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First-in-class thyrotropin-releasing hormone (TRH)-based compound binds to a pharmacologically distinct TRH receptor subtype in human brain and is effective in neurodegenerative models.
Neuropharmacology
Julie A Kelly, Noreen T Boyle, Natalie Cole +21 more
JAK4D, a first-in-class thyrotropin-releasing hormone (TRH)-based compound, is a prospective therapeutic candidate offering a multifaceted approach to treating neurodegeneration and other CNS conditions. The purpose of these studies was to determine the ability of JAK4D to bind to TRH receptors in human brain and to evaluate its neuropharmacological effects in neurodegenerative animal models. Additionally, JAK4D brain permeation was examined in mouse, and initial toxicology was assessed in vivo and in vitro. We report that JAK4D bound selectively with nanomolar affinity to native TRH receptors in human hippocampal tissue and showed for the first time that these receptors are pharmacologically distinct from TRH receptors in human pituitary, thus revealing a new TRH receptor subtype which represents a promising neurotherapeutic target in human brain. Systemic administration of JAK4D elicited statistically significant and clinically-relevant neuroprotective effects in three established neurodegenerative animal models: JAK4D reduced cognitive deficits when administered post-insult in a kainate (KA)-induced rat model of neurodegeneration; it protected against free radical release and neuronal damage evoked by intrastriatal microdialysis of KA in rat; and it reduced motor decline, weight loss, and lumbar spinal cord neuronal loss in G93A-SOD1 transgenic Amyotrophic Lateral Sclerosis mice. Ability to cross the blood-brain barrier and a clean initial toxicology profile were also shown. In light of these findings, JAK4D is an important tool for investigating the hitherto-unidentified central TRH receptor subtype reported herein and an attractive therapeutic candidate for neurodegenerative disorders.
Neuroprotective effect of novel cognitive enhancer noopept on AD-related cellular model involves the attenuation of apoptosis and tau hyperphosphorylation.
J Biomed Sci
Rita U Ostrovskaya, Yulia V Vakhitova, Uliyana Sh Kuzmina +5 more
Noopept (N-phenyl-acetyl-L-prolylglycine ethyl ester) was constructed as a dipeptide analog of the standard cognition enhancer, piracetam. Our previous experiments have demonstrated the cognition restoring effect of noopept in several animal models of Alzheimer disease (AD). Noopept was also shown to prevent ionic disbalance, excitotoxicity, free radicals and pro-inflammatory cytokines accumulation, and neurotrophine deficit typical for different kinds of brain damages, including AD. In this study, we investigated the neuroprotective action of noopept on cellular model of AD, Aβ 25-35-induced toxicity in PC12 cells and revealed the underlying mechanisms.
The dwarf phenotype in GH240B mice, haploinsufficient for the autism candidate gene Neurobeachin, is caused by ectopic expression of recombinant human growth hormone.
PLoS One
Kim Nuytens, Krizia Tuand, Quili Fu +5 more
Two knockout mouse models for the autism candidate gene Neurobeachin (Nbea) have been generated independently. Although both models have similar phenotypes, one striking difference is the dwarf phenotype observed in the heterozygous configuration of the GH240B model that is generated by the serendipitous insertion of a promoterless human growth hormone (hGH) genomic fragment in the Nbea gene. In order to elucidate this discrepancy, the dwarfism present in this Nbea mouse model was investigated in detail. The growth deficiency in Nbea+/- mice coincided with an increased percentage of fat mass and a decrease in bone mineral density. Low but detectable levels of hGH were detected in the pituitary and hypothalamus of Nbea+/- mice but not in liver, hippocampus nor in serum. As a consequence, several members of the mouse growth hormone (mGH) signaling cascade showed altered mRNA levels, including a reduction in growth hormone-releasing hormone mRNA in the hypothalamus. Moreover, somatotrope cells were less numerous in the pituitary of Nbea+/- mice and both contained and secreted significantly less mGH resulting in reduced levels of circulating insulin-like growth factor 1. These findings demonstrate that the random integration of the hGH transgene in this mouse model has not only inactivated Nbea but has also resulted in the tissue-specific expression of hGH causing a negative feedback loop, mGH hyposecretion and dwarfism.
Effect of delta sleep-inducing peptide on the expression of antioxidant enzyme genes in the brain and blood of rats during physiological aging.
