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Blood flow restricted resistance training attenuates myostatin gene expression in a patient with inclusion body myositis.
Biol Sport
A R Santos, M T Neves, B Gualano +5 more
Inclusion body myositis is a rare idiopathic inflammatory myopathy that produces extreme muscle weakness. Blood flow restricted resistance training has been shown to improve muscle strength and muscle hypertrophy in inclusion body myositis.
[Effect of deltaran and melatonin on immune system in rats with experimental contact dermatitis].
Fiziol Zh (1994)
O O Shandra
The aim of the work was investigation of both humoral and cell-mediated immunity together with leukocytes functional stability indexes in rats with the experimental contact dermatitis (ECD) in conditions of complex pharmacological correction using deltaran and melatonin. Experimental trials were performed under conditions of chronic experiment on model chrome-induced ECD. Both deltaran and melatonin either alone or in combination were used for complex pharmacological correction of humoral and cell-mediated immunity and also for stability of leukocytes. The data obtained showed the expressed disturbances of humoral and cell-mediated immunity and neutrophils' functional stability damage under conditions of chrome-induced ECD in rats. The revealed alterations in functional activity of the immune system were successfully corrected using the combined administration of deltaran and melatonin. The activity of medical complex had exponential character.
[Neuroprotective effects of peptides bioregulators in people of various age].
Adv Gerontol
R S Umnov, N S Lin'kova, V Kh Khavinson
The review presents comparative characteristics of 2 peptide neuroprotective groups: polypeptide complexes (cortexin, cerebrolizin) and short peptides (semax, kortagen, pinealon). The data of clinical applying of peptides in elderly and old age people and cellular and molecular mechanisms of their neuroprotective activity is described.
The role of oxytocin in plasticity, memory and attachment dynamics.
J Biol Regul Homeost Agents
F Orsucci, G Paoloni, C M Conti +2 more
The peptide hormones oxytocin (OT) and arginine vasopressin (AVP) have been implicated in the regulation of mammalian social behavior. There is considerable evidence implicating both oxytocin and vasopressin in social recognition and social memory. This review explores their role in attachment dynamics. Oxytocin is one element in a complex network of interactions observed in natural phenomena ranging from molecular biology, etology, social behavior and human psychology.
[Protective effect of selank on the model of mnestic function violation induced by pharmacological blockade of protein synthesis].
Eksp Klin Farmakol
I I Kozlovskiĭ, F Iu Belozertsev, L A Andreeva +1 more
We have studied the ability of peptide anxiolytic selank (Thr-Lyz-Pro-Arg-Pro-Gly-Pro) to compensate for mnestic dysfunction caused by the administration of actinomycin D, which inhibits protein synthesis by blocking DNA-dependent RNA polymerase. The experiments were performed on white rats with acquired adaptive ability of spatial visual orientation in a 16-door labyrinth. The learning was based on the avoidance of electric skin irritation at alternating sites of escape reaction (site reflex). Selank (0.5 mg/kg, i.p.) prevented or compensated for actinomycin D (250 mg/kg, i.p.) induced violation of the process of acquisition, improvement, and consolidation of memory trace during the development of a complex site reflex. The drug administration also reduced the time required for acquisition of the adaptive ability of spatial visual orientation in the labyrinth and restored the actinomycin D violated process of re-learning upon a change in the alternation of escape sites under free-choice conditions.
The effects of 11-ketotestosterone on ovarian physiology of previtellogenic captive hapuku (Polyprion oxygeneios).
