The melanocortin system regulates body pigmentation and social behaviour in a colour polymorphic cichlid fish†

PubMed Central

Maguire, Sean M.; Harris, Rayna M.; Rodriguez, Agosto A.; DeAngelis, Ross S.; Flores, Stephanie A.; Hofmann, Hans A.

2017-01-01

The melanocortin system is a neuroendocrine system that regulates a range of physiological and behavioural processes. We examined the extent to which the melanocortin system simultaneously regulates colour and behaviour in the cichlid fish Astatotilapia burtoni. We found that yellow males are more aggressive than blue males, in line with previous studies. We then found that exogenous α-melanocyte-stimulating hormone (α-MSH) increases yellowness of the body and dispersal of xanthophore pigments in both morphs. However, α-MSH had a morph-specific effect on aggression, with only blue males showing an increase in the rate of aggression. Exogenous agouti signalling peptide (ASIP), a melanocortin antagonist, did not affect coloration but reduced the rate of aggression in both colour morphs. Blue males had higher cortisol levels than yellow males. Neural gene expression of melanocortin receptors (mcr) and ligands was not differentially regulated between colour morphs. In the skin, however, mc1r and pro-opiomelanocortin (pomc) β were upregulated in blue males, while asip 1 was upregulated in yellow males. The effects of α-MSH on behaviour and body coloration, combined with morph-specific regulation of the stress response and the melanocortin system, suggest that the melanocortin system contributes to the polymorphism in behaviour and coloration in A. burtoni. PMID:28356453

Discovery of Mixed Pharmacology Melanocortin-3 Agonists and Melanocortin-4 Receptor Tetrapeptide Antagonist Compounds (TACOs) Based on the Sequence Ac-Xaa1-Arg-(pI)DPhe-Xaa4-NH2.

PubMed

Doering, Skye R; Freeman, Katie T; Schnell, Sathya M; Haslach, Erica M; Dirain, Marvin; Debevec, Ginamarie; Geer, Phaedra; Santos, Radleigh G; Giulianotti, Marc A; Pinilla, Clemencia; Appel, Jon R; Speth, Robert C; Houghten, Richard A; Haskell-Luevano, Carrie

2017-05-25

The centrally expressed melanocortin-3 and -4 receptors (MC3R/MC4R) have been studied as possible targets for weight management therapies, with a preponderance of studies focusing on the MC4R. Herein, a novel tetrapeptide scaffold [Ac-Xaa 1 -Arg-(pI)DPhe-Xaa 4 -NH 2 ] is reported. The scaffold was derived from results obtained from a MC3R mixture-based positional scanning campaign. From these results, a set of 48 tetrapeptides were designed and pharmacologically characterized at the mouse melanocortin-1, -3, -4, and -5 receptors. This resulted in the serendipitous discovery of nine compounds that were MC3R agonists (EC 50 < 1000 nM) and MC4R antagonists (5.7 < pA 2 < 7.8). The three most potent MC3R agonists, 18 [Ac-Arg-Arg-(pI)DPhe-Tic-NH 2 ], 1 [Ac-His-Arg-(pI)DPhe-Tic-NH 2 ], and 41 [Ac-Arg-Arg-(pI)DPhe-DNal(2')-NH 2 ] were more potent (EC 50 < 73 nM) than the melanocortin tetrapeptide Ac-His-DPhe-Arg-Trp-NH 2 . This template contains a sequentially reversed "Arg-(pI)DPhe" motif with respect to the classical "Phe-Arg" melanocortin signaling motif, which results in pharmacology that is first-in-class for the central melanocortin receptors.

Inflamed phenotype of the mesenteric microcirculation of melanocortin type 3 receptor-null mice after ischemia-reperfusion

PubMed Central

Leoni, Giovanna; Patel, Hetal B.; Sampaio, André L. F.; Gavins, Felicity N. E.; Murray, Joanne F.; Grieco, Paolo; Getting, Stephen J.; Perretti, Mauro

2008-01-01

The existence of anti-inflammatory circuits centered on melanocortin receptors (MCRs) has been supported by the inhibitory properties displayed by melanocortin peptides in models of inflammation and tissue injury. Here we addressed the pathophysiological effect that one MCR, MCR type 3 (MC3R), might have on vascular inflammation. After occlusion (35 min) and reopening of the superior mesenteric artery, MC3R-null mice displayed a higher degree of plasma extravasation (45 min postreperfusion) and cell adhesion and emigration (90 min postreperfusion). These cellular alterations were complemented by higher expression of mesenteric tissue CCL2 and CXCL1 (mRNA and protein) and myeloperoxydase, as compared with wild-type animals. MC1R and MC3R mRNA and protein were both expressed in the inflamed mesenteric tissue; however, no changes in vascular responses were observed in a mouse colony bearing an inactive MC1R. Pharmacological treatment of animals with a selective MC3R agonist ([d-Trp8]-γ-melanocyte-stimulating hormone; 10 μg i.v.) produced marked attenuation of cell adhesion, emigration, and chemokine generation; such effects were absent in MC3R-null mice. These new data reveal the existence of a tonic inhibitory signal provided by MC3R in the mesenteric microcirculation of the mouse, acting to down-regulate cell trafficking and local mediator generation.—Leoni, G., Patel, H. B., Sampaio, A. L. F., Gavins, F. N. E., Murray, J. F., Grieco, P., Getting, S. J., Perretti, M. Inflamed phenotype of the mesenteric microcirculation of melanocortin type 3 receptor-null mice after ischemia-reperfusion. PMID:18757499

Structure-Activity Relationship Studies on a Macrocyclic Agouti-Related Protein (AGRP) Scaffold Reveal Agouti Signaling Protein (ASP) Residue Substitutions Maintain Melanocortin-4 Receptor Antagonist Potency and Result in Inverse Agonist Pharmacology at the Melanocortin-5 Receptor.

PubMed

Ericson, Mark D; Freeman, Katie T; Schnell, Sathya M; Fleming, Katlyn A; Haskell-Luevano, Carrie

2017-10-12

The melanocortin system consists of five reported receptors, agonists from the proopiomelanocortin gene transcript, and two antagonists, agouti-signaling protein (ASP) and agouti-related protein (AGRP). For both ASP and AGRP, the hypothesized Arg-Phe-Phe pharmacophores are on exposed β-hairpin loops. In this study, the Asn and Ala positions of a reported AGRP macrocyclic scaffold (c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-DPro]) were explored with 14-compound and 8-compound libraries, respectively, to generate more potent, selective melanocortin receptor antagonists. Substituting diaminopropionic acid (Dap), DDap, and His at the Asn position yielded potent MC4R ligands, while replacing Ala with Ser maintained MC4R potency. Since these substitutions correlate to ASP loop residues, an additional Phe to Ala substitution was synthesized and observed to maintain MC4R potency. Seventeen compounds also possessed inverse agonist activity at the MC5R, the first report of this pharmacology. These findings are useful in developing molecular probes to study negative energy balance conditions and unidentified functions of the MC5R.

Apolipoprotein A-IV interacts synergistically with melanocortins to reduce food intake.

PubMed

Gotoh, Koro; Liu, Min; Benoit, Stephen C; Clegg, Deborah J; Davidson, W Sean; D'Alessio, David; Seeley, Randy J; Tso, Patrick; Woods, Stephen C

2006-01-01

Apolipoprotein (apo) A-IV is an anorexigenic gastrointestinal peptide that is also synthesized in the hypothalamus. The goal of these experiments was to determine whether apo A-IV interacts with the central melanocortin (MC) system in the control of feeding. The third ventricular (i3vt) administration of a subthreshold dose of apo A-IV (0.5 microg) potentiated i3vt MC-induced (metallothionein-II, 0.03 nmol) suppression of 30-min feeding in Long-Evans rats. A subthreshold dose of the MC antagonist (SHU9119, 0.1 nmol, i3vt) completely attenuated the anorectic effect of i3vt apo A-IV (1.5 microg). The i3vt apo A-IV significantly elevated the expression of c-Fos in neurons of the paraventricular nucleus of the hypothalamus, but not in the arcuate nucleus or median eminence. In addition, c-Fos expression was not colocalized with proopiomelanocortin-positive neurons. These data support a synergistic interaction between apo A-IV and melanocortins that reduces food intake by acting downstream of the arcuate.

Melanocortin MC1 receptor in human genetics and model systems

PubMed Central

Beaumont, Kimberley A.; Wong, Shu S.; Ainger, Stephen A.; Liu, Yan Yan; Patel, Mira P.; Millhauser, Glenn L.; Smith, Jennifer J.; Alewood, Paul F.; Leonard, J. Helen; Sturm, Richard A.

2011-01-01

The melanocortin MC1 receptor is a G -protein coupled receptor expressed in melanocytes of the skin and hair and is known for its key role in regulation of human pigmentation. Melanocortin MC1 receptor activation after ultraviolet radiation exposure results in a switch from the red/yellow pheomelanin to the brown/black eumelanin pigment synthesis within cutaneous melanocytes; this pigment is then transferred to the surrounding keratinocytes of the skin. The increase in melanin maturation and uptake results in tanning of the skin, providing a physical protection of skin cells from ultraviolet radiation induced DNA damage. Melanocortin MC 1 receptor polymorphism is widespread within the Caucasian population and some variant alleles are associated with red hair colour, fair skin, poor tanning and increased risk of skin cancer. Here we will discuss the use of mouse coat colour models, human genetic association studies, and in vitro cell culture studies to determine the complex functions of the melanocortin MC1 receptor and the molecular mechanisms underlying the association between melanocortin MC1 receptor variant alleles and the red hair colour phenotype. Recent research indicates that melanocortin MC1 receptor has many non-pigmentary functions, and that the increased risk of skin cancer conferred by melanocortin MC1 receptor variant alleles is to some extent independent of pigmentation phenotypes. The use of new transgenic mouse models, the study of novel melanocortin MC1 receptor response genes and the use of more advanced human skin models such as 3D skin reconstruction may provide key elements in understanding the pharmacogenetics of human melanocortin MC1 receptor polymorphism . PMID:21199646

Pulse transducer with artifact signal attenuator. [heart rate sensors

NASA Technical Reports Server (NTRS)

Cash, W. H., Jr.; Polhemus, J. T. (Inventor)

1980-01-01

An artifact signal attenuator for a pulse rate sensor is described. The circuit for attenuating background noise signals is connected with a pulse rate transducer which has a light source and a detector for light reflected from blood vessels of a living body. The heart signal provided consists of a modulated dc signal voltage indicative of pulse rate. The artifact signal resulting from light reflected from the skin of the body comprises both a constant dc signal voltage and a modulated dc signal voltage. The amplitude of the artifact signal is greater and the frequency less than that of the heart signal. The signal attenuator circuit includes an operational amplifier for canceling the artifact signal from the output signal of the transducer and has the capability of meeting packaging requirements for wrist-watch-size packages.

1,2,3-Triazole Rings as a Disulfide Bond Mimetic in Chimeric AGRP-Melanocortin Peptides: Design, Synthesis, and Functional Characterization.

PubMed

Tala, Srinivasa R; Singh, Anamika; Lensing, Cody J; Schnell, Sathya M; Freeman, Katie T; Rocca, James R; Haskell-Luevano, Carrie

2018-05-16

The melanocortin system is involved in the regulation of complex physiological functions, including energy and weight homeostasis, feeding behavior, inflammation, sexual function, pigmentation, and exocrine gland function. The five melanocortin receptors that belong to the superfamily of G protein-coupled receptors (GPCRs) are regulated by endogenously expressed agonists and antagonists. The aim of this study was to explore the potential of replacing the disulfide bridge in chimeric AGRP-melanocortin peptide Tyr-c[Cys-His-d-Phe-Arg-Trp-Asn-Ala-Phe-Cys]-Tyr-NH 2 (1) with 1,2,3-triazole moieties. A series of 1,2,3-triazole-bridged peptidomimetics were designed, synthesized, and pharmacologically evaluated at the mouse melanocortin receptors. The ligands possessed nanomolar to micromolar agonist cAMP signaling potency. A key finding was that the disulfide bond in peptide 1 can be replaced with the monotriazole ring with minimal effect on the functional activity at the melanocortin receptors. The 1,5-disubstituted triazole-bridged peptide 6 showed equipotent functional activity at the mMC3R and modest 5-fold decreased agonist potency at the mMC4R compared to those of 1. Interestingly, the 1,4- and 1,5-disubstituted isomers of the triazole ring resulted in different selectivities at the receptor subtypes, indicating subtle structural features that may be exploited in the generation of selective melanocortin ligands. Introducing cyclic and acyclic bis-triazole moieties into chimeric AGRP template 1 generally decreased agonist activity. These results will be useful for the further design of neuronal chemical probes for the melanocortin receptors as well as in other receptor systems.

Multiple melanocortin receptors are expressed in bone cells

NASA Technical Reports Server (NTRS)

Zhong, Qing; Sridhar, Supriya; Ruan, Ling; Ding, Ke-Hong; Xie, Ding; Insogna, Karl; Kang, Baolin; Xu, Jianrui; Bollag, Roni J.; Isales, Carlos M.

2005-01-01

Melanocortin receptors belong to the seven transmembrane domain, G-protein coupled family of receptors. There are five members of this receptor family labeled MC1R-MC5R. These receptors are activated by fragments derived from a larger molecule, proopiomelanocortin (POMC) and include ACTH, alpha beta and gamma-MSH and beta-endorphin. Because of in vitro and in vivo data suggesting direct effects of these POMC molecules on bone and bone turnover, we examined bone and bone derived cells for the presence of the various members of the melanocortin receptor family. We report that the five known melanocortin receptors are expressed to varying degrees in osteoblast-like and osteoclastic cells. POMC fragments increased proliferation and expression of a variety of genes in osteoblastic cells. Furthermore, POMC mRNA was detected in osteoclastic cells. These data demonstrate that POMC-derived peptide hormones acting through high affinity melanocortin receptors have specific effects on bone cells. Thus, in addition to the indirect effects of POMC-derived hormones on bone turnover through their modulation of steroid hormone secretion, POMC fragments may have direct and specific effects on bone cell subpopulations.

Chimeric NDP-MSH and MTII melanocortin peptides with agouti-related protein (AGRP) Arg-Phe-Phe amino acids possess agonist melanocortin receptor activity.

PubMed

Joseph, Christine G; Wilczynski, Andrzej; Holder, Jerry R; Xiang, Zhimin; Bauzo, Rayna M; Scott, Joseph W; Haskell-Luevano, Carrie

2003-12-01

Agouti-related protein (AGRP) is one of only two known endogenous antagonists of G-protein coupled receptors (GPCRs). Specifically, AGRP antagonizes the brain melanocortin-3 and -4 receptors involved in energy homeostasis, regulation of feeding behavior, and obesity. Alpha-melanocyte stimulating hormone (alpha-MSH) is one of the known endogenous agonists for these receptors. It has been hypothesized that the Arg-Phe-Phe (111-113) human AGRP amino acids may be mimicking the melanocortin agonist Phe-Arg-Trp (7-9) residue interactions with the melanocortin receptors that are important for both receptor molecular recognition and stimulation. To test this hypothesis, we generated thirteen chimeric peptide ligands based upon the melanocortin agonist peptides NDP-MSH (Ac-Ser-Tyr-Ser-Nle4-Glu-His-DPhe-Arg-Trp-Gly-Lys-Pro-Val-NH2) and MTII (Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH2). In these chimeric ligands, the agonist DPhe-Arg-Trp amino acids were replaced by the AGRP Arg-Phe-Phe residues, and resulted in agonist activity at the mouse melanocortin receptors (mMC1R and mMC3-5Rs), supporting the hypothesis that the AGRP antagonist ligand Arg-Phe-Phe residues mimic the agonist Phe-Arg-Trp amino acids. Interestingly, the Ac-Ser-Tyr-Ser-Nle4-Glu-His-Arg-DPhe-Phe-Gly-Lys-Pro-Val-NH2 peptide possessed 7 nM mMC1R agonist potency, and is 850-fold selective for the mMC1R versus the mMC3R, 2300-fold selective for the mMC1R versus the mMC4R, and 60-fold selective for the MC1R versus the mMC5R, resulting in the discovery of a new peptide template for the design of melanocortin receptor selective ligands.

An in vitro and in vivo investigation of bivalent ligands that display preferential binding and functional activity for different melanocortin receptor homodimers

PubMed Central

Lensing, Cody J.; Freeman, Katie T.; Schnell, Sathya M.; Adank, Danielle N.; Speth, Robert C.; Haskell-Luevano, Carrie

2017-01-01

Pharmacological probes for the melanocortin receptors have been utilized for studying various disease states including cancer, sexual function disorders, Alzheimer's disease, social disorders, cachexia, and obesity. This study focused on the design and synthesis of bivalent ligands to target melanocortin receptor homodimers. Lead ligands increased binding affinity by 14- to 25-fold and increased cAMP signaling potency by 3- to 5-fold compared to their monovalent counterparts. Unexpectedly, different bivalent ligands showed preferences for particular melanocortin receptor subtypes depending on the linker that connected the binding scaffolds suggesting structural differences between the various dimer subtypes. Homobivalent compound 12 (CJL-1-140) possessed a functional profile that was unique from its monovalent counterparts providing evidence of the discrete effects of bivalent ligands. Lead compound 7 (CJL-1-87) significantly decreased feeding in mice after intracerebroventricular administration. To the best of our knowledge, this is the first report of a melanocortin bivalent ligand's in vivo physiological effects. PMID:26959173

Role of G protein-coupled receptor kinases in the homologous desensitization of the human and mouse melanocortin 1 receptors.

PubMed

Sánchez-Más, Jesús; Guillo, Lidia A; Zanna, Paola; Jiménez-Cervantes, Celia; García-Borrón, José C

2005-04-01

The melanocortin 1 receptor, a G protein-coupled receptor positively coupled to adenylyl cyclase, is a key regulator of epidermal melanocyte proliferation and differentiation and a determinant of human skin phototype and skin cancer risk. Despite its potential importance for regulation of pigmentation, no information is available on homologous desensitization of this receptor. We found that the human melanocortin 1 receptor (MC1R) and its mouse ortholog (Mc1r) undergo homologous desensitization in melanoma cells. Desensitization is not dependent on protein kinase A, protein kinase C, calcium mobilization, or MAPKs, but is agonist dose-dependent. Both melanoma cells and normal melanocytes express two members of the G protein-coupled receptor kinase (GRK) family, GRK2 and GRK6. Cotransfection of the receptor and GRK2 or GRK6 genes in heterologous cells demonstrated that GRK2 and GRK6 impair agonist-dependent signaling by MC1R or Mc1r. However, GRK6, but not GRK2, was able to inhibit MC1R agonist-independent constitutive signaling. Expression of a dominant negative GRK2 mutant in melanoma cells increased their cAMP response to agonists. Agonist-stimulated cAMP production decreased in melanoma cells enriched with GRK6 after stable transfection. Therefore, GRK2 and GRK6 seem to be key regulators of melanocortin 1 receptor signaling and may be important determinants of skin pigmentation.

Biphasic Effect of Melanocortin Agonists on Metabolic Rate and Body Temperature

PubMed Central

Lute, Beth; Jou, William; Lateef, Dalya M.; Goldgof, Margalit; Xiao, Cuiying; Piñol, Ramón A.; Kravitz, Alexxai V.; Miller, Nicole R.; Huang, Yuning George; Girardet, Clemence; Butler, Andrew A.; Gavrilova, Oksana; Reitman, Marc L.

2014-01-01

Summary The melanocortin system regulates metabolic homeostasis and inflammation. Melanocortin agonists have contradictorily been reported to both increase and decrease metabolic rate and body temperature. We find two distinct physiologic responses occurring at similar doses. Intraperitoneal administration of the nonselective melanocortin agonist MTII causes a melanocortin-4 receptor (Mc4r) mediated hypermetabolism/hyperthermia. This is preceded by a profound, transient hypometabolism/hypothermia that is preserved in mice lacking any one of Mc1r, Mc3r, Mc4r, or Mc5r. Three other melanocortin agonists also caused hypothermia, which is actively achieved via seeking a cool environment, vasodilation, and inhibition of brown adipose tissue thermogenesis. These results suggest that the hypometabolic/hypothermic effect of MTII is not due to a failure of thermoregulation. The hypometabolism/hypothermia was prevented by dopamine antagonists and MTII selectively activated arcuate nucleus dopaminergic neurons; these neurons may contribute to the hypometabolism/hypothermia. We propose that the hypometabolism/hypothermia is a regulated response, potentially beneficial during extreme physiologic stress. PMID:24981835

The Role of the Melanocortin System in Metabolic Disease: New Developments and Advances.

PubMed

Hill, Jennifer W; Faulkner, Latrice D

2017-01-01

Obesity is increasing in prevalence across all sectors of society, and with it a constellation of associated ailments including hypertension, type 2 diabetes, and eating disorders. The melanocortin system is a critical neural system underlying the control of body weight and other functions. Deficits in the melanocortin system may promote or exacerbate the comorbidities of obesity. This system has therefore generated great interest as a potential target for treatment of obesity. However, drugs targeting melanocortin receptors are plagued by problematic side effects, including undesirable increases in sympathetic nervous system activity, heart rate, and blood pressure. Circumnavigating this roadblock will require a clearer picture of the precise neural circuits that mediate the functions of melanocortins. Recent, novel experimental approaches have significantly advanced our understanding of these pathways. We here review the latest advances in our understanding of the role of melanocortins in food intake, reward pathways, blood pressure, glucose control, and energy expenditure. The evidence suggests that downstream melanocortin-responsive circuits responsible for different physiological actions do diverge. Ultimately, a more complete understanding of melanocortin pathways and their myriad roles should allow treatments tailored to the mix of metabolic disorders in the individual patient. © 2016 The Author(s) Published by S. Karger AG, Basel.

Neuroanatomy of melanocortin-4 receptor pathway in the lateral hypothalamic area.

PubMed

Cui, Huxing; Sohn, Jong-Woo; Gautron, Laurent; Funahashi, Hisayuki; Williams, Kevin W; Elmquist, Joel K; Lutter, Michael

2012-12-15

The central melanocortin system regulates body energy homeostasis including the melanocortin-4 receptor (MC4R). The lateral hypothalamic area (LHA) receives dense melanocortinergic inputs from the arcuate nucleus of the hypothalamus and regulates multiple processes including food intake, reward behaviors, and autonomic function. By using a mouse line in which green fluorescent protein (GFP) is expressed under control of the MC4R gene promoter, we systemically investigated MC4R signaling in the LHA by combining double immunohistochemistry, electrophysiology, and retrograde tracing techniques. We found that LHA MC4R-GFP neurons coexpress neurotensin as well as the leptin receptor but do not coexpress other peptide neurotransmitters found in the LHA including orexin, melanin-concentrating hormone, and nesfatin-1. Furthermore, electrophysiological recording demonstrated that leptin, but not the MC4R agonist melanotan II, hyperpolarizes the majority of LHA MC4R-GFP neurons in an ATP- sensitive potassium channel-dependent manner. Retrograde tracing revealed that LHA MC4R-GFP neurons do not project to the ventral tegmental area, dorsal raphe nucleus, nucleus accumbens, and spinal cord, and only limited number of neurons project to the nucleus of the solitary tract and parabrachial nucleus. Our findings provide new insights into MC4R signaling in the LHA and its potential implications in homeostatic regulation of body energy balance. Copyright © 2012 Wiley Periodicals, Inc.

Neuroanatomy of melanocortin-4 receptor pathway in the lateral hypothalamic area

PubMed Central

Cui, Huxing; Sohn, Jong-Woo; Gautron, Laurent; Funahashi, Hisayuki; Williams, Kevin W.; Elmquist, Joel K.; Lutter, Michael

2013-01-01

The central melanocortin system regulates body energy homeostasis including the melanocortin-4 receptor (MC4R). The lateral hypothalamic area (LHA) receives dense melanocortinergic inputs from the arcuate nucleus of hypothalamus and regulates multiple processes including food intake, reward behaviors and autonomic function. Using a mouse line in which green fluorescent protein (GFP) is expressed under control of MC4R gene promoter, we systemically investigated MC4R signaling in the LHA by combining double immunohistochemistry, electrophysiology and retrograde tracing techniques. We found that LHA MC4R-GFP neurons co-express neurotensin as well as the leptin receptor but not with other peptide neurotransmitters found in the LHA including orexin, melanin concentrating hormone and nesfatin-1. Furthermore, electrophysiological recording demonstrated that leptin, but not the MC4R agonist melanotan II, hyperpolarizes the majority of LHA MC4R-GFP neurons in an ATP-sensitive potassium channel-dependent manner. Retrograde tracing revealed that LHA MC4R-GFP neurons do not project to the ventral tegmental area, dorsal raphe nucleus, nucleus accumbens and spinal cord, and only limited number of neurons project to the nucleus of solitary tract and parabrachial nucleus. Our findings provide new insight into MC4R signaling in the LHA and its potential implication in homeostatic regulation of body energy balance. PMID:22605619

Structure-activity relationships of the melanocortin tetrapeptide Ac-His-DPhe-Arg-Trp-NH(2) at the mouse melanocortin receptors: part 2 modifications at the Phe position.

PubMed

Holder, Jerry Ryan; Bauzo, Rayna M; Xiang, Zhimin; Haskell-Luevano, Carrie

2002-07-04

The melanocortin pathway is an important participant in skin pigmentation, steroidogenesis, obesity, energy homeostasis and exocrine gland function. The centrally located melanocortin-3 and melanocortin-4 receptors (MC3R, MC4R) are involved in the metabolic and food intake aspects of energy homeostasis and are stimulated by melanocortin agonists such as alpha-melanocyte stimulation hormone (alpha-MSH). The melanocortin agonists contain the putative message sequence "His-Phe-Arg-Trp," and it has been well-documented that inversion of chirality of the Phe to DPhe results in a dramatic increase in melanocortin receptor potency. Herein, we report a tetrapeptide library, based upon the template Ac-His-DPhe-Arg-Trp-NH(2), consisting of 26 members that have been modified at the DPhe(7) position (alpha-MSH numbering) and pharmacologically characterized for agonist and antagonist activity at the mouse melanocortin receptors MC1R, MC3R, MC4R, and MC5R. The most notable results of this study include the identification of the tetrapeptide Ac-His-(pI)DPhe-Arg-Trp-NH(2) that is a full nanomolar agonist at the mMC1 and mMC5 receptors, a mMC3R partial agonist with potent antagonist activity (pA(2) = 7.25, K(i) = 56 nM) and, but unexpectedly, is a potent agonist at the mMC4R (EC(50) = 25 nM). This ligand possesses novel melanocortin receptor pharmacology, as compared to previously reported peptides, and is potentially useful for in vivo studies to differentiate MC3R vs MC4R physiological roles in animal models, such as primates, where "knockout" animals are not viable options. The DNal(2') substitution for DPhe resulted in a mMC3R partial agonist with antagonist activity (pA(2) = 6.5, K(i) = 295 nM) and a mMC4R (pA(2) = 7.8, K(i) = 17 nM) antagonist possessing 60- and 425-fold decreased potency, respectively, as compared with SHU9119 at these receptors. Examination of this DNal(2')-containing tetrapeptide at the F254S and F259S mutant mMC4Rs resulted in agonist activity of this m

Ventromedial hypothalamic melanocortin receptor activation: regulation of activity energy expenditure and skeletal muscle thermogenesis.

PubMed

Gavini, Chaitanya K; Jones, William C; Novak, Colleen M

2016-09-15

The ventromedial hypothalamus (VMH) and the central melanocortin system both play vital roles in regulating energy balance by modulating energy intake and utilization. Recent evidence suggests that activation of the VMH alters skeletal muscle metabolism. We show that intra-VMH melanocortin receptor activation increases energy expenditure and physical activity, switches fuel utilization to fats, and lowers work efficiency such that excess calories are dissipated by skeletal muscle as heat. We also show that intra-VMH melanocortin receptor activation increases sympathetic nervous system outflow to skeletal muscle. Intra-VMH melanocortin receptor activation also induced significant changes in the expression of mediators of energy expenditure in muscle. These results support the role of melanocortin receptors in the VMH in the modulation of skeletal muscle metabolism. The ventromedial hypothalamus (VMH) and the brain melanocortin system both play vital roles in increasing energy expenditure (EE) and physical activity, decreasing appetite and modulating sympathetic nervous system (SNS) outflow. Because of recent evidence showing that VMH activation modulates skeletal muscle metabolism, we propose the existence of an axis between the VMH and skeletal muscle, modulated by brain melanocortins, modelled on the brain control of brown adipose tissue. Activation of melanocortin receptors in the VMH of rats using a non-specific agonist melanotan II (MTII), compared to vehicle, increased oxygen consumption and EE and decreased the respiratory exchange ratio. Intra-VMH MTII enhanced activity-related EE even when activity levels were held constant. MTII treatment increased gastrocnemius muscle heat dissipation during controlled activity, as well as in the home cage. Compared to vehicle-treated rats, rats with intra-VMH melanocortin receptor activation had higher skeletal muscle norepinephrine turnover, indicating an increased SNS drive to muscle. Lastly, intra-VMH MTII induced m

Structure-activity relationships of the melanocortin tetrapeptide Ac-His-DPhe-Arg-Trp-NH(2) at the mouse melanocortin receptors. 1. Modifications at the His position.

PubMed

Holder, Jerry Ryan; Bauzo, Rayna M; Xiang, Zhimin; Haskell-Luevano, Carrie

2002-06-20

The melanocortin pathway is an important participant in obesity and energy homeostasis. The centrally located melanocortin-3 and melanocortin-4 receptors (MC3R, MC4R) are involved in the metabolic and food intake aspects of energy homeostasis and are stimulated by melanocortin agonists such as alpha-melanocyte stimulation hormone (alpha-MSH). The melanocortin agonists contain the putative message sequence "His-Phe-Arg-Trp", and it has been well documented that inversion of chirality of the Phe to DPhe results in a dramatic increase in melanocortin receptor potency. Herein, we report a tetrapeptide library based on the template Ac-His-DPhe-Arg-Trp-NH(2), consisting of 17 members that have been modified at the His(6) position (alpha-MSH numbering) and pharmacologically characterized for agonist activity at the mouse melanocortin receptors MC1R, MC3R, MC4R, and MC5R. These studies provide further experimental evidence that the His(6) position can determine MC4R versus MC3R agonist selectivity and that chemically nonreactive side chains may be substituted for the imidazole ring (generally needs to be side chain protected in synthetic schemes) in the design of MC4R-selective, small-molecule, non-peptide agonists. Specifically, the tetrapeptide containing the amino-2-naphthylcarboxylic acid (Anc) amino acid at the His position resulted in a potent agonist at the mMC4R (EC(50) = 21 nM), was a weak mMC3R micromolar antagonist (pA(2) = 5.6, K(i) = 2.5 microM), and possessed >4700-fold agonist selectivity for the MC4R versus the MC3R. Substitution of the His(6) amino acid in the tetrapeptide template by the Phe, Anc, 3-(2-thienyl)alanine (2Thi), and 3-(4-pyridinyl)alanine (4-Pal) resulted in equipotency or only up to a 7-fold decrease in potency, compared to the His(6)-containing tetrapeptide at the mMC4R, demonstrating that these amino acid side chains may be substituted for the imidazole in the design of MC4R-selective non-peptide molecules.

MRAP2 regulates ghrelin receptor signaling and hunger sensing.

PubMed

Srisai, Dollada; Yin, Terry C; Lee, Abigail A; Rouault, Alix A J; Pearson, Nicole A; Grobe, Justin L; Sebag, Julien A

2017-09-28

Ghrelin is the only known circulating orexigenic hormone. It is primarily secreted by the stomach and acts at its receptor, the growth hormone secretagogue receptor 1a (GHSR1a), in the hypothalamus to signal hunger and promote food intake. The melanocortin receptor accessory protein 2 (MRAP2) was previously shown to regulate energy homeostasis through the modulation of the activity of the melanocortin-4 receptor and prokineticin receptors. In this study we identify MRAP2 as a partner of ghrelin-GHSR1a signaling. We show that MRAP2 interacts with GHSR1a and potentiates ghrelin-stimulated signaling both in vitro and in vivo. We demonstrate that in the absence of MRAP2, fasting fails to activate agouti-related protein neurons. In addition, we show that the orexigenic effect of ghrelin is lost in mice lacking MRAP2. Our results suggest that MRAP2 is an important modulator of the energy homeostasis machinery that operates through the regulation of multiple GPCRs throughout the hypothalamus.Melanocortin receptor accessory protein 2 (MRAP2) is an adaptor protein that contributes to melanocortin-4 receptor and prokineticin receptor 1 signalling. Here the authors show that MRAP2 also regulates ghrelin receptor signalling in the hypothalamus and starvation sensing in mice.

The Brain Melanocortin System, Sympathetic Control, and Obesity Hypertension

PubMed Central

do Carmo, Jussara M.; Wang, Zhen; Hall, John E.

2014-01-01

Excess weight gain is the most significant, preventable cause of increased blood pressure (BP) in patients with primary (essential) hypertension and increases the risk for cardiovascular and renal diseases. In this review, we discuss the role of the brain melanocortin system in causing increased sympathetic activity in obesity and other forms of hypertension. In addition, we highlight potential mechanisms by which the brain melanocortin system modulates metabolic and cardiovascular functions. PMID:24789984

Melanocortin 1 receptor genotype: an important determinant of the damage response of melanocytes to ultraviolet radiation

PubMed Central

Kadekaro, Ana Luisa; Leachman, Sancy; Kavanagh, Renny J.; Swope, Viki; Cassidy, Pamela; Supp, Dorothy; Sartor, Maureen; Schwemberger, Sandy; Babcock, George; Wakamatsu, Kazumasa; Ito, Shosuke; Koshoffer, Amy; Boissy, Raymond E.; Manga, Prashiela; Sturm, Richard A.; Abdel-Malek, Zalfa A.

2010-01-01

The melanocortin 1 receptor gene is a main determinant of human pigmentation, and a melanoma susceptibility gene, because its variants that are strongly associated with red hair color increase melanoma risk. To test experimentally the association between melanocortin 1 receptor genotype and melanoma susceptibility, we compared the responses of primary human melanocyte cultures naturally expressing different melanocortin 1 receptor variants to α-melanocortin and ultraviolet radiation. We found that expression of 2 red hair variants abolished the response to α-melanocortin and its photoprotective effects, evidenced by lack of functional coupling of the receptor, and absence of reduction in ultraviolet radiation-induced hydrogen peroxide generation or enhancement of repair of DNA photoproducts, respectively. These variants had different heterozygous effects on receptor function. Microarray data confirmed the observed differences in responses of melanocytes with functional vs. nonfunctional receptor to α-melanocortin and ultraviolet radiation, and identified DNA repair and antioxidant genes that are modulated by α-melanocortin. Our findings highlight the molecular mechanisms by which the melanocortin 1 receptor genotype controls genomic stability of and the mutagenic effect of ultraviolet radiation on human melanocytes.—Kadekaro, A. L., Leachman, S., Kavanagh, R. J., Swope, V., Cassidy, P., Supp, D., Sartor, M., Schwemberger, S., Babcock, G., Wakamatsu, K., Ito, S., Koshoffer, A., Boissy, R. E., Manga, P., Sturm, R. A., Abdel-Malek, Z. A. Melanocortin 1 receptor genotype: an important determinant of the damage response of melanocytes to ultraviolet radiation. PMID:20519635

Signal Attenuation Curve for Different Surface Detector Arrays

NASA Astrophysics Data System (ADS)

Vicha, J.; Travnicek, P.; Nosek, D.; Ebr, J.

2014-06-01

Modern cosmic ray experiments consisting of large array of particle detectors measure the signals of electromagnetic or muon components or their combination. The correction for an amount of atmosphere passed is applied to the surface detector signal before its conversion to the shower energy. Either Monte Carlo based approach assuming certain composition of primaries or indirect estimation using real data and assuming isotropy of arrival directions can be used. Toy surface arrays of different sensitivities to electromagnetic and muon components are assumed in MC simulations to study effects imposed on attenuation curves for varying composition or possible high energy anisotropy. The possible sensitivity of the attenuation curve to the mass composition is also tested for different array types focusing on a future apparatus that can separate muon and electromagnetic component signals.

Energy gradients for VT-signal migration in the CNS: studies on melanocortin receptors, mitochondrial uncoupling proteins and food intake.

PubMed

Agnati, L F; Vergoni, A V; Leo, G; Genedani, S; Franco, R; Bertolini, A; Fuxe, K

2004-01-01

The present paper enlightens a new point of view on brain homeostasis and communication, namely how the brain takes advantage of different chemical-physical phenomena such as pressure waves, and temperature and concentration gradients to allow the homeostasis of the brain internal milieu as well as some forms of intercellular communications (volume transmission, VT) at an energy cost much lower than the classical synaptic transmission (the prototype of wiring transmission, WT). The possible melanocortin control of uncoupling protein 2 (UCP2) expression (hence of local brain temperature gradients) has been studied in relation to food intake in male Wistar rats. Osmotic minipumps were subcutaneously (sc) implanted in the midscapular region for intracerebroventricular (icv) infusion. The control rats received an icv infusion of 0.5 microl/h of artificial cerebrospinal fluid (ACSF), while experimental rats received either an icv infusion of 0.16 nmol/h of HS024 or of 0.16 nmol/h of adrenocorticotropin-(1-24) [ACTH-(1-24)]. The ACTH-treated group ate significantly less than the ACSF-treated group during the first three days of infusion, while, subsequently, food intake of the two groups was similar. On the other hand, the HS024-treated group ate significantly more (up to 153% of the control value) than ACSF- and ACTH-treated rats during the entire period. UCP2 mRNA analysis in arcuate nuclei of ACTH, HS024 and ACSF-treated animals showed a significant 75% decrease (p<0.05 vs saline) of the total specific mRNA level in the HS024-treated group vs ACSF-treated animals (control group), while no significant change was observed between ACTH- and ACSF-treated animals. Melanocortin antagonist HS024 via blockade of MCR4 increases food intake and via a reduction of UCP2 expression enhances the food consumption ratio. This result underlines the fact that UCP2 expression and food intake can be differentially regulated. In other words, via a peptidergic control the central nervous

Melanocortin 3 Receptor Has a 5′ Exon That Directs Translation of Apically Localized Protein From the Second In-Frame ATG

PubMed Central

Park, Jeenah; Sharma, Neeraj

2014-01-01

Melanocortin-3 receptor (MC3R) is a canonical MSH receptor that plays an essential role in energy homeostasis. Variants in MC3R have been implicated in obesity in humans and mice. However, interpretation of the functional consequences of these variants is challenging because the translational start site of MC3R is unclear. Using 5′ rapid amplification of cDNA ends, we discovered a novel upstream exon that extends the length of the 5′ untranslated region (UTR) in MC3R without changing the open-reading frame. The full-length 5′ UTR directs utilization of an evolutionarily conserved second in-frame ATG as the primary translation start site. MC3R synthesized from the second ATG is localized to apical membranes of polarized Madin-Darby canine kidney cells, consistent with its function as a cell surface mediator of melanocortin signaling. Expression of MC3R causes relocalization of melanocortin receptor accessory protein 2, an accessory factor for melanocortin-2 receptor, to the apical membrane, coincident with the location of MC3R. In contrast, protein synthesized from MC3R cDNAs lacking the 5′ UTR displayed diffuse cytosolic distribution and has no effect on the distribution of melanocortin receptor accessory protein 2. Our findings demonstrate that a previously unannotated 5′ exon directs translation of MC3R protein that localizes to apical membranes of polarized cells. Together, our work provides insight on the structure of human MC3R and reveals a new pathway for regulation of energy metabolism. PMID:25051171

Electrostatic Similarity Analysis of Human β-Defensin Binding in the Melanocortin System

PubMed Central

Nix, Matthew A.; Kaelin, Christopher B.; Palomino, Rafael; Miller, Jillian L.; Barsh, Gregory S.; Millhauser, Glenn L.

2015-01-01

Summary The β-defensins are a class of small cationic proteins that serve as components of numerous systems in vertebrate biology, including the immune and melanocortin systems. Human β-defensin 3 (HBD3), which is produced in the skin, has been found to bind to melanocortin receptors 1 and 4 through complementary electrostatics, a unique mechanism of ligand-receptor interaction. This finding indicates that electrostatics alone, and not specific amino acid contact points, could be sufficient for function in this ligand-receptor system, and further suggests that other small peptide ligands could interact with these receptors in a similar fashion. Here, we conducted molecular-similarity analyses and functional studies of additional members of the human β-defensin family, examining their potential as ligands of melanocortin-1 receptor, through selection based on their electrostatic similarity to HBD3. Using Poisson-Boltzmann electrostatic calculations and molecular-similarity analysis, we identified members of the human β-defensin family that are both similar and dissimilar to HBD3 in terms of electrostatic potential. Synthesis and functional testing of a subset of these β-defensins showed that peptides with an HBD3-like electrostatic character bound to melanocortin receptors with high affinity, whereas those that were anticorrelated to HBD3 showed no binding affinity. These findings expand on the central role of electrostatics in the control of this ligand-receptor system and further demonstrate the utility of employing molecular-similarity analysis. Additionally, we identified several new potential ligands of melanocortin-1 receptor, which may have implications for our understanding of the role defensins play in melanocortin physiology. PMID:26536271

Characterization of a novel binding partner of the melanocortin-4 receptor: attractin-like protein.

PubMed Central

Haqq, Andrea M; René, Patricia; Kishi, Toshiro; Khong, Kathy; Lee, Charlotte E; Liu, Hongyan; Friedman, Jeffrey M; Elmquist, Joel K; Cone, Roger D

2003-01-01

The gene dosage effect of the MC4-R (melanocortin 4 receptor) on obesity suggests that regulation of MC4-R expression and function is critically important to the central control of energy homoeostasis. In order to identify putative MC4-R regulatory proteins, we performed a yeast two-hybrid screen of a mouse brain cDNA library using the mouse MC4-R intracellular tail (residues 303-332) as bait. We report here on one positive clone that shares 63% amino acid identity with the C-terminal part of the mouse attractin gene product, a single-transmembrane-domain protein characterized as being required for agouti signalling through the melanocortin 1 receptor. We confirmed a direct interaction between this ALP (attractin-like protein) and the C-terminus of the mouse MC4-R by glutathione S-transferase pulldown experiments, and mapped the regions involved in this interaction using N- and C-terminal truncation constructs; residues 303-313 in MC4-R and residues 1280-1317 in ALP are required for binding. ALP is highly expressed in brain, but also in heart, lung, kidney and liver. Furthermore, co-localization analyses in mice showed co-expression of ALP in cells expressing MC4-R in a number of regions known to be important in the regulation of energy homoeostasis by melanocortins, such as the paraventricular nucleus of hypothalamus and the dorsal motor nucleus of the vagus. PMID:14531729

Melanocortin 3 Receptor Signaling in Midbrain Dopamine Neurons Increases the Motivation for Food Reward.

PubMed

Pandit, Rahul; Omrani, Azar; Luijendijk, Mieneke C M; de Vrind, Véronne A J; Van Rozen, Andrea J; Ophuis, Ralph J A Oude; Garner, Keith; Kallo, Imre; Ghanem, Alexander; Liposits, Zsolt; Conzelmann, Karl-Klaus; Vanderschuren, Louk J M J; la Fleur, Susanne E; Adan, Roger A H

2016-08-01

The central melanocortin (MC) system mediates its effects on food intake via MC3 (MC3R) and MC4 receptors (MC4R). Although the role of MC4R in meal size determination, satiation, food preference, and motivation is well established, the involvement of MC3R in the modulation of food intake has been less explored. Here, we investigated the role of MC3R on the incentive motivation for food, which is a crucial component of feeding behavior. Dopaminergic neurons within the ventral tegmental area (VTA) have a crucial role in the motivation for food. We here report that MC3Rs are expressed on VTA dopaminergic neurons and that pro-opiomelanocortinergic (POMC) neurons in the arcuate nucleus of the hypothalamus (Arc) innervate these VTA dopaminergic neurons. Our findings show that intracerebroventricular or intra-VTA infusion of the selective MC3R agonist γMSH increases responding for sucrose under a progressive ratio schedule of reinforcement, but not free sucrose consumption in rats. Furthermore, ex vivo electrophysiological recordings show increased VTA dopaminergic neuronal activity upon γMSH application. Consistent with a dopamine-mediated effect of γMSH, the increased motivation for sucrose after intra-VTA infusion of γMSH was blocked by pretreatment with the dopamine receptor antagonist α-flupenthixol. Taken together, we demonstrate an Arc POMC projection onto VTA dopaminergic neurons that modulates motivation for palatable food via activation of MC3R signaling.

Entanglement sensitivity to signal attenuation and amplification

NASA Astrophysics Data System (ADS)

Filippov, Sergey N.; Ziman, Mário

2014-07-01

We analyze general laws of continuous-variable entanglement dynamics during the deterministic attenuation and amplification of the physical signal carrying the entanglement. These processes are inevitably accompanied by noises, so we find fundamental limitations on noise intensities that destroy entanglement of Gaussian and non-Gaussian input states. The phase-insensitive amplification Φ1⊗Φ2⊗⋯ΦN with the power gain κi≥2 (≈3 dB, i =1,...,N) is shown to destroy entanglement of any N-mode Gaussian state even in the case of quantum-limited performance. In contrast, we demonstrate non-Gaussian states with the energy of a few photons such that their entanglement survives within a wide range of noises beyond quantum-limited performance for any degree of attenuation or gain. We detect entanglement preservation properties of the channel Φ1⊗Φ2, where each mode is deterministically attenuated or amplified. Gaussian states of high energy are shown to be robust to very asymmetric attenuations, whereas non-Gaussian states are at an advantage in the case of symmetric attenuation and general amplification. If Φ1=Φ2, the total noise should not exceed 1/2√κ2+1 to guarantee entanglement preservation.

Hyperphagia in male melanocortin 4 receptor deficient mice promotes growth independently of growth hormone.

PubMed

Tan, H Y; Steyn, F J; Huang, L; Cowley, M; Veldhuis, J D; Chen, C

2016-12-15

Loss of function of the melanocortin 4 receptor (MC4R) results in hyperphagia, obesity and increased growth. Despite knowing that MC4Rs control food intake, we are yet to understand why defects in the function of the MC4R receptor contribute to rapid linear growth. We show that hyperphagia following germline loss of MC4R in male mice promotes growth while suppressing the growth hormone-insulin-like growth factor-1 (GH-IGF-1) axis. We propose that hyperinsulinaemia promotes growth while suppressing the GH-IGF-1 axis. It is argued that physiological responses essential to maintain energy flux override conventional mechanisms of pubertal growth to promote the storage of excess energy while ensuring growth. Defects in melanocortin-4-receptor (MC4R) signalling result in hyperphagia, obesity and increased growth. Clinical observations suggest that loss of MC4R function may enhance growth hormone (GH)-mediated growth, although this remains untested. Using male mice with germline loss of the MC4R, we assessed pulsatile GH release and insulin-like growth factor-1 (IGF-1) production and/or release relative to pubertal growth. We demonstrate early-onset suppression of GH release in rapidly growing MC4R deficient (MC4RKO) mice, confirming that increased linear growth in MC4RKO mice does not occur in response to enhanced activation of the GH-IGF-1 axis. The progressive suppression of GH release in MC4RKO mice occurred alongside increased adiposity and the progressive worsening of hyperphagia-associated hyperinsulinaemia. We next prevented hyperphagia in MC4RKO mice through restricting calorie intake in these mice to match that of wild-type (WT) littermates. Pair feeding of MC4RKO mice did not prevent increased adiposity, but attenuated hyperinsulinaemia, recovered GH release, and normalized linear growth rate to that seen in pair-fed WT littermate controls. We conclude that the suppression of GH release in MC4RKO mice occurs independently of increased adipose mass, and is a

Molecular biology and physiology of the melanocortin system in fish: a review.

PubMed

Metz, Juriaan R; Peters, Joris J M; Flik, Gert

2006-09-01

The melanocortin system consists of melanocortin peptides derived from the proopiomelanocortin gene (in particular adrenocorticotropic hormone, ACTH, and melanocyte-stimulating hormones, MSH) and five melanocortin receptor subtypes (MC1R-MC5R). Knowledge of the melanocortin system in fish is still limited, but information on the receptor part of the system is very rapidly growing. The melanocortin receptors (MCRs) have been recently cloned from several species of fish. The amino acid sequences appear remarkably well conserved. Pharmacological characterisation studies of the first identified piscine MCRs indicate that ACTH may be the original ligand for the MCRs, while the MSH peptides gained specialised functions in the course of evolution. Considering the tissue distribution of the MCRs, there are two distinctions between mammals and fish: where in mammals the MC4R is exclusively expressed in the central nervous system, in the fish species examined so far it is also peripherally expressed. It does however, alike the situation in mammals, likely play a key role in the central regulation of food intake and energy balance. Not only the MCRs, but also many other factors involved herewith, have been found in fish and roughly appear to function similarly as in mammals. The second difference is the distribution of the MC5R, which appears less widely expressed in fish than in mammals. Considering the available data it is predicted that, in mammals and fish alike, skin colouration is mediated via MC1R and steroidogenesis via MC2R. This review provides a short overview of the basic molecular characteristics, pharmacology, and tissue distribution of the MCRs in the fish investigated up to now, as well as their physiological role in the processes of skin colouration, steroidogenesis, and feeding behaviour.

Secure Communication via a Recycling of Attenuated Classical Signals

DOE Office of Scientific and Technical Information (OSTI.GOV)

Smith, IV, Amos M.

We describe a simple method of interleaving a classical and quantum signal in a secure communication system at a single wavelength. The system transmits data encrypted via a one-time pad on a classical signal and produces a single-photon reflection of the encrypted signal. This attenuated signal can be used to observe eavesdroppers and produce fresh secret bits. The system can be secured against eavesdroppers, detect simple tampering or classical bit errors, produces more secret bits than it consumes, and does not require any entanglement or complex wavelength division multiplexing, thus, making continuous secure two-way communication via one-time pads practical.

Secure Communication via a Recycling of Attenuated Classical Signals

DOE PAGES

Smith, IV, Amos M.

2017-01-12

We describe a simple method of interleaving a classical and quantum signal in a secure communication system at a single wavelength. The system transmits data encrypted via a one-time pad on a classical signal and produces a single-photon reflection of the encrypted signal. This attenuated signal can be used to observe eavesdroppers and produce fresh secret bits. The system can be secured against eavesdroppers, detect simple tampering or classical bit errors, produces more secret bits than it consumes, and does not require any entanglement or complex wavelength division multiplexing, thus, making continuous secure two-way communication via one-time pads practical.

General PFG signal attenuation expressions for anisotropic anomalous diffusion by modified-Bloch equations

NASA Astrophysics Data System (ADS)

Lin, Guoxing

2018-05-01

Anomalous diffusion exists widely in polymer and biological systems. Pulsed-field gradient (PFG) anomalous diffusion is complicated, especially in the anisotropic case where limited research has been reported. A general PFG signal attenuation expression, including the finite gradient pulse (FGPW) effect for free general anisotropic fractional diffusion { 0 < α , β ≤ 2 } based on the fractional derivative, has not been obtained, where α and β are time and space derivative orders. It is essential to derive a general PFG signal attenuation expression including the FGPW effect for PFG anisotropic anomalous diffusion research. In this paper, two recently developed modified-Bloch equations, the fractal differential modified-Bloch equation and the fractional integral modified-Bloch equation, were extended to obtain general PFG signal attenuation expressions for anisotropic anomalous diffusion. Various cases of PFG anisotropic anomalous diffusion were investigated, including coupled and uncoupled anisotropic anomalous diffusion. The continuous-time random walk (CTRW) simulation was also carried out to support the theoretical results. The theory and the CTRW simulation agree with each other. The obtained signal attenuation expressions and the three-dimensional fractional modified-Bloch equations are important for analyzing PFG anisotropic anomalous diffusion in NMR and MRI.

A serotonin and melanocortin circuit mediates D-fenfluramine anorexia.

PubMed

Xu, Yong; Jones, Juli E; Lauzon, Danielle A; Anderson, Jason G; Balthasar, Nina; Heisler, Lora K; Zinn, Andrew R; Lowell, Bradford B; Elmquist, Joel K

2010-11-03

D-Fenfluramine (D-Fen) increases serotonin (5-HT) content in the synaptic cleft and exerts anorexigenic effects in animals and humans. However, the neural circuits that mediate these effects are not fully identified. To address this issue, we assessed the efficacy of D-Fen-induced hypophagia in mouse models with manipulations of several genes in selective populations of neurons. Expectedly, we found that global deletion of 5-HT 2C receptors (5-HT(2C)Rs) significantly attenuated D-Fen-induced anorexia. These anorexigenic effects were restored in mice with 5-HT(2C)Rs expressed only in pro-opiomelanocortin (POMC) neurons. Further, we found that deletion of melanocortin 4 receptors (MC4Rs), a downstream target of POMC neurons, abolished anorexigenic effects of D-Fen. Reexpression of MC4Rs only in SIM1 neurons in the hypothalamic paraventricular nucleus and neurons in the amygdala was sufficient to restore the hypophagic property of D-Fen. Thus, our results identify a neurochemically defined neural circuit through which D-Fen influences appetite and thereby indicate that this 5-HT(2C)R/POMC-MC4R/SIM1 circuit may yield a more refined target to exploit for weight loss.

A Serotonin and Melanocortin Circuit Mediates d-Fenfluramine Anorexia

PubMed Central

Xu, Yong; Jones, Juli E.; Lauzon, Danielle A.; Anderson, Jason G.; Balthasar, Nina; Heisler, Lora K.; Zinn, Andrew R.; Lowell, Bradford B.; Elmquist, Joel K.

2012-01-01

d-Fenfluramine (d-Fen) increases serotonin (5-HT) content in the synaptic cleft and exerts anorexigenic effects in animals and humans. However, the neural circuits that mediate these effects are not fully identified. To address this issue, we assessed the efficacy of d-Fen-induced hypophagia in mouse models with manipulations of several genes in selective populations of neurons. Expectedly, we found that global deletion of 5-HT 2C receptors (5-HT2CRs) significantly attenuated d-Fen-induced anorexia. These anorexigenic effects were restored in mice with 5-HT2CRs expressed only in pro-opiomelanocortin (POMC) neurons. Further, we found that deletion of melanocortin 4 receptors (MC4Rs), a downstream target of POMC neurons, abolished anorexigenic effects of d-Fen. Reexpression of MC4Rs only in SIM1 neurons in the hypothalamic paraventricular nucleus and neurons in the amygdala was sufficient to restore the hypophagic property of d-Fen. Thus, our results identify a neurochemically defined neural circuit through which d-Fen influences appetite and thereby indicate that this 5-HT2CR/POMC-MC4R/SIM1 circuit may yield a more refined target to exploit for weight loss. PMID:21048120

Stereochemical studies of the monocyclic agouti-related protein (103-122) Arg-Phe-Phe residues: conversion of a melanocortin-4 receptor antagonist into an agonist and results in the discovery of a potent and selective melanocortin-1 agonist.

PubMed

Joseph, Christine G; Wang, Xiang S; Scott, Joseph W; Bauzo, Rayna M; Xiang, Zhimin; Richards, Nigel G; Haskell-Luevano, Carrie

2004-12-30

The agouti-related protein (AGRP) is an endogenous antagonist of the centrally expressed melanocortin receptors. The melanocortin-4 receptor (MC4R) is involved in energy homeostasis, food intake, sexual function, and obesity. The endogenous hAGRP protein is 132 amino acids in length, possesses five disulfide bridges at the C-terminus of the molecule, and is expressed in the hypothalamus of the brain. We have previously reported that a monocyclic hAGRP(103-122) peptide is an antagonist at the melanocortin receptors expressed in the brain. Stereochemical inversion from the endogenous l- to d-isomers of single or multiple amino acid modifications in this monocyclic truncated hAGRP sequence resulted in molecules that are converted from melanocortin receptor antagonists into melanocortin receptor agonists. The Asp-Pro-Ala-Ala-Thr-Ala-Tyr-cyclo[Cys-Arg-DPhe-DPhe-Asn-Ala-Phe-Cys]-Tyr-Ala-Arg-Lys-Leu peptide resulted in a 60 nM melanocortin-1 receptor agonist that is 100-fold selective versus the mMC4R, 1000-fold selective versus the mMC3R, and ca. 180-fold selective versus the mMC5R. In attempts to identify putative ligand-receptor interactions that may be participating in the agonist induced stimulation of the MC4R, selected ligands were docked into a homology molecular model of the mMC4R. These modeling studies have putatively identified hAGRP ligand DArg111-mMC4RAsn115 (TM3) and the hAGRP DPhe113-mMC4RPhe176 (TM4) interactions as important for agonist activity.

The role of the cholinergic system in the signal attenuation rat model of obsessive-compulsive disorder.

PubMed

Yankelevitch-Yahav, Roni; Roni, Yankelevitch-Yahav; Joel, Dapha; Daphna, Joel

2013-11-01

In comparison to studies of the involvement of the serotonergic, dopaminergic, and glutamatergic systems in the pathophysiology of obsessive-compulsive disorder (OCD), research on the involvement of the cholinergic system in this disorder has remained sparse. The aim of this study was to test the role of the cholinergic system in compulsive behavior using the signal attenuation rat model of OCD. In this model, "compulsive" behavior is induced by attenuating a signal indicating that a lever-press response was effective in producing food. The acetylcholinesterase inhibitor physostigmine (0.05, 0.10, and 0.15 mg/kg), the nicotinic agonist nicotine (0.03, 0.06, 0.10, 0.30, 0.60, and 1.00 mg/kg), the nicotinic antagonist mecamylamine (1, 3, 5, and 8 mg/kg), the muscarinic agonist oxotremorine (0.0075, 0.0150, and 0.0300 mg/kg), and the muscarinic antagonist scopolamine (0.15, 0.50, 1.00, and 1.50 mg/kg) were acutely administered to rats just before assessing their lever-press responding following signal attenuation (experiments 1, 3, 5, 7, and 9, respectively). Because the effects of signal attenuation are assessed under extinction conditions, drug doses that were effective in the above experiments were also tested in an extinction session of lever-press responding that was not preceded by signal attenuation (experiments 2, 4, 6, 8, and 10). Acute systemic administration of the cholinergic agents did not exert a selective anti- or pro-compulsive effect in the signal attenuation model. Acetylcholine does not seem to play a role in the signal attenuation rat model of OCD.

Melanocortin 1 Receptor Signaling Regulates Cholesterol Transport in Macrophages.

PubMed

Rinne, Petteri; Rami, Martina; Nuutinen, Salla; Santovito, Donato; van der Vorst, Emiel P C; Guillamat-Prats, Raquel; Lyytikäinen, Leo-Pekka; Raitoharju, Emma; Oksala, Niku; Ring, Larisa; Cai, Minying; Hruby, Victor J; Lehtimäki, Terho; Weber, Christian; Steffens, Sabine

2017-07-04

The melanocortin 1 receptor (MC1-R) is expressed by monocytes and macrophages, where it exerts anti-inflammatory actions on stimulation with its natural ligand α-melanocyte-stimulating hormone. The present study was designed to investigate the specific role of MC1-R in the context of atherosclerosis and possible regulatory pathways of MC1-R beyond anti-inflammation. Human and mouse atherosclerotic samples and primary mouse macrophages were used to study the regulatory functions of MC1-R. The impact of pharmacological MC1-R activation on atherosclerosis was assessed in apolipoprotein E-deficient mice. Characterization of human and mouse atherosclerotic plaques revealed that MC1-R expression localizes in lesional macrophages and is significantly associated with the ATP-binding cassette transporters ABCA1 and ABCG1, which are responsible for initiating reverse cholesterol transport. Using bone marrow-derived macrophages, we observed that α-melanocyte-stimulating hormone and selective MC1-R agonists similarly promoted cholesterol efflux, which is a counterregulatory mechanism against foam cell formation. Mechanistically, MC1-R activation upregulated the levels of ABCA1 and ABCG1. These effects were accompanied by a reduction in cell surface CD36 expression and in cholesterol uptake, further protecting macrophages from excessive lipid accumulation. Conversely, macrophages deficient in functional MC1-R displayed a phenotype with impaired efflux and enhanced uptake of cholesterol. Pharmacological targeting of MC1-R in atherosclerotic apolipoprotein E-deficient mice reduced plasma cholesterol levels and aortic CD36 expression and increased plaque ABCG1 expression and signs of plaque stability. Our findings identify a novel role for MC1-R in macrophage cholesterol transport. Activation of MC1-R confers protection against macrophage foam cell formation through a dual mechanism: It prevents cholesterol uptake while concomitantly promoting ABCA1- and ABCG1-mediated reverse

Functional characterization of the modified melanocortin peptides responsible for ligand selectivity at the human melanocortin receptors.

PubMed

Chen, Min; Georgeson, Keith E; Harmon, Carroll M; Haskell-Luevano, Carrie; Yang, Yingkui

2006-11-01

The melanocortin system plays an important role in energy homeostasis as well as skin pigmentation, steroidogenesis and exocrine gland function. In this study, we examined eight Ac-His-Phe-Arg-Trp-NH(2) tetrapeptides that were modified at the Phe position and pharmacologically characterized their activities at the human MCR wild-types and their mutants. Our results indicate that at the hMC1R, all D stereochemical modified residues at the Phe position of peptides increase cAMP production in a dose-dependent manner. At the hMC3R, the DPhe peptide dose dependently increases cAMP production but all other three tetrapeptides were not. At the hMC4R, both the DPhe and DNal(1') peptides induce cAMP production. However, both DTyr and DNal(2') were not able to induce cAMP production. Further studies indicated that at the hMC1R M128L mutant receptor, the all D-configured tetrapeptides reduce their potencies as compared to that of hMC1R wild-type. However, at the hMC3R and hMC4R L165M and L133M mutant receptors, the DNal(2') and DTyr tetrapeptides possess agonist activity. These findings indicate that DPhe in tetrapeptide plays an important role in ligand selectivity and specific residue TM3 of the melanocortin receptors is crucial for ligand selectivity.

DC attenuation meter

DOEpatents

Hargrove, Douglas L.

2004-09-14

A portable, hand-held meter used to measure direct current (DC) attenuation in low impedance electrical signal cables and signal attenuators. A DC voltage is applied to the signal input of the cable and feedback to the control circuit through the signal cable and attenuators. The control circuit adjusts the applied voltage to the cable until the feedback voltage equals the reference voltage. The "units" of applied voltage required at the cable input is the system attenuation value of the cable and attenuators, which makes this meter unique. The meter may be used to calibrate data signal cables, attenuators, and cable-attenuator assemblies.

Functional expression of Squalus acanthias melanocortin-5 receptor in CHO cells: ligand selectivity and interaction with MRAP.

PubMed

Reinick, Christina L; Liang, Liang; Angleson, Josepha K; Dores, Robert M

2012-04-05

The melanocortin-5 receptor (MC(5)) of the dogfish Squalus acanthias (SacMC(5) receptor) can be functionally expressed in CHO cells in the absence of the co-expression of an exogenous MRAP cDNA. Both human ACTH(1-24) and dogfish ACTH(1-25) were much better stimulators of the SacMC(5) receptor than any of the mammalian or dogfish MSH ligands that were tested. The order of ligand selectivity for the dogfish melanocortins was ACTH(1-25)>αMSH>γ-MSH=δ-MSH>β-MSH. Unlike mammalian MC(5) receptors, the functional expression of the SacMC(5) receptor was not negatively impacted when the receptor was co-expressed with a cartilaginous fish (Callorhinchus milii) MRAP2 cDNA. However, co-expression with either mouse mMRAP1 or zebrafish zfMRAP1 increased the sensitivity of SacMC(5) receptor for hACTH(1-24) by at least one order of magnitude. Hence, SacMC(5) receptor has the potential to interact with MRAP1 orthologs and in this regard behaved more like a melanocortin MC(2) receptor ortholog than a melanocortin MC(5) receptor ortholog. These observations are discussed in light of the evolution of the melanocortin receptor gene family in cartilaginous fish, and the physiological implications of these observations are considered. Copyright © 2012 Elsevier B.V. All rights reserved.

Comparative in Vivo Investigation of Intrathecal and Intracerebroventricular Administration with Melanocortin Ligands MTII and AGRP into Mice.

PubMed

Adank, Danielle N; Lunzer, Mary M; Lensing, Cody J; Wilber, Stacey L; Gancarz, Amy M; Haskell-Luevano, Carrie

2018-02-21

Central administration of melanocortin ligands has been used as a critical technique to study energy homeostasis. While intracerebroventricular (ICV) injection is the most commonly used method during these investigations, intrathecal (IT) injection can be equally efficacious for the central delivery of ligands. Importantly, intrathecal administration can optimize exploration of melanocortin receptors in the spinal cord. Herein, we investigate comparative IT and ICV administration of two melanocortin ligands, the synthetic MTII (Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH 2 ) MC4R agonist and agouti-related peptide [AGRP(87-132)] MC4R inverse agonist/antagonist, on the same batch of age-matched mice in TSE metabolic cages undergoing a nocturnal satiated paradigm. To our knowledge, this is the first study to test how central administration of these ligands directly to the spinal cord affects energy homeostasis. Results showed, as expected, that MTII IT administration caused a decrease in food and water intake and an overall negative energy balance without affecting activity. As anticipated, IT administration of AGRP caused weight gain, increase of food/water intake, and increase respiratory exchange ratio (RER). Unexpectantly, the prolonged activity of AGRP was notably shorter (2 days) compared to mice given ICV injections of the same concentrations in previous studies (7 days or more).1-4 It appears that IT administration results in a more sensitive response that may be a good approach for testing synthetic compound potency values ranging in nanomolar to high micromolar in vitro EC 50 values. Indeed, our investigation reveals that the spine influences a different melanocortin response compared to the brain for the AGRP ligand. This study indicates that IT administration can be a useful technique for future metabolic studies using melanocortin ligands and highlights the importance of exploring the role of melanocortin receptors in the spinal cord.

Brazilian Red Propolis Attenuates Inflammatory Signaling Cascade in LPS-Activated Macrophages

PubMed Central

Bueno-Silva, Bruno; Kawamoto, Dione; Ando-Suguimoto, Ellen S.; Alencar, Severino M.; Rosalen, Pedro L.; Mayer, Marcia P. A.

2015-01-01

Although previous studies suggested an anti-inflammatory property of Brazilian red propolis (BRP), the mechanisms involved in the anti-inflammatory effects of BRP and its activity on macrophages were still not elucidated. This study aimed to evaluate whether BRP attenuates the inflammatory effect of LPS on macrophages and to investigate its underlying mechanisms. BRP was added to RAW 264.7 murine macrophages after activation with LPS. NO production, cell viability, cytokines profile were evaluated. Activation of inflammatory signaling pathways and macrophage polarization were determined by RT-qPCR and Western blot. BRP at 50 μg/ml inhibited NO production by 78% without affecting cell viability. Cd80 and Cd86 were upregulated whereas mrc1 was down regulated by BRP indicating macrophage polarization at M1. BRP attenuated the production of pro-inflammatory mediators IL-12, GM-CSF, IFN-Ɣ, IL-1β in cell supernatants although levels of TNF- α and IL-6 were slightly increased after BRP treatment. Levels of IL-4, IL-10 and TGF-β were also reduced by BRP. BRP significantly reduced the up-regulation promoted by LPS of transcription of genes in inflammatory signaling (Pdk1, Pak1, Nfkb1, Mtcp1, Gsk3b, Fos and Elk1) and of Il1β and Il1f9 (fold-change rate > 5), which were further confirmed by the inhibition of NF-κB and MAPK signaling pathways. Furthermore, the upstream adaptor MyD88 adaptor-like (Mal), also known as TIRAP, involved in TLR2 and TLR4 signaling, was down- regulated in BRP treated LPS-activated macrophages. Given that BRP inhibited multiple signaling pathways in macrophages involved in the inflammatory process activated by LPS, our data indicated that BRP is a noteworthy food-source for the discovery of new bioactive compounds and a potential candidate to attenuate exhacerbated inflammatory diseases. PMID:26660901

Functions of transmembrane domain 3 of human melanocortin-4 receptor.

PubMed

Mo, Xiu-Lei; Yang, Rui; Tao, Ya-Xiong

2012-12-01

The melanocortin-4 receptor (MC4R) is a G protein-coupled receptor critical for maintaining energy homeostasis. Transmembrane domain 3 (TM3) of MC4R contains residues that were suggested to be essential in ligand binding and signaling. Several MC4R mutations in TM3 are associated with human obesity. To gain a better understanding of the functions of TM3, we analyzed the functions of 26 residues in TM3 using alanine-scanning mutagenesis. We showed that all mutants had normal cell-surface expression. Four mutants were defective in ligand binding and signaling and six mutants had normal ligand binding but impaired cAMP production. L140A had increased basal cAMP level. To further characterize the function of L140, we generated 17 additional L140 mutants. Fifteen L140 mutants had significantly decreased cell-surface expression, with L140R and L140V expressed normally. Ten L140 mutants had increased basal cAMP activities. Four L140 mutants were defective in ligand-stimulated cAMP generation. Interestingly, with the ERK1/2 pathway, we showed that nine constitutively active mutants had similar levels of basal pERK1/2 as that of WT, and two signaling defective mutants had similar levels of pERK1/2 as that of WT upon agonist stimulation, different from their cAMP signaling properties, suggesting biased signaling in these mutant receptors. In summary, we identified 13 residues in TM3 that were essential for ligand binding and/or signaling. Moreover, L140 was critical for locking MC4R in inactive conformation and several mutants showed biased signaling in cAMP and ERK1/2 signaling pathways.

Melanocortin 1 receptor-signaling deficiency results in an articular cartilage phenotype and accelerates pathogenesis of surgically induced murine osteoarthritis.

PubMed

Lorenz, Julia; Seebach, Elisabeth; Hackmayer, Gerit; Greth, Carina; Bauer, Richard J; Kleinschmidt, Kerstin; Bettenworth, Dominik; Böhm, Markus; Grifka, Joachim; Grässel, Susanne

2014-01-01

Proopiomelanocortin-derived peptides exert pleiotropic effects via binding to melanocortin receptors (MCR). MCR-subtypes have been detected in cartilage and bone and mediate an increasing number of effects in diathrodial joints. This study aims to determine the role of MC1-receptors (MC1) in joint physiology and pathogenesis of osteoarthritis (OA) using MC1-signaling deficient mice (Mc1re/e). OA was surgically induced in Mc1re/e and wild-type (WT) mice by transection of the medial meniscotibial ligament. Histomorphometry of Safranin O stained articular cartilage was performed with non-operated controls (11 weeks and 6 months) and 4/8 weeks past surgery. µCT-analysis for assessing epiphyseal bone architecture was performed as a longitudinal study at 4/8 weeks after OA-induction. Collagen II, ICAM-1 and MC1 expression was analysed by immunohistochemistry. Mc1re/e mice display less Safranin O and collagen II stained articular cartilage area compared to WT prior to OA-induction without signs of spontaneous cartilage surface erosion. This MC1-signaling deficiency related cartilage phenotype persisted in 6 month animals. At 4/8 weeks after OA-induction cartilage erosions were increased in Mc1re/e knees paralleled by weaker collagen II staining. Prior to OA-induction, Mc1re/e mice do not differ from WT with respect to bone parameters. During OA, Mc1re/e mice developed more osteophytes and had higher epiphyseal bone density and mass. Trabecular thickness was increased while concomitantly trabecular separation was decreased in Mc1re/e mice. Numbers of ICAM-positive chondrocytes were equal in non-operated 11 weeks Mc1re/e and WT whereas number of positive chondrocytes decreased during OA-progression. Unchallenged Mc1re/e mice display smaller articular cartilage covered area without OA-related surface erosions indicating that MC1-signaling is critical for proper cartilage matrix integrity and formation. When challenged with OA, Mc1re/e mice develop a more severe OA

Melanocortin 1 Receptor-Signaling Deficiency Results in an Articular Cartilage Phenotype and Accelerates Pathogenesis of Surgically Induced Murine Osteoarthritis

PubMed Central

Hackmayer, Gerit; Greth, Carina; Bauer, Richard J.; Kleinschmidt, Kerstin; Bettenworth, Dominik; Böhm, Markus; Grifka, Joachim; Grässel, Susanne

2014-01-01

Proopiomelanocortin-derived peptides exert pleiotropic effects via binding to melanocortin receptors (MCR). MCR-subtypes have been detected in cartilage and bone and mediate an increasing number of effects in diathrodial joints. This study aims to determine the role of MC1-receptors (MC1) in joint physiology and pathogenesis of osteoarthritis (OA) using MC1-signaling deficient mice (Mc1re/e). OA was surgically induced in Mc1re/e and wild-type (WT) mice by transection of the medial meniscotibial ligament. Histomorphometry of Safranin O stained articular cartilage was performed with non-operated controls (11 weeks and 6 months) and 4/8 weeks past surgery. µCT–analysis for assessing epiphyseal bone architecture was performed as a longitudinal study at 4/8 weeks after OA-induction. Collagen II, ICAM-1 and MC1 expression was analysed by immunohistochemistry. Mc1re/e mice display less Safranin O and collagen II stained articular cartilage area compared to WT prior to OA-induction without signs of spontaneous cartilage surface erosion. This MC1-signaling deficiency related cartilage phenotype persisted in 6 month animals. At 4/8 weeks after OA-induction cartilage erosions were increased in Mc1re/e knees paralleled by weaker collagen II staining. Prior to OA-induction, Mc1re/e mice do not differ from WT with respect to bone parameters. During OA, Mc1re/e mice developed more osteophytes and had higher epiphyseal bone density and mass. Trabecular thickness was increased while concomitantly trabecular separation was decreased in Mc1re/e mice. Numbers of ICAM-positive chondrocytes were equal in non-operated 11 weeks Mc1re/e and WT whereas number of positive chondrocytes decreased during OA-progression. Unchallenged Mc1re/e mice display smaller articular cartilage covered area without OA-related surface erosions indicating that MC1-signaling is critical for proper cartilage matrix integrity and formation. When challenged with OA, Mc1re/e mice develop a more severe OA

Supercritical Fluid Extract of Spent Coffee Grounds Attenuates Melanogenesis through Downregulation of the PKA, PI3K/Akt, and MAPK Signaling Pathways

PubMed Central

Huang, Huey-Chun; Wei, Chien-Mei; Siao, Jen-Hung; Tsai, Tsang-Chi; Ko, Wang-Ping; Chang, Kuei-Jen; Hii, Choon-Hoon; Chang, Tsong-Min

2016-01-01

The mode of action of spent coffee grounds supercritical fluid CO2 extract (SFE) in melanogenesis has never been reported. In the study, the spent coffee grounds were extracted by the supercritical fluid CO2 extraction method; the chemical constituents of the SFE were investigated by gas chromatography-mass spectrometry (GC-MS). The effects of the SFE and its major fatty acid components on melanogenesis were evaluated by mushroom tyrosinase activity assay and determination of intracellular tyrosinase activity and melanin content. The expression level of melanogenesis-related proteins was analyzed by western blotting assay. The results revealed that the SFE of spent coffee grounds (1–10 mg/mL) and its major fatty acids such as linoleic acid and oleic acid (6.25–50 μM) effectively suppressed melanogenesis in the B16F10 murine melanoma cells. Furthermore, the SFE decreased the expression of melanocortin 1 receptor (MC1R), microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related protein-1 (TRP-1), and tyrosinase-related protein-2 (TRP-2). The SFE also decreased the protein expression levels of p-JNK, p-p38, p-ERK, and p-CREB. Our results revealed that the SFE of spent coffee grounds attenuated melanogenesis in B16F10 cells by downregulation of protein kinase A (PKA), phosphatidylinositol-3-kinase (PI3K/Akt), and mitogen-activated protein kinases (MAPK) signaling pathways, which may be due to linoleic acid and oleic acid. PMID:27375763

Supercritical Fluid Extract of Spent Coffee Grounds Attenuates Melanogenesis through Downregulation of the PKA, PI3K/Akt, and MAPK Signaling Pathways.

PubMed

Huang, Huey-Chun; Wei, Chien-Mei; Siao, Jen-Hung; Tsai, Tsang-Chi; Ko, Wang-Ping; Chang, Kuei-Jen; Hii, Choon-Hoon; Chang, Tsong-Min

2016-01-01

The mode of action of spent coffee grounds supercritical fluid CO2 extract (SFE) in melanogenesis has never been reported. In the study, the spent coffee grounds were extracted by the supercritical fluid CO2 extraction method; the chemical constituents of the SFE were investigated by gas chromatography-mass spectrometry (GC-MS). The effects of the SFE and its major fatty acid components on melanogenesis were evaluated by mushroom tyrosinase activity assay and determination of intracellular tyrosinase activity and melanin content. The expression level of melanogenesis-related proteins was analyzed by western blotting assay. The results revealed that the SFE of spent coffee grounds (1-10 mg/mL) and its major fatty acids such as linoleic acid and oleic acid (6.25-50 μM) effectively suppressed melanogenesis in the B16F10 murine melanoma cells. Furthermore, the SFE decreased the expression of melanocortin 1 receptor (MC1R), microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related protein-1 (TRP-1), and tyrosinase-related protein-2 (TRP-2). The SFE also decreased the protein expression levels of p-JNK, p-p38, p-ERK, and p-CREB. Our results revealed that the SFE of spent coffee grounds attenuated melanogenesis in B16F10 cells by downregulation of protein kinase A (PKA), phosphatidylinositol-3-kinase (PI3K/Akt), and mitogen-activated protein kinases (MAPK) signaling pathways, which may be due to linoleic acid and oleic acid.

Synthesis and Pharmacology of α/β(3)-Peptides Based on the Melanocortin Agonist Ac-His-dPhe-Arg-Trp-NH2 Sequence.

PubMed

Singh, Anamika; Tala, Srinivasa R; Flores, Viktor; Freeman, Katie; Haskell-Luevano, Carrie

2015-05-14

The melanocortin-3 and -4 receptors are expressed in the brain and play key roles in regulating feeding behavior, metabolism, and energy homeostasis. In the present study, incorporation of β(3)-amino acids into a melanocortin tetrapeptide template was investigated. Four linear α/β(3)-hybrid tetrapeptides were designed with the modifications at the Phe, Arg, and Trp residues in the agonist sequence Ac-His-dPhe-Arg-Trp-NH2. The most potent mouse melanocortin-4 receptor (mMC4R) agonist, Ac-His-dPhe-Arg-β(3)hTrp-NH2 (8) showed 35-fold selectivity versus the mMC3R. The study presented here has identified a new template with heterogeneous backbone for designing potent and selective melanocortin receptor ligands.

Synthesis and Pharmacology of α/β3-Peptides Based on the Melanocortin Agonist Ac-His-dPhe-Arg-Trp-NH2 Sequence

PubMed Central

2015-01-01

The melanocortin-3 and -4 receptors are expressed in the brain and play key roles in regulating feeding behavior, metabolism, and energy homeostasis. In the present study, incorporation of β3-amino acids into a melanocortin tetrapeptide template was investigated. Four linear α/β3-hybrid tetrapeptides were designed with the modifications at the Phe, Arg, and Trp residues in the agonist sequence Ac-His-dPhe-Arg-Trp-NH2. The most potent mouse melanocortin-4 receptor (mMC4R) agonist, Ac-His-dPhe-Arg-β3hTrp-NH2 (8) showed 35-fold selectivity versus the mMC3R. The study presented here has identified a new template with heterogeneous backbone for designing potent and selective melanocortin receptor ligands. PMID:26005535

Deficient Binocular Combination Reveals Mechanisms of Anisometropic Amblyopia: Signal Attenuation and Interocular Inhibition

PubMed Central

Huang, Chang-Bing; Zhou, Jiawei; Lu, Zhong-Lin; Zhou, Yifeng

2012-01-01

Amblyopia is a developmental disorder that results in deficits of monocular and binocular vision. It's presently unclear whether these deficits result from attenuation of signals in the amblyopic eye, inhibition by signals in the fellow eye, or both. In this study, we characterize the mechanisms underlying anisometropic amblyopia using a binocular phase and contrast combination paradigm and a contrast-gain control model. Subjects dichoptically viewed two slightly different images and reported the perceived contrast and phase of the resulting cyclopean percept. We found that the properties of binocular combination were abnormal in many aspects, which is explained by a combination of (1) attenuated monocular signal in the amblyopic eye, (2) stronger interocular contrast-gain control from the fellow eye to the signal in amblyopic eye (direct interocular inhibition), and (3) stronger interocular contrast-gain control from the fellow eye to the contrast gain control signal from the amblyopic eye (indirect interocular inhibition). We conclude that anisometropic amblyopia led to both monocular and interocular deficits. A complete understanding of the mechanisms underlying amblyopia requires studies of both monocular deficits and binocular interactions. PMID:21546609

Profound and rapid reduction in body temperature induced by the melanocortin receptor agonists.

PubMed

Xu, Yuanzhong; Kim, Eun Ran; Fan, Shengjie; Xia, Yan; Xu, Yong; Huang, Cheng; Tong, Qingchun

2014-08-22

The melanocortin receptor 4 (MC4R) plays a major role in body weight regulation and its agonist MTII has been widely used to study the role of MC4Rs in energy expenditure promotion and feeding reduction. Unexpectedly, we observed that intraperitoneal (i.p.) administration of MTII induced a rapid reduction in both body temperature and energy expenditure, which was independent of its effect on feeding and followed by a prolonged increase in energy expenditure. The rapid reduction was at least partly mediated by brain neurons since intracerebroventricular (icv) administration of alpha melanocyte-stimulating hormone, an endogenous melanocortin receptor agonist, produced a similar response. In addition, the body temperature-lowering effect of MTII was independent of the presence of MC4Rs, but in a similar fashion to the previously shown effect on body temperature by 5'AMP. Moreover, β-adrenergic receptors (β-ARs) were required for the recovery from low body temperature induced by MTII and further pharmacological studies showed that the MTII's effect on body temperature may be partially mediated by the vasopressin V1a receptors. Collectively, our results reveal a previously unappreciated role for the melanocortin pathway in rapidly lowering body temperature. Copyright © 2014 Elsevier Inc. All rights reserved.

Profound and Rapid Reduction in Body Temperature Induced by the Melanocortin Receptor Agonists

PubMed Central

Xu, Yuanzhong; Kim, Eun Ran; Fan, Shengjie; Xia, Yan; Xu, Yong; Huang, Cheng; Tong, Qingchun

2014-01-01

The melanocortin receptor 4 (MC4R) plays a major role in body weight regulation and its agonist MTII has been widely used to study the role of MC4Rs in energy expenditure promotion and feeding reduction. Unexpectedly, we observed that intraperitoneal (i.p.) administration of MTII induced a rapid reduction in both body temperature and energy expenditure, which was independent of its effect on feeding and followed by a prolonged increase in energy expenditure. The rapid reduction was at least partly mediated by brain neurons since intracerebroventricular (icv) administration of alpha melanocyte-stimulating hormone, an endogenous melanocortin receptor agonist, produced a similar response. In addition, the body temperature-lowering effect of MTII was independent of the presence of MC4Rs, but in a similar fashion to the previously shown effect on body temperature by 5′AMP. Moreover, β-adrenergic receptors (β-ARs) were required for the recovery from low body temperature induced by MTII and further pharmacological studies showed that the MTII’s effect on body temperature may be partially mediated by the vasopressin V1a receptors. Collectively, our results reveal a previously unappreciated role for the melanocortin pathway in rapidly lowering body temperature. PMID:25065745

LeEix1 functions as a decoy receptor to attenuate LeEix2 signaling.

PubMed

Bar, Maya; Sharfman, Miya; Avni, Adi

2011-03-01

The receptors for the fungal elicitor EIX (LeEix1 and LeEix2) belong to a class of leucine-rich repeat cell-surface glycoproteins with a signal for receptor-mediated endocytosis. Both receptors are able to bind the EIX elicitor while only the LeEix2 receptor mediates defense responses. We show that LeEix1 acts as a decoy receptor and attenuates EIX induced internalization and signaling of the LeEix2 receptor. We demonstrate that BAK1 binds LeEix1 but not LeEix2. In plants where BAK1 was silenced, LeEix1 was no longer able to attenuate plant responses to EIX, indicating that BAK1 is required for this attenuation. We suggest that LeEix1 functions as a decoy receptor for LeEix2, a function which requires the kinase activity of BAK1.

