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Growth hormone secretagogues exert differential effects on skeletal muscle calcium homeostasis in male rats depending on the peptidyl/nonpeptidyl structure.
Endocrinology
Antonella Liantonio, Gianluca Gramegna, Giuseppe Carbonara +7 more
The orexigenic and anabolic effects induced by ghrelin and the synthetic GH secretagogues (GHSs) are thought to positively contribute to therapeutic approaches and the adjunct treatment of a number of diseases associated with muscle wasting such as cachexia and sarcopenia. However, many questions about the potential utility and safety of GHSs in both therapy and skeletal muscle function remain unanswered. By using fura-2 cytofluorimetric technique, we determined the acute effects of ghrelin, as well as of peptidyl and nonpeptidyl synthetic GHSs on calcium homeostasis, a critical biomarker of muscle function, in isolated tendon-to-tendon male rat skeletal muscle fibers. The synthetic nonpeptidyl GHSs, but not peptidyl ghrelin and hexarelin, were able to significantly increase resting cytosolic calcium [Ca²⁺]i. The nonpeptidyl GHS-induced [Ca²⁺]i increase was independent of GHS-receptor 1a but was antagonized by both thapsigargin/caffeine and cyclosporine A, indicating the involvement of the sarcoplasmic reticulum and mitochondria. Evaluation of the effects of a pseudopeptidyl GHS and a nonpeptidyl antagonist of the GHS-receptor 1a together with a drug-modeling study suggest the conclusion that the lipophilic nonpeptidyl structure of the tested compounds is the key chemical feature crucial for the GHS-induced calcium alterations in the skeletal muscle. Thus, synthetic GHSs can have different effects on skeletal muscle fibers depending on their molecular structures. The calcium homeostasis dysregulation specifically induced by the nonpeptidyl GHSs used in this study could potentially counteract the beneficial effects associated with these drugs in the treatment of muscle wasting of cachexia- or other age-related disorders.
Metabolism of growth hormone releasing peptides.
Anal Chem
Andreas Thomas, Philippe Delahaut, Oliver Krug +2 more
New, potentially performance enhancing compounds have frequently been introduced to licit and illicit markets and rapidly distributed via worldwide operating Internet platforms. Developing fast analytical strategies to follow these new trends is one the most challenging issues for modern doping control analysis. Even if reference compounds for the active drugs are readily obtained, their unknown metabolism complicates effective testing strategies. Recently, a new class of small C-terminally amidated peptides comprising four to seven amino acid residues received considerable attention of sports drug testing authorities due to their ability to stimulate growth hormone release from the pituitary. The most promising candidates are the growth hormone releasing peptide (GHRP)-1, -2, -4, -5, -6, hexarelin, alexamorelin, and ipamorelin. With the exemption of GHRP-2, the entity of these peptides represents nonapproved pharmaceuticals; however, via Internet providers, all compounds are readily available. To date, only limited information on the metabolism of these substances is available and merely one metabolite for GHRP-2 is established. Therefore, a comprehensive in vivo (po and iv administration in rats) and in vitro (with human serum and recombinant amidase) study was performed in order to generate information on urinary metabolites potentially useful for routine doping controls. The urine samples from the in vivo experiments were purified by mixed-mode cation-exchange solid-phase extraction and analyzed by ultrahigh-performance liquid chromatography (UHPLC) separation followed by high-resolution/high-accuracy mass spectrometry. Combining the high resolution power of a benchtop Orbitrap mass analyzer for the first metabolite screening and the speed of a quadrupole/time-of-flight (Q-TOF) instrument for identification, urinary metabolites were screened by means of a sensitive full scan analysis and subsequently confirmed by high-accuracy product ion scan experiments. Two deuterium-labeled internal standards (triply deuterated GHRP-4 and GHRP-2 metabolite) were used to optimize the extraction and analysis procedure. Overall, 28 metabolites (at least three for each GHRP) were identified from the in vivo samples and main metabolites were confirmed by the human in vitro model. All identified metabolites were formed due to exopeptidase- (amino- or carboxy-), amidase-, or endopeptidase activity.
Somatostatin, somatostatin analogs and somatostatin receptor dynamics in the biology of cancer progression.