Comp Biochem Physiol A Mol Integr Physiol
Yair Y Kohn, Jane E Symonds, P Mark Lokman
The present study investigated, for the first time in a perciform teleost, the effects of in vivo 11-ketotestosterone (11-KT) treatment using slow-release implants on ovarian development and gonadotropin receptor mRNA levels in captive previtellogenic females of hapuku (Polyprion oxygeneios). At the cellular/functional level, ovarian development and ovarian and hepatic total lipid levels were examined. At the molecular level, transcript abundance of ovarian follicle-stimulating hormone receptor (FSH-R) and luteinizing hormone receptor (LH-R) was measured. Additionally, cyclic adenosine monophosphate (cAMP) levels in ovarian fragments from placebo and 11-KT implanted fish incubated with or without human chorionic gonadotropin (hCG) in vitro were compared between groups. There were no significant differences between treatments with regard to oocyte size and lipid contents of liver and ovary. Messenger RNA levels of FSH-R and LH-R were significantly lower in the treated females. Similarly, cAMP levels were significantly lower in the ovarian fragments of the 11-KT implanted females. These results suggest that 11-KT specifically, but possibly androgens in general, may not have an important function in regulating gonadal development of previtellogenic female hapuku; indeed, if anything, 11-KT appeared to have a detrimental effect and its use will not be beneficial in advancing sexual maturity of hapuku in aquaculture.
Heart failure-induced skeletal myopathy in spontaneously hypertensive rats.
Int J Cardiol
R L Damatto, P F Martinez, A R R Lima +10 more
Although skeletal muscle atrophy and changes in myosin heavy chain (MyHC) isoforms have often been observed during heart failure, their pathophysiological mechanisms are not completely defined. In this study we tested the hypothesis that skeletal muscle phenotype changes are related to myogenic regulatory factors and myostatin/follistatin expression in spontaneously hypertensive rats (SHR) with heart failure.
Synthesis and characterization of time-resolved fluorescence probes for evaluation of competitive binding to melanocortin receptors.
Bioorg Med Chem
Ramesh Alleti, Josef Vagner, Dilani Chathurika Dehigaspitiya +10 more
Probes for use in time-resolved fluorescence competitive binding assays at melanocortin receptors based on the parental ligands MSH(4), MSH(7), and NDP-α-MSH were prepared by solid phase synthesis methods, purified, and characterized. The saturation binding of these probes was studied using HEK-293 cells engineered to overexpress the human melanocortin 4 receptor (hMC4R) as well as the human cholecystokinin 2 receptor (hCCK2R). The ratios of non-specific binding to total binding approached unity at high concentrations for each probe. At low probe concentrations, receptor-mediated binding and uptake was discernable, and so probe concentrations were kept as low as possible in determining Kd values. The Eu-DTPA-PEGO-MSH(4) probe exhibited low specific binding relative to non-specific binding, even at low nanomolar concentrations, and was deemed unsuitable for use in competition binding assays. The Eu-DTPA-PEGO probes based on MSH(7) and NDP-α-MSH exhibited Kd values of 27±3.9nM and 4.2±0.48nM, respectively, for binding with hMC4R. These probes were employed in competitive binding assays to characterize the interactions of hMC4R with monovalent and divalent MSH(4), MSH(7), and NDP-α-MSH constructs derived from squalene. Results from assays with both probes reflected only statistical enhancements, suggesting improper ligand spacing on the squalene scaffold for the divalent constructs. The Ki values from competitive binding assays that employed the MSH(7)-based probe were generally lower than the Ki values obtained when the probe based on NDP-α-MSH was employed, which is consistent with the greater potency of the latter probe. The probe based on MSH(7) was also competed with monovalent, divalent, and trivalent MSH(4) constructs that previously demonstrated multivalent binding in competitive binding assays against a variant of the probe based on NDP-α-MSH. Results from these assays confirm multivalent binding, but suggest a more modest increase in avidity for these MSH(4) constructs than was previously reported.
Mechano-growth factor peptide, the COOH terminus of unprocessed insulin-like growth factor 1, has no apparent effect on myoblasts or primary muscle stem cells.