Skull's acoustic attenuation and dispersion modeling on photoacoustic signal

NASA Astrophysics Data System (ADS)

Mohammadi, Leila; Behnam, Hamid; Tavakkoli, Jahan; Nasiriavanaki, Mohammadreza

2018-02-01

Despite the promising results of the recent novel transcranial photoacoustic (PA) brain imaging technology, it has been demonstrated that the presence of the skull severely affects the performance of this imaging modality. We theoretically investigate the effects of acoustic heterogeneity induced by skull on the PA signals generated from single particles, with firstly developing a mathematical model for this phenomenon and then explore experimental validation of the results. The model takes into account the frequency dependent attenuation and dispersion effects occur with wave reflection, refraction and mode conversion at the skull surfaces. Numerical simulations based on the developed model are performed for calculating the propagation of photoacoustic waves through the skull. The results show a strong agreement between simulation and ex-vivo study. The findings are as follow: The thickness of the skull is the most PA signal deteriorating factor that affects both its amplitude (attenuation) and phase (distortion). Also we demonstrated that, when the depth of target region is low and it is comparable to the skull thickness, however, the skull-induced distortion becomes increasingly severe and the reconstructed image would be strongly distorted without correcting these effects. It is anticipated that an accurate quantification and modeling of the skull transmission effects would ultimately allow for aberration correction in transcranial PA brain imaging.

Dusp6 attenuates Ras/MAPK signaling to limit zebrafish heart regeneration.

PubMed

Missinato, Maria A; Saydmohammed, Manush; Zuppo, Daniel A; Rao, Krithika S; Opie, Graham W; Kühn, Bernhard; Tsang, Michael

2018-03-06

Zebrafish regenerate cardiac tissue through proliferation of pre-existing cardiomyocytes and neovascularization. Secreted growth factors such as FGFs, IGF, PDGFs and Neuregulin play essential roles in stimulating cardiomyocyte proliferation. These factors activate the Ras/MAPK pathway, which is tightly controlled by the feedback attenuator Dual specificity phosphatase 6 (Dusp6), an ERK phosphatase. Here, we show that suppressing Dusp6 function enhances cardiac regeneration. Inactivation of Dusp6 by small molecules or by gene inactivation increased cardiomyocyte proliferation, coronary angiogenesis, and reduced fibrosis after ventricular resection. Inhibition of Erbb or PDGF receptor signaling suppressed cardiac regeneration in wild-type zebrafish, but had a milder effect on regeneration in dusp6 mutants. Moreover, in rat primary cardiomyocytes, NRG1-stimulated proliferation can be enhanced upon chemical inhibition of Dusp6 with BCI. Our results suggest that Dusp6 attenuates Ras/MAPK signaling during regeneration and that suppressing Dusp6 can enhance cardiac repair. © 2018. Published by The Company of Biologists Ltd.

Sulforaphane attenuates EGFR signaling in NSCLC cells.

PubMed

Chen, Chi-Yuan; Yu, Zhu-Yun; Chuang, Yen-Shu; Huang, Rui-Mei; Wang, Tzu-Chien V

2015-06-03

EGFR, a receptor tyrosine kinase (RTK), is frequently overexpressed and mutated in non-small cell lung cancer (NSCLC). Tyrosine kinase inhibitors (TKIs) have been widely used in the treatment of many cancers, including NSCLC. However, intrinsic and acquired resistance to TKI remains a common obstacle. One strategy that may help overcome EGFR-TKI resistance is to target EGFR for degradation. As EGFR is a client protein of heat-shock protein 90 (HSP90) and sulforaphane is known to functionally regulate HSP90, we hypothesized that sulforaphane could attenuate EGFR-related signaling and potentially be used to treat NSCLC. Our study revealed that sulforaphane displayed antitumor activity against NSCLC cells both in vitro and in vivo. The sensitivity of NSCLC cells to sulforaphane appeared to positively correlate with the inhibition of EGFR-related signaling, which was attributed to the increased proteasomal degradation of EGFR. Combined treatment of NSCLC cells with sulforaphane plus another HSP90 inhibitor (17-AAG) enhanced the inhibition of EGFR-related signaling both in vitro and in vivo. We have shown that sulforaphane is a novel inhibitory modulator of EGFR expression and is effective in inhibiting the tumor growth of EGFR-TKI-resistant NSCLC cells. Our findings suggest that sulforaphane should be further explored for its potential clinical applications against NSCLC.

MRAP and MRAP2 are bidirectional regulators of the melanocortin receptor family

PubMed Central

Chan, Li F.; Webb, Tom R.; Chung, Teng-Teng; Meimaridou, Eirini; Cooray, Sadani N.; Guasti, Leonardo; Chapple, J. Paul; Egertová, Michaela; Elphick, Maurice R.; Cheetham, Michael E.; Metherell, Louise A.; Clark, Adrian J. L.

2009-01-01

The melanocortin receptor (MCR) family consists of 5 G protein-coupled receptors (MC1R–MC5R) with diverse physiologic roles. MC2R is a critical component of the hypothalamic–pituitary–adrenal axis, whereas MC3R and MC4R have an essential role in energy homeostasis. Mutations in MC4R are the single most common cause of monogenic obesity. Investigating the way in which these receptors signal and traffic to the cell membrane is vital in understanding disease processes related to MCR dysfunction. MRAP is an MC2R accessory protein, responsible for adrenal MC2R trafficking and function. Here we identify MRAP2 as a unique homologue of MRAP, expressed in brain and the adrenal gland. We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). Collectively, our data identify MRAP and MRAP2 as unique bidirectional regulators of the MCR family. PMID:19329486

Comparative Functional Alanine Positional Scanning of the α-Melanocyte Stimulating Hormone and NDP-Melanocyte Stimulating Hormone Demonstrates Differential Structure-Activity Relationships at the Mouse Melanocortin Receptors.

PubMed

Todorovic, Aleksandar; Ericson, Mark D; Palusak, Ryan D; Sorensen, Nicholas B; Wood, Michael S; Xiang, Zhimin; Haskell-Luevano, Carrie

2016-07-20

The melanocortin system has been implicated in the regulation of various physiological functions including melanogenesis, steroidogenesis, energy homeostasis, and feeding behavior. Five melanocortin receptors have been identified to date and belong to the family of G protein-coupled receptors (GPCR). Post-translational modification of the proopiomelanocortin (POMC) prohormone leads to the biosynthesis of the endogenous melanocortin agonists, including α-melanocyte stimulating hormone (α-MSH), β-MSH, γ-MSH, and adrenocorticotropic hormone (ACTH). All the melanocortin agonists derived from the POMC prohormone contain a His-Phe-Arg-Trp tetrapeptide sequence that has been implicated in eliciting the pharmacological responses at the melanocortin receptors. Herein, an alanine (Ala) positional scan is reported for the endogenous α-MSH ligand and the synthetic, more potent, NDP-MSH peptide (Ac-Ser(1)-Tyr(2)-Ser(3)-Nle(4)-Glu(5)-His(6)-DPhe(7)-Arg(8)-Trp(9)-Gly(10)-Lys(11)-Pro(12)-Val(13)-NH2) at the cloned mouse melanocortin receptors to test the assumption that the structure-activity relationships of one ligand would apply to the other. Several residues outside of the postulated pharmacophore altered potency at the melanocortin receptors, most notably the 1560-, 37-, and 15-fold potency loss when the Glu(5) position of α-MSH was substituted with Ala at the mMC1R, mMC3R, and mMC4R, respectively. Importantly, the altered potencies due to Ala substitutions in α-MSH did not necessarily correlate with equivalent Ala substitutions in NDP-MSH, indicating that structural modifications and corresponding biological activities in one of these melanocortin ligands may not be predictive for the other agonist.

Real-Time Rain Rate Evaluation via Satellite Downlink Signal Attenuation Measurement

PubMed Central

Reggiannini, Ruggero; Moretti, Marco; Adirosi, Elisa; Baldini, Luca; Facheris, Luca; Melani, Samantha; Bacci, Giacomo; Petrolino, Antonio; Vaccaro, Attilio

2017-01-01

We present the NEFOCAST project (named by the contraction of “Nefele”, which is the Italian spelling for the mythological cloud nymph Nephele, and “forecast”), funded by the Tuscany Region, about the feasibility of a system for the detection and monitoring of precipitation fields over the regional territory based on the use of a widespread network of new-generation Eutelsat “SmartLNB” (smart low-noise block converter) domestic terminals. Though primarily intended for interactive satellite services, these devices can also be used as weather sensors, as they have the capability of measuring the rain-induced attenuation incurred by the downlink signal and relaying it on an auxiliary return channel. We illustrate the NEFOCAST system architecture, consisting of the network of ground sensor terminals, the space segment, and the service center, which has the task of processing the information relayed by the terminals for generating rain field maps. We discuss a few methods that allow the conversion of a rain attenuation measurement into an instantaneous rainfall rate. Specifically, we discuss an exponential model relating the specific rain attenuation to the rainfall rate, whose coefficients were obtained from extensive experimental data. The above model permits the inferring of the rainfall rate from the total signal attenuation provided by the SmartLNB and from the link geometry knowledge. Some preliminary results obtained from a SmartLNB installed in Pisa are presented and compared with the output of a conventional tipping bucket rain gauge. It is shown that the NEFOCAST sensor is able to track the fast-varying rainfall rate accurately with no delay, as opposed to a conventional gauge. PMID:28805692

Robotic assistance and general anaesthesia improve catheter stability and increase signal attenuation during atrial fibrillation ablation.

PubMed

Malcolme-Lawes, Louisa C; Lim, Phang Boon; Koa-Wing, Michael; Whinnett, Zachary I; Jamil-Copley, Shahnaz; Hayat, Sajad; Francis, Darrel P; Kojodjojo, Pipin; Davies, D Wyn; Peters, Nicholas S; Kanagaratnam, Prapa

2013-01-01

Recurrent arrhythmias after ablation procedures are often caused by recovery of ablated tissue. Robotic catheter manipulation systems increase catheter tip stability which improves energy delivery and could produce more transmural lesions. We tested this assertion using bipolar voltage attenuation as a marker of lesion quality comparing robotic and manual circumferential pulmonary vein ablation for atrial fibrillation (AF). Twenty patients were randomly assigned to robotic or manual AF ablation at standard radiofrequency (RF) settings for our institution (30 W 60 s manual, 25 W 30 s robotic, R30). A separate group of 10 consecutive patients underwent robotic ablation at increased RF duration, 25 W for 60 s (R60). Lesions were marked on an electroanatomic map before and after ablation to measure distance moved and change in bipolar electrogram amplitude during RF. A total of 1108 lesions were studied (761 robotic, 347 manual). A correlation was identified between voltage attenuation and catheter movement during RF (Spearman's rho -0.929, P < 0.001). The ablation catheter was more stable during robotic RF; 2.9 ± 2.3 mm (R30) and 2.6 ± 2.2 mm (R60), both significantly less than the manual group (4.3 ± 3.0 mm, P < 0.001). Despite improved stability, there was no difference in signal attenuation between the manual and R30 group. However, there was increased signal attenuation in the R60 group (52.4 ± 19.4%) compared with manual (47.7 ± 25.4%, P = 0.01). When procedures under general anaesthesia (GA) and conscious sedation were analysed separately, the improvement in signal attenuation in the R60 group was only significant in the procedures under GA. Robotically assisted ablation has the capability to deliver greater bipolar voltage attenuation compared with manual ablation with appropriate selection of RF parameters. General anaesthesia confers additional benefits of catheter stability and greater signal attenuation. These findings may have a significant impact on

Synthesis, Biophysical, and Pharmacological Evaluation of the Melanocortin Agonist AST3-88: Modifications of Peptide Backbone at Trp 7 Position Lead to a Potent, Selective, and Stable Ligand of the Melanocortin 4 Receptor (MC4R)

PubMed Central

2015-01-01

The melanocortin-3 (MC3R) and melanocortin-4 (MC4R) receptors are expressed in the brain and are implicated in the regulation of food intake and energy homeostasis. The endogenous agonist ligands for these receptors (α-, β-, γ-MSH and ACTH) are linear peptides with limited receptor subtype selectivity and metabolic stability, thus minimizing their use as probes to characterize the overlapping pharmacological and physiological functions of the melanocortin receptor subtypes. In the present study, an engineered template, in which the peptide backbone was modified by a heterocyclic reverse turn mimetic at the Trp7 residue, was synthesized using solid phase peptide synthesis and characterized by a β-galactosidase cAMP based reporter gene assay. The functional assay identified a ∼5 nM mouse MC4R agonist (AST3-88) with more than 50-fold selectivity over the mMC3R. Biophysical studies (2D 1H NMR spectroscopy and molecular dynamics) of AST3-88 identified a type VIII β-turn secondary structure spanning the pharmacophore domain stabilized by the intramolecular interactions between the side chains of the His and Trp residues. Enzymatic studies of AST3-88 revealed enhanced stability of AST3-88 over the α-MSH endogenous peptide in rat serum. Upon central administration of AST3-88 into rats, a decreased food intake response was observed. This is the first study to probe the in vivo physiological activity of this engineered peptide-heterocycle template. These findings advance the present knowledge of pharmacophore design for potent, selective, and metabolically stable melanocortin ligands. PMID:25141170

Characterization of ligand binding to melanocortin 4 receptors using fluorescent peptides with improved kinetic properties.

PubMed

Link, Reet; Veiksina, Santa; Rinken, Ago; Kopanchuk, Sergei

2017-03-15

Melanocortin 4 (MC 4 ) receptors are important drug targets as they regulate energy homeostasis, eating behaviour and sexual functions. The ligand binding process to these G protein-coupled receptors is subject to considerable complexity. Different steps in the complex dynamic regulation can be characterized by ligand binding kinetics. Optimization of these kinetic parameters in terms of on-rate and residence time can increase the rapid onset of drug action and reduce off-target effects. Fluorescence anisotropy (FA) is one of the homogeneous fluorescence-based assays that enable continuous online monitoring of ligand binding kinetics. FA has been implemented for the kinetic study of melanocortin MC 4 receptors expressed on budded baculoviruses. However, the slow dissociation of the fluorescently labelled peptide NDP-α-MSH does not enable reaching equilibrium nor enable more in-depth study of the binding mechanisms. To overcome this problem, two novel red-shifted fluorescent ligands were designed. These cyclized heptapeptide derivatives (UTBC101 and UTBC102) exhibited nanomolar affinity toward melanocortin MC 4 receptors but had relatively different kinetic properties. The dissociation half-lives of UTBC101 (τ 1/2 =160min) and UTBC102 (τ 1/2 =7min) were shorter compared to that what was previously reported for Cy3B-NDP-α-MSH (τ 1/2 =224min). The significantly shorter dissociation half-life of UTBC102 enables equilibrium in screening assays, whereas the higher affinity of UTBC101 helps to resolve a wider range of competitor potencies. These two ligands are suitable for further kinetic screening of novel melanocortin MC 4 receptor specific ligands and could complement each other in these studies. Copyright © 2017 Elsevier B.V. All rights reserved.

Alterations in the hypothalamic melanocortin pathway in amyotrophic lateral sclerosis.

PubMed

Vercruysse, Pauline; Sinniger, Jérôme; El Oussini, Hajer; Scekic-Zahirovic, Jelena; Dieterlé, Stéphane; Dengler, Reinhard; Meyer, Thomas; Zierz, Stephan; Kassubek, Jan; Fischer, Wilhelm; Dreyhaupt, Jens; Grehl, Torsten; Hermann, Andreas; Grosskreutz, Julian; Witting, Anke; Van Den Bosch, Ludo; Spreux-Varoquaux, Odile; Ludolph, Albert C; Dupuis, Luc

2016-04-01

Amyotrophic lateral sclerosis, the most common adult-onset motor neuron disease, leads to death within 3 to 5 years after onset. Beyond progressive motor impairment, patients with amyotrophic lateral sclerosis suffer from major defects in energy metabolism, such as weight loss, which are well correlated with survival. Indeed, nutritional intervention targeting weight loss might improve survival of patients. However, the neural mechanisms underlying metabolic impairment in patients with amyotrophic lateral sclerosis remain elusive, in particular due to the lack of longitudinal studies. Here we took advantage of samples collected during the clinical trial of pioglitazone (GERP-ALS), and characterized longitudinally energy metabolism of patients with amyotrophic lateral sclerosis in response to pioglitazone, a drug with well-characterized metabolic effects. As expected, pioglitazone decreased glycaemia, decreased liver enzymes and increased circulating adiponectin in patients with amyotrophic lateral sclerosis, showing its efficacy in the periphery. However, pioglitazone did not increase body weight of patients with amyotrophic lateral sclerosis independently of bulbar involvement. As pioglitazone increases body weight through a direct inhibition of the hypothalamic melanocortin system, we studied hypothalamic neurons producing proopiomelanocortin (POMC) and the endogenous melanocortin inhibitor agouti-related peptide (AGRP), in mice expressing amyotrophic lateral sclerosis-linked mutant SOD1(G86R). We observed lower Pomc but higher Agrp mRNA levels in the hypothalamus of presymptomatic SOD1(G86R) mice. Consistently, numbers of POMC-positive neurons were decreased, whereas AGRP fibre density was elevated in the hypothalamic arcuate nucleus of SOD1(G86R) mice. Consistent with a defect in the hypothalamic melanocortin system, food intake after short term fasting was increased in SOD1(G86R) mice. Importantly, these findings were replicated in two other amyotrophic

Time-frequency peak filtering for random noise attenuation of magnetic resonance sounding signal

NASA Astrophysics Data System (ADS)

Lin, Tingting; Zhang, Yang; Yi, Xiaofeng; Fan, Tiehu; Wan, Ling

2018-05-01

When measuring in a geomagnetic field, the method of magnetic resonance sounding (MRS) is often limited because of the notably low signal-to-noise ratio (SNR). Most current studies focus on discarding spiky noise and power-line harmonic noise cancellation. However, the effects of random noise should not be underestimated. The common method for random noise attenuation is stacking, but collecting multiple recordings merely to suppress random noise is time-consuming. Moreover, stacking is insufficient to suppress high-level random noise. Here, we propose the use of time-frequency peak filtering for random noise attenuation, which is performed after the traditional de-spiking and power-line harmonic removal method. By encoding the noisy signal with frequency modulation and estimating the instantaneous frequency using the peak of the time-frequency representation of the encoded signal, the desired MRS signal can be acquired from only one stack. The performance of the proposed method is tested on synthetic envelope signals and field data from different surveys. Good estimations of the signal parameters are obtained at different SNRs. Moreover, an attempt to use the proposed method to handle a single recording provides better results compared to 16 stacks. Our results suggest that the number of stacks can be appropriately reduced to shorten the measurement time and improve the measurement efficiency.

Structural Insights into Selective Ligand-Receptor Interactions Leading to Receptor Inactivation Utilizing Selective Melanocortin 3 Receptor Antagonists.

PubMed

Cai, Minying; Marelli, Udaya Kiran; Mertz, Blake; Beck, Johannes G; Opperer, Florian; Rechenmacher, Florian; Kessler, Horst; Hruby, Victor J

2017-08-15

Systematic N-methylated derivatives of the melanocortin receptor ligand, SHU9119, lead to multiple binding and functional selectivity toward melanocortin receptors. However, the relationship between N-methylation-induced conformational changes in the peptide backbone and side chains and melanocortin receptor selectivity is still unknown. We conducted comprehensive conformational studies in solution of two selective antagonists of the third isoform of the melanocortin receptor (hMC3R), namely, Ac-Nle-c[Asp-NMe-His 6 -d-Nal(2') 7 -NMe-Arg 8 -Trp 9 -Lys]-NH 2 (15) and Ac-Nle-c[Asp-His 6 -d-Nal(2') 7 -NMe-Arg 8 -NMe-Trp 9 -NMe-Lys]-NH 2 (17). It is known that the pharmacophore (His 6 -DNal 7 -Arg 8 -Trp 9 ) of the SHU-9119 peptides occupies a β II-turn-like region with the turn centered about DNal 7 -Arg 8 . The analogues with hMC3R selectivity showed distinct differences in the spatial arrangement of the Trp 9 side chains. In addition to our NMR studies, we also carried out molecular-level interaction studies of these two peptides at the homology model of hMC3R. Earlier chimeric human melanocortin 3 receptor studies revealed insights regarding the binding and functional sites of hMC3R selectivity. Upon docking of peptides 15 and 17 to the binding pocket of hMC3R, it was revealed that Arg 8 and Trp 9 side chains are involved in a majority of the interactions with the receptor. While Arg 8 forms polar contacts with D154 and D158 of hMC3R, Trp 9 utilizes π-π stacking interactions with F295 and F298, located on the transmembrane domain of hMC3R. It is hypothesized that as the frequency of Trp 9 -hMC3R interactions decrease, antagonistic activity increases. The absence of any interactions of the N-methyl groups with hMC3R suggests that their primary function is to modulate backbone conformations of the ligands.

Photoacoustic signal attenuation analysis for the assessment of thin layers thickness in paintings

NASA Astrophysics Data System (ADS)

Tserevelakis, George J.; Dal Fovo, Alice; Melessanaki, Krystalia; Fontana, Raffaella; Zacharakis, Giannis

2018-03-01

This study introduces a novel method for the thickness estimation of thin paint layers in works of art, based on photoacoustic signal attenuation analysis (PAcSAA). Ad hoc designed samples with acrylic paint layers (Primary Red Magenta, Cadmium Yellow, Ultramarine Blue) of various thicknesses on glass substrates were realized for the specific application. After characterization by Optical Coherence Tomography imaging, samples were irradiated at the back side using low energy nanosecond laser pulses of 532 nm wavelength. Photoacoustic waves undergo a frequency-dependent exponential attenuation through the paint layer, before being detected by a broadband ultrasonic transducer. Frequency analysis of the recorded time-domain signals allows for the estimation of the average transmitted frequency function, which shows an exponential decay with the layer thickness. Ultrasonic attenuation models were obtained for each pigment and used to fit the data acquired on an inhomogeneous painted mock-up simulating a real canvas painting. Thickness evaluation through PAcSAA resulted in excellent agreement with cross-section analysis with a conventional brightfield microscope. The results of the current study demonstrate the potential of the proposed PAcSAA method for the non-destructive stratigraphic analysis of painted artworks.

Structure-Activity Relationships of Peptides Incorporating a Bioactive Reverse-Turn Heterocycle at the Melanocortin Receptors: Identification of a 5,800-fold Mouse Melanocortin-3 Receptor (mMC3R) Selective Antagonist/Partial Agonist versus the Mouse Melanocortin-4 Receptor (mMC4R)

PubMed Central

Singh, Anamika; Dirain, Marvin; Witek, Rachel; Rocca, James R.; Edison, Arthur S; Haskell-Luevano, Carrie

2013-01-01

The melanocortin-3 (MC3) and melanocortin-4 (MC4) receptors regulate energy homeostasis, food intake, and associated physiological conditions. The MC4R has been studied extensively. Less is known about specific physiological roles of the MC3R. A major obstacle to this lack of knowledge is attributed to a limited number of identified MC3R selective ligands. We previously reported a spatial scanning approach of a 10-membered thioether-heterocycle ring incorporated into a chimeric peptide template that identified a lead nM MC4R ligand. Based upon those results, 17 compounds were designed and synthesized that focused upon modification in the pharmacophore domain. Notable results include the identification of a 0.13 nM potent 5800-fold mMC3R selective antagonist/slight partial agonist versus a 760 nM mMC4R full agonist (ligand 11). Biophysical experiments (2D 1H NMR and computer assisted molecular modeling) of this ligand resulted in the identification of an inverse γ-turn secondary structure in the ligand pharmacophore domain. PMID:23432160

FOXOs attenuate bone formation by suppressing Wnt signaling

PubMed Central

Iyer, Srividhya; Ambrogini, Elena; Bartell, Shoshana M.; Han, Li; Roberson, Paula K.; de Cabo, Rafael; Jilka, Robert L.; Weinstein, Robert S.; O’Brien, Charles A.; Manolagas, Stavros C.; Almeida, Maria

2013-01-01

Wnt/β-catenin/TCF signaling stimulates bone formation and suppresses adipogenesis. The hallmarks of skeletal involution with age, on the other hand, are decreased bone formation and increased bone marrow adiposity. These changes are associated with increased oxidative stress and decreased growth factor production, which activate members of the FOXO family of transcription factors. FOXOs in turn attenuate Wnt/β-catenin signaling by diverting β-catenin from TCF- to FOXO-mediated transcription. We show herein that mice lacking Foxo1, -3, and -4 in bipotential progenitors of osteoblast and adipocytes (expressing Osterix1) exhibited increased osteoblast number and high bone mass that was maintained in old age as well as decreased adiposity in the aged bone marrow. The increased bone mass in the Foxo-deficient mice was accounted for by increased proliferation of osteoprogenitor cells and bone formation resulting from upregulation of Wnt/β-catenin signaling and cyclin D1 expression, but not changes in redox balance. Consistent with this mechanism, β-catenin deletion in Foxo null cells abrogated both the increased cyclin D1 expression and proliferation. The elucidation of a restraining effect of FOXOs on Wnt signaling in bipotential progenitors suggests that FOXO activation by accumulation of age-associated cellular stressors may be a seminal pathogenetic mechanism in the development of involutional osteoporosis. PMID:23867625

Range safety signal attenuation by the Space Shuttle main engine exhaust plumes

NASA Technical Reports Server (NTRS)

Pearce, B. E.

1983-01-01

An analysis of attenuation of the range safety signal at 416.5 MHz observed after SRB separation and ending at hand over to Bermuda, during which transmission must pass through the LOX/H2 propelled main engine exhaust plumes, is summarized. Absorption by free electrons in the exhaust plume can account for the nearly constant magnitude of the observed attenuation during this period; it does not explain the short term transient increases that occur at one or more times during this portion of the flight. It is necessary to assume that a trace amount (about 0.5 ppm) of easily ionizable impurity must be present in the exhaust flow. Other mechanisms of attenuation, such as scattering by turbulent fluctuations of both free and bound electrons and absorption by water vapor, were examined but found to be inadequate to explain the observations.

Ac-Trp-DPhe(p-I)-Arg-Trp-NH2, a 250-Fold Selective Melanocortin-4 Receptor (MC4R) Antagonist over the Melanocortin-3 Receptor (MC3R), Affects Energy Homeostasis in Male and Female Mice Differently.

PubMed

Lensing, Cody J; Adank, Danielle N; Doering, Skye R; Wilber, Stacey L; Andreasen, Amy; Schaub, Jay W; Xiang, Zhimin; Haskell-Luevano, Carrie

2016-09-21

The melanocortin-4 receptor (MC4R) has been indicated as a therapeutic target for metabolic disorders such as anorexia, cachexia, and obesity. The current study investigates the in vivo effects on energy homeostasis of a 15 nM MC4R antagonist SKY2-23-7, Ac-Trp-DPhe(p-I)-Arg-Trp-NH2, that is a 3700 nM melanocortin-3 receptor (MC3R) antagonist with minimal MC3R and MC4R agonist activity. When monitoring both male and female mice in TSE metabolic cages, sex-specific responses were observed in food intake, respiratory exchange ratio (RER), and energy expenditure. A 7.5 nmol dose of SKY2-23-7 increased food intake, increased RER, and trended toward decreasing energy expenditure in male mice. However, this compound had minimal effect on female mice's food intake and RER at the 7.5 nmol dose. A 2.5 nmol dose of SKY2-23-7 significantly increased female food intake, RER, and energy expenditure while having a minimal effect on male mice at this dose. The observed sex differences of SKY2-23-7 administration result in the discovery of a novel chemical probe for elucidating the molecular mechanisms of the sexual dimorphism present within the melanocortin pathway. To further explore the melanocortin sexual dimorphism, hypothalamic gene expression was examined. The mRNA expression of the MC3R and proopiomelanocortin (POMC) were not significantly different between sexes. However, the expression of agouti-related peptide (AGRP) was significantly higher in female mice which may be a possible mechanism for the sex-specific effects observed with SKY2-23-7.

The caenorhabditis elegans CDT-2 ubiquitin ligase is required for attenuation of EGFR signalling in vulva precursor cells

PubMed Central

2010-01-01

Background Attenuation of the EGFR (Epidermal Growth Factor Receptor) signalling cascade is crucial to control cell fate during development. A candidate-based RNAi approach in C. elegans identified CDT-2 as an attenuator of LET-23 (EGFR) signalling. Human CDT2 is a component of the conserved CDT2/CUL4/DDB1 ubiquitin ligase complex that plays a critical role in DNA replication and G2/M checkpoint. Within this complex, CDT2 is responsible for substrate recognition. This ubiquitin ligase complex has been shown in various organisms, including C. elegans, to target the replication-licensing factor CDT1, and the CDK inhibitor p21. However, no previous link to EGFR signalling has been identified. Results We have characterised CDT-2's role during vulva development and found that it is a novel attenuator of LET-23 signalling. CDT-2 acts redundantly with negative modulators of LET-23 signalling and CDT-2 or CUL-4 downregulation causes persistent expression of the egl-17::cfp transgene, a marker of LET-23 signalling during vulva development. In addition, we show that CDT-2 physically interacts with SEM-5 (GRB2), a known negative modulator of LET-23 signalling that directly binds LET-23, and provide genetic evidence consistent with CDT-2 functioning at or downstream of LET-23. Interestingly, both SEM-5 and CDT-2 were identified independently in a screen for genes involved in receptor-mediated endocytosis in oocytes, suggesting that attenuation of LET-23 by CDT-2 might be through regulation of endocytosis. Conclusions In this study, we have shown that CDT-2 and CUL-4, members of the CUL-4/DDB-1/CDT-2 E3 ubiquitin ligase complex attenuate LET-23 signalling in vulval precursor cells. In future, it will be interesting to investigate the potential link to endocytosis and to determine whether other signalling pathways dependent on endocytosis, e.g. LIN-12 (Notch) could be regulated by this ubiquitin ligase complex. This work has uncovered a novel function for the CUL-4/DDB-1/CDT-2 E

Discovery of melanocortin ligands via a double simultaneous substitution strategy based on the Ac-His-DPhe-Arg-Trp-NH2 template.

PubMed

Todorovic, Aleksandar; Lensing, Cody J; Holder, Jerry Ryan; Scott, Joseph W; Sorensen, Nicholas B; Haskell-Luevano, Carrie

2018-05-21

The melanocortin system regulates an array of diverse physiological functions including pigmentation, feeding behavior, energy homeostasis, cardiovascular regulation, sexual function, and steroidogenesis. Endogenous melanocortin agonist ligands all possess the minimal messaging tetrapeptide sequence His-Phe-Arg-Trp. Based on this endogenous sequence, the Ac-His1-DPhe2-Arg3-Trp4-NH 2 tetrapeptide has previously been shown to be a useful scaffold when utilizing traditional positional scanning approaches to modify activity at the various melanocortin receptors (MC1-5R). The study reported herein was undertaken to evaluate a double simultaneous substitution strategy as an approach to further diversify the Ac-His1-DPhe2-Arg3-Trp4-NH 2 tetrapeptide with concurrent introduction of natural and unnatural amino acids at positions 1, 2, or 4 as well as an octanoyl residue at the N-terminus. The designed library includes the following combinations: (A) double simultaneous substitution at capping group position (Ac) together with position 1, 2, or 4, (B) double simultaneous substitution at position 1 and 2, (C) double simultaneous substitution at position 1 and 4, and (D) double simultaneous substitution at position 2 and 4. Several lead ligands with unique pharmacologies were discovered in the current study including antagonists targeting the neuronal mMC3R with minimal agonist activity and ligands with selective profiles for the various melanocortin subtypes. The results suggest that the double simultaneous substitution strategy is a suitable approach in altering melanocortin receptor potency, selectivity, or converting agonists into antagonists and vice versa.

Synthesis and characterization of trans-4-(4-chlorophenyl)pyrrolidine-3-carboxamides of piperazinecyclohexanes as ligands for the melanocortin-4 receptor.

PubMed

Chen, Caroline W; Tran, Joe A; Fleck, Beth A; Tucci, Fabio C; Jiang, Wanlong; Chen, Chen

2007-12-15

A series of trans-N-alkyl-4-(4-chlorophenyl)pyrrolidine-3-carboxamides of piperazinecyclohexanemethylamines was synthesized and characterized for binding and function at the melanocortin-4 receptor (MC4R), and several potent benzylamine derivatives were identified. Compound 18 v was found to bind MC4R with potent affinity (K(i)=0.5 nM) and high selectivity over the other melanocortin subtypes and behaved as a functional antagonist (IC(50)=48 nM).

Modified melanocortin tetrapeptide Ac-His-dPhe-Arg-Trp-NH at the arginine side chain with ureas and thioureas.

PubMed

Joseph, C G; Sorensen, N B; Wood, M S; Xiang, Z; Moore, M C; Haskell-Luevano, C

2005-11-01

The Ac-His-dPhe-Arg-Trp-NH2 tetrapeptide is a nonselective melanocortin agonist and replacement of Arg in the tetrapeptide with acidic, basic or neutral amino acids results in reduced potency at the melanocortin receptor (MCR) isoforms (MC1R and MC3-5R). To determine the importance of the positive charge and the guanidine moiety for melanocortin activity, a series of urea- and thiourea-substituted tetrapeptides were designed. Replacement of Arg with Lys or ornithine reduced agonist activity at the mouse mMC1 and mMC3-5 receptors, thus supporting the hypothesis that the guanidine moiety is important for receptor potency, particularly at the MC3-5 receptors. The Arg side chain-modified tetrapeptides examined in this study include substituted phenyl, naphthyl, and aliphatic urea and thiourea residues using a Lys side-chain template. These ligands elicit full-agonist pharmacology at the mouse MCRs examined in this study.

Analyzing signal attenuation in PFG anomalous diffusion via a non-Gaussian phase distribution approximation approach by fractional derivatives.

PubMed

Lin, Guoxing

2016-11-21

Anomalous diffusion exists widely in polymer and biological systems. Pulsed-field gradient (PFG) techniques have been increasingly used to study anomalous diffusion in nuclear magnetic resonance and magnetic resonance imaging. However, the interpretation of PFG anomalous diffusion is complicated. Moreover, the exact signal attenuation expression including the finite gradient pulse width effect has not been obtained based on fractional derivatives for PFG anomalous diffusion. In this paper, a new method, a Mainardi-Luchko-Pagnini (MLP) phase distribution approximation, is proposed to describe PFG fractional diffusion. MLP phase distribution is a non-Gaussian phase distribution. From the fractional derivative model, both the probability density function (PDF) of a spin in real space and the PDF of the spin's accumulating phase shift in virtual phase space are MLP distributions. The MLP phase distribution leads to a Mittag-Leffler function based PFG signal attenuation, which differs significantly from the exponential attenuation for normal diffusion and from the stretched exponential attenuation for fractional diffusion based on the fractal derivative model. A complete signal attenuation expression E α (-D f b α,β * ) including the finite gradient pulse width effect was obtained and it can handle all three types of PFG fractional diffusions. The result was also extended in a straightforward way to give a signal attenuation expression of fractional diffusion in PFG intramolecular multiple quantum coherence experiments, which has an n β dependence upon the order of coherence which is different from the familiar n 2 dependence in normal diffusion. The results obtained in this study are in agreement with the results from the literature. The results in this paper provide a set of new, convenient approximation formalisms to interpret complex PFG fractional diffusion experiments.

Type III Interferon-Mediated Signaling Is Critical for Controlling Live Attenuated Yellow Fever Virus Infection In Vivo.

PubMed

Douam, Florian; Soto Albrecht, Yentli E; Hrebikova, Gabriela; Sadimin, Evita; Davidson, Christian; Kotenko, Sergei V; Ploss, Alexander

2017-08-15

Yellow fever virus (YFV) is an arthropod-borne flavivirus, infecting ~200,000 people worldwide annually and causing about 30,000 deaths. The live attenuated vaccine strain, YFV-17D, has significantly contributed in controlling the global burden of yellow fever worldwide. However, the viral and host contributions to YFV-17D attenuation remain elusive. Type I interferon (IFN-α/β) signaling and type II interferon (IFN-γ) signaling have been shown to be mutually supportive in controlling YFV-17D infection despite distinct mechanisms of action in viral infection. However, it remains unclear how type III IFN (IFN-λ) integrates into this antiviral system. Here, we report that while wild-type (WT) and IFN-λ receptor knockout (λR -/- ) mice were largely resistant to YFV-17D, deficiency in type I IFN signaling resulted in robust infection. Although IFN-α/β receptor knockout (α/βR -/- ) mice survived the infection, mice with combined deficiencies in both type I signaling and type III IFN signaling were hypersusceptible to YFV-17D and succumbed to the infection. Mortality was associated with viral neuroinvasion and increased permeability of the blood-brain barrier (BBB). α/βR -/- λR -/- mice also exhibited distinct changes in the frequencies of multiple immune cell lineages, impaired T-cell activation, and severe perturbation of the proinflammatory cytokine balance. Taken together, our data highlight that type III IFN has critical immunomodulatory and neuroprotective functions that prevent viral neuroinvasion during active YFV-17D replication. Type III IFN thus likely represents a safeguard mechanism crucial for controlling YFV-17D infection and contributing to shaping vaccine immunogenicity. IMPORTANCE YFV-17D is a live attenuated flavivirus vaccine strain recognized as one of the most effective vaccines ever developed. However, the host and viral determinants governing YFV-17D attenuation and its potent immunogenicity are still unknown. Here, we analyzed the

Embryonic attenuated Wnt/β-catenin signaling defines niche location and long-term stem cell fate in hair follicle

PubMed Central

Xu, Zijian; Wang, Wenjie; Jiang, Kaiju; Yu, Zhou; Huang, Huanwei; Wang, Fengchao; Zhou, Bin; Chen, Ting

2015-01-01

Long-term adult stem cells sustain tissue regeneration throughout the lifetime of an organism. They were hypothesized to originate from embryonic progenitor cells that acquire long-term self-renewal ability and multipotency at the end of organogenesis. The process through which this is achieved often remains unclear. Here, we discovered that long-term hair follicle stem cells arise from embryonic progenitor cells occupying a niche location that is defined by attenuated Wnt/β-catenin signaling. Hair follicle initiation is marked by placode formation, which depends on the activation of Wnt/β-catenin signaling. Soon afterwards, a region with attenuated Wnt/β-catenin signaling emerges in the upper follicle. Embryonic progenitor cells residing in this region gain expression of adult stem cell markers and become definitive long-term hair follicle stem cells at the end of organogenesis. Attenuation of Wnt/β-catenin signaling is a prerequisite for hair follicle stem cell specification because it suppresses Sox9, which is required for stem cell formation. DOI: http://dx.doi.org/10.7554/eLife.10567.001 PMID:26653852

Role of Hypothalamic Melanocortin System in Adaptation of Food Intake to Food Protein Increase in Mice

PubMed Central

Pillot, Bruno; Duraffourd, Céline; Bégeot, Martine; Joly, Aurélie; Luquet, Serge; Houberdon, Isabelle; Naville, Danielle; Vigier, Michèle; Gautier-Stein, Amandine; Magnan, Christophe; Mithieux, Gilles

2011-01-01

The hypothalamic melanocortin system—the melanocortin receptor of type 4 (MC4R) and its ligands: α-melanin-stimulating hormone (α-MSH, agonist, inducing hypophagia), and agouti-related protein (AgRP, antagonist, inducing hyperphagia)—is considered to play a central role in the control of food intake. We tested its implication in the mediation of the hunger-curbing effects of protein-enriched diets (PED) in mice. Whereas there was a 20% decrease in food intake in mice fed on the PED, compared to mice fed on an isocaloric starch-enriched diet, there was a paradoxical decrease in expression of the hypothalamic proopiomelanocortin gene, precursor of α-MSH, and increase in expression of the gene encoding AgRP. The hypophagia effect of PED took place in mice with invalidation of either MC4R or POMC, and was even strengthened in mice with ablation of the AgRP-expressing neurons. These data strongly suggest that the hypothalamic melanocortin system does not mediate the hunger-curbing effects induced by changes in the macronutrient composition of food. Rather, the role of this system might be to defend the body against the variations in food intake generated by the nutritional environment. PMID:21544212

Contribution of regional brain melanocortin receptor subtypes to elevated activity energy expenditure in lean, active rats

PubMed Central

Shukla, Charu; Koch, Lauren G.; Britton, Steven L.; Cai, Minying; Hruby, Victor J.; Bednarek, Maria; Novak, Colleen M.

2015-01-01

Physical activity and non-exercise activity thermogenesis (NEAT) are crucial factors accounting for individual differences in body weight, interacting with genetic predisposition. In the brain, a number of neuroendocrine intermediates regulate food intake and energy expenditure (EE); this includes the brain melanocortin (MC) system, consisting of melanocortin peptides as well as their receptors (MCR). MC3R and MC4R have emerged as critical modulators of EE and food intake. To determine how variance in MC signaling may underlie individual differences in physical activity levels, we examined behavioral response to MC receptor agonists and antagonists in rats that show high and low levels of physical activity and NEAT, that is, high- and low-capacity runners (HCR, LCR), developed by artificial selection for differential intrinsic aerobic running capacity. Focusing on the hypothalamus, we identified brain region-specific elevations in expression of MCR 3, 4, and also MC5R, in the highly active, lean HCR relative to the less active and obesity-prone LCR. Further, the differences in activity and associated EE as a result of MCR activation or suppression using specific agonists and antagonists were similarly region-specific and directly corresponded to the differential MCR expression patterns. The agonists and antagonists investigated here did not significantly impact food intake at the doses used, suggesting that the differential pattern of receptor expression may by more meaningful to physical activity than to other aspects of energy balance regulation. Thus, MCR-mediated physical activity may be a key neural mechanism in distinguishing the lean phenotype and a target for enhancing physical activity and NEAT. PMID:26404873

Hypothalamic opioid-melanocortin appetitive balance and addictive craving.

PubMed

Reece, Albert Stuart

2011-01-01

Whilst the parallels between drug and food craving are receiving increasing attention, the recently elucidated complex physiology of the hypothalamic appetite regulatory centres has been largely overlooked in the efforts to understand drug craving which is one of the most refractory and problematic aspects of drug and behavioural addictions. Important conceptual gains could be made by researchers from both appetite and addiction neuroscience if they were to have an improved understanding of each others' disciplines. It is well known in addiction medicine that the use of many substances is elevated in opiate dependency. There is voluminous evidence of very high rates of drug use in opiate agonist maintained patients, and the real possibility exists that opiate agonist therapy therefore increases drug craving. Conversely, opiate antagonist therapy with naloxone or naltrexone has been shown to reduce most chemical and behavioural addictions, and naltrexone is now being developed together with bupropion as the anti-obesity drug "Contrave". Hypothalamic melanocortins, particularly α-MSH, are known to constitute the main brake to consumptive behaviour of food. There is a well described antagonism between melanocortins and opioids at many loci including the hypothalamus. Administration of exogenous opiates is known to both suppress α-MSH and to stimulate hedonic food consumption. Opiate maintenance programs are associated with weight gain. As monoamines, opioids and cannabinoids are known to be involved in appetite regulation, and as endorphin opioids are known to be perturbed in other addictions, further exploration of the hypothalamic appetite regulatory centre would appear to be an obvious, albeit presently largely overlooked, locus in which to study drug and other craving mechanisms. Copyright © 2010 Elsevier Ltd. All rights reserved.

Profound and rapid reduction in body temperature induced by the melanocortin receptor agonists

USDA-ARS?s Scientific Manuscript database

The melanocortin receptor 4 (MC4R) plays a major role in body weight regulation and its agonist MTII has been widely used to study the role of MC4Rs in energy expenditure promotion and feeding reduction. Unexpectedly, we observed that intraperitoneal (i.p.) administration of MTII induced a rapid red...

A local duplication of the Melanocortin receptor 1 locus in Astyanax

PubMed Central

Gross, Joshua B.; Weagley, James; Stahl, Bethany A.; Ma, Li; Espinasa, Luis; McGaugh, Suzanne E.

2017-01-01

In this study, we report evidence of a novel duplication of Melanocortin receptor 1 (Mc1r) in the cavefish genome. This locus was discovered following the observation of excessive allelic diversity in a ~820 bp fragment of Mc1r amplified via degenerate PCR from a natural population of Astyanax aeneus fish from Guerrero, Mexico. The cavefish genome reveals the presence of two closely related Mc1r open reading frames separated by a 1.46 kb intergenic region. One open reading frame corresponds to the previously reported Mc1r receptor, and the other open reading frame (duplicate copy) is 975 bp in length, encoding a receptor of 325 amino acids. Sequence similarity analyses position both copies in the syntenic region of the single Mc1r locus in 16 representative craniate genomes spanning bony fish (including Astyanax) to mammals, suggesting we discovered tandem duplicates of this important gene. The two Mc1r copies share ~89% sequence similarity, and, within Astyanax, are more similar to one another compared to other melanocortin family members. Future studies will inform the precise functional significance of the duplicated Mc1r locus, and if this novel copy number variant may have adaptive significance for the Astyanax lineage. PMID:28738163

Power line interference attenuation in multi-channel sEMG signals: Algorithms and analysis.

PubMed

Soedirdjo, S D H; Ullah, K; Merletti, R

2015-08-01

Electromyogram (EMG) recordings are often corrupted by power line interference (PLI) even though the skin is prepared and well-designed instruments are used. This study focuses on the analysis of some of the recent and classical existing digital signal processing approaches have been used to attenuate, if not eliminate, the power line interference from EMG signals. A comparison of the signal to interference ratio (SIR) of the output signals is presented, for four methods: classical notch filter, spectral interpolation, adaptive noise canceller with phase locked loop (ANC-PLL) and adaptive filter, applied to simulated multichannel monopolar EMG signals with different SIR. The effect of each method on the shape of the EMG signals is also analyzed. The results show that ANC-PLL method gives the best output SIR and lowest shape distortion compared to the other methods. Classical notch filtering is the simplest method but some information might be lost as it removes both the interference and the EMG signals. Thus, it is obvious that notch filter has the lowest performance and it introduces distortion into the resulting signals.

N-terminal fatty acylated His-dPhe-Arg-Trp-NH(2) tetrapeptides: influence of fatty acid chain length on potency and selectivity at the mouse melanocortin receptors and human melanocytes.

PubMed

Todorovic, Aleksandar; Holder, Jerry Ryan; Bauzo, Rayna M; Scott, Joseph Walker; Kavanagh, Renny; Abdel-Malek, Zalfa; Haskell-Luevano, Carrie

2005-05-05

The melanocortin system is involved in the regulation of a diverse number of physiologically important pathways including pigmentation, feeding behavior, weight and energy homeostasis, inflammation, and sexual function. All the endogenous melanocortin agonist ligands possess the conserved His-Phe-Arg-Trp tetrapeptide sequence that is postulated to be important for melanocortin receptor molecular recognition and stimulation. Previous studies by our laboratory resulted in the discovery that increasing alkyl chain length at the N-terminal "capping" region of the His-dPhe-Arg-Trp-NH(2) tetrapeptide resulted in a 100-fold increased melanocortin receptor agonist potency. This study was undertaken to systematically evaluate the pharmacological effects of increasing N-capping alkyl chain length of the CH(3)(CH(2))(n)CO-His-dPhe-Arg-Trp-NH(2) (n = 6-16) tetrapeptide template. Twelve analogues were synthesized and pharmacologically characterized at the mouse melanocortin receptors MC1R and MC3R-MC5R and human melanocytes known to express the MC1R. These peptides demonstrated melanocortin receptor selectivity profiles different from those of previously published tetrapeptides. The most notable results of enhanced ligand potency (20- to 200-fold) and receptor selectivity were observed at the MC1R. Tetrapeptides that possessed greater than nine alkyl groups were superior to alpha-MSH in terms of the stimulation of human melanocyte tyrosinase activity. Additionally, the n-pentadecanoyl derivative had a residual effect on tyrosinase activity that existed for at least 4 days after the peptide was removed from the human melanocyte culture medium. These data demonstrate the utility, potency, and residual effect of melanocortin tetrapeptides by adding N-terminal fatty acid moieties.

General pulsed-field gradient signal attenuation expression based on a fractional integral modified-Bloch equation

NASA Astrophysics Data System (ADS)

Lin, Guoxing

2018-10-01

Anomalous diffusion has been investigated in many polymer and biological systems. The analysis of PFG anomalous diffusion relies on the ability to obtain the signal attenuation expression. However, the general analytical PFG signal attenuation expression based on the fractional derivative has not been previously reported. Additionally, the reported modified-Bloch equations for PFG anomalous diffusion in the literature yielded different results due to their different forms. Here, a new integral type modified-Bloch equation based on the fractional derivative for PFG anomalous diffusion is proposed, which is significantly different from the conventional differential type modified-Bloch equation. The merit of the integral type modified-Bloch equation is that the original properties of the contributions from linear or nonlinear processes remain unchanged at the instant of the combination. From the modified-Bloch equation, the general solutions are derived, which includes the finite gradient pulse width (FGPW) effect. The numerical evaluation of these PFG signal attenuation expressions can be obtained either by the Adomian decomposition, or a direct integration method that is fast and practicable. The theoretical results agree with the continuous-time random walk (CTRW) simulations performed in this paper. Additionally, the relaxation effect in PFG anomalous diffusion is found to be different from that in PFG normal diffusion. The new modified-Bloch equations and their solutions provide a fundamental tool to analyze PFG anomalous diffusion in nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI).

Hypothalamic signaling in anorexia induced by indispensable amino acid deficiency

PubMed Central

Zhu, Xinxia; Krasnow, Stephanie M.; Roth-Carter, Quinn R.; Levasseur, Peter R.; Braun, Theodore P.; Grossberg, Aaron J.

2012-01-01

Animals exhibit a rapid and sustained anorexia when fed a diet that is deficient in a single indispensable amino acid (IAA). The chemosensor for IAA deficiency resides within the anterior piriform cortex (APC). Although the cellular and molecular mechanisms by which the APC detects IAA deficiency are well established, the efferent neural pathways that reduce feeding in response to an IAA-deficient diet remain to be fully characterized. In the present work, we investigated whether 1) central melanocortin signaling is involved in IAA deficiency-induced anorexia (IAADA) and 2) IAADA engages other key appetite-regulating neuronal populations in the hypothalamus. Rats and mice that consumed a valine-deficient diet (VDD) for 2–3 wk exhibited marked reductions in food intake, body weight, fat and lean body mass, body temperature, and white adipose tissue leptin gene expression, as well as a paradoxical increase in brown adipose tissue uncoupling protein-1 mRNA. Animals consuming the VDD had altered hypothalamic gene expression, typical of starvation. Pharmacological and genetic blockade of central melanocortin signaling failed to increase long-term food intake in this model. Chronic IAA deficiency was associated with a marked upregulation of corticotropin-releasing hormone expression in the lateral hypothalamus, particularly in the parasubthalamic nucleus, an area heavily innervated by efferent projections from the APC. Our observations indicate that the hypothalamic melanocortin system plays a minor role in acute, but not chronic, IAADA and suggest that the restraint on feeding is analogous to that observed after chronic dehydration. PMID:23047987

Brain-derived neurotrophic factor in human subjects with function-altering melanocortin-4 receptor variants

USDA-ARS?s Scientific Manuscript database

In rodents, hypothalamic brain-derived neurotrophic factor (BDNF) expression appears to be regulated by melanocortin-4 receptor (MC4R) activity. The impact of MC4R genetic variation on circulating BDNF in humans is unknown. The objective of this study is to compare BDNF concentrations of subjects wi...

The melanocortin receptor agonist NDP-MSH impairs the allostimulatory function of dendritic cells.

PubMed

Rennalls, La'Verne P; Seidl, Thomas; Larkin, James M G; Wellbrock, Claudia; Gore, Martin E; Eisen, Tim; Bruno, Ludovica

2010-04-01

As alpha-melanocyte-stimulating hormone (alpha-MSH) is released by immunocompetent cells and has potent immunosuppressive properties, it was determined whether human dendritic cells (DCs) express the receptor for this hormone. Reverse transcription-polymerase chain reaction detected messenger RNA specific for all of the known melanocortin receptors in DCs. Mixed lymphocyte reactions also revealed that treatment with [Nle(4), DPhe(7)]-alpha-MSH (NDP-MSH), a potent alpha-MSH analogue, significantly reduced the ability of DCs to stimulate allogeneic T cells. The expression of various cell surface adhesion, maturation and costimulatory molecules on DCs was also investigated. Although treatment with NDP-MSH did not alter the expression of CD83 and major histocompatibility complex class I and II, the surface expression of CD86 (B7.2), intercellular adhesion molecule (ICAM-1/CD54) and CD1a was reduced. In summary, our data indicate that NDP-MSH inhibits the functional activity of DCs, possibly by down-regulating antigen-presenting and adhesion molecules and that these events may be mediated via the extracellular signal-regulated kinase 1 and 2 pathway.

Site Effects, Attenuation and Signal Duration in the 1356 Basel Earthquake Area (Southern Upper Rhine Graben))

NASA Astrophysics Data System (ADS)

GRANET, M.; BOITEL, G.

2001-12-01

A field experiment has been carried out in the epicentral area of the Basel (northern Switzerland) earthquake of 18 October 1356, the largest historical earthquake in central Europe, with the aim to better characterize the spatial variability of the amplitudes of the seismic waves due to the local geology. Such site effects evaluation are needed in seismic engineering in order to establish effective building codes. In order to determine the site effects, we used a spectral ratio method, utilizing the data collected from a mobile network of 45 stations, installed from March to August 2000. As the main result, we found resonant peak amplitudes at 3, 4 and 6 Hz, which are more pronounced when the seismic stations are located on the sediments. From the same data set, attenuation laws have been calculated. They show the importance of the geometrical attenuation in this region and the influence of the local geology on the amplitude of ground velocities. Finally, we notice that the velocities are more amplified for the lower part of the observed seismic signal frequency band. The computation of relations linking the duration of the signal to the magnitude, the distance and the local geology shows a good correlation of stations characterized by long duration signals with those affected by site effects. As for ground velocities, the duration becomes also more significant at the low frequencies. Finally, we computed the quality factor QP using the spectral ratio method. Unfortunately does the limited number of available data prevent us to obtain a very detailed model. Nevertheless does QP show a very significant attenuation across the whole area, without large contrasts, and a decrease of the attenuation with increasing frequencies. To conclude, this newly collected data set from a dense array of 45 stations in this tectonically active and hazardous area shows large site effects associated with an increasing of both amplitudes and duration of the signal, especially at low

Promiscuous dimerization of the growth hormone secretagogue receptor (GHS-R1a) attenuates ghrelin-mediated signaling.

PubMed

Schellekens, Harriët; van Oeffelen, Wesley E P A; Dinan, Timothy G; Cryan, John F

2013-01-04

G protein-coupled receptors (GPCRs), such as the ghrelin receptor (GHS-R1a), the melanocortin 3 receptor (MC(3)), and the serotonin 2C receptor (5-HT(2C)), are well known for their key role in the homeostatic control of food intake and energy balance. Ghrelin is the only known gut peptide exerting an orexigenic effect and has thus received much attention as an anti-obesity drug target. In addition, recent data have revealed a critical role for ghrelin in dopaminergic mesolimbic circuits involved in food reward signaling. This study investigates the downstream signaling consequences and ligand-mediated co-internalization following heterodimerization of the GHS-R1a receptor with the dopamine 1 receptor, as well as that of the GHS-R1a-MC(3) heterodimer. In addition, a novel heterodimer between the GHS-R1a receptor and the 5-HT(2C) receptor was identified. Interestingly, dimerization of the GHS-R1a receptor with the unedited 5-HT(2C)-INI receptor, but not with the partially edited 5-HT(2C)-VSV isoform, significantly reduced GHS-R1a agonist-mediated calcium influx, which was completely restored following pharmacological blockade of the 5-HT(2C) receptor. These results combined suggest a potential novel mechanism for fine-tuning GHS-R1a receptor-mediated activity via promiscuous dimerization of the GHS-R1a receptor with other G protein-coupled receptors involved in appetite regulation and food reward. These findings may uncover novel mechanisms of significant relevance for the future pharmacological targeting of the GHS-R1a receptor in the homeostatic regulation of energy balance and in hedonic appetite signaling, both of which play a significant role in the development of obesity.

Prediction of attenuation of the 28 GHz COMSTAR beacon signal using radar and measured rain drop spectra

NASA Technical Reports Server (NTRS)

Goldhirsh, J.

1977-01-01

Disdrometer measurements and radar reflectivity measurements were injected into a computer program to estimate the path attenuation of the signal. Predicted attenuations when compared with the directly measured ones showed generally good correlation on a case by case basis and very good agreement statistically. The utility of using radar in conjunction with disdrometer measurements for predicting fade events and long term fade distributions associated with earth-satellite telecommunications is demonstrated.

Melanocortin antagonism ameliorates muscle wasting and inflammation in chronic kidney disease.

PubMed

Cheung, Wai W; Mak, Robert H

2012-11-01

Aberrant melanocortin signaling has been implicated in the pathogenesis of wasting in chronic kidney disease (CKD). Previously, we demonstrated that agouti-related peptide (AgRP), a melenocortin-4 receptor antagonist, reduced CKD-associated cachexia in CKD mice. Our previous studies with AgRP utilized dual energy X-ray (DXA) densitometry to assess the body composition in mice (Cheung W, Kuo HJ, Markison S, Chen C, Foster AC, Marks DL, Mak RH. J Am Soc Nephrol 18: 2517-2524, 2007; Cheung W, Yu PX, Little BM, Cone RD, Marks DL, Mak RH. J Clin Invest 115: 1659-1665, 2005). DXA is unable to differentiate water content in mice, and fluid retention in CKD may lead to an overestimate of lean mass. In this study, we employed quantitative magnetic resonance technique to evaluate body composition change following central administration of AgRP in a CKD mouse model. AgRP treatment improved energy expenditure, total body mass, fat mass, and lean body mass in CKD mouse. We also investigated the effect of CKD-associated cachexia on the signaling pathways leading to wasting in skeletal muscle, as well as whether these changes can be ameliorated by central administration of AgRP. AgRP treatment caused an overall decrease in proinflammatory cytokines, which may be one important mechanism of its effects. Muscle wasting in CKD may be due to the activation of proteolytic pathways as well as inhibition of myogenesis and muscle regeneration processes. Our results suggest that these aberrant pathological pathways leading to muscle wasting in CKD mice were ameliorated by central administration of AgRP.

Fluid-attenuated inversion recovery: correlations of hippocampal cell densities with signal abnormalities.

PubMed

Diehl, B; Najm, I; Mohamed, A; Wyllie, E; Babb, T; Ying, Z; Hilbig, A; Bingaman, W; Lüders, H O; Ruggieri, P

2001-09-25

Hippocampal sclerosis (HS) is characterized by hippocampal atrophy and increased signal on T2-weighted images and on fluid-attenuated inversion recovery (FLAIR) images. To quantitate cell loss and compare it with signal abnormalities on FLAIR images. Thirty-one patients with temporal lobe resection, pathologically proven HS, and Engel class I and II outcome were included: 20 with HS only and 11 with HS associated with pathologically proven cortical dysplasia (dual pathology). The signal intensity on FLAIR was rated as present or absent in the hippocampus and correlated with the neuronal losses in the hippocampus. FLAIR signal increases were present in 77% (24/31) of all patients studied. In patients with isolated HS, 90% (18/20) had ipsilateral signal increases, but in patients with dual pathology, only 55% (6/11; p < 0.02) showed FLAIR signal increase. Hippocampal cell losses were significantly higher in the isolated HS group. The average cell loss in patients with FLAIR signal abnormalities was 64.8 +/- 8.0% as compared with only 32.7 +/- 5.1% in patients with no FLAIR signal abnormalities. There was a significant positive correlation between the presence of signal abnormality and average hippocampal cell loss in both pathologic groups. Ipsilateral FLAIR signal abnormalities occur in the majority of patients with isolated HS but are less frequent in those with dual pathology. The presence of increased FLAIR signal is correlated with higher hippocampal cell loss.

Melanocortin-1 receptor activation is neuroprotective in mouse models of neuroinflammatory disease.

PubMed

Mykicki, Nadine; Herrmann, Alexander M; Schwab, Nicholas; Deenen, René; Sparwasser, Tim; Limmer, Andreas; Wachsmuth, Lydia; Klotz, Luisa; Köhrer, Karl; Faber, Cornelius; Wiendl, Heinz; Luger, Thomas A; Meuth, Sven G; Loser, Karin

2016-10-26

In inflammation-associated progressive neuroinflammatory disorders, such as multiple sclerosis (MS), inflammatory infiltrates containing T helper 1 (T H 1) and T H 17 cells cause demyelination and neuronal degeneration. Regulatory T cells (T reg ) control the activation and infiltration of autoreactive T cells into the central nervous system (CNS). In MS and experimental autoimmune encephalomyelitis (EAE) in mice, T reg function is impaired. We show that a recently approved drug, Nle 4 -d-Phe 7 -α-melanocyte-stimulating hormone (NDP-MSH), induced functional T reg , resulting in amelioration of EAE progression in mice. NDP-MSH also prevented immune cell infiltration into the CNS by restoring the integrity of the blood-brain barrier. NDP-MSH exerted long-lasting neuroprotective effects in mice with EAE and prevented excitotoxic death and reestablished action potential firing in mouse and human neurons in vitro. Neuroprotection by NDP-MSH was mediated via signaling through the melanocortin-1 and orphan nuclear 4 receptors in mouse and human neurons. NDP-MSH may be of benefit in treating neuroinflammatory diseases such as relapsing-remitting MS and related disorders. Copyright © 2016, American Association for the Advancement of Science.

Selective melanocortin MC4 receptor agonists reverse haemorrhagic shock and prevent multiple organ damage

PubMed Central

Giuliani, D; Mioni, C; Bazzani, C; Zaffe, D; Botticelli, A R; Capolongo, S; Sabba, A; Galantucci, M; Iannone, A; Grieco, P; Novellino, E; Colombo, G; Tomasi, A; Catania, A; Guarini, S

2007-01-01

Background and purpose: In circulatory shock, melanocortins have life-saving effects likely to be mediated by MC4 receptors. To gain direct insight into the role of melanocortin MC4 receptors in haemorrhagic shock, we investigated the effects of two novel selective MC4 receptor agonists. Experimental approach: Severe haemorrhagic shock was produced in rats under general anaesthesia. Rats were then treated with either the non-selective agonist [Nle4, D-Phe7]α-melanocyte-stimulating hormone (NDP-α-MSH) or with the selective MC4 agonists RO27-3225 and PG-931. Cardiovascular and respiratory functions were continuously monitored for 2 h; survival rate was recorded up to 24 h. Free radicals in blood were measured using electron spin resonance spectrometry; tissue damage was evaluated histologically 25 min or 24 h after treatment. Key results: All shocked rats treated with saline died within 30-35 min. Treatment with NDP-α-MSH, RO27-3225 and PG-931 produced a dose-dependent (13-108 nmol kg-1 i.v.) restoration of cardiovascular and respiratory functions, and improved survival. The three melanocortin agonists also markedly reduced circulating free radicals relative to saline-treated shocked rats. All these effects were prevented by i.p. pretreatment with the selective MC4 receptor antagonist HS024. Moreover, treatment with RO27-3225 prevented morphological and immunocytochemical changes in heart, lung, liver, and kidney, at both early (25 min) and late (24 h) intervals. Conclusions and Implications: Stimulation of MC4 receptors reversed haemorrhagic shock, reduced multiple organ damage and improved survival. Our findings suggest that selective MC4 receptor agonists could have a protective role against multiple organ failure following circulatory shock. PMID:17245369

Endogenous Melanocortin System Activity Contributes to the Elevated Arterial Pressure in Spontaneously Hypertensive Rats

PubMed Central

da Silva, Alexandre A.; do Carmo, Jussara M.; Kanyicska, Bela; Dubinion, John; Brandon, Elizabeth; Hall, John E.

2009-01-01

Previous studies suggest that activation of the CNS melanocortin system reduces appetite while increasing sympathetic activity and arterial pressure. The present study tested whether endogenous activity of the CNS melanocortin 3/4 receptors (MC3/4-R) contributes to elevated arterial pressure in the spontaneously hypertensive rat (SHR), a model of hypertension with increased sympathetic activity. A cannula was placed in the lateral ventricle of male SHR and Wistar (WKY) rats for chronic intracerebroventricular (ICV) infusions (0.5 μL/h). Mean arterial pressure (MAP) and heart rate (HR) were recorded 24 hour/d using telemetry. After 5-day control period, rats were infused with MC3/4-R antagonist (SHU-9119, 1 nmol/h-ICV) for 12 days, followed by 5-day posttreatment period. MC3/4-R antagonism increased food intake in SHR by 90% and in WKY by 125%, resulting in marked weight gain, insulin resistance, and hyperleptinemia in SHR and WKY. Despite weight gain, MC3/4-R antagonism reduced HR in SHR and WKY (≈40 bpm), while lowering MAP to a greater extent in SHR (−22±4 mm Hg) than WKY (−4±3 mm Hg). SHU9119 treatment failed to cause further reductions in MAP during chronic adrenergic blockade with propranolol and terazosin. These results suggest that endogenous activity of the CNS melanocortin system contributes to the maintenance of adrenergic tone and elevated arterial pressure in SHR even though mRNA levels for POMC and MC4R in the mediobasal hypothalamus were not increased compared to WKY. These results also support the hypothesis that weight gain does not raise arterial pressure in the absence of a functional MC3/4-R. PMID:18285617

Effect of vertical sleeve gastrectomy in melanocortin receptor 4-deficient rats.

PubMed

Mul, Joram D; Begg, Denovan P; Alsters, Suzanne I M; van Haaften, Gijs; Duran, Karen J; D'Alessio, David A; le Roux, Carel W; Woods, Stephen C; Sandoval, Darleen A; Blakemore, Alexandra I F; Cuppen, Edwin; van Haelst, Mieke M; Seeley, Randy J

2012-07-01

Bariatric surgery is currently the most effective treatment for obesity. Vertical sleeve gastrectomy (VSG), a commonly applied bariatric procedure, involves surgically incising most of the volume of the stomach. In humans, partial loss of melanocortin receptor-4 (MC4R) activity is the most common monogenic correlate of obesity regardless of lifestyle. At present it is unclear whether genetic alteration of MC4R signaling modulates the beneficial effects of VSG. Following VSG, we analyzed body weight, food intake, glucose sensitivity, and macronutrient preference of wild-type and MC4R-deficient (Mc4r(+/-) and Mc4r(-/-)) rats compared with sham-operated controls. VSG reduced body weight and fat mass and improved glucose metabolism and also shifted preference toward carbohydrates and away from fat. All of this occurred independently of MC4R activity. In addition, MC4R was resequenced in 46 human subjects who underwent VSG. We observed common genetic variations in the coding sequence of MC4R in five subjects. However, none of those variations appeared to affect the outcome of VSG. Taken together, these data suggest that the beneficial effect of VSG on body weight and glucose metabolism is not mediated by alterations in MC4R activity.

Effect of vertical sleeve gastrectomy in melanocortin receptor 4-deficient rats

PubMed Central

Mul, Joram D.; Begg, Denovan P.; Alsters, Suzanne I. M.; van Haaften, Gijs; Duran, Karen J.; D'Alessio, David A.; le Roux, Carel W.; Woods, Stephen C.; Sandoval, Darleen A.; Blakemore, Alexandra I. F.; Cuppen, Edwin; van Haelst, Mieke M.

2012-01-01

Bariatric surgery is currently the most effective treatment for obesity. Vertical sleeve gastrectomy (VSG), a commonly applied bariatric procedure, involves surgically incising most of the volume of the stomach. In humans, partial loss of melanocortin receptor-4 (MC4R) activity is the most common monogenic correlate of obesity regardless of lifestyle. At present it is unclear whether genetic alteration of MC4R signaling modulates the beneficial effects of VSG. Following VSG, we analyzed body weight, food intake, glucose sensitivity, and macronutrient preference of wild-type and MC4R-deficient (Mc4r+/− and Mc4r−/−) rats compared with sham-operated controls. VSG reduced body weight and fat mass and improved glucose metabolism and also shifted preference toward carbohydrates and away from fat. All of this occurred independently of MC4R activity. In addition, MC4R was resequenced in 46 human subjects who underwent VSG. We observed common genetic variations in the coding sequence of MC4R in five subjects. However, none of those variations appeared to affect the outcome of VSG. Taken together, these data suggest that the beneficial effect of VSG on body weight and glucose metabolism is not mediated by alterations in MC4R activity. PMID:22535749

Binding, Thermodynamics, and Selectivity of a Non-peptide Antagonist to the Melanocortin-4 Receptor

PubMed Central

Saleh, Noureldin; Kleinau, Gunnar; Heyder, Nicolas; Clark, Timothy; Hildebrand, Peter W.; Scheerer, Patrick

2018-01-01

The melanocortin-4 receptor (MC4R) is a potential drug target for treatment of obesity, anxiety, depression, and sexual dysfunction. Crystal structures for MC4R are not yet available, which has hindered successful structure-based drug design. Using microsecond-scale molecular-dynamics simulations, we have investigated selective binding of the non-peptide antagonist MCL0129 to a homology model of human MC4R (hMC4R). This approach revealed that, at the end of a multi-step binding process, MCL0129 spontaneously adopts a binding mode in which it blocks the agonistic-binding site. This binding mode was confirmed in subsequent metadynamics simulations, which gave an affinity for human hMC4R that matches the experimentally determined value. Extending our simulations of MCL0129 binding to hMC1R and hMC3R, we find that receptor subtype selectivity for hMC4R depends on few amino acids located in various structural elements of the receptor. These insights may support rational drug design targeting the melanocortin systems.

Linear scaffolds for multivalent targeting of melanocortin receptors.

PubMed

Dehigaspitiya, Dilani Chathurika; Anglin, Bobbi L; Smith, Kara R; Weber, Craig S; Lynch, Ronald M; Mash, Eugene A

2015-12-21

Molecules bearing one, two, three, or four copies of the tetrapeptide His-dPhe-Arg-Trp were attached to scaffolds based on ethylene glycol, glycerol, and d-mannitol by means of the copper-assisted azide-alkyne cyclization. The abilities of these compounds to block binding of a probe at the melanocortin 4 receptor were evaluated using a competitive binding assay. All of the multivalent molecules studied exhibited 30- to 40-fold higher apparent affinites when compared to a monovalent control. These results are consistent with divalent binding to receptor dimers. No evidence for tri- or tetravalent binding was obtained. Differences in the interligand spacing required for divalent binding, as opposed to tri- or tetravalent binding, may be responsible for these results.

IL-1β impairs retrograde flow of BDNF signaling by attenuating endosome trafficking.

PubMed

Carlos, Anthony J; Tong, Liqi; Prieto, G Aleph; Cotman, Carl W

2017-02-02

Pro-inflammatory cytokines accumulate in the brain with age and Alzheimer's disease and can impair neuron health and cognitive function. Brain-derived neurotrophic factor (BDNF) is a key neurotrophin that supports neuron health, function, and synaptic plasticity. The pro-inflammatory cytokine interleukin-1β (IL-1β) impairs BDNF signaling but whether it affects BDNF signaling endosome trafficking has not been studied. This study uses an in vitro approach in primary hippocampal neurons to evaluate the effect of IL-1β on BDNF signaling endosome trafficking. Neurons were cultured in microfluidic chambers that separate the environments of the cell body and its axon terminal, enabling us to specifically treat in axon compartments and trace vesicle trafficking in real-time. We found that IL-1β attenuates BDNF signaling endosomes throughout networks in cultures. In IL-1β-treated cells, overall BDNF endosomal density was decreased, and the colocalization of BDNF endosomes with presynaptic terminals was found to be more than two times higher than in control cultures. Selective IL-1β treatment to the presynaptic compartment in microfluidic chamber attenuated BDNF endosome flux, as measured by reduced BDNF-GFP endosome counts in the somal compartment. Further, IL-1β decreased the BDNF-induced phosphorylation of Erk5, a known BDNF retrograde trafficking target. Mechanistically, the deficiency in trafficking was not due to impaired endocytosis of the BDNF-TrkB complex, or impaired transport rate, since BDNF endosomes traveled at the same rate in both control and IL-1β treatment groups. Among the regulators of presynaptic endosome sorting is the post-translational modification, ubiquitination. In support of this possibility, the IL-1β-mediated suppression of BDNF-induced Erk5 phosphorylation can be rescued by exogenous ubiquitin C-terminal hydrolase L1 (UCH-L1), a deubiquitinating enzyme that regulates ubiquitin and endosomal trafficking. We observed a state of

The melanocortins and melanin-concentrating hormone in the central regulation of feeding behavior and energy homeostasis.

PubMed

Nahon, Jean-Louis

2006-08-01

A number of different neuropeptides exert powerful concerted controls on feeding behavior and energy balance, most of them being produced in hypothalamic neuronal networks under stimulation by anabolic and catabolic peripheral hormones such as ghrelin and leptin, respectively. These peptide-expressing neurons interconnect extensively to integrate the multiple opposing signals that mediate changes in energy expenditure. In the present review I have summarized our current knowledge about two key peptidic systems involved in regulating appetite and energy homeostasis, the melanocortin system (alpha-MSH, agouti and Agouti-related peptides, MC receptors and mahogany protein) and the melanin-concentrating hormone system (proMCH-derived peptides and MCH receptors) that contribute to satiety and feeding-initiation, respectively, with concurrent effects on energy expenditure. I have focused particularly on recent data concerning transgenic mice and the ongoing development of MC/MCH receptor antagonists/agonists that may represent promising drugs to treat human eating disorders on both sides of the energy balance (anorexia, obesity).

Chlorine signal attenuation in concrete.

PubMed

Naqvi, A A; Maslehuddin, M; Ur-Rehman, Khateeb; Al-Amoudi, O S B

2015-11-01

The intensity of prompt gamma-ray was measured at various depths from chlorine-contaminated silica fume (SF) concrete slab concrete specimens using portable neutron generator-based prompt gamma-ray setup. The intensity of 6.11MeV chloride gamma-rays was measured from the chloride contaminated slab at distance of 15.25, 20.25, 25.25, 30.25 and 35.25cm from neutron target in a SF cement concrete slab specimens. Due to attenuation of thermal neutron flux and emitted gamma-ray intensity in SF cement concrete at various depths, the measured intensity of chlorine gamma-rays decreases non-linearly with increasing depth in concrete. A good agreement was noted between the experimental results and the results of Monte Carlo simulation. This study has provided useful experimental data for evaluating the chloride contamination in the SF concrete utilizing gamma-ray attenuation method. Copyright © 2015 Elsevier Ltd. All rights reserved.

Melanocortin 1 Receptor Deficiency Promotes Atherosclerosis in Apolipoprotein E-/- Mice.

PubMed

Rinne, Petteri; Kadiri, James J; Velasco-Delgado, Mauricio; Nuutinen, Salla; Viitala, Miro; Hollmén, Maija; Rami, Martina; Savontaus, Eriika; Steffens, Sabine

2018-02-01

The MC1-R (melanocortin 1 receptor) is expressed by monocytes and macrophages where it mediates anti-inflammatory actions. MC1-R also protects against macrophage foam cell formation primarily by promoting cholesterol efflux through the ABCA1 (ATP-binding cassette transporter subfamily A member 1) and ABCG1 (ATP-binding cassette transporter subfamily G member 1). In this study, we aimed to investigate whether global deficiency in MC1-R signaling affects the development of atherosclerosis. Apoe -/- (apolipoprotein E deficient) mice were crossed with recessive yellow (Mc1r e/e ) mice carrying dysfunctional MC1-R and fed a high-fat diet to induce atherosclerosis. Apoe -/- Mc1r e/e mice developed significantly larger atherosclerotic lesions in the aortic sinus and in the whole aorta compared with Apoe -/- controls. In terms of plaque composition, MC1-R deficiency was associated with less collagen and smooth muscle cells and increased necrotic core, indicative of more vulnerable lesions. These changes were accompanied by reduced Abca1 and Abcg1 expression in the aorta. Furthermore, Apoe -/- Mc1r e/e mice showed a defect in bile acid metabolism that aggravated high-fat diet-induced hypercholesterolemia and hepatic lipid accumulation. Flow cytometric analysis of leukocyte profile revealed that dysfunctional MC1-R enhanced arterial accumulation of classical Ly6C high monocytes and macrophages, effects that were evident in mice fed a normal chow diet but not under high-fat diet conditions. In support of enhanced arterial recruitment of Ly6C high monocytes, these cells had increased expression of L-selectin and P-selectin glycoprotein ligand 1. The present study highlights the importance of MC1-R in the development of atherosclerosis. Deficiency in MC1-R signaling exacerbates atherosclerosis by disturbing cholesterol handling and by increasing arterial monocyte accumulation. © 2017 The Authors.

Identification of putative agouti-related protein(87-132)-melanocortin-4 receptor interactions by homology molecular modeling and validation using chimeric peptide ligands.

PubMed

Wilczynski, Andrzej; Wang, Xiang S; Joseph, Christine G; Xiang, Zhimin; Bauzo, Rayna M; Scott, Joseph W; Sorensen, Nicholas B; Shaw, Amanda M; Millard, William J; Richards, Nigel G; Haskell-Luevano, Carrie

2004-04-22

Agouti-related protein (AGRP) is one of only two naturally known antagonists of G-protein-coupled receptors (GPCRs) identified to date. Specifically, AGRP antagonizes the brain melanocortin-3 and -4 receptors involved in energy homeostasis. Alpha-melanocyte stimulating hormone (alpha-MSH) is one of the known endogenous agonists for these melanocortin receptors. Insight into putative interactions between the antagonist AGRP amino acids with the melanocortin-4 receptor (MC4R) may be important for the design of unique ligands for the treatment of obesity related diseases and is currently lacking in the literature. A three-dimensional homology molecular model of the mouse MC4 receptor complex with the hAGRP(87-132) ligand docked into the receptor has been developed to identify putative antagonist ligand-receptor interactions. Key putative AGRP-MC4R interactions include the Arg111 of hAGRP(87-132) interacting in a negatively charged pocket located in a cavity formed by transmembrane spanning (TM) helices 1, 2, 3, and 7, capped by the acidic first extracellular loop (EL1) and specifically with the conserved melanocortin receptor residues mMC4R Glu92 (TM2), mMC4R Asp114 (TM3), and mMC4R Asp118 (TM3). Additionally, Phe112 and Phe113 of hAGRP(87-132) putatively interact with an aromatic hydrophobic pocket formed by the mMC4 receptor residues Phe176 (TM4), Phe193 (TM5), Phe253 (TM6), and Phe254 (TM6). To validate the AGRP-mMC4R model complex presented herein from a ligand perspective, we generated nine chimeric peptide ligands based on a modified antagonist template of the hAGRP(109-118) (Tyr-c[Asp-Arg-Phe-Phe-Asn-Ala-Phe-Dpr]-Tyr-NH(2)). In these chimeric ligands, the antagonist AGRP Arg-Phe-Phe residues were replaced by the melanocortin agonist His/D-Phe-Arg-Trp amino acids. These peptides resulted in agonist activity at the mouse melanocortin receptors (mMC1R and mMC3-5Rs). The most notable results include the identification of a novel subnanomolar melanocortin peptide

Melanocortin tetrapeptide Ac-His-DPhe-Arg-Trp-NH2 modified at the para position of the benzyl side chain (DPhe): importance for mouse melanocortin-3 receptor agonist versus antagonist activity.

PubMed

Proneth, Bettina; Pogozheva, Irina D; Portillo, Federico P; Mosberg, Henry I; Haskell-Luevano, Carrie

2008-09-25

The melanocortin-3 and -4 receptors (MC3R, MC4R) have been implicated in energy homeostasis and obesity. Whereas the physiological role of the MC4R is extensively studied, little is known about the MC3R. One caveat is the limited availability of ligands that are selective for the MC3R. Previous studies identified Ac-His-DPhe(p-I)-Arg-Trp-NH 2, which possessed partial agonist/antagonist pharmacology at the mMC3R while retaining full nanomolar agonist pharmacology at the mMC4R. These data allowed for the hypothesis that the DPhe position in melanocortin tetrapeptides can be used to examine ligand side-chain determinants important for differentiation of mMC3R agonist versus antagonist activity. A series of 15 DPhe (7) modified Ac-His-DPhe (7)-Arg-Trp-NH 2 tetrapeptides has been synthesized and pharmacologically characterized. Most notable results include the identification of modifications that resulted in potent antagonists/partial agonists at the mMC3R and full, potent agonists at the mMC4R. These SAR studies provide experimental evidence that the molecular mechanism of antagonism at the mMC3R differentiates this subtype from the mMC4R.

Melanocortin Tetrapeptide Ac-His-DPhe-Arg-Trp-NH2 Modified at the Para Position of the Benzyl Side Chain (DPhe): Importance for Mouse Melanocortin-3 Receptor Agonist versus Antagonist Activity

PubMed Central

Proneth, Bettina; Pogozheva, Irina D.; Portillo, Federico P.; Mosberg, Henry I.; Haskell-Luevano, Carrie

2010-01-01

The melanocortin-3 and -4 receptors (MC3R, MC4R) have been implicated in energy homeostasis and obesity. Whereas the physiological role of the MC4R is extensively studied, little is known about the MC3R. One caveat is the limited availability of ligands that are selective for the MC3R. Previous studies identified Ac-His-DPhe(p-I)-Arg-Trp-NH2, which possessed partial agonist/antagonist pharmacology at the mMC3R while retaining full nanomolar agonist pharmacology at the mMC4R. These data allowed for the hypothesis that the DPhe position in melanocortin tetrapeptides can be used to examine ligand side-chain determinants important for differentiation of mMC3R agonist versus antagonist activity. A series of 15 DPhe7 modified Ac-His-DPhe7-Arg-Trp-NH2 tetrapeptides has been synthesized and pharmacologically characterized. Most notable results include the identification of modifications that resulted in potent antagonists/partial agonists at the mMC3R and full, potent agonists at the mMC4R. These SAR studies provide experimental evidence that the molecular mechanism of antagonism at the mMC3R differentiates this subtype from the mMC4R. PMID:18800761

Melanocortin systems on pigment dispersion in fish chromatophores.

PubMed

Kobayashi, Yuki; Mizusawa, Kanta; Saito, Yumiko; Takahashi, Akiyoshi

2012-01-01

α-Melanocyte-stimulating hormone (α-MSH) is responsible for pigment dispersion in the chromatophores of fish and other tetrapods such as amphibians and reptiles. Recently, we discovered that α-MSH did not always stimulate pigment dispersion because this hormonal peptide exerted no effects on the melanophores of flounders. We assumed that the reduction of α-MSH activity was related to the co-expression of different α-MSH receptor subtypes - termed melanocortin receptors (MCR) - a member of G-protein-coupled receptors (GPCR) - based on several reports demonstrating that GPCR forms heterodimers with various properties that are distinct from those of the corresponding monomers. In this review, we summarize the relationships between the pigment-dispersing activity of α-MSH-related peptides, molecular forms of α-MSH-related peptides, and mcr subtypes expressed in fish chromatophores.

Quercetin Attenuates Cell Survival, Inflammation, and Angiogenesis via Modulation of AKT Signaling in Murine T-Cell Lymphoma.

PubMed

Maurya, Akhilendra Kumar; Vinayak, Manjula

2017-04-01

AKT signaling is important to maintaining normal physiology. Hyperactivation of AKT signaling is frequent in cancer, which maintains a high oxidative state in a tumor microenvironment that is needed for tumor adaptation. Therefore, antioxidants are proposed to exhibit anticancer properties by interfering with the tumor microenvironment. Quercetin is an ubiquitous bioactive antioxidant rich in vegetables and beverages. The present study aimed to analyze cancer preventive property of quercetin in ascite cells of Dalton's lymphoma-bearing mice. Protein level was determined by Western blotting. Nitric oxide (NO) level was estimated spectrophotometrically using Griess reagent. Results show downregulation in phosphorylation of AKT and PDK1 by quercetin, which was consistent with decreased phosphorylation of downstream survival factors such as BAD, GSK-3β, mTOR, and IkBα. Further, quercetin attenuated the levels of angiogenic factor VEGF-A and inflammatory enzymes COX-2 and iNOS as well as NO levels, whereas it increased the levels of phosphatase PTEN. Overall results suggest that quercetin modulates AKT signaling leading to attenuation of cell survival, inflammation, and angiogenesis in lymphoma-bearing mice.

Effects of optical attenuation, heat diffusion, and acoustic coherence in photoacoustic signals produced by nanoparticles

NASA Astrophysics Data System (ADS)

Alba-Rosales, J. E.; Ramos-Ortiz, G.; Escamilla-Herrera, L. F.; Reyes-Ramírez, B.; Polo-Parada, L.; Gutiérrez-Juárez, G.

2018-04-01

The behavior of the photoacoustic signal produced by nanoparticles as a function of their concentration was studied in detail. As the concentration of nanoparticles is increased in a sample, the peak-to-peak photoacoustic amplitude increases linearly up to a certain value, after which an asymptotic saturated behavior is observed. To elucidate the mechanisms responsible for these observations, we evaluate the effects of nanoparticles concentration, the optical attenuation, and the effects of heat propagation from nano-sources to their surroundings. We found that the saturation effect of the photoacoustic signal as a function of the concentration of nanoparticles is explained by a combination of two different mechanisms. As has been suggested previously, but not modeled correctly, the most important mechanism is attributed to optical attenuation. The second mechanism is due to an interference destructive process attributed to the superimposition of the photoacoustic amplitudes generated for each nanoparticle, and this explanation is reinforced through our experimental and simulations results; based on this, it is found that the linear behavior of the photoacoustic amplitude could be restricted to optical densities ≤0.5.