Bull Exp Biol Med
D S Kutilin, T I Bondarenko, I V Kornienko +1 more
Subcutaneous injections of exogenous delta sleep-inducing peptide in a dose of 100 μg/kg (monthly, 5-day courses) to rats of various age groups (2-24 months) were followed by an increase in the expression of genes for SOD 1 (Sod1) and glutathione peroxidase 1 (Gpx1) in the brain and nucleated blood cells. The expression of these genes was shown to decrease during physiological aging of the body.
Effects of growth hormone administration for 6 months on bone turnover and bone marrow fat in obese premenopausal women.
Bone
Miriam A Bredella, Anu V Gerweck, Lauren A Barber +4 more
Abdominal adiposity is associated with low BMD and decreased growth hormone (GH) secretion, an important regulator of bone homeostasis. The purpose of our study was to determine the effects of a short course of GH on markers of bone turnover and bone marrow fat in premenopausal women with abdominal adiposity.
Cell death and tissue reorganization in Rhynchosciara americana (Sciaridae: Diptera) metamorphosis and their relation to molting hormone titers.
Arthropod Struct Dev
Amanda Dos Santos Brandão, Jônatas Bussador do Amaral, Paula Rezende-Teixeira +3 more
Programmed cell death (PCD) is a focal topic for understanding processes underlying metamorphosis in insects, especially so in holometabolous orders. During adult morphogenesis it allows for the elimination of larva-specific tissues and the reorganization of others for their functionalities in adult life. In Rhynchosciara, this PCD process could be classified as autophagic cell death, yet the expression of apoptosis-related genes and certain morphological aspects suggest that processes, autophagy and apoptosis may be involved. Aiming to reveal the morphological changes that salivary gland and fat body cells undergo during metamorphosis we conducted microscopy analyses to detect chromatin condensation and fragmentation, as well as alterations in the cytoplasm of late pupal tissues of Rhynchosciara americana. Transmission electron microscopy and confocal microscopy revealed cells in variable stages of death. By analyzing the morphological structure of the salivary gland we observed the presence of cells with autophagic vacuoles and apoptotic bodies and DNA fragmentation was confirmed with the TUNEL assay in salivary gland. The reorganization of fat body occurs with discrete detection of cell death by TUNEL assay. However, both salivary gland histolysis and fat body reorganization occur under control of the hormone ecdysone.
Alpha-melanocyte stimulating hormone: an emerging anti-inflammatory antimicrobial peptide.
Biomed Res Int
Madhuri Singh, Kasturi Mukhopadhyay
The alpha-melanocyte stimulating hormone (α-MSH) is a neuropeptide belonging to the melanocortin family. It is well known for its anti-inflammatory and antipyretic effects and shares several characteristics with antimicrobial peptides (AMPs). There have been some recent reports about the direct antimicrobial activity of α-MSH against various microbes belonging to both fungal and bacterial pathogens. Similar to α-MSH's anti-inflammatory properties, its C-terminal residues also exhibit antimicrobial activity parallel to that of the entire peptide. This review is focused on the current findings regarding the direct antimicrobial potential and immunomodulatory mechanism of α-MSH and its C-terminal fragments, with particular emphasis on the prospects of α-MSH based peptides as a strong anti-infective agent.
[Role of functional state of neuronal mitochondria of cerebral cortex in mechanisms of nootropic activity of neuroprotectors in rats with alloxan hyperglycemia].
Eksp Klin Farmakol
V I Zhiliuk, V I Mamchur, S V Pavlov
The influence of citicoline, phenylpiracetam, pentoxifylline and N-phenylacetyl-L-prolylglycine on cognitive processes and functional state of mitochondria in the neocortex of alloxan-diabetic rats has been studied. The drug effects on cognitive processes were assessed using passive avoidance tests in the dark-light camera. Latent period and the number of animals with amnesia skill on 6th and 20th days of drug administration were recorded. Functional status of mitochondria was assessed by mitochondrial pore opening and mitochondrial transmembrane potential (Y) on 20th day. It has been established that course administration of phenylpiracetam, citicoline and to a lesser extent N-phenylacetyl-L-prolylglycine, but not pentoxifylline, improves the processes of learning and storing conditional skill. At the same time, the nootropic activity of studied drugs was comparable to their effect on the functional state of mitochondria in neocortical neurons in rats with chronic hyperglycemia. According to mitoprotective activity (prevention of opening of mitochondrial cyclosporin-A-sensitive pores and restoration of mitochondrial transmembrane potential), the maximum potential was observed for citicoline and phenylpiracetam, and the minimum--for pentoxifylline. The results point out the importance of mitoprotective properties in nootropic effects of studied drugs.
