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[COMPARISON OF PHARMACOLOGICAL EFFECTS OF HEPTAPEPTIDE SELANK AFTER INTRANASAL AND INTRAPERITONEAL ADMINISTRATION TO BALB/c AND C57BL/6 MICE.].
Eksp Klin Farmakol
E V Vasil'eva, E A Kondrakhin, R M Salimov +1 more
Pharmacological effects of intraperitoneal (i.p.) and intranasal (i.n.) administration of heptapeptide selank (300 μg/kg/day for 5 days), known to possess anxiolytic and nootropic properties, were compared by studying the elevated-plus-maze behavior of inbred BALB/c and C57BL/6 mice and measuring the binding of markers to NMDA and GABA receptors of brain. The anxiolytic and nootropic efficiency of selank administered via both routes was observed only in BALB/c mice, which were characterized by initially reduced exploratory activity and higher levels of anxiety as compared to C57BL/6 mice. In BALB/c mice, i.p. selank increased the number of [G-(3)H]SR 95531 binding sites with GABA-receptors in the frontal cortex by 38%, without change in binding to NMDA receptors in the hippocampus. On the contrary, i.n. selank led to an increase in the density of [G-(3)H]MK-801 binding sites by 23% with no effect on GABA receptors. It is suggested that the differences in pharmacological spectra observed for the two routes of selank administration are determined by specific features of drug pharmacokinetics and biotransformation as well as by the dynamics of formation of the anxiolytic and nootropic effects of selank.
Changes in Sympathetic Innervation of the Heart in Rats with Experimental Myocardial Infarction. Effect of Semax.
Bull Exp Biol Med
S A Gavrilova, M A Markov, A B Berdalin +2 more
The effect of peptide Semax on remodeling of cardiac sympathetic innervation was examined in rats with experimental myocardial infarction. In 28 days after ischemia/reperfusion injury, Semax diminished the growth of sympathetic innervation of ventricular septum, although it produced no effect on the density of β1 and β2 adrenoceptors.
Rhythmoinotropic Response of Papillary Muscles in Rats with Different Severity of Postinfarction Cardiosclerosis.
Bull Exp Biol Med
D S Kondratieva, S A Afanasiev, V Yu Usov +1 more
We studied the dependence of post-rest positive inotropic response of isolated rat papillary muscles subjected to rhythmic stimulation on severity of postinfarction cardiosclerosis developed during 6 weeks after occlusion of the left descending coronary artery. The isolated papillary muscles were perfused with oxygenated Krebs-Henseleit solution and electrically stimulated at a rate of 0.5 Hz. In all rats, coronary occlusion provoked postinfarction cardiosclerosis with the formation of a scar occupying 20-50% (min-max of the sample) of the left ventricular wall. Despite the presence of large postinfarction scar in all rats, the positive post-rest inotropic responses greatly varied. The post-rest response in rats with scar occupying <37% left ventricular wall was similar to that in intact animals, but rats with scar area >44% demonstrated dramatically decreased inotropic response to rest periods.
The behavioral deficits and cognitive impairment are correlated with decreased IGF-II and ERK in depressed mice induced by chronic unpredictable stress.
Int J Neurosci
Ya Li, Yajing Chen, Xiaoxiao Gao +1 more
To investigate the behavioral deficits, cognitive impairment and possible mechanisms induced by chronic unpredictable stress (CUS) in mice of different ages.
[Transplantation of bone marrow mesenchymal stem cell improves antioxidant capacity and immune activity of aging model rats ].
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi
Zhihong Wang, Yun Lin, Weimin Chen +2 more
To investigate the impact of bone marrow mesenchymal stem cell( BMSC) transplantation on the antioxidant capacity and immune activity of aging rats induced by D-galactose.
Microtubule stabilising peptides rescue tau phenotypes in-vivo.