SORLA attenuates EphA4 signaling and amyloid β-induced neurodegeneration.

PubMed

Huang, Timothy Y; Zhao, Yingjun; Jiang, Lu-Lin; Li, Xiaoguang; Liu, Yan; Sun, Yu; Piña-Crespo, Juan C; Zhu, Bing; Masliah, Eliezer; Willnow, Thomas E; Pasquale, Elena B; Xu, Huaxi

2017-12-04

Sortilin-related receptor with LDLR class A repeats (SORLA, SORL1, or LR11) is a genetic risk factor associated with Alzheimer's disease (AD). Although SORLA is known to regulate trafficking of the amyloid β (Aβ) precursor protein to decrease levels of proteotoxic Aβ oligomers, whether SORLA can counteract synaptic dysfunction induced by Aβ oligomers remains unclear. Here, we show that SORLA interacts with the EphA4 receptor tyrosine kinase and attenuates ephrinA1 ligand-induced EphA4 clustering and activation to limit downstream effects of EphA4 signaling in neurons. Consistent with these findings, SORLA transgenic mice, compared with WT mice, exhibit decreased EphA4 activation and redistribution to postsynaptic densities, with milder deficits in long-term potentiation and memory induced by Aβ oligomers. Importantly, we detected elevated levels of active EphA4 in human AD brains, where EphA4 activation is inversely correlated with SORLA/EphA4 association. These results demonstrate a novel role for SORLA as a physiological and pathological EphA4 modulator, which attenuates synaptotoxic EphA4 activation and cognitive impairment associated with Aβ-induced neurodegeneration in AD. © 2017 Huang et al.

Hyperphagia in male melanocortin 4 receptor deficient mice promotes growth independently of growth hormone

PubMed Central

Tan, H. Y.; Huang, L.; Cowley, M.; Veldhuis, J. D.; Chen, C.

2016-01-01

Key points Loss of function of the melanocortin 4 receptor (MC4R) results in hyperphagia, obesity and increased growth.Despite knowing that MC4Rs control food intake, we are yet to understand why defects in the function of the MC4R receptor contribute to rapid linear growth.We show that hyperphagia following germline loss of MC4R in male mice promotes growth while suppressing the growth hormone–insulin‐like growth factor‐1 (GH–IGF‐1) axis.We propose that hyperinsulinaemia promotes growth while suppressing the GH–IGF‐1 axis.It is argued that physiological responses essential to maintain energy flux override conventional mechanisms of pubertal growth to promote the storage of excess energy while ensuring growth. Abstract Defects in melanocortin‐4‐receptor (MC4R) signalling result in hyperphagia, obesity and increased growth. Clinical observations suggest that loss of MC4R function may enhance growth hormone (GH)‐mediated growth, although this remains untested. Using male mice with germline loss of the MC4R, we assessed pulsatile GH release and insulin‐like growth factor‐1 (IGF‐1) production and/or release relative to pubertal growth. We demonstrate early‐onset suppression of GH release in rapidly growing MC4R deficient (MC4RKO) mice, confirming that increased linear growth in MC4RKO mice does not occur in response to enhanced activation of the GH–IGF‐1 axis. The progressive suppression of GH release in MC4RKO mice occurred alongside increased adiposity and the progressive worsening of hyperphagia‐associated hyperinsulinaemia. We next prevented hyperphagia in MC4RKO mice through restricting calorie intake in these mice to match that of wild‐type (WT) littermates. Pair feeding of MC4RKO mice did not prevent increased adiposity, but attenuated hyperinsulinaemia, recovered GH release, and normalized linear growth rate to that seen in pair‐fed WT littermate controls. We conclude that the suppression of GH release in MC4RKO mice occurs

Hypothesis and Theory: Revisiting Views on the Co-evolution of the Melanocortin Receptors and the Accessory Proteins, MRAP1 and MRAP2.

PubMed

Dores, Robert M

2016-01-01

The evolution of the melanocortin receptors (MCRs) is closely associated with the evolution of the melanocortin-2 receptor accessory proteins (MRAPs). Recent annotation of the elephant shark genome project revealed the sequence of a putative MRAP1 ortholog. The presence of this sequence in the genome of a cartilaginous fish raises the possibility that the mrap1 and mrap2 genes in the genomes of gnathostome vertebrates were the result of the chordate 2R genome duplication event. The presence of a putative MRAP1 ortholog in a cartilaginous fish genome is perplexing. Recent studies on melanocortin-2 receptor (MC2R) in the genomes of the elephant shark and the Japanese stingray indicate that these MC2R orthologs can be functionally expressed in CHO cells without co-expression of an exogenous mrap1 cDNA. The novel ligand selectivity of these cartilaginous fish MC2R orthologs is discussed. Finally, the origin of the mc2r and mc5r genes is reevaluated. The distinctive primary sequence conservation of MC2R and MC5R is discussed in light of the physiological roles of these two MCR paralogs.

Hypothesis and Theory: Revisiting Views on the Co-evolution of the Melanocortin Receptors and the Accessory Proteins, MRAP1 and MRAP2

PubMed Central

Dores, Robert M.

2016-01-01

The evolution of the melanocortin receptors (MCRs) is closely associated with the evolution of the melanocortin-2 receptor accessory proteins (MRAPs). Recent annotation of the elephant shark genome project revealed the sequence of a putative MRAP1 ortholog. The presence of this sequence in the genome of a cartilaginous fish raises the possibility that the mrap1 and mrap2 genes in the genomes of gnathostome vertebrates were the result of the chordate 2R genome duplication event. The presence of a putative MRAP1 ortholog in a cartilaginous fish genome is perplexing. Recent studies on melanocortin-2 receptor (MC2R) in the genomes of the elephant shark and the Japanese stingray indicate that these MC2R orthologs can be functionally expressed in CHO cells without co-expression of an exogenous mrap1 cDNA. The novel ligand selectivity of these cartilaginous fish MC2R orthologs is discussed. Finally, the origin of the mc2r and mc5r genes is reevaluated. The distinctive primary sequence conservation of MC2R and MC5R is discussed in light of the physiological roles of these two MCR paralogs. PMID:27445982

Application of a novel design paradigm to generate general nonpeptide combinatorial templates mimicking beta-turns: synthesis of ligands for melanocortin receptors.

PubMed

Webb, Thomas R; Jiang, Luyong; Sviridov, Sergey; Venegas, Ruben E; Vlaskina, Anna V; McGrath, Douglas; Tucker, John; Wang, Jian; Deschenes, Alain; Li, Rongshi

2007-01-01

We report the further application of a novel approach to template and ligand design by the synthesis of agonists of the melanocortin receptor. This design method uses the conserved structural data from the three-dimensional conformations of beta-turn peptides to design rigid nonpeptide templates that mimic the orientation of the main chain C-alpha atoms in a peptide beta-turn. We report details on a new synthesis of derivatives of template 1 that are useful for the synthesis of exploratory libraries. The utility of this technique is further exemplified by several iterative rounds of high-throughput synthesis and screening, which result in new partially optimized nonpeptide agonists for several melanocortin receptors.

Glutamate mediates the function of melanocortin receptor 4 on sim1 neurons in body weight regulation

USDA-ARS?s Scientific Manuscript database

The melanocortin receptor 4 (MC4R) is a well-established mediator of body weight homeostasis. However, the neurotransmitter(s) that mediate MC4R function remain largely unknown; as a result, little is known about the second-order neurons of the MC4R neural pathway. Single-minded 1 (Sim1)-expressing ...

Molecular cloning and pharmacological characterization of giant panda (Ailuropoda melanoleuca) melanocortin-4 receptor.

PubMed

Wang, Zhi-Qiang; Wang, Wei; Shi, Lin; Chai, Ji-Tian; Zhang, Xin-Jun; Tao, Ya-Xiong

2016-04-01

The melanocortin-4 receptor (MC4R) is critical in regulating mammalian food intake and energy expenditure. Giant panda (Ailuropoda melanoleuca), famous as the living fossil, is an endangered species endemic to China. We are interested in exploring the functions of the giant panda MC4R (amMC4R) in regulating energy homeostasis and report herein the molecular cloning and pharmacology of the amMC4R. Sequence analysis revealed that amMC4R was highly homologous (>88%) at nucleotide and amino acid sequences to several mammalian MC4Rs. Western blot revealed that the expression construct myc-amMC4R in pcDNA3.1 was successfully constructed and expressed in HEK293T cells. With human MC4R (hMC4R) as a control, pharmacological characteristics of amMC4R were analyzed with binding and signaling assays. Four agonists, including [Nle(4), D-Phe(7)]-α-melanocyte stimulating hormone (NDP-MSH), α- and β-MSH, and a small molecule agonist, THIQ, were used in binding and signaling assays. We showed that amMC4R bound NDP-MSH with the highest affinity followed by THIQ, α-MSH, and β-MSH, with the same ranking order as hMC4R. Treatment of HEK293T cells expressing amMC4R with different concentrations of agonists resulted in dose-dependent increase of intracellular cAMP levels, with similar EC50s for the four agonists. The results suggested that the cloned amMC4R encoded a functional MC4R. The availability of amMC4R and its binding and signaling properties will facilitate the investigation of amMC4R in regulating food intake and energy homeostasis. Copyright © 2016 Elsevier Inc. All rights reserved.

Structure-activity relationships of the unique and potent agouti-related protein (AGRP)-melanocortin chimeric Tyr-c[beta-Asp-His-DPhe-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH2 peptide template.

PubMed

Wilczynski, Andrzej; Wilson, Krista R; Scott, Joseph W; Edison, Arthur S; Haskell-Luevano, Carrie

2005-04-21

The melanocortin receptor system consists of endogenous agonists, antagonists, G-protein coupled receptors, and auxiliary proteins that are involved in the regulation of complex physiological functions such as energy and weight homeostasis, feeding behavior, inflammation, sexual function, pigmentation, and exocrine gland function. Herein, we report the structure-activity relationship (SAR) of a new chimeric hAGRP-melanocortin agonist peptide template Tyr-c[beta-Asp-His-DPhe-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) that was characterized using amino acids previously reported in other melanocortin agonist templates. Twenty peptides were examined in this study, and six peptides were selected for (1)H NMR and computer-assisted molecular modeling structural analysis. The most notable results include the identification that modification of the chimeric template at the His position with Pro and Phe resulted in ligands that were nM mouse melanocortin-3 receptor (mMC3R) antagonists and nM mouse melanocortin-4 receptor (mMC4R) agonists. The peptides Tyr-c[beta-Asp-His-DPhe-Ala-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) and Tyr-c[beta-Asp-His-DNal(1')-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) resulted in 730- and 560-fold, respectively, mMC4R versus mMC3R selective agonists that also possessed nM agonist potency at the mMC1R and mMC5R. Structural studies identified a reverse turn occurring in the His-DPhe-Arg-Trp domain, with subtle differences observed that may account for the differences in melanocortin receptor pharmacology. Specifically, a gamma-turn secondary structure involving the DPhe(4) in the central position of the Tyr-c[beta-Asp-Phe-DPhe-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) peptide may differentiate the mixed mMC3R antagonist and mMC4R agonist pharmacology.

Involvement of glucocorticoid-mediated Zn2+ signaling in attenuation of hippocampal CA1 LTP by acute stress.

PubMed

Takeda, Atsushi; Suzuki, Miki; Tamano, Haruna; Takada, Shunsuke; Ide, Kazuki; Oku, Naoto

2012-03-01

Glucocorticoid-glutamatergic interactions have been proposed as a potential model to explain stress-mediated impairment of cognition. However, it is unknown whether glucocorticoid-zincergic interactions are involved in this impairment. Histochemically reactive zinc (Zn(2+)) is co-released with glutamate from zincergic neurons. In the present study, involvement of synaptic Zn(2+) in stress-induced attenuation of CA1 LTP was examined in hippocampal slices from young rats after exposure to tail suspension stress for 30s, which significantly increased serum corticosterone. Stress-induced attenuation of CA1 LTP was ameliorated by administration of clioquinol, a membrane permeable zinc chelator, to rats prior to exposure to stress, implying that the reduction of synaptic Zn(2+) by clioquinol participates in this amelioration. To pursue the involvement of corticosterone-mediated Zn(2+) signal in the attenuated CA1 LTP by stress, dynamics of synaptic Zn(2+) was checked in hippocampal slices exposed to corticosterone. Corticosterone increased extracellular Zn(2+) levels measured with ZnAF-2 dose-dependently, as well as the intracellular Ca(2+) levels measured with calcium orange AM, suggesting that corticosterone excites zincergic neurons in the hippocampus and increases Zn(2+) release from the neuron terminals. Intracellular Zn(2+) levels measured with ZnAF-2DA were also increased dose-dependently, but not in the coexistence of CaEDTA, a membrane-impermeable zinc chelator, suggesting that intracellular Zn(2+) levels is increased by the influx of extracellular Zn(2+). Furthermore, corticosterone-induced attenuation of CA1 LTP was abolished in the coexistence of CaEDTA. The present study suggests that corticosterone-mediated increase in postsynaptic Zn(2+) signal in the cytosolic compartment is involved in the attenuation of CA1 LTP after exposure to acute stress. Copyright © 2012 Elsevier Ltd. All rights reserved.

Modeling skull's acoustic attenuation and dispersion on photoacoustic signal

NASA Astrophysics Data System (ADS)

Mohammadi, L.; Behnam, H.; Nasiriavanaki, M. R.

2017-03-01

Despite the great promising results of a recent new transcranial photoacoustic brain imaging technology, it has been shown that the presence of the skull severely affects the performance of this imaging modality. In this paper, we investigate the effect of skull on generated photoacoustic signals with a mathematical model. The developed model takes into account the frequency dependence attenuation and acoustic dispersion effects occur with the wave reflection and refraction at the skull surface. Numerical simulations based on the developed model are performed for calculating the propagation of photoacoustic waves through the skull. From the simulation results, it was found that the skull-induced distortion becomes very important and the reconstructed image would be strongly distorted without correcting these effects. In this regard, it is anticipated that an accurate quantification and modeling of the skull transmission effects would ultimately allow for skull aberration correction in transcranial photoacoustic brain imaging.

Peptide and small molecules rescue the functional activity and agonist potency of dysfunctional human melanocortin-4 receptor polymorphisms.

PubMed

Xiang, Zhimin; Pogozheva, Irina D; Sorenson, Nicholas B; Wilczynski, Andrzej M; Holder, Jerry Ryan; Litherland, Sally A; Millard, William J; Mosberg, Henry I; Haskell-Luevano, Carrie

2007-07-17

The melanocortin pathway, specifically the melanocortin-4 receptor and the cognate endogenous agonist and antagonist ligands, have been strongly implicated in the regulation of energy homeostasis and satiety. Genetic studies of morbidly obese human patients and normal weight control patients have resulted in the discovery of over 70 human melanocortin-4 receptor (MC4R) polymorphisms observed as both heterozygous and homozygous forms. A number of laboratories have been studying these hMC4R polymorphisms attempting to understand the molecular mechanism(s) that might explain the obese human phenotype. Herein, we have studied 13 polymorphic hMC4Rs that have been identified to possess statistically significant decreased endogenous agonist potency with synthetic peptides and small molecules attempting to identify ligands that can pharmacologically rescue the hMC4R polymorphic agonist response. The ligands examined in this study include NDP-MSH, MTII, Ac-His-DPhe-Arg-Trp-NH2 (JRH887-9), Ac-Anc-DPhe-Arg-Trp-NH2 (amino-2-naphtylcarboxylic acid, Anc, JRH420-12), Ac-His-(pI)DPhe-Arg-Trp-NH2 (JRH322-18), chimeric AGRP-melanocortin based ligands (Tyr-c[Cys-His-DPhe-Arg-Trp-Asn-Ala-Phe-Cys]-Tyr-NH2, AMW3-130 and Ac-mini-(His-DPhe-Arg-Trp)-hAGRP-NH2, AMW3-106), and the small molecules JB25 and THIQ. The hMC4R polymorphisms included in this study are S58C, N97D, I102S, L106P, S127L, T150I, R165Q, R165W, L250Q, G252S, C271Y, Y287Stop, and I301T. These studies resulted in the NDP-MSH, MTII, AMW3-130, THIQ, and AMW3-106 ligands possessing nanomolar to subnanomolar agonist potency at the hMC4R polymorphisms examined in this study. Thus, these ligands could generically rescue the potency and stimulatory response of the abnormally functioning hMC4Rs studied and may provide tools to further clarify the molecular mechanism(s) involving these receptor modifications.

Voluntary exercise prevents the obese and diabetic metabolic syndrome of the melanocortin-4 receptor knockout mouse.

PubMed

Haskell-Luevano, Carrie; Schaub, Jay W; Andreasen, Amy; Haskell, Kim R; Moore, Marcus C; Koerper, Lorraine M; Rouzaud, Francois; Baker, Henry V; Millard, William J; Walter, Glenn; Litherland, S A; Xiang, Zhimin

2009-02-01

Exercise is a mechanism for maintenance of body weight in humans. Morbidly obese human patients have been shown to possess single nucleotide polymorphisms in the melanocortin-4 receptor (MC4R). MC4R knockout mice have been well characterized as a genetic model that possesses phenotypic metabolic disorders, including obesity, hyperphagia, hyperinsulinemia, and hyperleptinemia, similar to those observed in humans possessing dysfunctional hMC4Rs. Using this model, we examined the effect of voluntary exercise of MC4R knockout mice that were allowed access to a running wheel for a duration of 8 wk. Physiological parameters that were measured included body weight, body composition of fat and lean mass, food consumption, body length, and blood levels of cholesterol and nonfasted glucose, insulin, and leptin. At the termination of the experiment, hypothalamic mRNA expression levels of neuropeptide Y (NPY), agouti-related protein (AGRP), proopiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART), orexin, brain-derived neurotropic factor (BDNF), phosphatase with tensin homology (Pten), melanocortin-3 receptor (MC3R), and NPY-Y1R were determined. In addition, islet cell distribution and function in the pancreas were examined. In the exercising MC4R knockout mice, the pancreatic islet cell morphology and other physiological parameters resembled those observed in the wild-type littermate controls. Gene expression profiles identified exercise as having a significant effect on hypothalamic POMC, orexin, and MC3R levels. Genotype had a significant effect on AGRP, POMC, CART, and NPY-Y1R, with an exercise and genotype interaction effect on NPY gene expression. These data support the hypothesis that voluntary exercise can prevent the genetic predisposition of melanocortin-4 receptor-associated obesity and diabetes.

Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation

PubMed Central

Steinbicker, Andrea U.; Sachidanandan, Chetana; Vonner, Ashley J.; Yusuf, Rushdia Z.; Deng, Donna Y.; Lai, Carol S.; Rauwerdink, Kristen M.; Winn, Julia C.; Saez, Borja; Cook, Colleen M.; Szekely, Brian A.; Roy, Cindy N.; Seehra, Jasbir S.; Cuny, Gregory D.; Scadden, David T.; Peterson, Randall T.; Bloch, Kenneth D.

2011-01-01

Anemia of inflammation develops in settings of chronic inflammatory, infectious, or neoplastic disease. In this highly prevalent form of anemia, inflammatory cytokines, including IL-6, stimulate hepatic expression of hepcidin, which negatively regulates iron bioavailability by inactivating ferroportin. Hepcidin is transcriptionally regulated by IL-6 and bone morphogenetic protein (BMP) signaling. We hypothesized that inhibiting BMP signaling can reduce hepcidin expression and ameliorate hypoferremia and anemia associated with inflammation. In human hepatoma cells, IL-6–induced hepcidin expression, an effect that was inhibited by treatment with a BMP type I receptor inhibitor, LDN-193189, or BMP ligand antagonists noggin and ALK3-Fc. In zebrafish, the induction of hepcidin expression by transgenic expression of IL-6 was also reduced by LDN-193189. In mice, treatment with IL-6 or turpentine increased hepcidin expression and reduced serum iron, effects that were inhibited by LDN-193189 or ALK3-Fc. Chronic turpentine treatment led to microcytic anemia, which was prevented by concurrent administration of LDN-193189 or attenuated when LDN-193189 was administered after anemia was established. Our studies support the concept that BMP and IL-6 act together to regulate iron homeostasis and suggest that inhibition of BMP signaling may be an effective strategy for the treatment of anemia of inflammation. PMID:21393479

Lorcaserin improves glycemic control via a melanocortin neurocircuit.

PubMed

Burke, Luke K; Ogunnowo-Bada, Emmanuel; Georgescu, Teodora; Cristiano, Claudia; de Morentin, Pablo B Martinez; Valencia Torres, Lourdes; D'Agostino, Giuseppe; Riches, Christine; Heeley, Nicholas; Ruan, Yue; Rubinstein, Marcelo; Low, Malcolm J; Myers, Martin G; Rochford, Justin J; Evans, Mark L; Heisler, Lora K

2017-10-01

The increasing prevalence of type 2 diabetes (T2D) and associated morbidity and mortality emphasizes the need for a more complete understanding of the mechanisms mediating glucose homeostasis to accelerate the identification of new medications. Recent reports indicate that the obesity medication lorcaserin, a 5-hydroxytryptamine (5-HT, serotonin) 2C receptor (5-HT 2C R) agonist, improves glycemic control in association with weight loss in obese patients with T2D. Here we evaluate whether lorcaserin has an effect on glycemia without body weight loss and how this effect is achieved. Murine models of common and genetic T2D were utilized to probe the direct effect of lorcaserin on glycemic control. Lorcaserin dose-dependently improves glycemic control in mouse models of T2D in the absence of reductions in food intake or body weight. Examining the mechanism of this effect, we reveal a necessary and sufficient neurochemical mediator of lorcaserin's glucoregulatory effects, brain pro-opiomelanocortin (POMC) peptides. To clarify further lorcaserin's therapeutic brain circuit, we examined the receptor target of POMC peptides. We demonstrate that lorcaserin requires functional melanocortin4 receptors on cholinergic preganglionic neurons (MC4R ChAT ) to exert its effects on glucose homeostasis. In contrast, MC4R ChAT signaling did not impact lorcaserin's effects on feeding, indicating a divergence in the neurocircuitry underpinning lorcaserin's therapeutic glycemic and anorectic effects. Hyperinsulinemic-euglycemic clamp studies reveal that lorcaserin reduces hepatic glucose production, increases glucose disposal and improves insulin sensitivity. These data suggest that lorcaserin's action within the brain represents a mechanistically novel treatment for T2D: findings of significance to a prevalent global disease. Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.

Myocardial signal density levels and beam-hardening artifact attenuation using dual-energy computed tomography.

PubMed

Rodriguez-Granillo, Gaston A; Carrascosa, Patricia; Cipriano, Silvina; de Zan, Macarena; Deviggiano, Alejandro; Capunay, Carlos; Cury, Ricardo C

2015-01-01

The assessment of myocardial perfusion using single-energy (SE) imaging is influenced by beam-hardening artifacts (BHA). We sought to explore the ability of dual-energy (DE) imaging to attenuate the presence of BHA. Myocardial signal density (SD) was evaluated in 2240 myocardial segments (112 for each energy level) and in 320 American Heart Association segments among the SE group. Compared to DE reconstructions at the best energy level, SE acquisitions showed no significant differences overall regarding myocardial SD or signal-to-noise ratio. The segments most commonly affected by BHA showed significantly lower myocardial SD at the lowest energy levels, progressively normalizing at higher energy levels. Copyright © 2015 Elsevier Inc. All rights reserved.

Involvement of the central melanocortin system in the effects of caffeine on anxiety-like behavior in mice.

PubMed

Bhorkar, Amita A; Dandekar, Manoj P; Nakhate, Kartik T; Subhedar, Nishikant K; Kokare, Dadasaheb M

2014-01-30

To investigate the role of the melanocortin (MC) system in the framework of the central nucleus of the amygdala (CeA) in the differential effects of the adenosine receptor blocker caffeine on anxiety-like behavior, using the social interaction (SI) test. Caffeine was injected intraperitoneally, alone or in combination with alpha-melanocyte stimulating hormone (α-MSH), the MC4 receptor agonist RO27-3225 or the antagonist HS014 via the intra-CeA route. The effects of chronic (21 days) caffeine, given alone or concurrently with α-MSH, or RO27-3225, were investigated. The effects of withdrawal of these treatments on SI time were also evaluated. Furthermore, the acute effects of HS014 were investigated in different sets of caffeine-withdrawn mice. Acute injection of caffeine, RO27-3225, or α-MSH produced anxiety-like behavior. Prior treatment with α-MSH, or RO27-3225 potentiated the caffeine-induced anxiety-like behavior. Subchronic treatment with HS014 increased the SI time, which was attenuated by caffeine. Chronic administration of caffeine resulted in tolerance to caffeine's anxiogenic effect, while abrupt discontinuation of the treatment produced peak anxiety-like behavior at 72 h post-withdrawal. Concurrent administration of α-MSH, or RO27-3225 with chronic caffeine delayed the development of tolerance and prevented withdrawal-induced anxiety-like behavior. Moreover, acute treatment with HS014 at 72 h post-withdrawal attenuated the anxiety-like behavior. α-MSH, possibly via MC4 receptor in the neuroanatomical framework of the CeA, may contribute to the acute, chronic and withdrawal actions of caffeine associated with anxiety-like behavior in the neuroanatomical framework of the CeA. Copyright © 2013 Elsevier Inc. All rights reserved.

GPR measurements of attenuation in concrete

NASA Astrophysics Data System (ADS)

Eisenmann, David; Margetan, Frank J.; Pavel, Brittney

2015-03-01

Ground-penetrating radar (GPR) signals from concrete structures are affected by several phenomenon, including: (1) transmission and reflection coefficients at interfaces; (2) the radiation patterns of the antenna(s) being used; and (3) the material properties of concrete and any embedded objects. In this paper we investigate different schemes for determining the electromagnetic (EM) attenuation of concrete from measured signals obtained using commercially-available GPR equipment. We adapt procedures commonly used in ultrasonic inspections where one compares the relative strengths of two or more signals having different travel paths through the material of interest. After correcting for beam spread (i.e., diffraction), interface phenomena, and equipment amplification settings, any remaining signal differences are assumed to be due to attenuation thus allowing the attenuation coefficient (say, in dB of loss per inch of travel) to be estimated. We begin with a brief overview of our approach, and then discuss how diffraction corrections were determined for our two 1.6 GHz GPR antennas. We then present results of attenuation measurements for two types of concrete using both pulse/echo and pitch/catch measurement setups.

Fibroblast growth factor 21 attenuates hepatic fibrogenesis through TGF-β/smad2/3 and NF-κB signaling pathways

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, Pengfei; Zhang, Yingjie; Liu, Yunye

2016-01-01

Fibroblast growth factor 21 (FGF-21) is a secreted protein, which has anti-diabetic and lipocaic effects, but its ability to protect against hepatic fibrosis has not been studied. In this study, we investigated the ability of FGF-21 to attenuate dimethylnitrosamine (DMN)-induced hepatic fibrogenesis in mice and the mechanism of its action. Hepatic fibrosis was induced by injection of DMN, FGF-21 was administered to the mice once daily in association with DMN injection till the end of the experiment. Histopathological examination, tissue 4-hydroxyproline content and expressions of smooth muscle α-actin (α-SMA) and collagen I were measured to assess hepatic fibrosis. Ethanol/PDGF-BB-activated hepaticmore » stellate cells (HSCs) were used to understand the mechanisms of FGF-21 inhibited hepatic fibrogenesis. Results showed that FGF-21 treatment attenuated hepatic fibrogenesis and was associated with a significant decrease in intrahepatic fibrogenesis, 4-hydroxyproline accumulation, α-SMA expression and collagen I deposition. FGF-21 treatment inhibited the activation of HSCs via down-regulating the expression of TGF-β, NF-κB nuclear translocation, phosphorylation levels of smad2/3 and IκBα. Besides, FGF-21 treatment caused activated HSC apoptosis with increasing expression of Caspase-3, and decreased the ratio of Bcl-2 to Bax. In conclusion, FGF-21 attenuates hepatic fibrogenesis and inhibits the activation of HSC warranting the use of FGF-21 as a potential therapeutic agent in the treatment of hepatic fibrosis. - Highlights: • Fibroblast growth factor 21 attenuates hepatic fibrogenesis. • Fibroblast growth factor 21 attenuates hepatic fibrogenesis via TGF-β/smad2/3 signaling pathways. • Fibroblast growth factor 21 attenuates hepatic fibrogenesis via NF-κB signaling pathways.« less

Embedded Spherical Localization for Micro Underwater Vehicles Based on Attenuation of Electro-Magnetic Carrier Signals

PubMed Central

Duecker, Daniel-André; Geist, A. René; Hengeler, Michael; Kreuzer, Edwin; Pick, Marc-André; Rausch, Viktor; Solowjow, Eugen

2017-01-01

Self-localization is one of the most challenging problems for deploying micro autonomous underwater vehicles (μAUV) in confined underwater environments. This paper extends a recently-developed self-localization method that is based on the attenuation of electro-magnetic waves, to the μAUV domain. We demonstrate a compact, low-cost architecture that is able to perform all signal processing steps present in the original method. The system is passive with one-way signal transmission and scales to possibly large μAUV fleets. It is based on the spherical localization concept. We present results from static and dynamic position estimation experiments and discuss the tradeoffs of the system. PMID:28445419

Embedded Spherical Localization for Micro Underwater Vehicles Based on Attenuation of Electro-Magnetic Carrier Signals.

PubMed

Duecker, Daniel-André; Geist, A René; Hengeler, Michael; Kreuzer, Edwin; Pick, Marc-André; Rausch, Viktor; Solowjow, Eugen

2017-04-26

Self-localization is one of the most challenging problems for deploying micro autonomous underwater vehicles ( μ AUV) in confined underwater environments. This paper extends a recently-developed self-localization method that is based on the attenuation of electro-magnetic waves, to the μ AUV domain. We demonstrate a compact, low-cost architecture that is able to perform all signal processing steps present in the original method. The system is passive with one-way signal transmission and scales to possibly large μ AUV fleets. It is based on the spherical localization concept. We present results from static and dynamic position estimation experiments and discuss the tradeoffs of the system.

Adjustable Optical-Fiber Attenuator

NASA Technical Reports Server (NTRS)

Buzzetti, Mike F.

1994-01-01

Adjustable fiber-optic attenuator utilizes bending loss to reduce strength of light transmitted along it. Attenuator functions without introducing measurable back-reflection or insertion loss. Relatively insensitive to vibration and changes in temperature. Potential applications include cable television, telephone networks, other signal-distribution networks, and laboratory instrumentation.

Interferon-beta signaling in retinal mononuclear phagocytes attenuates pathological neovascularization.

PubMed

Lückoff, Anika; Caramoy, Albert; Scholz, Rebecca; Prinz, Marco; Kalinke, Ulrich; Langmann, Thomas

2016-06-01

Age-related macular degeneration (AMD) is a leading cause of vision loss among the elderly. AMD pathogenesis involves chronic activation of the innate immune system including complement factors and microglia/macrophage reactivity in the retina. Here, we show that lack of interferon-β signaling in the retina accelerates mononuclear phagocyte reactivity and promotes choroidal neovascularization (CNV) in the laser model of neovascular AMD Complete deletion of interferon-α/β receptor (Ifnar) using Ifnar1(-/-) mice significantly enhanced early microglia and macrophage activation in lesion areas. This triggered subsequent vascular leakage and CNV at later stages. Similar findings were obtained in laser-treated Cx3cr1(Cre) (ER):Ifnar1(fl/fl) animals that allowed the tamoxifen-induced conditional depletion of Ifnar in resident mononuclear phagocytes only. Conversely, systemic IFN-β therapy of laser-treated wild-type animals effectively attenuated microgliosis and macrophage responses in the early stage of disease and significantly reduced CNV size in the late phase. Our results reveal a protective role of Ifnar signaling in retinal immune homeostasis and highlight a potential use for IFN-β therapy in the eye to limit chronic inflammation and pathological angiogenesis in AMD. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

A Functional Melanocortin System May Be Required for Chronic CNS-Mediated Antidiabetic and Cardiovascular Actions of Leptin

PubMed Central

da Silva, Alexandre A.; do Carmo, Jussara M.; Freeman, J. Nathan; Tallam, Lakshmi S.; Hall, John E.

2009-01-01

OBJECTIVE We recently showed that leptin has powerful central nervous system (CNS)-mediated antidiabetic and cardiovascular actions. This study tested whether the CNS melanocortin system mediates these actions of leptin in diabetic rats. RESEARCH DESIGN AND METHODS A cannula was placed in the lateral ventricle of Sprague-Dawley rats for intracerebroventricular infusions, and arterial and venous catheters were implanted to measure mean arterial pressure (MAP) and heart rate 24 h/day and for intravenous infusions. After recovery from surgery for 8 days, rats were injected with streptozotocin (STZ), and 5 days later, either saline or the melanocortin 3 and 4 receptor (MC3/4R) antagonist SHU-9119 (1 nmol/h) was infused intracerebroventricularly for 17 days. Seven days after starting the antagonist, leptin (0.62 μg/h) was added to the intracerebroventricular infusion for 10 days. Another group of diabetic rats was infused with the MC3/4R agonist MTII (10 ng/h i.c.v.) for 12 days, followed by 7 days at 50 ng/h. RESULTS Induction of diabetes caused hyperphagia, hyperglycemia, and decreases in heart rate (−76 bpm) and MAP (−7 mmHg). Leptin restored appetite, blood glucose, heart rate, and MAP back to pre-diabetic values in vehicle-treated rats, whereas it had no effect in SHU-9119–treated rats. MTII infusions transiently reduced blood glucose and raised heart rate and MAP, which returned to diabetic values 5–7 days after starting the infusion. CONCLUSIONS Although a functional melanocortin system is necessary for the CNS-mediated antidiabetic and cardiovascular actions of leptin, chronic MC3/4R activation is apparently not sufficient to mimic these actions of leptin that may involve interactions of multiple pathways. PMID:19491210

Prolonged maternal separation attenuates BDNF-ERK signaling correlated with spine formation in the hippocampus during early brain development.

PubMed

Ohta, Ken-Ichi; Suzuki, Shingo; Warita, Katsuhiko; Kaji, Tomohiro; Kusaka, Takashi; Miki, Takanori

2017-04-01

Maternal separation (MS) is known to affect hippocampal function such as learning and memory, yet the molecular mechanism remains unknown. We hypothesized that these impairments are attributed to abnormities of neural circuit formation by MS, and focused on brain-derived neurotrophic factor (BDNF) as key factor because BDNF signaling has an essential role in synapse formation during early brain development. Using rat offspring exposed to MS for 6 h/day during postnatal days (PD) 2-20, we estimated BDNF signaling in the hippocampus during brain development. Our results show that MS attenuated BDNF expression and activation of extracellular signal-regulated kinase (ERK) around PD 7. Moreover, plasticity-related immediate early genes, which are transcriptionally regulated by BDNF-ERK signaling, were also reduced by MS around PD 7. Interestingly, detailed analysis revealed that MS particularly reduced expression of BDNF gene and immediate early genes in the cornu ammonis 1 (CA1) of hippocampus at PD 7. Considering that BDNF-ERK signaling is involved in spine formation, we next evaluated spine formation in the hippocampus during the weaning period. Our results show that MS particularly reduced mature spine density in proximal apical dendrites of CA1 pyramidal neurons at PD 21. These results suggest that MS could attenuate BDNF-ERK signaling during primary synaptogenesis with a region-specific manner, which is likely to lead to decreased spine formation and maturation observed in the hippocampal CA1 region. It is speculated that this incomplete spine formation during early brain development has an influence on learning capabilities throughout adulthood. © 2017 International Society for Neurochemistry.

Exposure to inorganic mercury in vivo attenuates extrinsic apoptotic signaling in Staphylococcal aureus enterotoxin B stimulated T-cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Laiosa, Michael D.; Eckles, Kevin G.; Langdon, Margaret

2007-12-15

The heavy metal mercury (Hg) is known to have immunomodulatory properties affecting lymphocyte signal transduction, death receptor signaling and autoimmunity. In this study we tested the hypothesis that Hg exposure would attenuate T-cell activation and caspase 8 and 3 activity in response to antigenic stimuli. To test this hypothesis, BALB/cJ mice were exposed to 10 mg/l mercuric chloride (HgCl{sub 2}) in their drinking water for 2 weeks followed by injection with 20 {mu}g of the Staphylococcal aureus enterotoxin B (SEB) superantigen. Eighteen hours after SEB challenge, there was a statistically significant reduction in caspase 8 and caspase 3 enzyme activitymore » in the SEB reactive V{beta}8+ T-cells. The attenuated caspase activity in Hg-exposed mice persisted for 48 h after exposure. Moreover, activation of caspase 8 and caspase 3 was reduced by more than 60% in CD95 deficient MRL/MpJ-Fas{sup lpr} mice demonstrating that caspase 8 and 3 activation in response to SEB is CD95 dependent. In addition to the effects of Hg on caspase activity, expression of the T-cell activation marker CD69 was also attenuated in SEB reactive V{beta}8 T-cells in Hg-exposed mice. Moreover, CD69 expression in MRL/MpJ-Fas{sup lpr} mice was also reduced. Taken together the caspase and CD69 data support a role for CD95 in promoting a proapoptotic and activated state in SEB responsive T-lymphocytes and this state is attenuated by the autoimmune potentiating environmental agent mercury.« less

Meclozine Facilitates Proliferation and Differentiation of Chondrocytes by Attenuating Abnormally Activated FGFR3 Signaling in Achondroplasia

PubMed Central

Matsushita, Masaki; Kitoh, Hiroshi; Ohkawara, Bisei; Mishima, Kenichi; Kaneko, Hiroshi; Ito, Mikako; Masuda, Akio; Ishiguro, Naoki; Ohno, Kinji

2013-01-01

Achondroplasia (ACH) is one of the most common skeletal dysplasias with short stature caused by gain-of-function mutations in FGFR3 encoding the fibroblast growth factor receptor 3. We used the drug repositioning strategy to identify an FDA-approved drug that suppresses abnormally activated FGFR3 signaling in ACH. We found that meclozine, an anti-histamine drug that has long been used for motion sickness, facilitates chondrocyte proliferation and mitigates loss of extracellular matrix in FGF2-treated rat chondrosarcoma (RCS) cells. Meclozine also ameliorated abnormally suppressed proliferation of human chondrosarcoma (HCS-2/8) cells that were infected with lentivirus expressing constitutively active mutants of FGFR3-K650E causing thanatophoric dysplasia, FGFR3-K650M causing SADDAN, and FGFR3-G380R causing ACH. Similarly, meclozine alleviated abnormally suppressed differentiation of ATDC5 chondrogenic cells expressing FGFR3-K650E and -G380R in micromass culture. We also confirmed that meclozine alleviates FGF2-mediated longitudinal growth inhibition of embryonic tibia in bone explant culture. Interestingly, meclozine enhanced growth of embryonic tibia in explant culture even in the absence of FGF2 treatment. Analyses of intracellular FGFR3 signaling disclosed that meclozine downregulates phosphorylation of ERK but not of MEK in FGF2-treated RCS cells. Similarly, meclozine enhanced proliferation of RCS cells expressing constitutively active mutants of MEK and RAF but not of ERK, which suggests that meclozine downregulates the FGFR3 signaling by possibly attenuating ERK phosphorylation. We used the C-natriuretic peptide (CNP) as a potent inhibitor of the FGFR3 signaling throughout our experiments, and found that meclozine was as efficient as CNP in attenuating the abnormal FGFR3 signaling. We propose that meclozine is a potential therapeutic agent for treating ACH and other FGFR3-related skeletal dysplasias. PMID:24324705

Sinomenine attenuates renal fibrosis through Nrf2-mediated inhibition of oxidative stress and TGFβ signaling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Qin, Tian

Renal fibrosis is the common feature of chronic kidney disease and mainly mediated by TGFβ-associated pro-fibrogenic signaling, which causes excessive extracellular matrix accumulation and successive loss of kidney functions. Sinomenine (SIN), an alkaloid derived from medicinal herb extensively used in treatment of rheumatoid arthritis and various inflammatory disorders, displays renal protective properties in experimental animals; however its pharmacological potency against renal fibrosis is not explored. In this study we report that SIN possesses strong anti-renal fibrosis functions in kidney cell and in mouse fibrotic kidney. SIN beneficially modulated the pro-fibrogenic protein expression in TGFβ-treated kidney cells and attenuated the renalmore » fibrotic pathogenesis incurred by unilateral ureteral obstruction (UUO), which correlated with its activation of Nrf2 signaling - the key defender against oxidative stress with anti-fibrotic potentials. Further investigation on its regulation of Nrf2 downstream events revealed that SIN significantly balanced oxidative stress via improving the expression and activity of anti-oxidant and detoxifying enzymes, and interrupted the pro-fibrogenic signaling of TGFβ/Smad and Wnt/β-catenin. Even more impressively SIN achieved its anti-fibrotic activities in an Nrf2-dependent manner, suggesting that SIN regulation of Nrf2-associated anti-fibrotic activities constitutes a critical component of SIN's renoprotective functions. Collectively our studies have demonstrated a novel anti-fibrotic property of SIN and its upstream events and provided a molecular basis for SIN's potential applications in treatment of renal fibrosis-associated kidney disorders. - Highlights: • Sinomenine has strong potency of inhibiting renal fibrosis in UUO mouse kidney. • Sinomenine attenuates the expression of profibrogenic proteins. • Sinomenine balances renal fibrosis-associated oxidative stress. • Sinomenine mitigates profibrogenic

New Implications for the Melanocortin System in Alcohol Drinking Behavior in Adolescents: The Glial Dysfunction Hypothesis.

PubMed

Orellana, Juan A; Cerpa, Waldo; Carvajal, Maria F; Lerma-Cabrera, José M; Karahanian, Eduardo; Osorio-Fuentealba, Cesar; Quintanilla, Rodrigo A

2017-01-01

Alcohol dependence causes physical, social, and moral harms and currently represents an important public health concern. According to the World Health Organization (WHO), alcoholism is the third leading cause of death worldwide, after tobacco consumption and hypertension. Recent epidemiologic studies have shown a growing trend in alcohol abuse among adolescents, characterized by the consumption of large doses of alcohol over a short time period. Since brain development is an ongoing process during adolescence, short- and long-term brain damage associated with drinking behavior could lead to serious consequences for health and wellbeing. Accumulating evidence indicates that alcohol impairs the function of different components of the melanocortin system, a major player involved in the consolidation of addictive behaviors during adolescence and adulthood. Here, we hypothesize the possible implications of melanocortins and glial cells in the onset and progression of alcohol addiction. In particular, we propose that alcohol-induced decrease in α-MSH levels may trigger a cascade of glial inflammatory pathways that culminate in altered gliotransmission in the ventral tegmental area and nucleus accumbens (NAc). The latter might potentiate dopaminergic drive in the NAc, contributing to increase the vulnerability to alcohol dependence and addiction in the adolescence and adulthood.

Obesity-Induced Hypertension: Brain Signaling Pathways

PubMed Central

da Silva, Alexandre A.; Wang, Zhen; Fang, Taolin; Aberdein, Nicola; de Lara Rodriguez, Cecilia E. P.; Hall, John E.

2017-01-01

Obesity greatly increases the risk for cardiovascular, metabolic, and renal diseases and is one of the most significant and preventable causes of increased blood pressure (BP) in patients with essential hypertension. This review high-lights recent advances in our understanding of central nervous system (CNS) signaling pathways that contribute to the etiology and pathogenesis of obesity-induced hypertension. We discuss the role of excess adiposity and activation of the brain leptin-melanocortin system in causing increased sympathetic activity in obesity. In addition, we highlight other potential brain mechanisms by which increased weight gain modulates metabolic and cardiovascular functions. Unraveling the CNS mechanisms responsible for increased sympathetic activation and hypertension and how circulating hormones activate brain signaling pathways to control BP offer potentially important therapeutic targets for obesity and hypertension. PMID:27262997

Dietary intervention in acne: Attenuation of increased mTORC1 signaling promoted by Western diet.

PubMed

Melnik, Bodo

2012-01-01

The purpose of this paper is to highlight the endocrine signaling of Western diet, a fundamental environmental factor involved in the pathogenesis of epidemic acne. Western nutrition is characterized by high calorie uptake, high glycemic load, high fat and meat intake, as well as increased consumption of insulin- and IGF-1-level elevating dairy proteins. Metabolic signals of Western diet are sensed by the nutrient-sensitive kinase, mammalian target of rapamycin complex 1 (mTORC1), which integrates signals of cellular energy, growth factors (insulin, IGF-1) and protein-derived signals, predominantly leucine, provided in high amounts by milk proteins and meat. mTORC1 activates SREBP, the master transcription factor of lipogenesis. Leucine stimulates mTORC1-SREBP signaling and leucine is directly converted by sebocytes into fatty acids and sterols for sebaceous lipid synthesis. Over-activated mTORC1 increases androgen hormone secretion and most likely amplifies androgen-driven mTORC1 signaling of sebaceous follicles. Testosterone directly activates mTORC1. Future research should investigate the effects of isotretinoin on sebocyte mTORC1 activity. It is conceivable that isotretinoin may downregulate mTORC1 in sebocytes by upregulation of nuclear levels of FoxO1. The role of Western diet in acne can only be fully appreciated when all stimulatory inputs for maximal mTORC1 activation, i.e., glucose, insulin, IGF-1 and leucine, are adequately considered. Epidemic acne has to be recognized as an mTORC1-driven disease of civilization like obesity, type 2 diabetes, cancer and neurodegenerative diseases. These new insights into Western diet-mediated mTORC1-hyperactivity provide a rational basis for dietary intervention in acne by attenuating mTORC1 signaling by reducing (1) total energy intake, (2) hyperglycemic carbohydrates, (3) insulinotropic dairy proteins and (4) leucine-rich meat and dairy proteins. The necessary dietary changes are opposed to the evolution of

GPR measurements of attenuation in concrete

DOE Office of Scientific and Technical Information (OSTI.GOV)

Eisenmann, David, E-mail: djeisen@cnde.iastate.edu; Margetan, Frank J., E-mail: djeisen@cnde.iastate.edu; Pavel, Brittney, E-mail: djeisen@cnde.iastate.edu

2015-03-31

Ground-penetrating radar (GPR) signals from concrete structures are affected by several phenomenon, including: (1) transmission and reflection coefficients at interfaces; (2) the radiation patterns of the antenna(s) being used; and (3) the material properties of concrete and any embedded objects. In this paper we investigate different schemes for determining the electromagnetic (EM) attenuation of concrete from measured signals obtained using commercially-available GPR equipment. We adapt procedures commonly used in ultrasonic inspections where one compares the relative strengths of two or more signals having different travel paths through the material of interest. After correcting for beam spread (i.e., diffraction), interface phenomena,more » and equipment amplification settings, any remaining signal differences are assumed to be due to attenuation thus allowing the attenuation coefficient (say, in dB of loss per inch of travel) to be estimated. We begin with a brief overview of our approach, and then discuss how diffraction corrections were determined for our two 1.6 GHz GPR antennas. We then present results of attenuation measurements for two types of concrete using both pulse/echo and pitch/catch measurement setups.« less

Melanocortin-1 receptor gene variants affect pain and µ-opioid analgesia in mice and humans

PubMed Central

Mogil, J; Ritchie, J; Smith, S; Strasburg, K; Kaplan, L; Wallace, M; Romberg, R; Bijl, H; Sarton, E; Fillingim, R; Dahan, A

2005-01-01

Background: A recent genetic study in mice and humans revealed the modulatory effect of MC1R (melanocortin-1 receptor) gene variants on κ-opioid receptor mediated analgesia. It is unclear whether this gene affects basal pain sensitivity or the efficacy of analgesics acting at the more clinically relevant µ-opioid receptor. Objective: To characterise sensitivity to pain and µ-opioid analgesia in mice and humans with non-functional melanocortin-1 receptors. Methods: Comparisons of spontaneous mutant C57BL/6-Mc1re/e mice to C57BL/6 wildtype mice, followed by a gene dosage study of pain and morphine-6-glucuronide (M6G) analgesia in humans with MC1R variants. Results: C57BL/6-Mc1re/e mutant mice and human redheads—both with non-functional MC1Rs—display reduced sensitivity to noxious stimuli and increased analgesic responsiveness to the µ-opioid selective morphine metabolite, M6G. In both species the differential analgesia is likely due to pharmacodynamic factors, as plasma levels of M6G are similar across genotype. Conclusions: Genotype at MC1R similarly affects pain sensitivity and M6G analgesia in mice and humans. These findings confirm the utility of cross species translational strategies in pharmacogenetics. PMID:15994880

Quercetin attenuates mitochondrial dysfunction and biogenesis via upregulated AMPK/SIRT1 signaling pathway in OA rats.

PubMed

Qiu, Linan; Luo, Yuju; Chen, Xiaojuan

2018-07-01

Despite the severity of osteoarthritis (OA), current medical therapy strategies for OA aim at symptom control and pain reduction, as there is no ideal drug for effective OA treatment. OA rat model was used to explore the therapeutic function of quercetin on remission of OA, by determining the reactive oxygen species (ROS) levels, mitochondrial function and extracellular matrix integrity. Quercetin could attenuate ROS generation and augment the glutathione (GSH) and glutathione peroxidase (GPx) expression levels in OA rat. Quercetin not only enhanced mitochondrial membrane potential, oxygen consumption, adenosine triphosphate (ATP) levels in mitochondria, but also increased the mitochondrial copy number. Furthermore, the interlukin (IL)-1β-induced accumulation of nitric oxide (NO), matrixmetalloproteinase (MMP)-3) and MMP-13 could be suppressed by quercetin. Finally, we confirmed that the therapeutic properties of quercetin on OA might function through the adenosine monophosphate-activated protein kinase/sirtuin 1 (AMPK/SIRT1) signaling pathway. In summary, quercetin could alleviate OA through attenuating the ROS levels, reversing the mitochondrial dysfunction and keeping the integrality of extracellular matrix of joint cartilage. The underlying mechanism might involve the regulation of AMPK/SIRT1 signaling pathway. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Type III Interferon-Mediated Signaling Is Critical for Controlling Live Attenuated Yellow Fever Virus Infection In Vivo

PubMed Central

Douam, Florian; Soto Albrecht, Yentli E.; Hrebikova, Gabriela; Sadimin, Evita; Davidson, Christian; Kotenko, Sergei V.

2017-01-01

ABSTRACT Yellow fever virus (YFV) is an arthropod-borne flavivirus, infecting ~200,000 people worldwide annually and causing about 30,000 deaths. The live attenuated vaccine strain, YFV-17D, has significantly contributed in controlling the global burden of yellow fever worldwide. However, the viral and host contributions to YFV-17D attenuation remain elusive. Type I interferon (IFN-α/β) signaling and type II interferon (IFN-γ) signaling have been shown to be mutually supportive in controlling YFV-17D infection despite distinct mechanisms of action in viral infection. However, it remains unclear how type III IFN (IFN-λ) integrates into this antiviral system. Here, we report that while wild-type (WT) and IFN-λ receptor knockout (λR−/−) mice were largely resistant to YFV-17D, deficiency in type I IFN signaling resulted in robust infection. Although IFN-α/β receptor knockout (α/βR−/−) mice survived the infection, mice with combined deficiencies in both type I signaling and type III IFN signaling were hypersusceptible to YFV-17D and succumbed to the infection. Mortality was associated with viral neuroinvasion and increased permeability of the blood-brain barrier (BBB). α/βR−/− λR−/− mice also exhibited distinct changes in the frequencies of multiple immune cell lineages, impaired T-cell activation, and severe perturbation of the proinflammatory cytokine balance. Taken together, our data highlight that type III IFN has critical immunomodulatory and neuroprotective functions that prevent viral neuroinvasion during active YFV-17D replication. Type III IFN thus likely represents a safeguard mechanism crucial for controlling YFV-17D infection and contributing to shaping vaccine immunogenicity. PMID:28811340

Thymoquinone Attenuates Myocardial Ischemia/Reperfusion Injury Through Activation of SIRT1 Signaling.

PubMed

Lu, Yunyang; Feng, Yingda; Liu, Dan; Zhang, Zhiran; Gao, Kai; Zhang, Wei; Tang, Haifeng

2018-06-15

Myocardial ischemia/reperfusion (MI/R) injury is a leading factor responsible for damage in myocardial infarction, resulting in additional injury to cardiac tissues involved in oxidative stress, inflammation, and apoptosis. Thymoquinone (TQ), the main constituent of Nigella sativa L. seeds, has been reported to possess various biological activities. However, few reports regarding myocardial protection are available at present. Therefore, this study was conducted aiming to investigate the protective effect of TQ against MI/R injury and to clarify its potential mechanism. MI/R injury models of isolated rat hearts and neonatal rat cardiomyocytes were established. The Langendorff isolated perfused heart system, triphenyltetrazolium chloride staining, gene transfection, TransLaser scanning confocal microscopy, and western blotting were employed to evaluate the cardioprotection effect of TQ against MI/R injury. Compared with the MI/R group, TQ treatment could remarkably improve left ventricular function, decrease myocardial infarct size and production of lactate dehydrogenase (LDH), and attenuate mitochondrial oxidative damage by elevating superoxide dismutase (SOD) activity and reducing production of hydrogen peroxide (H2O2) and malonaldehyde (MDA). Moreover, the cardioprotective effect of TQ was accompanied by up-regulated expression of SIRT1 and inhibition of p53 acetylation. Additionally, TQ treatment could also enhance mitochondrial function and reduce the number of apoptotic cardiomyocytes. Nonetheless, the cardioprotective effect of TQ could be mitigated by SIRT1 inhibitor sirtinol and SIRT1 siRNA, respectively, which was achieved through inhibition of the SIRT1 signaling pathway. The findings in this study demonstrate that TQ is efficient in attenuating MI/R injury through activation of the SIRT1 signaling pathway, which can thus reduce mitochondrial oxidative stress damage and cardiomyocyte apoptosis. © 2018 The Author(s). Published by S. Karger AG, Basel.

Islet 1 specifies the identity of hypothalamic melanocortin neurons and is critical for normal food intake and adiposity in adulthood

PubMed Central

Nasif, Sofia; de Souza, Flavio S. J.; González, Laura E.; Yamashita, Miho; Orquera, Daniela P.; Rubinstein, Marcelo

2015-01-01

Food intake and body weight regulation depend on proper expression of the proopiomelanocortin gene (Pomc) in a group of neurons located in the mediobasal hypothalamus of all vertebrates. These neurons release POMC-encoded melanocortins, which are potent anorexigenic neuropeptides, and their absence from mice or humans leads to hyperphagia and severe obesity. Although the pathophysiology of hypothalamic POMC neurons is well understood, the genetic program that establishes the neuronal melanocortinergic phenotype and maintains a fully functional neuronal POMC phenotype throughout adulthood remains unknown. Here, we report that the early expression of the LIM-homeodomain transcription factor Islet 1 (ISL1) in the developing hypothalamus promotes the terminal differentiation of melanocortinergic neurons and is essential for hypothalamic Pomc expression since its initial onset and throughout the entire lifetime. We detected ISL1 in the prospective hypothalamus just before the onset of Pomc expression and, from then on, Pomc and Isl1 coexpress. ISL1 binds in vitro and in vivo to critical homeodomain binding DNA motifs present in the neuronal Pomc enhancers nPE1 and nPE2, and mutations of these sites completely disrupt the ability of these enhancers to drive reporter gene expression to hypothalamic POMC neurons in transgenic mice and zebrafish. ISL1 is necessary for hypothalamic Pomc expression during mouse and zebrafish embryogenesis. Furthermore, conditional Isl1 inactivation from POMC neurons impairs Pomc expression, leading to hyperphagia and obesity. Our results demonstrate that ISL1 specifies the identity of hypothalamic melanocortin neurons and is required for melanocortin-induced satiety and normal adiposity throughout the entire lifespan. PMID:25825735

Euflammation attenuates peripheral inflammation-induced neuroinflammation and mitigates immune-to-brain signaling.

PubMed

Liu, Xiaoyu; Nemeth, Daniel P; Tarr, Andrew J; Belevych, Natalya; Syed, Zunera W; Wang, Yufen; Ismail, Ahmad S; Reed, Nathaniel S; Sheridan, John F; Yajnik, Akul R; Disabato, Damon J; Zhu, Ling; Quan, Ning

2016-05-01

Peripheral inflammation can trigger a number of neuroinflammatory events in the CNS, such as activation of microglia and increases of proinflammatory cytokines. We have previously identified an interesting phenomenon, termed "euflammation", which can be induced by repeated subthreshold infectious challenges. Euflammation causes innate immune alterations without overt neuroimmune activation. In the current study, we examined the protective effect of euflammation against peripheral inflammation-induced neuroinflammation and the underlying mechanisms. When Escherichia coli or lipopolysaccharide (LPS) was injected inside or outside the euflammation induction locus (EIL), sickness behavior, global microglial activation, proinflammatory cytokine production in the brain, expression of endothelial cyclooxygenase II and induction of c-fos expression in the paraventricular nucleus of the hypothalamus were all attenuated in the euflammatory mice compared with those in the control unprimed mice. Euflammation also modulated innate immunity outside the EIL by upregulating receptors for pathogen-associated molecular patterns in spleen cells. In addition, euflammation attenuated CNS activation in response to an intra-airpouch (outside the EIL) injection of LPS without suppressing the cytokine expression in the airpouch. Collectively, our study demonstrates that signaling of peripheral inflammation to the CNS is modulated dynamically by peripheral inflammatory kinetics. Specifically, euflammation can offer effective protection against both bacterial infection and endotoxin induced neuroinflammation. Copyright © 2016 Elsevier Inc. All rights reserved.

Peripheral cannabinoid-1 receptor blockade restores hypothalamic leptin signaling.

PubMed

Tam, Joseph; Szanda, Gergő; Drori, Adi; Liu, Ziyi; Cinar, Resat; Kashiwaya, Yoshihiro; Reitman, Marc L; Kunos, George

2017-10-01

In visceral obesity, an overactive endocannabinoid/CB 1 receptor (CB 1 R) system promotes increased caloric intake and decreases energy expenditure, which are mitigated by global or peripheral CB 1 R blockade. In mice with diet-induced obesity (DIO), inhibition of food intake by the peripherally restricted CB 1 R antagonist JD5037 could be attributed to endogenous leptin due to the rapid reversal of hyperleptinemia that maintains leptin resistance, but the signaling pathway engaged by leptin has remained to be determined. We analyzed the hypothalamic circuitry targeted by leptin following chronic treatment of DIO mice with JD5037. Leptin treatment or an increase in endogenous leptin following fasting/refeeding induced STAT3 phosphorylation in neurons in the arcuate nucleus (ARC) in lean and JD5037-treated DIO mice, but not in vehicle-treated DIO animals. Co-localization of pSTAT3 in leptin-treated mice was significantly less common with NPY + than with POMC + ARC neurons. The hypophagic effect of JD5037 was absent in melanocortin-4 receptor (MC4R) deficient obese mice or DIO mice treated with a MC4R antagonist, but was maintained in NPY -/- mice kept on a high-fat diet. Peripheral CB 1 R blockade in DIO restores sensitivity to endogenous leptin, which elicits hypophagia via the re-activation of melanocortin signaling in the ARC. Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.

Attenuation of dopamine-modulated prefrontal value signals underlies probabilistic reward learning deficits in old age

PubMed Central

Axelsson, Jan; Riklund, Katrine; Nyberg, Lars; Dayan, Peter; Bäckman, Lars

2017-01-01

Probabilistic reward learning is characterised by individual differences that become acute in aging. This may be due to age-related dopamine (DA) decline affecting neural processing in striatum, prefrontal cortex, or both. We examined this by administering a probabilistic reward learning task to younger and older adults, and combining computational modelling of behaviour, fMRI and PET measurements of DA D1 availability. We found that anticipatory value signals in ventromedial prefrontal cortex (vmPFC) were attenuated in older adults. The strength of this signal predicted performance beyond age and was modulated by D1 availability in nucleus accumbens. These results uncover that a value-anticipation mechanism in vmPFC declines in aging, and that this mechanism is associated with DA D1 receptor availability. PMID:28870286

Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, inflammatory and cell death signaling pathways in diabetic cardiomyopathy

PubMed Central

Rajesh, Mohanraj; Mukhopadhyay, Partha; Bátkai, Sándor; Patel, Vivek; Saito, Keita; Matsumoto, Shingo; Kashiwaya, Yoshihiro; Horváth, Béla; Mukhopadhyay, Bani; Becker, Lauren; Haskó, György; Liaudet, Lucas; Wink, David A; Veves, Aristidis; Mechoulam, Raphael; Pacher, Pál

2010-01-01

Objectives In this study, we have investigated the effects of cannabidiol (CBD) on myocardial dysfunction, inflammation, oxidative/nitrosative stress, cell death and interrelated signaling pathways, using a mouse model of type I diabetic cardiomyopathy and primary human cardiomyocytes exposed to high glucose. Background CBD, the most abundant nonpsychoactive constituent of Cannabis sativa (marijuana) plant, exerts antiinflammatory effects in various disease models and alleviates pain and spasticity associated with multiple sclerosis in humans. Methods Left ventricular function was measured by pressure-volume system. Oxidative stress, cell death and fibrosis markers were evaluated by molecular biology/biochemical techniques, electron spin resonance spectroscopy and flow cytometry. Results Diabetic cardiomyopathy was characterized by declined diastolic and systolic myocardial performance associated with increased oxidative-nitrosative stress, NF-κB and MAPK (JNK and p-38, p38α) activation, enhanced expression of adhesion molecules (ICAM-1, VCAM-1), TNF-α, markers of fibrosis (TGF-β, CTGF, fibronectin, collagen-1, MMP-2 and MMP-9), enhanced cell death (caspase 3/7 and PARP activity, chromatin fragmentation and TUNEL) and diminished Akt phosphorylation. Remarkably, CBD attenuated myocardial dysfunction, cardiac fibrosis, oxidative/nitrosative stress, inflammation, cell death, and interrelated signaling pathways. Furthermore, CBD also attenuated the high glucose-induced increased reactive oxygen species generation, NF-κB activation and cell death in primary human cardiomyocytes. Conclusions Collectively, these results coupled with the excellent safety and tolerability profile of cannabidiol in humans, strongly suggest that it may have great therapeutic potential in the treatment of diabetic complications, and perhaps other cardiovascular disorders, by attenuating oxidative/nitrosative stress, inflammation, cell death and fibrosis. PMID:21144973

Central role for melanocortin-4 receptors in offspring hypertension arising from maternal obesity

PubMed Central

Samuelsson, Anne-Maj S.; Mullier, Amandine; Maicas, Nuria; Oosterhuis, Nynke R.; Eun Bae, Sung; Novoselova, Tatiana V.; Chan, Li F.; Pombo, Joaquim M.; Taylor, Paul D.; Joles, Jaap A.; Coen, Clive W.; Balthasar, Nina; Poston, Lucilla

2016-01-01

Melanocortin-4 receptor (Mc4r)–expressing neurons in the autonomic nervous system, particularly in the paraventricular nucleus of the hypothalamus (PVH), play an essential role in blood pressure (BP) control. Mc4r-deficient (Mc4rKO) mice are severely obese but lack obesity-related hypertension; they also show a reduced pressor response to salt loading. We have previously reported that lean juvenile offspring born to diet-induced obese rats (OffOb) exhibit sympathetic-mediated hypertension, and we proposed a role for postnatally raised leptin in its etiology. Here, we test the hypothesis that neonatal hyperleptinemia due to maternal obesity induces persistent changes in the central melanocortin system, thereby contributing to offspring hypertension. Working on the OffOb paradigm in both sexes and using transgenic technology to restore Mc4r in the PVH of Mc4rKO (Mc4rPVH) mice, we have now shown that these mice develop higher BP than Mc4rKO or WT mice. We have also found that experimental hyperleptinemia induced in the neonatal period in Mc4rPVH and WT mice, but not in the Mc4rKO mice, leads to heightened BP and severe renal dysfunction. Thus, Mc4r in the PVH appears to be required for early-life programming of hypertension arising from either maternal obesity or neonatal hyperleptinemia. Early-life exposure of the PVH to maternal obesity through postnatal elevation of leptin may have long-term consequences for cardiovascular health. PMID:27791019

Temporal quantitation of mutant Kit tyrosine kinase signaling attenuated by a novel thiophene kinase inhibitor OSI-930.

PubMed

Petti, Filippo; Thelemann, April; Kahler, Jen; McCormack, Siobhan; Castaldo, Linda; Hunt, Tony; Nuwaysir, Lydia; Zeiske, Lynn; Haack, Herbert; Sullivan, Laura; Garton, Andrew; Haley, John D

2005-08-01

OSI-930, a potent thiophene inhibitor of the Kit, KDR, and platelet-derived growth factor receptor tyrosine kinases, was used to selectively inhibit tyrosine phosphorylation downstream of juxtamembrane mutant Kit in the mast cell leukemia line HMC-1. Inhibition of Kit kinase activity resulted in a rapid dephosphorylation of Kit and inhibition of the downstream signaling pathways. Attenuation of Ras-Raf-Erk (phospho-Erk, phospho-p38), phosphatidyl inositol-3' kinase (phospho-p85, phospho-Akt, phospho-S6), and signal transducers and activators of transcription signaling pathways (phospho-STAT3/5/6) were measured by affinity liquid chromatography tandem mass spectrometry, by immunoblot, and by tissue microarrays of fixed cell pellets. To more globally define additional components of Kit signaling temporally altered by kinase inhibition, a novel multiplex quantitative isobaric peptide labeling approach was used. This approach allowed clustering of proteins by temporal expression patterns. Kit kinase, which dephosphorylates rapidly upon kinase inhibition, was shown to regulate both Shp-1 and BDP-1 tyrosine phosphatases and the phosphatase-interacting protein PSTPIP2. Interactions with SH2 domain adapters [growth factor receptor binding protein 2 (Grb2), Cbl, Slp-76] and SH3 domain adapters (HS1, cortactin, CD2BP3) were attenuated by inhibition of Kit kinase activity. Functional crosstalk between Kit and the non-receptor tyrosine kinases Fes/Fps, Fer, Btk, and Syk was observed. Inhibition of Kit modulated phosphorylation-dependent interactions with pathways controlling focal adhesion (paxillin, leupaxin, p130CAS, FAK1, the Src family kinase Lyn, Wasp, Fhl-3, G25K, Ack-1, Nap1, SH3P12/ponsin) and septin-actin complexes (NEDD5, cdc11, actin). The combined use of isobaric protein quantitation and expression clustering, immunoblot, and tissue microarray strategies allowed temporal measurement signaling pathways modulated by mutant Kit inhibition in a model of mast cell

Hypoxia attenuates inflammatory mediators production induced by Acanthamoeba via Toll-like receptor 4 signaling in human corneal epithelial cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pan, Hong; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University, 107, Wenhua Xi Road, Jinan 250012; Wu, Xinyi, E-mail: xywu8868@163.com

2012-04-13

Highlights: Black-Right-Pointing-Pointer Hypoxia attenuates Acanthamoeba-induced the production of IL-8 and IFN-{beta}. Black-Right-Pointing-Pointer Hypoxia inhibits TLR4 expression in a time-dependent manner in HCECs. Black-Right-Pointing-Pointer Hypoxia inhibits Acanthamoeba-induced the activation of NF-{kappa}B and ERK1/2 in HCECs. Black-Right-Pointing-Pointer Hypoxia decreases Acanthamoeba-induced inflammatory response via TLR4 signaling. Black-Right-Pointing-Pointer LPS-induced the secretion of IL-6 and IL-8 is abated by hypoxia via TLR4 signaling. -- Abstract: Acanthamoeba keratitis (AK) is a vision-threatening corneal infection that is intimately associated with contact lens use which leads to hypoxic conditions on the corneal surface. However, the effect of hypoxia on the Acanthamoeba-induced host inflammatory response of corneal epithelial cellsmore » has not been studied. In the present study, we investigated the effect of hypoxia on the Acanthamoeba-induced production of inflammatory mediators interleukin-8 (IL-8) and interferon-{beta} (IFN-{beta}) in human corneal epithelial cells and then evaluated its effects on the Toll-like receptor 4 (TLR4) signaling, including TLR4 and myeloid differentiation primary response gene (88) (MyD88) expression as well as the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-{kappa}B) and extracellular signal-regulated kinases 1/2 (ERK1/2). We then studied the effect of hypoxia on a TLR4-specific inflammatory response triggered by the TLR4 ligand lipopolysaccharide (LPS). Our data showed that hypoxia significantly decreased the production of IL-8 and IFN-{beta}. Furthermore, hypoxia attenuated Acanthamoeba-triggered TLR4 expression as well as the activation of NF-{kappa}B and ERK1/2, indicating that hypoxia abated Acanthamoeba-induced inflammatory responses by affecting TLR4 signaling. Hypoxia also inhibited LPS-induced IL-6 and IL-8 secretion, myeloid differentiation primary response

A missense mutation in melanocortin 1 receptor is associated with the red coat colour in donkeys.

PubMed

Abitbol, M; Legrand, R; Tiret, L

2014-12-01

The seven donkey breeds recognised by the French studbook are characterised by few coat colours: black, bay and grey. Normand bay donkeys seldom give birth to red foals, a colour more commonly seen and recognised in American miniature donkeys. Red resembles the equine chestnut colour, previously attributed to a mutation in the melanocortin 1 receptor gene (MC1R). We used a panel of 124 donkeys to identify a recessive missense c.629T>C variant in MC1R that showed a perfect association with the red coat colour. This variant leads to a methionine to threonine substitution at position 210 in the protein. We showed that methionine 210 is highly conserved among vertebrate melanocortin receptors. Previous in silico and in vitro analyses predicted this residue to lie within a functional site. Our in vivo results emphasised the pivotal role played by this residue, the alteration of which yielded a phenotype fully compatible with a loss of function of MC1R. We thus propose to name the c.629T>C allele in donkeys the e allele, which further enlarges the panel of recessive MC1R loss-of-function alleles described in animals and humans. © 2014 Stichting International Foundation for Animal Genetics.

New Implications for the Melanocortin System in Alcohol Drinking Behavior in Adolescents: The Glial Dysfunction Hypothesis

PubMed Central

Orellana, Juan A.; Cerpa, Waldo; Carvajal, Maria F.; Lerma-Cabrera, José M.; Karahanian, Eduardo; Osorio-Fuentealba, Cesar; Quintanilla, Rodrigo A.

2017-01-01

Alcohol dependence causes physical, social, and moral harms and currently represents an important public health concern. According to the World Health Organization (WHO), alcoholism is the third leading cause of death worldwide, after tobacco consumption and hypertension. Recent epidemiologic studies have shown a growing trend in alcohol abuse among adolescents, characterized by the consumption of large doses of alcohol over a short time period. Since brain development is an ongoing process during adolescence, short- and long-term brain damage associated with drinking behavior could lead to serious consequences for health and wellbeing. Accumulating evidence indicates that alcohol impairs the function of different components of the melanocortin system, a major player involved in the consolidation of addictive behaviors during adolescence and adulthood. Here, we hypothesize the possible implications of melanocortins and glial cells in the onset and progression of alcohol addiction. In particular, we propose that alcohol-induced decrease in α-MSH levels may trigger a cascade of glial inflammatory pathways that culminate in altered gliotransmission in the ventral tegmental area and nucleus accumbens (NAc). The latter might potentiate dopaminergic drive in the NAc, contributing to increase the vulnerability to alcohol dependence and addiction in the adolescence and adulthood. PMID:28424592

Attenuation of bone morphogenetic protein signaling during amphibian limb development results in the generation of stage-specific defects.

PubMed

Jones, Tamsin E M; Day, Robert C; Beck, Caroline W

2013-11-01

The vertebrate limb is one of the most intensively studied organs in the field of developmental biology. Limb development in tetrapod vertebrates is highly conserved and dependent on the interaction of several important molecular pathways. The bone morphogenetic protein (BMP) signaling cascade is one of these pathways and has been shown to be crucial for several aspects of limb development. Here, we have used a Xenopus laevis transgenic line, in which expression of the inhibitor Noggin is under the control of the heat-shock promoter hsp70 to examine the effects of attenuation of BMP signaling at different stages of limb development. Remarkably different phenotypes were produced at different stages, illustrating the varied roles of BMP in development of the limb. Very early limb buds appeared to be refractory to the effects of BMP attenuation, developing normally in most cases. Ectopic limbs were produced by overexpression of Noggin corresponding to a brief window of limb development at about stage 49/50, as recently described by Christen et al. (2012). Attenuation of BMP signaling in stage 51 or 52 tadpoles lead to a reduction in the number of digits formed, resulting in hypodactyly or ectrodactyly, as well as occasional defects in the more proximal tibia-fibula. Finally, inhibition at stage 54 (paddle stage) led to the formation of dramatically shortened digits resulting from loss of distal phalanges. Transcriptome analysis has revealed the possibility that more Noggin-sensitive members of the BMP family could be involved in limb development than previously suspected. Our analysis demonstrates the usefulness of heat-shock-driven gene expression as an effective method for inhibiting a developmental pathway at different times during limb development. © 2013 Anatomical Society.

Curcumin Attenuated Bupivacaine-Induced Neurotoxicity in SH-SY5Y Cells Via Activation of the Akt Signaling Pathway.

PubMed

Fan, You-Ling; Li, Heng-Chang; Zhao, Wei; Peng, Hui-Hua; Huang, Fang; Jiang, Wei-Hang; Xu, Shi-Yuan

2016-09-01

Bupivacaine is widely used for regional anesthesia, spinal anesthesia, and pain management. However, bupivacaine could cause neuronal injury. Curcumin, a low molecular weight polyphenol, has a variety of bioactivities and may exert neuroprotective effects against damage induced by some stimuli. In the present study, we tested whether curcumin could attenuate bupivacaine-induced neurotoxicity in SH-SY5Y cells. Cell injury was evaluated by examining cell viability, mitochondrial damage and apoptosis. We also investigated the levels of activation of the Akt signaling pathway and the effect of Akt inhibition by triciribine on cell injury following bupivacaine and curcumin treatment. Our findings showed that the bupivacaine treatment could induce neurotoxicity. Pretreatment of the SH-SY5Y cells with curcumin significantly attenuated bupivacaine-induced neurotoxicity. Interestingly, the curcumin treatment increased the levels of Akt phosphorylation. More significantly, the pharmacological inhibition of Akt abolished the cytoprotective effect of curcumin against bupivacaine-induced cell injury. Our data suggest that pretreating SH-SY5Y cells with curcumin provides a protective effect on bupivacaine-induced neuronal injury via activation of the Akt signaling pathway.

Attenuation of the NMR signal in a field gradient due to stochastic dynamics with memory

NASA Astrophysics Data System (ADS)

Lisý, Vladimír; Tóthová, Jana

2017-03-01

The attenuation function S(t) for an ensemble of spins in a magnetic-field gradient is calculated by accumulation of the phase shifts in the rotating frame resulting from the displacements of spin-bearing particles. The found S(t), expressed through the particle mean square displacement, is applicable for any kind of stationary stochastic motion of spins, including their non-markovian dynamics with memory. The known expressions valid for normal and anomalous diffusion are obtained as special cases in the long time approximation. The method is also applicable to the NMR pulse sequences based on the refocusing principle. This is demonstrated by describing the Hahn spin echo experiment. The attenuation of the NMR signal is also evaluated providing that the random motion of particle is modeled by the generalized Langevin equation with the memory kernel exponentially decaying in time. The models considered in our paper assume massive particles driven by much smaller particles.

The melanocortinergic pathway is rapidly recruited by emotional stress and contributes to stress-induced anorexia and anxiety-like behavior.

PubMed

Liu, Jing; Garza, Jacob C; Truong, Ha V; Henschel, John; Zhang, Wei; Lu, Xin-Yun

2007-11-01

Neurons producing melanocortin receptor agonist, alpha-MSH derived from proopiomelanocortin, and antagonist, agouti-related protein, are known to be sensitive to metabolic stress such as food deprivation and glucoprivation. However, how these neurons respond to emotional/psychological stress remained to be elucidated. We report here that acute emotional stressors, i.e. restraint and forced swim, evoked mRNA expression of c-fos, a neuronal activation marker, in a high percentage of proopiomelanocortin neurons (up to 53% for restraint stress and 62% for forced swim), with marked variations along the rostro-caudal axis of the arcuate nucleus. In contrast, only a small population of agouti-related protein neurons in this brain region was activated. These neuronal activation patterns were correlated with behavioral reactions. Both stressors suppressed feeding and induced anxiety-like behavior in the elevated plus-maze test, as reflected by a reduction in the percentage of entries and time spent in the open arms. Central pretreatment with SHU9119, a melanocortin receptor antagonist, dose dependently attenuated the anorectic and anxiogenic effects elicited by acute restraint or forced swim. These results indicate that the melancortinergic pathway can be rapidly recruited by acute emotional stress, and that activation of melanocortin signaling is involved in mediating stress-induced anorexia and anxiety.

Central proopiomelanocortin but not neuropeptide Y mediates sympathoexcitation and hypertension in fat fed conscious rabbits.

PubMed

Barzel, Benjamin; Lim, Kyungjoon; Davern, Pamela J; Burke, Sandra L; Armitage, James A; Head, Geoffrey A

2016-03-01

High-fat diet (HFD)-induced hypertension in rabbits is neurogenic because of the central sympathoexcitatory actions of leptin. Hypothalamic melanocortin and neuropeptide Y (NPY) neurons are recognized as the major signalling pathways through which leptin exerts its central effects. In this study, we assessed the effects of specific antagonists and agonists to melanocortin and NPY receptors on HFD-induced sympathoexcitation and hypertension. Rabbits were instrumented with intracerebroventricular cannula, renal sympathetic nerve activity (RSNA) electrode, and blood pressure telemetry transmitter. After 3 weeks HFD (13.5% fat, n = 12) conscious rabbits had higher RSNA (+3.8  nu, P = 0.02), blood pressure (+8.6  mmHg, P < 0.001) and heart rate (+15  b/min, P = 0.01), and brain-derived neurotrophic factor levels in the hypothalamus compared with rabbits fed a control diet (4.2% fat, n = 11). Intracerebroventricular administration of the melanocortin receptor antagonist SHU9119 reduced RSNA (-2.7  nu) and blood pressure (-8.5  mmHg) in HFD but not control rabbits, thus reversing 100% of the hypertension and 70% of the sympathoexcitation induced by a HFD. By contrast, blocking central NPY Y1 receptors with BVD10 increased RSNA only in HFD rabbits. Intracerebroventricular α-melanocortin stimulating hormone increased RSNA and heart rate (P < 0.001) in HFD rabbits but had no effect in control rabbits. These findings suggest that obesity-induced hypertension and increased RSNA are dependent on the balance between greater activation of melanocortin signalling through melanocortin receptors and lesser activation of NPY sympathoinhibitory signalling. The amplification of the sympathoexcitatory effects of α-melanocortin stimulating hormone also indicates that the underlying mechanism is related to facilitation of leptin-melanocortin signalling, possibly involving chronic activation of brain-derived neurotrophic factor.

Adenosine monophosphate-activated protein kinase attenuates cardiomyocyte hypertrophy through regulation of FOXO3a/MAFbx signaling pathway.

PubMed

Chen, Baolin; Wu, Qiang; Xiong, Zhaojun; Ma, Yuedong; Yu, Sha; Chen, Dandan; Huang, Shengwen; Dong, Yugang

2016-09-01

Control of cardiac muscle mass is thought to be determined by a dynamic balance of protein synthesis and degradation. Recent studies have demonstrated that atrophy-related forkhead box O 3a (FOXO3a)/muscle atrophy F-box (MAFbx) signaling pathway plays a central role in the modulation of proteolysis and exert inhibitory effect on cardiomyocyte hypertrophy. In this study, we tested the hypothesis that adenosine monophosphate-activated protein kinase (AMPK) activation attenuates cardiomyocyte hypertrophy by regulating FOXO3a/MAFbx signaling pathway and its downstream protein degradation. The results showed that activation of AMPK with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) attenuated cardiomyocyte hypertrophy induced by angiotensin II (Ang II). The antihypertrophic effects of AICAR were blunted by AMPK inhibitor Compound C. In addition, AMPK dramatically increased the activity of transcription factor FOXO3a, up-regulated the expression of its downstream ubiquitin ligase MAFbx, and enhanced cardiomyocyte proteolysis. Meanwhile, the effects of AMPK on protein degradation and cardiomyocyte hypertrophy were blocked after MAFbx was silenced by transfection of cardiomyocytes with MAFbx-siRNA. These results indicate that AMPK plays an important role in the inhibition of cardiomyocyte hypertrophy by activating protein degradation via FOXO3a/MAFbx signaling pathway. © The Author 2016. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Analyzing the effects of co-expression of chick (Gallus gallus) melanocortin receptors with either chick MRAP1 or MRAP2 in CHO cells on sensitivity to ACTH(1-24) or ACTH(1-13)NH2: Implications for the avian HPA axis and avian melanocortin circuits in the hypothalamus.

PubMed

Thomas, Alexa L; Maekawa, Fumihiko; Kawashima, Takaharu; Sakamoto, Hirotaka; Sakamoto, Tatsuya; Davis, Perry; Dores, Robert M

2018-01-15

In order to better understand the roles that melanocortin receptors (cMCRs) and melanocortin-2 receptor accessory proteins (cMRAP1 and cMRAP2) play in the HPA axis and hypothalamus, adrenal gland and hypothalamus mRNA from 1day-old white leghorn chicks (Gallus gallus), were analyzed by real-time PCR. mRNA was also made for kidney, ovary, and liver. Mrap1 mRNA could be detected in adrenal tissue, but not in any of the other tissues, and mrap2 mRNA was also detected in the adrenal gland. Finally, all five melanocortin receptors mRNAs could be detected in the adrenal gland; mc2r and mc5r mRNAs were the most abundant. To evaluate any potential interactions between MRAP1 and the MCRs that may occur in adrenal cells, individual chick mcr cDNA constructs were transiently expressed in CHO cells either in the presence or absence of a chick mrap1 cDNA, and the transfected cells were stimulated with hACTH(1-24) at concentrations ranging from 10 -13 M to 10 -6 M. As expected, MC2R required co-expression with MRAP1 for functional expression; whereas, co-expression of cMC3R with cMRAP1 had no statistically significant effect on sensitivity to hACTH(1-24). However, co-expression of MC4R and MC5R with MRAP1, increased sensitivity for ACTH(1-24) by approximately 35 fold and 365 fold, respectively. However, co-expressing of cMRAP2 with these melanocortin receptors had no effect on sensitivity to hACTH(1-24). Since the real-time PCR analysis detected mrap2 mRNA and mc4r mRNA in the hypothalamus, the interaction between cMC4R and cMRAP2 with respect to sensitivity to ACTH(1-13)NH 2 stimulation was also evaluated. However, no effect, either positive or negative, was observed. Finally, the highest levels of mc5r mRNA were detected in liver cells. This observation raises the possibility that in one-day old chicks, activation of the HPA axis may also involve a physiological response from liver cells. Copyright © 2017 Elsevier Inc. All rights reserved.

Ibudilast attenuates astrocyte apoptosis via cyclic GMP signalling pathway in an in vitro reperfusion model

PubMed Central

Takuma, K; Lee, E; Enomoto, R; Mori, K; Baba, A; Matsuda, T

2001-01-01

We examined the effect of 3-isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine (ibudilast), which has been clinically used for bronchial asthma and cerebrovascular disorders, on cell viability induced in a model of reperfusion injury. Ibudilast at 10 – 100 μM significantly attenuated the H2O2-induced decrease in cell viability. Ibudilast inhibited the H2O2-induced cytochrome c release, caspase-3 activation, DNA ladder formation and nuclear condensation, suggesting its anti-apoptotic effect. Phosphodiesterase inhibitors such as theophylline, pentoxyfylline, vinpocetine, dipyridamole and zaprinast, which increased the guanosine-3′,5′-cyclic monophosphate (cyclic GMP) level, and dibutyryl cyclic GMP attenuated the H2O2-induced injury in astrocytes. Ibudilast increased the cyclic GMP level in astrocytes. The cyclic GMP-dependent protein kinase inhibitor KT5823 blocked the protective effects of ibudilast and dipyridamole on the H2O2-induced decrease in cell viability, while the cyclic AMP-dependent protein kinase inhibitor KT5720, the cyclic AMP antagonist Rp-cyclic AMPS, the mitogen-activated protein/extracellular signal-regulated kinase inhibitor PD98059 and the leukotriene D4 antagonist LY 171883 did not. KT5823 also blocked the effect of ibudilast on the H2O2-induced cytochrome c release and caspase-3-like protease activation. These findings suggest that ibudilast prevents the H2O2-induced delayed apoptosis of astrocytes via a cyclic GMP, but not cyclic AMP, signalling pathway. PMID:11454657

Conformational study on cyclic melanocortin ligands and new insight into their binding mode at the MC4 receptor.