Am J Physiol Endocrinol Metab
Mara Fornaro, Aaron C Hinken, Saul Needle +12 more
A splice form of IGF-1, IGF-1Eb, is upregulated after exercise or injury. Physiological responses have been ascribed to the 24-amino acid COOH-terminal peptide that is cleaved from the NH3-terminal 70-amino acid mature IGF-1 protein. This COOH-terminal peptide was termed "mechano-growth factor" (MGF). Activities claimed for the MGF peptide included enhancing muscle satellite cell proliferation and delaying myoblast fusion. As such, MGF could represent a promising strategy to improve muscle regeneration. Thus, at our two pharmaceutical companies, we attempted to reproduce the claimed effect of MGF peptides on human and mouse muscle myoblast proliferation and differentiation in vitro. Concentrations of peptide up to 500 ng/ml failed to increase the proliferation of C2C12 cells or primary human skeletal muscle myoblasts. In contrast, all cell types exhibited a proliferative response to mature IGF-1 or full-length IGF-1Eb. MGF also failed to inhibit the differentiation of myoblasts into myotubes. To address whether the response to MGF was lost in these tissue culture lines, we measured proliferation and differentiation of primary mouse skeletal muscle stem cells exposed to MGF. This, too, failed to demonstrate a significant effect. Finally, we tested whether MGF could alter a separate documented in vitro effect of the peptide, activation of p-ERK, but not p-Akt, in cardiac myocytes. Although a robust response to IGF-1 was observed, there were no demonstrated activating responses from the native or a stabilized MGF peptide. These results call in to question whether there is a physiological role for MGF.
[Metabolic effects of delta-sleep inducing peptide during physiological aging of the organism].
Eksp Klin Farmakol
T I Bondarenko, E A Maĭboroda, I I Mikhaleva +1 more
Subcutaneous injection of delta-sleep inducing peptide (DSIP) to postnatal rats (aged from 2 to 24 months) during 5 consecutive days every months at a dose of 10 microg/100 g body weight favors normalization of the age-related changes in carbohydrate metabolism and shows hypoglycemic effect, as manifested by a decrease in the level of glycosylated hemoglobin in erythrocytes of test rats. The administration of DSIP in postnatal rats of different age also led to a decrease in serum total lipid level, total cholesterol level, and atherogenicity index and an increase in the level of high-density lipoprotein cholesterol.
Single administration of tripeptide α-MSH(11-13) attenuates brain damage by reduced inflammation and apoptosis after experimental traumatic brain injury in mice.
PLoS One
Eva-Verena Schaible, Arne Steinsträßer, Antje Jahn-Eimermacher +7 more
Following traumatic brain injury (TBI) neuroinflammatory processes promote neuronal cell loss. Alpha-melanocyte-stimulating hormone (α-MSH) is a neuropeptide with immunomodulatory properties, which may offer neuroprotection. Due to short half-life and pigmentary side-effects of α-MSH, the C-terminal tripeptide α-MSH(11-13) may be an anti-inflammatory alternative. The present study investigated the mRNA concentrations of the precursor hormone proopiomelanocortin (POMC) and of melanocortin receptors 1 and 4 (MC1R/MC4R) in naive mice and 15 min, 6, 12, 24, and 48 h after controlled cortical impact (CCI). Regulation of POMC and MC4R expression did not change after trauma, while MC1R levels increased over time with a 3-fold maximum at 12 h compared to naive brain tissue. The effect of α-MSH(11-13) on secondary lesion volume determined in cresyl violet stained sections (intraperitoneal injection 30 min after insult of 1 mg/kg α-MSH(11-13) or 0.9% NaCl) showed a considerable smaller trauma in α-MSH(11-13) injected mice. The expression of the inflammatory markers TNF-α and IL-1β as well as the total amount of Iba-1 positive cells were not reduced. However, cell branch counting of Iba-1 positive cells revealed a reduced activation of microglia. Furthermore, tripeptide injection reduced neuronal apoptosis analyzed by cleaved caspase-3 and NeuN staining. Based on the results single α-MSH(11-13) administration offers a promising neuroprotective property by modulation of inflammation and prevention of apoptosis after traumatic brain injury.
Ageing is associated with diminished muscle re-growth and myogenic precursor cell expansion early after immobility-induced atrophy in human skeletal muscle.