Sci Rep
Shmma Quraishe, Megan Sealey, Louise Cranfield +1 more
The microtubule cytoskeleton is a highly dynamic, filamentous network underpinning cellular structure and function. In Alzheimer's disease, the microtubule cytoskeleton is compromised, leading to neuronal dysfunction and eventually cell death. There are currently no disease-modifying therapies to slow down or halt disease progression. However, microtubule stabilisation is a promising therapeutic strategy that is being explored. We previously investigated the disease-modifying potential of a microtubule-stabilising peptide NAP (NAPVSIPQ) in a well-established Drosophila model of tauopathy characterised by microtubule breakdown and axonal transport deficits. NAP prevented as well as reversed these phenotypes even after they had become established. In this study, we investigate the neuroprotective capabilities of an analogous peptide SAL (SALLRSIPA). We found that SAL mimicked NAP's protective effects, by preventing axonal transport disruption and improving behavioural deficits, suggesting both NAP and SAL may act via a common mechanism. Both peptides contain a putative 'SIP' (Ser-Ile-Pro) domain that is important for interactions with microtubule end-binding proteins. Our data suggests this domain may be central to the microtubule stabilising function of both peptides and the mechanism by which they rescue phenotypes in this model of tauopathy. Our observations support microtubule stabilisation as a promising disease-modifying therapeutic strategy for tauopathies like Alzheimer's disease.
Risks of unregulated use of alpha-melanocyte-stimulating hormone analogues: a review.
Int J Dermatol
Louis Habbema, Anne Berthe Halk, Martino Neumann +1 more
Recently, the unregulated use of untested synthetic alpha-melanocyte-stimulating hormone (α-MSH) analogues, commonly known as melanotan I and II, appears to have increased. These analogues are primarily used for their tan-stimulating effects. Dermatologists see many patients in their clinic who tan. This review provides an overview of the risks of the unregulated use of these substances. Other topics discussed here include the history and safety of afamelanotide, which is the only α-MSH analogue that is approved for use in a limited number of medical indications. Although afamelanotide has been thoroughly tested and deemed safe, illegal melanotans are likely risky for several reasons. There are questions regarding the preparation, administration, and dosage of these substances. In addition to these general risks, increasing numbers of case reports indicate that the unregulated use of both melanotan I and II is associated with cutaneous complications, particularly melanocytic changes in existing moles and newly emerging (dysplastic) nevi. Four case reports have described melanomas emerging from existing moles either during or shortly after the use of melanotan. Although conclusive evidence linking these phenomena is lacking, publications have stressed the importance of awareness that melanotan is a part of a 'tanning culture' in certain subpopulations. Multiple national health organizations have issued safety warnings regarding the use of melanotan I and II.
Comparative Proteomic and Transcriptomic Analysis of Follistatin-Induced Skeletal Muscle Hypertrophy.
J Proteome Res
Caroline Barbé, Fabrice Bray, Marine Gueugneau +5 more
Skeletal muscle, the most abundant body tissue, plays vital roles in locomotion and metabolism. Myostatin is a negative regulator of skeletal muscle mass. In addition to increasing muscle mass, Myostatin inhibition impacts muscle contractility and energy metabolism. To decipher the mechanisms of action of the Myostatin inhibitors, we used proteomic and transcriptomic approaches to investigate the changes induced in skeletal muscles of transgenic mice overexpressing Follistatin, a physiological Myostatin inhibitor. Our proteomic workflow included a fractionation step to identify weakly expressed proteins and a comparison of fast versus slow muscles. Functional annotation of altered proteins supports the phenotypic changes induced by Myostatin inhibition, including modifications in energy metabolism, fiber type, insulin and calcium signaling, as well as membrane repair and regeneration. Less than 10% of the differentially expressed proteins were found to be also regulated at the mRNA level but the Biological Process annotation, and the KEGG pathways analysis of transcriptomic results shows a great concordance with the proteomic data. Thus this study describes the most extensive omics analysis of muscle overexpressing Follistatin, providing molecular-level insights to explain the observed muscle phenotypic changes.
Antimicrobial Peptide Potency is Facilitated by Greater Conformational Flexibility when Binding to Gram-negative Bacterial Inner Membranes.
