An increase in the latent period along with reduction of the VEP amplitude after photostress action upon the macular part of retina have been observed in patients with diabetes, these effects were more pronounced in the subgroup with retinopathy. The restoration of VEP characteristics in 73.5 ± 3.3 s from the moment of photostress was observed in the control group, while this index in both subgroups of diabetic patients without and with retinopathy was 88.7 ± 5.9 and 137.2 ± 11.3 s, respectively. Treatment with deltalicin (daily dose of 0.0003 g of delta sleep-inducing peptide intranasally for two months) decreased the latent period and led to less pronounced depression of VEP amplitude in patients with diabetic retinopathy, and reduced the period of restoration of VEP characteristics to 95.1 ± 6.8 s.

[Influence of delta-sleep inducing peptide on the state of lysosomal membranes and intensity of lysosomal proteolysis in different rat tissues during physiological aging of the organism].

Adv Gerontol

D S Kutilin, T I Bondarenko, I I Mikhaleva

It is shown that subcutaneous injection of exogenous delta-sleep inducing peptide (DSIP) to rats aged 2-24 months in a dose of 100 μg/kg animal body weight by courses of 5 consecutive days per month has a stabilizing effect on the state of lysosomal membranes in rat tissues (brain, heart muscle and liver) at different ontogenetic stages, and this effect is accompanied by increasing intensity of lysosomal proteolysis in these tissues.

[Influence of delta-sleep peptide on the enzymes activity of mitochondrial electron transport chain in various rat tissues during aging of the organism].

Adv Gerontol

T I Bondarenko, D S Kutilin, I I Mikhaleva

It is shown that subcutaneous injection of exogenous delta-sleep inducing peptide (DSIP) to rats aged 2-24 months in a dose of 100 μg/kg animal body weight by courses of 5 consecutive days per month has a stabilizing effect on the NADH-dehydrogenase activity in the mitochondrial fractions of various tissues, which together with increasing capacity of the antioxidant system should reduce the production of free radicals and their adverse action on cells macromolecule, herewith the activity of succinate dehydrogenase did not change.

Detecting peptidic drugs, drug candidates and analogs in sports doping: current status and future directions.

Expert Rev Proteomics

Mario Thevis, Andreas Thomas, Wilhelm Schänzer

With the growing availability of mature systems and strategies in biotechnology and the continuously expanding knowledge of cellular processes and involved biomolecules, human sports drug testing has become a considerably complex field in the arena of analytical chemistry. Proving the exogenous origin of peptidic drugs and respective analogs at lowest concentration levels in biological specimens (commonly blood, serum and urine) of rather limited volume is required to pursue an action against cheating athletes. Therefore, approaches employing chromatographic-mass spectrometric, electrophoretic, immunological and combined test methods have been required and developed. These allow detecting the misuse of peptidic compounds of lower (such as growth hormone-releasing peptides, ARA-290, TB-500, AOD-9604, CJC-1295, desmopressin, luteinizing hormone-releasing hormones, synacthen, etc.), intermediate (e.g., insulins, IGF-1 and analogs, 'full-length' mechano growth factor, growth hormone, chorionic gonadotropin, erythropoietin, etc.) and higher (e.g., stamulumab) molecular mass with desired specificity and sensitivity. A gap between the technically possible detection and the day-to-day analytical practice, however, still needs to be closed.

[Clinical consequences of immunosenescence in chronic kidney diseases].

Med Sci (Paris)

Jamal Bamoulid, Clémence Carron, Thomas Crépin +2 more

Transcriptome analysis of the mammary gland from GH transgenic goats during involution.

Gene

Jian Lin, Ze Kun Bao, Qiang Zhang +3 more

Mammary glands are organs for milk production in female mammals. Growth hormone (GH) is known to affect the growth and development of the mammary gland, as well as to increase milk production in dairy goats. This study performed a comprehensive expression profiling of genes expressed in the mammary gland of early involution GH transgenic (n=4) and non-transgenic goats (n=4) by RNA sequencing. RNA was extracted from mammary gland tissues collected at day 3 of involution. Gene expression analysis was conducted by Illumina RNA sequencing and sequence reads were assembled and analyzed using TopHat. FPKM (fragments per kilobase of exon per million) values were analyzed for differentially expressed genes using the Cufflinks package. Gene ontology analysis of differentially expressed genes was categorized using agriGO, while KEGG pathway analysis was performed with the online KEGG automatic annotation server. Our results revealed that 75% of NCBI goat annotated genes were expressed during early involution. A total of 18,323 genes were expressed during early involution in GH transgenic goats, compared with 18,196 expressed genes during early involution of non-transgenic goats. In these expressed genes, the majority (17,589) were ubiquitously expressed in GH transgenic and non-transgenic goats. However, there were 745 differentially expressed genes, 421 of which were upregulated and 324 were downregulated in GH transgenic goats. GO and KEGG pathway analysis showed that these genes were involved in mammary gland physiology, including cell adhesion molecules, ECM-receptor interaction, Jak-STAT signaling pathway, and fat metabolism. Our results demonstrated that the GH receptor was strongly affected in GH transgenic goats, which may activate the IGF-1/Stat3 signaling pathway. Overall, our study provided a global view of the transcriptome during involution of GH transgenic and non-transgenic goats, which increases our understanding of the biology of involution in the goat.