Curr Mol Med
M Ruscica, M Arvigo, L Steffani +2 more
The pharmacological effects (i.e., inhibition of endocrine secretion and cell proliferation) mediated by the hormone somatostatin (SRIF) are derived from its universal high-affinity binding to five different G proteincoupled receptors (GPCRs), named sst1-5. However, SRIF has a half-life of less than 3 min, whereas the available mono- and bi-specific SRIF preferential analogs show prolonged half-life and increased potency. These compounds may control tumor development, cell proliferation and metastatization by direct actions, including cell division arrest in G0/G1 phase (i.e., induction of cyclin-dependent kinase inhibitor p27(kip1) or p21(Cip1)), induction of apoptosis (i.e., induction of p53 and Bax) and suppression of cell invasion. Along with these direct actions on the biology of cancer progression, in vivo SRIF analogs may also regulate tumor growth through indirect actions, by suppressing the secretion of growth-promoting hormones and growth factors and angiogenesis. Interestingly, when ssts are co-expressed, they may interact forming homo- or heterodimers, also with other GPCRs such as type 2 dopamine receptor and the μ-opioid receptor 1, altering their original pharmacological and functional properties. Dimers can be not only constitutive, but perhaps also ligandpromoted: hence, compounds with high affinity for different ssts isoforms may be used to achieve effects elicited by specific dimers. Future developments in the knowledge of ssts dynamics upon SRIF and SRIF analogs binding in neoplastic tissues may allow the full elucidation of the pathophysiological role of this system and the exploitation of the therapeutic potential of its modulation.
The anti-wrinkle efficacy of argireline, a synthetic hexapeptide, in Chinese subjects: a randomized, placebo-controlled study.
Am J Clin Dermatol
Yuan Wang, Mei Wang, Shengxiang Xiao +3 more
Argireline is a synthetic peptide that is patterned from the N-terminal end of the protein SNAP-25 and has been shown to reduce the degree of facial wrinkles. It is reported to inhibit vesicle docking by preventing formation of the ternary SNARE complex and by interfering in catecholamine release. The anti-wrinkle efficacy of argireline has not been studied in Chinese subjects.
Atypical melanocytic naevi following melanotan injection.
Ir Med J
C Reid, T Fitzgerald, A Fabre +1 more
Melanotan is a synthetic analogue of alpha melanocyte stimulating hormone (a-MSH) that stimulates melanogenesis. It is sold on the internet and tanning salons as a quick 'tanning jab'. We report a patient who developed multiple new onset atypical naevi within one week of receiving two Melanotan injections. This case highlights the potential risk of Melanotan in stimulating dysplastic naevi or possibly malignant melanoma.
The synthetic melanocortin (CKPV)2 exerts anti-fungal and anti-inflammatory effects against Candida albicans vaginitis via inducing macrophage M2 polarization.
PLoS One
Hai-xia Ji, Yu-lian Zou, Jing-jing Duan +14 more
In this study, we examined anti-fungal and anti-inflammatory effects of the synthetic melanocortin peptide (Ac-Cys-Lys-Pro-Val-NH2)2 or (CKPV)2 against Candida albicans vaginitis. Our in vitro results showed that (CKPV)2 dose-dependently inhibited Candida albicans colonies formation. In a rat Candida albicans vaginitis model, (CKPV)2 significantly inhibited vaginal Candida albicans survival and macrophages sub-epithelial mucosa infiltration. For mechanisms study, we observed that (CKPV)2 inhibited macrophages phagocytosis of Candida albicans. Meanwhile, (CKPV)2 administration inhibited macrophage pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) release, while increasing the arginase activity and anti-inflammatory cytokine IL-10 production, suggesting macrophages M1 to M2 polarization. Cyclic AMP (cAMP) production was also induced by (CKPV)2 administration in macrophages. These above effects on macrophages by (CKPV)2 were almost reversed by melanocortin receptor-1(MC1R) siRNA knockdown, indicating the requirement of MC1R in the process. Altogether, our results suggest that (CKPV)2 exerted anti-fungal and anti-inflammatory activities against Candida albicans vaginitis probably through inducing macrophages M1 to M2 polarization and MC1R activation.
Ubiquitous Gasp1 overexpression in mice leads mainly to a hypermuscular phenotype.
BMC Genomics
Olivier Monestier, Caroline Brun, Katy Heu +5 more
Myostatin, a member of the TGFβ superfamily, is well known as a potent and specific negative regulator of muscle growth. Targeting the myostatin signalling pathway may offer promising therapeutic strategies for the treatment of muscle-wasting disorders. In the last decade, various myostatin-binding proteins have been identified to be able to inhibit myostatin activity. One of these is GASP1 (Growth and Differentiation Factor-Associated Serum Protein-1), a protein containing a follistatin domain as well as multiple domains associated with protease inhibitors. Despite in vitro data, remarkably little is known about in vivo functions of Gasp1. To further address the role of GASP1 during mouse development and in adulthood, we generated a gain-of-function transgenic mouse model that overexpresses Gasp1 under transcriptional control of the human cytomegalovirus immediate-early promoter/enhancer.