Sci Rep
Sarah-Beth T A Amos, Louic S Vermeer, Philip M Ferguson +6 more
The interaction of antimicrobial peptides (AMPs) with the inner membrane of Gram-negative bacteria is a key determinant of their abilities to exert diverse bactericidal effects. Here we present a molecular level understanding of the initial target membrane interaction for two cationic α-helical AMPs that share structural similarities but have a ten-fold difference in antibacterial potency towards Gram-negative bacteria. The binding and insertion from solution of pleurocidin or magainin 2 to membranes representing the inner membrane of Gram-negative bacteria, comprising a mixture of 128 anionic and 384 zwitterionic lipids, is monitored over 100 ns in all atom molecular dynamics simulations. The effects of the membrane interaction on both the peptide and lipid constituents are considered and compared with new and published experimental data obtained in the steady state. While both magainin 2 and pleurocidin are capable of disrupting bacterial membranes, the greater potency of pleurocidin is linked to its ability to penetrate within the bacterial cell. We show that pleurocidin displays much greater conformational flexibility when compared with magainin 2, resists self-association at the membrane surface and penetrates further into the hydrophobic core of the lipid bilayer. Conformational flexibility is therefore revealed as a key feature required of apparently α-helical cationic AMPs for enhanced antibacterial potency.
Randomized Trial of Icatibant for Angiotensin-Converting Enzyme Inhibitor-Induced Upper Airway Angioedema.
J Allergy Clin Immunol Pract
Richard Sinert, Phillip Levy, Jonathan A Bernstein +7 more
Upper airway angioedema is a rare, unpredictable, and at times life-threatening adverse effect of angiotensin-converting enzyme inhibitors (ACE-Is) with no existing effective pharmacologic treatment. Icatibant is a bradykinin B2 receptor antagonist that may be beneficial in patients with ACE-I-induced angioedema.
Peptides semax and selank affect the behavior of rats with 6-OHDA induced PD-like parkinsonism.
Dokl Biol Sci
P A Slominsky, M I Shadrina, T A Kolomin +5 more
Parkinson's disease (PD) is the second most common severe neurodegenerative disorder that is characterized by progressive degeneration of dopaminergic neurons (DA neurons) in the substantia nigra pars compacta (SNpc) region of the brain. In the present study, we investigated the effects of the synthetic regulatory peptides Semax (analog of an ACTH 4-10 fragment (ACTH4-10)) and Selank (analog of immunomodulatory taftsin) on behavior of rats with 6-hydroxidopamine (6-OHDA) induced PD-like parkinsonism. It was showed that both peptides did not affect motor activity of rats in elevated cross shaped maze and passive defensive behavior of the animals. At the same time, Selank decreased level of anxiety of rats with toxic damage of DA neurons in elevated cross shaped maze. Previously such effects of Selank were revealed in healthy rodents (rats and mice) with different models of psycho-emotional stress. Therefore, toxic damage of substantia nigra does not affect the response of the rat organism on this peptide.
Role of central neurotensin in regulating feeding: Implications for the development and treatment of body weight disorders.
Biochim Biophys Acta Mol Basis Dis
Laura E Schroeder, Gina M Leinninger
The peptide neurotensin (Nts) was discovered within the brain over 40years ago and is implicated in regulating analgesia, body temperature, blood pressure, locomotor activity and feeding. Recent evidence suggests, however, that these disparate processes may be controlled via specific populations of Nts neurons and receptors. The neuronal mediators of Nts anorectic action are now beginning to be understood, and, as such, modulating specific Nts pathways might be useful in treating feeding and body weight disorders. This review considers mechanisms through which Nts normally regulates feeding and how disruptions in Nts signaling might contribute to the disordered feeding and body weight of schizophrenia, Parkinson's disease, anorexia nervosa, and obesity. Defining how Nts specifically mediates feeding vs. other aspects of physiology will inform the design of therapeutics that modify body weight without disrupting other important Nts-mediated physiology.
Orally Targeted Delivery of Tripeptide KPV via Hyaluronic Acid-Functionalized Nanoparticles Efficiently Alleviates Ulcerative Colitis.