PubMed

Grieco, Paolo; Brancaccio, Diego; Novellino, Ettore; Hruby, Victor J; Carotenuto, Alfonso

2011-09-01

The melanocortin receptors are involved in many physiological functions, including pigmentation, sexual function, feeding behavior, and energy homeostasis, making them potential targets to treat obesity, sexual dysfunction, etc. Understanding the basis of the ligand-receptor interactions is crucial for the design of potent and selective ligands for these receptors. The conformational preferences of the cyclic melanocortin ligands MTII (Ac-Nle(4)-c[Asp(5)-His(6)-DPhe(7)-Arg(8)-Trp(9)-Lys(10)]-NH(2)) and SHU9119 (Ac-Nle(4)-c[Asp(5)-His(6)-DNal(2')(7)-Arg(8)-Trp(9)-Lys(10)]-NH(2)), which show agonist and antagonist activity at the h-MC4R, respectively, were comprehensively investigated by solution NMR spectroscopy in different environments. In particular, water and water/DMSO (8:2) solutions were used as isotropic solutions and an aqueous solution of DPC (dodecylphosphocholine) micelles was used as a membrane mimetic environment. NMR-derived conformations of these two ligands were docked within h-MC4R models. NMR and docking studies revealed intriguing differences which can help explain the different activities of these two ligands. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Diagnosis of retrodiscal tissue in painful temporomandibular joint (TMJ) by fluid-attenuated inversion recovery (FLAIR) signal intensity.

PubMed

Kuroda, Migiwa; Otonari-Yamamoto, Mika; Sano, Tsukasa; Fujikura, Mamiko; Wakoh, Mamoru

2014-09-09

Aims: The purpose of the present study is to analyze the fluid-attenuated inversion recovery (FLAIR) signal intensity of the retrodiscal tissue in a painful temporomandibular joint (TMJ), and to develop a diagnostic system based on FLAIR data. Methodology: The study was based on 33 joints of 17 patients referred for MR imaging of the TMJ. Regions of interest were placed over retrodiscal tissue and gray matter (GM) on FLAIR images. Using signal intensities of GM as reference points, signal intensity ratios (SIR) of retrodiscal tissue were calculated. SIRs in painful TMJ were compared with those in painless TMJ. Wilcoxon's Rank Sum Test was used to analyze the difference in SIRs between the painful and painless groups (P<0·05). Results: The SIRs of retrodiscal tissue were significantly higher in painful joints than in painless joints. Conclusion: FLAIR sequences provide a high signal in patients having painful TMJ, and it suggests that retrodiscal tissue in painful TMJ contains elements such as protein.

Diagnosis of retrodiscal tissue in painful temporomandibular joint (TMJ) by fluid-attenuated inversion recovery (FLAIR) signal intensity.

PubMed

Kuroda, Migiwa; Otonari-Yamamoto, Mika; Sano, Tsukasa; Fujikura, Mamiko; Wakoh, Mamoru

2015-10-01

The purpose of the present study is to analyze the fluid-attenuated inversion recovery (FLAIR) signal intensity of the retrodiscal tissue in a painful temporomandibular joint (TMJ), and to develop a diagnostic system based on FLAIR data. The study was based on 33 joints of 17 patients referred for MR imaging of the TMJ. Regions of interest were placed over retrodiscal tissue and gray matter (GM) on FLAIR images. Using signal intensities of GM as reference points, signal intensity ratios (SIR) of retrodiscal tissue were calculated. SIRs in painful TMJ were compared with those in painless TMJ. Wilcoxon's Rank Sum Test was used to analyze the difference in SIRs between the painful and painless groups (P<0·05). The SIRs of retrodiscal tissue were significantly higher in painful joints than in painless joints. FLAIR sequences provide a high signal in patients having painful TMJ, and it suggests that retrodiscal tissue in painful TMJ contains elements such as protein.

Ultrasound-targeted microbubble destruction enhances delayed BMC delivery and attenuates post-infarction cardiac remodelling by inducing engraftment signals.

PubMed

Chen, Yanmei; Zhang, Chuanxi; Shen, Shuxin; Guo, Shengcun; Zhong, Lintao; Li, Xinzhong; Chen, Guojun; Chen, Gangbin; He, Xiang; Huang, Chixiong; He, Nvqin; Liao, Wangjun; Liao, Yulin; Bin, Jianping

2016-12-01

Delayed administration of bone marrow cells (BMCs) at 2-4 weeks after successful reperfusion in patients with acute myocardial infarction (MI) does not improve cardiac function. The reduction in engraftment signals observed following this time interval might impair the effects of delayed BMC treatment. In the present study, we aimed to determine whether ultrasound-targeted microbubble destruction (UTMD) treatment could increase engraftment signals, enhance the delivery of delayed BMCs and subsequently attenuate post-infarction cardiac remodelling. A myocardial ischaemia/reperfusion (I/R) model was induced in Wistar rats via left coronary ligation for 45 min followed by reperfusion. Western blotting revealed that engraftment signals peaked at 7 days post-I/R and were dramatically lower at 14 days post-I/R. The lower engraftment signals at 14 days post-I/R could be triggered by UTMD treatment at a mechanical index of 1.0-1.9. The troponin I levels in the 1.9 mechanical index group were higher than in the other groups. Simultaneous haematoxylin and eosin staining and fluorescence revealed that the number of engrafted BMCs in the ischaemic zone was greater in the group treated with both UTMD and delayed BMC transplantation than in the control groups (P<0.05). Both UTMD and delayed BMC transplantation improved cardiac function and decreased cardiac fibrosis at 4 weeks after treatment, as compared with control groups (both P<0.05). Histopathology demonstrated that UTMD combined with delayed BMC transplantation increased capillary density, myocardial cell proliferation and c-kit + cell proliferation. These findings indicated that UTMD treatment could induce engraftment signals and enhance homing of delayed BMCs to ischaemic myocardium, attenuating post-infarction cardiac remodelling by promoting neovascularization, cardiomyogenesis and expansion of cardiac c-kit + cells. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Mapping of the gene encoding the melanocortin-1 ([alpha]-melanocyte stimulating hormone) receptor (MC1R) to human chromosome 16q24. 3 by fluorescence in situ hybridization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gantz, I.; Yamada, Tadataka; Tashiro, Takao

1994-01-15

[alpha]-Melanocyte stimulating hormone ([alpha]-MSH), a hormone originally named for its ability to regulate pigmentation of melanocytes, is a 13-amino-acid post-translational product of the pro-opiomelanocortin (POMC) gene. [alpha]-MSH and the other products of POMC processing, which share the core heptapeptide amino acid sequence Met-Glu (Gly)-His-Phe-Arg-Trp-Gly (Asp), the adrenocorticotropic hormone (ACTH), [beta]-MSH, and [gamma]-MSH, are collectively referred to as melanocortins. While best known for their effects on the melanocyte (pigmentation) and adrenal cortical cells (steroidogenesis), melanocortins have been postulated to function in diverse activities, including enhancement of learning and memory, control of the cardiovascular system, analgesia, thermoregulation, immunomodulation, parturition, and neurotrophism. Tomore » identify the chromosomal band encoding the human melanocortin-1 receptor gene, 1 [mu]g of an EMBL clone coding region of the human MC1R and approximately 15 kb of surrounding DNA was labeled with biotin and hybridized to human metaphase chromosomes as previously described. The results indicate that the human MC1R gene is localized to 16q24.3. 15 refs., 1 fig.« less

Potentiation of ghrelin signaling attenuates cancer anorexia–cachexia and prolongs survival

PubMed Central

Fujitsuka, N; Asakawa, A; Uezono, Y; Minami, K; Yamaguchi, T; Niijima, A; Yada, T; Maejima, Y; Sedbazar, U; Sakai, T; Hattori, T; Kase, Y; Inui, A

2011-01-01

Cancer anorexia–cachexia syndrome is characterized by decreased food intake, weight loss, muscle tissue wasting and psychological distress, and this syndrome is a major source of increased morbidity and mortality in cancer patients. This study aimed to clarify the gut–brain peptides involved in the pathogenesis of the syndrome and determine effective treatment for cancer anorexia–cachexia. We show that both ghrelin insufficiency and resistance were observed in tumor-bearing rats. Corticotropin-releasing factor (CRF) decreased the plasma level of acyl ghrelin, and its receptor antagonist, α-helical CRF, increased food intake of these rats. The serotonin 2c receptor (5-HT2cR) antagonist SB242084 decreased hypothalamic CRF level and improved anorexia, gastrointestinal (GI) dysmotility and body weight loss. The ghrelin receptor antagonist (D-Lys3)-GHRP-6 worsened anorexia and hastened death in tumor-bearing rats. Ghrelin attenuated anorexia–cachexia in the short term, but failed to prolong survival, as did SB242084 administration. In addition, the herbal medicine rikkunshito improved anorexia, GI dysmotility, muscle wasting, and anxiety-related behavior and prolonged survival in animals and patients with cancer. The appetite-stimulating effect of rikkunshito was blocked by (D-Lys3)-GHRP-6. Active components of rikkunshito, hesperidin and atractylodin, potentiated ghrelin secretion and receptor signaling, respectively, and atractylodin prolonged survival in tumor-bearing rats. Our study demonstrates that the integrated mechanism underlying cancer anorexia–cachexia involves lowered ghrelin signaling due to excessive hypothalamic interactions of 5-HT with CRF through the 5-HT2cR. Potentiation of ghrelin receptor signaling may be an attractive treatment for anorexia, muscle wasting and prolong survival in patients with cancer anorexia–cachexia. PMID:22832525

Forskolin, a hedgehog signalling inhibitor, attenuates carbon tetrachloride-induced liver fibrosis in rats.

PubMed

El-Agroudy, Nermeen N; El-Naga, Reem N; El-Razeq, Rania Abd; El-Demerdash, Ebtehal

2016-11-01

Liver fibrosis is one of the leading causes of morbidity and mortality worldwide with very limited therapeutic options. Given the pivotal role of activated hepatic stellate cells in liver fibrosis, attention has been directed towards the signalling pathways underlying their activation and fibrogenic functions. Recently, the hedgehog (Hh) signalling pathway has been identified as a potentially important therapeutic target in liver fibrosis. The present study was designed to explore the antifibrotic effects of the potent Hh signalling inhibitor, forskolin, and the possible molecular mechanisms underlying these effects. Male Sprague-Dawley rats were treated with either CCl 4 and/or forskolin for 6 consecutive weeks. Serum hepatotoxicity markers were determined, and histopathological evaluation was performed. Hepatic fibrosis was assessed by measuring α-SMA expression and collagen deposition by Masson's trichrome staining and hydroxyproline content. The effects of forskolin on oxidative stress markers (GSH, GPx, lipid peroxides), inflammatory markers (NF-κB, TNF-α, COX-2, IL-1β), TGF-β1 and Hh signalling markers (Ptch-1, Smo, Gli-2) were also assessed. Hepatic fibrosis induced by CCl 4 was significantly reduced by forskolin, as indicated by decreased α-SMA expression and collagen deposition. Forskolin co-treatment significantly attenuated oxidative stress and inflammation, reduced TGF-β1 levels and down-regulated mRNA expression of Ptch-1, Smo and Gli-2 through cAMP-dependent PKA activation. In our model, forskolin exerted promising antifibrotic effects which could be partly attributed to its antioxidant and anti-inflammatory effects, as well as to its inhibition of Hh signalling, mediated by cAMP-dependent activation of PKA. © 2016 The British Pharmacological Society.

Forskolin, a hedgehog signalling inhibitor, attenuates carbon tetrachloride‐induced liver fibrosis in rats

PubMed Central

El‐Agroudy, Nermeen N; El‐Naga, Reem N; El‐Razeq, Rania Abd

2016-01-01

Background and Purpose Liver fibrosis is one of the leading causes of morbidity and mortality worldwide with very limited therapeutic options. Given the pivotal role of activated hepatic stellate cells in liver fibrosis, attention has been directed towards the signalling pathways underlying their activation and fibrogenic functions. Recently, the hedgehog (Hh) signalling pathway has been identified as a potentially important therapeutic target in liver fibrosis. The present study was designed to explore the antifibrotic effects of the potent Hh signalling inhibitor, forskolin, and the possible molecular mechanisms underlying these effects. Experimental Approach Male Sprague‐Dawley rats were treated with either CCl4 and/or forskolin for 6 consecutive weeks. Serum hepatotoxicity markers were determined, and histopathological evaluation was performed. Hepatic fibrosis was assessed by measuring α‐SMA expression and collagen deposition by Masson's trichrome staining and hydroxyproline content. The effects of forskolin on oxidative stress markers (GSH, GPx, lipid peroxides), inflammatory markers (NF‐κB, TNF‐α, COX‐2, IL‐1β), TGF‐β1 and Hh signalling markers (Ptch‐1, Smo, Gli‐2) were also assessed. Key Results Hepatic fibrosis induced by CCl4 was significantly reduced by forskolin, as indicated by decreased α‐SMA expression and collagen deposition. Forskolin co‐treatment significantly attenuated oxidative stress and inflammation, reduced TGF‐β1 levels and down‐regulated mRNA expression of Ptch‐1, Smo and Gli‐2 through cAMP‐dependent PKA activation. Conclusion and Implications In our model, forskolin exerted promising antifibrotic effects which could be partly attributed to its antioxidant and anti‐inflammatory effects, as well as to its inhibition of Hh signalling, mediated by cAMP–dependent activation of PKA. PMID:27590029

Incorporation of a Bio-Active Reverse-Turn Heterocycle into a Peptide Template Using Solid-Phase Synthesis to Probe Melanocortin Receptor Selectivity and Ligand Conformations by 2D 1H NMR

PubMed Central

Singh, Anamika; Wilczynski, Andrzej; Holder, Jerry R.; Witek, Rachel M.; Dirain, Marvin L.; Xiang, Zhimin; Edison, Arthur S.; Haskell-Luevano, Carrie

2011-01-01

Using a solid-phase synthetic approach, a bioactive reverse turn heterocyclic was incorporated into a cyclic peptide template to probe melanocortin receptor potency and ligand structural conformations. The five melanocortin receptor isoforms (MC1R-MC5R) are G-protein coupled receptors (GPCRs) that are regulated by endogenous agonists and antagonists. This pathway is involved in pigmentation, weight, and energy homeostasis. Herein, we report novel analogues of the chimeric AGRP-melanocortin peptide template integrated with a small molecule moiety to probe the structural and functional consequences of the core His-Phe-Arg-Trp peptide domain using a reverse-turn heterocycle. A series of six compounds are reported that result in inactive to full agonists with nM potency. Biophysical structural analysis [2D 1H NMR and computer-assisted molecular modeling (CAMM)] were performed on selected analogues, resulting in the identification that these peptide-small molecule hybrids possessed increased flexibility and fewer discrete conformational families as compared to the reference peptide and result in a novel template for further structure-function studies. PMID:21306168

Iron regulation of hepcidin despite attenuated Smad1,5,8 signaling in mice without transferrin receptor 2 or Hfe

PubMed Central

Corradini, Elena; Rozier, Molly; Meynard, Delphine; Odhiambo, Adam; Lin, Herbert Y.; Feng, Qi; Migas, Mary C.; Britton, Robert S.; Babitt, Jodie L.; Fleming, Robert E.

2011-01-01

Background & Aims HFE and transferrin receptor 2 (TFR2) are each necessary for the normal relationship between body iron status and liver hepcidin expression. In murine Hfe and Tfr2 knockout models of hereditary hemochromatosis (HH), signal transduction to hepcidin via the bone morphogenetic protein 6 (Bmp6)/Smad1,5,8 pathway is attenuated. We examined the effect of dietary iron on regulation of hepcidin expression via the Bmp6/Smad1,5,8 pathway using mice with targeted disruption of Tfr2, Hfe, or both genes. Methods Hepatic iron concentrations and mRNA expression of Bmp6 and hepcidin were compared with wild-type mice in each of the HH models on standard or iron-loading diets. Liver phospho-Smad (P-Smad)1,5,8 and Id1 mRNA levels were measured as markers of Bmp/Smad signaling. Results While Bmp6 expression was increased, liver hepcidin and Id1 expression were decreased in each of the HH models compared with wild-type mice. Each of the HH models also demonstrated attenuated P-Smad1,5,8 levels relative to liver iron status. Mice with combined Hfe/Tfr2 disruption were most affected. Dietary iron loading increased hepcidin and Id1 expression in each of the HH models. Compared with wild-type mice, HH mice demonstrated attenuated (Hfe knockout) or no increases in P-Smad1,5,8 levels in response to dietary iron loading. Conclusions These observations demonstrate that Tfr2 and Hfe are each required for normal signaling of iron status to hepcidin via Bmp6/Smad1,5,8 pathway. Mice with combined loss of Hfe and Tfr2 up-regulate hepcidin in response to dietary iron loading without increases in liver BMP6 mRNA or steady-state P-Smad1,5,8 levels. PMID:21745449

Computer-controlled attenuator.

PubMed

Mitov, D; Grozev, Z

1991-01-01

Various possibilities for applying electronic computer-controlled attenuators for the automation of physiological experiments are considered. A detailed description is given of the design of a 4-channel computer-controlled attenuator, in two of the channels of which the output signal can change by a linear step, in the other two channels--by a logarithmic step. This, together with the existence of additional programmable timers, allows to automate a wide range of studies in different spheres of physiology and psychophysics, including vision and hearing.

Association between melanocortin-4 receptor mutations and eating behaviors in obese patients: a case--control study.

PubMed

Valette, M; Poitou, C; Kesse-Guyot, E; Bellisle, F; Carette, C; Le Beyec, J; Hercberg, S; Clément, K; Czernichow, S

2014-06-01

Melanocortin-4 receptor (MC4R) gene mutations are involved in the leptin-melanocortin pathways that control food intake. The effect of these mutations on eating behavior phenotypes is still debated. To determine the association between functional MC4R mutations and eating behaviors, dietary intake and physical activity, we sequenced the MC4R gene in 4653 obese adults. Among them, 19 adults carriers of functional MC4R mutation were matched on age, sex and body mass index with two randomly-paired controls without MC4R mutation (n=57). We found that eating behaviors and physical activity did not differ between groups. In particular, cases were not at increased risk of binge eating disorders. Subjects carriers of MC4R mutation reported a higher proportion of dietary carbohydrates intakes (43.2±7.1 and 39.2±8.1% of total energy intake, respectively, P=0.048) and a lower proportion of dietary lipids (34.3±6.7 and 38.5±6.7% of total energy intake, respectively, P=0.018). In conclusion, mutation carriers differ from controls by a higher consumption of carbohydrates counterbalanced by a lower consumption of lipids expressed as percentage of total energy intake. However, functional MC4R mutations do not have a higher risk of compulsive eating contrary to what was previously suggested.

Pharmacological and pharmacokinetic characterization of 2-piperazine-alpha-isopropyl benzylamine derivatives as melanocortin-4 receptor antagonists.

PubMed

Chen, Chen; Tucci, Fabio C; Jiang, Wanlong; Tran, Joe A; Fleck, Beth A; Hoare, Sam R; Wen, Jenny; Chen, Takung; Johns, Michael; Markison, Stacy; Foster, Alan C; Marinkovic, Dragan; Chen, Caroline W; Arellano, Melissa; Harman, John; Saunders, John; Bozigian, Haig; Marks, Daniel

2008-05-15

A series of 2-piperazine-alpha-isopropylbenzylamine derivatives were synthesized and characterized as melanocortin-4 receptor (MC4R) antagonists. Attaching an amino acid to benzylamines 7 significantly increased their binding affinity, and the resulting compounds 8-12 bound selectively to MC4R over other melanocortin receptor subtypes and behaved as functional antagonists. These compounds were also studied for their permeability using Caco-2 cell monolayers and metabolic stability in human liver microsomes. Most compounds exhibited low permeability and high efflux ratio possibly due to their high molecular weights. They also showed moderate metabolic stability which might be associated with their moderate to high lipophilicity. Pharmacokinetic properties of these MC4R antagonists, including brain penetration, were studied in mice after oral and intravenous administrations. Two compounds identified to possess high binding affinity and selectivity, 10d and 11d, were studied in a murine cachexia model. After intraperitoneal (ip) administration of 1mg/kg dose, mice treated with 10d had significantly more food intake and weight gain than the control animals, demonstrating efficacy by blocking the MC4 receptor. Similar in vivo effects were also observed when 11d was dosed orally at 20mg/kg. These results provide further evidence that a potent and selective MC4R antagonist has potential in the treatment of cancer cachexia.

Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH2 induces penile erection via brain and spinal melanocortin receptors.

PubMed

Wessells, H; Hruby, V J; Hackett, J; Han, G; Balse-Srinivasan, P; Vanderah, T W

2003-01-01

Penile erection induced by alpha-melanocyte-stimulating hormone and melanocortin receptors (MC-R) in areas of the spinal cord and periphery has not been demonstrated. To elucidate sites of the proerectile action of melanocortin peptides, in awake male rats we administered the MC-R agonist Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH(2) (MT-II) i.c.v., intrathecal (i.th.) and i.v. and scored penile erection and yawning. Injection of the MC-R antagonist Ac-Nle-c[Asp-His-DNal(2')-Arg-Trp-Lys]-NH(2) (SHU-9119) i.c.v. or i.th. in combination with i.th. MT-II differentiated spinal from supraspinal effects. To exclude a site of action in the penis, we recorded intracavernous pressure responses to intracavernosal injection of MT-II in the anesthetized rat.I.c.v., i.th., and i.v. MT-II induced penile erections in a dose-dependent fashion. Yawning was observed with i.c.v. and i.v. MT-II, while spinal injection did not produce this behavior. Intrathecal delivery of MT-II to the lumbosacral spinal cord was more efficacious in inducing erections than i.c.v. or i.v. administration; SHU-9119 blocked the erectile responses to i.th. MT-II when injected i.th. but not i.c.v. Intracavernosal MT-II neither increased intracavernous pressure nor augmented neurostimulated erectile responses. We confirmed the central proerectile activity of MT-II and demonstrated that in addition to a site of action in the brain, the distal spinal cord contains melanocortin receptors that can initiate penile erection independent of higher centers. These results provide new insight into the central melanocortinergic pathways that mediate penile erection and may allow for more efficacious melanotropin-based therapy for erectile dysfunction.

Taraxerol, a pentacyclic triterpene from Abroma augusta leaf, attenuates acute inflammation via inhibition of NF-κB signaling.

PubMed

Khanra, Ritu; Dewanjee, Saikat; Dua, Tarun K; Bhattacharjee, Niloy

2017-04-01

Abroma augusta L. (Malvaceae) leaf is traditionally used to treat inflammatory disorders. In our laboratory, we have scientifically validated the anti-inflammatory effect of A. augusta leaf extract. In this study, it has been aimed to evaluate in vivo anti-inflammatory effect of taraxerol isolated from the methanol extract of A. augusta leaf. It was further intended to find out the probable mechanism of anti-inflammatory effect of taraxerol. The anti-inflammatory effect of taraxerol (5 and 10mg/kg, i.p.) was measured employing carrageenan-induced paw edema model of acute inflammation. The carrageenan injection resulted significant edema formation in the right paw when compared with un-injected left paw. However, taraxerol (10mg/kg) treatment could significantly (p<0.05-0.01) attenuate carrageenan induced paw edema 2h onward. The effect of taraxerol at the dose of 5mg/kg was found to be significant (p<0.05) only after 4h of carrageenan treatment. Taraxerol (10mg/kg) treatment could significantly (p<0.01) attenuate carrageenan mediated up-regulation in the levels of IL 1β, IL 6, IL 12 and TNF α in the right paw tissues. In search of molecular mechanism, taraxerol (10mg/kg) could significantly (p<0.05-0.01) reinstate carrageenan provoked NF-κB signaling and thereby caused significant down-regulation in the expressions of COX-2 (p<0.01) and iNOS (p<0.05). In conclusion, taraxerol would attenuate acute inflammation via inhibition of NF-κB signaling. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Hydrogen Sulfide Attenuates the Recruitment of CD11b+Gr-1+ Myeloid Cells and Regulates Bax/Bcl-2 Signaling in Myocardial Ischemia Injury

PubMed Central

Zhang, Youen; Li, Hua; Zhao, Gang; Sun, Aijun; Zong, Nobel C.; Li, Zhaofeng; Zhu, Hongming; Zou, Yunzeng; Yang, Xiangdong; Ge, Junbo

2014-01-01

Hydrogen sulfide, an endogenous signaling molecule, plays an important role in the physiology and pathophysiology of the cardiovascular system. Using a mouse model of myocardial infarction, we investigated the anti-inflammatory and anti-apoptotic effects of the H2S donor sodium hydrosulfide (NaHS). The results demonstrated that the administration of NaHS improved survival, preserved left ventricular function, limited infarct size, and improved H2S levels in cardiac tissue to attenuate the recruitment of CD11b+Gr-1+ myeloid cells and to regulate the Bax/Bcl-2 pathway. Furthermore, the cardioprotective effects of NaHS were enhanced by inhibiting the migration of CD11b+Gr-1+ myeloid cells from the spleen into the blood and by attenuating post-infarction inflammation. These observations suggest that the novel mechanism underlying the cardioprotective function of H2S is secondary to a combination of attenuation the recruitment of CD11b+Gr-1+ myeloid cells and regulation of the Bax/Bcl-2 apoptotic signaling. PMID:24758901

Hunger and Satiety Signaling: Modeling Two Hypothalamomedullary Pathways for Energy Homeostasis.

PubMed

Nakamura, Kazuhiro; Nakamura, Yoshiko

2018-06-04

The recent discovery of the medullary circuit driving "hunger responses" - reduced thermogenesis and promoted feeding - has greatly expanded our knowledge on the central neural networks for energy homeostasis. However, how hypothalamic hunger and satiety signals generated under fasted and fed conditions, respectively, control the medullary autonomic and somatic motor mechanisms remains unknown. Here, in reviewing this field, we propose two hypothalamomedullary neural pathways for hunger and satiety signaling. To trigger hunger signaling, neuropeptide Y activates a group of neurons in the paraventricular hypothalamic nucleus (PVH), which then stimulate an excitatory pathway to the medullary circuit to drive the hunger responses. In contrast, melanocortin-mediated satiety signaling activates a distinct group of PVH neurons, which then stimulate a putatively inhibitory pathway to the medullary circuit to counteract the hunger signaling. The medullary circuit likely contains inhibitory and excitatory premotor neurons whose alternate phasic activation generates the coordinated masticatory motor rhythms to promote feeding. © 2018 The Authors. BioEssays Published by WILEY Periodicals, Inc.

Inhibition of Siah2 ubiquitin ligase by vitamin K3 (menadione) attenuates hypoxia and MAPK signaling and blocks melanoma tumorigenesis.

PubMed

Shah, Meera; Stebbins, John L; Dewing, Antimone; Qi, Jianfei; Pellecchia, Maurizio; Ronai, Ze'ev A

2009-12-01

The E3 ubiquitin ligase Siah2 has been implicated in the regulation of the hypoxia response, as well as in the control of Ras, JNK/p38/NF-kappaB signaling pathways. Both Ras/mitogen-activated protein kinase (MAPK) and hypoxia pathways are important for melanoma development and progression, pointing to the possible use of Siah2 as target for treatment of this tumor type. In the present study, we have established a high-throughput electro-chemiluninescent-based assay in order to screen and identify inhibitors of Siah2 ubiquitin ligase activity. Of 1840 compounds screened, we identified and characterized menadione (MEN) as a specific inhibitor of Siah2 ligase activity. MEN attenuated Siah2 self-ubiquitination, and increased expression of its substrates PHD3 and Sprouty2, with concomitant decrease in levels of HIF-1alpha and pERK, the respective downstream effectors. MEN treatment no longer affected PHD3 or Sprouty2 in Siah-KO cells, pointing to its Siah-dependent effects. Further, MEN inhibition of Siah2 was not attenuated by free radical scavenger, suggesting it is ROS-independent. Significantly, growth of xenograft melanoma tumors was inhibited following the administration of MEN or its derivative. These findings reveal an efficient platform for the identification of Siah inhibitors while identifying and characterizing MEN as Siah inhibitor that attenuates hypoxia and MAPK signaling, and inhibits melanoma tumorigenesis.

An Essential Role for the K+-dependent Na+/Ca2+-exchanger, NCKX4, in Melanocortin-4-receptor-dependent Satiety*

PubMed Central

Li, Xiao-Fang; Lytton, Jonathan

2014-01-01

K+-dependent Na+/Ca2+-exchangers are broadly expressed in various tissues, and particularly enriched in neurons of the brain. The distinct physiological roles for the different members of this Ca2+ transporter family are, however, not well described. Here we show that gene-targeted mice lacking the K+-dependent Na+/Ca2+-exchanger, NCKX4 (gene slc24a4 or Nckx4), display a remarkable anorexia with severe hypophagia and weight loss. Feeding and satiety are coordinated centrally by melanocortin-4 receptors (MC4R) in neurons of the hypothalamic paraventricular nucleus (PVN). The hypophagic response of Nckx4 knock-out mice is accompanied by hyperactivation of neurons in the PVN, evidenced by high levels of c-Fos expression. The activation of PVN neurons in both fasted Nckx4 knock-out and glucose-injected wild-type animals is blocked by Ca2+ removal and MC4R antagonists. In cultured hypothalamic neurons, melanocyte stimulating hormone induces an MC4R-dependent and sustained Ca2+ signal, which requires phospholipase C activity and plasma membrane Ca2+ entry. The Ca2+ signal is enhanced in hypothalamic neurons from Nckx4 knock-out animals, and is depressed in cells in which NCKX4 is overexpressed. Finally, MC4R-dependent oxytocin expression in the PVN, a key essential step in satiety, is prevented by blocking phospholipase C activation or Ca2+ entry. These findings highlight an essential, and to our knowledge previously unknown, role for Ca2+ signaling in the MC4R pathway that leads to satiety, and a novel non-redundant role for NCKX4-mediated Ca2+ extrusion in controlling MC4R signaling and feeding behavior. Together, these findings highlight a novel pathway that potentially could be exploited to develop much needed new therapeutics to tackle eating disorders and obesity. PMID:25096581

Sitagliptin decreases ventricular arrhythmias by attenuated glucose-dependent insulinotropic polypeptide (GIP)-dependent resistin signalling in infarcted rats.

PubMed

Lee, Tsung-Ming; Chen, Wei-Ting; Chang, Nen-Chung

2016-01-25

Myocardial infarction (MI) was associated with insulin resistance, in which resistin acts as a critical mediator. We aimed to determine whether sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, can attenuate arrhythmias by regulating resistin-dependent nerve growth factor (NGF) expression in postinfarcted rats. Normoglycaemic male Wistar rats after ligating coronary artery were randomized to either vehicle or sitagliptin for 4 weeks starting 24 h after operation. Post-infarction was associated with increased myocardial noradrenaline [norepinephrine (NE)] levels and sympathetic hyperinnervation. Compared with vehicle, sympathetic innervation was blunted after administering sitagliptin, as assessed by immunofluorescent analysis of tyrosine hydroxylase, growth-associated factor 43 and neurofilament and western blotting and real-time quantitative RT-PCR of NGF. Arrhythmic scores in the sitagliptin-treated infarcted rats were significantly lower than those in vehicle. Furthermore, sitagliptin was associated with reduced resistin expression and increased Akt activity. Ex vivo studies showed that glucose-dependent insulinotropic polypeptide (GIP) infusion, but not glucagon-like peptide-1 (GLP-1), produced similar reduction in resistin levels to sitagliptin in postinfarcted rats. Furthermore, the attenuated effects of sitagliptin on NGF levels can be reversed by wortmannin (a phosphatidylinositol 3-kinase antagonist) and exogenous resistin infusion. Sitagliptin protects ventricular arrhythmias by attenuating sympathetic innervation in the non-diabetic infarcted rats. Sitagliptin attenuated resistin expression via the GIP-dependent pathway, which inhibited sympathetic innervation through a signalling pathway involving phosphatidylinositol 3-kinase (PI3K) and Akt protein. © 2016 Authors.

Attenuation of T cell receptor signaling by serine phosphorylation-mediated lysine 30 ubiquitination of SLP-76 protein.

PubMed

Wang, Xiaohong; Li, Ju-Pi; Chiu, Li-Li; Lan, Joung-Liang; Chen, Der-Yuan; Boomer, Jonathan; Tan, Tse-Hua

2012-10-05

SLP-76 (SH2 domain-containing leukocyte protein of 76 kDa) is an adaptor protein that is essential for T cell development and T cell receptor (TCR) signaling activation. Previous studies have identified an important negative feedback regulation of SLP-76 by HPK1 (hematopoietic progenitor kinase 1; MAP4K1)-induced Ser-376 phosphorylation. Ser-376 phosphorylation of SLP-76 mediates 14-3-3 binding, resulting in the attenuation of SLP-76 activation and downstream signaling; however, the underlying mechanism of this action remains unknown. Here, we report that phosphorylated SLP-76 is ubiquitinated and targeted for proteasomal degradation during TCR signaling. SLP-76 ubiquitination is mediated by Ser-376 phosphorylation. Furthermore, Lys-30 is identified as a ubiquitination site of SLP-76. Loss of Lys-30 ubiquitination of SLP-76 results in enhanced anti-CD3 antibody-induced ERK and JNK activation. These results reveal a novel regulation mechanism of SLP-76 by ubiquitination and proteasomal degradation of activated SLP-76, which is mediated by Ser-376 phosphorylation, leading to down-regulation of TCR signaling.

Attenuation of T Cell Receptor Signaling by Serine Phosphorylation-mediated Lysine 30 Ubiquitination of SLP-76 Protein*

PubMed Central

Wang, Xiaohong; Li, Ju-Pi; Chiu, Li-Li; Lan, Joung-Liang; Chen, Der-Yuan; Boomer, Jonathan; Tan, Tse-Hua

2012-01-01

SLP-76 (SH2 domain-containing leukocyte protein of 76 kDa) is an adaptor protein that is essential for T cell development and T cell receptor (TCR) signaling activation. Previous studies have identified an important negative feedback regulation of SLP-76 by HPK1 (hematopoietic progenitor kinase 1; MAP4K1)-induced Ser-376 phosphorylation. Ser-376 phosphorylation of SLP-76 mediates 14-3-3 binding, resulting in the attenuation of SLP-76 activation and downstream signaling; however, the underlying mechanism of this action remains unknown. Here, we report that phosphorylated SLP-76 is ubiquitinated and targeted for proteasomal degradation during TCR signaling. SLP-76 ubiquitination is mediated by Ser-376 phosphorylation. Furthermore, Lys-30 is identified as a ubiquitination site of SLP-76. Loss of Lys-30 ubiquitination of SLP-76 results in enhanced anti-CD3 antibody-induced ERK and JNK activation. These results reveal a novel regulation mechanism of SLP-76 by ubiquitination and proteasomal degradation of activated SLP-76, which is mediated by Ser-376 phosphorylation, leading to down-regulation of TCR signaling. PMID:22902619

Inhibition of SDF-1α/CXCR4 Signalling in Subchondral Bone Attenuates Post-Traumatic Osteoarthritis

PubMed Central

Dong, Yonghui; Liu, Hui; Zhang, Xuejun; Xu, Fei; Qin, Liang; Cheng, Peng; Huang, Hui; Guo, Fengjing; Yang, Qing; Chen, Anmin

2016-01-01

Previous studies showed that SDF-1α is a catabolic factor that can infiltrate cartilage, decrease proteoglycan content, and increase MMP-13 activity. Inhibiting the SDF-1α/CXCR4 signalling pathway can attenuate the pathogenesis of osteoarthritis (OA). Recent studies have also shown that SDF-1α enhances chondrocyte proliferation and maturation. These results appear to be contradictory. In the current study, we used a destabilisation OA animal model to investigate the effects of SDF-1α/CXCR4 signalling in the tibial subchondral bone and the OA pathological process. Post-traumatic osteoarthritis (PTOA) mice models were prepared by transecting the anterior cruciate ligament (ACLT), or a sham surgery was performed, in a total of 30 mice. Mice were treated with phosphate buffer saline (PBS) or AMD3100 (an inhibitor of CXCR4) and sacrificed at 30 days post ACLT or sham surgery. Tibial subchondral bone status was quantified by micro-computed tomography (μCT). Knee-joint histology was analysed to examine the articular cartilage and joint degeneration. The levels of SDF-1α and collagen type I c-telopeptidefragments (CTX-I) were quantified by ELISA. Bone marrow mononuclear cells (BMMCs) were used to clarify the effects of SDF-1α on osteoclast formation and activity in vivo. μCT analysis revealed significant loss of trabecular bone from tibial subchondral bone post-ACLT, which was effectively prevented by AMD3100. AMD3100 could partially prevent bone loss and articular cartilage degeneration. Serum biomarkers revealed an increase in SDF-1α and bone resorption, which were also reduced by AMD3100. SDF-1α can promote osteoclast formation and the expression oftartrate resistant acid phosphatase (TRAP), cathepsin K (CK), and matrix metalloproteinase (MMP)-9 in osteoclasts by activating the MAPK pathway, including ERK and p38, but not JNK. In conclusion, inhibition of SDF-1α/CXCR4signalling was able to prevent trabecular bone loss and attenuated cartilage degeneration in

Melanocortin-3 receptors expressed in Nkx2.1(+ve) neurons are sufficient for controlling appetitive responses to hypocaloric conditioning

PubMed Central

Girardet, Clémence; Mavrikaki, Maria M.; Stevens, Joseph R.; Miller, Courtney A.; Marks, Daniel L.; Butler, Andrew A.

2017-01-01

Melanocortin-3 receptors (MC3R) have a contextual role in appetite control that is amplified with hypocaloric conditioning. C57BL/6J (B6) mice subjected to hypocaloric feeding schedules (HFS) exhibit compulsive behavioral responses involving food anticipatory activity (FAA) and caloric loading following food access. These homeostatic responses to calorie-poor environs are attenuated in B6 mice in which Mc3r transcription is suppressed by a lox-stop-lox sequence in the 5’UTR (Mc3rTB/TB). Here, we report that optimization of caloric loading in B6 mice subject to HFS, characterized by increased meal size and duration, is not observed in Mc3rTB/TB mice. Analysis of hypothalamic and neuroendocrine responses to HFS throughout the light-dark cycle suggests uncoupling of hypothalamic responses involving appetite-stimulating fasting-responsive hypothalamic neurons expressing agouti-related peptide (AgRP) and neuropeptide Y (Npy). Rescuing Mc3rs expression in Nkx2.1(+ve) neurons is sufficient to restore normal hypothalamic responses to negative energy balance. In addition, Mc3rs expressed in Nkx2.1(+ve) neurons are also sufficient to restore FAA and caloric loading of B6 mice subjected to HFS. In summary, MC3Rs expressed in Nkx2.1(+ve) neurons are sufficient to coordinate hypothalamic response and expression of compulsive behavioral responses involving meal anticipation and consumption of large meals during situations of prolonged negative energy balance. PMID:28294152

Phosphatidylcholine transfer protein interacts with thioesterase superfamily member 2 to attenuate insulin signaling.

PubMed

Ersoy, Baran A; Tarun, Akansha; D'Aquino, Katharine; Hancer, Nancy J; Ukomadu, Chinweike; White, Morris F; Michel, Thomas; Manning, Brendan D; Cohen, David E

2013-07-30

Phosphatidylcholine transfer protein (PC-TP) is a phospholipid-binding protein that is enriched in liver and that interacts with thioesterase superfamily member 2 (THEM2). Mice lacking either protein exhibit improved hepatic glucose homeostasis and are resistant to diet-induced diabetes. Insulin receptor substrate 2 (IRS2) and mammalian target of rapamycin complex 1 (mTORC1) are key effectors of insulin signaling, which is attenuated in diabetes. We found that PC-TP inhibited IRS2, as evidenced by insulin-independent IRS2 activation after knockdown, genetic ablation, or chemical inhibition of PC-TP. In addition, IRS2 was activated after knockdown of THEM2, providing support for a role for the interaction of PC-TP with THEM2 in suppressing insulin signaling. Additionally, we showed that PC-TP bound to tuberous sclerosis complex 2 (TSC2) and stabilized the components of the TSC1-TSC2 complex, which functions to inhibit mTORC1. Preventing phosphatidylcholine from binding to PC-TP disrupted interactions of PC-TP with THEM2 and TSC2, and disruption of the PC-TP-THEM2 complex was associated with increased activation of both IRS2 and mTORC1. In livers of mice with genetic ablation of PC-TP or that had been treated with a PC-TP inhibitor, steady-state amounts of IRS2 were increased, whereas those of TSC2 were decreased. These findings reveal a phospholipid-dependent mechanism that suppresses insulin signaling downstream of its receptor.

Phosphatidylcholine Transfer Protein Interacts with Thioesterase Superfamily Member 2 to Attenuate Insulin Signaling

PubMed Central

Ersoy, Baran A.; Tarun, Akansha; D’Aquino, Katharine; Hancer, Nancy J.; Ukomadu, Chinweike; White, Morris F.; Michel, Thomas; Manning, Brendan D.; Cohen, David E.

2014-01-01

Phosphatidylcholine transfer protein (PC-TP) is a phospholipid-binding protein that is enriched in liver and that interacts with thioesterase superfamily member 2 (THEM2). Mice lacking either protein exhibit improved hepatic glucose homeostasis and are resistant to diet-induced diabetes. Insulin receptor substrate 2 (IRS2) and mammalian target of rapamycin complex 1 (mTORC1) are key effectors of insulin signaling, which is attenuated in diabetes. We found that PC-TP inhibited IRS2, as evidenced by insulin-independent IRS2 activation following knockdown, genetic ablation, or chemical inhibition of PC-TP. In addition, IRS2 was activated after knockdown of THEM2, providing support for a role for the interaction of PC-TP with THEM2 in suppressing insulin signaling. Additionally, we showed that PC-TP bound to tuberous sclerosis complex 2 (TSC2) and stabilized the components of the TSC1-TSC2 complex, which functions to inhibit mTORC1. Preventing phosphatidylcholine from binding to PC-TP disrupted interactions of PC-TP with THEM2 and TSC2, and disruption of the PC-TP–THEM2 complex was associated with increased activation of both IRS2 and mTORC1. In livers of mice with genetic ablation of PC-TP or that had been treated with a PC-TP inhibitor, steady-state amounts of IRS2 were increased, whereas those of TSC2 were decreased. These findings reveal a phospholipid-dependent mechanism that suppresses insulin signaling downstream of its receptor. PMID:23901139

Inhibition of Siah2 ubiquitin ligase by vitamin K3 (menadione) attenuates hypoxia and MAPK signaling and blocks melanoma tumorigenesis

PubMed Central

Shah, Meera; Stebbins, John L.; Dewing, Antimone; Qi, Jianfei; Pellecchia, Maurizio; Ronai, Ze’ev A.

2010-01-01

Summary The E3 ubiquitin ligase Siah2 has been implicated in the regulation of the hypoxia response, as well as in the control of Ras, JNK/p38/NF-κB signaling pathways. Both Ras/mitogen-activated protein kinase (MAPK) and hypoxia pathways are important for melanoma development and progression, pointing to the possible use of Siah2 as target for treatment of this tumor type. In the present study, we have established a high-throughput electro-chemiluninescent-based assay in order to screen and identify inhibitors of Siah2 ubiquitin ligase activity. Of 1840 compounds screened, we identified and characterized menadione (MEN) as a specific inhibitor of Siah2 ligase activity. MEN attenuated Siah2 self-ubiquitination, and increased expression of its substrates PHD3 and Sprouty2, with concomitant decrease in levels of HIF-1α and pERK, the respective downstream effectors. MEN treatment no longer affected PHD3 or Sprouty2 in Siah-KO cells, pointing to its Siah-dependent effects. Further, MEN inhibition of Siah2 was not attenuated by free radical scavenger, suggesting it is ROS-independent. Significantly, growth of xenograft melanoma tumors was inhibited following the administration of MEN or its derivative. These findings reveal an efficient platform for the identification of Siah inhibitors while identifying and characterizing MEN as Siah inhibitor that attenuates hypoxia and MAPK signaling, and inhibits melanoma tumorigenesis. PMID:19712206

All-trans retinoic acid attenuates bleomycin-induced pulmonary fibrosis via downregulating EphA2-EphrinA1 signaling.

PubMed

Leem, Ah Young; Shin, Mi Hwa; Douglas, Ivor S; Song, Joo Han; Chung, Kyung Soo; Kim, Eun Young; Jung, Ji Ye; Kang, Young Ae; Chang, Joon; Kim, Young Sam; Park, Moo Suk

2017-09-23

The role of all-trans retinoic acid (ATRA) in pulmonary fibrosis is relatively unknown, although this metabolite modulates cell differentiation, proliferation, and development. We aimed to evaluate the role of ATRA in bleomycin-induced pulmonary fibrosis, and whether the mechanism involves EphA2-EphrinA1 and PI3K-Akt signaling. We evaluated three groups of mice: a control group (intraperitoneal DMSO injection 3 times weekly after PBS instillation), bleomycin group (intraperitoneal DMSO injection 3 times weekly after bleomycin instillation), and bleomycin + ATRA group (intraperitoneal ATRA injection 3 times weekly after bleomycin instillation). The cell counts and protein concentration in the bronchoalveolar lavage fluid (BALF), changes in histopathology, Ashcroft score, hydroxyproline assay, expression of several signal pathway proteins including EphA2-EphrinA1, and PI3K-Akt, and cytokine levels were compared among the groups. We found that bleomycin significantly increased the protein concentration in the BALF, Ashcroft score in lung tissue, and hydroxyproline contents in lung lysates. Furthermore, bleomycin upregulated EphA2, EphrinA1, PI3K 110γ, Akt, IL-6 and TNF-α. However, administration of ATRA attenuated the upregulation of EphA2-EphrinA1 and PI3K-Akt after bleomycin instillation, and decreased pulmonary fibrosis. In addition, ATRA suppressed IL-6 and TNF-α production induced by bleomycin-induced injury. Collectively, these data suggest that ATRA attenuates bleomycin-induced pulmonary fibrosis by regulating EphA2-EphrinA1 and PI3K-Akt signaling. Copyright © 2017 Elsevier Inc. All rights reserved.

Micro-opioid receptor agonist diminishes POMC gene expression and anorexia by central insulin in neonatal chicks.

PubMed

Shiraishi, Jun-Ichi; Yanagita, Kouchi; Fujita, Masanori; Bungo, Takashi

2008-07-18

Pro-opiomelanocortin (POMC) neurons in the hypothalamus are direct targets of peripheral satiety signals, such as leptin and insulin in mammals. The stimulation of these signals activates hypothalamic POMC neurons and elevates POMC-derived melanocortin peptides that inhibit food intake in mammals. On the other hand, it has been recognized that beta-endorphin, a post-translational processing of POMC, acts in an autoreceptor manner to the micro-opioid receptor (MOR) on POMC neurons, diminishing POMC neuronal activity in mammals. Recently, we found that central insulin functions as an anorexic peptide in chicks. Thus, the present study was done to elucidate whether beta-endorphin affects the activation of POMC neurons by insulin in neonatal chicks. Consequently, quantitative real-time PCR analysis shows that intracerebroventricular (ICV) injection of insulin with beta-endorphin significantly decreases brain POMC mRNA expression when compared with insulin alone. In addition, co-injection of MOR agonist (beta-endorphin or [d-Ala2, N-MePhe4, Gly5-ol]-enkephalin (DAMGO)) significantly attenuates insulin-induced hypophagia in chicks. These data suggest that beta-endorphin regulates the activity of the central melanocortin system, and its activation may provide an inhibitory feedback mechanism in the brain of neonatal chicks.

Arg-Phe-Phe D-Amino Acid Stereochemistry Scan in the Macrocyclic Agouti-Related Protein Antagonist Scaffold c[Pro-Arg-Phe-Phe-Xaa-Ala-Phe-DPro] Results in Unanticipated Melanocortin-1 Receptor Agonist Profiles.

PubMed

Ericson, Mark D; Koerperich, Zoe M; Freeman, Katie T; Fleming, Katlyn A; Haskell-Luevano, Carrie

2018-06-20

The melanocortin-3 and melanocortin-4 receptors (MC3R and MC4R), endogenous agonists derived from the proopiomelanocortin gene transcript, and naturally-occurring antagonists agouti and agouti-related protein (AGRP) have been linked to biological pathways associated with energy homeostasis. The active tripeptide sequence of AGRP, Arg111-Phe112-Phe113, is located on a hypothesized β-hairpin loop. Herein, stereochemical modifications of the Arg-Phe-Phe sequence were examined in the octapeptide AGRP-derived macrocyclic scaffold c[Pro-Arg-Phe-Phe-Xxx-Ala-Phe-DPro], where Xxx was Asn or diaminopropionic acid (Dap). Macrocyclic peptides were synthesized with one, two, or three residues of the Arg-Phe-Phe sequence substituted with the corresponding D-isomer(s), generating a 14 compound library. While L-to-D inversions of the Arg-Phe-Phe sequence in a 20-residue AGRP-derived ligand previously resulted in agonist activity at the MC1R, MC3R, MC4R, and MC5R, only the MC1R was consistently stimulated by the macrocyclic ligands in the present study, with varying ligand potencies and efficacies observed at the MC1R. A general trend of increased MC4R antagonist potency was observed for Dap-containing compounds, while MC5R inverse agonist activity was observed for select ligands. It was observed that stereochemical modification of the Arg-Phe-Phe active tripeptide sequence was insufficient to convert melanocortin antagonist into agonists. Overall, these observations are important in the design of melanocortin ligands possessing potent and selective agonist and antagonist activities.

Fructose downregulates miR-330 to induce renal inflammatory response and insulin signaling impairment: Attenuation by morin.

PubMed

Gu, Ting-Ting; Song, Lin; Chen, Tian-Yu; Wang, Xing; Zhao, Xiao-Juan; Ding, Xiao-Qin; Yang, Yan-Zi; Pan, Ying; Zhang, Dong-Mei; Kong, Ling-Dong

2017-08-01

Fructose induces insulin resistance with kidney inflammation and injury. MicroRNAs are emerged as key regulators of insulin signaling. Morin has insulin-mimetic effect with the improvement of insulin resistance and kidney injury. This study investigated the protective mechanisms of morin against fructose-induced kidney injury, with particular focus on miR-330 expression change, inflammatory response, and insulin signaling impairment. miR-330, sphingosine kinase 1 (SphK1)/sphingosine-1-phosphate (S1P)/S1P receptor (S1PR)1/3 signaling, nuclear factor-κB (NF-κB)/NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome, and insulin signaling were detected in kidney cortex of fructose-fed rats and fructose-exposed HK-2 cells, respectively. Whether miR-330 mediated inflammatory response to affect insulin signaling was examined using SphK1 inhibitor, S1PR1/3 short interfering RNA, or miR-330 mimic/inhibitor, respectively. Fructose was found to downregulate miR-330 expression to increase SphK1/S1P/S1PR1/3 signaling, and then activate NF-κB/NLRP3 inflammasome to produce IL-1β, causing insulin signaling impairment. Moreover, morin upregulated miR-330 and partly attenuated inflammatory response and insulin signaling impairment to alleviate kidney injury. These findings suggest that morin protects against fructose-induced kidney insulin signaling impairment by upregulating miR-330 to reduce inflammatory response. Morin may be a potential therapeutic agent for the treatment of kidney injury associated with fructose-induced inflammation and insulin signaling impairment. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Edaravone attenuates neuronal apoptosis in hypoxic-ischemic brain damage rat model via suppression of TRAIL signaling pathway.

PubMed

Li, Chunyi; Mo, Zhihuai; Lei, Junjie; Li, Huiqing; Fu, Ruying; Huang, Yanxia; Luo, Shijian; Zhang, Lei

2018-06-01

Edaravone is a new type of oxygen free radical scavenger and able to attenuate various brain damage including hypoxic-ischemic brain damage (HIBD). This study was aimed at investigating the neuroprotective mechanism of edaravone in rat hypoxic-ischemic brain damage model and its correlation with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling pathway. 75 seven-day-old Sprague-Dawley neonatal rats were equally divided into three groups: sham-operated group (sham), HIBD group and HIBD rats injected with edaravone (HIBD + EDA) group. Neurological severity and space cognitive ability of rats in each group were evaluated using Longa neurological severity score and Morris water maze testing. TUNEL assay and flow cytometry were used to determine brain cell apoptosis. Western blot was used to estimate the expression level of death receptor-5 (DR5), Fas-associated protein with death domain (FADD), caspase 8, B-cell lymphoma-2 (Bcl-2) and Bcl-2 associated X protein (Bax). In addition, immunofluorescence was performed to detect caspase 3. Edaravone reduced neurofunctional damage caused by HIBD and improved the cognitive capability of rats. The above experiment results suggested that edaravone could down-regulate the expression of active caspase 3 protein, thereby relieving neuronal apoptosis. Taken together, edaravone could attenuate neuronal apoptosis in rat hypoxic-ischemic brain damage model via suppression of TRAIL signaling pathway, which also suggested that edaravone might be an effective therapeutic strategy for HIBD clinical treatment. Copyright © 2018 Elsevier Ltd. All rights reserved.

MODIS Solar Diffuser Attenuation Screen Modeling Results

NASA Technical Reports Server (NTRS)

Waluschka, Eugene; Xuong, Xiaoxiong; Guenther, Bruce; Barnes, William

2004-01-01

On-orbit calibration of the reflected solar bands on the EOS Moderate Resolution Imaging Spectroradiometer (MODIS) is accomplished by have the instrument view a high reflectance diffuse surface illuminated by the sun. For some of the spectral bands this proves to be much too bright a signal that results in the saturation of detectors designed for measuring low reflectance (ocean) surfaces signals. A mechanical attenuation device in the form of a pin hole screen is used to reduce the signals to calibrate these bands. The sensor response to solar illumination of the SD with and without the attenuation screen in place will be presented. The MODIS detector response to the solar diffuser is smooth when the attenuation screen is absent, but has structures up to a few percent when the attenuation screen is present. This structure corresponds to non-uniform illumination from the solar diffuser. Each pin hole produces a pin-hole image of the sun on the solar diffuser, and there are very many pin hole images of the sun on the solar diffuser for each MODIS detector. Even though there are very many pin-hole images of the sun on the solar diffuser, it is no longer perfectly uniformly illuminated. This non-uniformly illuminated solar diffuser produces intensity variation on the focal planes. The results of a very detailed simulation will be discussed which show how the illumination of the focal plane changes as a result of the attenuation, and the impacts on the calibration will be discussed.

Full Wave Analysis of RF Signal Attenuation in a Lossy Cave using a High Order Time Domain Vector Finite Element Method

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pingenot, J; Rieben, R; White, D

2004-12-06

We present a computational study of signal propagation and attenuation of a 200 MHz dipole antenna in a cave environment. The cave is modeled as a straight and lossy random rough wall. To simulate a broad frequency band, the full wave Maxwell equations are solved directly in the time domain via a high order vector finite element discretization using the massively parallel CEM code EMSolve. The simulation is performed for a series of random meshes in order to generate statistical data for the propagation and attenuation properties of the cave environment. Results for the power spectral density and phase ofmore » the electric field vector components are presented and discussed.« less

Inhibition of EphA2/EphrinA1 signal attenuates lipopolysaccharide-induced lung injury.

PubMed

Hong, Ji Young; Shin, Mi Hwa; Douglas, Ivor S; Chung, Kyung Soo; Kim, Eun Young; Jung, Ji Ye; Kang, Young Ae; Kim, Se Kyu; Chang, Joon; Kim, Young Sam; Park, Moo Suk

2016-11-01

Eph-Ephrin signalling mediates various cellular processes, including vasculogenesis, angiogenesis, cell migration, axon guidance, fluid homoeostasis and repair after injury. Although previous studies have demonstrated that stimulation of the EphA receptor induces increased vascular permeability and inflammatory response in lung injury, the detailed mechanisms of EphA2 signalling are unknown. In the present study, we evaluated the role of EphA2 signalling in mice with lipopolysaccharide (LPS)-induced lung injury. Acute LPS exposure significantly up-regulated EphA2 and EphrinA1 expression. Compared with LPS+IgG mice (IgG instillation after LPS exposure), LPS+EphA2 mAb mice [EphA2 monoclonal antibody (mAb) instillation posttreatment after LPS exposure] had attenuated lung injury and reduced cell counts and protein concentration of bronchoalveolar lavage fluid (BALF). EphA2 mAb posttreatment down-regulated the expression of phosphoinositide 3-kinases (PI3K) 110γ, phospho-Akt, phospho-NF-κB p65, phospho-Src and phospho-S6K in lung lysates. In addition, inhibiting the EphA2 receptor augmented the expression of E-cadherin, which is involved in cell-cell adhesion. Our study identified EphA2 receptor as an unrecognized modulator of several signalling pathways-including PI3K-Akt-NF-kB, Src-NF-κB, E-cadherin and mTOR-in LPS-induced lung injury. These results suggest that EphA2 receptor inhibitors may function as novel therapeutic agents for LPS-induced lung injury. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

TSG-6 secreted by human umbilical cord-MSCs attenuates severe burn-induced excessive inflammation via inhibiting activations of P38 and JNK signaling.

PubMed

Liu, Lingying; Song, Huifeng; Duan, Hongjie; Chai, Jiake; Yang, Jing; Li, Xiao; Yu, Yonghui; Zhang, Xulong; Hu, Xiaohong; Xiao, Mengjing; Feng, Rui; Yin, Huinan; Hu, Quan; Yang, Longlong; Du, Jundong; Li, Tianran

2016-07-22

The hMSCs have become a promising approach for inflammation treatment in acute phase. Our previous study has demonstrated that human umbilical cord-MSCs could alleviate the inflammatory reaction of severely burned wound. In this study, we further investigated the potential role and mechanism of the MSCs on severe burn-induced excessive inflammation. Wistar rats were randomly divided into following groups: Sham, Burn, Burn+MSCs, Burn+MAPKs inhibitors, and Burn, Burn+MSCs, Burn+Vehicle, Burn+siTSG-6, Burn+rhTSG-6 in the both experiments. It was found that MSCs could only down-regulate P38 and JNK signaling, but had no effect on ERK in peritoneal macrophages of severe burn rats. Furthermore, suppression of P38 and JNK activations significantly reduced the excessive inflammation induced by severe burn. TSG-6 was secreted by MSCs using different inflammatory mediators. TSG-6 from MSCs and recombinant human (rh)TSG-6 all significantly reduced activations of P38 and JNK signaling induced by severe burn and then attenuated excessive inflammations. On the contrary, knockdown TSG-6 in the cells significantly increased phosphorylation of P38 and JNK signaling and reduced therapeutic effect of the MSCs on excessive inflammation. Taken together, this study suggested TSG-6 from MSCs attenuated severe burn-induced excessive inflammation via inhibiting activation of P38 and JNK signaling.

A Macrocyclic Agouti-Related Protein/[Nle4,DPhe7]α-Melanocyte Stimulating Hormone Chimeric Scaffold Produces Subnanomolar Melanocortin Receptor Ligands.

PubMed

Ericson, Mark D; Freeman, Katie T; Schnell, Sathya M; Haskell-Luevano, Carrie

2017-01-26

The melanocortin system consists of five receptor subtypes, endogenous agonists, and naturally occurring antagonists. These receptors and ligands have been implicated in numerous biological pathways including processes linked to obesity and food intake. Herein, a truncation structure-activity relationship study of chimeric agouti-related protein (AGRP)/[Nle4,DPhe7]α-melanocyte stimulating hormone (NDP-MSH) ligands is reported. The tetrapeptide His-DPhe-Arg-Trp or tripeptide DPhe-Arg-Trp replaced the Arg-Phe-Phe sequence in the AGRP active loop derivative c[Pro-Arg-Phe-Phe-Xxx-Ala-Phe-DPro], where Xxx was the native Asn of AGRP or a diaminopropionic (Dap) acid residue previously shown to increase antagonist potency at the mMC4R. The Phe, Ala, and Dap/Asn residues were successively removed to generate a 14-member library that was assayed for agonist activity at the mouse MC1R, MC3R, MC4R, and MC5R. Two compounds possessed nanomolar agonist potency at the mMC4R, c[Pro-His-DPhe-Arg-Trp-Asn-Ala-Phe-DPro] and c[Pro-His-DPhe-Arg-Trp-Dap-Ala-DPro], and may be further developed to generate novel melanocortin probes and ligands for understanding and treating obesity.

Signal-Preserving Erratic Noise Attenuation via Iterative Robust Sparsity-Promoting Filter

DOE PAGES

Zhao, Qiang; Du, Qizhen; Gong, Xufei; ...

2018-04-06

Sparse domain thresholding filters operating in a sparse domain are highly effective in removing Gaussian random noise under Gaussian distribution assumption. Erratic noise, which designates non-Gaussian noise that consists of large isolated events with known or unknown distribution, also needs to be explicitly taken into account. However, conventional sparse domain thresholding filters based on the least-squares (LS) criterion are severely sensitive to data with high-amplitude and non-Gaussian noise, i.e., the erratic noise, which makes the suppression of this type of noise extremely challenging. Here, in this paper, we present a robust sparsity-promoting denoising model, in which the LS criterion ismore » replaced by the Huber criterion to weaken the effects of erratic noise. The random and erratic noise is distinguished by using a data-adaptive parameter in the presented method, where random noise is described by mean square, while the erratic noise is downweighted through a damped weight. Different from conventional sparse domain thresholding filters, definition of the misfit between noisy data and recovered signal via the Huber criterion results in a nonlinear optimization problem. With the help of theoretical pseudoseismic data, an iterative robust sparsity-promoting filter is proposed to transform the nonlinear optimization problem into a linear LS problem through an iterative procedure. The main advantage of this transformation is that the nonlinear denoising filter can be solved by conventional LS solvers. Lastly, tests with several data sets demonstrate that the proposed denoising filter can successfully attenuate the erratic noise without damaging useful signal when compared with conventional denoising approaches based on the LS criterion.« less

Signal-Preserving Erratic Noise Attenuation via Iterative Robust Sparsity-Promoting Filter

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhao, Qiang; Du, Qizhen; Gong, Xufei

Sparse domain thresholding filters operating in a sparse domain are highly effective in removing Gaussian random noise under Gaussian distribution assumption. Erratic noise, which designates non-Gaussian noise that consists of large isolated events with known or unknown distribution, also needs to be explicitly taken into account. However, conventional sparse domain thresholding filters based on the least-squares (LS) criterion are severely sensitive to data with high-amplitude and non-Gaussian noise, i.e., the erratic noise, which makes the suppression of this type of noise extremely challenging. Here, in this paper, we present a robust sparsity-promoting denoising model, in which the LS criterion ismore » replaced by the Huber criterion to weaken the effects of erratic noise. The random and erratic noise is distinguished by using a data-adaptive parameter in the presented method, where random noise is described by mean square, while the erratic noise is downweighted through a damped weight. Different from conventional sparse domain thresholding filters, definition of the misfit between noisy data and recovered signal via the Huber criterion results in a nonlinear optimization problem. With the help of theoretical pseudoseismic data, an iterative robust sparsity-promoting filter is proposed to transform the nonlinear optimization problem into a linear LS problem through an iterative procedure. The main advantage of this transformation is that the nonlinear denoising filter can be solved by conventional LS solvers. Lastly, tests with several data sets demonstrate that the proposed denoising filter can successfully attenuate the erratic noise without damaging useful signal when compared with conventional denoising approaches based on the LS criterion.« less

Parametric detection and measurement of perfusion defects in attenuated contrast echocardiographic images.

PubMed

Yoshifuku, Shiro; Chen, Shigao; McMahon, Eileen; Korinek, Josef; Yoshikawa, Akiko; Ochiai, Izuru; Sengupta, Partho P; Belohlavek, Marek

2007-06-01

Attenuation of radio frequency (RF) signals limits the use of contrast echocardiography. The harmonic-to-fundamental ratio (HFR) of the RF signals compensates for attenuation. We tested whether HFR analysis measures the left ventricular nonperfused area under simulated experimental attenuation. Radio frequency image data from short axis systolic projections were obtained from 11 open-chest dogs with left anterior descending or left circumflex coronary artery occlusion followed by left atrial bolus injection of a perflutren microbubble contrast agent. Clinical attenuation was simulated by calibrated silicone pads interposed between the epicardial surface and the transducer to induce mild (7-dB) and severe (14-dB) reduction of the backscattered RF signals. Harmonic-to-fundamental ratio values were calculated for each image pixel for 0-, 7-, and 14-dB attenuation conditions and reproducibly showed a "perfused area" and a "nonperfused area." A reference nonperfused area was obtained by manual delineation in high-quality contrast scans. Correlations of the HFR-detected and manually outlined perfusion defect areas were R = 0.92 for 0 dB, R = 0.94 for 7 dB, and R = 0.90 for 14 dB; the mean difference was less than 0.36 cm(2) (negligible) in all 3 attenuation settings. Conclusions. Attenuation compensation by our HFR method allows precise measurement of myocardial perfusion defect areas in contrast scans with simulated high level of attenuation.

Adrenocorticotropic Hormone (ACTH) Responses Require Actions of the Melanocortin-2 Receptor Accessory Protein on the Extracellular Surface of the Plasma Membrane.

PubMed

Malik, Sundeep; Dolan, Terrance M; Maben, Zachary J; Hinkle, Patricia M

2015-11-13

The melanocortin-2 (MC2) receptor is a G protein-coupled receptor that mediates responses to ACTH. The MC2 receptor acts in concert with the MC2 receptor accessory protein (MRAP) that is absolutely required for ACTH binding and signaling. MRAP has a single transmembrane domain and forms a highly unusual antiparallel homodimer that is stably associated with MC2 receptors at the plasma membrane. Despite the physiological importance of the interaction between the MC2 receptor and MRAP, there is little understanding of how the accessory protein works. The dual topology of MRAP has made it impossible to determine whether highly conserved and necessary regions of MRAP are required on the intracellular or extracellular face of the plasma membrane. The strategy used here was to fix the orientation of two antiparallel MRAP molecules and then introduce inactivating mutations on one side of the membrane or the other. This was achieved by engineering proteins containing tandem copies of MRAP fused to the amino terminus of the MC2 receptor. The data firmly establish that only the extracellular amino terminus (Nout) copy of MRAP, oriented with critical segments on the extracellular side of the membrane, is essential. The transmembrane domain of MRAP is also required in only the Nout orientation. Finally, activity of MRAP-MRAP-MC2-receptor fusion proteins with inactivating mutations in either MRAP or the receptor was rescued by co-expression of free wild-type MRAP or free wild-type receptor. These results show that the basic MRAP-MRAP-receptor signaling unit forms higher order complexes and that these multimers signal. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

The binding protein BiP attenuates stress-induced cell death in soybean via modulation of the N-rich protein-mediated signaling pathway.

PubMed

Reis, Pedro A A; Rosado, Gustavo L; Silva, Lucas A C; Oliveira, Luciana C; Oliveira, Lucas B; Costa, Maximiller D L; Alvim, Fátima C; Fontes, Elizabeth P B

2011-12-01

The molecular chaperone binding protein (BiP) participates in the constitutive function of the endoplasmic reticulum (ER) and protects the cell against stresses. In this study, we investigated the underlying mechanism by which BiP protects plant cells from stress-induced cell death. We found that enhanced expression of BiP in soybean (Glycine max) attenuated ER stress- and osmotic stress-mediated cell death. Ectopic expression of BiP in transgenic lines attenuated the leaf necrotic lesions that are caused by the ER stress inducer tunicamycin and also maintained shoot turgidity upon polyethylene glycol-induced dehydration. BiP-mediated attenuation of stress-induced cell death was confirmed by the decreased percentage of dead cell, the reduced induction of the senescence-associated marker gene GmCystP, and reduced DNA fragmentation in BiP-overexpressing lines. These phenotypes were accompanied by a delay in the induction of the cell death marker genes N-RICH PROTEIN-A (NRP-A), NRP-B, and GmNAC6, which are involved in transducing a cell death signal generated by ER stress and osmotic stress through the NRP-mediated signaling pathway. The prosurvival effect of BiP was associated with modulation of the ER stress- and osmotic stress-induced NRP-mediated cell death signaling, as determined in transgenic tobacco (Nicotiana tabacum) lines with enhanced (sense) and suppressed (antisense) BiP levels. Enhanced expression of BiP prevented NRP- and NAC6-mediated chlorosis and the appearance of senescence-associated markers, whereas silencing of endogenous BiP accelerated the onset of leaf senescence mediated by NRPs and GmNAC6. Collectively, these results implicate BiP as a negative regulator of the stress-induced NRP-mediated cell death response.

Detection test of wireless network signal strength and GPS positioning signal in underground pipeline

NASA Astrophysics Data System (ADS)

Li, Li; Zhang, Yunwei; Chen, Ling

2018-03-01

In order to solve the problem of selecting positioning technology for inspection robot in underground pipeline environment, the wireless network signal strength and GPS positioning signal testing are carried out in the actual underground pipeline environment. Firstly, the strength variation of the 3G wireless network signal and Wi-Fi wireless signal provided by China Telecom and China Unicom ground base stations are tested, and the attenuation law of these wireless signals along the pipeline is analyzed quantitatively and described. Then, the receiving data of the GPS satellite signal in the pipeline are tested, and the attenuation of GPS satellite signal under underground pipeline is analyzed. The testing results may be reference for other related research which need to consider positioning in pipeline.

Leptin attenuates BACE1 expression and Amyloid-β genesis via the activation of SIRT1 signaling pathway

PubMed Central

Marwarha, Gurdeep; Raza, Shaneabbas; Meiers, Craig; Ghribi, Othman

2014-01-01

The aspartyl protease β-site AβPP-cleaving enzyme 1 (BACE1) catalyzes the rate-limiting step in Aβ production, a peptide at the nexus of neurodegenerative cascades in Alzheimer Disease (AD). The adipocytokine leptin has been demonstrated to reduce Aβ production and decrease BACE1 activity and expression levels. However, the signaling cascades involved in the leptin-induced mitigation in Aβ levels and BACE1 expression levels have not been elucidated. We have demonstrated that the transcription factor nuclear factor – kappa B (NF-κB) positively regulates BACE1 transcription. NF-κB activity is tightly regulated by the mammalian sirtuin SIRT1. Multiple studies have cogently evinced that leptin activates the metabolic master regulator SIRT1. In this study, we determined the extent to which SIRT1 expression and activity regulate the leptin-induced attenuation in BACE1 expression and Aβ levels in cultured human neuroblastoma SH-SY5Y cells. This study also elucidated and delineated the signal transduction pathways involved in the leptin induced mitigation in BACE1 expression. Our results demonstrate for the first time that leptin attenuates the activation and transcriptional activity of NF-κB by reducing the acetylation of the p65 subunit in a SIRT1-dependent manner. Furthermore, our data shows that leptin reduces the NF-κB – mediated transcription of BACE1 and consequently reduces Amyloid-β genesis. Our study provides a valuable insight and a novel mechanism by which leptin reduces BACE1 expression and Amyloid-β production and may help design potential therapeutic interventions. PMID:24874077

The Synthetic Melanocortin (CKPV)2 Exerts Anti-Fungal and Anti-Inflammatory Effects against Candida albicans Vaginitis via Inducing Macrophage M2 Polarization

PubMed Central

Jia, Zhi-rong; Li, Xian-jing; Wang, Zhuo; Li, Li; Li, Yong-wen; Liu, Gen-yan; Tong, Ming-Qing; Li, Xiao-yi; Zhang, Guo-hui; Dai, Xiang-rong; He, Ling; Li, Zhi-yu; Cao, Cong; Yang, Yong

2013-01-01

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. PMID:23457491

The evolutionary stability of attenuators that mask information about animals that social partners can exploit.

PubMed

Hackett, Sean; Ruxton, Graeme D

2018-05-01

Signals and cues are fundamental to social interactions. A well-established concept in the study of animal communication is an amplifier, defined as a trait that does not add extra information to that already present in the original cue or signal, but rather enhances the fidelity with which variation in the original cue or signal is correctly perceived. Attenuators as the logical compliment of amplifiers: attenuators act to reduce the fidelity with which variation in a signal or cue can be reliably evaluated by the perceivers. Where amplifiers reduce the effect of noise on the perception of variation, attenuators add noise. Attenuators have been subject to much less consideration than amplifiers; however, they will be the focus of our theoretical study. We utilize an extension of a well-established model incorporated signal or cue inaccuracy and costly investments by emitter and perceiver in sending and attending to the signal or cue. We present broad conditions involving some conflict of interest between emitter and perceiver where it may be advantageous for emitters to invest in costly attenuators to mask cues from potential perceivers, and a subset of these conditions where the perceiver may be willing to invest in costly anti-attenuators to mitigate the loss of information to them. We demonstrate that attenuators can be evolutionary stable even if they are costly, even if they are sometimes disadvantageous and even if a perceiver can mount counter-measures to them. As such, we feel that attenuators of cues may be deserving of much more research attention. © 2018 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2018 European Society For Evolutionary Biology.

Central insulin signaling is attenuated by long-term insulin exposure via insulin receptor substrate-1 serine phosphorylation, proteasomal degradation, and lysosomal insulin receptor degradation.

PubMed

Mayer, Christopher M; Belsham, Denise D

2010-01-01

Central insulin signaling is critical for the prevention of insulin resistance. Hyperinsulinemia contributes to insulin resistance, but it is not yet clear whether neurons are subject to cellular insulin resistance. We used an immortalized, hypothalamic, clonal cell line, mHypoE-46, which exemplifies neuronal function and expresses the components of the insulin signaling pathway, to determine how hyperinsulinemia modifies neuronal function. Western blot analysis indicated that prolonged insulin treatment of mHypoE-46 cells attenuated insulin signaling through phospho-Akt. To understand the mechanisms involved, time-course analysis was performed. Insulin exposure for 4 and 8 h phosphorylated Akt and p70-S6 kinase (S6K1), whereas 8 and 24 h treatment decreased insulin receptor (IR) and IR substrate 1 (IRS-1) protein levels. Insulin phosphorylation of S6K1 correlated with IRS-1 ser1101 phosphorylation and the mTOR-S6K1 pathway inhibitor rapamycin prevented IRS-1 serine phosphorylation. The proteasomal inhibitor epoxomicin and the lysosomal pathway inhibitor 3-methyladenine prevented the degradation of IRS-1 and IR by insulin, respectively, and pretreatment with rapamycin, epoxomicin, or 3-methyladenine prevented attenuation of insulin signaling by long-term insulin exposure. Thus, a sustained elevation of insulin levels diminishes neuronal insulin signaling through mTOR-S6K1-mediated IRS-1 serine phosphorylation, proteasomal degradation of IRS-1 and lysosomal degradation of the IR.

Crataegus oxycantha extract attenuates apoptotic incidence in myocardial ischemia-reperfusion injury by regulating Akt and HIF-1 signaling pathways.

PubMed

Jayachandran, Kesavan S; Khan, Mahmood; Selvendiran, Karuppaiyah; Devaraj, S Niranjali; Kuppusamy, Periannan

2010-11-01

The objective of the present study was to evaluate the efficacy and mechanism of Crataegus oxycantha (COC) extract in preventing ischemia-reperfusion (IR) injury in an in vivo rat model of acute myocardial infarction induced by a 30-minute regional ischemia followed by 72 hours of reperfusion. The COC extract [100 mg/(kg body weight)] was administered 12 hours after the surgical procedure and then at 24-hour intervals for 3 days. Animals treated with COC extract showed a significant decrease in creatine kinase activity and infarct size. At the molecular level, COC administration resulted in a significant attenuation of PTEN (phosphatase and tensin homolog deleted on chromosome 10) and upregulation of phospho-Akt and c-Raf levels in the heart. As a consequence, cleaved caspase-9 and cleaved caspase-7 levels were significantly downregulated, indicating negative regulation of apoptosis by COC extract. In part with the hypoxia-inducible factor (HIF) signaling pathway, COC extract administration significantly upregulated the prolyl hydroxylase-2 level. In contrast, other proapoptotic proteins such as nuclear factor-κB, cytochrome c, apoptosis-inducing factor, and cleaved poly(adenosine diphosphate-ribose) polymerase levels were significantly downregulated in the COC-treated group when compared with the untreated control group. The results suggested that COC extract attenuated apoptotic incidence in the experimental myocardial ischemia-reperfusion model by regulating Akt and HIF-1 signaling pathways.

Premature terminator analysis sheds light on a hidden world of bacterial transcriptional attenuation.

PubMed

Naville, Magali; Gautheret, Daniel

2010-01-01

Bacterial transcription attenuation occurs through a variety of cis-regulatory elements that control gene expression in response to a wide range of signals. The signal-sensing structures in attenuators are so diverse and rapidly evolving that only a small fraction have been properly annotated and characterized to date. Here we apply a broad-spectrum detection tool in order to achieve a more complete view of the transcriptional attenuation complement of key bacterial species. Our protocol seeks gene families with an unusual frequency of 5' terminators found across multiple species. Many of the detected attenuators are part of annotated elements, such as riboswitches or T-boxes, which often operate through transcriptional attenuation. However, a significant fraction of candidates were not previously characterized in spite of their unmistakable footprint. We further characterized some of these new elements using sequence and secondary structure analysis. We also present elements that may control the expression of several non-homologous genes, suggesting co-transcription and response to common signals. An important class of such elements, which we called mobile attenuators, is provided by 3' terminators of insertion sequences or prophages that may be exapted as 5' regulators when inserted directly upstream of a cellular gene. We show here that attenuators involve a complex landscape of signal-detection structures spanning the entire bacterial domain. We discuss possible scenarios through which these diverse 5' regulatory structures may arise or evolve.

Potent and selective agonists of alpha-melanotropin (alphaMSH) action at human melanocortin receptor 5; linear analogs of alpha-melanotropin.

PubMed

Bednarek, Maria A; MacNeil, Tanya; Tang, Rui; Fong, Tung M; Cabello, M Angeles; Maroto, Marta; Teran, Ana

2007-05-01

Alpha-melanotropin, Ac-Ser(1)-Tyr-Ser-Met-Glu-His(6)-Phe(7)-Arg(8)-Trp(9)-Gly-Lys-Pro-Val(13)-NH(2)(1), is a non-selective endogenous agonist for the melanocortin receptor 5; the receptor present in various peripheral tissues and in the brain, cortex and cerebellum. Most of the synthetic analogs of alphaMSH, including a broadly used and more potent the NDP-alphaMSH peptide, Ac-Ser(1)-Tyr-Ser-Nle(4)-Glu-His(6)-D-Phe(7)-Arg(8)-Trp(9)-Gly-Lys-Pro-Val(13)-NH(2), are also not particularly selective for MC5R. To elucidate physiological functions of the melanocortin receptor 5 in rodents and humans, the receptor subtype selective research tools are needed. We report herein syntheses and pharmacological evaluation in vitro of several analogs of NDP-alphaMSH which are highly potent and specific agonists for the human MC5R. The new linear peptides, of structures and solubility properties similar to those of the endogenous ligand alphaMSH, are exemplified by compound 7, Ac-Ser(1)-Tyr-Ser-Met-Glu-Oic(6)-D-4,4'-Bip(7)-Pip(8)-Trp(9)-Gly-Lys-Pro-Val(13)-NH(2) (Oic: octahydroindole-2-COOH, 4,4'-Bip: 4,4'-biphenylalanine, Pip: pipecolic acid), shortly NODBP-alphaMSH, which has an IC(50)=0.74 nM (binding assay) and EC(50)=0.41 (cAMP production assay) at hMC5R nM and greater than 3500-fold selectivity with respect to the melanocortin receptors 1b, 3 and 4. A shorter peptide derived from NODBP-alphaMSH: Ac-Nle-Glu-Oic(6)-D-4,4'-Bip(7)-Pip(8)-Trp(9) -NH(2) (17) was measured to be an agonist only 10-fold less potent at hMC5R than the full length parent peptide. In the structure of this smaller analog, the Nle-Glu-Oic(6)-D-4,4'-Bip(7)-Pip(8) segment was found to be critical for high agonist potency, while the C-terminal Trp(9) residue was shown to be required for high hMC5R selectivity versus hMC1b,3,4R.

Quantitative RNFL attenuation coefficient measurements by RPE-normalized OCT data

NASA Astrophysics Data System (ADS)

Vermeer, K. A.; van der Schoot, J.; Lemij, H. G.; de Boer, J. F.

2012-03-01

We demonstrate significantly different scattering coefficients of the retinal nerve fiber layer (RNFL) between normal and glaucoma subjects. In clinical care, SD-OCT is routinely used to assess the RNFL thickness for glaucoma management. In this way, the full OCT data set is conveniently reduced to an easy to interpret output, matching results from older (non- OCT) instruments. However, OCT provides more data, such as the signal strength itself, which is due to backscattering in the retinal layers. For quantitative analysis, this signal should be normalized to adjust for local differences in the intensity of the beam that reaches the retina. In this paper, we introduce a model that relates the OCT signal to the attenuation coefficient of the tissue. The average RNFL signal (within an A-line) was then normalized based on the observed RPE signal, resulting in normalized RNFL attenuation coefficient maps. These maps showed local defects matching those found in thickness data. The average (normalized) RNFL attenuation coefficient of a fixed band around the optic nerve head was significantly lower in glaucomatous eyes than in normal eyes (3.0mm-1 vs. 4.9mm-1, P<0.01, Mann-Whitney test).

Unusual Attenuation Recovery Process After Fiber Optic Cable Irradiation

NASA Astrophysics Data System (ADS)

Konečná, Z.; Plaček, V.; Havránek, P.

2017-11-01

At present, the number of optical cables in nuclear power plants has been increasing. Fiber optic cables are commonly used at nuclear power plants in instrumentation and control systems but they are usually used in environments without radiation. Nevertheless, currently, the number of applications in NPP containment with radiation is increasing. One of the most prevalent effects of radiation exposure is an increase of signal attenuation (signal loss). This is the result of fiber darkening due to radiation exposure and it is the main limitation factor in application of fiber optics in radiation environment. However, after the irradiation, the fiber optics go through a “recovery process” during which the optical properties improve again; i.e. attenuation decreases. However, we have found cable, where the expected healing process after few days changed its trend and the attenuation increased again to a value well above the attenuation just after the irradiation. This paper describes experiments that were carried out to explain this unusual recovery behaviour.

Chlorogenic Acid Attenuates Lipopolysaccharide-Induced Acute Kidney Injury by Inhibiting TLR4/NF-κB Signal Pathway.

PubMed

Ye, Han-Yang; Jin, Jian; Jin, Ling-Wei; Chen, Yan; Zhou, Zhi-Hong; Li, Zhan-Yuan

2017-04-01

Chlorogenic acid (CGA), a polyphenolic compound, exists widely in medicinal herbs, which has been shown a strong antioxidant and anti-inflammatory effect. This study investigated the protective effects and mechanism of CGA on lipopolysaccharide (LPS)-induced acute kidney injury (AKI). Treatment of CGA successfully ameliorates LPS-induced renal function and pathological damage. Moreover, CGA dose-dependently suppressed LPS-induced blood urea nitrogen (BUN), creatinine levels, and inflammatory cytokines TNF-α, IL-6, and IL-1β in serum and tissue. The relative proteins' expression of TLR4/NF-κB signal pathway was assessed by western blot analysis. Our results showed that CGA dose-dependently attenuated LPS-induced kidney histopathologic changes, serum BUN, and creatinine levels. CGA also suppressed LPS-induced TNF-α, IL-6, and IL-1β production both in serum and kidney tissues. Furthermore, our results showed that CGA significantly inhibited the LPS-induced expression of phosphorylated NF-κB p65 and IκB as well as the expression of TLR4 signal. In conclusion, our results provide a mechanistic explanation for the anti-inflammatory effects of CGA in LPS-induced AKI mice through inhibiting TLR4/NF-κB signaling pathway.

Effect of interactions of polymorphisms in the Melanocortin-4 receptor gene with dietary factors on the risk of obesity and Type 2 diabetes: a systematic review.

PubMed

Koochakpoor, G; Hosseini-Esfahani, F; Daneshpour, M S; Hosseini, S A; Mirmiran, P

2016-08-01

To perform a systematic review of the effect of interaction between Melanocortin-4 receptor (MC4R) single nucleotide polymorphisms and diet on the development of obesity and Type 2 diabetes. Environmental factors, such as nutrient intakes or feeding behaviours, can modulate the association of polymorphism in the MC4R gene with obesity and Type 2 diabetes mellitus. A systematic literature search was conducted in the PubMed, Scopus and Google Scholar databases, with a combination of the following keywords: Diet*, nutr*, melanocortin receptor, melanocortin 4 receptor and MC4R. To assess the quality of observational studies, we used a 12-item quality checklist, derived from the STREGA statement. A total of 14 articles were selected based on the inclusion and exclusion criteria. Consumption of highly salty foods and adherence to a Mediterranean dietary pattern can modulate the association between MC4R polymorphisms and the risk of obesity or Type 2 diabetes. Despite the highly contradictory results of intervention studies, after short-term lifestyle interventions, children with variant alleles of MC4R single nucleotide polymorphisms can lose more body weight, compared with non-carriers, although they may have difficulty in maintaining this weight loss in the long-term. To interpret the results of studies on adults, we need further studies. The interaction between MC4R genes with dietary factors plays a significant role in the development of obesity or Type 2 diabetes phenotypes. Early detection of MC4R risk alleles in individuals and modification of their diet based on these results could be an efficient strategy to prevent obesity or diabetes in these subgroups. © 2015 Diabetes UK.