Role of ionotropic glutamate receptors in the control of prolactin secretion by other neurotransmitters and neuropeptides at the level of the pituitary.
Endocr Regul
S K Jain, D Zelena
Although prolactin (PRL) plays an important role in the milk production, it has also many other functions. PRL secretion can be inhibited by dopamine and stimulated by serotonin, thyrotropin releasing hormone (TRH), and vasoactive intestinal peptide (VIP). However, the exact mechanisms of PRL regulation are still not fully understood. Glutamate is also a potent elevator of PRL secretion. It has several receptors: ionotropic NMDA (N-methyl-D-aspartate) and non-NMDA as well as metabotropic receptors. Our interest was to find out whether endogenous glutamate may act at the hypophyseal level and affect the PRL regulating neurotransmitters (dopamine, serotonin, TRH, VIP).
[Delta-sleep inducing peptide entrapment and release from polymer hydrogels based on modified polyvinyl alcohol in vitro].
Biomed Khim
T V Sukhanova, A A Artiukhov, I A Prudchenko +4 more
The aim of the study was to entrap delta-sleep inducing peptide (DSIP) in cross-linked poly(vinyl alcohol)-based hydrogels of different structures and to evaluate peptide release kinetics from these hydrogels using an in vitro model. Isotropic and macroporous hydrogels on the basis of poly(vinyl alcohol) acrylic derivative (Acr-PVA) as well as macroporous hydogels containing epoxy groups which were synthesized by copolymerization of this monomer with glycidyl methacrylate. The isotropic hydrogels were fabricated at positive temperatures while the macroporous hydrogels (cryogels) were prepared at the temperatures below zero. The peptide was entrapped into macroporous modified PVA hydrogels by addition of a peptide solution on previously fabricated matrices, while into PVA-GMA hydrogels containing epoxy groups peptide immobilization was carried out by incubation of hydrogel matrices in the peptide solution. In the case of isotropic hydrogels the peptide was added into the polymer mixture at a hydrogel formation reaction. The peptide release kinetics was studied by incubation of hydrogels in PBS (pH 7.4), in physiological solution (0.9% NaCl) and in water. DSIP concentration in supernatants was determined by phase-reverse HPLC. DSIP release from the macroporous PVA hydrogel after 30 min incubation was 74, 70 and 64% in water, PBS and 0.9% NaCl, relatively, and it was completed in 3 hs. From the isotropic hydrogel the release neither peptide nor products of its degradation was not observed even after 48 hs of incubation. For freshly prepared hydrogel the release kinetics was as follows: 27 and 78% in 30 and 33 hs, relatively. In the case of the lyophilized hydrogel samples the peptide release was 63% in 30 min incubation while drying patterns at room temperature for 3 days resulted in significant peptide loss because its structure damage.
The polyfunctionality of human memory CD8+ T cells elicited by acute and chronic virus infections is not influenced by age.
PLoS Pathog
Alina Lelic, Chris P Verschoor, Mario Ventresca +6 more
As humans age, they experience a progressive loss of thymic function and a corresponding shift in the makeup of the circulating CD8+ T cell population from naïve to memory phenotype. These alterations are believed to result in impaired CD8+ T cell responses in older individuals; however, evidence that these global changes impact virus-specific CD8+ T cell immunity in the elderly is lacking. To gain further insight into the functionality of virus-specific CD8+ T cells in older individuals, we interrogated a cohort of individuals who were acutely infected with West Nile virus (WNV) and chronically infected with Epstein Barr virus (EBV) and Cytomegalovirus (CMV). The cohort was stratified into young (<40 yrs), middle-aged (41-59 yrs) and aged (>60 yrs) groups. In the aged cohort, the CD8+ T cell compartment displayed a marked reduction in the frequency of naïve CD8+ T cells and increased frequencies of CD8+ T cells that expressed CD57 and lacked CD28, as previously described. However, we did not observe an influence of age on either the frequency of virus-specific CD8+ T cells within the circulating pool nor their functionality (based on the production of IFNγ, TNFα, IL2, Granzyme B, Perforin and mobilization of CD107a). We did note that CD8+ T cells specific for WNV, CMV or EBV displayed distinct functional profiles, but these differences were unrelated to age. Collectively, these data fail to support the hypothesis that immunosenescence leads to defective CD8+ T cell immunity and suggest that it should be possible to develop CD8+ T cell vaccines to protect aged individuals from infections with novel emerging viruses.