Mol Ther
Bo Xiao, Zhigang Xu, Emilie Viennois +6 more
Overcoming adverse effects and selectively delivering drug to target cells are two major challenges in the treatment of ulcerative colitis (UC). Lysine-proline-valine (KPV), a naturally occurring tripeptide, has been shown to attenuate the inflammatory responses of colonic cells. Here, we loaded KPV into hyaluronic acid (HA)-functionalized polymeric nanoparticles (NPs). The resultant HA-KPV-NPs had a desirable particle size (∼272.3 nm) and a slightly negative zeta potential (∼-5.3 mV). These NPs successfully mediated the targeted delivery of KPV to key UC therapy-related cells (colonic epithelial cells and macrophages). In addition, these KPV-loaded NPs appear to be nontoxic and biocompatible with intestinal cells. Intriguingly, we found that HA-KPV-NPs exert combined effects against UC by both accelerating mucosal healing and alleviating inflammation. Oral administration of HA-KPV-NPs encapsulated in a hydrogel (chitosan/alginate) exhibited a much stronger capacity to prevent mucosa damage and downregulate TNF-α, thus they showed a much better therapeutic efficacy against UC in a mouse model, compared with a KPV-NP/hydrogel system. These results collectively demonstrate that our HA-KPV-NP/hydrogel system has the capacity to release HA-KPV-NPs in the colonic lumen and that these NPs subsequently penetrate into colitis tissues and enable KPV to be internalized into target cells, thereby alleviating UC.
Serelaxin for the treatment of acute heart failure: a review with a focus on end-organ protection.
Eur Heart J Cardiovasc Pharmacother
Javier Díez, Luis M Ruilope
Acute heart failure (AHF) is a complex clinical syndrome characterized by fluid overload and haemodynamic abnormalities (short-term clinical consequences) and the development of end-organ damage (long-term consequences). Current therapies for the treatment of AHF, such as loop diuretics and vasodilators, help to relieve haemodynamic imbalance and congestion, but have not been shown to prevent (and may even contribute to) end-organ damage, or to provide long-term clinical benefit. Serelaxin is the recombinant form of human relaxin-2, a naturally occurring hormone involved in mediating haemodynamic changes during pregnancy. Preclinical and clinical studies have investigated the effects mediated by serelaxin and the suitability of this agent for the treatment of patients with AHF. Data suggest that serelaxin acts via multiple pathways to improve haemodynamics at the vascular, cardiac, and renal level and provide effective congestion relief. In addition, this novel agent may protect the heart, kidneys, and liver from damage by inhibiting inflammation, oxidative stress, cell death, and tissue fibrosis, and stimulating angiogenesis. Serelaxin may therefore improve both short- and long-term outcomes in patients with AHF. In this review, we examine the unique mechanisms underlying the potential benefits of serelaxin for the treatment of AHF, in particular, those involved in mediating end-organ protection.
Humanin promotes mitochondrial biogenesis in pancreatic MIN6 β-cells.
Biochem Biophys Res Commun
Qingqing Qin, Jieqiong Jin, Fang He +4 more
Mitochondrial dysfunction is associated with β-cell failure and insulin resistance in diabetes. Humanin is an endogenous cytoprotective peptide. In the current study, we aimed to define the effects of Humanin on mitochondrial biogenesis in pancreatic β-cells. Our findings demonstrated that Humanin treatment significantly increased the expression of PGC-1α and its downstream target genes NRF1 and TFAM in MIN6 β-cells. Notably, Humanin treatment significantly promoted mitochondrial biogenesis by increasing mitochondrial mass, elevating mtDNA/nDNA ratio, and stimulating the expression of cytochrome B, which were suppressed by the specific AMPK inhibitor compound C. Indeed, Humanin treatment caused the phosphorylation of AMPK, which was involved in the induction of PGC-1α, NRF1, and TFAM by Humanin. Importantly, our findings indicate that Humanin treatment led to a possible functional gain of the mitochondria by increasing ATP levels and respiratory rate. Our findings provided a new insight into the molecular mechanisms of action by which Humanin improves pancreatic β-cell function via enhanced mitochondrial mass and performance.
Ghrelin as a Survival Hormone.
Trends Endocrinol Metab
Bharath K Mani, Jeffrey M Zigman
Ghrelin administration induces food intake and body weight gain. Based on these actions, the ghrelin system was initially proposed as an antiobesity target. Subsequent studies using genetic mouse models have raised doubts about the role of the endogenous ghrelin system in mediating body weight homeostasis or obesity. However, this is not to say that the endogenous ghrelin system is not important metabolically or otherwise. Here we review an emerging concept in which the endogenous ghrelin system serves an essential function during extreme nutritional and psychological challenges to defend blood glucose, protect body weight, avoid exaggerated depression, and ultimately allow survival.