The innate immune sensor NLRC3 attenuates Toll-like receptor signaling via modification of the signaling adaptor TRAF6 and transcription factor NF-κB.

PubMed

Schneider, Monika; Zimmermann, Albert G; Roberts, Reid A; Zhang, Lu; Swanson, Karen V; Wen, Haitao; Davis, Beckley K; Allen, Irving C; Holl, Eda K; Ye, Zhengmao; Rahman, Adeeb H; Conti, Brian J; Eitas, Timothy K; Koller, Beverly H; Ting, Jenny P-Y

2012-09-01

Several members of the NLR family of sensors activate innate immunity. In contrast, we found here that NLRC3 inhibited Toll-like receptor (TLR)-dependent activation of the transcription factor NF-κB by interacting with the TLR signaling adaptor TRAF6 to attenuate Lys63 (K63)-linked ubiquitination of TRAF6 and activation of NF-κB. We used bioinformatics to predict interactions between NLR and TRAF proteins, including interactions of TRAF with NLRC3. In vivo, macrophage expression of Nlrc3 mRNA was diminished by the administration of lipopolysaccharide (LPS) but was restored when cellular activation subsided. To assess biologic relevance, we generated Nlrc3(-/-) mice. LPS-treated Nlrc3(-/-) macrophages had more K63-ubiquitinated TRAF6, nuclear NF-κB and proinflammatory cytokines. Finally, LPS-treated Nlrc3(-/-) mice had more signs of inflammation. Thus, signaling via NLRC3 and TLR constitutes a negative feedback loop. Furthermore, prevalent NLR-TRAF interactions suggest the formation of a 'TRAFasome' complex.

Honokiol activates the LKB1–AMPK signaling pathway and attenuates the lipid accumulation in hepatocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Seo, Min Suk; Kim, Jung Hwan; Kim, Hye Jung

Honokiol is a bioactive neolignan compound isolated from the species of Magnolia. This study was designed to elucidate the cellular mechanism by which honokiol alleviates the development of non-alcoholic steatosis. HepG2 cells were treated with honokiol for 1 h, and then exposed to 1 mM free fatty acid (FFA) for 24 h to simulate non-alcoholic steatosis in vitro. C57BL/6 mice were fed with a high-fat diet for 28 days, and honokiol (10 mg/kg/day) was daily treated. Honokiol concentration-dependently attenuated intracellular fat overloading and triglyceride (TG) accumulation in FFA-exposed HepG2 cells. These effects were blocked by pretreatment with an AMP-activated proteinmore » kinase (AMPK) inhibitor. Honokiol significantly inhibited sterol regulatory element-binding protein-1c (SREBP-1c) maturation and the induction of lipogenic proteins, stearoyl-CoA desaturase-1 (SCD-1) and fatty acid synthase (FAS) in FFA-exposed HepG2 cells, but these effects were blocked by pretreatment of an AMPK inhibitor. Honokiol induced AMPK phosphorylation and subsequent acetyl-CoA carboxylase (ACC) phosphorylation, which were inhibited by genetic deletion of liver kinase B1 (LKB1). Honokiol stimulated LKB1 phosphorylation, and genetic deletion of LKB1 blocked the effect of honokiol on SREBP-1c maturation and the induction of SCD-1 and FAS proteins in FFA-exposed HepG2 cells. Honokiol attenuated the increases in hepatic TG and lipogenic protein levels and fat accumulation in the mice fed with high-fat diet, while significantly induced LKB1 and AMPK phosphorylation. Taken together, our findings suggest that honokiol has an anti-lipogenic effect in hepatocytes, and this effect may be mediated by the LKB1–AMPK signaling pathway, which induces ACC phosphorylation and inhibits SREBP-1c maturation in hepatocytes. - Highlights: • Honokiol attenuates lipid accumulation induced by free fatty acid in hepatocyte. • Honokiol inhibits the increase in lipogenic enzyme levels induced by free

Ebselen pretreatment attenuates ischemia/reperfusion injury and prevents hyperglycemia by improving hepatic insulin signaling and β-cell survival in gerbils.

PubMed

Park, S; Kang, S; Kim, D S; Shin, B K; Moon, N R; Daily, J W

2014-08-01

Transient carotid artery occlusion causes ischemia/reperfusion (I/R) injury resulting in neuron and pancreatic β-cell death with consequential post-stroke hyperglycemia, which can lead to diabetes and may accelerate the development of Alzheimer's disease. Antioxidants have been shown to protect against the I/R injury and destruction of neurons. However, it is unknown whether the protection against I/R injury extends to the pancreatic β-cells. Therefore, we investigated whether treatment with ebselen, a glutathione peroxidase mimic, prevents neuronal and β-cell death following I/R in gerbils susceptible to stroke. After 28 days post artery occlusion, there was widespread neuronal cell death in the CA1 of the hippocampus and elevated IL-1β and TNF-α levels. Pretreatment with ebselen prevented the death by 56% and attenuated neurological damage (abnormal eyelid drooping, hair bristling, muscle tone, flexor reflex, posture, and walking patterns). Ischemic gerbils also exhibited impaired glucose tolerance and insulin sensitivity which induced post-stroke hyperglycemia associated with decreased β-cell mass due to increased β-cell apoptosis. Ebselen prevented the increased β-cell apoptosis, possibly by decreasing IL-1β and TNF-α in islets. Ischemia also attenuated hepatic insulin signaling, and expression of GLUT2 and glucokinase, whereas ebselen prevented the attenuation and suppressed gluconeogenesis by decreasing PEPCK expression. In conclusion, antioxidant protection by ebselen attenuated I/R injury of neurons and pancreatic β-cells and prevented subsequent impairment of glucose regulation that could lead to diabetes and Alzheimer's disease.

Fatty acid–induced gut-brain signaling attenuates neural and behavioral effects of sad emotion in humans

PubMed Central

Van Oudenhove, Lukas; McKie, Shane; Lassman, Daniel; Uddin, Bilal; Paine, Peter; Coen, Steven; Gregory, Lloyd; Tack, Jan; Aziz, Qasim

2011-01-01

Although a relationship between emotional state and feeding behavior is known to exist, the interactions between signaling initiated by stimuli in the gut and exteroceptively generated emotions remain incompletely understood. Here, we investigated the interaction between nutrient-induced gut-brain signaling and sad emotion induced by musical and visual cues at the behavioral and neural level in healthy nonobese subjects undergoing functional magnetic resonance imaging. Subjects received an intragastric infusion of fatty acid solution or saline during neutral or sad emotion induction and rated sensations of hunger, fullness, and mood. We found an interaction between fatty acid infusion and emotion induction both in the behavioral readouts (hunger, mood) and at the level of neural activity in multiple pre-hypothesized regions of interest. Specifically, the behavioral and neural responses to sad emotion induction were attenuated by fatty acid infusion. These findings increase our understanding of the interplay among emotions, hunger, food intake, and meal-induced sensations in health, which may have important implications for a wide range of disorders, including obesity, eating disorders, and depression. PMID:21785220

Resveratrol inhibits LPS-induced mice mastitis through attenuating the MAPK and NF-κB signaling pathway.

PubMed

Zhang, Xu; Wang, Yanan; Xiao, Chong; Wei, Zhengkai; Wang, Jingjing; Yang, Zhengtao; Fu, Yunhe

2017-06-01

Resveratrol is a natural polyphenol extracted from mangy plants. It has been reported that resveratrol show multitudinous positive role in biology such as anti-oxidant, anti-nociception and anti-inflammatory effects. Therefore, the present study devotes to test the effect of resveratrol on LPS-induced mastitis in mice. Resveratrol was administered intraperitoneally 1 h before LPS treatment. And the anti-inflammatory effect of resveratrol was measured by histopathological examination, MPO assay, real-time PCR and western blotting analysis. The results showed that resveratrol significantly reduced the LPS-induced mammary histopathological changes. Meanwhile, it sharply attenuated the activity of MPO. The result also indicated that the resveratrol can decrease the expression of pro-inflammatory cytokines TNF-α and IL-1β. From the results of western blotting, resveratrol suppressed the expression of phosphorylation of p65 and IκB from NF-κB signal pathway and phosphorylation of p38 and ERK from MAPK signal pathway. These findings suggested that resveratrol may inhibit the inflammatory response in the mastitis. Copyright © 2017 Elsevier Ltd. All rights reserved.

Fatty acid-induced gut-brain signaling attenuates neural and behavioral effects of sad emotion in humans.

PubMed

Van Oudenhove, Lukas; McKie, Shane; Lassman, Daniel; Uddin, Bilal; Paine, Peter; Coen, Steven; Gregory, Lloyd; Tack, Jan; Aziz, Qasim

2011-08-01

Although a relationship between emotional state and feeding behavior is known to exist, the interactions between signaling initiated by stimuli in the gut and exteroceptively generated emotions remain incompletely understood. Here, we investigated the interaction between nutrient-induced gut-brain signaling and sad emotion induced by musical and visual cues at the behavioral and neural level in healthy nonobese subjects undergoing functional magnetic resonance imaging. Subjects received an intragastric infusion of fatty acid solution or saline during neutral or sad emotion induction and rated sensations of hunger, fullness, and mood. We found an interaction between fatty acid infusion and emotion induction both in the behavioral readouts (hunger, mood) and at the level of neural activity in multiple pre-hypothesized regions of interest. Specifically, the behavioral and neural responses to sad emotion induction were attenuated by fatty acid infusion. These findings increase our understanding of the interplay among emotions, hunger, food intake, and meal-induced sensations in health, which may have important implications for a wide range of disorders, including obesity, eating disorders, and depression.

Altered hepatic lipid metabolism in mice lacking both the melanocortin type 4 receptor and low density lipoprotein receptor.

PubMed

Lede, Vera; Meusel, Andrej; Garten, Antje; Popkova, Yulia; Penke, Melanie; Franke, Christin; Ricken, Albert; Schulz, Angela; Kiess, Wieland; Huster, Daniel; Schöneberg, Torsten; Schiller, Jürgen

2017-01-01

Obesity is often associated with dyslipidemia and hepatosteatosis. A number of animal models of non-alcoholic fatty liver disease (NAFLD) are established but they significantly differ in the molecular and biochemical changes depending on the genetic modification and diet used. Mice deficient for melanocortin type 4 receptor (Mc4rmut) develop hyperphagia, obesity, and subsequently NAFLD already under regular chow and resemble more closely the energy supply-driven obesity found in humans. This animal model was used to assess the molecular and biochemical consequences of hyperphagia-induced obesity on hepatic lipid metabolism. We analyzed transcriptome changes in Mc4rmut mice by RNA sequencing and used high resolution 1H magic angle spinning NMR spectroscopy and MALDI-TOF mass spectrometry to assess changes in the lipid composition. On the transcriptomic level we found significant changes in components of the triacylglycerol metabolism, unsaturated fatty acids biosynthesis, peroxisome proliferator-activated receptor signaling pathways, and lipid transport and storage compared to the wild-type. These findings were supported by increases in triacylglycerol, monounsaturated fatty acid, and arachidonic acid levels. The transcriptome signatures significantly differ from those of other NAFLD mouse models supporting the concept of hepatic subphenotypes depending on the genetic background and diet. Comparative analyses of our data with previous studies allowed for the identification of common changes and genotype-specific components and pathways involved in obesity-associated NAFLD.

Leptin attenuates BACE1 expression and amyloid-β genesis via the activation of SIRT1 signaling pathway.

PubMed

Marwarha, Gurdeep; Raza, Shaneabbas; Meiers, Craig; Ghribi, Othman

2014-09-01

The aspartyl protease β-site AβPP-cleaving enzyme 1 (BACE1) catalyzes the rate-limiting step in Aβ production, a peptide at the nexus of neurodegenerative cascades in Alzheimer Disease (AD). The adipocytokine leptin has been demonstrated to reduce Aβ production and decrease BACE1 activity and expression levels. However, the signaling cascades involved in the leptin-induced mitigation in Aβ levels and BACE1 expression levels have not been elucidated. We have demonstrated that the transcription factor nuclear factor - kappa B (NF-κB) positively regulates BACE1 transcription. NF-κB activity is tightly regulated by the mammalian sirtuin SIRT1. Multiple studies have cogently evinced that leptin activates the metabolic master regulator SIRT1. In this study, we determined the extent to which SIRT1 expression and activity regulate the leptin-induced attenuation in BACE1 expression and Aβ levels in cultured human neuroblastoma SH-SY5Y cells. This study also elucidated and delineated the signal transduction pathways involved in the leptin induced mitigation in BACE1 expression. Our results demonstrate for the first time that leptin attenuates the activation and transcriptional activity of NF-κB by reducing the acetylation of the p65 subunit in a SIRT1-dependent manner. Furthermore, our data shows that leptin reduces the NF-κB-mediated transcription of BACE1 and consequently reduces Amyloid-β genesis. Our study provides a valuable insight and a novel mechanism by which leptin reduces BACE1 expression and Amyloid-β production and may help design potential therapeutic interventions. Copyright © 2014 Elsevier B.V. All rights reserved.

Melanocortin 4 receptor is not required for estrogenic regulations on energy homeostasis and reproduction.

PubMed

Xu, Pingwen; Zhu, Liangru; Saito, Kenji; Yang, Yongjie; Wang, Chunmei; He, Yanlin; Yan, Xiaofeng; Hyseni, Ilirjana; Tong, Qingchun; Xu, Yong

2017-05-01

Brain estrogen receptor-α (ERα) is essential for estrogenic regulation of energy homeostasis and reproduction. We previously showed that ERα expressed by pro-opiomelanocortin (POMC) neurons mediates estrogen's effects on food intake, body weight, negative regulation of hypothalamic-pituitary-gonadal axis (HPG axis) and fertility. We report here that global deletion of a key downstream receptor for POMC peptide, the melanocortin 4 receptor (MC4R), did not affect normal negative feedback regulation of estrogen on the HPG axis, estrous cyclicity and female fertility. Furthermore, loss of the MC4R did not influence estrogenic regulation on food intake and body weight. These results indicate that the MC4R is not required for estrogen's effects on metabolic and reproductive functions. Copyright © 2016 Elsevier Inc. All rights reserved.

Central inhibition of IKKβ/NF-κB signaling attenuates high-fat diet-induced obesity and glucose intolerance.

PubMed

Benzler, Jonas; Ganjam, Goutham K; Pretz, Dominik; Oelkrug, Rebecca; Koch, Christiane E; Legler, Karen; Stöhr, Sigrid; Culmsee, Carsten; Williams, Lynda M; Tups, Alexander

2015-06-01

Metabolic inflammation in the central nervous system might be causative for the development of overnutrition-induced metabolic syndrome and related disorders, such as obesity, leptin and insulin resistance, and type 2 diabetes. Here we investigated whether nutritive and genetic inhibition of the central IκB kinase β (IKKβ)/nuclear factor-κB (NF-κB) pathway in diet-induced obese (DIO) and leptin-deficient mice improves these metabolic impairments. A known prominent inhibitor of IKKβ/NF-κB signaling is the dietary flavonoid butein. We initially determined that oral, intraperitoneal, and intracerebroventricular administration of this flavonoid improved glucose tolerance and hypothalamic insulin signaling. The dose-dependent glucose-lowering capacity was profound regardless of whether obesity was caused by leptin deficiency or high-fat diet (HFD). To confirm the apparent central role of IKKβ/NF-κB signaling in the control of glucose and energy homeostasis, we genetically inhibited this pathway in neurons of the arcuate nucleus, one key center for control of energy homeostasis, via specific adeno-associated virus serotype 2-mediated overexpression of IκBα, which inhibits NF-κB nuclear translocation. This treatment attenuated HFD-induced body weight gain, body fat mass accumulation, increased energy expenditure, and reduced arcuate suppressor of cytokine signaling 3 expression, indicative for enhanced leptin signaling. These results reinforce a specific role of central proinflammatory IKKβ/NF-κB signaling in the development and potential treatment of DIO-induced comorbidities. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

The Role of Leptin, Melanocortin, and Neurotrophin System Genes on Body Weight in Anorexia Nervosa and Bulimia Nervosa

PubMed Central

Yilmaz, Zeynep; Kaplan, Allan S.; Tiwari, Arun K.; Levitan, Robert D.; Piran, Sara; Bergen, Andrew W.; Kaye, Walter H.; Hakonarson, Hakon; Wang, Kai; Berrettini, Wade H.; Brandt, Harry A.; Bulik, Cynthia M.; Crawford, Steve; Crow, Scott; Fichter, Manfred M.; Halmi, Katherine A.; Johnson, Craig L.; Keel, Pamela K.; Klump, Kelly L.; Magistretti, Pierre; Mitchell, James E.; Strober, Michael; Thornton, Laura M.; Treasure, Janet; Woodside, D. Blake; Knight, Joanne; Kennedy, James L.

2014-01-01

Objective Although low weight is a key factor contributing to the high mortality in anorexia nervosa (AN), it is unclear how AN patients sustain low weight compared with bulimia nervosa (BN) patients with similar psychopathology. Studies of genes involved in appetite and weight regulation in eating disorders have yielded variable findings in part due to small sample size and clinical heterogeneity. This study: (1) assessed the role of leptin, melanocortin, and neurotrophin genetic variants in conferring risk for AN and BN and (2) explored the involvement of these genes in body mass index (BMI) variations within AN and BN. Method Our sample consisted of 745 individuals with AN without a history of BN, 245 with BN without a history of AN, and 321 controls. We genotyped 20 markers with known or putative function among genes selected from leptin, melanocortin, and neurotrophin systems. Results There were no significant differences in allele frequencies among individuals with AN, BN, and controls. AGRP rs13338499 polymorphism was associated with lowest illness-related BMI in those with AN (p=0.0013), and NTRK2 rs1042571 was associated with highest BMI in those with BN (p=0.0018). Discussion To our knowledge, this is the first study to address the issue of clinical heterogeneity in eating disorder genetics and to explore the role of known or putatively functional markers in genes regulating appetite and weight in individuals with AN and BN. If replicated, our results may serve as an important first step toward gaining a better understanding of weight regulation in eating disorders. PMID:24831852

Design of a new peptidomimetic agonist for the melanocortin receptors based on the solution structure of the peptide ligand, Ac-Nle-cyclo[Asp-Pro-DPhe-Arg-Trp-Lys]-NH(2).

PubMed

Fotsch, Christopher; Smith, Duncan M; Adams, Jeffrey A; Cheetham, Janet; Croghan, Michael; Doherty, Elizabeth M; Hale, Clarence; Jarosinski, Mark A; Kelly, Michael G; Norman, Mark H; Tamayo, Nuria A; Xi, Ning; Baumgartner, James W

2003-07-21

The solution structure of a potent melanocortin receptor agonist, Ac-Nle-cyclo[Asp-Pro-DPhe-Arg-Trp-Lys]-NH(2) (1) was calculated using distance restraints determined from 1H NMR spectroscopy. Eight of the lowest energy conformations from this study were used to identify non-peptide cores that mimic the spatial arrangement of the critical tripeptide region, DPhe-Arg-Trp, found in 1. From these studies, compound 2a, containing the cis-cyclohexyl core, was identified as a functional agonist of the melanocortin-4 receptor (MC4R) with an IC(50) and EC(50) below 10 nM. Compound 2a also showed 36- and 7-fold selectivity over MC3R and MC1R, respectively, in the binding assays. Subtle changes in cyclohexane stereochemistry and removal of functional groups led to analogues with lower affinity for the MC receptors.

Technique for extending the range of a signal measuring circuit

DOEpatents

Chaprnka, Anthony G.; Sun, Shan C.; Vercellotti, Leonard C.

1978-01-01

An input signal supplied to a signal measuring circuit is either amplified or attenuated as necessary to establish the magnitude of the input signal within the defined dynamic range of the measuring circuit and the output signal developed by the measuring circuit is subsequently readjusted through amplification or attenuation to develop an output signal which corresponds to the magnitude of the initial input signal.

LL-37 attenuates inflammatory impairment via mTOR signaling-dependent mitochondrial protection.

PubMed

Sun, Wenyan; Zheng, Yan; Lu, Zhuoyang; Wang, Hui; Feng, Zhihui; Wang, Juan; Xiao, Shengxiang; Liu, Feng; Liu, Jiankang

2014-09-01

The human cationic antimicrobial protein LL-37 is a multifunctional host defense peptide with a wide range of immunomodulatory activities. Previous work has shown that LL-37 exerts both pro- and anti-inflammatory effects. The role of mitochondria in the skin inflammatory effects of LL-37 has not been well studied. Therefore, our aim was to investigate the immunomodulatory effect of LL-37 in HaCaT cells and to delineate the underlying mechanisms related to mitochondrial function. Immunohistochemistry results from tissue microarrays showed strong cytoplasmic LL-37 staining in inflammatory cells in chronic dermatic inflammation. Using exogenous LL-37 stimulation and LL-37 knockdown and overexpression, LL-37 was demonstrated to dramatically reduce the mRNA levels and protein secretion of inflammatory cytokines including IL-6, IL-8, IL-1α and tumor necrosis factor-α (TNF-α), which are induced by lipopolysaccharides (LPS). The anti-inflammatory effects of LL-37 are dependent upon its ability to increase mitochondrial biogenesis and to maintain mitochondrial homeostasis. Furthermore, we observed that LL-37 enhances the LPS-induced phosphorylation of extracellular signal-regulated kinase (ERK1/2) and mammalian target of rapamycin (mTOR). The mTOR inhibitor rapamycin can neutralize the protective effects of LL-37 on mitochondria. In conclusion, these results suggest that high LL-37 expression levels correlate with chronic skin inflammation; mitochondrial dysfunction occurs in HaCaT cells during inflammation; and LL-37 attenuates inflammatory impairment by stimulating mitochondrial biogenesis and protecting mitochondrial function, which are dependent upon mTOR signaling. These findings provide new insights into targeting mitochondria with LL-37 to prevent skin inflammatory reactions. Copyright © 2014 Elsevier Ltd. All rights reserved.

Design, synthesis, and testing of multivalent compounds targeted to melanocortin receptors

NASA Astrophysics Data System (ADS)

Dehigaspitiya, Dilani Chathurika

Our focus is on developing non-invasive molecular imaging reagents, which target human cancers that presently are difficult to detect, such as melanoma. We wish to apply the multivalency concept to differentiate between healthy cells and melanoma cells. Melanoma cells are known to over-express alpha melanocyte stimulating hormone receptors. A successful multivalent construct should show greater avidity towards melanoma cells than healthy cells due to the synergistic effects arising from multivalency. Both oligomeric and shorter linear constructs bearing the minimum active sequence of melanocyte stimulating hormone, His-DPhe-Arg-Trp-NH2(MSH4), which binds with low micromolar affinity to alpha melanocyte stimulating hormone receptors, were synthesized. Binding affinities of these constructs were evaluated in a competitive binding assay by competing with labeled ligands, Eu-DTPA-PEGO-MSH7 and/or Eu-DTPA-PEGO-NDP-alpha-MSH on the engineered cell line HEK293 CCK2R/hMC4R, which is genetically modified to over-express both the cholecystokinin 2 receptor (CCK2R) and human melanocortin 4 receptor (hMC4R). The oligomers were rapidly assembled using microwave-assisted copper catalyzed azide-alkyne cycloaddition between a dialkyne derivative of MSH4 and a diazide derivative of (Pro-Gly)3 as co-monomers. Three oligomer mixtures were further analyzed based on their degree of oligomerization and the route by which the MSH4 monomers were oligomerized, protected vs deprotected. Completive binding assay against Eu-DTPA-PEGO-MSH7 showed only a statistical enhancement of binding when calculated based on the total MSH4 concentration. However, when the calculation of avidity is based on an estimation of the particles numbers, there was a seven times enhancement of binding compared to a monovalent MSH4 control. The shorter linear multivalent MSH4 constructs were synthesized using ethylene glycol, glycerol, and mannitol as core scaffolds with maximum inter-ligand distances ranging from 27

Hyperbaric oxygen attenuates neuropathic pain and reverses inflammatory signaling likely via the Kindlin-1/Wnt-10a signaling pathway in the chronic pain injury model in rats.

PubMed

Zhao, Baisong; Pan, Yongying; Xu, Haiping; Song, Xingrong

2017-12-01

Hyperbaric oxygen (HBO) therapy is proven to attenuate neuropathic pain in rodents. The goal of the present study was to determine the potential involvement of the Kindlin-1/Wnt-10a signaling pathway during astrocyte activation and inflammation in a rodent model of neuropathic pain. Rats were assigned into sham operation, chronic constriction injury (CCI), and CCI + HBO treatment groups. Neuropathic pain developed in rats following CCI of the sciatic nerve. Rats in the CCI + HBO group received HBO treatment for five consecutive days beginning on postoperative day 1. The mechanical withdrawal threshold (MWT) and the thermal withdrawal latency (TWL) tests were performed to determine mechanical and heat hypersensitivity of animals, respectively. Kindlin-1, Wnt-10a and β-catenin protein expression was examined by immunohistochemistry and Western blot analysis. Expression of tumor necrosis factor (TNF)-α was also determined by ELISA. Our findings demonstrated that HBO treatment significantly suppressed mechanical and thermal hypersensitivity in the CCI neuropathic pain model in rats. HBO therapy significantly reversed the up-regulation of Kindlin-1 in dorsal root ganglia (DRG), spinal cord, and hippocampus of CCI rats. CCI-induced astrocyte activation and increased levels of TNF-α were efficiently reversed by HBO (P < 0.05 vs. CCI). HBO also reversed Wnt-10a up-regulation induced by CCI in the DRG, spinal cord, and hippocampus (P < 0.05 vs. CCI). Our findings demonstrate that HBO attenuated CCI-induced rat neuropathic pain and inflammatory responses, possibly through regulation of the Kindlin-1/Wnt-10a signaling pathway.

Salicylic acid signaling inhibits apoplastic reactive oxygen species signaling

PubMed Central

2014-01-01

Background Reactive oxygen species (ROS) are used by plants as signaling molecules during stress and development. Given the amount of possible challenges a plant face from their environment, plants need to activate and prioritize between potentially conflicting defense signaling pathways. Until recently, most studies on signal interactions have focused on phytohormone interaction, such as the antagonistic relationship between salicylic acid (SA)-jasmonic acid and cytokinin-auxin. Results In this study, we report an antagonistic interaction between SA signaling and apoplastic ROS signaling. Treatment with ozone (O3) leads to a ROS burst in the apoplast and induces extensive changes in gene expression and elevation of defense hormones. However, Arabidopsis thaliana dnd1 (defense no death1) exhibited an attenuated response to O3. In addition, the dnd1 mutant displayed constitutive expression of defense genes and spontaneous cell death. To determine the exact process which blocks the apoplastic ROS signaling, double and triple mutants involved in various signaling pathway were generated in dnd1 background. Simultaneous elimination of SA-dependent and SA-independent signaling components from dnd1 restored its responsiveness to O3. Conversely, pre-treatment of plants with SA or using mutants that constitutively activate SA signaling led to an attenuation of changes in gene expression elicited by O3. Conclusions Based upon these findings, we conclude that plants are able to prioritize the response between ROS and SA via an antagonistic action of SA and SA signaling on apoplastic ROS signaling. PMID:24898702

Salicylic acid signaling inhibits apoplastic reactive oxygen species signaling.

PubMed

Xu, Enjun; Brosché, Mikael

2014-06-04

Reactive oxygen species (ROS) are used by plants as signaling molecules during stress and development. Given the amount of possible challenges a plant face from their environment, plants need to activate and prioritize between potentially conflicting defense signaling pathways. Until recently, most studies on signal interactions have focused on phytohormone interaction, such as the antagonistic relationship between salicylic acid (SA)-jasmonic acid and cytokinin-auxin. In this study, we report an antagonistic interaction between SA signaling and apoplastic ROS signaling. Treatment with ozone (O3) leads to a ROS burst in the apoplast and induces extensive changes in gene expression and elevation of defense hormones. However, Arabidopsis thaliana dnd1 (defense no death1) exhibited an attenuated response to O3. In addition, the dnd1 mutant displayed constitutive expression of defense genes and spontaneous cell death. To determine the exact process which blocks the apoplastic ROS signaling, double and triple mutants involved in various signaling pathway were generated in dnd1 background. Simultaneous elimination of SA-dependent and SA-independent signaling components from dnd1 restored its responsiveness to O3. Conversely, pre-treatment of plants with SA or using mutants that constitutively activate SA signaling led to an attenuation of changes in gene expression elicited by O3. Based upon these findings, we conclude that plants are able to prioritize the response between ROS and SA via an antagonistic action of SA and SA signaling on apoplastic ROS signaling.

Gene expression in hypothalamus, liver and adipose tissues and feed intake response to melanocortin-4 receptor (MC4R) agonist in pigs expressing (MC4R) mutations

USDA-ARS?s Scientific Manuscript database

Transcriptional profiling was used to identify genes and pathways that responded to intracerebroventricular (ICV) injection of melanocortin-4 receptor (MC4R) agonist, NDP-MSH, in pigs homozygous for the missense mutation in the MC4R, D298 allele (n = 12), N298 allele (n = 12) or heterozygous (n = 12...

Costunolide ameliorates lipoteichoic acid-induced acute lung injury via attenuating MAPK signaling pathway.

PubMed

Chen, Zhengxu; Zhang, Dan; Li, Man; Wang, Baolong

2018-06-12

Lipoteichoic acid (LTA)-induced acute lung injury (ALI) is an experimental model for mimicking Gram-positive bacteria-induced pneumonia that is a refractory disease with lack of effective medicines. Here, we reported that costunolide, a sesquiterpene lactone, ameliorated LTA-induced ALI. Costunolide treatment reduced LTA-induced neutrophil lung infiltration, cytokine and chemokine production (TNF-α, IL-6 and KC), and pulmonary edema. In response to LTA challenge, treatment with costunolide resulted less iNOS expression and produced less inflammatory cytokines in bone marrow derived macrophages (BMDMs). Pretreatment with costunolide also attenuated the LTA-induced the phosphorylation of p38 MAPK and ERK in BMDMs. Furthermore, costunolide treatment reduced the phosphorylation of TAK1 and inhibited the interaction of TAK1 with Tab1. In conclusion, we have demonstrated that costunolide protects against LTA-induced ALI via inhibiting TAK1-mediated MAPK signaling pathway, and our studies suggest that costunolide is a promising agent for treatment of Gram-positive bacteria-mediated pneumonia. Copyright © 2018 Elsevier B.V. All rights reserved.

Melanocortin 1 receptor and skin pathophysiology: beyond colour, much more than meets the eye.

PubMed

García-Borrón, José Carlos; Olivares, Concepción

2014-06-01

The melanocortin 1 receptor (MC1R), a G protein-coupled receptor preferentially expressed in melanocytes, mediates the pigmentary effects of α melanocyte-stimulating hormone (αMSH). MC1R is also expressed in other cutaneous cell types, particularly keratinocytes and dermal fibroblasts, suggesting non-pigmentary actions of the αMSH/MC1R system. Böhm and Stegemann now report a dramatic effect of mouse Mc1r functional status on susceptibility to skin fibrosis and collagen types I and III metabolism, in a study combining the powerful mouse model provided by the natural Mc1r(e/e) knockout and an established model of skin fibrosis. The study underscores the antifibrotic role for the skin αMSH/MC1R system. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The nonstationary strain filter in elastography: Part I. Frequency dependent attenuation.

PubMed

Varghese, T; Ophir, J

1997-01-01

The accuracy and precision of the strain estimates in elastography depend on a myriad number of factors. A clear understanding of the various factors (noise sources) that plague strain estimation is essential to obtain quality elastograms. The nonstationary variation in the performance of the strain filter due to frequency-dependent attenuation and lateral and elevational signal decorrelation are analyzed in this and the companion paper for the cross-correlation-based strain estimator. In this paper, we focus on the role of frequency-dependent attenuation in the performance of the strain estimator. The reduction in the signal-to-noise ratio (SNRs) in the RF signal, and the center frequency and bandwidth downshift with frequency-dependent attenuation are incorporated into the strain filter formulation. Both linear and nonlinear frequency dependence of attenuation are theoretically analyzed. Monte-Carlo simulations are used to corroborate the theoretically predicted results. Experimental results illustrate the deterioration in the precision of the strain estimates with depth in a uniformly elastic phantom. Theoretical, simulation and experimental results indicate the importance of high SNRs values in the RF signals, because the strain estimation sensitivity, elastographic SNRe and dynamic range deteriorate rapidly with a decrease in the SNRs. In addition, a shift in the strain filter toward higher strains is observed at large depths in tissue due to the center frequency downshift.

Attenuation of Cisplatin-Induced Renal Injury by Inhibition of Soluble Epoxide Hydrolase Involves Nuclear Factor κB Signaling

PubMed Central

Liu, Yingmei; Webb, Heather K.; Fukushima, Hisayo; Micheli, Janine; Markova, Svetlana; Olson, Jean L.

2012-01-01

Acute kidney injury is associated with a significant inflammatory response that has been the target of renoprotection strategies. Epoxyeicosatrienoic acids (EETs) are anti-inflammatory cytochrome P450-derived eicosanoids that are abundantly produced in the kidney and metabolized by soluble epoxide hydrolase (sEH; Ephx2) to less active dihydroxyeicosatrienoic acids. Genetic disruption of Ephx2 and chemical inhibition of sEH were used to test whether the anti-inflammatory effects of EETs, and other lipid epoxide substrates of sEH, afford protection against cisplatin-induced nephrotoxicity. EET hydrolysis was significantly reduced in Ephx2(−/−) mice and was associated with an attenuation of cisplatin-induced increases in serum urea nitrogen and creatinine levels. Histological evidence of renal tubular damage and neutrophil infiltration was also reduced in the Ephx2(−/−) mice. Likewise, cisplatin had no effect on renal function, neutrophil infiltration, or tubular structure and integrity in mice treated with the potent sEH inhibitor 1-adamantan-1-yl-3-(1-methylsulfonyl-piperidin-4-yl-urea) (AR9273). Consistent with the ability of EETs to interfere with nuclear factor-κB (NF-κB) signaling, the observed renoprotection was associated with attenuation of renal NF-κB activity and corresponding decreases in the expression of tumor necrosis factor (TNF) α, TNF receptor (TNFR) 1, TNFR2, and intercellular adhesive molecule-1 before the detection of tubular injury. These data suggest that EETs or other fatty acid epoxides can attenuate cisplatin-induced kidney injury and sEH inhibition is a novel renoprotective strategy. PMID:22414856

Rivaroxaban attenuates thrombosis by targeting the NF-κB signaling pathway in a rat model of deep venous thrombus

PubMed Central

Ma, Junhao; Li, Xinxi; Wang, Yang; Yang, Zhenwei; Luo, Jun

2017-01-01

Anticoagulant therapy is commonly used for the prevention and treatment of patients with deep venous thrombus. Evidence has shown that rivaroxaban is a potential oral anticoagulant drug for the acute treatment of venous thromboembolism. However, the rivaroxaban-mediated molecular mechanism involved in the progression of deep venous thrombosis has not been investigated. In the present study, we investigated the efficacy of rivaroxaban and the underlying signaling pathways in the prevention and treatment of rats with deep venous thrombosis. A rat model with deep vein thrombus formation was established and received treatment with rivaroxaban or PBS as control. The thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1) were analyzed both in vitro and in vivo. The progression of thrombosis and stroke was evaluated after treatment with rivaroxaban or PBS. Nuclear factor-κB (NF-κB) signaling pathway in venous endothelial cells and in the rat model of deep venous thrombus was assessed. The therapeutic effects of rivaroxaban were evaluated as determined by changes in deep venous thrombosis in the rat model. Our results showed that rivaroxaban markedly inhibited TAFI and PAI-1 expression levels, neutrophils, tissue factor, neutrophil extracellular traps (NETs), myeloperoxidase and macrophages in venous endothelial cells and in the rat model of deep venous thrombus. Expression levels of ADP, PAIs, von Willebrand factor (vWF) and thromboxane were downregulated in vein endothelial cells and in serum from the experimental rats. Importantly, the incidences of inferior vena cava filter thrombus were protected by rivaroxaban during heparin-induced thrombolysis deep venous thrombosis in the rat model. We observed that activity of the NF-κB signaling pathway was inhibited by rivaroxaban in vein endothelial cells both in vitro and in vivo. Notably, immunohistology indicated that rivaroxaban attenuated deep venous thrombosis and the

Rivaroxaban attenuates thrombosis by targeting the NF-κB signaling pathway in a rat model of deep venous thrombus.

PubMed

Ma, Junhao; Li, Xinxi; Wang, Yang; Yang, Zhenwei; Luo, Jun

2017-12-01

Anticoagulant therapy is commonly used for the prevention and treatment of patients with deep venous thrombus. Evidence has shown that rivaroxaban is a potential oral anticoagulant drug for the acute treatment of venous thromboembolism. However, the rivaroxaban-mediated molecular mechanism involved in the progression of deep venous thrombosis has not been investigated. In the present study, we investigated the efficacy of rivaroxaban and the underlying signaling pathways in the prevention and treatment of rats with deep venous thrombosis. A rat model with deep vein thrombus formation was established and received treatment with rivaroxaban or PBS as control. The thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1) were analyzed both in vitro and in vivo. The progression of thrombosis and stroke was evaluated after treatment with rivaroxaban or PBS. Nuclear factor-κB (NF-κB) signaling pathway in venous endothelial cells and in the rat model of deep venous thrombus was assessed. The therapeutic effects of rivaroxaban were evaluated as determined by changes in deep venous thrombosis in the rat model. Our results showed that rivaroxaban markedly inhibited TAFI and PAI-1 expression levels, neutrophils, tissue factor, neutrophil extracellular traps (NETs), myeloperoxidase and macrophages in venous endothelial cells and in the rat model of deep venous thrombus. Expression levels of ADP, PAIs, von Willebrand factor (vWF) and thromboxane were downregulated in vein endothelial cells and in serum from the experimental rats. Importantly, the incidences of inferior vena cava filter thrombus were protected by rivaroxaban during heparin-induced thrombolysis deep venous thrombosis in the rat model. We observed that activity of the NF-κB signaling pathway was inhibited by rivaroxaban in vein endothelial cells both in vitro and in vivo. Notably, immunohistology indicated that rivaroxaban attenuated deep venous thrombosis and the

Recombinant human parainfluenza virus type 2 with mutations in V that permit cellular interferon signaling are not attenuated in non-human primates

PubMed Central

Schaap-Nutt, Anne; D’Angelo, Christopher; Amaro-Carambot, Emerito; Nolan, Sheila M.; Davis, Stephanie; Wise, Shenelle-Marie; Higgins, Caraline; Bradley, Konrad; Kim, Olivia; Mayor, Reina; Skiadopoulos, Mario H.; Collins, Peter L.; Murphy, Brian R.; Schmidt, Alexander C.

2010-01-01

The HPIV2 V protein inhibits type I interferon (IFN) induction and signaling. To manipulate the V protein, whose coding sequence overlaps that of the polymerase-associated phosphoprotein (P), without altering the P protein, we generated an HPIV2 virus in which P and V are expressed from separate genes (rHPIV2-P+V). rHPIV2-P+V replicated like HPIV2-WT in vitro and in non-human primates. HPIV2-P+V was modified by introducing two separate mutations into the V protein to create rHPIV2-L101E/L102E and rHPIV2-Δ122–127. In contrast to HPIV2-WT, both mutant viruses were unable to degrade STAT2, leaving virus-infected cells susceptible to IFN. Neither mutant, nor HPIV2-WT, induced significant amounts of IFN-β in infected cells. Surprisingly, neither rHPIV2-L101E/L102E nor rHPIV2-Δ122–127 was attenuated in two species of non-human primates. This indicates that loss of HPIV2's ability to inhibit IFN signaling is insufficient to attenuate virus replication in vivo as long as IFN induction is still inhibited. PMID:20667570

The role of leptin, melanocortin, and neurotrophin system genes on body weight in anorexia nervosa and bulimia nervosa.

PubMed

Yilmaz, Zeynep; Kaplan, Allan S; Tiwari, Arun K; Levitan, Robert D; Piran, Sara; Bergen, Andrew W; Kaye, Walter H; Hakonarson, Hakon; Wang, Kai; Berrettini, Wade H; Brandt, Harry A; Bulik, Cynthia M; Crawford, Steven; Crow, Scott; Fichter, Manfred M; Halmi, Katherine A; Johnson, Craig L; Keel, Pamela K; Klump, Kelly L; Magistretti, Pierre; Mitchell, James E; Strober, Michael; Thornton, Laura M; Treasure, Janet; Woodside, D Blake; Knight, Joanne; Kennedy, James L

2014-08-01

Although low weight is a key factor contributing to the high mortality in anorexia nervosa (AN), it is unclear how AN patients sustain low weight compared with bulimia nervosa (BN) patients with similar psychopathology. Studies of genes involved in appetite and weight regulation in eating disorders have yielded variable findings, in part due to small sample size and clinical heterogeneity. This study: (1) assessed the role of leptin, melanocortin, and neurotrophin genetic variants in conferring risk for AN and BN; and (2) explored the involvement of these genes in body mass index (BMI) variations within AN and BN. Our sample consisted of 745 individuals with AN without a history of BN, 245 individuals with BN without a history of AN, and 321 controls. We genotyped 20 markers with known or putative function among genes selected from leptin, melanocortin, and neurotrophin systems. There were no significant differences in allele frequencies among individuals with AN, BN, and controls. AGRP rs13338499 polymorphism was associated with lowest illness-related BMI in those with AN (p = 0.0013), and NTRK2 rs1042571 was associated with highest BMI in those with BN (p = 0.0018). To our knowledge, this is the first study to address the issue of clinical heterogeneity in eating disorder genetic research and to explore the role of known or putatively functional markers in genes regulating appetite and weight in individuals with AN and BN. If replicated, our results may serve as an important first step toward gaining a better understanding of weight regulation in eating disorders. Copyright © 2014 Elsevier Ltd. All rights reserved.

Optical coherence tomography for blood glucose monitoring through signal attenuation

NASA Astrophysics Data System (ADS)

De Pretto, Lucas R.; Yoshimura, Tania M.; Ribeiro, Martha S.; de Freitas, Anderson Z.

2016-03-01

Development of non-invasive techniques for glucose monitoring is crucial to improve glucose control and treatment adherence in patients with diabetes. Hereafter, Optical Coherence Tomography (OCT) may offer a good alternative for portable glucometers, since it uses light to probe samples. Changes in the object of interest can alter the intensity of light returning from the sample and, through it, one can estimate the sample's attenuation coefficient (μt) of light. In this work, we aimed to explore the behavior of μt of mouse's blood under increasing glucose concentrations. Different samples were prepared in four glucose concentrations using a mixture of heparinized blood, phosphate buffer saline and glucose. Blood glucose concentrations were measured with a blood glucometer, for reference. We have also prepared other samples diluting the blood in isotonic saline solution to check the effect of a higher multiple-scattering component on the ability of the technique to differentiate glucose levels based on μt. The OCT system used was a commercial Spectral Radar OCT with 930 nm central wavelength and spectral bandwidth (FWHM) of 100 nm. The system proved to be sensitive for all blood glucose concentrations tested, with good correlations with the obtained attenuation coefficients. A linear tendency was observed, with an increase in attenuation with higher values of glucose. Statistical difference was observed between all groups (p<0.001). This work opens the possibility towards a non-invasive diagnostic modality using OCT for glycemic control, which eliminates the use of analytes and/or test strips, as in the case with commercially available glucometers.

Effect of Melanotan-II on Brain Fos Immunoreactivity and Oxytocin Neuronal Activity and Secretion in Rats.

PubMed

Paiva, L; Sabatier, N; Leng, G; Ludwig, M

2017-02-01

Melanocortins stimulate the central oxytocin systems that are involved in regulating social behaviours. Alterations in central oxytocin have been linked to neurological disorders such as autism, and melanocortins have been proposed for therapeutic treatment. In the present study, we investigated how systemic administration of melanotan-II (MT-II), a melanocortin agonist, affects oxytocin neuronal activity and secretion in rats. The results obtained show that i.v., but not intranasal, administration of MT-II markedly induced Fos expression in magnocellular neurones of the supraoptic (SON) and paraventricular nuclei (PVN) of the hypothalamus, and this response was attenuated by prior i.c.v. administration of the melanocortin antagonist, SHU-9119. Electrophysiological recordings from identified magnocellular neurones of the SON showed that i.v. administration of MT-II increased the firing rate in oxytocin neurones but did not trigger somatodendritic oxytocin release within the SON as measured by microdialysis. Our data suggest that, after i.v., but not intranasal, administration of MT-II, the activity of magnocellular neurones of the SON is increased. Because previous studies showed that SON oxytocin neurones are inhibited in response to direct application of melanocortin agonists, the actions of i.v. MT-II are likely to be mediated at least partly indirectly, possibly by activation of inputs from the caudal brainstem, where MT-II also increased Fos expression. © 2016 British Society for Neuroendocrinology.

Validation of attenuation, beam blockage, and calibration estimation methods using two dual polarization X band weather radars

NASA Astrophysics Data System (ADS)

Diederich, M.; Ryzhkov, A.; Simmer, C.; Mühlbauer, K.

2011-12-01

The amplitude a of radar wave reflected by meteorological targets can be misjudged due to several factors. At X band wavelength, attenuation of the radar beam by hydro meteors reduces the signal strength enough to be a significant source of error for quantitative precipitation estimation. Depending on the surrounding orography, the radar beam may be partially blocked when scanning at low elevation angles, and the knowledge of the exact amount of signal loss through beam blockage becomes necessary. The phase shift between the radar signals at horizontal and vertical polarizations is affected by the hydrometeors that the beam travels through, but remains unaffected by variations in signal strength. This has allowed for several ways of compensating for the attenuation of the signal, and for consistency checks between these variables. In this study, we make use of several weather radars and gauge network measuring in the same area to examine the effectiveness of several methods of attenuation and beam blockage corrections. The methods include consistency checks of radar reflectivity and specific differential phase, calculation of beam blockage using a topography map, estimating attenuation using differential propagation phase, and the ZPHI method proposed by Testud et al. in 2000. Results show the high effectiveness of differential phase in estimating attenuation, and potential of the ZPHI method to compensate attenuation, beam blockage, and calibration errors.

Brain signaling systems in the Type 2 diabetes and metabolic syndrome: promising target to treat and prevent these diseases

PubMed Central

Shpakov, Alexander O; Derkach, Kira V; Berstein, Lev M

2015-01-01

The changes in the brain signaling systems play an important role in etiology and pathogenesis of Type 2 diabetes mellitus (T2DM) and metabolic syndrome (MS), being a possible cause of these diseases. Therefore, their restoration at the early stages of T2DM and MS can be regarded as a promising way to treat and prevent these diseases and their complications. The data on the functional state of the brain signaling systems regulated by insulin, IGF-1, leptin, dopamine, serotonin, melanocortins and glucagon-like peptide-1, in T2DM and MS, are analyzed. The pharmacological approaches to restoration of these systems and improvement of insulin sensitivity, energy expenditure, lipid metabolism, and to prevent diabetic complications are discussed. PMID:28031898

The bias and signal attenuation present in conventional pollen-based climate reconstructions as assessed by early climate data from Minnesota, USA.

PubMed

St Jacques, Jeannine-Marie; Cumming, Brian F; Sauchyn, David J; Smol, John P

2015-01-01

The inference of past temperatures from a sedimentary pollen record depends upon the stationarity of the pollen-climate relationship. However, humans have altered vegetation independent of changes to climate, and consequently modern pollen deposition is a product of landscape disturbance and climate, which is different from the dominance of climate-derived processes in the past. This problem could cause serious signal distortion in pollen-based reconstructions. In the north-central United States, direct human impacts have strongly altered the modern vegetation and hence the pollen rain since Euro-American settlement in the mid-19th century. Using instrumental temperature data from the early 1800 s from Fort Snelling (Minnesota), we assessed the signal distortion and bias introduced by using the conventional method of inferring temperature from pollen assemblages in comparison to a calibration set from pre-settlement pollen assemblages and the earliest instrumental climate data. The early post-settlement calibration set provides more accurate reconstructions of the 19th century instrumental record, with less bias, than the modern set does. When both modern and pre-industrial calibration sets are used to reconstruct past temperatures since AD 1116 from pollen counts from a varve-dated record from Lake Mina, Minnesota, the conventional inference method produces significant low-frequency (centennial-scale) signal attenuation and positive bias of 0.8-1.7 °C, resulting in an overestimation of Little Ice Age temperature and likely an underestimation of the extent and rate of anthropogenic warming in this region. However, high-frequency (annual-scale) signal attenuation exists with both methods. Hence, we conclude that any past pollen spectra from before Euro-American settlement in this region should be interpreted using a pre-Euro-American settlement pollen set, paired to the earliest instrumental climate records. It remains to be explored how widespread this problem is

Attenuation of Vibrio fischeri quorum sensing using rationally designed polymers.

PubMed

Piletska, Elena V; Stavroulakis, Georgios; Karim, Kal; Whitcombe, Michael J; Chianella, Iva; Sharma, Anant; Eboigbodin, Kevin E; Robinson, Gary K; Piletsky, Sergey A

2010-04-12

A first attempt to attenuate the quorum sensing (QS) of a marine heterotroph microorganism, Vibrio fischeri , using signal molecule-sequestering polymers (SSPs) is presented. A set of rationally designed polymers with affinity toward a signal molecule of V. fischeri , N-(beta-ketocaproyl)-l-homoserine lactone (3-oxo-C6-AHL) was produced. It is reported that computationally designed polymers could sequester a signal molecule of V. fischeri and prevent QS-controlled phenotypes (in this case, bioluminescence) from being up-regulated. It was proven that the attenuation of bioluminescence of V. fischeri was due to sequestration of the signal molecule by specific polymers and not due to the toxicity of polymer or nonspecific depletion of nutrients. The ability to disrupt the bacterial communication using easy to synthesize and chemically inert polymers could provide a new concept for the development of pharmaceuticals and susceptible device coatings such as catheters.

Activation of Wnt3α/β-catenin signal pathway attenuates apoptosis of the cerebral microvascular endothelial cells induced by oxygen-glucose deprivation.

PubMed

Zhang, Jianshui; Zhang, Junfeng; Qi, Cunfang; Yang, Pengbo; Chen, Xinlin; Liu, Yong

2017-08-19

Brain microvascular endothelial cells (BMECs) play vital roles in cerebral ischemia, during which many signal pathways mediate BMECs apoptosis. In this study, we explored the potential role of Wnt3α/β-catenin signal in BMECs apoptosis induced by ischemia. Here, we found that oxygen-glucose deprivation (OGD) could induce apoptosis of BMECs with Wnt3a mRNA expression decrease. Meanwhile, activation Wnt3a/β-catenin signal with exogenous Wnt3α protein (100 ng/ml) or Lithium Chloride (LiCl, 4 mM) decreased significantly apoptosis of BMECs induced by OGD with increasing expression of Bcl-2 in the whole cell and β-catenin in the nucleus. But, inhibition Wnt3a/β-catenin signal with DKK1 (100 ng/ml) or 2.4-diamino quinazoline (DQ, 0.2 μM) increased apoptosis of BMECs with decreasing expression of Bcl-2. These results suggest that activation Wnt3α/β-catenin signal attenuate apoptosis of BMECs induced by ischemia. Copyright © 2017 Elsevier Inc. All rights reserved.

Dangguishaoyao-San attenuates LPS-induced neuroinflammation via the TLRs/NF-κB signaling pathway.

PubMed

Ding, Rui-Rui; Chen, Wang; Guo, Cong-Ying; Liao, Wei-Tao; Yang, Xia; Liao, Feng-Er; Lin, Jing-Ming; Mei, Han-Fang; Zeng, Yu

2018-05-29

Dangguishaoyao-San (DSS) is composed of six traditional Chinese medicines, including Angelica sinensis, Paeoniae radix, Rhizoma Ligusticum, Poria cocos, Rhizoma Atractylodis Macrocephalae, and Rhizoma Alismatis. DSS has been reported to be effective in alleviating the symptoms of Alzheimer's disease (AD). The aim of this study was to investigate the mechanism of action of DSS in vitro using lipopolysaccharide (LPS)-stimulated BV-2 microglia cells. BV-2 cells were pretreated with 0.58-1.16 mg/mL of DSS for 2 h and then treated with 1 μg/mL LPS for 24 h. Cell viability was determined by an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The protein expression levels were measured by Western blots. Inflammatory factors were detected by enzyme-linked immunosorbent assays (ELISAs). The mRNA levels of inflammatory factors were analyzed by quantitative real-time PCR (qRT-PCR). DSS treatment at concentrations of 0.58-1.16 mg/mL resulted in no significant cytotoxicity. DSS attenuated the release of pro-inflammatory factors, such as interleukin-1β (IL-1β), iNOS and tumor necrosis factor-α (TNF-α) in LPS-induced BV-2 cells. DSS attenuated the mRNA expression of pro-inflammatory cytokines, TLR2, and TLR4 and decreased TLR4 and TLR protein levels as well as the phosphorylation of IκB in LPS-induced BV-2 cells. DSS also down-regulated the nuclear translocation of p65. This study demonstrated that DSS has a protective effect on neuroinflammation in LPS-induced BV-2 microglia cells through the TLRs/NF-κB signaling pathway. Copyright © 2018. Published by Elsevier Masson SAS.

Latency-Associated Expression of Human Cytomegalovirus US28 Attenuates Cell Signaling Pathways To Maintain Latent Infection

PubMed Central

Krishna, Benjamin A.; Poole, Emma L.; Smit, Martine J.; Wills, Mark R.

2017-01-01

ABSTRACT Reactivation of human cytomegalovirus (HCMV) latent infection from early myeloid lineage cells constitutes a threat to immunocompromised or immune-suppressed individuals. Consequently, understanding the control of latency and reactivation to allow targeting and killing of latently infected cells could have far-reaching clinical benefits. US28 is one of the few viral genes that is expressed during latency and encodes a cell surface G protein-coupled receptor (GPCR), which, during lytic infection, is a constitutive cell-signaling activator. Here we now show that in monocytes, which are recognized sites of HCMV latency in vivo, US28 attenuates multiple cell signaling pathways, including mitogen-activated protein (MAP) kinase and NF-κB, and that this is required to establish a latent infection; viruses deleted for US28 initiate a lytic infection in infected monocytes. We also show that these monocytes then become potent targets for the HCMV-specific host immune response and that latently infected cells treated with an inverse agonist of US28 also reactivate lytic infection and similarly become immune targets. Consequently, we suggest that the use of inhibitors of US28 could be a novel immunotherapeutic strategy to reactivate the latent viral reservoir, allowing it to be targeted by preexisting HCMV-specific T cells. PMID:29208743

Melatonin attenuates titanium particle-induced osteolysis via activation of Wnt/β-catenin signaling pathway.

PubMed

Ping, Zichuan; Hu, Xuanyang; Wang, Liangliang; Shi, Jiawei; Tao, Yunxia; Wu, Xiexing; Hou, Zhenyang; Guo, Xiaobin; Zhang, Wen; Yang, Huilin; Xu, Yaozeng; Wang, Zhirong; Geng, Dechun

2017-03-15

Wear debris-induced inhibition of bone regeneration and extensive bone resorption were common features in peri-prosthetic osteolysis (PPO). Here, we investigated the effect of melatonin on titanium particle-stimulated osteolysis in a murine calvariae model and mouse-mesenchymal-stem cells (mMSCs) culture system. Melatonin inhibited titanium particle-induced osteolysis and increased bone formation at osteolytic sites, confirmed by radiological and histomorphometric data. Furthermore, osteoclast numbers decreased dramatically in the low- and high-melatonin administration mice, as respectively, compared with the untreated animals. Melatonin alleviated titanium particle-induced depression of osteoblastic differentiation and mineralization in mMSCs. Mechanistically, melatonin was found to reduce the degradation of β-catenin, levels of which were decreased in presence of titanium particles both in vivo and in vitro. To further ensure whether the protective effect of melatonin was mediated by the Wnt/β-catenin signaling pathway, ICG-001, a selective β-catenin inhibitor, was added to the melatonin-treated groups and was found to attenuate the effect of melatonin on mMSC mineralization. We also demonstrated that melatonin modulated the balance between receptor activator of nuclear factor kappa-B ligand and osteoprotegerin via activation of Wnt/β-catenin signaling pathway. These findings strongly suggest that melatonin represents a promising candidate in the treatment of PPO. Peri-prosthetic osteolysis, initiated by wear debris-induced inhibition of bone regeneration and extensive bone resorption, is the leading cause for implant failure and reason for revision surgery. In the current study, we demonstrated for the first time that melatonin can induce bone regeneration and reduce bone resorption at osteolytic sites caused by titanium-particle stimulation. These effects might be mediated by activating Wnt/β-catenin signaling pathway and enhancing osteogenic

Light attenuation characteristics of glacially-fed lakes

NASA Astrophysics Data System (ADS)

Rose, Kevin C.; Hamilton, David P.; Williamson, Craig E.; McBride, Chris G.; Fischer, Janet M.; Olson, Mark H.; Saros, Jasmine E.; Allan, Mathew G.; Cabrol, Nathalie

2014-07-01

Transparency is a fundamental characteristic of aquatic ecosystems and is highly responsive to changes in climate and land use. The transparency of glacially-fed lakes may be a particularly sensitive sentinel characteristic of these changes. However, little is known about the relative contributions of glacial flour versus other factors affecting light attenuation in these lakes. We sampled 18 glacially-fed lakes in Chile, New Zealand, and the U.S. and Canadian Rocky Mountains to characterize how dissolved absorption, algal biomass (approximated by chlorophyll a), water, and glacial flour contributed to attenuation of ultraviolet radiation (UVR) and photosynthetically active radiation (PAR, 400-700 nm). Variation in attenuation across lakes was related to turbidity, which we used as a proxy for the concentration of glacial flour. Turbidity-specific diffuse attenuation coefficients increased with decreasing wavelength and distance from glaciers. Regional differences in turbidity-specific diffuse attenuation coefficients were observed in short UVR wavelengths (305 and 320 nm) but not at longer UVR wavelengths (380 nm) or PAR. Dissolved absorption coefficients, which are closely correlated with diffuse attenuation coefficients in most non-glacially-fed lakes, represented only about one quarter of diffuse attenuation coefficients in study lakes here, whereas glacial flour contributed about two thirds across UVR and PAR. Understanding the optical characteristics of substances that regulate light attenuation in glacially-fed lakes will help elucidate the signals that these systems provide of broader environmental changes and forecast the effects of climate change on these aquatic ecosystems.

Central melanocortins regulate the motivation for sucrose reward.

PubMed

Pandit, Rahul; van der Zwaal, Esther M; Luijendijk, Mieneke C M; Brans, Maike A D; van Rozen, Andrea J; Oude Ophuis, Ralph J A; Vanderschuren, Louk J M J; Adan, Roger A H; la Fleur, Susanne E

2015-01-01

The role of the melanocortin (MC) system in feeding behavior is well established. Food intake is potently suppressed by central infusion of the MC 3/4 receptor agonist α-melanocyte stimulating hormone (α-MSH), whereas the MC 3/4 receptor inverse-agonist Agouti Related Peptide (AGRP) has the opposite effect. MC receptors are widely expressed in both hypothalamic and extra-hypothalamic brain regions, including nuclei involved in food reward and motivation, such as the nucleus accumbens (NAc) and the ventral tegmental area. This suggests that MCs modulate motivational aspects of food intake. To test this hypothesis, rats were injected intracerebroventricularly with α-MSH or AGRP and their motivation for sucrose was tested under a progressive ratio schedule of reinforcement. Food motivated behavior was dose-dependently decreased by α-MSH. Conversely, AGRP increased responding for sucrose, an effect that was blocked by pretreatment with the dopamine receptor antagonist α-flupenthixol. In contrast to progressive ratio responding, free intake of sucrose remained unaltered upon α-MSH or AGRP infusion. In addition, we investigated whether the effects of α-MSH and AGRP on food motivation were mediated by the NAc shell. In situ hybridization of MC3 and MC4 receptor expression confirmed that the MC4 receptor was expressed throughout the NAc, and injection of α-MSH and AGRP into the NAc shell caused a decrease and an increase in motivation for sucrose, respectively. These data show that the motivation for palatable food is modulated by MC4 receptors in the NAc shell, and demonstrate cross-talk between the MC and dopamine system in the modulation of food motivation.

A robust signalling system for land mobile satellite services

NASA Technical Reports Server (NTRS)

Irish, Dale; Shmith, Gary; Hart, Nick; Wines, Marie

1989-01-01

Presented here is a signalling system optimized to ensure expedient call set-up for satellite telephony services in a land mobile environment. In a land mobile environment, the satellite to mobile link is subject to impairments from multipath and shadowing phenomena, which result in signal amplitude and phase variations. Multipath, caused by signal scattering and reflections, results in sufficient link margin to compensate for these variations. Direct signal attenuation caused by shadowing due to buildings and vegetation may result in attenuation values in excess of 10 dB and commonly up to 20 dB. It is not practical to provide a link with sufficient margin to enable communication when the signal is blocked. When a moving vehicle passes these obstacles, the link will experience rapid changes in signal strength due to shadowing. Using statistical models of attenuation as a function of distance travelled, a communication strategy has been defined for the land mobile environment.

Valsartan attenuates pulmonary hypertension via suppression of mitogen activated protein kinase signaling and matrix metalloproteinase expression in rodents.

PubMed

Lu, Yuyan; Guo, Haipeng; Sun, Yuxi; Pan, Xin; Dong, Jia; Gao, Di; Chen, Wei; Xu, Yawei; Xu, Dachun

2017-08-01

It has previously been demonstrated that the renin-angiotensin system is involved in the pathogenesis and development of pulmonary hypertension (PH). However, the efficacy of angiotensin II type I (AT1) receptor blockers in the treatment of PH is variable. The present study examined the effects of the AT1 receptor blocker valsartan on monocrotaline (MCT)‑induced PH in rats and chronic hypoxia‑induced PH in mice. The results demonstrated that valsartan markedly attenuated development of PH in rats and mice, as indicated by reduced right ventricular systolic pressure, diminished lung vascular remodeling and decreased right ventricular hypertrophy, compared with vehicle treated animals. Immunohistochemical analyses of proliferating cell nuclear antigen expression revealed that valsartan suppressed smooth muscle cell proliferation. Western blot analysis demonstrated that valsartan limited activation of p38, c‑Jun N‑terminal kinase 1/2 and extracellular signal‑regulated kinase 1/2 signaling pathways and significantly reduced MCT‑induced upregulation of pulmonary matrix metalloproteinases‑2 and ‑9, and transforming growth factor‑β1 expression. The results suggested that valsartan attenuates development of PH in rodents by reducing expression of extracellular matrix remodeling factors and limiting smooth muscle cell proliferation to decrease pathological vascular remodeling. Therefore, valsartan may be a valuable future therapeutic approach for the treatment of PH.

The Binding Protein BiP Attenuates Stress-Induced Cell Death in Soybean via Modulation of the N-Rich Protein-Mediated Signaling Pathway1[C][W][OA

PubMed Central

Reis, Pedro A.A.; Rosado, Gustavo L.; Silva, Lucas A.C.; Oliveira, Luciana C.; Oliveira, Lucas B.; Costa, Maximiller D.L.; Alvim, Fátima C.; Fontes, Elizabeth P.B.

2011-01-01

The molecular chaperone binding protein (BiP) participates in the constitutive function of the endoplasmic reticulum (ER) and protects the cell against stresses. In this study, we investigated the underlying mechanism by which BiP protects plant cells from stress-induced cell death. We found that enhanced expression of BiP in soybean (Glycine max) attenuated ER stress- and osmotic stress-mediated cell death. Ectopic expression of BiP in transgenic lines attenuated the leaf necrotic lesions that are caused by the ER stress inducer tunicamycin and also maintained shoot turgidity upon polyethylene glycol-induced dehydration. BiP-mediated attenuation of stress-induced cell death was confirmed by the decreased percentage of dead cell, the reduced induction of the senescence-associated marker gene GmCystP, and reduced DNA fragmentation in BiP-overexpressing lines. These phenotypes were accompanied by a delay in the induction of the cell death marker genes N-RICH PROTEIN-A (NRP-A), NRP-B, and GmNAC6, which are involved in transducing a cell death signal generated by ER stress and osmotic stress through the NRP-mediated signaling pathway. The prosurvival effect of BiP was associated with modulation of the ER stress- and osmotic stress-induced NRP-mediated cell death signaling, as determined in transgenic tobacco (Nicotiana tabacum) lines with enhanced (sense) and suppressed (antisense) BiP levels. Enhanced expression of BiP prevented NRP- and NAC6-mediated chlorosis and the appearance of senescence-associated markers, whereas silencing of endogenous BiP accelerated the onset of leaf senescence mediated by NRPs and GmNAC6. Collectively, these results implicate BiP as a negative regulator of the stress-induced NRP-mediated cell death response. PMID:22007022

The role of the reflection coefficient in precision measurement of ultrasonic attenuation

NASA Technical Reports Server (NTRS)

Generazio, E. R.

1984-01-01

Ultrasonic attenuation measurements using contact, pulse-echo techniques are sensitive to surface roughness and couplant thickness variations. This can reduce considerable inaccuracies in the measurement of the attenuation coefficient for broadband pulses. Inaccuracies arise from variations in the reflection coefficient at the buffer-couplant-sample interface. The reflection coefficient is examined as a function of the surface roughness and corresponding couplant thickness variations. Interrelations with ultrasonic frequency are illustrated. Reliable attenuation measurements are obtained only when the frequency dependence of the reflection coefficient is incorporated in signal analysis. Data are given for nickel 200 samples and a silicon nitride ceramic bar having surface roughness variations in the 0.3 to 3.0 microns range for signal bandwidths in the 50 to 100 MHz range.

Cyclopropanyldehydrocostunolide LJ attenuates high glucose-induced podocyte injury by suppressing RANKL/RANK-mediated NF-κB and MAPK signaling pathways.

PubMed

Chen, Xiao-Wen; Liu, Wen-Ting; Wang, Yu-Xian; Chen, Wen-Jing; Li, Hong-Yu; Chen, Yi-Hua; Du, Xiao-Yan; Peng, Fen-Fen; Zhou, Wei-Dong; Xu, Zhao-Zhong; Long, Hai-Bo

2016-07-01

The aim of this research was to investigate the effects of cyclopropanyldehydrocostunolide (also named LJ), a derivative of sesquiterpene lactones (SLs), on high glucose (HG)-induced podocyte injury and the associated molecular mechanisms. Differentiated mouse podocytes were incubated in different treatments. The migration and albumin filtration of podocytes were examined by Transwell filters. The protein and mRNA levels of MCP-1 were measured using enzyme-linked immunosorbent assay (ELISA) and quantitative real-time PCR (q-PCR). Protein expression and phosphorylation were detected by western blot, and the nuclear translocation of NF-κB was performed with a confocal microscope. The gene expression of the receptor activator for NF-κB (RANK) was silenced by small interfering RNA (siRNA). Our results showed that HG enhanced migration, albumin filtration and MCP-1 expression in podocytes. At the molecular level, HG promoted the phosphorylation of NF-κB/p65, IKKβ, IκBα, mitogen-activated protein kinase (MAPK) and the nuclear translocation of p65. LJ reversed the effects of HG in a dose-dependent manner. Furthermore, our data provided the first demonstration that the receptor activator for NF-κB ligand (RANKL) and its cognate receptor RANK were overexpressed in HG-induced podocytes and were downregulated by LJ. RANK siRNA also attenuated HG-induced podocyte injury and markedly inhibited the activation of NF-κB and MAPK signaling pathways. LJ attenuates HG-induced podocyte injury by suppressing RANKL/RANK-mediated NF-κB and MAPK signaling pathways. Copyright © 2016 Elsevier Inc. All rights reserved.

The cAMP-dependent protein kinase inhibitor H-89 attenuates the bioluminescence signal produced by Renilla Luciferase.

PubMed

Herbst, Katie J; Allen, Michael D; Zhang, Jin

2009-05-21

Investigations into the regulation and functional roles of kinases such as cAMP-dependent protein kinase (PKA) increasingly rely on cellular assays. Currently, there are a number of bioluminescence-based assays, for example reporter gene assays, that allow the study of the regulation, activity, and functional effects of PKA in the cellular context. Additionally there are continuing efforts to engineer improved biosensors that are capable of detecting real-time PKA signaling dynamics in cells. These cell-based assays are often utilized to test the involvement of PKA-dependent processes by using H-89, a reversible competitive inhibitor of PKA. We present here data to show that H-89, in addition to being a competitive PKA inhibitor, attenuates the bioluminescence signal produced by Renilla luciferase (RLuc) variants in a population of cells and also in single cells. Using 10 microM of luciferase substrate and 10 microM H-89, we observed that the signal from RLuc and RLuc8, an eight-point mutation variant of RLuc, in cells was reduced to 50% (+/-15%) and 54% (+/-14%) of controls exposed to the vehicle alone, respectively. In vitro, we showed that H-89 decreased the RLuc8 bioluminescence signal but did not compete with coelenterazine-h for the RLuc8 active site, and also did not affect the activity of Firefly luciferase. By contrast, another competitive inhibitor of PKA, KT5720, did not affect the activity of RLuc8. The identification and characterization of the adverse effect of H-89 on RLuc signal will help deconvolute data previously generated from RLuc-based assays looking at the functional effects of PKA signaling. In addition, for the current application and future development of bioluminscence assays, KT5720 is identified as a more suitable PKA inhibitor to be used in conjunction with RLuc-based assays. These principal findings also provide an important lesson to fully consider all of the potential effects of experimental conditions on a cell-based assay readout

Full Wave Analysis of RF Signal Attenuation in a Lossy Rough Surface Cave using a High Order Time Domain Vector Finite Element Method

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pingenot, J; Rieben, R; White, D

2005-10-31

We present a computational study of signal propagation and attenuation of a 200 MHz planar loop antenna in a cave environment. The cave is modeled as a straight and lossy random rough wall. To simulate a broad frequency band, the full wave Maxwell equations are solved directly in the time domain via a high order vector finite element discretization using the massively parallel CEM code EMSolve. The numerical technique is first verified against theoretical results for a planar loop antenna in a smooth lossy cave. The simulation is then performed for a series of random rough surface meshes in ordermore » to generate statistical data for the propagation and attenuation properties of the antenna in a cave environment. Results for the mean and variance of the power spectral density of the electric field are presented and discussed.« less

Measurement of acoustic attenuation in South Pole ice

NASA Astrophysics Data System (ADS)

IceCube Collaboration; Abbasi, R.; Abdou, Y.; Abu-Zayyad, T.; Adams, J.; Aguilar, J. A.; Ahlers, M.; Andeen, K.; Auffenberg, J.; Bai, X.; Baker, M.; Barwick, S. W.; Bay, R.; Bazo Alba, J. L.; Beattie, K.; Beatty, J. J.; Bechet, S.; Becker, J. K.; Becker, K.-H.; Benabderrahmane, M. L.; Berdermann, J.; Berghaus, P.; Berley, D.; Bernardini, E.; Bertrand, D.; Besson, D. Z.; Bissok, M.; Blaufuss, E.; Boersma, D. J.; Bohm, C.; Böser, S.; Botner, O.; Bradley, L.; Braun, J.; Buitink, S.; Carson, M.; Chirkin, D.; Christy, B.; Clem, J.; Clevermann, F.; Cohen, S.; Colnard, C.; Cowen, D. F.; D'Agostino, M. V.; Danninger, M.; de Clercq, C.; Demirörs, L.; Depaepe, O.; Descamps, F.; Desiati, P.; de Vries-Uiterweerd, G.; Deyoung, T.; Díaz-Vélez, J. C.; Dreyer, J.; Dumm, J. P.; Duvoort, M. R.; Ehrlich, R.; Eisch, J.; Ellsworth, R. W.; Engdegård, O.; Euler, S.; Evenson, P. A.; Fadiran, O.; Fazely, A. R.; Feusels, T.; Filimonov, K.; Finley, C.; Foerster, M. M.; Fox, B. D.; Franckowiak, A.; Franke, R.; Gaisser, T. K.; Gallagher, J.; Ganugapati, R.; Geisler, M.; Gerhardt, L.; Gladstone, L.; Glüsenkamp, T.; Goldschmidt, A.; Goodman, J. A.; Grant, D.; Griesel, T.; Groß, A.; Grullon, S.; Gunasingha, R. M.; Gurtner, M.; Gustafsson, L.; Ha, C.; Hallgren, A.; Halzen, F.; Han, K.; Hanson, K.; Helbing, K.; Herquet, P.; Hickford, S.; Hill, G. C.; Hoffman, K. D.; Homeier, A.; Hoshina, K.; Hubert, D.; Huelsnitz, W.; Hülß, J.-P.; Hulth, P. O.; Hultqvist, K.; Hussain, S.; Imlay, R. L.; Ishihara, A.; Jacobsen, J.; Japaridze, G. S.; Johansson, H.; Joseph, J. M.; Kampert, K.-H.; Kappes, A.; Karg, T.; Karle, A.; Kelley, J. L.; Kemming, N.; Kenny, P.; Kiryluk, J.; Kislat, F.; Klein, S. R.; Knops, S.; Köhne, J.-H.; Kohnen, G.; Kolanoski, H.; Köpke, L.; Koskinen, D. J.; Kowalski, M.; Kowarik, T.; Krasberg, M.; Krings, T.; Kroll, G.; Kuehn, K.; Kuwabara, T.; Labare, M.; Lafebre, S.; Laihem, K.; Landsman, H.; Lauer, R.; Lehmann, R.; Lennarz, D.; Lünemann, J.; Madsen, J.; Majumdar, P.; Maruyama, R.; Mase, K.; Matis, H. S.; Matusik, M.; Meagher, K.; Merck, M.; Mészáros, P.; Meures, T.; Middell, E.; Milke, N.; Montaruli, T.; Morse, R.; Movit, S. M.; Nahnhauer, R.; Nam, J. W.; Naumann, U.; Nießen, P.; Nygren, D. R.; Odrowski, S.; Olivas, A.; Olivo, M.; Ono, M.; Panknin, S.; Paul, L.; Pérez de Los Heros, C.; Petrovic, J.; Piegsa, A.; Pieloth, D.; Porrata, R.; Posselt, J.; Price, P. B.; Prikockis, M.; Przybylski, G. T.; Rawlins, K.; Redl, P.; Resconi, E.; Rhode, W.; Ribordy, M.; Rizzo, A.; Rodrigues, J. P.; Roth, P.; Rothmaier, F.; Rott, C.; Roucelle, C.; Ruhe, T.; Rutledge, D.; Ruzybayev, B.; Ryckbosch, D.; Sander, H.-G.; Sarkar, S.; Schatto, K.; Schlenstedt, S.; Schmidt, T.; Schneider, D.; Schukraft, A.; Schultes, A.; Schulz, O.; Schunck, M.; Seckel, D.; Semburg, B.; Seo, S. H.; Sestayo, Y.; Seunarine, S.; Silvestri, A.; Slipak, A.; Spiczak, G. M.; Spiering, C.; Stamatikos, M.; Stanev, T.; Stephens, G.; Stezelberger, T.; Stokstad, R. G.; Stoyanov, S.; Strahler, E. A.; Straszheim, T.; Sullivan, G. W.; Swillens, Q.; Taboada, I.; Tamburro, A.; Tarasova, O.; Tepe, A.; Ter-Antonyan, S.; Tilav, S.; Toale, P. A.; Tosi, D.; Turčan, D.; van Eijndhoven, N.; Vandenbroucke, J.; van Overloop, A.; van Santen, J.; Voigt, B.; Walck, C.; Waldenmaier, T.; Wallraff, M.; Walter, M.; Wendt, C.; Westerhoff, S.; Whitehorn, N.; Wiebe, K.; Wiebusch, C. H.; Wikström, G.; Williams, D. R.; Wischnewski, R.; Wissing, H.; Woschnagg, K.; Xu, C.; Xu, X. W.; Yanez, J. P.; Yodh, G.; Yoshida, S.; Zarzhitsky, P.; IceCube Collaboration

2011-01-01

Using the South Pole Acoustic Test Setup (SPATS) and a retrievable transmitter deployed in holes drilled for the IceCube experiment, we have measured the attenuation of acoustic signals by South Pole ice at depths between 190 m and 500 m. Three data sets, using different acoustic sources, have been analyzed and give consistent results. The method with the smallest systematic uncertainties yields an amplitude attenuation coefficient α = 3.20 ± 0.57 km-1 between 10 and 30 kHz, considerably larger than previous theoretical estimates. Expressed as an attenuation length, the analyses give a consistent result for λ ≡ 1/α of ˜300 m with 20% uncertainty. No significant depth or frequency dependence has been found.

Attenuation of p38α MAPK stress response signaling delays the in vivo aging of skeletal muscle myofibers and progenitor cells.

PubMed

Papaconstantinou, John; Wang, Chen Z; Zhang, Min; Yang, San; Deford, James; Bulavin, Dmitry V; Ansari, Naseem H

2015-09-01

Functional competence and self-renewal of mammalian skeletal muscle myofibers and progenitor cells declines with age. Progression of the muscle aging phenotype involves the decline of juvenile protective factorsi.e., proteins whose beneficial functions translate directly to the quality of life, and self-renewal of progenitor cells. These characteristics occur simultaneously with the age-associated increase of p38α stress response signaling. This suggests that the maintenance of low levels of p38α activity of juvenile tissues may delay or attenuate aging. We used the dominant negative haploinsufficient p38α mouse (DN-p38α(AF/+)) to demonstrate that in vivo attenuation of p38α activity in the gastrocnemius of the aged mutant delays age-associated processes that include: a) the decline of the juvenile protective factors, BubR1, aldehyde dehydrogenase 1A (ALDH1A1), and aldehyde dehydrogenase 2 (ALDH2); b) attenuated expression of p16(Ink4a) and p19(Arf) tumor suppressor genes of the Cdkn2a locus; c) decreased levels of hydroxynonenal protein adducts, expression of COX2 and iNOS; d) decline of the senescent progenitor cell pool level and d) the loss of gastrocnemius muscle mass. We propose that elevated P-p38α activity promotes skeletal muscle aging and that the homeostasis of p38α impacts the maintenance of a beneficial healthspan.

Color-coded fluid-attenuated inversion recovery images improve inter-rater reliability of fluid-attenuated inversion recovery signal changes within acute diffusion-weighted image lesions.

PubMed

Kim, Bum Joon; Kim, Yong-Hwan; Kim, Yeon-Jung; Ahn, Sung Ho; Lee, Deok Hee; Kwon, Sun U; Kim, Sang Joon; Kim, Jong S; Kang, Dong-Wha

2014-09-01

Diffusion-weighted image fluid-attenuated inversion recovery (FLAIR) mismatch has been considered to represent ischemic lesion age. However, the inter-rater agreement of diffusion-weighted image FLAIR mismatch is low. We hypothesized that color-coded images would increase its inter-rater agreement. Patients with ischemic stroke <24 hours of a clear onset were retrospectively studied. FLAIR signal change was rated as negative, subtle, or obvious on conventional and color-coded FLAIR images based on visual inspection. Inter-rater agreement was evaluated using κ and percent agreement. The predictive value of diffusion-weighted image FLAIR mismatch for identification of patients <4.5 hours of symptom onset was evaluated. One hundred and thirteen patients were enrolled. The inter-rater agreement of FLAIR signal change improved from 69.9% (k=0.538) with conventional images to 85.8% (k=0.754) with color-coded images (P=0.004). Discrepantly rated patients on conventional, but not on color-coded images, had a higher prevalence of cardioembolic stroke (P=0.02) and cortical infarction (P=0.04). The positive predictive value for patients <4.5 hours of onset was 85.3% and 71.9% with conventional and 95.7% and 82.1% with color-coded images, by each rater. Color-coded FLAIR images increased the inter-rater agreement of diffusion-weighted image FLAIR recovery mismatch and may ultimately help identify unknown-onset stroke patients appropriate for thrombolysis. © 2014 American Heart Association, Inc.

Attenuating GABAA Receptor Signaling in Dopamine Neurons Selectively Enhances Reward Learning and Alters Risk Preference in Mice

PubMed Central

Parker, Jones G.; Wanat, Matthew J.; Soden, Marta E.; Ahmad, Kinza; Zweifel, Larry S.; Bamford, Nigel S.; Palmiter, Richard D.

2011-01-01

Phasic dopamine transmission encodes the value of reward-predictive stimuli and influences both learning and decision-making. Altered dopamine signaling is associated with psychiatric conditions characterized by risky choices such as pathological gambling. These observations highlight the importance of understanding how dopamine neuron activity is modulated. While excitatory drive onto dopamine neurons is critical for generating phasic dopamine responses, emerging evidence suggests that inhibitory signaling also modulates these responses. To address the functional importance of inhibitory signaling in dopamine neurons, we generated mice lacking the β3 subunit of the GABAA receptor specifically in dopamine neurons (β3-KO mice) and examined their behavior in tasks that assessed appetitive learning, aversive learning, and risk preference. Dopamine neurons in midbrain slices from β3-KO mice exhibited attenuated GABA-evoked inhibitory post-synaptic currents. Furthermore, electrical stimulation of excitatory afferents to dopamine neurons elicited more dopamine release in the nucleus accumbens of β3-KO mice as measured by fast-scan cyclic voltammetry. β3-KO mice were more active than controls when given morphine, which correlated with potential compensatory upregulation of GABAergic tone onto dopamine neurons. β3-KO mice learned faster in two food-reinforced learning paradigms, but extinguished their learned behavior normally. Enhanced learning was specific for appetitive tasks, as aversive learning was unaffected in β3-KO mice. Finally, we found that β3-KO mice had enhanced risk preference in a probabilistic selection task that required mice to choose between a small certain reward and a larger uncertain reward. Collectively, these findings identify a selective role for GABAA signaling in dopamine neurons in appetitive learning and decision-making. PMID:22114279

Melatonin attenuates memory impairment induced by Klotho gene deficiency via interactive signaling between MT2 receptor, ERK, and Nrf2-related antioxidant potential.

PubMed

Shin, Eun-Joo; Chung, Yoon Hee; Le, Hoang-Lan Thi; Jeong, Ji Hoon; Dang, Duy-Khanh; Nam, Yunsung; Wie, Myung Bok; Nah, Seung-Yeol; Nabeshima, Yo-Ichi; Nabeshima, Toshitaka; Kim, Hyoung-Chun

2014-12-30

We demonstrated that oxidative stress plays a crucial role in cognitive impairment in klotho mutant mice, a genetic model of aging. Since down-regulation of melatonin due to aging is well documented, we used this genetic model to determine whether the antioxidant property of melatonin affects memory impairment. First, we examined the effects of melatonin on hippocampal oxidative parameters and the glutathione/oxidized glutathione (GSH/GSSG) ratio and memory dysfunction of klotho mutant mice. Second, we investigated whether a specific melatonin receptor is involved in the melatonin-mediated pharmacological response by application with melatonin receptor antagonists. Third, we examined phospho-extracellular-signal-regulated kinase (ERK) expression, nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation, Nrf2 DNA binding activity, and glutamate-cysteine ligase (GCL) mRNA expression. Finally, we examined effects of the ERK inhibitor SL327 in response to antioxidant efficacy and memory enhancement mediated by melatonin. Treatment with melatonin resulted in significant attenuations of oxidative damage, a decrease in the GSH/GSSG ratio, and a significant amelioration of memory impairment in this aging model. These effects of melatonin were significantly counteracted by the selective MT2 receptor antagonist 4-P-PDOT. Importantly, 4-P-PDOT or SL327 also counteracted melatonin-mediated attenuation in response to the decreases in phospho-ERK expression, Nrf2 nuclear translocation, Nrf2 DNA-binding activity, and GCL mRNA expression in the hippocampi of klotho mutant mice. SL327 also counteracted the up-regulation of the GSH/GSSG ratio and the memory enhancement mediated by melatonin in klotho mutant mice. Melatonin attenuates oxidative stress and the associated memory impairment induced by klotho deficiency via signaling interaction between the MT2 receptor and ERK- and Nrf2-related antioxidant potential. © The Author 2015. Published by Oxford University

Melatonin Attenuates Memory Impairment Induced by Klotho Gene Deficiency Via Interactive Signaling Between MT2 Receptor, ERK, and Nrf2-Related Antioxidant Potential

PubMed Central

Shin, Eun-Joo; Chung, Yoon Hee; Le, Hoang-Lan Thi; Jeong, Ji Hoon; Dang, Duy-Khanh; Nam, Yunsung; Wie, Myung Bok; Nah, Seung-Yeol; Nabeshima, Yo-Ichi; Nabeshima, Toshitaka; Kim, Hyoung-Chun

2015-01-01

Background: We demonstrated that oxidative stress plays a crucial role in cognitive impairment in klotho mutant mice, a genetic model of aging. Since down-regulation of melatonin due to aging is well documented, we used this genetic model to determine whether the antioxidant property of melatonin affects memory impairment. Methods: First, we examined the effects of melatonin on hippocampal oxidative parameters and the glutathione/oxidized glutathione (GSH/GSSG) ratio and memory dysfunction of klotho mutant mice. Second, we investigated whether a specific melatonin receptor is involved in the melatonin-mediated pharmacological response by application with melatonin receptor antagonists. Third, we examined phospho-extracellular-signal-regulated kinase (ERK) expression, nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation, Nrf2 DNA binding activity, and glutamate-cysteine ligase (GCL) mRNA expression. Finally, we examined effects of the ERK inhibitor SL327 in response to antioxidant efficacy and memory enhancement mediated by melatonin. Results: Treatment with melatonin resulted in significant attenuations of oxidative damage, a decrease in the GSH/GSSG ratio, and a significant amelioration of memory impairment in this aging model. These effects of melatonin were significantly counteracted by the selective MT2 receptor antagonist 4-P-PDOT. Importantly, 4-P-PDOT or SL327 also counteracted melatonin-mediated attenuation in response to the decreases in phospho-ERK expression, Nrf2 nuclear translocation, Nrf2 DNA-binding activity, and GCL mRNA expression in the hippocampi of klotho mutant mice. SL327 also counteracted the up-regulation of the GSH/GSSG ratio and the memory enhancement mediated by melatonin in klotho mutant mice. Conclusions: Melatonin attenuates oxidative stress and the associated memory impairment induced by klotho deficiency via signaling interaction between the MT2 receptor and ERK- and Nrf2-related antioxidant potential. PMID

Activation of Sirt1/FXR Signaling Pathway Attenuates Triptolide-Induced Hepatotoxicity in Rats.