J Physiol
C Suetta, U Frandsen, A L Mackey +9 more
Recovery of skeletal muscle mass from immobilisation-induced atrophy is faster in young than older individuals, yet the cellular mechanisms remain unknown. We examined the cellular and molecular regulation of muscle recovery in young and older human subjects subsequent to 2 weeks of immobility-induced muscle atrophy. Retraining consisted of 4 weeks of supervised resistive exercise in 9 older (OM: mean age) 67.3, range 61-74 yrs) and 11 young (YM: mean age 24.4, range 21-30 yrs) males. Measures of myofibre area (MFA), Pax7-positive satellite cells (SCs) associated with type I and type II muscle fibres, as well as gene expression analysis of key growth and transcription factors associated with local skeletal muscle milieu, were performed after 2 weeks immobility (Imm) and following 3 days (+3d) and 4 weeks (+4wks) of retraining. OM demonstrated no detectable gains in MFA (vastus lateralis muscle) and no increases in number of Pax7-positive SCs following 4wks retraining, whereas YM increased their MFA (P < 0.05), number of Pax7-positive cells, and had more Pax7-positive cells per type II fibre than OM at +3d and +4wks (P < 0.05). No age-related differences were observed in mRNA expression of IGF-1Ea, MGF, MyoD1 and HGF with retraining, whereas myostatin expression levels were more down-regulated in YM compared to OM at +3d (P < 0.05). In conclusion, the diminished muscle re-growth after immobilisation in elderly humans was associated with a lesser response in satellite cell proliferation in combination with an age-specific regulation of myostatin. In contrast, expression of local growth factors did not seem to explain the age-related difference in muscle mass recovery.
[Olygopeptide KND as a putative endogenous prototype of delta sleep inducing peptide (DSIP). Comparative study of biological properties].
Bioorg Khim
I I Mikhaleva, V T Ivanov, V B Voĭtenkov +2 more
We have undertaken a comparative study on physiological activity of well known neuropeptide DSIP (WAGGDASG E) and new closely related peptide KND (WKGGNASGE) in vivo assays. The sequence of K2, N5-DSIP (KND) was found recently by the computer search for DSIP homologous sequences in available nucleotide and protein databases at 324-332 site of Lysine-specific demethylase 3 B (EC 1.14.11, Swiss-Prot: Q7LBC6.1, 1-1761aa). This human lysine-specific histone demethylase is a representative of the recently discovered family of so called JmjC-domain-containing histone demethylases encoded by JMJD1B gene and ubiquitously expressed in tissues of various mammalian species. Biological investigations performed in this work confirm our preliminary data that DSIP-related peptide KND exhibits the similar biological properties in comparison with DSIP. Assessed by us antioxidative, anticonvulsive and behavioral effects of KND were even more expressed than in DSIP case. These results provide the additional evidences to support our suggestion that KND can be a possible endogenous prototype of "real" DSIP.
[Effects of the δ-sleep inducing peptide on neuronal activity in the dorsal hippocampus of rats with different behavior in the open field after stimulation of the positive and negative emotionalistic structures of the brain].
Zh Vyssh Nerv Deiat Im I P Pavlova
O S Grigorchuk
We studied the cerebral mechanisms of positive and negative emotions in rats with different behavior in open field, reflecting stress resistance and neuronal effects of delta-sleep-inducing peptide (DSIP). In 20 male Wistar rats 107 neurons of dorsal hippocampus (57 neurons in active in open field--prognostically resistant to emotional stress and 50 inpassive--prognostically predisposed rats) were registered after positive (lateral hypothalamus--LH) and negative (ventromedial hypothalamus--VMH) emotional centers electric stimulation. Hippocampal neurons in active rats were less sensitive to stimulation of LH and VMH compared with passive ones. DSIP microiontophoretic application before LH stimulation decreases neuronal responses in both active and passive animals. DSIP increases dorsal hippocampus neurons sensitivity to VMH stimulation in active rats and decreases in passive ones.
Melanotan-associated melanoma in situ.