Serelaxin treatment promotes adaptive hypertrophy but does not prevent heart failure in experimental peripartum cardiomyopathy.
Cardiovasc Res
Justus Nonhoff, Melanie Ricke-Hoch, Mirco Mueller +8 more
Peripartum cardiomyopathy (PPCM) is a systolic left ventricular dysfunction developing in the peripartum phase in previously healthy women. Relaxin-2 is a pregnancy hormone with potential beneficial effects in heart failure patients. We evaluated Relaxin-2 as a potential diagnostic marker and/or a therapeutic agent in PPCM.
[Pinealon and Cortexin influence on behavior and neurochemical processes in 18-month aged rats within hypoxia and hypothermia].
Adv Gerontol
A M Mendzheritsky, G V Karantysh, G A Ryzhak +1 more
The research of Cortexin and Pinealon within two models of stress, acute hypobaric hypoxia and mild hypothermia, within 18-month aged rats has been held. The peculiarities of peptide preparations' influence on behavior and neurochemical indeces have been identified. Cortexin shows a more pronounced effect on free radical processes and caspase 3 activity in brain than Pinealon. Both preparations forward an accumulation of adrenergic mediator within rats' brains in the model of acute hypobaric hypoxia, as well as serotonin within cerebrum cortex in the model of mild hypothermia, which may underlie their geroprotective effects.
The actions of relaxin on the human cardiovascular system.
Br J Pharmacol
Mohsin Sarwar, Xiao-Jun Du, Thomas B Dschietzig +1 more
The insulin-like peptide relaxin, originally identified as a hormone of pregnancy, is now known to exert a range of pleiotropic effects including vasodilatory, anti-fibrotic, angiogenic, anti-apoptotic and anti-inflammatory effects in both males and females. Relaxin produces these effects by binding to a cognate receptor RXFP1 and activating a variety of signalling pathways including cAMP, cGMP and MAPKs as well as by altering gene expression of TGF-β, MMPs, angiogenic growth factors and endothelin receptors. The peptide has been shown to be effective in halting or reversing many of the adverse effects including fibrosis in animal models of cardiovascular disease including ischaemia/reperfusion injury, myocardial infarction, hypertensive heart disease and cardiomyopathy. Relaxin given to humans is safe and produces favourable haemodynamic changes. Serelaxin, the recombinant form of relaxin, is now in extended phase III clinical trials for the treatment of acute heart failure. Previous clinical studies indicated that a 48 h infusion of relaxin improved 180 day mortality, yet the mechanism underlying this effect is not clear. This article provides an overview of the cellular mechanism of effects of relaxin and summarizes its beneficial actions in animal models and in the clinic. We also hypothesize potential mechanisms for the clinical efficacy of relaxin, identify current knowledge gaps and suggest new ways in which relaxin could be useful therapeutically.
Effect of 3-substituted 1,4-benzodiazepin-2-ones on bradykinin-induced smooth muscle contraction.
Ukr Biochem J
P A Virych, O V Shelyuk, T A Kabanova +4 more
Biochemical properties of 3-substituted 1,4-benzodiazepine determined by the characteristics of their chemical structure. Influence of 3-substituted 1,4-benzodiazepin-2-ones on maximal normalized rate and amplitudes of isometric smooth muscle contraction in rats was investigated. Compounds MX-1775 and MX-1828 demonstrated the similar inhibition effect on bradykinin-induced contraction of smooth muscle like competitive inhibitor des-arg9-bradykinin-acetate to bradykinin B2-receptors. MX-1626 demonstrated unidirectional changes of maximal normalized rate and force of smooth muscle that proportionally depended on bradykinin concentration in the range 10-10-10-6 M. MX-1828 has statistically significant decrease of normalized rate of smooth muscle contraction for bradykinin concentrations 10-10 and 10-9 M by 20.7 and 8.6%, respectively, but for agonist concentration 10-6 M, this parameter increased by 10.7% and amplitude was reduced by 29.5%. Compounds MX-2011, MX-1785 and MX-2004 showed no natural effect on bradykinin-induced smooth muscle contraction. Compounds MX-1775, MX-1828, MX-1626 were selected for further research of their influence on kinin-kallikrein system and pain perception.