PubMed

Yang, Jing; Sun, Lixin; Wang, Lu; Hassan, Hozeifa M; Wang, Xuan; Hylemon, Phillip B; Wang, Tao; Zhou, Huiping; Zhang, Luyong; Jiang, Zhenzhou

2017-01-01

Triptolide (TP), a diterpenoid isolated from Tripterygium wilfordii Hook F, has an excellent pharmacological profile of immunosuppression and anti-tumor activities, but its clinical applications are severely restricted due to its severe and cumulative toxicities. The farnesoid X receptor (FXR) is the master bile acid nuclear receptor and plays an important role in maintaining hepatic metabolism homeostasis. Hepatic Sirtuin (Sirt1) is a key regulator of the FXR signaling pathway and hepatic metabolism homeostasis. The aims of this study were to determine whether Sirt1/FXR signaling pathway plays a critical role in TP-induced hepatotoxicity. Our study revealed that the intragastric administration of TP (400 μg/kg body weight) for 28 consecutive days increased bile acid accumulation, suppressed hepatic gluconeogenesis in rats. The expression of bile acid transporter BSEP was significantly reduced and cholesterol 7α-hydroxylase (CYP7A1) was markedly increased in the TP-treated group, whereas the genes responsible for hepatic gluconeogenesis were suppressed in the TP-treated group. TP also modulated the FXR and Sirt1 by decreasing its expression both in vitro and in vivo . The Sirt1 agonist SRT1720 and the FXR agonist obeticholic acid (OCA) were used both in vivo and in vitro . The remarkable liver damage induced by TP was attenuated by treatment with either SRT1720 or OCA, as reflected by decreased levels of serum total bile acids and alkaline phosphatase and increased glucose levels. Meanwhile, SRT1720 significantly alleviated TP-induced FXR suppression and FXR-targets involved in hepatic lipid and glucose metabolism. Based on these results, we conclude that Sirt1/FXR inactivation plays a critical role in TP-induced hepatotoxicity. Moreover, Sirt1/FXR axis represents a novel therapeutic target that could potentially ameliorate TP-induced hepatotoxicity.

Transcriptional activation of melanocortin 2 receptor accessory protein by PPARγ in adipocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Nam Soo; Kim, Yoon-Jin; Cho, Si Young

2013-09-27

Highlights: •MRAP enhanced HSL expression. •ACTH-mediated MRAP reduced glycerol release. •PPARγ induced MRAP expression. •PPARγ bound to the MRAP promoter. -- Abstract: Adrenocorticotropic hormone (ACTH) in rodents decreases lipid accumulation and body weight. Melanocortin receptor 2 (MC2R) and MC2R accessory protein (MRAP) are specific receptors for ACTH in adipocytes. Peroxisome proliferator-activated receptor γ (PPARγ) plays a role in the transcriptional regulation of metabolic pathways such as adipogenesis and β-oxidation of fatty acids. In this study we investigated the transcriptional regulation of MRAP expression during differentiation of 3T3-L1 cells. Stimulation with ACTH affected lipolysis in murine mature adipocytes via MRAP. Putativemore » peroxisome proliferator response element (PPRE) was identified in the MRAP promoter region. In chromatin immunoprecipitation and reporter assays, we observed binding of PPARγ to the MRAP promoter. The mutagenesis experiments showed that the −1209/−1198 region of the MRAP promoter could function as a PPRE site. These results suggest that PPARγ is required for transcriptional activation of the MRAP gene during adipogenesis, which contributes to understanding of the molecular mechanism of lipolysis in adipocytes.« less

Valsartan attenuates cardiac and renal hypertrophy in rats with experimental cardiorenal syndrome possibly through down-regulating galectin-3 signaling.

PubMed

Zhang, M-J; Gu, Y; Wang, H; Zhu, P-F; Liu, X-Y; Wu, J

2016-01-01

Aortocaval fistula (AV) induced chronic volume overload in rats with preexisting mild renal dysfunction (right kidney remove: UNX) could mimic the type 4 cardiorenal syndrome (CRS): chronic renocardiac syndrome. Galectin-3, a β-galactoside binding lectin, is an emerging biomarker in cardiovascular as well as renal diseases. We observed the impact of valsartan on cardiac and renal hypertrophy and galectin-3 changes in this model. Adult male Sprague-Dawley (SD) rats (200-250 g) were divided into S (Sham, n = 7), M (UNX+AV, n = 7) and M+V (UNX+AV+valsartan, n = 7) groups. Eight weeks later, cardiac function was measured by echocardiography. Renal outcome was measured by glomerular filtration rate, effective renal plasma flow, renal blood flow and 24 hours albuminuria. Immunohistochemistry and real-time PCR were used to evaluate the expressions of galectin-3 in heart and renal. Cardiac hypertrophy and renal hypertrophy as well as cardiac enlargement were evidenced in this AV shunt induced chronic volume overload rat model with preexisting mild renal dysfunction. Cardiac and renal hypertrophy were significantly attenuated but cardiac enlargement was unaffected by valsartan independent of its blood pressure lowering effect. 24 hours urine albumin was significantly increased, which was significantly reduced by valsartan in this model. Immunohistochemistry and real-time PCR evidenced significantly up-regulated galectin-3 expression in heart and kidney and borderline increased myocardial collagen I expression, which tended to be lower post valsartan treatment. Up-regulated galectin-3 signaling might also be involved in the pathogenesis in this CRS model. The beneficial effects of valsartan in terms of attenuating cardiac and renal hypertrophy and reducing 24 hours albumin in this model might partly be mediated through down-regulating galectin-3 signal pathway.

Calibrating an Ionosonde for Ionospheric Attenuation Measurements.

PubMed

Gilli, Lorenzo; Sciacca, Umberto; Zuccheretti, Enrico

2018-05-15

Vertical ionospheric soundings have been performed at almost all ionospheric observatories with little attention to measuring the attenuation of the signal between transmission and reception. When the absorption has been determined, this has been achieved by comparing the received power after the first and second reflections, but this method has some limitations due to the unknown reflection coefficient of the ground and the non-continuous presence of the second reflection. This paper deals with a different method based on precise calibration of the sounding system, allowing determination of absolute signal attenuation after a single reflection. This approach is affected by a systematic error due to imperfect calibration of the antennas, but when the focus of interest is to measure a trend over a specified period, it is very accurate. The article describes how calibration was implemented, the measurement output formats, and finally it presents some results from a meaningful set of measurements in order to demonstrate what this method can accomplish.

Using a LIDAR Vegetation Model to Predict UHF SAR Attenuation in Coniferous Forests

PubMed Central

Swanson, Alan; Huang, Shengli; Crabtree, Robert

2009-01-01

Attenuation of radar signals by vegetation can be a problem for target detection and GPS reception, and is an important parameter in models describing vegetation backscatter. Here we first present a model describing the 3D distribution of stem and foliage structure based on small footprint scanning LIDAR data. Secondly we present a model that uses ray-tracing methodology to record detailed interactions between simulated radar beams and vegetation components. These interactions are combined over the SAR aperture and used to predict two-way attenuation of the SAR signal. Accuracy of the model is demonstrated using UHF SAR observations of large trihedral corner reflectors in coniferous forest stands. Our study showed that the model explains between 66% and 81% of the variability in observed attenuation. PMID:22573972

Association of estradiol on expression of melanocortin receptors and their accessory proteins in the liver of chicken (Gallus gallus).

PubMed

Ren, Junxiao; Li, Yanmin; Xu, Naiyi; Li, Hong; Li, Cuicui; Han, Ruili; Wang, Yanbin; Li, Zhuanjian; Kang, Xiangtao; Liu, Xiaojun; Tian, Yadong

2017-01-01

The melanocortin receptor accessory proteins (MRAP and MRAP2) are small single-pass transmembrane proteins that regulate the biological functions of the melanocortin receptor (MCR) family. MCRs comprise five receptors (MC1R-MC5R) with diverse physiological roles in mammals. Five MCR members and two MRAPs were also predicted in the chicken (Gallus gallus) genome. However, little is known about their expression, regulation and biological functions. In this study, we cloned the MRAP and MRAP2 genes. Sequencing analysis revealed that the functional domains of MRAP and MRAP2 were conserved among species, suggesting that the physiological roles of chicken MRAP and MRAP2 could be similar to their mammalian counterparts. Tissue expression analysis demonstrated that MRAP was expressed in the adrenal gland, liver, spleen, glandular stomach and lungs, while MRAP2 is predominantly expressed in the adrenal gland. All five MCRs were present in the adrenal gland, but showed different expression patterns in other tissues. The MC5R was the only MCR member that was expressed in the chicken liver. The expression levels of MRAP in chicken liver were significantly increased at sexual maturity stage, and were significantly up-regulated (P<0.05) when chickens and chicken primary hepatocytes were treated with 17β-estradiol in vivo and in vitro, respectively; however, expression levels of PPARγ were down-regulated, and no effect on MC5R was observed. Our results suggested that estrogen could stimulate the expression of MRAP in the liver of chicken through inhibiting the expression of transcription regulation factor PPARγ, and MRAP might play its biological role in a different way rather than forming an MRAP/MC2R complex in chicken liver during the egg-laying period. Copyright © 2016 Elsevier Inc. All rights reserved.

Accuracies and Contrasts of Models of the Diffusion-Weighted-Dependent Attenuation of the MRI Signal at Intermediate b-values.

PubMed

Nicolas, Renaud; Sibon, Igor; Hiba, Bassem

2015-01-01

The diffusion-weighted-dependent attenuation of the MRI signal E(b) is extremely sensitive to microstructural features. The aim of this study was to determine which mathematical model of the E(b) signal most accurately describes it in the brain. The models compared were the monoexponential model, the stretched exponential model, the truncated cumulant expansion (TCE) model, the biexponential model, and the triexponential model. Acquisition was performed with nine b-values up to 2500 s/mm(2) in 12 healthy volunteers. The goodness-of-fit was studied with F-tests and with the Akaike information criterion. Tissue contrasts were differentiated with a multiple comparison corrected nonparametric analysis of variance. F-test showed that the TCE model was better than the biexponential model in gray and white matter. Corrected Akaike information criterion showed that the TCE model has the best accuracy and produced the most reliable contrasts in white matter among all models studied. In conclusion, the TCE model was found to be the best model to infer the microstructural properties of brain tissue.

The Attenuation of Central Angiotensin II-dependent Pressor Response and Intra-neuronal Signaling by Intracarotid Injection of Nanoformulated Copper/Zinc Superoxide Dismutase

PubMed Central

Rosenbaugh, Erin G.; Roat, James; Gao, Lie; Yang, Rui-Fang; Manickam, Devika S.; Yin, Jing-Xiang; Schultz, Harold D.; Bronich, Tatiana K.; Batrakova, Elena V.; Kabanov, Alexander V.; Zucker, Irving H.; Zimmerman, Matthew C.

2010-01-01

Adenoviral-mediated overexpression of the intracellular superoxide (O2•−) scavenging enzyme copper/zinc superoxide dismutase (CuZnSOD) in the brain attenuates central angiotensin II (AngII)-induced cardiovascular responses. However, the therapeutic potential for adenoviral vectors is weakened by toxicity and the inability of adenoviral vectors to target the brain following peripheral administration. Therefore, we developed a non-viral delivery system in which CuZnSOD protein is electrostatically bound to a synthetic poly(ethyleneimine)-poly(ethyleneglycol) (PEI-PEG) polymer to form a polyion complex (CuZnSOD nanozyme). We hypothesized that PEI-PEG polymer increases transport of functional CuZnSOD to neurons, which inhibits AngII intra-neuronal signaling. The AngII-induced increase in O2•−, as measured by dihydroethidium fluorescence and electron paramagnetic resonance spectroscopy, was significantly inhibited in CuZnSOD nanozyme-treated neurons compared to free CuZnSOD- and non-treated neurons. CuZnSOD nanozyme also attenuated the AngII-induced inhibition of K+ current in neurons. Intracarotid injection of CuZnSOD nanozyme into rabbits significantly inhibited the pressor response of intracerebroventricular-delivered AngII; however, intracarotid injection of free CuZnSOD or PEI-PEG polymer alone failed to inhibit this response. Importantly, neither the PEI-PEG polymer alone nor the CuZnSOD nanozyme induced neuronal toxicity. These findings indicate that CuZnSOD nanozyme inhibits AngII intra-neuronal signaling in vitro and in vivo. PMID:20378166

Using Tectonic Tremor to Constrain Seismic-wave Attenuation in Cascadia

NASA Astrophysics Data System (ADS)

Littel, G.; Thomas, A.; Baltay, A.

2017-12-01

In addition to fast, seismic slip, many subduction zones also host slow, largely aseismic slip, accompanied by a weak seismic signal known as tectonic tremor. Tremor is a small amplitude, low-frequency seismic signal that originates at the plate interface, down-dip of where large earthquakes typically occur. The Cascadia subduction zone has not seen a large megathrust earthquake since 1700, yet its recurrence interval of 350-500 years motivates heightened interest in understanding the seismic hazard of the region. Of great importance is to understand the degree to which waves are attenuated as they leave the plate interface and travel towards populated regions of interest. Ground motion prediction equations (GMPEs) relate ground motion to a number of parameters, including earthquake magnitude, depth, style of faulting, and anelastic attenuation, and are typically determined empirically from earthquake ground motion recordings. In Cascadia, however, earthquakes of the moderate size typically used to constrain GMPEs occur relatively infrequently compared to tectonic tremor events, which, in contrast, occur periodically approximately every 10-19 months. Studies have shown that the abundant tectonic tremor in Cascadia, despite its small amplitudes, can be used to constrain seismic wave attenuation in GMPEs. Here we quantify seismic wave attenuation and determine its spatial variations in Cascadia by performing an inversion using tremor ground motion amplitudes, taken as peak ground acceleration (PGA) and peak ground velocity (PGV) from 1 min window waveforms of each individual tremor event. We estimate the anelastic attenuation parameter for varying regional sections along the Cascadia margin. Changes in seismic-wave attenuation along the Cascadia Subduction Zone could result in significantly different ground motions in the event of a very large earthquake, hence quantifying attenuation may help to better estimate the severity of shaking in densely populated

Rapamycin attenuates BAFF-extended proliferation and survival via disruption of mTORC1/2 signaling in normal and neoplastic B-lymphoid cells.

PubMed

Zeng, Qingyu; Qin, Shanshan; Zhang, Hai; Liu, Beibei; Qin, Jiamin; Wang, Xiaoxue; Zhang, Ruijie; Liu, Chunxiao; Dong, Xiaoqing; Zhang, Shuangquan; Huang, Shile; Chen, Long

2018-01-01

B cell activating factor from the TNF family (BAFF) stimulates B-cell proliferation and survival, but excessive BAFF promotes the development of aggressive B cells leading to malignant and autoimmune diseases. Recently, we have reported that rapamycin, a macrocyclic lactone, attenuates human soluble BAFF (hsBAFF)-stimulated B-cell proliferation/survival by suppressing mTOR-mediated PP2A-Erk1/2 signaling pathway. Here, we show that the inhibitory effect of rapamycin on hsBAFF-promoted B cell proliferation/survival is also related to blocking hsBAFF-stimulated phosphorylation of Akt, S6K1, and 4E-BP1, as well as expression of survivin in normal and B-lymphoid (Raji and Daudi) cells. It appeared that both mTORC1 and mTORC2 were involved in the inhibitory activity of rapamycin, as silencing raptor or rictor enhanced rapamycin's suppression of hsBAFF-induced survivin expression and proliferation/viability in B cells. Also, PP242, an mTORC1/2 kinase inhibitor, repressed survivin expression, and cell proliferation/viability more potently than rapamycin (mTORC1 inhibitor) in B cells in response to hsBAFF. Of interest, ectopic expression of constitutively active Akt (myr-Akt) or constitutively active S6K1 (S6K1-ca), or downregulation of 4E-BP1 conferred resistance to rapamycin's attenuation of hsBAFF-induced survivin expression and B-cell proliferation/viability, whereas overexpression of dominant negative Akt (dn-Akt) or constitutively hypophosphorylated 4E-BP1 (4EBP1-5A), or downregulation of S6K1, or co-treatment with Akt inhibitor potentiated the inhibitory effects of rapamycin. The findings indicate that rapamycin attenuates excessive hsBAFF-induced cell proliferation/survival via blocking mTORC1/2 signaling in normal and neoplastic B-lymphoid cells. Our data underscore that rapamycin may be a potential agent for preventing excessive BAFF-evoked aggressive B-cell malignancies and autoimmune diseases. © 2017 Wiley Periodicals, Inc.

A role for the melanocortin 4 receptor in sexual function.

PubMed

Van der Ploeg, Lex H T; Martin, William J; Howard, Andrew D; Nargund, Ravi P; Austin, Christopher P; Guan, Xiaoming; Drisko, Jennifer; Cashen, Doreen; Sebhat, Iyassu; Patchett, Arthur A; Figueroa, David J; DiLella, Anthony G; Connolly, Brett M; Weinberg, David H; Tan, Carina P; Palyha, Oksana C; Pong, Sheng-Shung; MacNeil, Tanya; Rosenblum, Charles; Vongs, Aurawan; Tang, Rui; Yu, Hong; Sailer, Andreas W; Fong, Tung Ming; Huang, Cathy; Tota, Michael R; Chang, Ray S; Stearns, Ralph; Tamvakopoulos, Constantin; Christ, George; Drazen, Deborah L; Spar, Brian D; Nelson, Randy J; MacIntyre, D Euan

2002-08-20

By using a combination of genetic, pharmacological, and anatomical approaches, we show that the melanocortin 4 receptor (MC4R), implicated in the control of food intake and energy expenditure, also modulates erectile function and sexual behavior. Evidence supporting this notion is based on several findings: (i) a highly selective non-peptide MC4R agonist augments erectile activity initiated by electrical stimulation of the cavernous nerve in wild-type but not Mc4r-null mice; (ii) copulatory behavior is enhanced by administration of a selective MC4R agonist and is diminished in mice lacking Mc4r; (iii) reverse transcription (RT)-PCR and non-PCR based methods demonstrate MC4R expression in rat and human penis, and rat spinal cord, hypothalamus, brainstem, pelvic ganglion (major autonomic relay center to the penis), but not in rat primary corpus smooth muscle cavernosum cells; and (iv) in situ hybridization of glans tissue from the human and rat penis reveal MC4R expression in nerve fibers and mechanoreceptors in the glans of the penis. Collectively, these data implicate the MC4R in the modulation of penile erectile function and provide evidence that MC4R-mediated proerectile responses may be activated through neuronal circuitry in spinal cord erectile centers and somatosensory afferent nerve terminals of the penis. Our results provide a basis for the existence of MC4R-controlled neuronal pathways that control sexual function.

Identification of tetrapeptides from a mixture based positional scanning library that can restore nM full agonist function of the L106P, I69T, I102S, A219V, C271Y, and C271R human melanocortin-4 polymorphic receptors (hMC4Rs).

PubMed

Haslach, Erica M; Huang, Huisuo; Dirain, Marvin; Debevec, Ginamarie; Geer, Phaedra; Santos, Radleigh G; Giulianotti, Marc A; Pinilla, Clemencia; Appel, Jon R; Doering, Skye R; Walters, Michael A; Houghten, Richard A; Haskell-Luevano, Carrie

2014-06-12

Human obesity has been linked to genetic factors and single nucleotide polymorphisms (SNPs). Melanocortin-4 receptor (MC4R) SNPs have been associated with up to 6% frequency in morbidly obese children and adults. A potential therapy for individuals possessing such genetic modifications is the identification of molecules that can restore proper receptor signaling and function. These compounds could serve as personalized medications improving quality of life issues as well as alleviating diseases symptoms associated with obesity including type 2 diabetes. Several hMC4 SNP receptors have been pharmacologically characterized in vitro to have a decreased, or a lack of response, to endogenous agonists such as α-, β-, and γ2-melanocyte stimulating hormones (MSH) and adrenocorticotropin hormone (ACTH). Herein we report the use of a mixture based positional scanning combinatorial tetrapeptide library to discover molecules with nM full agonist potency and efficacy to the L106P, I69T, I102S, A219V, C271Y, and C271R hMC4Rs. The most potent compounds at all these hMC4R SNPs include Ac-His-(pI)DPhe-Tic-(pNO2)DPhe-NH2, Ac-His-(pCl)DPhe-Tic-(pNO2)DPhe-NH2, Ac-His-(pCl)DPhe-Arg-(pI)Phe-NH2, and Ac-Arg-(pCl)DPhe-Tic-(pNO2)DPhe-NH2, revealing new ligand pharmacophore models for melanocortin receptor drug design strategies.

Identification of Tetrapeptides from a Mixture Based Positional Scanning Library That Can Restore nM Full Agonist Function of the L106P, I69T, I102S, A219V, C271Y, and C271R Human Melanocortin-4 Polymorphic Receptors (hMC4Rs)

PubMed Central

2015-01-01

Human obesity has been linked to genetic factors and single nucleotide polymorphisms (SNPs). Melanocortin-4 receptor (MC4R) SNPs have been associated with up to 6% frequency in morbidly obese children and adults. A potential therapy for individuals possessing such genetic modifications is the identification of molecules that can restore proper receptor signaling and function. These compounds could serve as personalized medications improving quality of life issues as well as alleviating diseases symptoms associated with obesity including type 2 diabetes. Several hMC4 SNP receptors have been pharmacologically characterized in vitro to have a decreased, or a lack of response, to endogenous agonists such as α-, β-, and γ2-melanocyte stimulating hormones (MSH) and adrenocorticotropin hormone (ACTH). Herein we report the use of a mixture based positional scanning combinatorial tetrapeptide library to discover molecules with nM full agonist potency and efficacy to the L106P, I69T, I102S, A219V, C271Y, and C271R hMC4Rs. The most potent compounds at all these hMC4R SNPs include Ac-His-(pI)DPhe-Tic-(pNO2)DPhe-NH2, Ac-His-(pCl)DPhe-Tic-(pNO2)DPhe-NH2, Ac-His-(pCl)DPhe-Arg-(pI)Phe-NH2, and Ac-Arg-(pCl)DPhe-Tic-(pNO2)DPhe-NH2, revealing new ligand pharmacophore models for melanocortin receptor drug design strategies. PMID:24517312

The peptide NDP-MSH induces phenotype changes in the heart that resemble ischemic preconditioning.

PubMed

Catania, Anna; Lonati, Caterina; Sordi, Andrea; Leonardi, Patrizia; Carlin, Andrea; Gatti, Stefano

2010-01-01

alpha-Melanocyte-stimulating hormone (alpha-MSH) is a pro-opiomelanocortin (POMC)-derived peptide that exerts multiple protective effects on host cells. Previous investigations showed that treatment with alpha-MSH or synthetic melanocortin agonists reduces heart damage in reperfusion injury and transplantation. The aim of this preclinical research was to determine whether melanocortin treatment induces preconditioning-like cardioprotection. In particular, the plan was to assess whether melanocortin administration causes phenotype changes similar to those induced by repetitive ischemic events. The idea was conceived because both ischemic preconditioning and melanocortin signaling largely depend on cAMP response element binding protein (CREB) phosphorylation. Rats received single i.v. injections of 750microg/kg of the alpha-MSH analogue Nle(4),DPhe(7)-alpha-MSH (NDP-MSH) or saline and were sacrificed at 0.5, 1, 3, or 5h. Western blot analysis showed that rat hearts expressed melanocortin 1 receptor (MC1R) protein. Treatment with NDP-MSH was associated with early and marked increase in interleukin 6 (IL-6) mRNA. This was followed by signal transducer and activator of transcription 3 (STAT3) phosphorylation and induction of suppressor of cytokine signaling 3 (SOCS3). There were no changes in expression of other cytokines of the IL-6 family. Expression of IL-10, IL-1beta, and TNF-alpha was likewise unaltered. In hearts of rats treated with NDP-MSH there was increased expression of the orphan nuclear receptor Nur77. The data indicate that NDP-MSH induces phenotype changes that closely resemble ischemic preconditioning and likely contribute to its established protection against reperfusion injury. In addition, the increased expression of Nur77 and SOCS3 could be part of a broader anti-inflammatory effect.

Hybrid photonic signal processing

NASA Astrophysics Data System (ADS)

Ghauri, Farzan Naseer

This thesis proposes research of novel hybrid photonic signal processing systems in the areas of optical communications, test and measurement, RF signal processing and extreme environment optical sensors. It will be shown that use of innovative hybrid techniques allows design of photonic signal processing systems with superior performance parameters and enhanced capabilities. These applications can be divided into domains of analog-digital hybrid signal processing applications and free-space---fiber-coupled hybrid optical sensors. The analog-digital hybrid signal processing applications include a high-performance analog-digital hybrid MEMS variable optical attenuator that can simultaneously provide high dynamic range as well as high resolution attenuation controls; an analog-digital hybrid MEMS beam profiler that allows high-power watt-level laser beam profiling and also provides both submicron-level high resolution and wide area profiling coverage; and all optical transversal RF filters that operate on the principle of broadband optical spectral control using MEMS and/or Acousto-Optic tunable Filters (AOTF) devices which can provide continuous, digital or hybrid signal time delay and weight selection. The hybrid optical sensors presented in the thesis are extreme environment pressure sensors and dual temperature-pressure sensors. The sensors employ hybrid free-space and fiber-coupled techniques for remotely monitoring a system under simultaneous extremely high temperatures and pressures.

Unique players in the BMP pathway: Small C-terminal domain phosphatases dephosphorylate Smad1 to attenuate BMP signaling

PubMed Central

Knockaert, Marie; Sapkota, Gopal; Alarcón, Claudio; Massagué, Joan; Brivanlou, Ali H.

2006-01-01

Smad transcription factors are key signal transducers for the TGF-β/bone morphogenetic protein (BMP) family of cytokines and morphogens. C-terminal serine phosphorylation by TGF-β and BMP membrane receptors drives Smads into the nucleus as transcriptional regulators. Dephosphorylation and recycling of activated Smads is an integral part of this process, which is critical for agonist sensing by the cell. However, the nuclear phosphatases involved have remained unknown. Here we provide functional, biochemical, and embryological evidence identifying the SCP (small C-terminal domain phosphatase) family of nuclear phosphatases as mediators of Smad1 dephosphorylation in the BMP signaling pathway in vertebrates. Xenopus SCP2/Os4 inhibits BMP activity in the presumptive ectoderm and leads to neuralization. In Xenopus embryos, SCP2/Os4 and human SCP1, 2, and 3 cause selective dephosphorylation of Smad1 compared with Smad2, inhibiting BMP- and Smad1-dependent transcription and leading to the induction of the secondary dorsal axis. In human cells, RNAi-mediated depletion of SCP1 and SCP2 increases the extent and duration of Smad1 phosphorylation in response to BMP, the transcriptional action of Smad1, and the strength of endogenous BMP gene responses. The present identification of the SCP family as Smad C-terminal phosphatases sheds light on the events that attenuate Smad signaling and reveals unexpected links to the essential phosphatases that control RNA polymerase II in eukaryotes. PMID:16882717

Detection of genetic diversity and selection at the coding region of the melanocortin receptor 1 (MC1R) gene in Tibetan pigs and Landrace pigs.

PubMed

Liu, Rui; Jin, Long; Long, Keren; Chai, Jie; Ma, Jideng; Tang, Qianzi; Tian, Shilin; Hu, Yaodong; Lin, Ling; Wang, Xun; Jiang, Anan; Li, Xuewei; Li, Mingzhou

2016-01-10

Domestication and subsequent selective pressures have produced a large variety of pig coat colors in different regions and breeds. The melanocortin 1 receptor (MC1R) gene plays a crucial role in determining coat color of mammals. Here, we investigated genetic diversity and selection at the coding region of the porcine melanocortin receptor 1 (MC1R) in Tibetan pigs and Landrace pigs. By contrast, genetic variability was much lower in Landrace pigs than in Tibetan pigs. Meanwhile, haplotype analysis showed that Tibetan pigs possessed shared haplotypes, suggesting a possibility of recent introgression event by way of crossbreeding with neighboring domestic pigs or shared ancestral polymorphism. Additionally, we detected positive selection at the MC1R in both Tibetan pigs and Landrace pigs through the dN/dS analysis. These findings suggested that novel phenotypic change (dark coat color) caused by novel mutations may help Tibetan pigs against intensive solar ultraviolet (UV) radiation and camouflage in wild environment, whereas white coat color in Landrace were intentionally selected by human after domestication. Furthermore, both the phylogenetic analysis and the network analysis provided clues that MC1R in Asian and European wild boars may have initially experienced different selective pressures, and MC1R alleles diversified in modern domesticated pigs. Copyright © 2015 Elsevier B.V. All rights reserved.

Synthesis and characterization of time-resolved fluorescence probes for evaluation of competitive binding to melanocortin receptors.

PubMed

Alleti, Ramesh; Vagner, Josef; Dehigaspitiya, Dilani Chathurika; Moberg, Valerie E; Elshan, N G R D; Tafreshi, Narges K; Brabez, Nabila; Weber, Craig S; Lynch, Ronald M; Hruby, Victor J; Gillies, Robert J; Morse, David L; Mash, Eugene A

2013-09-01

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

Edaravone attenuates lipopolysaccharide-induced acute respiratory distress syndrome associated early pulmonary fibrosis via amelioration of oxidative stress and transforming growth factor-β1/Smad3 signaling.

PubMed

Wang, Xida; Lai, Rongde; Su, Xiangfen; Chen, Guibin; Liang, Zijing

2018-01-01

Pulmonary fibrosis is responsible for the both short-term and long-term outcomes in patients with acute respiratory distress syndrome (ARDS). There is still no effective cure to improve prognosis. The purpose of this study was to investigate whether edaravone, a free radical scavenger, have anti-fibrosis effects in the rat model of ARDS associated early pulmonary fibrosis by lipopolysaccharide (LPS) administration. Rats were subjected to intravenous injection of LPS, and edaravone was given intraperitoneally after LPS administration daily for 7 consecutive days. LPS treatment rapidly increased lung histopathology abnormalities, coefficient of lung, hydroxyproline and collagen I levels, stimulated myofibroblast differentiation and induced expression of TGF-β1 and activation of TGF-β1/Smad3 signaling as early as day 7 after LPS injection. Moreover, LPS intoxication significantly increased the contents of malondialdehyde (MDA), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), whereas it dramatically decreased superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activities from day 1 after LPS treatment. On the contrary, edaravone treatment ameliorated LPS-induced myofibroblast differentiation and pulmonary fibrosis, simultaneously, and attenuated LPS-stimulated oxidative stress and activation of TGF-β1/Smad3 signaling. Collectively, edaravone may attenuate ARDS associated early pulmonary fibrosis through amelioration of oxidative stress and TGF-β1/Smad3 signaling pathway. Edaravone may be a promising drug candidate for the treatment of ARDS-related pulmonary fibrosis in early period. Copyright © 2017 Elsevier Inc. All rights reserved.

Earth-Space Link Attenuation Estimation via Ground Radar Kdp

NASA Technical Reports Server (NTRS)

Bolen, Steven M.; Benjamin, Andrew L.; Chandrasekar, V.

2003-01-01

A method of predicting attenuation on microwave Earth/spacecraft communication links, over wide areas and under various atmospheric conditions, has been developed. In the area around the ground station locations, a nearly horizontally aimed polarimetric S-band ground radar measures the specific differential phase (Kdp) along the Earth-space path. The specific attenuation along a path of interest is then computed by use of a theoretical model of the relationship between the measured S-band specific differential phase and the specific attenuation at the frequency to be used on the communication link. The model includes effects of rain, wet ice, and other forms of precipitation. The attenuation on the path of interest is then computed by integrating the specific attenuation over the length of the path. This method can be used to determine statistics of signal degradation on Earth/spacecraft communication links. It can also be used to obtain real-time estimates of attenuation along multiple Earth/spacecraft links that are parts of a communication network operating within the radar coverage area, thereby enabling better management of the network through appropriate dynamic routing along the best combination of links.

Human β-Defensin 1 and β-Defensin 3 (Mouse Ortholog mBD14) Function as Full Endogenous Agonists at Select Melanocortin Receptors.

PubMed

Ericson, Mark D; Singh, Anamika; Tala, Srinivasa R; Haslach, Erica M; Dirain, Marvin L S; Schaub, Jay W; Flores, Viktor; Eick, Natalie; Lensing, Cody J; Freeman, Katie T; Smeester, Branden A; Adank, Danielle N; Wilber, Stacey L; Speth, Robert; Haskell-Luevano, Carrie

2018-04-26

β-Defensin 3 (BD3) was identified as a ligand for the melanocortin receptors (MCRs) in 2007, although the pharmacology activity of BD3 has not been clearly elucidated. Herein, it is demonstrated that human BD3 and mouse BD3 are full micromolar agonists at the MCRs. Furthermore, mouse β-defensin 1 (BD1) and human BD1 are also MCR micromolar agonists. This work identifies BD1 as an endogenous MCR ligand and clarifies the controversial role of BD3 as a micromolar agonist.

Signal intensity on fluid-attenuated inversion recovery images of condylar marrow changes correspond with slight pain in patients with temporomandibular joint disorders.

PubMed

Kodama, Sayaka; Otonari-Yamamoto, Mika; Sano, Tsukasa; Sakamoto, Junichirou; Imoto, Kenichi; Wakoh, Mamoru

2014-01-01

Edema and necrosis of the temporomandibular joint (TMJ) have been described in terms of bone marrow signal abnormalities in magnetic resonance imaging (MRI). However, painful joints often show no such signaling abnormalities, making the diagnosis of TMJ disorders difficult in the clinical setting. An association has been suggested between TMJ bone marrow change and TMJ pain, but even when such change results in slight pain, it may be too slight to be visually apparent on MR images. We hypothesized that fluid-attenuated inversion recovery (FLAIR) can be used to detect such minimal changes. The purpose of this study was to determine whether there is an association between signal intensity on FLAIR images and pain in the TMJ. The study included 85 TMJs in 45 patients referred to our department for MRI. The signal intensity on FLAIR images was measured. Pain was evaluated based on the visual analog scale. An unpaired t test and Pearson's product-moment correlation coefficient were used for the statistical analysis. A p value of <0.05 was considered statistically significant. Signal intensity on the FLAIR images was significantly higher in painful than in nonpainful TMJs, although a significant correlation was not observed between the signal intensity and the pain score. The results of this study suggest an association between abnormalities in the marrow of the mandibular condyle and pain. They also indicate that FLAIR imaging is a useful tool in the clinical diagnosis of painful TMJs.

Liraglutide attenuates the osteoblastic differentiation of MC3T3-E1 cells by modulating AMPK/mTOR signaling

PubMed Central

Hu, Xiong-Ke; Yin, Xin-Hua; Zhang, Hong-Qi; Guo, Chao-Feng; Tang, Ming-Xing

2016-01-01

Liraglutide, a synthetic analogue of glucagon-like peptide-1, is utilized in the treatment of type 2 diabetes and obesity. Liraglutide has been previously demonstrated to prevent osteoblastic differentiation of human vascular smooth muscle cells, resulting in the slowing of arterial calcification, however, its effect on bone formation remains unclear. The present study investigated the effect of liraglutide on osteoblastic differentiation using Alizarin Red S staining, and examined the molecular mechanisms underlying the regulatory effect by western blot analysis. The present study demonstrated that protein expression levels of phosphorylated adenosine monophosphate-activated protein kinase (p-AMPK) were downregulated in MC3T3-E1 cells during osteoblastic differentiation in commercial osteogenic differentiation medium, whereas protein expression levels of transforming growth factor-β (TGF-β) and phosphorylated mammalian target of rapamycin (p-mTOR) increased. Liraglutide was subsequently demonstrated to dose-dependently attenuate the osteoblastic differentiation of MC3T3-E1 cells, to upregulate p-AMPK, and downregulate p-mTOR and TGF-β protein expression levels. Treatment with an AMPK-specific inhibitor, Compound C, eradicated the effect of liraglutide on osteoblastic differentiation, and p-mTOR and TGF-β downregulation. An mTOR activator, MHY1485, also abolished the inhibitory effect of liraglutide on osteoblastic differentiation, and resulted in p-mTOR and TGF-β downregulation, but did not attenuate the liraglutide-induced increase in p-AMPK protein expression levels. The results of the present study demonstrate that liraglutide attenuates osteoblastic differentiation of MC3T3-E1 cells via modulation of AMPK/mTOR signaling. The present study revealed a novel function of liraglutide, which contributes to the understanding of its pharmacological and physiological effects in clinical settings. PMID:27600753

Association of melanocortin-4 receptor gene polymorphisms with obesity-related parameters in Malaysian Malays.

PubMed

Apalasamy, Yamunah Devi; Ming, Moy Foong; Rampal, Sanjay; Bulgiba, Awang; Mohamed, Zahurin

2013-01-01

Melanocortin-4 receptor (MC4R) is an important regulator of body weight and energy intake. Genetic polymorphisms of the MC4R gene have been found to be linked to obesity in many recent studies across the globe. This study aimed to examine the effects of MC4R polymorphisms on obesity parameters, Linkage disequilibrium (LD) pattern and haplotypes in Malaysian Malays. The study subjects were 652 Malaysian Malays. Genomic DNA was extracted from buccal swabs. Genotyping was performed using Sequenom MassARRAY® iPLEX platform. Anthropometric and blood lipid profiles were measured. MC4R rs571312 SNP was associated with logBMI (p = 0.008) and systolic blood pressure (p = 0.005), while MC4R rs2229616 SNP was associated with total cholesterol (TC) levels (p = 0.016). The MC4R rs7227255 SNP did not show any association with obesity parameters. The strength of LD of the MC4R gene region is low and the haplotypes were not associated with obesity in Malaysian Malays.

MC1R and cAMP signaling inhibit cdc25B activity and delay cell cycle progression in melanoma cells

PubMed Central

Lyons, Jesse; Bastian, Boris C.; McCormick, Frank

2013-01-01

The melanocortin 1 receptor (MC1R) mediates the tanning response through induction of cAMP and downstream pigmentary enzymes. Diminished function alleles of MC1R are associated with decreased tanning and increased melanoma risk, which has been attributed to increased rates of mutation. We have found that MC1R or cAMP signaling also directly decreases proliferation in melanoma cell lines. MC1R overexpression, treatment with the MC1R ligand, or treatment with small-molecule activators of cAMP signaling causes delayed progression from G2 into mitosis. This delay is caused by phosphorylation and inhibition of cdc25B, a cyclin dependent kinase 1-activating phosphatase, and is rescued by expression of a cdc25B mutant that cannot be phosphorylated at the serine 323 residue. These results show that MC1R and cAMP signaling can directly inhibit melanoma growth through regulation of the G2/M checkpoint. PMID:23908401

Allelic Variants of Melanocortin 3 Receptor Gene (MC3R) and Weight Loss in Obesity: A Randomised Trial of Hypo-Energetic High- versus Low-Fat Diets

PubMed Central

Santos, José L.; De la Cruz, Rolando; Holst, Claus; Grau, Katrine; Naranjo, Carolina; Maiz, Alberto; Astrup, Arne; Saris, Wim H. M.; MacDonald, Ian; Oppert, Jean-Michel; Hansen, Torben; Pedersen, Oluf; Sorensen, Thorkild I. A.; Martinez, J. Alfredo

2011-01-01

Introduction The melanocortin system plays an important role in energy homeostasis. Mice genetically deficient in the melanocortin-3 receptor gene have a normal body weight with increased body fat, mild hypophagia compared to wild-type mice. In humans, Thr6Lys and Val81Ile variants of the melanocortin-3 receptor gene (MC3R) have been associated with childhood obesity, higher BMI Z-score and elevated body fat percentage compared to non-carriers. The aim of this study is to assess the association in adults between allelic variants of MC3R with weight loss induced by energy-restricted diets. Subjects and Methods This research is based on the NUGENOB study, a trial conducted to assess weight loss during a 10-week dietary intervention involving two different hypo-energetic (high-fat and low-fat) diets. A total of 760 obese patients were genotyped for 10 single nucleotide polymorphisms covering the single exon of MC3R gene and its flanking regions, including the missense variants Thr6Lys and Val81Ile. Linear mixed models and haplotype-based analysis were carried out to assess the potential association between genetic polymorphisms and differential weight loss, fat mass loss, waist change and resting energy expenditure changes. Results No differences in drop-out rate were found by MC3R genotypes. The rs6014646 polymorphism was significantly associated with weight loss using co-dominant (p = 0.04) and dominant models (p = 0.03). These p-values were not statistically significant after strict control for multiple testing. Haplotype-based multivariate analysis using permutations showed that rs3827103–rs1543873 (p = 0.06), rs6014646–rs6024730 (p = 0.05) and rs3746619–rs3827103 (p = 0.10) displayed near-statistical significant results in relation to weight loss. No other significant associations or gene*diet interactions were detected for weight loss, fat mass loss, waist change and resting energy expenditure changes. Conclusion The study provided

Chondroprotective and anti-inflammatory role of melanocortin peptides in TNF-α activated human C-20/A4 chondrocytes

PubMed Central

Kaneva, Magdalena K; Kerrigan, Mark JP; Grieco, Paolo; Curley, G Paul; Locke, Ian C; Getting, Stephen J

2012-01-01

BACKGROUND AND PURPOSE Melanocortin MC1 and MC3 receptors, mediate the anti-inflammatory effects of melanocortin peptides. Targeting these receptors could therefore lead to development of novel anti-inflammatory therapeutic agents. We investigated the expression of MC1 and MC3 receptors on chondrocytes and the role of α-melanocyte-stimulating hormone (α-MSH) and the selective MC3 receptor agonist, [DTRP8]-γ-MSH, in modulating production of inflammatory cytokines, tissue-destructive proteins and induction of apoptotic pathway(s) in the human chondrocytic C-20/A4 cells. EXPERIMENTAL APPROACH Effects of α-MSH, [DTRP8]-γ-MSH alone or in the presence of the MC3/4 receptor antagonist, SHU9119, on TNF-α induced release of pro-inflammatory cytokines, MMPs, apoptotic pathway(s) and cell death in C-20/A4 chondrocytes were investigated, along with their effect on the release of the anti-inflammatory cytokine IL-10. KEY RESULTS C-20/A4 chondrocytes expressed functionally active MC1,3 receptors. α-MSH and [DTRP8]-γ-MSH treatment, for 30 min before TNF-α stimulation, provided a time-and-bell-shaped concentration-dependent decrease in pro-inflammatory cytokines (IL-1β, IL-6 and IL-8) release and increased release of the chondroprotective and anti-inflammatory cytokine, IL-10, whilst decreasing expression of MMP1, MMP3, MMP13 genes.α-MSH and [DTRP8]-γ-MSH treatment also inhibited TNF-α-induced caspase-3/7 activation and chondrocyte death. The effects of [DTRP8]-γ-MSH, but not α-MSH, were abolished by the MC3/4 receptor antagonist, SHU9119. CONCLUSION AND IMPLICATIONS Activation of MC1/MC3 receptors in C-20/A4 chondrocytes down-regulated production of pro-inflammatory cytokines and cartilage-destroying proteinases, inhibited initiation of apoptotic pathways and promoted release of chondroprotective and anti-inflammatory cytokines. Developing small molecule agonists to MC1/MC3 receptors could be a viable approach for developing chondroprotective and anti

Gender-specific roles for the melanocortin-3 receptor in the regulation of the mesolimbic dopamine system in mice.

PubMed

Lippert, Rachel N; Ellacott, Kate L J; Cone, Roger D

2014-05-01

The melanocortin-3 receptor (MC3R) and MC4R are known to play critical roles in energy homeostasis. However, the physiological functions of the MC3R remain poorly understood. Earlier reports indicated that the ventral tegmental area (VTA) is one of the highest sites of MC3R expression, and we sought to determine the function of the receptor in this brain region. A MC3R-green-fluorescent protein transgenic mouse and a MC3R knockout mouse strain were used to characterize the neurochemical identity of the MC3R neurons in the VTA and to determine the effects of global MC3R deletion on VTA dopamine (DA) homeostasis. We demonstrate that the MC3R, but not MC4R, is expressed in up to a third of dopaminergic neurons of the VTA. Global deletion of the MC3R increases total dopamine by 42% in the VTA and decreases sucrose intake and preference in female but not male mice. Ovariectomy restores dopamine levels to normal, but aberrant decreased VTA dopamine levels are also observed in prepubertal female mice. Because arcuate Agouti-related peptide/neuropeptide Y neurons are known to innervate and regulate VTA signaling, the MC3R in dopaminergic neurons provides a specific input for communication of nutritional state within the mesolimbic dopamine system. Data provided here suggest that this input may be highly sexually dimorphic, functioning as a specific circuit regulating effects of estrogen on VTA dopamine levels and on sucrose preference. Overall, this data support a sexually dimorphic function of MC3R in regulation of the mesolimbic dopaminergic system and reward.

The Self in Action Effects: Selective Attenuation of Self-Generated Sounds

ERIC Educational Resources Information Center

Weiss, Carmen; Herwig, Arvid; Schutz-Bosbach, Simone

2011-01-01

The immediate experience of self-agency, that is, the experience of generating and controlling our actions, is thought to be a key aspect of selfhood. It has been suggested that this experience is intimately linked to internal motor signals associated with the ongoing actions. These signals should lead to an attenuation of the sensory consequences…

Association between polymorphism in the melanocortin 1 receptor gene and E locus plumage color phenotype.

PubMed

Dávila, S G; Gil, M G; Resino-Talaván, P; Campo, J L

2014-05-01

The purpose of this study was to investigate the effect of the melanocortin 1 receptor (MC1R) gene on plumage color in chickens. The gene was sequenced in 77 males and 77 females from 13 Spanish breeds, carrying 6 different alleles in the E locus (E*E, E*R, E*WH, E*N, E*B, E*BC), a recessive wheaten (yellowish-white) tester line (E*Y), and a White Leghorn population (heterozygous E*E). A total of 11 significant SNP were detected. Nine of them were nonsynonymous (T212C, G274A, G376A, T398AC, G409A, A427G, C637T, A644C, and G646A, corresponding to amino acid changes Met72Thr, Glu92Lys, Val126Ile, Leu133GlnPro, Ala137Thr, Thr143Ala, Arg213Cys, His215Pro, and Val216Ile), and 2 were synonymous (C69T and C834T). With respect to the significant SNP, 7 had an allelic frequency of 0.5 or greater for some of the alleles at the E locus. These results indicated a significant correlation between MC1R polymorphism and the presence of different alleles at the E locus. All the populations carrying the E*E or E*R alleles, except the Birchen Leonesa, had the G274A polymorphism. Eleven haplotypes were made with 7 of the significant SNP. The distribution of these haplotypes in the different alleles of the E locus showed that each haplotype was predominantly associated to one allele. The number of haplotypes was greatest for the Black Menorca, Birchen Leonesa, and Blue Andaluza breeds, whereas the Quail Castellana and Red-barred Vasca breeds were monomorphic. Our results suggested that the Glu92Lys mutation may be responsible of the activation of the receptor for eumelanin production, being necessary but not sufficient to express the extended black phenotype. They also suggested that the Arg213Cys mutation may be the cause of the loss or the decrease of function of the receptor to produce eumelanin, and the Ala137Thr mutation may be a candidate to attenuate the Glu92Lys effect. The observed co-segregation of the E locus alleles and polymorphisms in MC1R confirms that the E locus is

Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma

PubMed Central

Balakrishnan, Ilango; Harris, Peter; Birks, Diane K; Griesinger, Andrea; Amani, Vladimir; Cristiano, Brian; Remke, Marc; Taylor, Michael D; Handler, Michael; Foreman, Nicholas K; Vibhakar, Rajeev

2014-01-01

Medulloblastoma is a pediatric brain tumor with a variable prognosis due to clinical and genomic heterogeneity. Among the 4 major genomic sub-groups, patients with MYC amplified tumors have a particularly poor prognosis despite therapy with surgery, radiation and chemotherapy. Targeting the MYC oncogene has traditionally been problematic. Here we report that MYC driven medulloblastoma can be targeted by inhibition of the bromodomain protein BRD4. We show that bromodomain inhibition with JQ1 restricts c-MYC driven transcriptional programs in medulloblastoma, suppresses medulloblastoma cell growth and induces a cell cycle arrest. Importantly JQ1 suppresses stem cell associated signaling in medulloblastoma cells and inhibits medulloblastoma tumor cell self-renewal. Additionally JQ1 also promotes senescence in medulloblastoma cells by activating cell cycle kinase inhibitors and inhibiting activity of E2F1. Furthermore BRD4 inhibition displayed an anti-proliferative, pro-senescence effect in a medulloblastoma model in vivo. In clinical samples we found that transcriptional programs suppressed by JQ1 are associated with adverse risk in medulloblastoma patients. Our work indicates that BRD4 inhibition attenuates stem cell signaling in MYC driven medulloblastoma and demonstrates the feasibility BET domain inhibition as a therapeutic approach in vivo. PMID:24796395

[6]-Gingerol isolated from ginger attenuates sodium arsenite induced oxidative stress and plays a corrective role in improving insulin signaling in mice.

PubMed

Chakraborty, Debrup; Mukherjee, Avinaba; Sikdar, Sourav; Paul, Avijit; Ghosh, Samrat; Khuda-Bukhsh, Anisur Rahman

2012-04-05

Arsenic toxicity induces type 2 diabetes via stress mediated pathway. In this study, we attempt to reveal how sodium arsenite (iAs) could induce stress mediated impaired insulin signaling in mice and if an isolated active fraction of ginger, [6]-gingerol could attenuate the iAs intoxicated hyperglycemic condition of mice and bring about improvement in their impaired insulin signaling. [6]-Gingerol treatment reduced elevated blood glucose level and oxidative stress by enhancing activity of super oxide dismutase (SOD), catalase, glutathione peroxidase (GPx) and GSH. [6]-Gingerol also helped in increasing plasma insulin level, brought down after iAs exposure. iAs treatment to primary cell culture of β-cells and hepatocytes in vitro produced cyto-degenerative effect and accumulated reactive oxygen species (ROS) in pancreatic β-cells and hepatocytes of mice. [6]-Gingerol appeared to inhibit/intervene iAs induced cyto-degeneration of pancreatic β-cells and hepatocytes, helped in scavenging the free radicals. The over-expression of TNFα and IL6 in iAs intoxicated mice was down-regulated by [6]-gingerol treatment. iAs intoxication reduced expression levels of GLUT4, IRS-1, IRS-2, PI3K, AKT, PPARγ signaling molecules; [6]-gingerol mediated its action through enhancing the expressions of these signaling molecules, both at protein and mRNA levels. Thus, our results suggest that [6]-gingerol possesses an anti-hyperglycemic property and can improve impaired insulin signaling in arsenic intoxicated mice. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Manipulating central nervous mechanisms of food intake and body weight regulation by intranasal administration of neuropeptides in man.

PubMed

Hallschmid, Manfred; Benedict, Christian; Born, Jan; Fehm, Horst-Lorenz; Kern, Werner

2004-10-30

Maintaining a stable body weight set-point is assumed to rely on a homeostatic central nervous system (CNS) regulation of body fat with the particular involvement of hypothalamic pathways. The peripheral adiposity signals insulin and leptin convey information on the amount of energy stored as body fat to the arcuate nucleus of the hypothalamus, where anabolic/orexigenic and catabolic/anorexigenic pathways interact to regulate food intake and energy expenditure. One of the most prominent orexigenic messengers is neuropeptide Y (NPY), whereas melanocortins, including alpha-melanocyte-stimulating hormone (alpha-MSH), are essential for inducing anorexigenic effects. The melanocortin receptor 4 (MC4-R) plays the most important role in mediating catabolic effects of alpha-MSH. In this review, we present a series of own studies on NPY, insulin and MSH/ACTH4-10, an MC4-R agonist. The studies were all based on the intranasal route of administration which enables a direct access of the peptides to hypothalamic functions. NPY acutely attenuated electrocortical signs of meal-related satiety. Prolonged intranasal administration of insulin as well as of MSH induced weight loss in healthy human subjects. However, overweight subjects did not lose body fat after MSH administration. The results corroborate in humans the significance of all three messengers for the central nervous regulation of adiposity and might contribute to the future development of medical strategies against body-weight-related disorders.

Association of Melanocortin (MC4R) and Myostatin (MSTN) genes with carcass quality in rabbit.

PubMed

El-Sabrout, Karim; Aggag, Sarah

2018-03-01

The aim of this study was to investigate the association of Melanocortin (MC4R) and Myostatin (MSTN) with the carcass quality of V-line and Alexandria line rabbits. MC4R and MSTN were screened by single-strand conformational polymorphism analysis (SSCP) then DNA was sequenced. The results identified four novel SNPs using the four studied primers of the MC4R and MSTN genes. The genotype (BB) has significant higher body weight (BW), carcass weight (CW) and dressing percentage (DP) than AA rabbits. There were no significant differences within the two lines in the carcass color (light pink) and carcass fat (CF). GLM analysis for the effect of genotypes on carcass traits demonstrated that the genotype (BB) was significantly associated with high carcass weight (CW) and dressing percentage (DP). The detected mutations and the analysis of carcass quality means revealed a significant association between MSTN and MC4R polymorphisms with some carcass traits that affect meat quality of rabbits. Copyright © 2017 Elsevier Ltd. All rights reserved.

Tanreqing Injection Attenuates Lipopolysaccharide-Induced Airway Inflammation through MAPK/NF-κB Signaling Pathways in Rats Model

PubMed Central

Liu, Wei; Jiang, Hong-li; Cai, Lin-li; Yan, Min; Dong, Shou-jin; Mao, Bing

2016-01-01

Background. Tanreqing injection (TRQ) is a commonly used herbal patent medicine for treating inflammatory airway diseases in view of its outstanding anti-inflammatory properties. In this study, we explored the signaling pathways involved in contributions of TRQ to LPS-induced airway inflammation in rats. Methods/Design. Adult male Sprague Dawley (SD) rats randomly divided into different groups received intratracheal instillation of LPS and/or intraperitoneal injection of TRQ. Bronchoalveolar Lavage Fluid (BALF) and lung samples were collected at 24 h, 48 h, and 96 h after TRQ administration. Protein and mRNA levels of tumor necrosis factor- (TNF-) α, Interleukin- (IL-) 1β, IL-6, and IL-8 in BALF and lung homogenate were observed by ELISA and real-time PCR, respectively. Lung sections were stained for p38 MAPK and NF-κB detection by immunohistochemistry. Phospho-p38 MAPK, phosphor-extracellular signal-regulated kinases ERK1/2, phospho-SAPK/JNK, phospho-NF-κB p65, phospho-IKKα/β, and phospho-IκB-α were measured by western blot analysis. Results. The results showed that TRQ significantly counteracted LPS-stimulated release of TNF-α, IL-1β, IL-6, and IL-8, attenuated cells influx in BALF, mitigated mucus hypersecretion, suppressed phosphorylation of NF-κB p65, IκB-α, ΙKKα/β, ERK1/2, JNK, and p38 MAPK, and inhibited p38 MAPK and NF-κB p65 expression in rat lungs. Conclusions. Results of the current research indicate that TRQ possesses potent exhibitory effects in LPS-induced airway inflammation by, at least partially, suppressing the MAPKs and NF-κB signaling pathways, in a general dose-dependent manner. PMID:27366191

Molecular Therapy of Melanocortin-4-Receptor Obesity by an Autoregulatory BDNF Vector.

PubMed

Siu, Jason J; Queen, Nicholas J; Liu, Xianglan; Huang, Wei; McMurphy, Travis; Cao, Lei

2017-12-15

Mutations in the melanocortin-4-receptor ( MC4R ) comprise the most common monogenic form of severe early-onset obesity, and conventional treatments are either ineffective long-term or contraindicated. Immediately downstream of MC4R-in the pathway for regulating energy balance-is brain-derived neurotrophic factor (BDNF). Our previous studies show that adeno-associated virus (AAV)-mediated hypothalamic BDNF gene transfer alleviates obesity and diabetes in both diet-induced and genetic models. To facilitate clinical translation, we developed a built-in autoregulatory system to control therapeutic gene expression mimicking the body's natural feedback systems. This autoregulatory approach leads to a sustainable plateau of body weight after substantial weight loss is achieved. Here, we examined the efficacy and safety of autoregulatory BDNF gene therapy in Mc4r heterozygous mice, which best resemble MC4R obese patients. Mc4r heterozygous mice were treated with either autoregulatory BDNF vector or YFP control and monitored for 30 weeks. BDNF gene therapy prevented the development of obesity and metabolic syndromes characterized by decreasing body weight and adiposity, suppressing food intake, alleviating hyperleptinemia and hyperinsulinemia, improving glucose and insulin tolerance, and increasing energy expenditure, without adverse cardiovascular function or behavioral disturbances. These safety and efficacy data provide preclinical evidence that BDNF gene therapy is a compelling treatment option for MC4R -deficient obese patients.

Houttuynia cordata attenuates lipid accumulation via activation of AMP-activated protein kinase signaling pathway in HepG2 cells.

PubMed

Kang, Hyun; Koppula, Sushruta

2014-01-01

Houttuynia cordata (H. cordata) from the family Saururaceae is a perennial herb native to Southeast Asia. It possesses a range of medicinal properties to treat several disease symptoms including allergic inflammation and anaphylaxis. In the present investigation, we provided the molecular mechanisms underlying the role of H. cordata extract (HCE) in the prevention of high glucose-induced lipid accumulation in human HepG2 hepatocytes. HepG2 cells were pre-treated with various concentrations of HCE (0, 10, 20, 40, and 80 μg/mL) and treated with serum-free medium with normal glucose (5 mM) for 1 h, followed by exposure to high glucose (25 mM D-glucose) for 24 h. HCE significantly and dose-dependently attenuated lipid accumulation in human HepG2 hepatocytes when exposed to high glucose (25 mM D-glucose) (p < 0.05, p < 0.01 and p < 0.001 at 20, 40, and 80 μg/mL concentrations, respectively). Further, HCE attenuated the expression of fatty acid synthase (FAS), sterol regulatory element-binding protein-1 and glycerol 3-phosphate acyltransferases (GPATs). The adenosine monophosphate-activated protein kinase (AMPK) was also activated by HCE treatment when exposed to high glucose (25 mM D-glucose) in human HepG2 hepatocytes. This study suggests the hypolipidemic effects of HCE by the inhibition of lipid biosynthesis mediated through AMPK signaling, which may play an active role and can be developed as an anti-obesity agent.

Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death

PubMed Central

Mukhopadhyay, Partha; Rajesh, Mohanraj; Horváth, Béla; Bátkai, Sándor; Park, Ogyi; Tanashian, Galin; Gao, Rachel Y; Patel, Vivek; Wink, David A.; Liaudet, Lucas; Haskó, György; Mechoulam, Raphael; Pacher, Pál

2011-01-01

Ischemia-reperfusion (I/R) is a pivotal mechanism of liver damage following liver transplantation or hepatic surgery. We have investigated the effects of cannabidiol(CBD), the non-psychotropic constituent of marijuana, in a mouse model of hepatic I/R injury. I/R triggered time-dependent increases/changes in markers of liver injury (serum transaminases), hepatic oxidative/nitrative stress (4-hydroxy-2-nonenal, nitrotyrosine content/staining, gp91phox and inducible nitric oxide synthase mRNA), mitochondrial dysfunction (decreased complex I activity), inflammation (tumor necrosis factor alpha (TNF-α), cyclooxygenase 2, macrophage inflammatory protein-1α/2, inter-cellular adhesion molecule 1 mRNA levels, tissue neutrophil infiltration, nuclear factor kappa B (NF-KB) activation), stress signaling (p38MAPK and JNK) and cell death (DNA fragmentation, PARP activity, and TUNEL). CBD significantly reduced the extent of liver inflammation, oxidative/nitrative stress and cell death, and also attenuated the bacterial endotoxin-triggered NF-KB activation and TNF-α production in isolated Kupffer cells, likewise the adhesion molecules expression in primary human liver sinusoidal endothelial cells stimulated with TNF-α, and attachment of human neutrophils to the activated endothelium. These protective effects were preserved in CB2 knockout mice and were not prevented by CB1/2 antagonists in vitro. Thus, CBD may represent a novel, protective strategy against I/R injury by attenuating key inflammatory pathways and oxidative/nitrative tissue injury, independent from classical CB1/2 receptors. PMID:21362471

Dapper1 attenuates hepatic gluconeogenesis and lipogenesis by activating PI3K/Akt signaling.

PubMed

Kuang, Jian-Ren; Zhang, Zhi-Hui; Leng, Wei-Ling; Lei, Xiao-Tian; Liang, Zi-Wen

2017-05-15

Studies have shown that hepatic insulin resistance, a disorder of glucose and lipid metabolism, plays a vital role in type 2 diabetes (T2D). To clarify the function of Dapper1 in glucose and lipid metabolism in the liver, we investigated the relationships between Dapper1 and adenosine triphosphate (ATP)- and Ca 2+ -mediated activation of PI3K/Akt. We observed a reduction in hepatic Dapper1 in db/db (mice that are homozygous for a spontaneous diabetes mutation) and HFD-induced diabetic mice with T2D. Hepatic overexpression of Dapper1 improved hyperglycemia, insulin resistance, and fatty liver. It also increased Akt (pAkt) signaling and repressed both gluconeogenesis and lipogenesis. Conversely, Ad-shDapper1-induced knockdown of hepatic Dapper1 promoted gluconeogenesis and lipogenesis. Furthermore, Dapper1 activated PI3K p110α/Akt in an insulin-independent manner by inducing ATP production and secretion in vitro. Blockade of P2 ATP receptors, the downstream phospholipase C (PLC), or the inositol triphosphate receptor (IP3R all reduced the Dapper1-induced increase in cytosolic free calcium and Dapper1-mediated PI3K/Akt activation, as did removal of calcium in the medium. In conclusion, Dapper1 attenuates hepatic gluconeogenesis and lipogenesis in T2D. Copyright © 2017 Elsevier B.V. All rights reserved.

Omega-3 free fatty acids attenuate insulin-promoted breast cancer cell proliferation.

PubMed

Guo, Yang; Zhu, Sheng-Long; Wu, Yi-Kuan; He, Zhao; Chen, Yong-Quan

2017-06-01

High insulin levels in obese people are considered as a risk factor to induce breast carcinogenesis. And consumption of fish oils which mainly contain omega-3 fatty acids is associated with a reduced risk of breast cancer. However, whether omega-3 free fatty acids (FFAs) modulate insulin signaling pathway to prevent breast cancer is poorly understood. The current study tested the hypothesis that omega-3 FFAs attenuate insulin-induced breast cancer cell proliferation and regulate insulin signaling pathway. We show here that omega-3 FFAs attenuate MCF-7 cell proliferation and Akt and Erk1/2 phosphorylation levels stimulated by insulin. Knockdown Shp2 by siRNA resulted in significantly elevated omega-3 FFAs-activated Akt phosphorylation but failed to change insulin-stimulated Akt and Erk1/2 phosphorylation. And viable cell number was not affected by either downregulation of Shp2 expression or Erk1/2 inhibitor U0126 treatment. These observations indicated that omega-3 FFAs attenuate insulin-promoted breast cancer cell proliferation and insulin-activated Akt phosphorylation. Copyright © 2017 Elsevier Inc. All rights reserved.

Development and in vivo Quantitative Magnetic Resonance Imaging of Polymer Micelles Targeted to the Melanocortin 1 Receptor

PubMed Central

Barkey, Natalie M.; Preihs, Christian; Cornnell, Heather H.; Martinez, Gary; Carie, Adam; Vagner, Josef; Xu, Liping; Lloyd, Mark C.; Lynch, Vincent M.; Hruby, Victor J.; Sessler, Jonathan L.; Sill, Kevin N.; Gillies, Robert J.; Morse, David L.

2013-01-01

Recent emphasis has focused on the development of rationally-designed polymer-based micelle carriers for drug delivery. The current work tests the hypothesis that target specificity can be enhanced by micelles with cancer-specific ligands. In particular, we describe the synthesis and characterization of a new gadolinium texaphyrin (Gd-Tx) complex encapsulated in an IVECT™ micellar system, stabilized through Fe(III) crosslinking and targeted with multiple copies of a specific ligand for the melanocortin 1 receptor (MC1R), which has been evaluated as a cell-surface marker for melanoma. On the basis of comparative MRI experiments, we have been able to demonstrate that these Gd-Tx micelles are able to target MC1R-expressing xenograft tumors in vitro and in vivo more effectively than various control systems, including untargeted and/or uncrosslinked Gd-Tx micelles. Taken in concert, the findings reported herein support the conclusion that appropriately designed micelles are able to deliver contrast agent payloads to tumors expressing the MC1R. PMID:23863078

AC signal characterization for optimization of a CMOS single-electron pump

NASA Astrophysics Data System (ADS)

Murray, Roy; Perron, Justin K.; Stewart, M. D., Jr.; Zimmerman, Neil M.

2018-02-01

Pumping single electrons at a set rate is being widely pursued as an electrical current standard. Semiconductor charge pumps have been pursued in a variety of modes, including single gate ratchet, a variety of 2-gate ratchet pumps, and 2-gate turnstiles. Whether pumping with one or two AC signals, lower error rates can result from better knowledge of the properties of the AC signal at the device. In this work, we operated a CMOS single-electron pump with a 2-gate ratchet style measurement and used the results to characterize and optimize our two AC signals. Fitting this data at various frequencies revealed both a difference in signal path length and attenuation between our two AC lines. Using this data, we corrected for the difference in signal path length and attenuation by applying an offset in both the phase and the amplitude at the signal generator. Operating the device as a turnstile while using the optimized parameters determined from the 2-gate ratchet measurement led to much flatter, more robust charge pumping plateaus. This method was useful in tuning our device up for optimal charge pumping, and may prove useful to the semiconductor quantum dot community to determine signal attenuation and path differences at the device.

Okanin, effective constituent of the flower tea Coreopsis tinctoria, attenuates LPS-induced microglial activation through inhibition of the TLR4/NF-κB signaling pathways

NASA Astrophysics Data System (ADS)

Hou, Yue; Li, Guoxun; Wang, Jian; Pan, Yingni; Jiao, Kun; Du, Juan; Chen, Ru; Wang, Bing; Li, Ning

2017-04-01

The EtOAc extract of Coreopsis tinctoria Nutt. significantly inhibited LPS-induced nitric oxide (NO) production, as judged by the Griess reaction, and attenuated the LPS-induced elevation in iNOS, COX-2, IL-1β, IL-6 and TNF-α mRNA levels, as determined by quantitative real-time PCR, when incubated with BV-2 microglial cells. Immunohistochemical results showed that the EtOAc extract significantly decreased the number of Iba-1-positive cells in the hippocampal region of LPS-treated mouse brains. The major effective constituent of the EtOAc extract, okanin, was further investigated. Okanin significantly suppressed LPS-induced iNOS expression and also inhibited IL-6 and TNF-α production and mRNA expression in LPS-stimulated BV-2 cells. Western blot analysis indicated that okanin suppressed LPS-induced activation of the NF-κB signaling pathway by inhibiting the phosphorylation of IκBα and decreasing the level of nuclear NF-κB p65 after LPS treatment. Immunofluorescence staining results showed that okanin inhibited the translocation of the NF-κB p65 subunit from the cytosol to the nucleus. Moreover, okanin significantly inhibited LPS-induced TLR4 expression in BV-2 cells. In summary, okanin attenuates LPS-induced activation of microglia. This effect may be associated with its capacity to inhibit the TLR4/NF-κB signaling pathways. These results suggest that okanin may have potential as a nutritional preventive strategy for neurodegenerative disorders.

Agrp neurons mediate Sirt1’s action on the melanocortin system and energy balance: roles for Sirt1 in neuronal firing and synaptic plasticity

PubMed Central

Dietrich, Marcelo O.; Antunes, Catiele; Geliang, Gan; Liu, Zhong-Wu; Borok, Erzsebet; Nie, Yongzhan; Xu, Allison W.; Souza, Diogo O.; Gao, Qian; Diano, Sabrina; Gao, Xiao-Bing; Horvath, Tamas L.

2010-01-01

Sirt1 has been associated with various effects of calorie restriction, including an increase in lifespan. Here we show in mice that a central regulatory component in energy metabolism, the hypothalamic melanocortin system, is affected by Sirt1, which promotes the activity and connectivity of this system resulting in negative energy balance. In adult mice, the pharmacological inhibition of brain Sirt1 activity decreased the inhibitory tone on the anorexigenic POMC neurons, as measured by the number of synaptic inputs to these neurons. When a Sirt1 inhibitor (EX-527) was injected either peripherally (i.p., 10mg/kg) or directly into the brain (i.c.v., 1.5 nmol/mouse), it decreased both food intake during the dark cycle and ghrelin-induced food intake. This effect on feeding is mediated by upstream melanocortin receptors, because the MC4R antagonist, SHU9119, reversed Sirt1’s effect on food intake. This action of Sirt1 required an appropriate shift in the mitochondrial redox state: in the absence of such an adaptation enabled by the mitochondrial protein, UCP2, Sirt1-induced cellular and behavioral responses were impaired. The selective knockout of Sirt1 in hypothalamic Agrp neurons through the use of Cre-Lox technology decreased electric responses of Agrp neurons to ghrelin and decreased food intake, leading to decreased lean mass, fat mass and body weight. The present data indicate that Sirt1 has a central mode of action by acting on the NPY/Agrp neurons to affect body metabolism. PMID:20810901

The Effects of Aronia melanocarpa 'Viking' Extracts in Attenuating RANKL-Induced Osteoclastic Differentiation by Inhibiting ROS Generation and c-FOS/NFATc1 Signaling.

PubMed

Ghosh, Mithun; Kim, In Sook; Lee, Young Min; Hong, Seong Min; Lee, Taek Hwan; Lim, Ji Hong; Debnath, Trishna; Lim, Beong Ou

2018-03-08

This study aimed to determine the anti-osteoclastogenic effects of extracts from Aronia melanocarpa 'Viking' (AM) and identify the underlying mechanisms in vitro. Reactive oxygen species (ROS) are signal mediators in osteoclast differentiation. AM extracts inhibited ROS production in RAW 264.7 cells in a dose-dependent manner and exhibited strong radical scavenging activity. The extracts also attenuated the number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated osteoclasts. To attain molecular insights, the effect of the extracts on the signaling pathways induced by receptor activator of nuclear factor kappa B ligand (RANKL) were also investigated. RANKL triggers many transcription factors through the activation of mitogen-activated protein kinase (MAPK) and ROS, leading to the induction of osteoclast-specific genes. The extracts significantly suppressed RANKL-induced activation of MAPKs, such as extracellular signal-regulated kinase (ERK), c-Jun- N -terminal kinase (JNK) and p38 and consequently led to the downregulation of c-Fos and nuclear factor of activated T cells 1 (NFATc1) protein expression which ultimately suppress the activation of the osteoclast-specific genes, cathepsin K, TRAP, calcitonin receptor and integrin β₃. In conclusion, our findings suggest that AM extracts inhibited RANKL-induced osteoclast differentiation by downregulating ROS generation and inactivating JNK/ERK/p38, nuclear factor kappa B (NF-κB)-mediated c-Fos and NFATc1 signaling pathway.

Sulforaphane attenuates microglia-mediated neuronal necroptosis through down-regulation of MAPK/NF-κB signaling pathways in LPS-activated BV-2 microglia.

PubMed

Qin, Sisi; Yang, Canhong; Huang, Weihua; Du, Shuhua; Mai, Hantao; Xiao, Jijie; Lü, Tianming

2018-01-31

Sulforaphane (SFN), a natural dietary isothiocyanate in cruciferous vegetables such as broccoli and cabbage, has very strong anti-inflammatory activity. Activation of microglia leads to overexpression of a series of pro-inflammatory mediators, which play a vital role in neuronal damage. SFN may have neuroprotective effects in different neurodegenerative diseases related to inflammation. However, the mechanisms underlying SFN's protection of neurons against microglia-mediated neuronal damage are not fully understood. Here, we investigated how SFN attenuated microglia-mediated neuronal damage. Our results showed that SFN could not directly protect the viability of neurons following pro-inflammatory mediators, but increased the viability of BV-2 microglia and down-regulated the mRNA and protein levels of pro-inflammatory mediators including TNF-α, IL-1β, IL-6 and iNOS in a concentration-dependent manner in BV-2 cells. SFN also significantly blocked the phosphorylation of MAPKs (p38, JNK, and ERK1/2) and NF-κB p65, both by itself and with MAPK inhibitors (SB203580, SP 600125, and U0126) or an NF-κB inhibitor (PDTC). The expression of pro-inflammatory proteins was also blocked by SFN with or without inhibitors. Further, SFN indirectly increased the viability and maintained the morphology of neurons, and the protein expression of RIPK3 and MLKL was significantly suppressed by SFN in neuronal necroptosis through p38, JNK, and NF-κB p65 but not ERK1/2 signaling pathways. Together, our results demonstrate that SFN attenuates LPS-induced pro-inflammatory responses through down-regulation of MAPK/NF-κB signaling pathway in BV-2 microglia and thus indirectly suppresses microglia-mediated neuronal damage. Copyright © 2018 Elsevier Ltd. All rights reserved.

Vision 20/20: Magnetic resonance imaging-guided attenuation correction in PET/MRI: Challenges, solutions, and opportunities

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mehranian, Abolfazl; Arabi, Hossein; Zaidi, Habib, E-mail: habib.zaidi@hcuge.ch

Attenuation correction is an essential component of the long chain of data correction techniques required to achieve the full potential of quantitative positron emission tomography (PET) imaging. The development of combined PET/magnetic resonance imaging (MRI) systems mandated the widespread interest in developing novel strategies for deriving accurate attenuation maps with the aim to improve the quantitative accuracy of these emerging hybrid imaging systems. The attenuation map in PET/MRI should ideally be derived from anatomical MR images; however, MRI intensities reflect proton density and relaxation time properties of biological tissues rather than their electron density and photon attenuation properties. Therefore, inmore » contrast to PET/computed tomography, there is a lack of standardized global mapping between the intensities of MRI signal and linear attenuation coefficients at 511 keV. Moreover, in standard MRI sequences, bones and lung tissues do not produce measurable signals owing to their low proton density and short transverse relaxation times. MR images are also inevitably subject to artifacts that degrade their quality, thus compromising their applicability for the task of attenuation correction in PET/MRI. MRI-guided attenuation correction strategies can be classified in three broad categories: (i) segmentation-based approaches, (ii) atlas-registration and machine learning methods, and (iii) emission/transmission-based approaches. This paper summarizes past and current state-of-the-art developments and latest advances in PET/MRI attenuation correction. The advantages and drawbacks of each approach for addressing the challenges of MR-based attenuation correction are comprehensively described. The opportunities brought by both MRI and PET imaging modalities for deriving accurate attenuation maps and improving PET quantification will be elaborated. Future prospects and potential clinical applications of these techniques and their integration in

Vision 20/20: Magnetic resonance imaging-guided attenuation correction in PET/MRI: Challenges, solutions, and opportunities.

PubMed

Mehranian, Abolfazl; Arabi, Hossein; Zaidi, Habib

2016-03-01

Attenuation correction is an essential component of the long chain of data correction techniques required to achieve the full potential of quantitative positron emission tomography (PET) imaging. The development of combined PET/magnetic resonance imaging (MRI) systems mandated the widespread interest in developing novel strategies for deriving accurate attenuation maps with the aim to improve the quantitative accuracy of these emerging hybrid imaging systems. The attenuation map in PET/MRI should ideally be derived from anatomical MR images; however, MRI intensities reflect proton density and relaxation time properties of biological tissues rather than their electron density and photon attenuation properties. Therefore, in contrast to PET/computed tomography, there is a lack of standardized global mapping between the intensities of MRI signal and linear attenuation coefficients at 511 keV. Moreover, in standard MRI sequences, bones and lung tissues do not produce measurable signals owing to their low proton density and short transverse relaxation times. MR images are also inevitably subject to artifacts that degrade their quality, thus compromising their applicability for the task of attenuation correction in PET/MRI. MRI-guided attenuation correction strategies can be classified in three broad categories: (i) segmentation-based approaches, (ii) atlas-registration and machine learning methods, and (iii) emission/transmission-based approaches. This paper summarizes past and current state-of-the-art developments and latest advances in PET/MRI attenuation correction. The advantages and drawbacks of each approach for addressing the challenges of MR-based attenuation correction are comprehensively described. The opportunities brought by both MRI and PET imaging modalities for deriving accurate attenuation maps and improving PET quantification will be elaborated. Future prospects and potential clinical applications of these techniques and their integration in commercial

PKD signaling and pancreatitis

PubMed Central

Yuan, Jingzhen; Pandol, Stephen J.

2016-01-01

Background Acute pancreatitis is a serious medical disorder with no current therapies directed to the molecular pathogenesis of the disorder. Inflammation, inappropriate intracellular activation of digestive enzymes, and parenchymal acinar cell death by necrosis are the critical pathophysiologic processes of acute pancreatitis. Thus, it is necessary to elucidate the key molecular signals that mediate these pathobiologic processes and develop new therapeutic strategies to attenuate the appropriate signaling pathways in order to improve outcomes for this disease. A novel serine/threonine protein kinase D (PKD) family has emerged as key participants in signal transduction, and this family is increasingly being implicated in the regulation of multiple cellular functions and diseases. Methods This review summarizes recent findings of our group and others regarding the signaling pathway and the biological roles of the PKD family in pancreatic acinar cells. In particular, we highlight our studies of the functions of PKD in several key pathobiologic processes associated with acute pancreatitis in experimental models. Results Our findings reveal that PKD signaling is required for NF-κB activation/inflammation, intracellular zymogen activation, and acinar cell necrosis in rodent experimental pancreatitis. Novel small-molecule PKD inhibitors attenuate the severity of pancreatitis in both in vitro and in vivo experimental models. Further, this review emphasizes our latest advances in the therapeutic application of PKD inhibitors to experimental pancreatitis after the initiation of pancreatitis. Conclusions These novel findings suggest that PKD signaling is a necessary modulator in key initiating pathobiologic processes of pancreatitis, and that it constitutes a novel therapeutic target for treatments of this disorder. PMID:26879861

Long-term orexigenic effects of AgRP-(83---132) involve mechanisms other than melanocortin receptor blockade.

PubMed

Hagan, M M; Rushing, P A; Pritchard, L M; Schwartz, M W; Strack, A M; Van Der Ploeg, L H; Woods, S C; Seeley, R J

2000-07-01

Overexpression of agouti-related peptide (AgRP), an endogenous melanocortin (MC) 3 and 4 receptor antagonist (MC3/4-R), causes obesity. Exogenous AgRP-(83---132) increases food intake, but its duration and mode of action are unknown. We report herein that doses as low as 10 pmol can have a potent effect on food intake of rats over a 24-h period after intracerebroventricular injection. Additionally, a single third ventricular dose as low as 100 pmol in rats produces a robust increase in food intake that persists for an entire week. AgRP-(83---132) completely blocks the anorectic effect of MTII (MC3/4-R agonist), given simultaneously, consistent with a competitive antagonist action. However, when given 24 h prior to MTII, AgRP-(83---132) is ineffective at reversing the anorectic effects of the agonist. These results support a critical role of MC tone in limiting food intake and indicate that the orexigenic effects of AgRP-(83---132) are initially mediated by competitive antagonism at MC receptors but are sustained by alternate mechanisms.

The stimulatory G protein Gsα is required in melanocortin 4 receptor-expressing cells for normal energy balance, thermogenesis and glucose metabolism.

PubMed

Podyma, Brandon; Sun, Hui; Wilson, Eric A; Carlson, Bradley; Pritikin, Ethan; Gavrilova, Oksana; Weinstein, Lee S; Chen, Min

2018-05-24

Central melanocortin 4 receptors (MC4Rs) stimulate energy expenditure and inhibit food intake. MC4Rs activate the G protein G s α, but whether G s α mediates all MC4R actions has not been established. Individuals with Albright hereditary osteodystrophy (AHO), who have heterozygous G s α-inactivating mutations, only develop obesity when the G s α mutation is present on the maternal allele because of tissue-specific genomic imprinting. Furthermore, evidence in mice implicates G s α imprinting within the central nervous system (CNS) in this disorder. In this study we examined the effects of G s α in MC4R-expressing cells on metabolic regulation. Mice with homozygous G s α deficiency in MC4R-expressing cells (MC4RGsKO) developed significant obesity with increased food intake and decreased energy expenditure, along with impaired insulin sensitivity and cold-induced thermogenesis. Moreover, the ability of the MC4R agonist melanotan-II (MTII) to stimulate energy expenditure and to inhibit food intake was impaired in MC4RGsKO mice. MTII failed to stimulate the secretion of the anorexigenic hormone peptide YY (PYY) from enteroendocrine L cells, a physiological response mediated by MC4R-G s α signaling, even though baseline PYY levels were elevated in these mice. In G s α heterozygotes, mild obesity and reduced energy expenditure were present only in mice with a G s α deletion on the maternal allele in MC4R-expressing cells, while food intake was unaffected. These results demonstrate that G s α signaling in MC4R-expressing cells is required for controlling energy balance, thermogenesis, and peripheral glucose metabolism. They further indicate that G s α imprinting in MC4R-expressing cells contributes to obesity in G s α KO mice and likely in individuals with AHO as well. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

Danshen attenuates osteoarthritis-related cartilage degeneration through inhibition of NF-κB signaling pathway in vivo and in vitro.

PubMed

Xu, Xilin; Lv, Hang; Li, Xiaodong; Su, Hui; Zhang, Xiaofeng; Yang, Jun

2017-12-01

Danshen (Salvia miltiorrhiza) is a traditional Chinese medicine herb that can alleviate the symptoms of osteoarthritis (OA) (Söder et al. 2006) in animals. However, the underlying mechanisms remain poorly understood and require further investigation. In this study, rabbits with experimentally induced OA were given an intra-articular injection of danshen (0.7 mL/day) for 5 weeks. In addition to attenuating the cartilage degeneration of OA in the rabbits, danshen decreased the expression and activity of matrix metalloproteinase 9 (MMP-9) and MMP-13, and increased the expression of their natural inhibitors: tissue inhibitor of matrix metalloproteinase 1 (TIMP-1) and TIMP-2. Apoptosis in osteoarthritic cartilage tissues was attenuated by danshen, accompanied with increased expression of B cell lymphoma 2 (Bcl-2) and decreased levels of Bcl-2-associated X protein (Bax). Further, danshen inhibited the nuclear accumulation of nuclear factor kappa-B (NF-κB) p65 in osteoarthritic cartilage. The therapeutic effects of danshen in vivo were comparable to that of sodium hyaluronate, which is a drug used clinically for the treatment OA. In vitro, sodium nitroprusside (SNP) was used to stimulate apoptosis in primary rabbit chondrocytes. We found that the SNP-induced apoptosis was mitigated by danshen. BAY11-7028, an inhibitor of the NF-κB pathway, augmented danshen's anti-apoptotic effects in cells exposed to SNP. When these results are considered together, they indicate that danshen alleviates the cartilage injury in rabbit OA through inhibition of the NF-κB signaling pathway.