Australas J Dermatol
Suyin Ong, Jonathan Bowling
Injectable synthetic melanotropic peptides (often called melanotan) to enhance tanning are available over the Internet despite being unlicensed compounds with an unproven safety record. There have been reports of dysplastic naevi and melanoma associated with the use of melanotropic peptides. We report a case of melanotan-associated melanoma in situ.
Rapid and reversible impairments of short- and long-term social recognition memory are caused by acute isolation of adult rats via distinct mechanisms.
PLoS One
Hadar Shahar-Gold, Rotem Gur, Shlomo Wagner
Mammalian social organizations require the ability to recognize and remember individual conspecifics. This social recognition memory (SRM) can be examined in rodents using their innate tendency to investigate novel conspecifics more persistently than familiar ones. Here we used the SRM paradigm to examine the influence of housing conditions on the social memory of adult rats. We found that acute social isolation caused within few days a significant impairment in acquisition of short-term SRM of male and female rats. Moreover, SRM consolidation into long-term memory was blocked following only one day of social isolation. Both impairments were reversible, but with different time courses. Furthermore, only the impairment in SRM consolidation was reversed by systemic administration of arginine-vasopressin (AVP). In contrast to SRM, object recognition memory was not affected by social isolation. We conclude that acute social isolation rapidly induces reversible changes in the brain neuronal and molecular mechanisms underlying SRM, which hamper its acquisition and completely block its consolidation. These changes occur via distinct, AVP sensitive and insensitive mechanisms. Thus, acute social isolation of rats swiftly causes changes in their brain and interferes with their normal social behavior.
A multi-institutional, phase II open-label study of ganitumab (AMG 479) in advanced carcinoid and pancreatic neuroendocrine tumors.
Endocr Relat Cancer
J R Strosberg, J A Chan, D P Ryan +9 more
The IGF pathway has been implicated in the regulation of neuroendocrine tumor (NET) growth, and preliminary studies suggested that ganitumab (AMG 479), a human MAB against IGF1R, may have antitumor activity in this setting. We performed a two-cohort phase II study of ganitumab in patients with metastatic progressive carcinoid or pancreatic NETs (pNETs). This open-label study enrolled patients (≥18 years) with metastatic low- and intermediate-grade carcinoid or pNETs. Inclusion criteria included evidence of progressive disease (by Response Evaluation Criteria in Solid Tumors (RECIST)) within 12 months of enrollment, ECOG PS 0-2, and fasting blood sugar <160  mg/dl. Prior treatments were allowed and concurrent somatostatin analog therapy was permitted. The primary endpoint was objective response. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. Sixty patients (30 carcinoid and 30 pNETs) were treated with ganitumab 18  mg/kg every 3 weeks, among whom 54 patients were evaluable for survival and 53 patients for response. There were no objective responders by RECIST. The median PFS duration was 6.3 months (95% CI, 4.2-12.6) for the entire cohort; 10.5 months for carcinoid patients, and 4.2 months for pNET patients. The OS rate at 12 months was 66% (95% CI, 52-77%) for the entire cohort. The median OS has not been reached. Grade 3/4 AEs were rare and consisted of hyperglycemia (4%), neutropenia (4%), thrombocytopenia (4%), and infusion reaction (1%). Although well tolerated, treatment with single-agent ganitumab failed to result in significant tumor responses among patients with metastatic well-differentiated carcinoid or pNET.
Genetic variants and effects on milk traits of the caprine paired-like homeodomain transcription factor 2 (PITX2) gene in dairy goats.