Diversity and clonal selection in the human T-cell repertoire.
Proc Natl Acad Sci U S A
Qian Qi, Yi Liu, Yong Cheng +7 more
T-cell receptor (TCR) diversity, a prerequisite for immune system recognition of the universe of foreign antigens, is generated in the first two decades of life in the thymus and then persists to an unknown extent through life via homeostatic proliferation of naïve T cells. We have used next-generation sequencing and nonparametric statistical analysis to estimate a lower bound for the total number of different TCR beta (TCRB) sequences in human repertoires. We arrived at surprisingly high minimal estimates of 100 million unique TCRB sequences in naïve CD4 and CD8 T-cell repertoires of young adults. Naïve repertoire richness modestly declined two- to fivefold in healthy elderly. Repertoire richness contraction with age was even less pronounced for memory CD4 and CD8 T cells. In contrast, age had a major impact on the inequality of clonal sizes, as estimated by a modified Gini-Simpson index clonality score. In particular, large naïve T-cell clones that were distinct from memory clones were found in the repertoires of elderly individuals, indicating uneven homeostatic proliferation without development of a memory cell phenotype. Our results suggest that a highly diverse repertoire is maintained despite thymic involution; however, peripheral fitness selection of T cells leads to repertoire perturbations that can influence the immune response in the elderly.
Introduction of the human AVPR1A gene substantially alters brain receptor expression patterns and enhances aspects of social behavior in transgenic mice.
Dis Model Mech
Rhonda Charles, Takeshi Sakurai, Nagahide Takahashi +4 more
Central arginine vasopressin receptor 1A (AVPR1A) modulates a wide range of behaviors, including stress management and territorial aggression, as well as social bonding and recognition. Inter- and intra-species variations in the expression pattern of AVPR1A in the brain and downstream differential behavioral phenotypes have been attributed to differences in the non-coding regions of the AVPR1A gene, including polymorphic elements within upstream regulatory areas. Gene association studies have suggested a link between AVPR1A polymorphisms and autism, and AVPR1A has emerged as a potential pharmacological target for treatment of social cognitive impairments and mood and anxiety disorders. To further investigate the genetic mechanism giving rise to species differences in AVPR1A expression patterns and associated social behaviors, and to create a preclinical mouse model useful for screening drugs targeting AVPR1A, we engineered and extensively characterized bacterial artificial chromosome (BAC) transgenic mice harboring the entire human AVPR1A locus with the surrounding regulatory elements. Compared with wild-type animals, the humanized mice displayed a more widely distributed ligand-AVPR1A binding pattern, which overlapped with that of primates. Furthermore, humanized AVPR1A mice displayed increased reciprocal social interactions compared with wild-type animals, but no differences in social approach and preference for social novelty were observed. Aspects of learning and memory, specifically novel object recognition and spatial relocation recognition, were unaffected. The biological alterations in humanized AVPR1A mice resulted in the rescue of the prepulse inhibition impairments that were observed in knockout mice, indicating conserved functionality. Although further behavioral paradigms and additional cohorts need to be examined in humanized AVPR1A mice, the results demonstrate that species-specific variations in the genomic content of regulatory regions surrounding the AVPR1A locus are responsible for differential receptor protein expression patterns across species and that they are likely to contribute to species-specific behavioral variation. The humanized AVPR1A mouse is a potential preclinical model for further understanding the regulation of receptor gene expression and the impact of variation in receptor expression on behaviors, and should be useful for screening drugs targeting human AVPR1A, taking advantage of the expression of human AVPR1A in human-relevant brain regions.
Delta-sleep inducing peptide entrapment in the charged macroporous matrices.
Mater Sci Eng C Mater Biol Appl
Tatiana V Sukhanova, Alexander A Artyukhov, Yakov M Gurevich +4 more
Various biomolecules, for example proteins, peptides etc., entrapped in polymer matrices, impact interactions between matrix and cells, including stimulation of cell adhesion and proliferation. Delta-sleep inducing peptide (DSIP) possesses numerous beneficial properties, including its abilities in burn treatment and neuronal protection. DSIP entrapment in two macroporous polymer matrices based on copolymer of dimethylaminoethyl methacrylate and methylen-bis-acrylamide (Co-DMAEMA-MBAA) and copolymer of acrylic acid and methylen-bis-acrylamide (Co-AA-MBAA) has been studied. Quite 100% of DSIP has been entrapped into positively charged Co-DMAEMA-MBAA matrix, while the quantity of DSIP adsorbed on negatively charged Co-AA-MBAA was only 2-6%. DSIP release from Co-DMAEMA-MBAA was observed in saline solutions (0.9% NaCl and PBS) while there was no DSIP release in water or 25% ethanol, thus ionic strength was a reason of this process.