Dental artifacts in the head and neck region: implications for Dixon-based attenuation correction in PET/MR.

PubMed

Ladefoged, Claes N; Hansen, Adam E; Keller, Sune H; Fischer, Barbara M; Rasmussen, Jacob H; Law, Ian; Kjær, Andreas; Højgaard, Liselotte; Lauze, Francois; Beyer, Thomas; Andersen, Flemming L

2015-12-01

In the absence of CT or traditional transmission sources in combined clinical positron emission tomography/magnetic resonance (PET/MR) systems, MR images are used for MR-based attenuation correction (MR-AC). The susceptibility effects due to metal implants challenge MR-AC in the neck region of patients with dental implants. The purpose of this study was to assess the frequency and magnitude of subsequent PET image distortions following MR-AC. A total of 148 PET/MR patients with clear visual signal voids on the attenuation map in the dental region were included in this study. Patients were injected with [(18)F]-FDG, [(11)C]-PiB, [(18)F]-FET, or [(64)Cu]-DOTATATE. The PET/MR data were acquired over a single-bed position of 25.8 cm covering the head and neck. MR-AC was based on either standard MR-ACDIXON or MR-ACINPAINTED where the susceptibility-induced signal voids were substituted with soft tissue information. Our inpainting algorithm delineates the outer contour of signal voids breaching the anatomical volume using the non-attenuation-corrected PET image and classifies the inner air regions based on an aligned template of likely dental artifact areas. The reconstructed PET images were evaluated visually and quantitatively using regions of interests in reference regions. The volume of the artifacts and the computed relative differences in mean and max standardized uptake value (SUV) between the two PET images are reported. The MR-based volume of the susceptibility-induced signal voids on the MR-AC attenuation maps was between 1.6 and 520.8 mL. The corresponding/resulting bias of the reconstructed tracer distribution was localized mainly in the area of the signal void. The mean and maximum SUVs averaged across all patients increased after inpainting by 52% (± 11%) and 28% (± 11%), respectively, in the corrected region. SUV underestimation decreased with the distance to the signal void and correlated with the volume of the susceptibility artifact on the MR

Molecular Imaging and Radionuclide Therapy of Melanoma Targeting the Melanocortin 1 Receptor

PubMed Central

Zhang, Chengcheng; Lin, Kuo-Shyan; Bénard, François

2017-01-01

Melanoma is a deadly disease at late metastatic stage, and early diagnosis and accurate staging remain the key aspects for managing melanoma. The melanocortin 1 receptor (MC1 R) is overexpressed in primary and metastatic melanomas, and its endogenous ligand, the α-melanocyte-stimulating hormone (αMSH), has been extensively studied for the development of MC1 R-targeted molecular imaging and therapy of melanoma. Natural αMSH is not well suited for this purpose due to low stability in vivo. Unnatural amino acid substitutions substantially stabilized the peptide, while cyclization via lactam bridge and metal coordination further improved binding affinity and stability. In this study, we summarized the development and the in vitro and in vivo characteristics of the radiolabeled αMSH analogues, including 99mTc-, 111In-, 67 Ga-, or 125I-labeled αMSH analogues for imaging with single-photon emission computed tomography; 68Ga-, 64Cu-, or 18F-labeled αMSH analogues for imaging with positron emission tomography; and 188Re-, 177Lu-, 90Y-, or 212Pb-labeled αMSH analogues for radionuclide therapy. These radiolabeled αMSH analogues showed promising results with high tumor uptake and rapid normal tissue activity clearance in the preclinical model of B16F1 and B16F10 mouse melanomas. These results highlight the potential of using radiolabeled αMSH analogues in clinical applications for molecular imaging and radionuclide therapy of melanoma. PMID:29182034

Impact of Scattering Model on Disdrometer Derived Attenuation Scaling

NASA Technical Reports Server (NTRS)

Zemba, Michael; Luini, Lorenzo; Nessel, James; Riva, Carlo (Compiler)

2016-01-01

NASA Glenn Research Center (GRC), the Air Force Research Laboratory (AFRL), and the Politecnico di Milano (POLIMI) are currently entering the third year of a joint propagation study in Milan, Italy utilizing the 20 and 40 GHz beacons of the Alphasat TDP5 Aldo Paraboni scientific payload. The Ka- and Q-band beacon receivers were installed at the POLIMI campus in June of 2014 and provide direct measurements of signal attenuation at each frequency. Collocated weather instrumentation provides concurrent measurement of atmospheric conditions at the receiver; included among these weather instruments is a Thies Clima Laser Precipitation Monitor (optical disdrometer) which records droplet size distributions (DSD) and droplet velocity distributions (DVD) during precipitation events. This information can be used to derive the specific attenuation at frequencies of interest and thereby scale measured attenuation data from one frequency to another. Given the ability to both predict the 40 GHz attenuation from the disdrometer and the 20 GHz timeseries as well as to directly measure the 40 GHz attenuation with the beacon receiver, the Milan terminal is uniquely able to assess these scaling techniques and refine the methods used to infer attenuation from disdrometer data.In order to derive specific attenuation from the DSD, the forward scattering coefficient must be computed. In previous work, this has been done using the Mie scattering model, however, this assumes a spherical droplet shape. The primary goal of this analysis is to assess the impact of the scattering model and droplet shape on disdrometer derived attenuation predictions by comparing the use of the Mie scattering model to the use of the T-matrix method, which does not assume a spherical droplet. In particular, this paper will investigate the impact of these two scattering approaches on the error of the resulting predictions as well as on the relationship between prediction error and rain rate.

Impact of Scattering Model on Disdrometer Derived Attenuation Scaling

NASA Technical Reports Server (NTRS)

Zemba, Michael; Luini, Lorenzo; Nessel, James; Riva, Carlo

2016-01-01

NASA Glenn Research Center (GRC), the Air Force Research Laboratory (AFRL), and the Politecnico di Milano (POLIMI) are currently entering the third year of a joint propagation study in Milan, Italy utilizing the 20 and 40 GHz beacons of the Alphasat TDP#5 Aldo Paraboni scientific payload. The Ka- and Q-band beacon receivers were installed at the POLIMI campus in June of 2014 and provide direct measurements of signal attenuation at each frequency. Collocated weather instrumentation provides concurrent measurement of atmospheric conditions at the receiver; included among these weather instruments is a Thies Clima Laser Precipitation Monitor (optical disdrometer) which records droplet size distributions (DSD) and droplet velocity distributions (DVD) during precipitation events. This information can be used to derive the specific attenuation at frequencies of interest and thereby scale measured attenuation data from one frequency to another. Given the ability to both predict the 40 gigahertz attenuation from the disdrometer and the 20 gigahertz time-series as well as to directly measure the 40 gigahertz attenuation with the beacon receiver, the Milan terminal is uniquely able to assess these scaling techniques and refine the methods used to infer attenuation from disdrometer data. In order to derive specific attenuation from the DSD, the forward scattering coefficient must be computed. In previous work, this has been done using the Mie scattering model, however, this assumes a spherical droplet shape. The primary goal of this analysis is to assess the impact of the scattering model and droplet shape on disdrometer-derived attenuation predictions by comparing the use of the Mie scattering model to the use of the T-matrix method, which does not assume a spherical droplet. In particular, this paper will investigate the impact of these two scattering approaches on the error of the resulting predictions as well as on the relationship between prediction error and rain rate.

Pituitary Adenylate Cyclase-Activating Peptide in the Central Amygdala Causes Anorexia and Body Weight Loss via the Melanocortin and the TrkB Systems.

PubMed

Iemolo, Attilio; Ferragud, Antonio; Cottone, Pietro; Sabino, Valentina

2015-07-01

Growing evidence suggests that the pituitary adenylate cyclase-activating polypeptide (PACAP)/PAC1 receptor system represents one of the main regulators of the behavioral, endocrine, and autonomic responses to stress. Although induction of anorexia is a well-documented effect of PACAP, the central sites underlying this phenomenon are poorly understood. The present studies addressed this question by examining the neuroanatomical, behavioral, and pharmacological mechanisms mediating the anorexia produced by PACAP in the central nucleus of the amygdala (CeA), a limbic structure implicated in the emotional components of ingestive behavior. Male rats were microinfused with PACAP (0-1 μg per rat) into the CeA and home-cage food intake, body weight change, microstructural analysis of food intake, and locomotor activity were assessed. Intra-CeA (but not intra-basolateral amygdala) PACAP dose-dependently induced anorexia and body weight loss without affecting locomotor activity. PACAP-treated rats ate smaller meals of normal duration, revealing that PACAP slowed feeding within meals by decreasing the regularity and maintenance of feeding from pellet-to-pellet; postprandial satiety was unaffected. Intra-CeA PACAP-induced anorexia was blocked by coinfusion of either the melanocortin receptor 3/4 antagonist SHU 9119 or the tyrosine kinase B (TrKB) inhibitor k-252a, but not the CRF receptor antagonist D-Phe-CRF(12-41). These results indicate that the CeA is one of the brain areas through which the PACAP system promotes anorexia and that PACAP preferentially lessens the maintenance of feeding in rats, effects opposite to those of palatable food. We also demonstrate that PACAP in the CeA exerts its anorectic effects via local melanocortin and the TrKB systems, and independently from CRF.

Chronic suppression of μ-opioid receptor signaling in the nucleus accumbens attenuates development of diet-induced obesity in rats.

PubMed

Lenard, N R; Zheng, H; Berthoud, H-R

2010-06-01

To test the hypothesis that micro-opioid receptor signaling in the nucleus accumbens contributes to hedonic (over)eating and obesity. To investigate the effects of chronic micro-opioid antagonism in the nucleus accumbens core or shell on intake of a palatable diet, and the development of diet-induced obesity in rats. Chronic blockade of micro-opioid receptor signaling in the nucleus accumbens core or shell was achieved by means of repeated injections (every 4-5 days) of the irreversible receptor antagonist beta-funaltrexamine (BFNA) over 3-5 weeks. The diet consisted of either a choice of high-fat chow, chocolate-flavored Ensure and regular chow (each nutritionally complete) or regular chow only. Intake of each food item, body weight and body fat mass were monitored throughout the study. The BFNA injections aimed at either the core or shell of the nucleus accumbens resulted in significantly attenuated intake of palatable diet, body weight gain and fat accretion, compared with vehicle control injections. The injection of BFNA in the core did not significantly change these parameters in chow-fed control rats. The injection of BFNA in the core and shell differentially affected intake of the two palatable food items: in the core, BFNA significantly reduced the intake of high-fat, but not of Ensure, whereas in the shell, it significantly reduced the intake of Ensure, but not of high-fat, compared with vehicle treatment. Endogenous micro-opioid receptor signaling in the nucleus accumbens core and shell is necessary for palatable diet-induced hyperphagia and obesity to fully develop in rats. Sweet and non-sweet fatty foods may be differentially processed in subcomponents of the ventral striatum.

Characterizing Englacial Attenuation and Grounding Zone Geometry Using Airborne Radar Sounding

NASA Astrophysics Data System (ADS)

Schroeder, D. M.; Grima, C.; Blankenship, D. D.

2014-12-01

The impact of warm ocean water on ice sheet retreat and stability is a one of the primary drivers and sources of uncertainty for the rate of global sea level rise. One critical but challenging observation required to understand and model this impact is the location and extent of grounding ice sheet zones. However, existing surface topography based techniques do not directly detect the location where ocean water reaches (or breaches) grounded ice at the bed, which can significantly affect ice sheet stability. The primary geophysical tool for directly observing the basal properties of ice sheets is airborne radar sounding. However, uncertainty in englacial attenuation from unknown ice temperature and chemistry can lead to erroneous interpretation of subglacial conditions from bed echo strengths alone . Recently developed analysis techniques for radar sounding data have overcome this challenge by taking advantage of information in the angular distribution of bed echo energy and joint modeling of radar returns and water routing. We have developed similar approaches to analyze the spatial pattern and character of echoes to address the problems of improved characterization of grounding zone geometry and englacial attenuation. The spatial signal of the transition from an ice-bed interface to an ice-ocean interface is an increase in bed echo strength. However, rapidly changing attenuation near the grounding zone prevents the unambiguous interpretation of this signal in typical echo strength profiles and violates the assumptions of existing empirical attenuation correction techniques. We present a technique that treat bed echoes as continuous signals to take advantage of along-profile ice thickness and echo strength variations to constrain the spatial pattern of attenuation and detect the grounding zone transition. The transition from an ice-bed interface to an ice-ocean interface will also result in a change in the processes that determine basal interface morphology (e

Radar attenuation tomography using the centroid frequency downshift method

USGS Publications Warehouse

Liu, L.; Lane, J.W.; Quan, Y.

1998-01-01

A method for tomographically estimating electromagnetic (EM) wave attenuation based on analysis of centroid frequency downshift (CFDS) of impulse radar signals is described and applied to cross-hole radar data. The method is based on a constant-Q model, which assumes a linear frequency dependence of attenuation for EM wave propagation above the transition frequency. The method uses the CFDS to construct the projection function. In comparison with other methods for estimating attenuation, the CFDS method is relatively insensitive to the effects of geometric spreading, instrument response, and antenna coupling and radiation pattern, but requires the data to be broadband so that the frequency shift and variance can be easily measured. The method is well-suited for difference tomography experiments using electrically conductive tracers. The CFDS method was tested using cross-hole radar data collected at the U.S. Geological Survey Fractured Rock Research Site at Mirror Lake, New Hampshire (NH) during a saline-tracer injection experiment. The attenuation-difference tomogram created with the CFDS method outlines the spatial distribution of saline tracer within the tomography plane. ?? 1998 Elsevier Science B.V. All rights reserved.

A Nampt inhibitor FK866 mimics vitamin B3 deficiency by causing senescence of human fibroblastic Hs68 cells via attenuation of NAD(+)-SIRT1 signaling.

PubMed

Song, Tuzz-Ying; Yeh, Shu-Lan; Hu, Miao-Lin; Chen, Mei-Yau; Yang, Nae-Cherng

2015-12-01

Vitamin B3 (niacin) deficiency can cause pellagra with symptoms of dermatitis, diarrhea and dementia. However, it is unclear whether the vitamin B3 deficiency causes human aging. FK866 (a Nampt inhibitor) can reduce intracellular NAD(+) level and induce senescence of human Hs68 cells. However, the mechanisms underlying FK866-induced senescence of Hs68 cells are unclear. In this study, we used FK866 to mimic the effects of vitamin B3 deficiency to reduce the NAD(+) level and investigated the mechanisms of FK866-induced senescence of Hs68 cells. We hypothesized that FK866 induced the senescence of Hs68 cells via an attenuation of NAD(+)-silent information regulator T1 (SIRT1) signaling. We found that FK866 induced cell senescence and diminished cellular NAD(+) levels and SIRT1 activity (detected by acetylation of p53), and these effects were dramatically antagonized by co-treatment with nicotinic acid, nicotinamide, or NAD(+). In contrast, the protein expression of SIRT1, AMP-activated protein kinase, mammalian target of rapamycin, and nicotinamide phosphoribosyltransferase (Nampt) was not affected by FK866. In addition, the role of GSH in the FK866-induced cells senescence may be limited, as N-acetylcysteine did not antagonize FK866-induced cell senescence. These results suggest that FK866 induces cell senescence via attenuation of NAD(+)-SIRT1 signaling. The effects of vitamin B3 deficiency on human aging warrant further investigation.

5-HMF attenuates striatum oxidative damage via Nrf2/ARE signaling pathway following transient global cerebral ischemia.

PubMed

Ya, Bai-Liu; Li, Hong-Fang; Wang, Hai-Ying; Wu, Fei; Xin, Qing; Cheng, Hong-Ju; Li, Wen-Juan; Lin, Na; Ba, Zai-Hua; Zhang, Ru-Juan; Liu, Qian; Li, Ya-Nan; Bai, Bo; Ge, Feng

2017-01-01

Recent studies have shown 5-hydroxymethyl-2-furfural (5-HMF) has favorable biological effects, and its neuroprotection in a variety of neurological diseases has been noted. Our previous study showed that treatment of 5-HMF led to protection against permanent global cerebral ischemia. However, the underlying mechanisms in cerebral ischemic injury are not fully understood. This study was conducted to investigate the neuroprotective effect of 5-HMF and elucidate the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway mechanism in the striatum after transient global cerebral ischemia. C57BL/6 mice were subjected to bilateral common carotid artery occlusion for 20 min and sacrificed 24 h after reperfusion. 5-HMF (12 mg/kg) or an equal volume of vehicle was intraperitoneally injected 30 min before ischemia and 5 min after the onset of reperfusion. At 24 h after reperfusion, neurological function was evaluated by neurological disability status scale, locomotor activity test and inclined beam walking test. Histological injury of the striatum was observed by cresyl violet staining and terminal deoxynucleotidyl transferase (TdT)-mediated dNTP nick end labeling (TUNEL) staining. Oxidative stress was evaluated by the carbonyl groups introduced into proteins, and malondialdehyde (MDA) levels. An enzyme-linked immunosorbent assay (ELISA)-based measurement was used to detect Nrf2 DNA binding activity. Nrf2 and its downstream ARE pathway protein expression such as heme oxygenase-1, NAD (P)H:quinone oxidoreductase 1, glutamate-cysteine ligase catalytic subunit and glutamate-cysteine ligase modulatory subunit were detected by western blot. Our results showed that 5-HMF treatment significantly ameliorated neurological deficits, reduced brain water content, attenuated striatum neuronal damage, decreased the carbonyl groups and MDA levels, and activated Nrf2/ARE signaling pathway. Taken together, these results demonstrated that

A real-time chirp-coded imaging system with tissue attenuation compensation.

PubMed

Ramalli, A; Guidi, F; Boni, E; Tortoli, P

2015-07-01

In ultrasound imaging, pulse compression methods based on the transmission (TX) of long coded pulses and matched receive filtering can be used to improve the penetration depth while preserving the axial resolution (coded-imaging). The performance of most of these methods is affected by the frequency dependent attenuation of tissue, which causes mismatch of the receiver filter. This, together with the involved additional computational load, has probably so far limited the implementation of pulse compression methods in real-time imaging systems. In this paper, a real-time low-computational-cost coded-imaging system operating on the beamformed and demodulated data received by a linear array probe is presented. The system has been implemented by extending the firmware and the software of the ULA-OP research platform. In particular, pulse compression is performed by exploiting the computational resources of a single digital signal processor. Each image line is produced in less than 20 μs, so that, e.g., 192-line frames can be generated at up to 200 fps. Although the system may work with a large class of codes, this paper has been focused on the test of linear frequency modulated chirps. The new system has been used to experimentally investigate the effects of tissue attenuation so that the design of the receive compression filter can be accordingly guided. Tests made with different chirp signals confirm that, although the attainable compression gain in attenuating media is lower than the theoretical value expected for a given TX Time-Bandwidth product (BT), good SNR gains can be obtained. For example, by using a chirp signal having BT=19, a 13 dB compression gain has been measured. By adapting the frequency band of the receiver to the band of the received echo, the signal-to-noise ratio and the penetration depth have been further increased, as shown by real-time tests conducted on phantoms and in vivo. In particular, a 2.7 dB SNR increase has been measured through a

Propofol Attenuates Airway Inflammation in a Mast Cell-Dependent Mouse Model of Allergic Asthma by Inhibiting the Toll-like Receptor 4/Reactive Oxygen Species/Nuclear Factor κB Signaling Pathway.

PubMed

Li, Hong-Yi; Meng, Jing-Xia; Liu, Zhen; Liu, Xiao-Wen; Huang, Yu-Guang; Zhao, Jing

2018-06-01

Propofol, an intravenous anesthetic agent widely used in clinical practice, is the preferred anesthetic for asthmatic patients. This study was designed to determine the protective effect and underlying mechanisms of propofol on airway inflammation in a mast cell-dependent mouse model of allergic asthma. Mice were sensitized by ovalbumin (OVA) without alum and challenged with OVA three times. Propofol was given intraperitoneally 0.5 h prior to OVA challenge. The inflammatory cell count and production of cytokines in the bronchoalveolar lavage fluid (BALF) were detected. The changes of lung histology and key molecules of the toll-like receptor 4 (TLR4)/reactive oxygen species (ROS)/NF-κB signaling pathway were also measured. The results showed that propofol significantly decreased the number of eosinophils and the levels of IL-4, IL-5, IL-6, IL-13, and TNF-α in BALF. Furthermore, propofol significantly attenuated airway inflammation, as characterized by fewer infiltrating inflammatory cells and decreased mucus production and goblet cell hyperplasia. Meanwhile, the expression of TLR4, and its downstream signaling adaptor molecules--myeloid differentiation factor 88 (MyD88) and NF-κB, were inhibited by propofol. The hydrogen peroxide and methane dicarboxylic aldehyde levels were decreased by propofol, and the superoxide dismutase activity was increased in propofol treatment group. These findings indicate that propofol may attenuate airway inflammation by inhibiting the TLR4/MyD88/ROS/NF-κB signaling pathway in a mast cell-dependent mouse model of allergic asthma.

Removal and attenuation of sewage effluent combined tracer signals of phosphorus, caffeine and saccharin in soil.

PubMed

Richards, Samia; Withers, Paul J A; Paterson, Eric; McRoberts, Colin W; Stutter, Marc

2017-04-01

Contaminants in septic tank effluent (STE) are expected to be removed by the soil system before discharging to the environment. However, potential contaminants such as phosphorus (P), caffeine and artificial sweeteners do find their way to watercourses impacting aquatic eco systems. In this study, the attenuation of STE P, caffeine and saccharin were investigated in untreated soil and in soil with reduced microbial activity, in aqueous solutions and in the complex matrix of STE. Time series sorption and desorption experiments using batch equilibrium and a column experiment of STE P attenuation were conducted. The results revealed that the soil distribution coefficients (K d ) were: P 81.57 > caffeine 22.16 > saccharin 5.98 cm 3 /g, suggesting greater soil affinity to P adsorption. The data revealed that 80% of saccharin and 33% of caffeine attenuation was associated with microbial activities rather than adsorption processes. However, a complete removal of saccharin and caffeine did not occur during the equilibration period, suggesting their leaching potential. The dominant mechanism of P attenuation was adsorption (chemical and physical), yielding P retention of >73% and 35% for P in aqueous solution and in STE matrix, respectively, for batch equilibrium. The soil in the column acted as effluent P sink retaining 125 μg P/g soil of effluent P. The attenuation of P, caffeine and saccharin in the aqueous solution was greater than in STE, suggesting that the complex composition of STE reduced soil adsorption ability, and that other substances present in STE may be competing for soil binding sites. The data revealed that caffeine and P had similarities in the interaction with soils and thus caffeine may be considered as a STE tracer of anthropogenic source of P in receiving waters. Copyright © 2017 Elsevier Ltd. All rights reserved.

Role of adenosine A{sub 2A} receptor signaling in the nicotine-evoked attenuation of reflex cardiac sympathetic control

DOE Office of Scientific and Technical Information (OSTI.GOV)

El-Mas, Mahmoud M., E-mail: mahelm@hotmail.com; El-gowilly, Sahar M.; Fouda, Mohamed A.

. - Research Highlights: > The role of central adenosinergic sites in the nicotine-baroreflex interaction was investigated. > Inhibition of reflex sympathoinhibition mediates the BRS depressant action of nicotine. > Nicotine preferentially impairs reflex tachycardia via disruption of adenosine A{sub 2A} signaling. > The attenuation by nicotine of reflex sympathetic activity is clinically important.« less

Fumaric acid attenuates the eotaxin-1 expression in TNF-α-stimulated fibroblasts by suppressing p38 MAPK-dependent NF-κB signaling.

PubMed

Roh, Kyung-Baeg; Jung, Eunsun; Park, Deokhoon; Lee, Jongsung

2013-08-01

Eotaxin-1 is a potent chemoattractant for eosinophils and a critical mediator during the development of eosinophilic inflammation. Fumaric acid is an intermediate product of the citric acid cycle, which is source of intracellular energy. Although fumaric acid ameliorates psoriasis and multiple sclerosis, its involvement in eotaxin-1-mediated effects has not been assessed. In this study, we investigated the effects of fumaric acid on eotaxin-1 expression in a mouse fibroblast cell line. We found that fumaric acid significantly inhibited tumor necrosis factor-α (TNF-α-induced eotaxin-1 expression. This fumaric acid effect was mediated through the inhibition of p38 mitogen-activated protein kinase (MAPK)-dependent nuclear factor (NF)-κB signaling. We also found that fumaric acid operates downstream of MEKK3 during TNF-α-induced NF-κB signaling, which upregulated eotaxin-1 expression. In addition, fumaric acid attenuated expression of CC-chemokine receptor 3 (CCR3), an eotaxin-1 receptor, and adhesion molecules that play important roles in eosinophil binding to induce allergic inflammation. Taken together, these findings indicate that inhibiting TNF-α-induced eotaxin-1 expression by fumaric acid occurs primarily through suppression of NF-κB signaling, which is mediated by inhibiting p38 MAPK and suggest that fumaric acid may be used as a complementary treatment option for eotaxin-1-mediated diseases. Copyright © 2013 Elsevier Ltd. All rights reserved.

Geo-spatial distribution of cloud cover and influence of cloud induced attenuation and noise temperature on satellite signal propagation over Nigeria

NASA Astrophysics Data System (ADS)

Ojo, Joseph Sunday

2017-05-01

The study of the influence of cloud cover on satellite propagation links is becoming more demanding due to the requirement of larger bandwidth for different satellite applications. Cloud attenuation is one of the major factors to consider for optimum performance of Ka/V and other higher frequency bands. In this paper, the geo-spatial distribution of cloud coverage over some chosen stations in Nigeria has been considered. The substantial scale spatial dispersion of cloud cover based on synoptic meteorological data and the possible impact on satellite communication links at higher frequency bands was also investigated. The investigation was based on 5 years (2008-2012) achieved cloud cover data collected by the Nigerian Meteorological Agency (NIMET) Federal Ministry of Aviation, Oshodi Lagos over four synoptic hours of the day covering day and night. The performances of satellite signals as they traverse through the cloud and cloud noise temperature at different seasons and over different hours of days at Ku/W-bands frequency are also examined. The overall result shows that the additional total atmospheric noise temperature due to the clear air effect and the noise temperature from the cloud reduces the signal-to-noise ratio of the satellite receiver systems, leading to more signal loss and if not adequately taken care of may lead to significant outage. The present results will be useful for Earth-space link budgeting, especially for the proposed multi-sensors communication satellite systems in Nigeria.

Regulatory Alterations of Energy Homeostasis in Spontaneously Hypertensive Rats (SHR).

PubMed

Furedi, Nora; Miko, Alexandra; Aubrecht, Bianka; Gaszner, Balazs; Feller, Diana; Rostas, Ildiko; Tenk, Judit; Soos, Szilvia; Balasko, Marta; Balogh, Andras; Pap, Marianna; Petervari, Erika

2016-08-01

Spontaneously hypertensive rats (SHR) have high sympathetic tone and progressive hypertension. Chronic calorie-restriction prevents hypertension. Their food intake (FI) and body weight are lower than in normotensive (NT) controls, even on a high-fat diet, suggesting a dysregulation of energy homeostasis. We assumed enhanced activity of hypothalamic anorexigenic melanocortins and diminished tone of orexigenic neuropeptide Y (NPY) in the background. FI of male SHR and NT Wistar rats was recorded in a FeedScale system upon intracerebroventricular injection of NPY, melanocortin ligands alpha-melanocyte-stimulating hormone (alpha-MSH), and agouti-related peptide (AgRP) or during a 7-day intracerebroventricular infusion of melanocortin antagonist HS024. Alpha-MSH, NPY, and AgRP immunoreactivities were semi-quantified in the arcuate (ARC) and paraventricular (PVN) nuclei of the hypothalamus in NT vs. SHR. Proopiomelanocortin gene expression was also assessed by quantitative RT-PCR in the ARC. Melanocortin-induced anorexia was stronger, FI induced by NPY or HS024 was smaller and delayed in SHR. Cellular alpha-MSH-specific signal density was higher in the ARC of SHR as evaluated by immunofluerescence, which was supported by PCR data. In the PVN, no differences in alpha-MSH-, NPY-, or AgRP-immunosignal were observed. Our results suggest that a higher melanocortin production/responsiveness and lower NPY responsiveness may contribute to the body weight dysregulation of SHR.

Evidence that Melanocortin Receptor Agonist Melanotan-II Synergistically Augments the Ability of Naltrexone to Blunt Binge-Like Ethanol Intake in Male C57BL/6J Mice

PubMed Central

Navarro, Montserrat; Carvajal, Francisca; Lerma-Cabrera, Jose Manuel; Cubero, Inmaculada; Picker, Mitchell J.; Thiele, Todd E.

2015-01-01

Background The non-selective opioid receptor antagonist, naltrexone (NAL), reduces alcohol (ethanol) consumption in animals and humans and is an approved medication for treating alcohol abuse disorders. Proopiomelanocortin (POMC)-derived melanocortin (MC) and opioid peptides are produced in the same neurons in the brain, and recent pre-clinical evidence shows that MC receptor (MCR) agonists reduce excessive ethanol drinking in animal models. Interestingly, there is a growing body of literature revealing interactions between the MC and opioid systems in the modulation of pain, drug tolerance, and food intake. Method In the present report, a mouse model of binge ethanol drinking was employed to determine if the MCR agonist, melanotan-II (MTII), would improve the effectiveness of NAL in reducing excessive binge-like ethanol drinking when these drugs were co-administered prior to ethanol access. Results Both NAL and MTII blunt binge-like ethanol drinking and associated blood ethanol levels, and when administered together, a low dose of MTII (0.26 mg/kg) produces a 7.6-fold increase in the effectiveness of NAL in reducing binge-like ethanol drinking. Using isobolographic analysis, it is demonstrated that MTII increases the effectiveness of NAL in a synergistic manner. Conclusions The current observations suggest that activators of MC signaling may represent a new approach to treating alcohol abuse disorders, and a way to potentially improve existing NAL-based therapies. PMID:26108334

A depolarization and attenuation experiment using the CTS satellite. Volume 1: Experiment description

NASA Technical Reports Server (NTRS)

Bostian, C. W.; Holt, S. B., Jr.; Kauffman, S. R.; Manus, E. A.; Marshall, R. E.; Stutzman, W. L.; Wiley, P. H.

1976-01-01

An experiment for measuring precipitation attenuation and depolarization on the Communications Technology Satellite (CTS) 11.7 GHz downlink is described. Attenuation and depolarization of the signal received from the spacecraft is monitored on a 24 hour basis. Data is correlated with ground weather conditions. Theoretical models for millimeter wave propagation through rain are refined for maximum agreement with observed data. Techniques are developed for predicting and mimimizing the effects of rain scatter and depolarization on future satellite communication systems.

On Limitations of the Ultrasonic Characterization of Pieces Manufactured with Highly Attenuating Materials

NASA Astrophysics Data System (ADS)

Ramos, A.; Moreno, E.; Rubio, B.; Calas, H.; Galarza, N.; Rubio, J.; Diez, L.; Castellanos, L.; Gómez, T.

Some technical aspects of two Spanish cooperation projects, funded by DPI and Innpacto Programs of the R&D National Plan, are discussed. The objective is to analyze the common belief about than the ultrasonic testing in MHz range is not a tool utilizable to detect internal flaws in highly attenuating pieces made of coarse-grained steel. In fact high-strength steels, used in some safe industrial infrastructures of energy & transport sectors, are difficult to be inspected using the conventional "state of the art" in ultrasonic technology, due to their internal microstructures are very attenuating and coarse-grained. It is studied if this inspection difficulty could be overcome by finding intense interrogating pulses and advanced signal processing of the acquired echoes. A possible solution would depend on drastically improving signal-to-noise-ratios, by applying new advances on: ultrasonic transduction, HV electronics for intense pulsed driving of the testing probes, and an "ad-hoc" digital processing or focusing of the received noisy signals, in function of each material to be inspected. To attain this challenging aim on robust steel pieces would open the possibility of obtaining improvements in inspecting critical industrial components made of highly attenuating & dispersive materials, as new composites in aeronautic and motorway bridges, or new metallic alloys in nuclear area, where additional testing limitations often appear.

Narrow Angle Diversity using ACTS Ka-band Signal with Two USAT Ground Stations

NASA Technical Reports Server (NTRS)

Kalu, A.; Emrich, C.; Ventre, J.; Wilson, W.; Acosta, R.

1998-01-01

Two ultra small aperture terminal (USAT) ground stations, separated by 1.2 km in a narrow angle diversity configuration, received a continuous Ka-band tone sent from Cleveland Link Evaluation Terminal (LET). The signal was transmitted to the USAT ground stations via NASA's Advanced Communications Technology Satellite (ACTS) steerable beam. Received signal power at the two sites was measured and analyzed. A dedicated datalogger at each site recorded time-of-tip data from tipping bucket rain gauges, providing rain amount and instantaneous rain rate. WSR-88D data was also obtained for the collection period. Eleven events with ground-to-satellite slant-path precipitation and resultant signal attenuation were observed during the data collection period. Fade magnitude and duration were compared at the two sites and diversity gain was calculated. These results exceeded standard diversity gain model predictions by several decibels. Rain statistics from tipping bucket data and from radar data were also compared to signal attenuation. The nature of Florida's subtropical rainfall, specifically its impact on signal attenuation at the sites, was addressed.

Minocycline attenuates the development of diabetic neuropathy by inhibiting spinal cord Notch signaling in rat.

PubMed

Yang, Cheng; Gao, Jie; Wu, Banglin; Yan, Nuo; Li, Hui; Ren, Yiqing; Kan, Yufei; Liang, Jiamin; Jiao, Yang; Yu, Yonghao

2017-10-01

We studied the effects of minocycline (an inhibitor of microglial activation) on the expression and activity of Notch-1 receptor, and explored the therapeutic efficacy of minocycline combined with Notch inhibitor DAPT in the treatment of diabetic neuropathic pain (DNP). Diabetic rat model was established by intraperitoneal injection (ip) of Streptozotocin (STZ). Expression and activity of Notch-1 and expression of macrophage/microglia marker Iba-1 were detected by WB. Diabetes induction significantly attenuated sciatic nerve conduction velocity, and dramatically augmented the expression and the activity of Notch-1 in the lumbar enlargement of the spinal cord. Minocycline treatment, however, accelerated the decreased conduction velocity of sciatic nerve and suppressed Notch-1expression and activity in diabetic rats. Similar to DAPT treatment, minocycline administration also prolonged thermal withdrawal latency (TWL) and increase mechanical withdrawal threshold (MWT) in diabetic rats in response to heat or mechanical stimulation via inhibition the expression and the activity of Notch-1 in spinal cord. Combination of DAPT and minocycline further inhibited Notch-1 receptor signaling and reduce neuropathic pain exhibited as improved TWL and MWT. Our study revealed a novel mechanism of Notch-1 receptor inhibition in spinal cord induced by minocycline administration, and suggested that the combination of minocycline and DAPT has the potential to treat DNP. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

NF-κB Activation in Hypothalamic Pro-opiomelanocortin Neurons Is Essential in Illness- and Leptin-induced Anorexia*

PubMed Central

Jang, Pil-Geum; Namkoong, Cherl; Kang, Gil Myoung; Hur, Man-Wook; Kim, Seung-Whan; Kim, Geun Hyang; Kang, Yeoungsup; Jeon, Min-Jae; Kim, Eun Hee; Lee, Myung-Shik; Karin, Michael; Baik, Ja-Hyun; Park, Joong-Yeol; Lee, Ki-Up; Kim, Young-Bum; Kim, Min-Seon

2010-01-01

Anorexia and weight loss are prevalent in infectious diseases. To investigate the molecular mechanisms underlying these phenomena, we established animal models of infection-associated anorexia by administrating bacterial and viral products, lipopolysaccharide (LPS) and human immunodeficiency virus-1 transactivator protein (Tat). In these models, we found that the nuclear factor-κB (NF-κB), a pivotal transcription factor for inflammation-related proteins, was activated in the hypothalamus. In parallel, administration of LPS and Tat increased hypothalamic pro-inflammatory cytokine production, which was abrogated by inhibition of hypothalamic NF-κB. In vitro, NF-κB activation directly stimulated the transcriptional activity of pro-opiomelanocortin (POMC), a precursor of anorexigenic melanocortin, and mediated the stimulatory effects of LPS, Tat, and pro-inflammatory cytokines on POMC transcription, implying the involvement of NF-κB in controlling feeding behavior. Consistently, hypothalamic injection of LPS and Tat caused a significant reduction in food intake and body weight, which was prevented by blockade of NF-κB and melanocortin. Furthermore, disruption of IκB kinase-β, an upstream kinase of NF-κB, in POMC neurons attenuated LPS- and Tat-induced anorexia. These findings suggest that infection-associated anorexia and weight loss are mediated via NF-κB activation in hypothalamic POMC neurons. In addition, hypothalamic NF-κB was activated by leptin, an important anorexigenic hormone, and mediates leptin-stimulated POMC transcription, indicating that hypothalamic NF-κB also serves as a downstream signaling pathway of leptin. PMID:20097762

NF-kappaB activation in hypothalamic pro-opiomelanocortin neurons is essential in illness- and leptin-induced anorexia.

PubMed

Jang, Pil-Geum; Namkoong, Cherl; Kang, Gil Myoung; Hur, Man-Wook; Kim, Seung-Whan; Kim, Geun Hyang; Kang, Yeoungsup; Jeon, Min-Jae; Kim, Eun Hee; Lee, Myung-Shik; Karin, Michael; Baik, Ja-Hyun; Park, Joong-Yeol; Lee, Ki-Up; Kim, Young-Bum; Kim, Min-Seon

2010-03-26

Anorexia and weight loss are prevalent in infectious diseases. To investigate the molecular mechanisms underlying these phenomena, we established animal models of infection-associated anorexia by administrating bacterial and viral products, lipopolysaccharide (LPS) and human immunodeficiency virus-1 transactivator protein (Tat). In these models, we found that the nuclear factor-kappaB (NF-kappaB), a pivotal transcription factor for inflammation-related proteins, was activated in the hypothalamus. In parallel, administration of LPS and Tat increased hypothalamic pro-inflammatory cytokine production, which was abrogated by inhibition of hypothalamic NF-kappaB. In vitro, NF-kappaB activation directly stimulated the transcriptional activity of pro-opiomelanocortin (POMC), a precursor of anorexigenic melanocortin, and mediated the stimulatory effects of LPS, Tat, and pro-inflammatory cytokines on POMC transcription, implying the involvement of NF-kappaB in controlling feeding behavior. Consistently, hypothalamic injection of LPS and Tat caused a significant reduction in food intake and body weight, which was prevented by blockade of NF-kappaB and melanocortin. Furthermore, disruption of I kappaB kinase-beta, an upstream kinase of NF-kappaB, in POMC neurons attenuated LPS- and Tat-induced anorexia. These findings suggest that infection-associated anorexia and weight loss are mediated via NF-kappaB activation in hypothalamic POMC neurons. In addition, hypothalamic NF-kappaB was activated by leptin, an important anorexigenic hormone, and mediates leptin-stimulated POMC transcription, indicating that hypothalamic NF-kappaB also serves as a downstream signaling pathway of leptin.

Zinc-mediated attenuation of hippocampal mossy fiber long-term potentiation induced by forskolin.

PubMed

Ando, Masaki; Oku, Naoto; Takeda, Atsushi

2010-11-01

The rise in presynaptic calcium induced by high-frequency stimulation activates the calcium-calmodulin-sensitive adenylyl cyclase (AC) 1 followed by the induction of long-term potentiation (LTP) at the hippocampal mossy fiber-CA3 synapse. Zinc is released with glutamate from mossy fiber terminals. However, the role of the zinc in mossy fiber LTP is controversial. In the present study, the mechanism of zinc-mediated attenuation of mossy fiber LTP was examined in that induced by forskolin, an AC activator. Mossy fiber LTP induced by tetanic stimulation (100 Hz for 1 s) was attenuated in the presence of 5 microM ZnCl(2), whereas that induced by forskolin under test stimulation (0.1 Hz) was not attenuated. Forskolin-induced mossy fiber LTP was attenuated by perfusion with 100 microM ZnCl(2) prior to the induction. However, the zinc (100 microM) pre-perfusion did not attenuate mossy fiber LTP induced by Sp-cAMPS, an activator of protein kinase A, under test stimulation. Zinc is necessary to be taken up into mossy fiber boutons for effectively inhibiting AC activity. In hippocampal slices labeled with ZnAF-2 DA, a membrane-permeable zinc indicator, intracellular ZnAF-2 signal was increased during tetanic stimulation in the presence of 5 microM ZnCl(2), but not under test stimulation. Intracellular ZnAF-2 signal was increased under test stimulation in the presence of 100 microM ZnCl(2). These results suggest that zinc taken up into mossy fibers attenuates forskolin-induced mossy fiber LTP via inhibition of AC activity. The significance of endogenous zinc uptake by mossy fibers is discussed focused on tetanus-induced mossy fiber LTP. Copyright 2010 Elsevier Ltd. All rights reserved.

Resistance Exercise Reduces Seizure Occurrence, Attenuates Memory Deficits and Restores BDNF Signaling in Rats with Chronic Epilepsy.

PubMed

de Almeida, Alexandre Aparecido; Gomes da Silva, Sérgio; Lopim, Glauber Menezes; Vannucci Campos, Diego; Fernandes, Jansen; Cabral, Francisco Romero; Arida, Ricardo Mario

2017-04-01

Epilepsy is a disease characterized by recurrent, unprovoked seizures. Cognitive impairment is an important comorbidity of chronic epilepsy. Human and animal model studies of epilepsy have shown that aerobic exercise induces beneficial structural and functional changes and reduces the number of seizures. However, little is yet understood about the effects of resistance exercise on epilepsy. We evaluated the effects of a resistance exercise program on the number of seizures, long-term memory and expression/activation of signaling proteins in rats with epilepsy. The number of seizures was quantified by video-monitoring and long-term memory was assessed by an inhibitory avoidance test. Using western blotting, multiplex and enzyme-linked immunosorbent assays, we determined the effects of a 4-week resistance exercise program on IGF-1 and BDNF levels and ERK, CREB, mTOR activation in the hippocampus of rats with epilepsy. Rats with epilepsy submitted to resistance exercise showed a decrease in the number of seizures compared to non-exercised epileptic rats. Memory deficits were attenuated by resistance exercise. Rats with epilepsy showed an increase in IGF-1 levels which were restored to control levels by resistance exercise. BDNF levels and ERK and mTOR activation were decreased in rats with epilepsy and resistance exercise restored these to control levels. In conclusion, resistance exercise reduced seizure occurrence and mitigated memory deficits in rats with epilepsy. These resistance exercise-induced beneficial effects can be related to changes in IGF-1 and BDNF levels and its signaling protein activation. Our findings indicate that the resistance exercise might be included as complementary therapeutic strategy for epilepsy treatment.

Comparison of Instantaneous Frequency Scaling from Rain Attenuation and Optical Disdrometer Measurements at K/Q bands

NASA Technical Reports Server (NTRS)

Nessel, James; Zemba, Michael; Luini, Lorenzo; Riva, Carlo

2015-01-01

Rain attenuation is strongly dependent on the rain rate, but also on the rain drop size distribution (DSD). Typically, models utilize an average drop size distribution, such as those developed by Laws and Parsons, or Marshall and Palmer. However, individual rain events may possess drop size distributions which could be significantly different from the average and will impact, for example, fade mitigation techniques which utilize channel performance estimates from a signal at a different frequency. Therefore, a good understanding of the characteristics and variability of the raindrop size distribution is extremely important in predicting rain attenuation and instantaneous frequency scaling parameters on an event-toevent basis. Since June 2014, NASA Glenn Research Center (GRC) and the Politecnico di Milano (POLIMI) have measured the attenuation due to rain in Milan, Italy, on the 20/40 GHz beacon signal broadcast from the Alphasat TDP#5 Aldo Paraboni Q/V-band Payload. Concomitant with these measurements are the measurements of drop size distribution and rain rate utilizing a Thies Clima laser precipitation monitor (disdrometer). In this paper, we discuss the comparison of the predicted rain attenuation at 20 and 40 GHz derived from the drop size distribution data with the measured rain attenuation. The results are compared on statistical and real-time bases. We will investigate the performance of the rain attenuation model, instantaneous frequency scaling, and the distribution of the scaling factor. Further, seasonal rain characteristics will be analysed.

Assessment of C-band Polarimetric Radar Rainfall Measurements During Strong Attenuation.

NASA Astrophysics Data System (ADS)

Paredes-Victoria, P. N.; Rico-Ramirez, M. A.; Pedrozo-Acuña, A.

2016-12-01

In the modern hydrological modelling and their applications on flood forecasting systems and climate modelling, reliable spatiotemporal rainfall measurements are the keystone. Raingauges are the foundation in hydrology to collect rainfall data, however they are prone to errors (e.g. systematic, malfunctioning, and instrumental errors). Moreover rainfall data from gauges is often used to calibrate and validate weather radar rainfall, which is distributed in space. Therefore, it is important to apply techniques to control the quality of the raingauge data in order to guarantee a high level of confidence in rainfall measurements for radar calibration and numerical weather modelling. Also, the reliability of radar data is often limited because of the errors in the radar signal (e.g. clutter, variation of the vertical reflectivity profile, beam blockage, attenuation, etc) which need to be corrected in order to increase the accuracy of the radar rainfall estimation. This paper presents a method for raingauge-measurement quality-control correction based on the inverse distance weighted as a function of correlated climatology (i.e. performed by using the reflectivity from weather radar). Also a Clutter Mitigation Decision (CMD) algorithm is applied for clutter filtering process, finally three algorithms based on differential phase measurements are applied for radar signal attenuation correction. The quality-control method proves that correlated climatology is very sensitive in the first 100 kilometres for this area. The results also showed that ground clutter affects slightly the radar measurements due to the low gradient of the terrain in the area. However, strong radar signal attenuation is often found in this data set due to the heavy storms that take place in this region and the differential phase measurements are crucial to correct for attenuation at C-band frequencies. The study area is located in Sabancuy-Campeche, Mexico (Latitude 18.97 N, Longitude 91.17º W) and

Is amplitude loss of sonic waveforms due to intrinsic attenuation or source coupling to the medium?

USGS Publications Warehouse

Lee, Myung W.

2006-01-01

Sonic waveforms acquired in gas-hydrate-bearing sediments indicate strong amplitude loss associated with an increase in sonic velocity. Because the gas hydrate increases sonic velocities, the amplitude loss has been interpreted as due to intrinsic attenuation caused by the gas hydrate in the pore space, which apparently contradicts conventional wave propagation theory. For a sonic source in a fluid-filled borehole, the signal amplitude transmitted into the formation depends on the physical properties of the formation, including any pore contents, in the immediate vicinity of the source. A signal in acoustically fast material, such as gas-hydrate-bearing sediments, has a smaller amplitude than a signal in acoustically slower material. Therefore, it is reasonable to interpret the amplitude loss in the gas-hydrate-bearing sediments in terms of source coupling to the surrounding medium as well as intrinsic attenuation. An analysis of sonic waveforms measured at the Mallik 5L-38 well, Northwest Territories, Canada, indicates that a significant part of the sonic waveform's amplitude loss is due to a source-coupling effect. All amplitude analyses of sonic waveforms should include the effect of source coupling in order to accurately characterize the formation's intrinsic attenuation.

Betaine Attenuates Alcohol-Induced Pancreatic Steatosis.

PubMed

Yang, Wenjuan; Gao, Jinhang; Tai, Yang; Chen, Meng; Huang, Luming; Wen, Shilei; Huang, Zhiyin; Liu, Rui; Li, Jing; Tang, Chengwei

2016-07-01

To explore the effect of betaine on alcoholic pancreatic steatosis and its mechanism. Rats were randomly assigned to control, ethanol, or ethanol + betaine groups. Changes in pancreatic morphology; serum lipid levels; and pancreatic lipid, amylase and lipase levels were determined. The serum and adipose tissue adiponectin level was measured by an enzyme-linked immunoassay. Adiponectin receptor-1 (AdipoR1), AdipoR2, sterol regulatory element binding protein-1c (SREBP-1c), SREBP-2, and fatty acid synthetase expression levels were quantified. The SREBP-1c expression in SW1990 cells treated with various concentrations of ethanol or ethanol plus betaine and/or adiponectin was assessed. Alcohol-induced changes in pancreatic morphology were attenuated by betaine. Pancreatic triglyceride, free fatty acid and expression levels of SREBP-1c and fatty acid synthetase were elevated after ethanol feeding but remained at control levels after betaine supplementation. Alcohol-induced decreases in serum and adipose tissue adiponectin, pancreatic AdipoR1, amylase, and lipase were attenuated by betaine. Serum triglyceride and free fatty acid levels were elevated after alcohol consumption and remained higher after betaine supplementation compared with controls. Betaine and/or adiponectin suppressed alcohol-induced SREBP-1c upregulation in vitro. Betaine attenuated alcoholic-induced pancreatic steatosis most likely by suppressing pancreatic SREBP-1c both directly and through the restoration of adiponectin signaling.

Rain depolarization and attenuation measurements at 11.7, 19.04, and 28.56 GHz - A description of the experiment and some preliminary results

NASA Technical Reports Server (NTRS)

Bostian, C. W.; Holt, S. B., Jr.; Kauffman, S. R.; Manus, E. A.; Marshall, R. E.; Stuzman, W. L.; Wiley, P. H.

1977-01-01

The considered investigation made use of the Communications Technology Satellite (CTS) downlink and the beacons carried by the Comstar satellites. The general behavior of rain attenuation and depolarization is illustrated with the aid of data from a storm which took place on July 15, 1976. The effect of the rain on the copolarized signal is indicated in a graph. Another graph shows the behavior of the cross-polarized signal component. Phase effects are also considered together with statistical curves for attenuation. The considered data from CTS indicate that, at least during summer convective storms, attenuation at 11.7 GHz is much more severe than anticipated. Attenuation may be a more serious impediment to dual polarized satellite links at this frequency than is depolarization.

N-Acetylcysteine Attenuates Hexavalent Chromium-Induced Hypersensitivity through Inhibition of Cell Death, ROS-Related Signaling and Cytokine Expression

PubMed Central

Huang, Chien-Cheng; Sheu, Hamm-Ming; Tsai, Jui-Chen; Lin, Chia-Ho; Wang, Ying-Jan; Wang, Bour-Jr

2014-01-01

Chromium hypersensitivity (chromium-induced allergic contact dermatitis) is an important issue in occupational skin disease. Hexavalent chromium (Cr (VI)) can activate the Akt, Nuclear factor κB (NF-κB), and Mitogen-activated protein kinase (MAPK) pathways and induce cell death, via the effects of reactive oxygen species (ROS). Recently, cell death stimuli have been proposed to regulate the release of inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1). However, the exact effects of ROS on the signaling molecules and cytotoxicity involved in Cr(VI)-induced hypersensitivity have not yet been fully demonstrated. N-acetylcysteine (NAC) could increase glutathione levels in the skin and act as an antioxidant. In this study, we investigated the effects of NAC on attenuating the Cr(VI)-triggered ROS signaling in both normal keratinocyte cells (HaCaT cells) and a guinea pig (GP) model. The results showed the induction of apoptosis, autophagy and ROS were observed after different concentrations of Cr(VI) treatment. HaCaT cells pretreated with NAC exhibited a decrease in apoptosis and autophagy, which could affect cell viability. In addition, Cr (VI) activated the Akt, NF-κB and MAPK pathways thereby increasing IL-1α and TNF-α production. However, all of these stimulation phenomena could be inhibited by NAC in both of in vitro and in vivo studies. These novel findings indicate that NAC may prevent the development of chromium hypersensitivity by inhibiting of ROS-induced cell death and cytokine expression. PMID:25248126

In vitro attenuation of impact shock in equine digits.

PubMed

Lanovaz, J L; Clayton, H M; Watson, L G

1998-09-01

This study was designed to test the impact characteristics of the equine digit in vitro with the objective of providing a better understanding of the role of the digital structures in the attenuation of impact shock. Uni-axial accelerometers were mounted on cadaver digits on the distolateral hoof wall, the proximolateral hoof wall, the dorsal surface of the second phalanx, and the mid-lateral first phalanx. The hoof-mounted accelerometers were aligned with the hoof tubules while the bone-mounted accelerometers were oriented along the longitudinal axis of the bone. Each digit was mounted in a test apparatus designed to simulate impact of the hoof with the ground during locomotion. The digits were subjected to 3 impact trials against a barrier at each of 3 vertical impact velocities that simulated a forward trotting velocity in the range of 2.67 to 4.46 m/s. The impact deceleration tended to increase with impact velocity. Attenuation of the impact shock by the digital tissues resulted in a reduction in impact decleration in the more proximal measuring locations. The interphalangeal joints appeared to play a larger role in amplitude attenuation than the hoof wall or the soft tissue structures within the hoof wall. The signal frequency data showed that the soft tissues within the hoof acted as a 'lowpass' filter, attenuating the higher deceleration frequencies. The hoof wall and the interphalangeal joints showed little frequency attenuation.

N-Acetylcysteine and Allopurinol Confer Synergy in Attenuating Myocardial Ischemia Injury via Restoring HIF-1α/HO-1 Signaling in Diabetic Rats

PubMed Central

Mao, Xiaowen; Wang, Tingting; Liu, Yanan; Irwin, Michael G.; Ou, Jing-song; Liao, Xiao-long; Gao, Xia; Xu, Yuan; Ng, Kwok F. J.; Vanhoutte, Paul M.; Xia, Zhengyuan

2013-01-01

Objectives To determine whether or not the antioxidants N-acetylcysteine (NAC) and allopurinol (ALP) confer synergistic cardioprotection against myocardial ischemia/reperfusion (MI/R) injury by stabilizing hypoxia inducible factor 1α (HIF-1α)/heme oxygenase 1 (HO-1) signaling in diabetic myocardium. Methods Control or diabetic [streptozotocin (STZ)-induced] Sprague Dawley rats received vehicle or NAC, ALP or their combination for four weeks starting one week after STZ injection. The animals were then subjected to thirty minutes of coronary artery occlusion followed by two hours reperfusion in the absence or presence of the selective HO-1 inhibitor, tin protoporphyrin-IX (SnPP-IX) or the HIF-1α inhibitor 2-Methoxyestradiol (2ME2). Cardiomyocytes exposed to high glucose were subjected to hypoxia/re-oxygenation in the presence or absence of HIF-1α and HO-1 achieved by gene knock-down with related siRNAs. Results Myocardial and plasma levels of 15-F2t-isoprostane, an index of oxidative stress, were significantly increased in diabetic rats while cardiac HO-1 protein and activity were reduced; this was accompanied with reduced cardiac protein levels of HIF-1α, and increased post-ischemic myocardial infarct size and cellular injury. NAC and ALP given alone and in particular their combination normalized cardiac levels of HO-1 and HIF-1α protein expression and prevented the increase in 15-F2t-isoprostane, resulting in significantly attenuated post-ischemic myocardial infarction. NAC and ALP also attenuated high glucose-induced post-hypoxic cardiomyocyte death in vitro. However, all the above protective effects of NAC and ALP were cancelled either by inhibition of HO-1 or HIF-1α with SnPP-IX and 2ME2 in vivo or by HO-1 or HIF-1α gene knock-down in vitro. Conclusion NAC and ALP confer synergistic cardioprotection in diabetes via restoration of cardiac HIF-1α and HO-1 signaling. PMID:23874823

Mixture model based joint-MAP reconstruction of attenuation and activity maps in TOF-PET

NASA Astrophysics Data System (ADS)

Hemmati, H.; Kamali-Asl, A.; Ghafarian, P.; Ay, M. R.

2018-06-01

A challenge to have quantitative positron emission tomography (PET) images is to provide an accurate and patient-specific photon attenuation correction. In PET/MR scanners, the nature of MR signals and hardware limitations have led to a real challenge on the attenuation map extraction. Except for a constant factor, the activity and attenuation maps from emission data on TOF-PET system can be determined by the maximum likelihood reconstruction of attenuation and activity approach (MLAA) from emission data. The aim of the present study is to constrain the joint estimations of activity and attenuation approach for PET system using a mixture model prior based on the attenuation map histogram. This novel prior enforces non-negativity and its hyperparameters can be estimated using a mixture decomposition step from the current estimation of the attenuation map. The proposed method can also be helpful on the solving of scaling problem and is capable to assign the predefined regional attenuation coefficients with some degree of confidence to the attenuation map similar to segmentation-based attenuation correction approaches. The performance of the algorithm is studied with numerical and Monte Carlo simulations and a phantom experiment and was compared with MLAA algorithm with and without the smoothing prior. The results demonstrate that the proposed algorithm is capable of producing the cross-talk free activity and attenuation images from emission data. The proposed approach has potential to be a practical and competitive method for joint reconstruction of activity and attenuation maps from emission data on PET/MR and can be integrated on the other methods.

Melanocortin Receptor Agonists Facilitate Oxytocin-Dependent Partner Preference Formation in the Prairie Vole.

PubMed

Modi, Meera E; Inoue, Kiyoshi; Barrett, Catherine E; Kittelberger, Kara A; Smith, Daniel G; Landgraf, Rainer; Young, Larry J

2015-07-01

The central melanocortin (MC) system has been widely studied for its effects on food intake and sexual behavior. However, the MC system, and more specifically the MC4 receptor (MC4R), also interacts with neurochemical systems that regulate socioemotional behaviors, including oxytocin (OT) and dopamine. In monogamous prairie voles, OT and dopamine interact to promote partner preference formation, a laboratory measure of an enduring social bond between mates. Here we investigated the effects of MC receptor activation on partner preference formation in prairie voles, as well as the interaction between the MC and OT systems during this process. Peripheral administration of the brain penetrant MC3/4R receptor peptide agonist, Melanotan II (MTII), and the highly selective, small-molecule MC4R agonist, Pf-446687, enhanced partner preference formation in the prairie vole, but not in the non-monogamous meadow vole. MTII-induced partner preferences were enduring, as they were present 1 week after drug manipulation. The prosocial effects of MCR agonists may be mediated, in part, through modulation of OT, as coadministration of an OT receptor antagonist prevented MTII-induced partner preferences. MTII also selectively activated hypothalamic OT neurons and potentiated central OT release. As OT has been shown to enhance some aspects of social cognition in humans, our data suggest that the MC4R may be a viable therapeutic target for enhancing social function in psychiatric disorders, including autism spectrum disorders and schizophrenia, potentially through activation of the OT system.

Melanocortin Receptor Agonists Facilitate Oxytocin-Dependent Partner Preference Formation in the Prairie Vole

PubMed Central

Modi, Meera E; Inoue, Kiyoshi; Barrett, Catherine E; Kittelberger, Kara A; Smith, Daniel G; Landgraf, Rainer; Young, Larry J

2015-01-01

The central melanocortin (MC) system has been widely studied for its effects on food intake and sexual behavior. However, the MC system, and more specifically the MC4 receptor (MC4R), also interacts with neurochemical systems that regulate socioemotional behaviors, including oxytocin (OT) and dopamine. In monogamous prairie voles, OT and dopamine interact to promote partner preference formation, a laboratory measure of an enduring social bond between mates. Here we investigated the effects of MC receptor activation on partner preference formation in prairie voles, as well as the interaction between the MC and OT systems during this process. Peripheral administration of the brain penetrant MC3/4R receptor peptide agonist, Melanotan II (MTII), and the highly selective, small-molecule MC4R agonist, Pf-446687, enhanced partner preference formation in the prairie vole, but not in the non-monogamous meadow vole. MTII-induced partner preferences were enduring, as they were present 1 week after drug manipulation. The prosocial effects of MCR agonists may be mediated, in part, through modulation of OT, as coadministration of an OT receptor antagonist prevented MTII-induced partner preferences. MTII also selectively activated hypothalamic OT neurons and potentiated central OT release. As OT has been shown to enhance some aspects of social cognition in humans, our data suggest that the MC4R may be a viable therapeutic target for enhancing social function in psychiatric disorders, including autism spectrum disorders and schizophrenia, potentially through activation of the OT system. PMID:25652247

SIRT1 protects rat lung tissue against severe burn-induced remote ALI by attenuating the apoptosis of PMVECs via p38 MAPK signaling

PubMed Central

Bai, Xiaozhi; Fan, Lei; He, Ting; Jia, Wenbin; Yang, Longlong; Zhang, Jun; Liu, Yang; Shi, Jihong; Su, Linlin; Hu, Dahai

2015-01-01

Silent information regulator type-1 (SIRT1) has been reported to be involved in the cardiopulmonary protection. However, its role in the pathogenesis of burn-induced remote acute lung injury (ALI) is currently unknown. The present study aims to investigate the role of SIRT1 in burn-induced remote ALI and the involved signaling pathway. We observed that SIRT1 expression in rat lung tissue after burn injury appeared an increasing trend after a short period of suppression. The upregulation of SIRT1 stimulated by resveratrol exhibited remission of histopathologic changes, reduction of cell apoptosis, and downregulation of pro-inflammatory cytokines in rat pulmonary tissues suffering from severe burn. We next used primary pulmonary microvascular endothelial cells (PMVECs) challenged by burn serum (BS) to simulate in vivo rat lung tissue after burn injury, and found that BS significantly suppressed SIRT1 expression, increased cell apoptosis, and activated p38 MAPK signaling. The use of resveratrol reversed these effects, while knockdown of SIRT1 by shRNA further augmented BS-induced increase of cell apoptosis and activation of p38 MAPK. Taken together, these results indicate that SIRT1 might protect lung tissue against burn-induced remote ALI by attenuating PMVEC apoptosis via p38 MAPK signaling, suggesting its potential therapeutic effects on the treatment of ALI. PMID:25992481

Increased ceramide content and NFkB signaling may contribute to the attenuation of anabolic signaling after resistance exercise in aged males

USDA-ARS?s Scientific Manuscript database

One of the most fundamental adaptive physiological events is the response of skeletal muscle to high-intensity resistance exercise, resulting in increased protein synthesis and ultimately larger muscle mass. However, muscle growth in response to contraction is attenuated in older humans. Impaired co...

Purification and growth of melanocortin 1 receptor (Mc1r)-defective primary murine melanocytes is dependent on stem cell factor from keratinocyte-conditioned media

PubMed Central

Scott, Timothy L.; Wakamatsu, Kazumasa; Ito, Shosuke; D’Orazio, John A.

2015-01-01

Summary The melanocortin 1 receptor (MC1R) is a transmembrane Gs-coupled surface protein found on melanocytes that binds melanocyte stimulating hormone (MSH) and mediates activation of adenylyl cyclase and generation of the second messenger cAMP. MC1R regulates growth and differentiation of melanocytes and protects against carcinogenesis. Persons with loss-of-function polymorphisms of MC1R tend to be UV-sensitive (fair-skinned and with a poor tanning response) and are at high risk for melanoma. Mechanistic studies of the role of MC1R in melanocytic UV responses, however, have been hindered in part because Mc1r-defective primary murine melanocytes have been difficult to culture in vitro. Until now, effective growth of murine melanocytes has depended on cAMP stimulation with adenylyl cyclase activating or phosphodiesterase inhibiting agents. However, rescuing cAMP in the setting of defective MC1R signaling would be expected to confound experiments directly testing MC1R function on melanocytic UV responses. Here we report a novel method of culturing primary murine melanocytes in the absence of pharmacologic cAMP stimulation by incorporating conditioned supernatants containing stem cell factor (SCF) derived from primary keratinocytes. Importantly, this method seems to permit similar pigment expression by cultured melanocytes as that found in the skin of their parental murine strains. This novel approach will allow mechanistic investigation into MC1R’s role in protection against UV-mediated carcinogenesis and determination of the role of melanin pigment subtypes on UV-mediated melanocyte responses. PMID:19633898

SNPs of melanocortin 4 receptor (MC4R) associated with body weight in Beagle dogs.

PubMed

Zeng, Ruixia; Zhang, Yibo; Du, Peng

2014-01-01

Melanocortin 4 receptor (MC4R), which is associated with inherited human obesity, is involoved in food intake and body weight of mammals. To study the relationships between MC4R gene polymorphism and body weight in Beagle dogs, we detected and compared the nucleotide sequence of the whole coding region and 3'- and 5'- flanking regions of the dog MC4R gene (1214 bp). In 120 Beagle dogs, two SNPs (A420C, C895T) were identified and their relation with body weight was analyzed with RFLP-PCR method. The results showed that the SNP at A420C was significantly associated with canine body weight trait when it changed amino acid 101 of the MC4R protein from asparagine to threonine, while canine body weight variations were significant in female dogs when MC4R nonsense mutation at C895T. It suggested that the two SNPs might affect the MC4R gene's function which was relative to body weight in Beagle dogs. Therefore, MC4R was a candidate gene for selecting different size dogs with the MC4R SNPs (A420C, C895T) being potentially valuable as a genetic marker.

7A.06: MATERNAL OBESITY AND THE DEVELOPMENTAL PROGRAMMING OF HYPERTENSION: ALTERED LEPTIN SIGNALLING PATHWAY IN THE CENTRAL NERVOUS SYSTEM.

PubMed

Lim, J; Burke, S; Head, G A

2015-06-01

The prevalence of obesity in women among child baring age is increasing and this has been parallel to the increase in obesity in general population around the world. We investigated the trans-generational 'programming' of leptin signalling in the central nervous system (CNS) to increase blood pressure (BP), heart rate (HR) and renal sympathetic nerve activity (RSNA) following a high fat diet (HFD)feeding in mothers. Female New Zealand White rabbits were fed a high fat (13%) diet (mHFD) or a control diet (mCD) prior mating and during pregnancy. Kittens from mCD rabbits were subdivided and fed HFD for 10days (mCD10dHFD) at 15 weeks of age. All rabbits received an intracerebroventricular (ICV) catheter into the lateral ventricle and a recording electrode on the left renal nerve. Experiments were conducted in conscious rabbits and BP, HR and RSNA was measured. Rabbits received an increasing doses of ICV Melanocortin receptor antagonist (SHU9119),alpha-Melanocortin stimulating hormone (alpha-MSH) and a single dose of Leptin antagonist. ICV SHU9119 reduced BP (-5.8 ± 0.7mmHg and -4.1 ± 0.9mmHg) and RSNA (-2.4 ± 0.3 nu and -0.7 ± 0.3 nu) in mHFD and mCD10dHFD rabbits (P < 0.001). Leptin antagonist reduced BP and RSNA only in mHFD rabbits (-2.1 ± 0.5mmHg and -2.7nu, respectively). alpha-MSH injection increased BP, HR and RSNA in both mHFD and mNFD10dHFD rabbits (P < 0.05). Total % fat was increased (50%) in all rabbits that had HFD. Obesity during pregnancy 'programs' leptin signalling pathway in the CNS of the offspring during development. Leptin via activation of melanocirtin pathway plays a key role in the CNS contributing to the pressor and tachycardic effects as well as renal sympathetic nerve activity in the pathophysiology of obesity.

Prevalence of melanocortin receptor 4 (MC4R) V103I gene variant and its association with obesity among the Kampar Health Clinic cohort, Perak, Malaysia.

PubMed

Chua, H N; Fan, S H; Say, Y H

2012-04-01

This study investigated the prevalence of the Melanocortin receptor 4 (MC4R) V1031 gene variant and its association with obesity among a cohort of 254 patients (101 males; 118 obese) attending the Kampar Health Clinic. Genotyping revealed the mutated I allele frequency of 0.02, no homozygous mutated (II), and similar distribution of V and I alleles across BMI groups, genders and ethnic groups. No significant difference was found for the means of anthropometric measurements between alleles. Prevalence of this gene variant among the Malaysian cohort was similar with previous populations (2-4% of mutated allele carrier), but was not associated with obesity.

Scion on a Stock Producing siRNAs of Potato Spindle Tuber Viroid (PSTVd) Attenuates Accumulation of the Viroid

PubMed Central

Kasai, Atsushi; Sano, Teruo; Harada, Takeo

2013-01-01

Plants can attenuate the replication of plant viruses and viroids by RNA silencing induced by virus and viroid infection. In higher plants, silencing signals such as small interfering RNAs (siRNAs) produced by RNA silencing can be transported systemically through phloem, so it is anticipated that antiviral siRNA signals produced in a stock would have the potential to attenuate propagation of viruses or viroids in the scion. To test whether this is indeed the case, we prepared transgenic tobacco (Nicotiana benthamiana) expressing a hairpin RNA (hpRNA) of Potato spindle tuber viroid (PSTVd) in companion cells by using a strong companion cell-specific promoter. A grafting experiment of the wild type tobacco scion on the top of the transgenic tobacco stock revealed that accumulation of PSTVd challenge-inoculated into the scion was apparently attenuated compared to the control grafted plants. These results indicate that genetically modified rootstock expressing viroid-specific siRNAs can attenuate viroid accumulation in a non-genetically modified scion grafted on the stock. PMID:23469061

The self in action effects: selective attenuation of self-generated sounds.

PubMed

Weiss, Carmen; Herwig, Arvid; Schütz-Bosbach, Simone

2011-11-01

The immediate experience of self-agency, that is, the experience of generating and controlling our actions, is thought to be a key aspect of selfhood. It has been suggested that this experience is intimately linked to internal motor signals associated with the ongoing actions. These signals should lead to an attenuation of the sensory consequences of one's own actions and thereby allow classifying them as self-generated. The discovery of shared representations of actions between self and other, however, challenges this idea and suggests similar attenuation of one's own and other's sensory action effects. Here, we tested these assumptions by comparing sensory attenuation of self-generated and observed sensory effects. More specifically, we compared the loudness perception of sounds that were either self-generated, generated by another person or a computer. In two experiments, we found a reduced perception of loudness intensity specifically related to self-generation. Furthermore, the perception of sounds generated by another person and a computer did not differ from each other. These findings indicate that one's own agentive influence upon the outside world has a special perceptual quality which distinguishes it from any sort of external influence, including human and non-human sources. This suggests that a real sense of self-agency is not a socially shared but rather a unique and private experience. Copyright © 2011 Elsevier B.V. All rights reserved.

Effect of the melanocortin-3 receptor Thr6Lys and Val81Ile genetic variants on body composition and substrate oxidation in Chilean obese children.

PubMed

Obregón, Ana M; Diaz, Erik; Santos, Jose L

2012-03-01

Mice genetically deficient in the melanocortin-3 receptor gene are characterized by normal body weight, increased body fat, mild hypophagia, reduced locomotor activity, and increased respiratory quotient compared with wild-type mice. In humans, the 6Lys-81Ile haplotype of melanocortin-3 receptor (MC3R) gene has been associated with childhood obesity, higher body fat percentage, and reduced fat oxidation compared to non-carriers. The aim of this study was to evaluate the association between MC3R 6Lys-81Ile haplotype with body composition and substrate oxidation in response to moderate exercise in obese children. Eight Chilean obese children (aged 8-12) carriers of MC3R 6Lys-81Ile haplotype were compared with eight age-gender-matched obese non-carriers. Children were identified through a previous cross-sectional study on genetic determinants of childhood obesity (n = 229). Genotypes for MC3R Thr6Lys and Val81Ile were determined by polymerase chain reaction-restriction fragment length polymorphism. Body composition was assessed by the four-compartment model (dual-energy X-ray absorptiometry, total body water by the deuterium dilution technique, and total fat mass by air-displacement plethysmography). Substrate oxidation was assessed by indirect calorimetry in response to moderate exercise (60% VO(2 max)). Wilcoxon matched-pairs test was used to compare quantitative variables. No significant differences among carriers and non-carriers were found in anthropometrical and body composition measurements. The Carriers of the 6Lys-81Ile haplotype showed higher respiratory quotient (p = 0.06) and a significantly higher glucose oxidation (p = 0.01) compared with non-carriers after standardization for fat-free mass. Our results are consistent with a possible participation of MC3R 6Lys-81Ile variants in glucose oxidation in response to moderate exercise.

Seismic evidence for broad attenuation anomalies in the asthenosphere beneath the Pacific Ocean

NASA Astrophysics Data System (ADS)

Adenis, Alice; Debayle, Eric; Ricard, Yanick

2017-06-01

We present QADR17, a global model of Rayleigh-wave attenuation based on a massive surface wave data set (372 629 frequency-dependent attenuation curves in the period range 50-260 s). We correct for focusing-defocusing effects and geometrical spreading, and perform a stringent selection to only keep robust observations. Then, data with close epicentres recorded at the same station are clustered, as they sample the same Earth's structure. After this pre-selection, our data set consists of about 35 000 curves that constrain the Rayleigh-wave intrinsic attenuation in the upper mantle. The logarithms of the attenuation along the individual rays are then inverted to obtain global maps of the logarithm of the local attenuation. After a first inversion, outliers are rejected and a second inversion yields a variance reduction of about 45 per cent. Our attenuation maps present strong agreement with surface tectonics at periods lower than 200 s, with low attenuation under continents and high attenuation under oceans. Over oceans, attenuation decreases with increasing crustal ages, but at periods sensitive to the uppermost 150 km, mid-ocean ridges are not characterized by a very localized anomaly, in contrast to what is commonly observed for seismic velocity models. Attenuation is rather well correlated with hotspots, especially in the Pacific ocean, where a strong attenuating anomaly is observed in the long wavelength component of our signal at periods sampling the oceanic asthenosphere. We suggest that this anomaly results from the horizontal spreading of several thermal plumes within the asthenosphere. Strong velocity reductions associated with high attenuation anomalies of moderate amplitudes beneath the East Pacific Rise, the Red Sea and the eastern part of Asia may require additional mechanisms, such as partial melting.

Gating-signal propagation by a feed-forward neural motif

NASA Astrophysics Data System (ADS)

Liang, Xiaoming; Yanchuk, Serhiy; Zhao, Liang

2013-07-01

We study the signal propagation in a feed-forward motif consisting of three bistable neurons: Two input neurons receive input signals and the third output neuron generates the output. We find that a weak input signal can be propagated from the input neurons to the output neuron without amplitude attenuation. We further reveal that the initial states of the input neurons and the coupling strength act as signal gates and determine whether the propagation is enhanced or not. We also investigate the effect of the input signal frequency on enhanced signal propagation.

RANK-c attenuates aggressive properties of ER-negative breast cancer by inhibiting NF-κB activation and EGFR signaling.

PubMed

Sirinian, Chaido; Papanastasiou, Anastasios D; Schizas, Michail; Spella, Magda; Stathopoulos, Georgios T; Repanti, Maria; Zarkadis, Ioannis K; King, Tari A; Kalofonos, Haralabos P

2018-05-29

The RANK/RANKL axis emerges as a key regulator of breast cancer initiation, progression, and metastasis. RANK-c is a RANK receptor isoform produced through alternative splicing of the TNFRSF11A (RANK) gene and a dominant-negative regulator of RANK-induced nuclear factor-κB (NF-κB) activation. Here we report that RANK-c transcript is expressed in 3.2% of cases in The Cancer Genome Atlas breast cancer cohort evenly between ER-positive and ER-negative cases. Nevertheless, the ratio of RANK to RANK-c (RANK/RANK-c) is increased in ER-negative breast cancer cell lines compared to ER-positive breast cancer cell lines. In addition, forced expression of RANK-c in ER-negative breast cancer cell lines inhibited stimuli-induced NF-κB activation and attenuated migration, invasion, colony formation, and adhesion of cancer cells. Further, RANK-c expression in MDA-MB-231 cells inhibited lung metastasis and colonization in vivo. The RANK-c-mediated inhibition of cancer cell aggressiveness and nuclear factor-κB (NF-κB) activation in breast cancer cells seems to rely on a RANK-c/TNF receptor-associated factor-2 (TRAF2) protein interaction. This was further confirmed by a mutated RANK-c that is unable to interact with TRAF2 and abolishes the ability to attenuate NF-κB activation, migration, and invasion. Additional protein interaction characterization revealed epidermal growth factor receptor (EGFR) as a novel interacting partner for RANK-c in breast cancer cells with a negative effect on EGFR phosphorylation and EGF-dependent downstream signaling pathway activation. Our findings further elucidate the complex molecular biology of the RANKL/RANK system in breast cancer and provide preliminary data for RANK-c as a possible marker for disease progression and aggressiveness.

Structure-activity relationship of linear tetrapeptides Tic-DPhe-Arg-Trp-NH2 at the human melanocortin-4 receptor and effects on feeding behaviors in rat.

PubMed

Ye, Zhixiong; MacNeil, Tanya; Weinberg, David H; Kalyani, Rubana N; Tang, Rui; Strack, Alison M; Murphy, Beth A; Mosley, Ralph T; Euan MacIntyre, D; Van der Ploeg, Lex H T; Patchett, Arthur A; Wyvratt, Matthew J; Nargund, Ravi P

2005-10-01

The melanocortin subtype-4 receptor (MC4R) has been implicated in the control of feeding behavior and body weight regulation. A series of tetrapeptides, based on Tic-DPhe-Arg-Trp-NH2-a mimic of the putative message sequence "His-Phe-Arg-Trp" and modified at the DPhe position, were prepared and pharmacologically characterized for potency and selectivity. Substitution of His with Tic gave peptides with significant increases in selectivity. The effects of the substitution pattern of DPhe were investigated and it has significant influences on potency and the level of the maximum cAMP accumulation. Intracerebroventricular administration of peptide 10 induced significant inhibition of cumulative overnight food intake and feeding duration in rats.

Attenuation of co- and cross-polarized electric fields of waves through a layer of dielectric spheroids

NASA Astrophysics Data System (ADS)

Russchenberg, H. W. J.; Ligthart, L. P.; de Wolf, David A.

1991-02-01

A recent model (de Wolf et al., Sept. 1990) for analyzing radar reflections from the layer of melting ice hydrometeors is adjusted and expanded for analyzing line-of-sight attenuation of copolar and cross-polar signals at wavelengths that are comparable to the particle sizes. Expressions for copolar and cross-polar attenuation discrimination are derived. It is shown with a parametric study that these quantities have the expected behavior.

Ketoconazole attenuates radiation-induction of tumor necrosis factor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hallahan, D.E.; Virudachalam, S.; Kufe, D.W.

1994-07-01

Previous work has demonstrated that inhibitors of phospholipase A2 attenuate ionizing radiation-induced arachidonic acid production, protein kinase C activation, and prevent subsequent induction of the tumor necrosis factor gene. Because arachidonic acid contributes to radiation-induced tumor necrosis factor expression, the authors analyzed the effects of agents which alter arachidonate metabolism on the regulation of this gene. Phospholipase A2 inhibitors quinicrine, bromphenyl bromide, and pentoxyfylline or the inhibitor of lipoxygenase (ketoconazole) or the inhibitor of cycloxygenase (indomethacine) were added to cell culture 1 h prior to irradiation. Radiation-induced tumor necrosis factor gene expression was attenuated by each of the phospholipase A2more » inhibitors (quinicrine, bromphenylbromide, and pentoxyfylline). Furthermore, ketoconazole attenuated X ray induced tumor necrosis factor gene expression. Conversely, indomethacin enhanced tumor necrosis factor expression following irradiation. The finding that radiation-induced tumor necrosis factor gene expression was attenuated by ketoconazole suggests that the lipoxygenase pathway participates in signal transduction preceding tumor necrosis factor induction. Enhancement of tumor necrosis factor expression by indomethacin following irradiation suggests that prostaglandins produced by cyclooxygenase act as negative regulators of tumor necrosis factor expression. Inhibitors of tumor necrosis factor induction ameliorate acute and subacute sequelae of radiotherapy. The authors propose therefore, that ketoconazole may reduce acute radiation sequelae such as mucositis and esophagitis through a reduction in tumor necrosis factor induction or inhibition of phospholipase A2 in addition to its antifungal activity. 25 refs., 2 figs.« less

Adolescent Alcohol Exposure-Induced Changes in Alpha-Melanocyte Stimulating Hormone and Neuropeptide Y Pathways via Histone Acetylation in the Brain During Adulthood.

PubMed

Kokare, Dadasaheb M; Kyzar, Evan J; Zhang, Huaibo; Sakharkar, Amul J; Pandey, Subhash C

2017-09-01

Adolescent intermittent ethanol exposure causes long-lasting alterations in brain epigenetic mechanisms. Melanocortin and neuropeptide Y signaling interact and are affected by ethanol exposure in the brain. Here, the persistent effects of adolescent intermittent ethanol on alpha-melanocyte stimulating hormone, melanocortin 4 receptor, and neuropeptide Y expression and their regulation by histone acetylation mechanisms were investigated in adulthood. Male rats were exposed to adolescent intermittent ethanol (2 g/kg, i.p.) or volume-matched adolescent intermittent saline from postnatal days 28 to 41 and allowed to grow to postnatal day 92. Anxiety-like behaviors were measured by the elevated plus-maze test. Brain regions from adult rats were used to examine changes in alpha-melanocyte stimulating hormone, melanocortin 4 receptor, and neuropeptide Y expression and the histone acetylation status of their promoters. Adolescent intermittent ethanol-exposed adult rats displayed anxiety-like behaviors and showed increased pro-opiomelanocortin mRNA levels in the hypothalamus and increased melanocortin 4 receptor mRNA levels in both the amygdala and hypothalamus compared with adolescent intermittent saline-exposed adult rats. The alpha-Melanocyte stimulating hormone and melanocortin 4 receptor protein levels were increased in the central and medial nucleus of the amygdala, paraventricular nucleus, and arcuate nucleus of the hypothalamus in adolescent intermittent ethanol-exposed compared with adolescent intermittent saline-exposed adult rats. Neuropeptide Y protein levels were decreased in the central and medial nucleus of the amygdala of adolescent intermittent ethanol-exposed compared with adolescent intermittent saline-exposed adult rats. Histone H3K9/14 acetylation was decreased in the neuropeptide Y promoter in the amygdala but increased in the melanocortin 4 receptor gene promoter in the amygdala and the melanocortin 4 receptor and pro-opiomelanocortin promoters in the

A simple model for deep tissue attenuation correction and large organ analysis of Cerenkov luminescence imaging

NASA Astrophysics Data System (ADS)

Habte, Frezghi; Natarajan, Arutselvan; Paik, David S.; Gambhir, Sanjiv S.

2014-03-01

Cerenkov luminescence imaging (CLI) is an emerging cost effective modality that uses conventional small animal optical imaging systems and clinically available radionuclide probes for light emission. CLI has shown good correlation with PET for organs of high uptake such as kidney, spleen, thymus and subcutaneous tumors in mouse models. However, CLI has limitations for deep tissue quantitative imaging since the blue-weighted spectral characteristics of Cerenkov radiation attenuates highly by mammalian tissue. Large organs such as the liver have also shown higher signal due to the contribution of emission of light from a greater thickness of tissue. In this study, we developed a simple model that estimates the effective tissue attenuation coefficient in order to correct the CLI signal intensity with a priori estimated depth and thickness of specific organs. We used several thin slices of ham to build a phantom with realistic attenuation. We placed radionuclide sources inside the phantom at different tissue depths and imaged it using an IVIS Spectrum (Perkin-Elmer, Waltham, MA, USA) and Inveon microPET (Preclinical Solutions Siemens, Knoxville, TN). We also performed CLI and PET of mouse models and applied the proposed attenuation model to correct CLI measurements. Using calibration factors obtained from phantom study that converts the corrected CLI measurements to %ID/g, we obtained an average difference of less that 10% for spleen and less than 35% for liver compared to conventional PET measurements. Hence, the proposed model has a capability of correcting the CLI signal to provide comparable measurements with PET data.

The downregulation of sweet taste receptor signaling in enteroendocrine L-cells mediates 3-deoxyglucosone-induced attenuation of high glucose-stimulated GLP-1 secretion.

PubMed

Wang, Fei; Song, Xiudao; Zhou, Liang; Liang, Guoqiang; Huang, Fei; Jiang, Guorong; Zhang, Lurong

2017-12-26

Sweet taste receptors (STRs) involve in regulating the release of glucose-stimulated glucagon-like peptide-1 (GLP-1). Our in vivo and in vitro studies found that 3-deoxyglucosone (3DG) inhibited glucose-stimulated GLP-1 secretion. This study investigated the role of STRs in 3DG-induced inhibition of high glucose-stimulated GLP-1 secretion. STC-1 cells were incubated with lactisole or 3DG for 1 h under 25 mM glucose conditions. Western blotting was used to study the expression of STRs signaling molecules and ELISA was used to analyse GLP-1 and cyclic adenosine monophosphate (cAMP) levels. Lactisole inhibited GLP-1 secretion. Exposure to 25 mM glucose increased the expressions of STRs subunits when compared with 5.6 mM glucose. 3DG decreased GLP-1 secretion and STRs subunits expressions, with affecting other components of STRs pathway, including the downregulation of transient receptor potential cation channel subfamily M member 5 (TRPM5) expression and the reduction of intracellular cAMP levels. 3DG attenuates high glucose-stimulated GLP-1 secretion by reducing STR subunit expression and downstream signaling components.

Short-term pyrrolidine dithiocarbamate administration attenuates cachexia-induced alterations to muscle and liver in ApcMin/+ mice.