Administration of donepezil does not rescue galanin-induced spatial learning deficits.
Int J Neurosci
Jonathan J Sabbagh, Chelcie F Heaney, Monica M Bolton +3 more
The neuropeptide galanin inhibits the evoked release of several neurotransmitters including acetylcholine and modulates adenylate cyclase (AC) activity. Galanin has also been established to impair various forms of learning and memory in rodents. However, whether galanin produces learning deficits by inhibiting cholinergic activity or decreasing AC function has not been clearly established. The current study investigated if donepezil, an acetylcholinesterase inhibitor utilized in Alzheimer's disease, could rescue galanin-induced Morris water task deficits in rats. The results demonstrated that donepezil did not alter the previously established deficits induced by galanin. These findings suggest that galanin-mediated spatial learning deficits may be unrelated to its modulation of the cholinergic system.
[The diagnostics of adaptive reactions of blood on application the stress-modulating therapy in patients with brain chronic ischemia].
Klin Lab Diagn
V N Krylov, A V Deriugina, E A Antipenko +1 more
The article deals with the results of analysis of electrophoretic mobility of erythrocytes and leukogram in patients with dyscirculatory encephalopathy on different stages of disease on application therapy with inclusion of stress-modulating pharmaceuticals into course of treatment. It is established that the electrophoretic mobiliy of erythrocytes makes it possible to evaluate the adaptive indicators blood in patients with dyscirculatory encephalopathy. The consideration of these indicators makes feasible the substantiation of inclusion of stress-modulating therapy into complex treatment of patients with chronic cerebrovascular inefficiency.
A single ascending-dose study of muscle regulator ACE-031 in healthy volunteers.
Muscle Nerve
Kenneth M Attie, Niels G Borgstein, Yijun Yang +7 more
ACE-031 is a soluble form of activin receptor type IIB (ActRIIB). ACE-031 promotes muscle growth by binding to myostatin and other negative regulators of muscle mass.
Copper-62 labeled ReCCMSH peptide analogs for melanoma PET imaging.
Curr Radiopharm
Xiuli Zhang, Zhiwei Yue, Bao-Yuan Lu +7 more
High-specific activity radiolabeled melanocortin peptide preparations are necessary for optimal melanoma imaging due to the relatively low number of melanocortin-1 receptors (MC1-Rs) per tumor cell. In this study, a one-step synthesis of 62Cu-labeled MC1-R targeting peptide Re(Arg11)CCMSH was developed, which yielded high specific activity radiolabeled peptide preparations that required no post-labeling purification. DOTA and NOTA conjugated Re(Arg11)CCMSH peptides were synthesized and examined for 62Cu radiolabeling and cell binding properties. Biodistribution and PET imaging studies were performed to assess the in vivo tumor targeting and imaging characteristics of the optimal radiolabeled peptide. Melanoma cell binding affinities for NOTA-, NOTA-GGG-, and NOTA-GSG- conjugated Re(Arg11)CCMSH were determined to be 1.3×10-9 M, 1.9×10-9 M and 6.0×10-9 M. The 62Cu radiolabeling efficiencies of DOTA- and NOTA- conjugated Re(Arg11)CCMSH analogs were 30% and > 98% after 2 min at 24° C, while 0.5 μg of NOTA-GGG-peptide could be labeled to > 95% with a maximum specific activity of 138 Ci/μmol. Tumor uptake of 62Cu- NOTA-GGG-Re(Arg11)CCMSH in B16/F1 melanoma bearing mice was 4.65±0.48% ID/g and 9.43±2.69% ID/g at 20 and 40 min post injection and was visualized by PET imaging. High specific activity 62Cu-NOTA-GGG-Re(Arg11)CCMSH was prepared in a one-step procedure at 24°C in 6 min. 62Cu-NOTA-GGG-Re(Arg11)CCMSH exhibited MC1-R selective binding and rapid tumor uptake in B16/F1 melanoma bearing mice that was confirmed by PET imaging studies. High specific activity 62Cu from a 62Zn/62Cu generator coupled with simple one step radiolabeling procedures makes 62Cu an attractive radionuclide for PET imaging of low-density receptor targets.
Neuronal activity in the dorsal hippocampus after lateral hypothalamus stimulation: effects of delta-sleep-inducing peptide.