The influence of deltalycyn and transcranial cerebellar stimulation upon recovery of retina after photo stress in patients with diabetic retinopathy.
Rev Med Chir Soc Med Nat Iasi
Nataliya Valentinivna Kresyun
The characteristics of visual evoked potentials (VEP) have been studied in diabetic patients with and without diabetic retinopathy.
Identification of thyrotropin-releasing hormone as hippocampal glutaminyl cyclase substrate in neurons and reactive astrocytes.
Biochim Biophys Acta
Alexander Waniek, Maike Hartlage-Rübsamen, Corinna Höfling +4 more
Recently, Aβ peptide variants with an N-terminal truncation and pyroglutamate modification were identified and shown to be highly neurotoxic and prone to aggregation. This modification of Aβ is catalyzed by glutaminyl cyclase (QC) and pharmacological inhibition of QC diminishes Aβ deposition and accompanying gliosis and ameliorates memory impairment in transgenic mouse models of Alzheimer's disease (AD). QC expression was initially described in the hypothalamus, where thyrotropin-releasing hormone (TRH) is one of its physiological substrates. In addition to its hormonal role, a novel neuroprotective function of TRH following excitotoxicity and Aβ-mediated neurotoxicity has been reported in the hippocampus. Functionally matching this finding, we recently demonstrated QC expression by hippocampal interneurons in mouse brain. Here, we detected neuronal co-expression of QC and TRH in the hippocampus of young adult wild type mice using double immunofluorescence labeling. This provides evidence for TRH being a physiological QC substrate in hippocampus. Additionally, in neocortex of aged but not of young mice transgenic for amyloid precursor protein an increase of QC mRNA levels was found compared to wild type littermates. This phenomenon was not observed in hippocampus, which is later affected by Aβ pathology. However, in hippocampus of transgenic - but not of wild type mice - a correlation between QC and TRH mRNA levels was revealed. This co-regulation of the enzyme QC and its substrate TRH was reflected by a co-induction of both proteins in reactive astrocytes in proximity of Aβ deposits. Also, in primary mouse astrocytes a co-induction of QC and TRH was demonstrated upon Aβ stimulation.
Continuous infusion of substance P into rat striatum alleviates nociceptive behavior via phosphorylation of extracellular signal-regulated kinase 1/2.
J Neurochem
Yoki Nakamura, Hiroki Izumi, Ryo Fukushige +6 more
Intraplantar injection of 0.4% formalin into the rat hind paw leads to a biphasic nociceptive response; an 'acute' phase (0-15 min) and 'tonic' phase (16-120 min), which is accompanied by significant phosphorylation of extracellular signal-regulated kinase (ERK)1/2 in the contralateral striatum at 120 min post-formalin injection. To uncover a possible relationship between the slow-onset substance P (SP) release and increased ERK1/2 phosphorylation in the striatum, continuous infusion of SP into the striatum by reverse microdialysis (0.4 μg/mL in microdialysis fiber, 1 μL/min) was performed to mimic volume neurotransmission of SP. Continuous infusion for 3 h of SP reduced the duration of 'tonic' phase nociception, and this SP effect was mediated by neurokinin 1 (NK1) receptors since pre-treatment with NK1 receptor antagonist CP96345 (10 μM) blocked the effect of SP infusion. However, formalin-induced 'tonic' phase nociception was significantly prolonged following acute injection of the MAP/ERK kinase 1/2 inhibitor PD0325901 (100 pmol) by microinjection. The coinfusion of SP and PD0325901 significantly increased the 'tonic' phase of nociception. These data demonstrate that volume transmission of striatal SP triggered by peripheral nociceptive stimulation does not lead to pain facilitation but a significant decrease of tonic nociception by the activation of the SP-NK1 receptor-ERK1/2 system. Noxious stimulation induces a slow-onset substance P (SP) release as a volume transmitter, activating extra-synaptic NK1 receptors, and evokes phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. The SP-NK1-ERK1/2 system in the striatum decreases tonic nociception.
Efficacy of peptide anxiolytic selank during modeling of withdrawal syndrome in rats with stable alcoholic motivation.