Gene
Haiyu Zhao, Xianfeng Wu, Hanfang Cai +4 more
The paired-like homeodomain transcription factor 2 (PITX2) gene plays a critical role in cell proliferation, differentiation, hematopoiesis and organogenesis. This gene regulates several genes' expressions in the Wnt/beta-catenin and POU1F1 pathways, thereby probably affecting milk performance. The goal of this study was to characterize the genetic variants of the PITX2 gene and test their associations with milk traits in dairy goats. Herein, four novel single nucleotide polymorphisms (SNPs), AC_000163:g.18117T>C, g.18161C>G, g.18322C>A and g.18353T>C, within the caprine PITX2 gene, were found in two famous Chinese dairy goat breeds. These SNPs mapping at Cys28Arg, Pro42Pro, IVS1+79C>A and IVS1+110T>C, were genotyped by the MvaI, SmaI, MspI and RsaI aCRS-RFLP or PCR-RFLP methods, respectively. Accordingly, two main haplotypes (CGCT and CGCC) were identified among the specimens. Association testing revealed that the SmaI and RsaI polymorphisms were significantly associated with the milk fat content, milk lactose content and milk density (P<0.05 or P<0.01) in the Guanzhong (GZ) dairy goats, respectively. At the same time, the RsaI locus was also found to significantly link to the second lactation milk yield, milk fat content, milk lactose content, milk density and milk total solid content (P<0.05 or P<0.01) in the Xinong Saanen (XNSN) dairy goats, respectively. These results indicated that the caprine PITX2 gene had the significant effects on milk traits. Hence, the RsaI and SmaI loci could be regarded as two DNA markers for selecting superior milk performance in dairy goats. These preliminary findings not only would extend the spectrum of genetic variation of the goat PITX2 gene, but also would contribute to implementing marker-assisted selection (MAS) in breeding and genetics in dairy goats.
Increased muscle force production and bone mineral density in ActRIIB-Fc-treated mature rodents.
J Gerontol A Biol Sci Med Sci
Chi-Sung Chiu, Norbert Peekhaus, Hans Weber +19 more
Myostatin is a highly conserved member of the transforming growth factor-β ligand family known to regulate muscle growth via activation of activin receptors. A fusion protein consisting of the extracellular ligand-binding domain of activin type IIB receptor with the Fc portion of human immunoglobulin G (ActRIIB-Fc) was used to inhibit signaling through this pathway. Here, we study the effects of this fusion protein in adult, 18-month-old, and orchidectomized mice. Significant muscle growth and enhanced muscle function were observed in adult mice treated for 3 days with ActRIIB-Fc. The ActRIIB-Fc-treated mice had enhanced fast fatigable muscle function, with only minor enhancement of fatigue-resistant fiber function. The ActRIIB-Fc-treated 18-month-old mice and orchidectomized mice showed significantly improved muscle function. Treatment with ActRIIB-Fc also increased bone mineral density and serum levels of a marker of bone formation. These observations highlight the potential of targeting ActRIIB receptor to treat age-related and hypogonadism-associated musculoskeletal degeneration.
Skeletal muscle hypertrophy and regeneration: interplay between the myogenic regulatory factors (MRFs) and insulin-like growth factors (IGFs) pathways.
Cell Mol Life Sci
Nadège Zanou, Philippe Gailly
Adult skeletal muscle can regenerate in response to muscle damage. This ability is conferred by the presence of myogenic stem cells called satellite cells. In response to stimuli such as injury or exercise, these cells become activated and express myogenic regulatory factors (MRFs), i.e., transcription factors of the myogenic lineage including Myf5, MyoD, myogenin, and Mrf4 to proliferate and differentiate into myofibers. The MRF family of proteins controls the transcription of important muscle-specific proteins such as myosin heavy chain and muscle creatine kinase. Different growth factors are secreted during muscle repair among which insulin-like growth factors (IGFs) are the only ones that promote both muscle cell proliferation and differentiation and that play a key role in muscle regeneration and hypertrophy. Different isoforms of IGFs are expressed during muscle repair: IGF-IEa, IGF-IEb, or IGF-IEc (also known as mechano growth factor, MGF) and IGF-II. MGF is expressed first and is observed in satellite cells and in proliferating myoblasts whereas IGF-Ia and IGF-II expression occurs at the state of muscle fiber formation. Interestingly, several studies report the induction of MRFs in response to IGFs stimulation. Inversely, IGFs expression may also be regulated by MRFs. Various mechanisms are proposed to support these interactions. In this review, we describe the general process of muscle hypertrophy and regeneration and decipher the interactions between the two groups of factors involved in the process.