Bull Exp Biol Med
O S Grigorchuk, P E Umriukhin
We studied central effects of delta-sleep-inducing peptide in the mechanisms of positive emotional state formation in rats. In Wistar rats preliminary tested in an open field, the reactions of 57 neurons of the dorsal hippocampus were analyzed during lateral hypothalamus stimulation and microionophoretic application of delta-sleep-inducing peptide. It was found that the number of neurons not responding to stimulation in the lateral hypothalamus surpassed the number of sensitive neurons (63 and 37%, respectively). Hippocampal neurons in active animals were less sensitive to stimulation of the lateral hypothalamus than in passive rats (33 vs. 42%) After application of delta-sleep-inducing peptide, only 28% neurons responded to stimulation. Thus, delta-sleep-inducing peptide reduced the sensitivity of hippocampal neurons to stimulation of the lateral hypothalamus.
Mechano growth factor (MGF) promotes proliferation and inhibits differentiation of porcine satellite cells (PSCs) by down-regulation of key myogenic transcriptional factors.
Mol Cell Biochem
Li-Li Qin, Xiao-Kui Li, Jian Xu +8 more
Porcine satellite cells represent an ideal model system for studying the cellular and molecular basis regulating myogenic stem cell proliferation and differentiation and for exploring the experimental conditions for myoblast transplantation. Here, we investigated the effects of mechano growth factor (MGF), a spliced variant of the IGF-1 gene, on porcine satellite cells. We show that MGF potently stimulated proliferation while inhibited differentiation of porcine satellite cells. MGF-treatment acutely down-regulates the expression of myogenic determination factor (MyoD) and the cyclin-dependent kinase inhibitor p21. MGF-treatment also markedly reduced the overall expression of cyclin B1 and key factors of the myogenic regulatory and myocyte enhancer families, including Myogenein and MEF2A. Taken together, the gene expression data from MGF-treated porcine satellite cells are in favor of a molecular model in which MGF inhibits porcine satellite cell differentiation by down-regulating either the activity or expression of MyoD, which, in turn, suppresses the expression of key genes required for cell cycle progression and differentiation, such as p21, Myogenin, and MEF2. Overall, our findings are in support of the previous suggestion that MGF may be used in vivo and in vitro to promote proliferation of myogenic stem cells to prevent and treat age-related muscle degenerative diseases.
Melanotan II injection resulting in systemic toxicity and rhabdomyolysis.
Clin Toxicol (Phila)
Michael E Nelson, Sean M Bryant, Steven E Aks
Melanotan products are currently purchased over the Internet and are designed to induce melanogenesis to create sunless tanning as well are used as sexual stimulants. We report a novel case of systemic toxicity with sympathomimetic excess and rhabdomyolysis after use of Melanotan II.
[Expression of mechano-growth factor and its roles in tissue repairs and regeneration].
Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi
Bingyu Zhang, Guanbin Song, Qing Luo +1 more
To review the expression of mechano-growth factor (MGF) and its roles in tissue repairs and regeneration.
Ghrelin regulates the hypothalamic-pituitary-adrenal axis and restricts anxiety after acute stress.
Biol Psychiatry
Sarah J Spencer, Lu Xu, Melanie A Clarke +5 more
Ghrelin plays important roles in glucose metabolism, appetite, and body weight regulation, and recent evidence suggests ghrelin prevents excessive anxiety under conditions of chronic stress.
Somatostatin analogs and chimeric somatostatin-dopamine molecules differentially regulate human growth hormone and prolactin gene expression and secretion in vitro.
Mol Cell Endocrinol
Anna Gruszka, Michael D Culler, Shlomo Melmed
We tested effects of selective somatostatin receptor 2 (SST2) agonist BIM-23120, SST5 agonist BIM-23206 and chimeric somatostatin-dopamine molecules (SRIF/DA) BIM-23A760 and BIM-23A761 on GH and PRL secretion and gene expression in human GH/PRL-secreting pituitary tumors in vitro. In "responders" group BIM-23120 suppressed GH levels by 26±4%, BIM-23206 by 31±5%, BIM-23A760 by 23±4%, BIM-23A761 by 39±8% and D(2)-dopamine agonist BIM-53097 by 31±5%. Using real-time PCR we demonstrated that GH inhibition was not accompanied by decreased GH mRNA levels. PRL secretion was inhibited by BIM-23A760 (29±5%), BIM-23A761 (34±4%), BIM-23206 (26±4%) and BIM-53097 (36±2%). SRIF/DA and BIM-53097 also suppressed PRL mRNA levels. Concluding, SST2 and SST5 agonists and SRIF/DA inhibit GH secretion, but do not suppress GH gene transcription. SRIF/DA and BIM-53097 inhibit both PRL secretion and PRL gene expression. SST5 agonist inhibits PRL secretion, but does not suppress PRL gene expression. D(2) affinity is crucial in SRIF/DA action on PRL gene expression.