Bull Exp Biol Med
L G Kolik, A V Nadorova, M M Kozlovskaya
We studied the effects of selank on the development of symptoms of acute 48-h alcohol withdrawal in outbred rats drinking 10 % ethanol as the only source of fluid for 24 weeks. In alcohol-preferring animals (mean daily ethanol intake >5.0 g/kg) allowed free choice between 10 % ethanol and water, single intraperitoneal injection of selank in a dose of 0.3 mg/kg eliminated anxiety induced by ethanol withdrawal in tests elevated plus maze and social interaction tests and prevented the formation of mechanical allodynia without affecting ethanol consumption. The fi ndings suggest that selank is effective in eliminating of alcohol withdrawal symptoms in rats.
Short peptides stimulate serotonin expression in cells of brain cortex.
Bull Exp Biol Med
V Kh Khavinson, N S Lin'kova, S I Tarnovskaya +3 more
Peptides Glu-Asp-Arg and Lys-Glu-Asp stimulate serotonin expression in aging cultures of brain cortex cells. Peptide regulation of 5-tryptophan hydroxylase gene encoding the enzyme involved in serotonin synthesis was demonstrated by the molecular docking method. The CCTGCC nucleotide sequence in 5-tryptophan hydroxylase gene was found to be complementary to these peptides. Hence, Glu-Asp-Arg and Lys-Glu-Asp peptides epigenetically regulate serotonin synthesis in the brain cortex, which indicates their neuro- and geroprotective activities.
Actions of NPY, and its Y1 and Y2 receptors on pulsatile growth hormone secretion during the fed and fasted state.
J Neurosci
Lili Huang, Hwee Y Tan, Matthew J Fogarty +5 more
The hypothalamic NPY system plays an important role in regulating food intake and energy expenditure. Different biological actions of NPY are assigned to NPY receptor subtypes. Recent studies demonstrated a close relationship between food intake and growth hormone (GH) secretion; however, the mechanism through which endogenous NPY modulates GH release remains unknown. Moreover, conclusive evidence demonstrating a role for NPY and Y-receptors in regulating the endogenous pulsatile release of GH does not exist. We used genetically modified mice (germline Npy, Y1, and Y2 receptor knock-out mice) to assess pulsatile GH secretion under both fed and fasting conditions. Deletion of NPY did not impact fed GH release; however, it reversed the fasting-induced suppression of pulsatile GH secretion. The recovery of GH secretion was associated with a reduction in hypothalamic somatotropin release inhibiting factor (Srif; somatostatin) mRNA expression. Moreover, observations revealed a differential role for Y1 and Y2 receptors, wherein the postsynaptic Y1 receptor suppresses GH secretion in fasting. In contrast, the presynaptic Y2 receptor maintains normal GH output under long-term ad libitum-fed conditions. These data demonstrate an integrated neural circuit that modulates GH release relative to food intake, and provide essential information to address the differential roles of Y1 and Y2 receptors in regulating the release of GH under fed and fasting states.
An in-depth case examination of an exotic dancer's experience of melanotan.
Int J Drug Policy
Marie Claire Van Hout, Rebekah Brennan
Cultural values placed on tanned skin equating with perceived health and attractiveness in the Western world have stimulated the development, sale and use of synthetic tanning agents. These agents are synthetic analogues of the naturally occurring melanocyte-stimulating hormones (α-MSHs) which stimulate melanogenesis or pigmentation of the skin. There is a lack of research on prevalence of use, user experiences and outcomes, despite evident 'health marketability' and diffusion of use via the Internet.
Long-term efficacy and safety of pegvisomant in combination with long-acting somatostatin analogs in acromegaly.
J Clin Endocrinol Metab
S J C M M Neggers, S E Franck, F W M de Rooij +8 more
Treatment for acromegaly patients with long-acting somatotropin release-inhibiting factor (LA-SRIF) often does not result in complete normalization of IGF-1. Addition of pegvisomant (PEGV), a GH receptor antagonist, could improve this; however, the literature has not described long-term follow-up.
Associations between insulin resistance, free fatty acids, and oocyte quality in polycystic ovary syndrome during in vitro fertilization.
J Clin Endocrinol Metab
Zhihong Niu, Nan Lin, Ruihuan Gu +2 more
Both polycystic ovary syndrome (PCOS) and obesity are associated with specific reproductive health complications, including lower oocyte quality and clinical pregnancy rates in assisted conception cycles, which may be a result of metabolism-induced changes in the oocyte through the microenvironment of follicular fluid. Free fatty acids (FFAs) are important biomedical indicators of abnormal lipid metabolism and have pronounced effects on cells, leading to changes in metabolism, cell growth, and differentiation.