PubMed

Narsale, Aditi A; Puppa, Melissa J; Hardee, Justin P; VanderVeen, Brandon N; Enos, Reilly T; Murphy, E Angela; Carson, James A

2016-09-13

Cancer cachexia is a complex wasting condition characterized by chronic inflammation, disrupted energy metabolism, and severe muscle wasting. While evidence in pre-clinical cancer cachexia models have determined that different systemic inflammatory inhibitors can attenuate several characteristics of cachexia, there is a limited understanding of their effects after cachexia has developed, and whether short-term administration is sufficient to reverse cachexia-induced signaling in distinctive target tissues. Pyrrolidine dithiocarbamate (PDTC) is a thiol compound having anti-inflammatory and antioxidant properties which can inhibit STAT3 and nuclear factor κB (NF-κB) signaling in mice. This study examined the effect of short-term PDTC administration to ApcMin/+ mice on cachexia-induced disruption of skeletal muscle protein turnover and liver metabolic function. At 16 weeks of age ApcMin/+ mice initiating cachexia (7% BW loss) were administered PDTC (10mg/kg bw/d) for 2 weeks. Control ApcMin/+ mice continued to lose body weight during the treatment period, while mice receiving PDTC had no further body weight decrease. PDTC had no effect on either intestinal tumor burden or circulating IL-6. In muscle, PDTC rescued signaling disrupting protein turnover regulation. PDTC suppressed the cachexia induction of STAT3, increased mTORC1 signaling and protein synthesis, and suppressed the induction of Atrogin-1 protein expression. Related to cachectic liver metabolic function, PDTC treatment attenuated glycogen and lipid content depletion independent to the activation of STAT3 and mTORC1 signaling. Overall, these results demonstrate short-term PDTC treatment to cachectic mice attenuated cancer-induced disruptions to muscle and liver signaling, and these changes were independent to altered tumor burden and circulating IL-6.

Short-term pyrrolidine dithiocarbamate administration attenuates cachexia-induced alterations to muscle and liver in ApcMin/+ mice

PubMed Central

VanderVeen, Brandon N.; Enos, Reilly T.; Murphy, E. Angela; Carson, James A.

2016-01-01

Cancer cachexia is a complex wasting condition characterized by chronic inflammation, disrupted energy metabolism, and severe muscle wasting. While evidence in pre-clinical cancer cachexia models have determined that different systemic inflammatory inhibitors can attenuate several characteristics of cachexia, there is a limited understanding of their effects after cachexia has developed, and whether short-term administration is sufficient to reverse cachexia-induced signaling in distinctive target tissues. Pyrrolidine dithiocarbamate (PDTC) is a thiol compound having anti-inflammatory and antioxidant properties which can inhibit STAT3 and nuclear factor κB (NF-κB) signaling in mice. This study examined the effect of short-term PDTC administration to ApcMin/+ mice on cachexia-induced disruption of skeletal muscle protein turnover and liver metabolic function. At 16 weeks of age ApcMin/+ mice initiating cachexia (7% BW loss) were administered PDTC (10mg/kg bw/d) for 2 weeks. Control ApcMin/+ mice continued to lose body weight during the treatment period, while mice receiving PDTC had no further body weight decrease. PDTC had no effect on either intestinal tumor burden or circulating IL-6. In muscle, PDTC rescued signaling disrupting protein turnover regulation. PDTC suppressed the cachexia induction of STAT3, increased mTORC1 signaling and protein synthesis, and suppressed the induction of Atrogin-1 protein expression. Related to cachectic liver metabolic function, PDTC treatment attenuated glycogen and lipid content depletion independent to the activation of STAT3 and mTORC1 signaling. Overall, these results demonstrate short-term PDTC treatment to cachectic mice attenuated cancer-induced disruptions to muscle and liver signaling, and these changes were independent to altered tumor burden and circulating IL-6. PMID:27449092

PDGFRα depletion attenuates glioblastoma stem cells features by modulation of STAT3, RB1 and multiple oncogenic signals.

PubMed

Cenciarelli, Carlo; Marei, Hany E; Felsani, Armando; Casalbore, Patrizia; Sica, Gigliola; Puglisi, Maria Ausiliatrice; Cameron, Angus J M; Olivi, Alessandro; Mangiola, Annunziato

2016-08-16

Platelet derived growth factor receptors (PDGFRs) play an important role in tumor pathogenesis, and they are frequently overexpressed in glioblastoma (GBM). Earlier we have shown a higher protein expression of PDGFR isoforms (α and β) in peritumoral-tissue derived cancer stem cells (p-CSC) than in tumor core (c-CSC) of several GBM affected patients. In the current study, in order to assess the activity of PDGFRα/PDGF-AA signaling axis, we performed time course experiments to monitor the effects of exogenous PDGF-AA on the expression of downstream target genes in c-CSC vs p-CSC. Interestingly, in p-CSC we detected the upregulation of Y705-phosphorylated Stat3, concurrent with a decrement of Rb1 protein in its active state, within minutes of PDGF-AA addition. This finding prompted us to elucidate the role of PDGFRα in self-renewal, invasion and differentiation in p-CSC by using short hairpin RNA depletion of PDGFRα expression. Notably, in PDGFRα-depleted cells, protein analysis revealed attenuation of stemness-related and glial markers expression, alongside early activation of the neuronal marker MAP2a/b that correlated with the induction of tumor suppressor Rb1. The in vitro reduction of the invasive capacity of PDGFRα-depleted CSC as compared to parental cells correlated with the downmodulation of markers of epithelial-mesenchymal transition phenotype and angiogenesis. Surprisingly, we observed the induction of anti-apoptotic proteins and compensatory oncogenic signals such as EDN1, EDNRB, PRKCB1, PDGF-C and PDGF-D. To conclude, we hypothesize that the newly discovered PDGFRα/Stat3/Rb1 regulatory axis might represent a potential therapeutic target for GBM treatment.

Evidence that Melanocortin Receptor Agonist Melanotan-II Synergistically Augments the Ability of Naltrexone to Blunt Binge-Like Ethanol Intake in Male C57BL/6J Mice.

PubMed

Navarro, Montserrat; Carvajal, Francisca; Lerma-Cabrera, Jose Manuel; Cubero, Inmaculada; Picker, Mitchell J; Thiele, Todd E

2015-08-01

The nonselective opioid receptor antagonist, naltrexone (NAL), reduces alcohol (ethanol [EtOH]) consumption in animals and humans and is an approved medication for treating alcohol abuse disorders. Proopiomelanocortin (POMC)-derived melanocortin (MC) and opioid peptides are produced in the same neurons in the brain, and recent preclinical evidence shows that MC receptor (MCR) agonists reduce excessive EtOH drinking in animal models. Interestingly, there is a growing body of literature revealing interactions between the MC and the opioid systems in the modulation of pain, drug tolerance, and food intake. In the present report, a mouse model of binge EtOH drinking was employed to determine whether the MCR agonist, melanotan-II (MTII), would improve the effectiveness of NAL in reducing excessive binge-like EtOH drinking when these drugs were co-administered prior to EtOH access. Both NAL and MTII blunt binge-like EtOH drinking and associated blood EtOH levels, and when administered together, a low dose of MTII (0.26 mg/kg) produces a 7.6-fold increase in the effectiveness of NAL in reducing binge-like EtOH drinking. Using isobolographic analysis, it is demonstrated that MTII increases the effectiveness of NAL in a synergistic manner. The current observations suggest that activators of MC signaling may represent a new approach to treating alcohol abuse disorders and a way to potentially improve existing NAL-based therapies. Copyright © 2015 by the Research Society on Alcoholism.

Adaptive data rate control TDMA systems as a rain attenuation compensation technique

NASA Technical Reports Server (NTRS)

Sato, Masaki; Wakana, Hiromitsu; Takahashi, Takashi; Takeuchi, Makoto; Yamamoto, Minoru

1993-01-01

Rainfall attenuation has a severe effect on signal strength and impairs communication links for future mobile and personal satellite communications using Ka-band and millimeter wave frequencies. As rain attenuation compensation techniques, several methods such as uplink power control, site diversity, and adaptive control of data rate or forward error correction have been proposed. In this paper, we propose a TDMA system that can compensate rain attenuation by adaptive control of transmission rates. To evaluate the performance of this TDMA terminal, we carried out three types of experiments: experiments using a Japanese CS-3 satellite with Ka-band transponders, in house IF loop-back experiments, and computer simulations. Experimental results show that this TDMA system has advantages over the conventional constant-rate TDMA systems, as resource sharing technique, in both bit error rate and total TDMA burst lengths required for transmitting given information.

Signals generating anorexia during acute illness.

PubMed

Langhans, Wolfgang

2007-08-01

Anorexia is part of the body's acute-phase response to illness. Microbial products such as lipopolysaccharides (LPS), which are also commonly used to model acute illness, trigger the acute-phase response and cause anorexia mainly through pro-inflammatory cytokines. LPS stimulate cytokine production through the cell-surface structural molecule CD14 and toll-like receptor-4. Cytokines ultimately change neural activity in brain areas controlling food intake and energy balance. The blood-brain barrier endothelial cells (BBB EC) are an important site of cytokine action in this context. BBB EC and perivascular cells (microglia and macrophages) form a complex regulatory interface that modulates neuronal activity by the release of messengers (e.g. PG, NO) in response to peripheral challenges. Serotonergic neurons originating in the raphe nuclei and glucagon-like peptide-1-expressing neurons in the hindbrain may be among the targets of these messengers, because serotonin (5-HT), acting through the 5-HT2C receptor, and glucagon-like peptide-1 have recently emerged as neurochemical mediators of LPS anorexia. The central melanocortin system, which is a downstream target of serotonergic neurons, also appears to be involved in mediation of LPS anorexia. Interestingly, LPS also reduce orexin expression and the activity of orexin neurons in the lateral hypothalamic area of fasted mice. As the eating-stimulatory properties of orexin are apparently related to arousal, the inhibitory effect of LPS on orexin neurons might be involved in LPS-induced inactivity and anorexia. In summary, the immune signalling pathways of LPS-induced, and presumably acute illness-induced, anorexia converge on central neural signalling systems that control food intake and energy balance in healthy individuals.

Suppression of Pax2 attenuates allodynia and hyperalgesia through ET-1-ETAR-NFAT5 signaling in a rat model of neuropathic pain.

PubMed

Tai, Lydia Wai; Pan, Zhiqiang; Sun, Liting; Li, Haobo; Gu, Pan; Wong, Stanley Sau Ching; Chung, Sookja K; Cheung, Chi Wai

2018-05-27

Endothelin-1 (ET-1) and its receptors (ETAR/ETBR) emerge to be a key signaling axis in neuropathic pain processing and are recognized as new therapeutic targets. Yet, little is known on the functional regulation of ET-1 axis during neuropathic pain. Bioinformatics analysis indicated that paired box gene 2 (Pax2) or nuclear factor of activated T-cells 5 (NFAT5), two transcription factors involved in the modulation of neurotransmission, may regulate ET-1. Therefore, we hypothesized that ET-1 axis may be regulated by Pax2 or NFAT5 in the development of neuropathic pain. After partial sciatic nerve ligation (pSNL), rats displayed allodynia and hyperalgesia, which was associated with increased mRNA and protein expressions of spinal Pax2, NFAT5, and mRNA levels of ET-1 and ETAR, but not ETBR. Knockdown of Pax2 or NFAT5 with siRNA, or inhibition of ETAR with BQ-123 attenuated pSNL-induced pain-like behaviors. At molecular level, Pax2 siRNA, but not NFAT5 siRNA, downregulated ET-1 and ETAR, while ETAR inhibitor reduced NFAT5, indicating Pax2 in the upstream of ET-1 axis with NFAT5 in the downstream. Further, suppression of Pax2 (inhibiting ET-1) or impairment of ET-1 signaling (inhibition of ETAR and/or decrease of NFAT5) deactivated mitogen-activated protein kinases (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways, supporting the significance of functional regulation of ET-1 axis in neuropathic pain signaling. These findings demonstrate that Pax2 targeting ET-1-ETAR-NFAT5 is a novel regulatory mechanism underlying neuropathic pain. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

A highly attenuating and frequency tailorable annular hole phononic crystal for surface acoustic waves.

PubMed

Ash, B J; Worsfold, S R; Vukusic, P; Nash, G R

2017-08-02

Surface acoustic wave (SAW) devices are widely used for signal processing, sensing and increasingly for lab-on-a-chip applications. Phononic crystals can control the propagation of SAW, analogous to photonic crystals, enabling components such as waveguides and cavities. Here we present an approach for the realisation of robust, tailorable SAW phononic crystals, based on annular holes patterned in a SAW substrate. Using simulations and experiments, we show that this geometry supports local resonances which create highly attenuating phononic bandgaps at frequencies with negligible coupling of SAWs into other modes, even for relatively shallow features. The enormous bandgap attenuation is up to an order-of-magnitude larger than that achieved with a pillar phononic crystal of the same size, enabling effective phononic crystals to be made up of smaller numbers of elements. This work transforms the ability to exploit phononic crystals for developing novel SAW device concepts, mirroring contemporary progress in photonic crystals.The control and manipulation of propagating sound waves on a surface has applications in on-chip signal processing and sensing. Here, Ash et al. deviate from standard designs and fabricate frequency tailorable phononic crystals with an order-of-magnitude increase in attenuation.

Functional interplay between secreted ligands and receptors in melanoma.

PubMed

Herraiz, Cecilia; Jiménez-Cervantes, Celia; Sánchez-Laorden, Berta; García-Borrón, José C

2018-06-01

Melanoma, the most aggressive form of skin cancer, results from the malignant transformation of melanocytes located in the basement membrane separating the epidermal and dermal skin compartments. Cutaneous melanoma is often initiated by solar ultraviolet radiation (UVR)-induced mutations. Melanocytes intimately interact with keratinocytes, which provide growth factors and melanocortin peptides acting as paracrine regulators of proliferation and differentiation. Keratinocyte-derived melanocortins activate melanocortin-1 receptor (MC1R) to protect melanocytes from the carcinogenic effect of UVR. Accordingly, MC1R is a major determinant of susceptibility to melanoma. Despite extensive phenotypic heterogeneity and high mutation loads, the molecular basis of melanomagenesis and the molecules mediating the crosstalk between melanoma and stromal cells are relatively well understood. Mutations of intracellular effectors of receptor tyrosine kinase (RTK) signalling, notably NRAS and BRAF, are major driver events more frequent than mutations in RTKs. Nevertheless, melanomas often display aberrant signalling from RTKs such as KIT, ERRB1-4, FGFR, MET and PDGFR, which contribute to disease progression and resistance to targeted therapies. Progress has also been made to unravel the role of the tumour secretome in preparing the metastatic niche. However, key aspects of the melanoma-stroma interplay, such as the molecular determinants of dormancy, remain poorly understood. Copyright © 2017 Elsevier Ltd. All rights reserved.

Influence of vitamin C and vitamin E on redox signaling: Implications for exercise adaptations.

PubMed

Cobley, James N; McHardy, Helen; Morton, James P; Nikolaidis, Michalis G; Close, Graeme L

2015-07-01

The exogenous antioxidants vitamin C (ascorbate) and vitamin E (α-tocopherol) often blunt favorable cell signaling responses to exercise, suggesting that redox signaling contributes to exercise adaptations. Current theories posit that this antioxidant paradigm interferes with redox signaling by attenuating exercise-induced reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation. The well-documented in vitro antioxidant actions of ascorbate and α-tocopherol and characterization of the type and source of the ROS/RNS produced during exercise theoretically enable identification of redox-dependent mechanisms responsible for the blunting of favorable cell signaling responses to exercise. This review aimed to apply this reasoning to determine how the aforementioned antioxidants might attenuate exercise-induced ROS/RNS production. The principal outcomes of this analysis are (1) neither antioxidant is likely to attenuate nitric oxide signaling either directly (reaction with nitric oxide) or indirectly (reaction with derivatives, e.g., peroxynitrite); (2) neither antioxidant reacts appreciably with hydrogen peroxide, a key effector of redox signaling; (3) ascorbate but not α-tocopherol has the capacity to attenuate exercise-induced superoxide generation; and (4) alternate mechanisms, namely pro-oxidant side reactions and/or reduction of bioactive oxidized macromolecule adducts, are unlikely to interfere with exercise-induced redox signaling. Out of all the possibilities considered, ascorbate-mediated suppression of superoxide generation with attendant implications for hydrogen peroxide signaling is arguably the most cogent explanation for blunting of favorable cell signaling responses to exercise. However, this mechanism is dependent on ascorbate accumulating at sites rich in NADPH oxidases, principal contributors to contraction-mediated superoxide generation, and outcompeting nitric oxide and superoxide dismutase isoforms. The major conclusions of

Inferring watershed hydraulics and cold-water habitat persistence using multi-year air and stream temperature signals.

PubMed

Briggs, Martin A; Johnson, Zachary C; Snyder, Craig D; Hitt, Nathaniel P; Kurylyk, Barret L; Lautz, Laura; Irvine, Dylan J; Hurley, Stephen T; Lane, John W

2018-09-15

Streams strongly influenced by groundwater discharge may serve as "climate refugia" for sensitive species in regions of increasingly marginal thermal conditions. The main goal of this study is to develop paired air and stream water annual temperature signal analysis techniques to elucidate the relative groundwater contribution to stream water and the effective groundwater flowpath depth. Groundwater discharge to streams attenuates surface water temperature signals, and this attenuation can be diagnostic of groundwater gaining systems. Additionally, discharge from shallow groundwater flowpaths can theoretically transfer lagged annual temperature signals from aquifer to stream water. Here we explore this concept using multi-year temperature records from 120 stream sites located across 18 mountain watersheds of Shenandoah National Park, VA, USA and a coastal watershed in Massachusetts, USA. Both areas constitute important cold-water habitat for native brook trout (Salvelinus fontinalis). Observed annual temperature signals indicate a dominance of shallow groundwater discharge to streams in the National Park, in contrast to the coastal watershed that has strong, apparently deeper, groundwater influence. The average phase lag from air to stream signals in Shenandoah National Park is 11 d; however, extended lags of approximately 1 month were observed in a subset of streams. In contrast, the coastal stream has pronounced attenuation of annual temperature signals without notable phase lag. To better understand these observed differences in signal characteristics, analytical and numerical models are used to quantify mixing of the annual temperature signals of surface and groundwater. Simulations using a total heat budget numerical model indicate groundwater-induced annual temperature signal phase lags are likely to show greater downstream propagation than the related signal amplitude attenuation. The measurement of multi-seasonal paired air and water temperatures offers

Attenuated-Signal Plaque Progression Predicts Long-Term Mortality After Heart Transplantation: IVUS Assessment of Cardiac Allograft Vasculopathy.

PubMed

Okada, Kozo; Fearon, William F; Luikart, Helen; Kitahara, Hideki; Otagiri, Kyuhachi; Tanaka, Shigemitsu; Kimura, Takumi; Yock, Paul G; Fitzgerald, Peter J; Yeung, Alan C; Valantine, Hannah A; Khush, Kiran K; Honda, Yasuhiro

2016-07-26

Although cardiac allograft vasculopathy (CAV) is typically characterized by diffuse coronary intimal thickening with pathological vessel remodeling, plaque instability may also play an important role in CAV. Previous studies of native coronary atherosclerosis have demonstrated associations between attenuated-signal plaque (ASP), plaque instability, and adverse clinical events. This study's aim was to characterize the association between ASP and long-term mortality post-heart transplantation. In 105 heart transplant recipients, serial (baseline and 1-year post-transplant) intravascular ultrasound was performed in the first 50 mm of the left anterior descending artery. The ASP score was calculated by grading the measured angle of attenuation from grades 0 to 4 (specifically, 0°, 1° to 90°, 91° to 180°, 181° to 270°, and >270°) at 1-mm intervals. The primary endpoint was all-cause death or retransplantation. At 1-year post-transplant, 10.5% of patients demonstrated ASP progression (newly developed or increased ASP). Patients with ASP progression had a higher incidence of acute cellular rejection during the first year (63.6% vs. 22.3%; p = 0.006) and tendency for greater intimal growth (percent intimal volume: 9.2 ± 9.3% vs. 4.4 ± 5.3%; p = 0.07) than those without. Over a median follow-up of 4.6 years, there was a significantly lower event-free survival rate in patients with ASP progression at 1-year post-transplant compared with those without. In contrast, maximum intimal thickness did not predict long-term mortality. ASP progression appears to reflect chronic inflammation related to acute cellular rejection and is an independent predictor of long-term mortality after heart transplantation. Serial assessments of plaque instability may enhance identification of high-risk patients who may benefit from closer follow-up and targeted medical therapies. Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Baicalein attenuates inflammatory responses by suppressing TLR4 mediated NF-κB and MAPK signaling pathways in LPS-induced mastitis in mice.

PubMed

He, Xuexiu; Wei, Zhengkai; Zhou, Ershun; Chen, Libin; Kou, Jinhua; Wang, Jingjing; Yang, Zhengtao

2015-09-01

Baicalein is a phenolic flavonoid presented in the dry roots of Scutellaria baicalensis Georgi. It has been reported that baicalein possesses a number of biological properties, such as antiviral, antioxidative, anti-inflammatory, antithrombotic, and anticancer properties. However, the effect of baicalein on mastitis has not yet been reported. This research aims to detect the effect of baicalein on lipopolysaccharide (LPS)-induced mastitis in mice and to investigate the molecular mechanisms. Baicalein was administered intraperitoneally 1h before and 12h after LPS treatment. The results indicated that baicalein treatment markedly attenuated the damage of the mammary gland induced by LPS, suppressed the activity of myeloperoxidase (MPO) and the levels of tumor necrosis factor (TNF-α) and interleukin (IL-1β) in mice with LPS-induced mastitis. Besides, baicalein blocked the expression of Toll-like receptor 4 (TLR4) and then suppressed the phosphorylation of nuclear transcription factor-kappaB (NF-κB) p65 and degradation inhibitor of NF-κBα (IκBα) and, and inhibited the phosphorylation of p38, extracellular signal-regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK) in mitogen-activated protein kinase (MAPK) signal pathway. These findings suggested that baicalein may have a potential prospect against mastitis. Copyright © 2015. Published by Elsevier B.V.

Stress wave attenuation in thin structures by ultrasonic through-transmission

NASA Technical Reports Server (NTRS)

Lee, S. S.; Williams, J. H., Jr.

1980-01-01

The steady state amplitude of the output of an ultrasonic through transmission measurement is analyzed and the result is given in closed form. Provided that the product of the input and output transduction ratios; the specimen-transducer reflection coefficient; the specimen-transducer phase shift parameter; and the material phase velocity are known, this analysis gives a means for determining the through-thickness attenuation of an individual thin sample. Multiple stress wave reflections are taken into account and so signal echoes do not represent a difficulty. An example is presented for a graphite fiber epoxy composite (Hercules AS/3501-6). A direct method for continuous or intermittent monitoring of through thickness attenuation of plate structures which may be subject to service structural degradation is provided.

Ultrasonic Attenuation Results of Thermoplastic Resin Composites Undergoing Thermal and Fatigue Loading

NASA Technical Reports Server (NTRS)

Madaras, Eric I.

1998-01-01

As part of an effort to obtain the required information about new composites for aviation use, materials and NDE researchers at NASA are jointly performing mechanical and NDE measurements on new composite materials. The materials testing laboratory at NASA is equipped with environmental chambers mounted on load frames that can expose composite materials to thermal and loading cycles representative of flight protocols. Applying both temperature and load simultaneously will help to highlight temperature and load interactions during the aging of these composite materials. This report highlights our initial ultrasonic attenuation results from thermoplastic composite samples that have undergone over 4000 flight cycles to date. Ultrasonic attenuation measurements are a standard method used to assess the effects of material degradation. Recently, researchers have shown that they could obtain adequate contrast in the evaluation of thermal degradation in thermoplastic composites by using frequencies of ultrasound on the order of 24 MHz. In this study, we address the relationship of attenuation measured at lower frequencies in thermoplastic composites undergoing both thermal and mechanical loading. We also compare these thermoplastic results with some data from thermoset composites undergoing similar protocols. The composite s attenuation is reported as the slope of attenuation with respect to frequency, defined as b = Da(f)/Df. The slope of attenuation is an attractive parameter since it is quantitative, yet does not require interface corrections like conventional quantitative attenuation measurements. This latter feature is a consequence of the assumption that interface correction terms are frequency independent. Uncertainty in those correction terms can compromise the value of conventional quantitative attenuation data. Furthermore, the slope of the attenuation more directly utilizes the bandwidth information and in addition, the bandwidth can be adjusted in the post

Development of Novel Melanocortin Receptor Agonists Based on the Cyclic Peptide Framework of Sunflower Trypsin Inhibitor-1.

PubMed

Durek, Thomas; Cromm, Philipp M; White, Andrew M; Schroeder, Christina I; Kaas, Quentin; Weidmann, Joachim; Ahmad Fuaad, Abdullah; Cheneval, Olivier; Harvey, Peta J; Daly, Norelle L; Zhou, Yang; Dellsén, Anita; Österlund, Torben; Larsson, Niklas; Knerr, Laurent; Bauer, Udo; Kessler, Horst; Cai, Minying; Hruby, Victor J; Plowright, Alleyn T; Craik, David J

2018-04-26

Ultrastable cyclic peptide frameworks offer great potential for drug design due to their improved bioavailability compared to their linear analogues. Using the sunflower trypsin inhibitor-1 (SFTI-1) peptide scaffold in combination with systematic N-methylation of the grafted pharmacophore led to the identification of novel subtype selective melanocortin receptor (MCR) agonists. Multiple bicyclic peptides were synthesized and tested toward their activity at MC1R and MC3-5R. Double N-methylated compound 18 showed a p K i of 8.73 ± 0.08 ( K i = 1.92 ± 0.34 nM) and a pEC 50 of 9.13 ± 0.04 (EC 50 = 0.75 ± 0.08 nM) at the human MC1R and was over 100 times more selective for MC1R. Nuclear magnetic resonance structural analysis of 18 emphasized the role of peptide bond N-methylation in shaping the conformation of the grafted pharmacophore. More broadly, this study highlights the potential of cyclic peptide scaffolds for epitope grafting in combination with N-methylation to introduce receptor subtype selectivity in the context of peptide-based drug discovery.

Receptor density balances signal stimulation and attenuation in membrane-assembled complexes of bacterial chemotaxis signaling proteins

PubMed Central

Besschetnova, Tatiana Y.; Montefusco, David J.; Asinas, Abdalin E.; Shrout, Anthony L.; Antommattei, Frances M.; Weis, Robert M.

2008-01-01

All cells possess transmembrane signaling systems that function in the environment of the lipid bilayer. In the Escherichia coli chemotaxis pathway, the binding of attractants to a two-dimensional array of receptors and signaling proteins simultaneously inhibits an associated kinase and stimulates receptor methylation—a slower process that restores kinase activity. These two opposing effects lead to robust adaptation toward stimuli through a physical mechanism that is not understood. Here, we provide evidence of a counterbalancing influence exerted by receptor density on kinase stimulation and receptor methylation. Receptor signaling complexes were reconstituted over a range of defined surface concentrations by using a template-directed assembly method, and the kinase and receptor methylation activities were measured. Kinase activity and methylation rates were both found to vary significantly with surface concentration—yet in opposite ways: samples prepared at high surface densities stimulated kinase activity more effectively than low-density samples, whereas lower surface densities produced greater methylation rates than higher densities. FRET experiments demonstrated that the cooperative change in kinase activity coincided with a change in the arrangement of the membrane-associated receptor domains. The counterbalancing influence of density on receptor methylation and kinase stimulation leads naturally to a model for signal regulation that is compatible with the known logic of the E. coli pathway. Density-dependent mechanisms are likely to be general and may operate when two or more membrane-related processes are influenced differently by the two-dimensional concentration of pathway elements. PMID:18711126

Practical limitations on the use of diurnal temperature signals to quantify groundwater upwelling

USGS Publications Warehouse

Briggs, Martin A.; Lautz, Laura K.; Buckley, Sean F.; Lane, John W.

2014-01-01

Groundwater upwelling to streams creates unique habitat by influencing stream water quality and temperature; upwelling zones also serve as vectors for contamination when groundwater is degraded. Temperature time series data acquired along vertical profiles in the streambed have been applied to simple analytical models to determine rates of vertical fluid flux. These models are based on the downward propagation characteristics (amplitude attenuation and phase-lag) of the surface diurnal signal. Despite the popularity of these models, there are few published characterizations of moderate-to-strong upwelling. We attribute this limitation to the thermodynamics of upwelling, under which the downward conductive signal transport from the streambed interface occurs opposite the upward advective fluid flux. Governing equations describing the advection–diffusion of heat within the streambed predict that under upwelling conditions, signal amplitude attenuation will increase, but, counterintuitively, phase-lag will decrease. Therefore the extinction (measurable) depth of the diurnal signal is very shallow, but phase lag is also short, yielding low signal to noise ratio and poor model sensitivity. Conversely, amplitude attenuation over similar sensor spacing is strong, yielding greater potential model sensitivity. Here we present streambed thermal time series over a range of moderate to strong upwelling sites in the Quashnet River, Cape Cod, Massachusetts. The predicted inverse relationship between phase-lag and rate of upwelling was observed in the field data over a range of conditions, but the observed phase-lags were consistently shorter than predicted. Analytical solutions for fluid flux based on signal amplitude attenuation return results consistent with numerical models and physical seepage meters, but the phase-lag analytical model results are generally unreasonable. Through numerical modeling we explore reasons why phase-lag may have been over-predicted by the

Downhole microseismic signal-to-noise ratio enhancement via strip matching shearlet transform

NASA Astrophysics Data System (ADS)

Li, Juan; Ji, Shuo; Li, Yue; Qian, Zhihong; Lu, Weili

2018-04-01

Shearlet transform has been proved effective in noise attenuation. However, because of the low magnitude and high frequency of downhole microseismic signals, the coefficient values of valid signals and noise are similar in the shearlet domain. As a result, it is hard to suppress the noise. In this paper, we present a novel signal-to-noise ratio enhancement scheme called strip matching shearlet transform. The method takes into account the directivity of microseismic events and shearlets. Through strip matching, the matching degree in direction between them has been promoted. Then the coefficient values of valid signals are much larger than those of the noise. Consequently, we can separate them well with the help of thresholding. The experimental results on both synthetic records and field data illustrate that our proposed method preserves the useful components and attenuates the noise well.

STAT3 selectively interacts with Smad3 to antagonize TGF-β signaling

PubMed Central

Wang, Gaohang; Yu, Yi; Sun, Chuang; Liu, Ting; Liang, Tingbo; Zhan, Lixing; Lin, Xia; Feng, Xin-Hua

2015-01-01

Smad and STAT proteins are critical signal transducers and transcription factors in controlling cell growth and tumorigenesis. Here we report that the STAT3 signaling pathway attenuates TGF-β-induced responses through a direct Smad3-STAT3 interplay. Activated STAT3 blunts TGF-β-mediated signaling. Depletion of STAT3 promotes TGF-β-mediated transcriptional and physiological responses, including cell cycle arrest, apoptosis and epithelial-to-mesenchymal transition. STAT3 directly interacts with Smad3 in vivo and in vitro, resulting in attenuation of the Smad3-Smad4 complex formation and suppression of DNA-binding ability of Smad3. The N-terminal region of DNA-binding domain of STAT3 is responsible for the STAT3-Smad3 interaction and also indispensable for STAT3-mediated inhibition of TGF-β signaling. Thus, our finding illustrates a direct crosstalk between the STAT3 and Smad3 signaling pathways that may contribute to tumor development and inflammation. PMID:26616859

Experimental Demonstration of Microwave Signal/Electric Thruster Plasma Interaction Effects

NASA Technical Reports Server (NTRS)

Zaman, Afroz J.; Lambert, Kevin M.; Curran, Frank M.

1995-01-01

An experiment was designed and conducted in the Electric Propulsion Laboratory of NASA Lewis Research Center to assess the impact of ion thruster exhaust plasma plume on electromagnetic signal propagation. A microwave transmission experiment was set up inside the propulsion test bed using a pair of broadband horn antennas and a 30 cm 2.3 kW ion thruster. Frequency of signal propagation covered from 6.5 to 18 GHz range. The stainless steel test bed when enclosed can be depressurized to simulate a near vacuum environment. A pulsed CW system with gating hardware was utilized to eliminate multiple chamber reflections from the test signal. Microwave signal was transmitted and received between the two hours when the thruster was operating at a given power level in such a way that the signal propagation path crossed directly through the plume volume. Signal attenuation and phase shift due to the plume was measured for the entire frequency band. Results for this worst case configuration simulation indicate that the effects of the ion thruster plume on microwave signals is a negligible attenuation (within 0.15 dB) and a small phase shift (within 8 deg.). This paper describes the detailed experiment and presents some of the results.

Seismic Linear Noise Attenuation with Use of Radial Transform

NASA Astrophysics Data System (ADS)

Szymańska-Małysa, Żaneta

2018-03-01

One of the goals of seismic data processing is to attenuate the recorded noise in order to enable correct interpretation of the image. Radial transform has been used as a very effective tool in the attenuation of various types of linear noise, both numerical and real (such as ground roll, direct waves, head waves, guided waves etc). The result of transformation from offset - time (X - T) domain into apparent velocity - time (R - T) domain is frequency separation between reflections and linear events. In this article synthetic and real seismic shot gathers were examined. One example was targeted at far offset area of dataset where reflections and noise had similar apparent velocities and frequency bands. Another example was a result of elastic modelling where linear artefacts were produced. Bandpass filtering and scaling operation executed in radial domain attenuated all discussed types of linear noise very effectively. After noise reduction all further processing steps reveal better results, especially velocity analysis, migration and stacking. In all presented cases signal-to-noise ratio was significantly increased and reflections covered previously by noise were revealed. Power spectra of filtered seismic records preserved real dynamics of reflections.

Ultrasonic attenuation - Q measurements on 70215,29. [lunar rock

NASA Technical Reports Server (NTRS)

Warren, N.; Trice, R.; Stephens, J.

1974-01-01

Ultrasonic attenuation measurements have been made on an aluminum alloy, obsidian, and rock samples including lunar sample 70215,29. The measurement technique is based on a combination of the pulse transmission method and the forced resonance method. The technique is designed to explore the problem of defining experimentally, the Q of a medium or sample in which mode conversion may occur. If modes are coupled, the measured attenuation is strongly dependent on individual modes of vibration, and a range of Q-factors may be measured over various resonances or from various portions of a transient signal. On 70215,29, measurements were made over a period of a month while the sample outgassed in hard varuum. During this period, the highest measured Q of this sample increased from a few hundred into the range of 1000-1300.

Mangiferin attenuates the symptoms of dextran sulfate sodium-induced colitis in mice via NF-κB and MAPK signaling inactivation

PubMed Central

Dou, Wei; Zhang, Jingjing; Ren, Gaiyan; Ding, Lili; Sun, Aning; Deng, Chao; Wu, Xiaojun; Wei, Xiaohui; Mani, Sridhar; Wang, Zhengtao

2015-01-01

Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory disorder of the gastrointestinal (GI) tract, and currently no curative treatment available. Mangiferin, a natural glucosylxanthone mainly from the fruit, leaves and stem bark of the mango tree, has strong anti-inflammatory activity. We sought to investigate whether mangiferin attenuates inflammation in a mouse model of chemically induced IBD. Pre-administration of mangiferin significantly attenuated dextran sulfate sodium (DSS)-induced body weight loss, diarrhea, colon shortening and histological injury, which correlated with the decline in the activity of myeloperoxidase (MPO) and the level of tumor necrosis factor-α (TNF-α) in the colon. DSS-induced degradation of inhibitory κBα (IκBα) and the phosphorylation of nuclear factor-kappa B (NF-κB) p65 as well as the mRNA expression of pro-inflammatory mediators (inducible NO synthase (iNOS), intercellular adhesion molecule-1 (ICAM-1), TNF-α, interleukin-1β (IL-1β) and IL-6) in the colon were also downregulated by mangiferin treatment. Additionally, the phosphorylation/activation of DSS-induced mitogen-activated protein kinase (MAPK) proteins was also inhibited by mangiferin treatment. In accordance with the in vivo results, mangiferin exposure blocked TNF-α-stimulated nuclear translocation of NF-κB in RAW264.7 mouse macrophage cells. Transient transfection gene reporter assay performed in TNF-α-stimulated HT-29 human colorectal adenocarcinoma cells indicated that mangiferin inhibits NF-κB transcriptional activity in a dose-dependent manner. The current study clearly demonstrates a protective role for mangiferin in experimental IBD through NF-κB and MAPK signaling inhibition. Since mangiferin is a natural compound with little toxicity, the results may contribute to the effective utilization of mangiferin in the treatment of human IBD. PMID:25194678

Mangiferin attenuates the symptoms of dextran sulfate sodium-induced colitis in mice via NF-κB and MAPK signaling inactivation.

PubMed

Dou, Wei; Zhang, Jingjing; Ren, Gaiyan; Ding, Lili; Sun, Aning; Deng, Chao; Wu, Xiaojun; Wei, Xiaohui; Mani, Sridhar; Wang, Zhengtao

2014-11-01

Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory disorder of the gastrointestinal (GI) tract, and currently no curative treatment is available. Mangiferin, a natural glucosylxanthone mainly from the fruit, leaves and stem bark of a mango tree, has a strong anti-inflammatory activity. We sought to investigate whether mangiferin attenuates inflammation in a mouse model of chemically induced IBD. Pre-administration of mangiferin significantly attenuated dextran sulfate sodium (DSS)-induced body weight loss, diarrhea, colon shortening and histological injury, which correlated with the decline in the activity of myeloperoxidase (MPO) and the level of tumor necrosis factor-α (TNF-α) in the colon. DSS-induced degradation of inhibitory κBα (IκBα) and the phosphorylation of nuclear factor-kappa B (NF-κB) p65 as well as the mRNA expression of pro-inflammatory mediators (inducible NO synthase (iNOS), intercellular adhesion molecule-1 (ICAM-1), TNF-α, interleukin-1β (IL-1β) and IL-6) in the colon were also downregulated by mangiferin treatment. Additionally, the phosphorylation/activation of DSS-induced mitogen-activated protein kinase (MAPK) proteins was also inhibited by mangiferin treatment. In accordance with the in vivo results, mangiferin exposure blocked TNF-α-stimulated nuclear translocation of NF-κB in RAW264.7 mouse macrophage cells. Transient transfection gene reporter assay performed in TNF-α-stimulated HT-29 human colorectal adenocarcinoma cells indicated that mangiferin inhibits NF-κB transcriptional activity in a dose-dependent manner. The current study clearly demonstrates a protective role for mangiferin in experimental IBD through NF-κB and MAPK signaling inhibition. Since mangiferin is a natural compound with little toxicity, the results may contribute to the effective utilization of mangiferin in the treatment of human IBD. Copyright © 2014 Elsevier B.V. All rights reserved.

Control algorithms for dynamic attenuators

PubMed Central

Hsieh, Scott S.; Pelc, Norbert J.

2014-01-01

Purpose: The authors describe algorithms to control dynamic attenuators in CT and compare their performance using simulated scans. Dynamic attenuators are prepatient beam shaping filters that modulate the distribution of x-ray fluence incident on the patient on a view-by-view basis. These attenuators can reduce dose while improving key image quality metrics such as peak or mean variance. In each view, the attenuator presents several degrees of freedom which may be individually adjusted. The total number of degrees of freedom across all views is very large, making many optimization techniques impractical. The authors develop a theory for optimally controlling these attenuators. Special attention is paid to a theoretically perfect attenuator which controls the fluence for each ray individually, but the authors also investigate and compare three other, practical attenuator designs which have been previously proposed: the piecewise-linear attenuator, the translating attenuator, and the double wedge attenuator. Methods: The authors pose and solve the optimization problems of minimizing the mean and peak variance subject to a fixed dose limit. For a perfect attenuator and mean variance minimization, this problem can be solved in simple, closed form. For other attenuator designs, the problem can be decomposed into separate problems for each view to greatly reduce the computational complexity. Peak variance minimization can be approximately solved using iterated, weighted mean variance (WMV) minimization. Also, the authors develop heuristics for the perfect and piecewise-linear attenuators which do not require a priori knowledge of the patient anatomy. The authors compare these control algorithms on different types of dynamic attenuators using simulated raw data from forward projected DICOM files of a thorax and an abdomen. Results: The translating and double wedge attenuators reduce dose by an average of 30% relative to current techniques (bowtie filter with tube current

Control algorithms for dynamic attenuators.

PubMed

Hsieh, Scott S; Pelc, Norbert J

2014-06-01

The authors describe algorithms to control dynamic attenuators in CT and compare their performance using simulated scans. Dynamic attenuators are prepatient beam shaping filters that modulate the distribution of x-ray fluence incident on the patient on a view-by-view basis. These attenuators can reduce dose while improving key image quality metrics such as peak or mean variance. In each view, the attenuator presents several degrees of freedom which may be individually adjusted. The total number of degrees of freedom across all views is very large, making many optimization techniques impractical. The authors develop a theory for optimally controlling these attenuators. Special attention is paid to a theoretically perfect attenuator which controls the fluence for each ray individually, but the authors also investigate and compare three other, practical attenuator designs which have been previously proposed: the piecewise-linear attenuator, the translating attenuator, and the double wedge attenuator. The authors pose and solve the optimization problems of minimizing the mean and peak variance subject to a fixed dose limit. For a perfect attenuator and mean variance minimization, this problem can be solved in simple, closed form. For other attenuator designs, the problem can be decomposed into separate problems for each view to greatly reduce the computational complexity. Peak variance minimization can be approximately solved using iterated, weighted mean variance (WMV) minimization. Also, the authors develop heuristics for the perfect and piecewise-linear attenuators which do not require a priori knowledge of the patient anatomy. The authors compare these control algorithms on different types of dynamic attenuators using simulated raw data from forward projected DICOM files of a thorax and an abdomen. The translating and double wedge attenuators reduce dose by an average of 30% relative to current techniques (bowtie filter with tube current modulation) without

Food deprivation reduces and leptin increases the amplitude of an active sensory and communication signal in a weakly electric fish.

PubMed

Sinnett, Philip M; Markham, Michael R

2015-05-01

Energetic demands of social communication signals can constrain signal duration, repetition, and magnitude. The metabolic costs of communication signals are further magnified when they are coupled to active sensory systems that require constant signal generation. Under such circumstances, metabolic stress incurs additional risk because energy shortfalls could degrade sensory system performance as well as the social functions of the communication signal. The weakly electric fish Eigenmannia virescens generates electric organ discharges (EODs) that serve as both active sensory and communication signals. These EODs are maintained at steady frequencies of 200-600Hz throughout the lifespan, and thus represent a substantial metabolic investment. We investigated the effects of metabolic stress (food deprivation) on EOD amplitude (EODa) and EOD frequency (EODf) in E. virescens and found that only EODa decreases during food deprivation and recovers after restoration of feeding. Cortisol did not alter EODa under any conditions, and plasma cortisol levels were not changed by food deprivation. Both melanocortin hormones and social challenges caused transient EODa increases in both food-deprived and well-fed fish. Intramuscular injections of leptin increased EODa in food-deprived fish but not well-fed fish, identifying leptin as a novel regulator of EODa and suggesting that leptin mediates EODa responses to metabolic stress. The sensitivity of EODa to dietary energy availability likely arises because of the extreme energetic costs of EOD production in E. virescens and also could reflect reproductive strategies of iteroparous species that reduce social signaling and reproduction during periods of stress to later resume reproductive efforts when conditions improve. Copyright © 2015. Published by Elsevier Inc.

A novel power spectrum calculation method using phase-compensation and weighted averaging for the estimation of ultrasound attenuation.

PubMed

Heo, Seo Weon; Kim, Hyungsuk

2010-05-01

An estimation of ultrasound attenuation in soft tissues is critical in the quantitative ultrasound analysis since it is not only related to the estimations of other ultrasound parameters, such as speed of sound, integrated scatterers, or scatterer size, but also provides pathological information of the scanned tissue. However, estimation performances of ultrasound attenuation are intimately tied to the accurate extraction of spectral information from the backscattered radiofrequency (RF) signals. In this paper, we propose two novel techniques for calculating a block power spectrum from the backscattered ultrasound signals. These are based on the phase-compensation of each RF segment using the normalized cross-correlation to minimize estimation errors due to phase variations, and the weighted averaging technique to maximize the signal-to-noise ratio (SNR). The simulation results with uniform numerical phantoms demonstrate that the proposed method estimates local attenuation coefficients within 1.57% of the actual values while the conventional methods estimate those within 2.96%. The proposed method is especially effective when we deal with the signal reflected from the deeper depth where the SNR level is lower or when the gated window contains a small number of signal samples. Experimental results, performed at 5MHz, were obtained with a one-dimensional 128 elements array, using the tissue-mimicking phantoms also show that the proposed method provides better estimation results (within 3.04% of the actual value) with smaller estimation variances compared to the conventional methods (within 5.93%) for all cases considered. Copyright 2009 Elsevier B.V. All rights reserved.

A Novel Melanocortin-4 Receptor Mutation MC4R-P272L Associated with Severe Obesity Has Increased Propensity To Be Ubiquitinated in the ER in the Face of Correct Folding

PubMed Central

Granell, Susana; Serra-Juhé, Clara; Martos-Moreno, Gabriel Á.; Díaz, Francisca; Pérez-Jurado, Luis A.; Baldini, Giulia; Argente, Jesús

2012-01-01

Heterozygous mutations in the melanocortin-4 receptor (MC4R) gene represent the most frequent cause of monogenic obesity in humans. MC4R mutation analysis in a cohort of 77 children with morbid obesity identified previously unreported heterozygous mutations (P272L, N74I) in two patients inherited from their obese mothers. A rare polymorphism (I251L, allelic frequency: 1/100) reported to protect against obesity was found in another obese patient. When expressed in neuronal cells, the cell surface abundance of wild-type MC4R and of the N74I and I251L variants and the cAMP generated by these receptors in response to exposure to the agonist, α-MSH, were not different. Conversely, MC4R P272L was retained in the endoplasmic reticulum and had reduced cell surface expression and signaling (by ≈3-fold). The chemical chaperone PBA, which promotes protein folding of wild-type MC4R, had minimal effects on the distribution and signaling of the P272L variant. In contrast, incubation with UBE-41, a specific inhibitor of ubiquitin activating enzyme E1, inhibited ubiquitination of MC4R P272L and increased its cell surface expression and signaling to similar levels as wild-type MC4R. UBE41 had much less profound effects on MC4R I316S, another obesity-linked MC4R variant trapped in the ER. These data suggest that P272L is retained in the ER by a propensity to be ubiquitinated in the face of correct folding, which is only minimally shared by MC4R I316S. Thus, studies that combine clinical screening of obese patients and investigation of the functional defects of the obesity-linked MC4R variants can identify specific ways to correct these defects and are the first steps towards personalized medicine. PMID:23251400

A newly synthesized macakurzin C-derivative attenuates acute and chronic skin inflammation: The Nrf2/heme oxygenase signaling as a potential target

DOE Office of Scientific and Technical Information (OSTI.GOV)

Akram, Muhammad

Impaired immune responses in skin play a pivotal role in the development and progression of chemical-associated inflammatory skin disorders. In this study, we synthesized new flavonoid derivatives from macakurzin C, and identified in vitro and in vivo efficacy of a potent anti-inflammatory flavonoid, Compound 14 (CPD 14), with its underlying mechanisms. In lipopolysaccharide (LPS)-stimulated murine macrophages and IFN-γ/TNF-α-stimulated human keratinocytes, CPD 14 significantly inhibited the release of inflammatory mediators including nitric oxide (NO), prostaglandins, and cytokines (IC{sub 50} for NO inhibition in macrophages: 4.61 μM). Attenuated NF-κB signaling and activated Nrf2/HO-1 pathway were responsible for the anti-inflammatory effects of CPDmore » 14. The in vivo relevance was examined in phorbol 12-myristate 13-acetate (TPA)-induced acute skin inflammation and oxazolone-induced atopic dermatitis models. Topically applied CPD 14 significantly protected both irritation- and sensitization-associated skin inflammation by suppressing the expression of inflammatory mediators. In summary, we demonstrated that a newly synthesized flavonoid, CPD 14, has potent inhibitory effects on skin inflammation, suggesting it is a potential therapeutic candidate to treat skin disorders associated with excessive inflammation. - Highlights: • An anti-inflammatory flavonoid CPD 14 was newly synthesized from macakurzin C. • CPD 14 potently inhibited inflammatory reaction in keratinocytes and macrophages. • Dermal toxicity by irritation or sensitization in rats was protected by CPD 14. • Attenuated NF-κB and activated Nrf2/HO-1 were main mechanisms of CPD 14 action.« less

Measurement of breast-tissue x-ray attenuation by spectral mammography: solid lesions

NASA Astrophysics Data System (ADS)

Fredenberg, Erik; Kilburn-Toppin, Fleur; Willsher, Paula; Moa, Elin; Danielsson, Mats; Dance, David R.; Young, Kenneth C.; Wallis, Matthew G.

2016-04-01

Knowledge of x-ray attenuation is essential for developing and evaluating x-ray imaging technologies. For instance, techniques to distinguish between cysts and solid tumours at mammography screening would be highly desirable to reduce recalls, but the development requires knowledge of the x-ray attenuation for cysts and tumours. We have previously measured the attenuation of cyst fluid using photon-counting spectral mammography. Data on x-ray attenuation for solid breast lesions are available in the literature, but cover a relatively wide range, likely caused by natural spread between samples, random measurement errors, and different experimental conditions. In this study, we have adapted a previously developed spectral method to measure the linear attenuation of solid breast lesions. A total of 56 malignant and 5 benign lesions were included in the study. The samples were placed in a holder that allowed for thickness measurement. Spectral (energy-resolved) images of the samples were acquired and the image signal was mapped to equivalent thicknesses of two known reference materials, which can be used to derive the x-ray attenuation as a function of energy. The spread in equivalent material thicknesses was relatively large between samples, which is likely to be caused mainly by natural variation and only to a minor extent by random measurement errors and sample inhomogeneity. No significant difference in attenuation was found between benign and malignant solid lesions. The separation between cyst-fluid and tumour attenuation was, however, significant, which suggests it may be possible to distinguish cystic from solid breast lesions, and the results lay the groundwork for a clinical trial. In addition, the study adds a relatively large sample set to the published data and may contribute to a reduction in the overall uncertainty in the literature.

Novel orally active epoxyeicosatrienoic acid (EET) analogs attenuate cisplatin nephrotoxicity

PubMed Central

Khan, Md. Abdul Hye; Liu, Jing; Kumar, Ganesh; Skapek, Stephen X.; Falck, John R.; Imig, John D.

2013-01-01

Nephrotoxicity severely limits the use of the anticancer drug cisplatin. Oxidative stress, inflammation, and endoplasmic reticulum (ER) stress contribute to cisplatin-induced nephrotoxicity. We developed novel orally active epoxyeicosatrienoic acid (EET) analogs and investigated their prophylactic effect in cisplatin-induced nephrotoxicity in rats. Cisplatin-induced nephrotoxicity was manifested by increases in blood urea nitrogen, plasma creatinine, urinary N-acetyl-β-(d)-glucosaminidase activity, kidney injury molecule 1, and histopathology. EET analogs (10 mg/kg/d) attenuated cisplatin-induced nephrotoxicity by reducing these renal injury markers by 40–80% along with a 50–70% reduction in renal tubular cast formation. This attenuated renal injury is associated with reduced oxidative stress, inflammation, and ER stress evident from reduction in related biomarkers and in the renal expression of genes involved in these pathways. Moreover, we demonstrated that the attenuated nephrotoxicity correlated with decreased apoptosis that is associated with 50–90% reduction in Bcl-2 protein family mediated proapoptotic signaling, reduced renal caspase-12 expression, and a 50% reduction in renal caspase-3 activity. We further demonstrated in vitro that the protective activity of EET analogs does not compromise the anticancer effects of cisplatin. Collectively, our data provide evidence that EET analogs attenuate cisplatin-induced nephrotoxicity by reducing oxidative stress, inflammation, ER stress, and apoptosis without affecting the chemotherapeutic effects of cisplatin.—Khan, Md. A. H., Liu, J., Kumar, G., Skapek, S. X., Falck, J. R., Imig, J. D. Novel orally active epoxyeicosatrienoic acid (EET) analogs attenuate cisplatin nephrotoxicity. PMID:23603837

Poricoic acid ZA, a novel RAS inhibitor, attenuates tubulo-interstitial fibrosis and podocyte injury by inhibiting TGF-β/Smad signaling pathway.

PubMed

Wang, Ming; Chen, Dan-Qian; Wang, Min-Chang; Chen, Hua; Chen, Lin; Liu, Dan; Zhao, Hui; Zhao, Ying-Yong

2017-12-01

The pathogenesis of tubulo-interstitial fibrosis and glomerulosclerosisis was characterized by cellular hypertrophy, extracellular matrix accumulation and podocyte detachment. Poricoic acid ZA (PZA) is a tetracyclic triterpenoid compound extracted from the surface layer of Poria cocos (LPC), which have been used extensively for diuretic and renoprotective effects. The anti-fibrotic effect of PZA is investigated in HK-2 cells and podocytes induced by TGF-β1 and angiotensin II (ANGII). qRT-PCR, siRNA, immunofluorescence staining, co-immunoprecipitation and Western blot analyses are used to evaluate the expression of RAS signaling, TGF-β/Smad pathway, epithelial-to-mesenchymal transition (EMT) and podocyte markers. PZA restores the mRNA and protein expression of EMT in HK-2 cells. Specific TGF-β1-siRNA efficiently blocks ANGII-induced protein expression of TGF-β1 and further inhibits activated Smad signaling. PZA significantly attenuates up-regulation of angiotensinogen, renin, ACE and AT1. Further, PZA reverses up-regulation of TGFβRII and suppresses Smad proteins. Simultaneously, PZA inhibits the protein interaction of TGF-β receptor and Smads and PZA also inhibits activated RAS and TGF-β/Smad signaling cascade and up-regulates protein expression of podocyte markers and mitigates podocyte injury. This study demonstrated the beneficial role of PZA in renal fibrosis and podocyte injury. Our study highlighted that PZA inhibits RAS and further suppresses TGF-β/Smad pathway through inhibiting Smad2/3 phosphorylation via blocking Smad2/3-TGFβRI protein interaction. PZA is implicated in activation of RAS/TGF-β/Smad axis in HK-2 cells and podocytes. PZA could be considered as a novel RAS inhibitor for treating CKD. Copyright © 2017 Elsevier GmbH. All rights reserved.

Tracer attenuation in groundwater

NASA Astrophysics Data System (ADS)

Cvetkovic, Vladimir

2011-12-01

The self-purifying capacity of aquifers strongly depends on the attenuation of waterborne contaminants, i.e., irreversible loss of contaminant mass on a given scale as a result of coupled transport and transformation processes. A general formulation of tracer attenuation in groundwater is presented. Basic sensitivities of attenuation to macrodispersion and retention are illustrated for a few typical retention mechanisms. Tracer recovery is suggested as an experimental proxy for attenuation. Unique experimental data of tracer recovery in crystalline rock compare favorably with the theoretical model that is based on diffusion-controlled retention. Non-Fickian hydrodynamic transport has potentially a large impact on field-scale attenuation of dissolved contaminants.

SIGNALING PATHWAYS IN MELANOSOME BIOGENESIS AND PATHOLOGY

PubMed Central

Schiaffino, Maria Vittoria

2010-01-01

Melanosomes are the specialized intracellular organelles of pigment cells devoted to the synthesis, storage and transport of melanin pigments, which are responsible for most visible pigmentation in mammals and other vertebrates. As a direct consequence, any genetic mutation resulting in alteration of melanosomal function, either because affecting pigment cell survival, migration and differentiation, or because interfering with melanosome biogenesis, transport and transfer to keratinocytes, is immediately translated into color variations of skin, fur, hair or eyes. Thus, over one hundred genes and proteins have been identified as pigmentary determinants in mammals, providing us with a deep understanding of this biological system, which functions by using mechanisms and processes that have parallels in other tissues and organs. In particular, many genes implicated in melanosome biogenesis have been characterized, so that melanosomes represent an incredible source of information and a model for organelles belonging to the secretory pathway. Furthermore, the function of melanosomes can be associated with common physiological phenotypes, such as variation of pigmentation among individuals, and with rare pathological conditions, such as albinism, characterized by severe visual defects. Among the most relevant mechanisms operating in melanosome biogenesis are the signal transduction pathways mediated by two peculiar G protein-coupled receptors: the melanocortin-1 receptor (MC1R), involved in the fair skin/red hair phenotype and skin cancer; and OA1 (GPR143), whose loss-of-function results in X-linked ocular albinism. This review will focus on the most recent novelties regarding the functioning of these two receptors, by highlighting emerging signaling mechanisms and general implications for cell biology and pathology. PMID:20381640

Synthesis and characterization of a Eu-DTPA-PEGO-MSH(4) derivative for evaluation of binding of multivalent molecules to melanocortin receptors.

PubMed

Xu, Liping; Vagner, Josef; Alleti, Ramesh; Rao, Venkataramanarao; Jagadish, Bhumasamudram; Morse, David L; Hruby, Victor J; Gillies, Robert J; Mash, Eugene A

2010-04-15

A labeled variant of MSH(4), a tetrapeptide that binds to the human melanocortin 4 receptor (hMC4R) with low microM affinity, was prepared by solid-phase synthesis methods, purified, and characterized. The labeled ligand, Eu-DTPA-PEGO-His-dPhe-Arg-Trp-NH(2), exhibited a K(d) for hMC4R of 9.1+/-1.4 microM, approximately 10-fold lower affinity than the parental ligand. The labeled MSH(4) derivative was employed in a competitive binding assay to characterize the interactions of hMC4R with monovalent and divalent MSH(4) constructs derived from squalene. The results were compared with results from a similar assay that employed a more potent labeled ligand, Eu-DTPA-NDP-alpha-MSH. While results from the latter assay reflected only statistical effects, results from the former assay reflected a mixture of statistical, proximity, and/or cooperative binding effects. Copyright 2010 Elsevier Ltd. All rights reserved.

AiiA, an enzyme that inactivates the acylhomoserine lactone quorum-sensing signal and attenuates the virulence of Erwinia carotovora

PubMed Central

Dong, Yi-Hu; Xu, Jin-Ling; Li, Xian-Zhen; Zhang, Lian-Hui

2000-01-01

N-acylhomoserine lactones, known as autoinducers (AIs), are widely conserved signal molecules present in quorum-sensing systems of many Gram-negative bacteria. AIs are involved in the regulation of diverse biological functions, including expression of pathogenic genes in the plant pathogens Pseudomonas solanacearum, several Erwinia species, and the human pathogen Pseudomonas aeruginosa. A bacterial isolate, Bacillus sp. 240B1, is capable of enzymatic inactivation of AIs. The gene (aiiA) for AI inactivation from Bacillus sp. 240B1 has been cloned and shown to encode a protein of 250 amino acids. Sequence alignment indicates that AiiA contains a “HXHXDH” zinc-binding motif that is conserved in several groups of metallohydrolases. Site-directed mutagenesis showed that conserved aspartate and most histidine residues are required for AiiA activity. Expression of aiiA in transformed Erwinia carotovora strain SCG1 significantly reduces the release of AI, decreases extracellular pectolytic enzyme activities, and attenuates pathogenicity on potato, eggplant, Chinese cabbage, carrot, celery, cauliflower, and tobacco. Our results indicate that the AI-inactivation approach represents a promising strategy for prevention of diseases in which virulence is regulated by AIs. PMID:10716724

Transient Inhibition of FGFR2b-Ligands Signaling Leads to Irreversible Loss of Cellular β-Catenin Organization and Signaling in AER during Mouse Limb Development

PubMed Central

Tabatabai, Reza; Baptista, Sheryl; Tiozzo, Caterina; Carraro, Gianni; Wheeler, Matthew; Barreto, Guillermo; Braun, Thomas; Li, Xiaokun; Hajihosseini, Mohammad K.; Bellusci, Saverio

2013-01-01

The vertebrate limbs develop through coordinated series of inductive, growth and patterning events. Fibroblast Growth Factor receptor 2b (FGFR2b) signaling controls the induction of the Apical Ectodermal Ridge (AER) but its putative roles in limb outgrowth and patterning, as well as in AER morphology and cell behavior have remained unclear. We have investigated these roles through graded and reversible expression of soluble dominant-negative FGFR2b molecules at various times during mouse limb development, using a doxycycline/transactivator/tet(O)-responsive system. Transient attenuation (≤24 hours) of FGFR2b-ligands signaling at E8.5, prior to limb bud induction, leads mostly to the loss or truncation of proximal skeletal elements with less severe impact on distal elements. Attenuation from E9.5 onwards, however, has an irreversible effect on the stability of the AER, resulting in a progressive loss of distal limb skeletal elements. The primary consequences of FGFR2b-ligands attenuation is a transient loss of cell adhesion and down-regulation of P63, β1-integrin and E-cadherin, and a permanent loss of cellular β-catenin organization and WNT signaling within the AER. Combined, these effects lead to the progressive transformation of the AER cells from pluristratified to squamous epithelial-like cells within 24 hours of doxycycline administration. These findings show that FGFR2b-ligands signaling has critical stage-specific roles in maintaining the AER during limb development. PMID:24167544

NEU3 inhibitory effect of naringin suppresses cancer cell growth by attenuation of EGFR signaling through GM3 ganglioside accumulation.

PubMed

Yoshinaga, Ayana; Kajiya, Natsuki; Oishi, Kazuki; Kamada, Yuko; Ikeda, Asami; Chigwechokha, Petros Kingstone; Kibe, Toshiro; Kishida, Michiko; Kishida, Shosei; Komatsu, Masaharu; Shiozaki, Kazuhiro

2016-07-05

Naringin, which is one of the flavonoids contained in citrus fruits, is well known to possess various healthy functions to humans. It has been reported that naringin suppresses cancer cell growth in vitro and in vivo, although the underlying mechanisms are not fully understood. Recently, the roles of glycoconjugates, such as gangliosides, in cancer cells have been focused because of their regulatory effects of malignant phenotypes. Here, to clarify the roles of naringin in the negative-regulation of cancer cell growth, the alteration of glycoconjugates induced by naringin exposure and its significance on cell signaling were investigated. Human cancer cells, HeLa and A549, were exposed to various concentrations of naringin. Naringin treatment induced the suppression of cell growth toward HeLa and A549 cells accompanied with an increase of apoptotic cells. In naringin-exposed cells, GM3 ganglioside was drastically increased compared to the GM3 content prior to the treatment. Furthermore, naringin inhibited NEU3 sialidase, a GM3 degrading glycosidase. Similarly, NEU3 inhibition activities were also detected by other flavanone, such as hesperidin and neohesperidin dihydrocalcone, but their aglycones showed less inhibitions. Naringin-treated cancer cells showed suppressed EGFR and ERK phosphorylation levels. These results suggest a novel mechanism of naringin in the suppression of cancer cell growth through the alteration of glycolipids. NEU3 inhibitory effect of naringin induced GM3 accumulation in HeLa and A549 cells, leading the attenuation of EGFR/ERK signaling accompanied with a decrease in cell growth. Copyright © 2016 Elsevier B.V. All rights reserved.

Multiple attenuation to reflection seismic data using Radon filter and Wave Equation Multiple Rejection (WEMR) method

DOE Office of Scientific and Technical Information (OSTI.GOV)

Erlangga, Mokhammad Puput

Separation between signal and noise, incoherent or coherent, is important in seismic data processing. Although we have processed the seismic data, the coherent noise is still mixing with the primary signal. Multiple reflections are a kind of coherent noise. In this research, we processed seismic data to attenuate multiple reflections in the both synthetic and real seismic data of Mentawai. There are several methods to attenuate multiple reflection, one of them is Radon filter method that discriminates between primary reflection and multiple reflection in the τ-p domain based on move out difference between primary reflection and multiple reflection. However, inmore » case where the move out difference is too small, the Radon filter method is not enough to attenuate the multiple reflections. The Radon filter also produces the artifacts on the gathers data. Except the Radon filter method, we also use the Wave Equation Multiple Elimination (WEMR) method to attenuate the long period multiple reflection. The WEMR method can attenuate the long period multiple reflection based on wave equation inversion. Refer to the inversion of wave equation and the magnitude of the seismic wave amplitude that observed on the free surface, we get the water bottom reflectivity which is used to eliminate the multiple reflections. The WEMR method does not depend on the move out difference to attenuate the long period multiple reflection. Therefore, the WEMR method can be applied to the seismic data which has small move out difference as the Mentawai seismic data. The small move out difference on the Mentawai seismic data is caused by the restrictiveness of far offset, which is only 705 meter. We compared the real free multiple stacking data after processing with Radon filter and WEMR process. The conclusion is the WEMR method can more attenuate the long period multiple reflection than the Radon filter method on the real (Mentawai) seismic data.« less

Determining attenuation properties of interfering fast and slow ultrasonic waves in cancellous bone.

PubMed

Nelson, Amber M; Hoffman, Joseph J; Anderson, Christian C; Holland, Mark R; Nagatani, Yoshiki; Mizuno, Katsunori; Matsukawa, Mami; Miller, James G

2011-10-01

Previous studies have shown that interference between fast waves and slow waves can lead to observed negative dispersion in cancellous bone. In this study, the effects of overlapping fast and slow waves on measurements of the apparent attenuation as a function of propagation distance are investigated along with methods of analysis used to determine the attenuation properties. Two methods are applied to simulated data that were generated based on experimentally acquired signals taken from a bovine specimen. The first method uses a time-domain approach that was dictated by constraints imposed by the partial overlap of fast and slow waves. The second method uses a frequency-domain log-spectral subtraction technique on the separated fast and slow waves. Applying the time-domain analysis to the broadband data yields apparent attenuation behavior that is larger in the early stages of propagation and decreases as the wave travels deeper. In contrast, performing frequency-domain analysis on the separated fast waves and slow waves results in attenuation coefficients that are independent of propagation distance. Results suggest that features arising from the analysis of overlapping two-mode data may represent an alternate explanation for the previously reported apparent dependence on propagation distance of the attenuation coefficient of cancellous bone. © 2011 Acoustical Society of America

Determining attenuation properties of interfering fast and slow ultrasonic waves in cancellous bone

PubMed Central

Nelson, Amber M.; Hoffman, Joseph J.; Anderson, Christian C.; Holland, Mark R.; Nagatani, Yoshiki; Mizuno, Katsunori; Matsukawa, Mami; Miller, James G.

2011-01-01

Previous studies have shown that interference between fast waves and slow waves can lead to observed negative dispersion in cancellous bone. In this study, the effects of overlapping fast and slow waves on measurements of the apparent attenuation as a function of propagation distance are investigated along with methods of analysis used to determine the attenuation properties. Two methods are applied to simulated data that were generated based on experimentally acquired signals taken from a bovine specimen. The first method uses a time-domain approach that was dictated by constraints imposed by the partial overlap of fast and slow waves. The second method uses a frequency-domain log-spectral subtraction technique on the separated fast and slow waves. Applying the time-domain analysis to the broadband data yields apparent attenuation behavior that is larger in the early stages of propagation and decreases as the wave travels deeper. In contrast, performing frequency-domain analysis on the separated fast waves and slow waves results in attenuation coefficients that are independent of propagation distance. Results suggest that features arising from the analysis of overlapping two-mode data may represent an alternate explanation for the previously reported apparent dependence on propagation distance of the attenuation coefficient of cancellous bone. PMID:21973378

[STUDYING THE ROLE OF BRAIN MELANOCORTIN RECEPTORS IN THE SUPPRESSING OF FOOD INTAKE UNDER ETHER STRESS IN MICE].

PubMed

Bazhan, N M; Kulikova, E V; Makarova, E N; Yakovleva, T V; Kazantseva, A Yu

2015-12-01

Melanocortin (MC) system regulates food intake under the rest conditions. Stress inhibits food intake. It is not clear whether brain MC system is involved in stress-induced anorexia in mice. The aim of the work was to investigate the effect of pharmacological blockade and activation of brain MC receptors on food intake under stress. C57B1/6J male mice were subjected to ether stress (0.5 minute ether anesthesia) before the administration of saline solution or synthetic non-selective blocker (SHU9119) or agonist (Melanotan II) of MC receptors into the lateral brain ventricle. Food intake was pre-stimulated with 17 hours of fasting in all mice. Ether stress decreased food intake, increased the plasma corticosterone level and hypothalamic mRNA AgRP (natural MC receptor antagonist) level at 1 hour after the stress. Pharmacological blockade of the MC receptors weakened stress-induced anorexia and decreased mRNA AgRP level in the hypothalamus. Pharmacological stimulation of the MC receptors enhanced ether stress-induced anorexia and hypercortisolism. Thus, our data demonstrated that the central MC system was involved in the development of stress-induced anorexia in mice.

Brain-targeted ACE2 overexpression attenuates neurogenic hypertension by inhibiting COX mediated inflammation

PubMed Central

Sriramula, Srinivas; Xia, Huijing; Xu, Ping; Lazartigues, Eric

2014-01-01

Overactivity of the renin angiotensin system (RAS), oxidative stress, and cyclooxygenases (COX) in the brain are implicated in the pathogenesis of hypertension. We previously reported that Angiotensin-Converting Enzyme 2 (ACE2) overexpression in the brain attenuates the development of DOCA-salt hypertension, a neurogenic hypertension model with enhanced brain RAS and sympathetic activity. To elucidate the mechanisms involved, we investigated whether oxidative stress, mitogen activated protein kinase signaling and cyclooxygenase (COX) activation in the brain are modulated by ACE2 in neurogenic hypertension. DOCA-salt hypertension significantly increased expression of Nox-2 (+61 ±5 %), Nox-4 (+50 ±13 %) and nitrotyrosine (+89 ±32 %) and reduced activity of the antioxidant enzymes, catalase (−29 ±4 %) and SOD (−31 ±7 %), indicating increased oxidative stress in the brain of non-transgenic mice. This increased oxidative stress was attenuated in transgenic mice overexpressing ACE2 in the brain. DOCA-salt-induced reduction of nNOS expression (−26 ±7 %) and phosphorylated eNOS/total eNOS (−30 ±3 %), and enhanced phosphorylation of Akt and ERK1/2 in the paraventricular nucleus (PVN), were reversed by ACE2 overexpression. In addition, ACE2 overexpression blunted the hypertension-mediated increase in gene and protein expression of COX-1 and COX-2 in the PVN. Furthermore, gene silencing of either COX-1 or COX-2 in the brain, reduced microglial activation and accompanied neuro-inflammation, ultimately attenuating DOCA-salt hypertension. Together, these data provide evidence that brain ACE2 overexpression reduces oxidative stress and COX-mediated neuro-inflammation, improves anti-oxidant and nitric oxide signaling, and thereby attenuates the development of neurogenic hypertension. PMID:25489058

Variable laser attenuator

DOEpatents

Foltyn, Stephen R.

1988-01-01

The disclosure relates to low loss, high power variable attenuators comprng one or more transmissive and/or reflective multilayer dielectric filters. The attenuator is particularly suitable to use with unpolarized lasers such as excimer lasers. Beam attenuation is a function of beam polarization and the angle of incidence between the beam and the filter and is controlled by adjusting the angle of incidence the beam makes to the filter or filters. Filters are selected in accordance with beam wavelength.

Variable laser attenuator

DOEpatents

Foltyn, S.R.

1987-05-29

The disclosure relates to low loss, high power variable attenuators comprising one or more transmissive and/or reflective multilayer dielectric filters. The attenuator is particularly suitable to use with unpolarized lasers such as excimer lasers. Beam attenuation is a function of beam polarization and the angle of incidence between the beam and the filter and is controlled by adjusting the angle of incidence the beam makes to the filter or filters. Filters are selected in accordance with beam wavelength. 9 figs.

Attenuation Compensation of Ultrasonic Wave in Soft Tissue for Acoustic Impedance Measurement of In vivo Bone by Transducer Vibration Method

NASA Astrophysics Data System (ADS)

Yoshizawa, Masasumi; Nakamura, Yuuta; Ishiguro, Masataka; Moriya, Tadashi

2007-07-01

In this paper, we describe a method of compensating the attenuation of the ultrasound caused by soft tissue in the transducer vibration method for the measurement of the acoustic impedance of in vivo bone. In the in vivo measurement, the acoustic impedance of bone is measured through soft tissue; therefore, the amplitude of the ultrasound reflected from the bone is attenuated. This attenuation causes an error of the order of -20 to -30% when the acoustic impedance is determined from the measured signals. To compensate the attenuation, the attenuation coefficient and length of the soft tissue are measured by the transducer vibration method. In the experiment using a phantom, this method allows the measurement of the acoustic impedance typically with an error as small as -8 to 10%.

Accounting for the Spatial Observation Window in the 2-D Fourier Transform Analysis of Shear Wave Attenuation.

PubMed

Rouze, Ned C; Deng, Yufeng; Palmeri, Mark L; Nightingale, Kathryn R

2017-10-01

Recent measurements of shear wave propagation in viscoelastic materials have been analyzed by constructing the 2-D Fourier transform (2DFT) of the shear wave signal and measuring the phase velocity c(ω) and attenuation α(ω) from the peak location and full width at half-maximum (FWHM) of the 2DFT signal at discrete frequencies. However, when the shear wave is observed over a finite spatial range, the 2DFT signal is a convolution of the true signal and the observation window, and measurements using the FWHM can yield biased results. In this study, we describe a method to account for the size of the spatial observation window using a model of the 2DFT signal and a non-linear, least-squares fitting procedure to determine c(ω) and α(ω). Results from the analysis of finite-element simulation data agree with c(ω) and α(ω) calculated from the material parameters used in the simulation. Results obtained in a viscoelastic phantom indicate that the measured attenuation is independent of the observation window and agree with measurements of c(ω) and α(ω) obtained using the previously described progressive phase and exponential decay analysis. Copyright © 2017 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Radar antenna pointing for optimized signal to noise ratio.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Doerry, Armin Walter; Marquette, Brandeis

2013-01-01

The Signal-to-Noise Ratio (SNR) of a radar echo signal will vary across a range swath, due to spherical wavefront spreading, atmospheric attenuation, and antenna beam illumination. The antenna beam illumination will depend on antenna pointing. Calculations of geometry are complicated by the curved earth, and atmospheric refraction. This report investigates optimizing antenna pointing to maximize the minimum SNR across the range swath.

Hyperoside attenuates hydrogen peroxide-induced L02 cell damage via MAPK-dependent Keap{sub 1}-Nrf{sub 2}-ARE signaling pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xing, Hai-Yan; Liu, Yao; Chen, Jian-Hong

Highlights: {yields} Hyperoside attenuated H{sub 2}O{sub 2}-induced L02 cell damage. {yields} Hyperoside up-regulated HO-1 expression at both mRNA and protein levels. {yields} Hyperoside activated both Nrf{sub 2} nuclear translocation and gene expression. {yields} Hyperoside may inhibit Keap{sub 1} mRNA translation or protein degradation. {yields} Phosphorylation of ERK and p38 is involved in hyperoside-mediated Nrf{sub 2} activation. -- Abstract: The flavonoid hyperoside has been reported to elicit cytoprotection against oxidative stress partly by increasing the activity of antioxidant enzymes, such as glutathione peroxidase, superoxide dismutase and catalase. However, the cellular and molecular mechanisms underlying this effect remain unclear. Here, hepatic L02more » cells exposed to H{sub 2}O{sub 2} (100 {mu}M) were used to demonstrate that hyperoside protected cells by significantly inhibiting overproduction of intracellular ROS, depletion of the mitochondrial membrane potential and leakage of lactate dehydrogenase. Hyperoside further enhanced the cellular antioxidant defense system through increasing the activity of heme oxygenase-1 (HO-1), and by up-regulating HO-1 expression. Meanwhile, real time PCR, western blot and immunofluorescence studies revealed that hyperoside stimulated nuclear translocation of the Nrf{sub 2} transcription factor in a dose-dependent manner, and this effect was significantly suppressed by pharmacological inhibition of the mitogen-activated protein kinases (MAPK) p38 and ERK. Collectively, our data provide the first description of the mechanism underlying hyperoside's ability to attenuate H{sub 2}O{sub 2}-induced cell damage, namely this compound interacts with the MAPK-dependent Keap{sub 1}-Nrf{sub 2}-ARE signaling pathway to up-regulate HO-1 expression and enhance intracellular antioxidant activity.« less

Preclinical evaluation of melanocortin-1 receptor (MC1-R) specific 68Ga- and 44Sc-labeled DOTA-NAPamide in melanoma imaging.

PubMed

Nagy, Gábor; Dénes, Noémi; Kis, Adrienn; Szabó, Judit P; Berényi, Ervin; Garai, Ildikó; Bai, Péter; Hajdu, István; Szikra, Dezső; Trencsényi, György

2017-08-30

Alpha melanocyte stimulating hormone (α-MSH) enhances melanogenesis in melanoma malignum by binding to melanocortin-1 receptors (MC1-R). Earlier studies demonstrated that alpha-MSH analog NAPamide molecule specifically binds to MC1-R receptor. Radiolabeled NAPamide is a promising radiotracer for the non-invasive detection of melanin producing melanoma tumors by Positron Emission Tomography (PET). In this present study the MC1-R selectivity of the newly developed Sc-44-labeled DOTA-NAPamide was investigated in vitro and in vivo using melanoma tumors. DOTA-NAPamide was labeled with Ga-68 and Sc-44 radionuclides. The MC1-R specificity of Ga-68- and Sc-44-labeled DOTA-NAPamide was investigated in vitro and in vivo using MC1-R positive (B16-F10) and negative (A375) melanoma cell lines. For in vivo imaging studies B16-F10 and A375 tumor-bearing mice were injected with 44 Sc/ 68 Ga-DOTA-NAPamide (in blocking studies with α-MSH) and whole body PET/MRI scans were acquired. Radiotracer uptake was expressed in terms of standardized uptake values (SUVs). 44 Sc/ 68 Ga-labeled DOTA-NAPamide were produced with high specific activity (approx. 19 GBq/μmol) and with excellent radiochemical purity (99%<). MC1-R positive B16-F10 cells showed significantly (p≤0.01) higher in vitro radiotracer accumulation than that of receptor negative A375 melanoma cells. In animal experiments, also significantly (p≤0.01) higher Ga-68-DOTA-NAPamide (SUVmean: 0.38±0.02), and Sc-44-DOTA-NAPamide (SUVmean: 0.52±0.13) uptake was observed in subcutaneously growing B16-F10 tumors, than in receptor negative A375 tumors, where the SUVmean values of Ga-68-DOTA-NAPamide and Sc-44-DOTA-NAPamide were 0.04±0.01 and 0.07±0.01, respectively. Tumor-to-muscle (T/M SUVmean) ratios were approximately 15-fold higher in B16-F10 tumor-bearing mice, than that of A375 tumors, and this difference was also significant (p≤0.01) using both radiotracers after 60 min incubation time. Our newly synthesized 44 Sc

Astragaloside IV attenuates injury caused by myocardial ischemia/reperfusion in rats via regulation of toll-like receptor 4/nuclear factor-κB signaling pathway.

PubMed

Lu, Meili; Tang, Futian; Zhang, Jing; Luan, Aina; Mei, Meng; Xu, Chonghua; Zhang, Suping; Wang, Hongxin; Maslov, Leonid N

2015-04-01

Myocardial ischemia/reperfusion (MI/R) injury, in which inflammatory response and cell apoptosis play a vital role, is frequently encountered in clinical practice. Astragaloside IV (AsIV), a small molecular saponin of Astragalus membranaceus, has been shown to confer protective effects against many cardiovascular diseases. The present study was aimed to investigate the antiinflammatory and antiapoptotic effects and the possible mechanism of AsIV on MI/R injury in rats. Rats were randomly divided into sham operation group, MI/R group and groups with combinations of MI/R and different doses of AsIV. The results showed that the expressions of myocardial toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) were significantly increased, and apoptosis of cardiomyocytes was induced in MI/R group compared with that in sham operation group. Administration of AsIV attenuated MI/R injury, downregulated the expressions of TLR4 and NF-κB and inhibited cell apoptosis as evidenced by decreased terminal deoxynucleotidyl transferase dUTP nick end labeling positive cells, B-cell lymphoma-2 associated X protein and caspase-3 expressions and increased B-cell lymphoma-2 expression compared with that in MI/R group. In addition, AsIV treatment reduced levels of inflammatory cytokines induced by MI/R injury. In conclusion, our results demonstrated that AsIV downregulates TLR4/NF-κB signaling pathway and inhibits cell apoptosis, subsequently attenuating MI/R injury in rats. Copyright © 2015 John Wiley & Sons, Ltd.

Site response and attenuation in the Puget Lowland, Washington State

USGS Publications Warehouse

Pratt, T.L.; Brocher, T.M.

2006-01-01

Simple spectral ratio (SSR) and horizontal-to-vertical (HN) site-response estimates at 47 sites in the Puget Lowland of Washington State document significant attenuation of 1.5- to 20-Hz shear waves within sedimentary basins there. Amplitudes of the horizontal components of shear-wave arrivals from three local earthquakes were used to compute SSRs with respect to the average of two bedrock sites and H/V spectral ratios with respect to the vertical component of the shear-wave arrivals at each site. SSR site-response curves at thick basin sites show peak amplifications of 2 to 6 at frequencies of 3 to 6 Hz, and decreasing spectra amplification with increasing frequency above 6 Hz. SSRs at nonbasin sites show a variety of shapes and larger resonance peaks. We attribute the spectral decay at frequencies above the amplification peak at basin sites to attenuation within the basin strata. Computing the frequency-independent, depth-dependent attenuation factor (Qs,int) from the SSR spectral decay between 2 and 20 Hz gives values of 5 to 40 for shallow sedimentary deposits and about 250 for the deepest sedimentary strata (7 km depth). H/V site responses show less spectral decay than the SSR responses but contain many of the same resonance peaks. We hypothesize that the H/V method yields a flatter response across the frequency spectrum than SSRs because the H/V reference signal (vertical component of the shear-wave arrivals) has undergone a degree of attenuation similar to the horizontal component recordings. Correcting the SSR site responses for attenuation within the basins by removing the spectral decay improves agreement between SSR and H/V estimates.

Ginkgo biloba extract EGb761 attenuates brain death-induced renal injury by inhibiting pro-inflammatory cytokines and the SAPK and JAK-STAT signalings

PubMed Central

Li, Yifu; Xiong, Yunyi; Zhang, Huanxi; Li, Jun; Wang, Dong; Chen, Wenfang; Yuan, Xiaopeng; Su, Qiao; Li, Wenwen; Huang, Huiting; Bi, Zirong; Liu, Longshan; Wang, Changxi

2017-01-01

This study aimed to investigate the protective effects of EGb761, a Ginkgo Biloba extract, against brain death-induced kidney injury. Sixty male Sprague Dawley rats were randomly divided into six groups: sham, brain-death (BD), BD + EGb b48h (48 hours before BD), BD + EGb 2 h (2 hours after BD), BD + EGb 1 h, and BD + EGb 0.5 h. Six hours after BD, serum sample and kidney tissues were collected for analyses. The levels of blood urea nitrogen (BUN) and serum creatinine significantly elevated in the BD group than in sham group. In all the EGb761-treated BD animals except for the BD + Gb 2 h group, the levels of BUN and serum creatinine significantly reduced (all P < 0.01). EGb761 attenuated tubular injury and lowered the histological score. In addition, the longer duration of drug treatment was, the better protective efficacy could be observed. EGb761 significantly reduced IL-1β, IL-6, TNF-α, MCP-1, IP-10 mRNA expression and macrophage infiltration in the kidney. EGb761 treatment at 48 hour before brain death significantly attenuate the levels of p-JNK-MAPK, p-p38-MAPK, and p-STAT3 proteins (all P < 0.05, compared to BD group). In summary, our data showed that EGb761 treatment protected donor kidney from BD-induced damages by blocking SAPK and JAK-STAT signalings. Early administration of EGb761 can provide better protective efficacy. PMID:28332628

Oleanolic acid supplement attenuates liquid fructose-induced adipose tissue insulin resistance through the insulin receptor substrate-1/phosphatidylinositol 3-kinase/Akt signaling pathway in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Ying; Wang, Jianwei, E-mail: wangjianwei1968@gmail.com; Gu, Tieguang

-IR in fructose-fed rats. • OA attenuated fructose-induced increase in Adipo-IR index and NEFA concentrations. • OA modulated adipose IRS-1/phosphatidylinositol 3-kinase/Akt signaling. • OA ameliorates Adipo-IR via the IRS-1/PI3K/Akt signaling pathway in rats.« less

Detailed study of seismic wave attenuation from four oilfields in Abu Dhabi, United Arab Emirates

NASA Astrophysics Data System (ADS)

Bouchaala, F.; Ali, M. Y.; Matsushima, J.

2018-02-01

In the present study, we provide a detailed study of seismic wave attenuation obtained from four oilfields. The reservoir zones of these oilfields are complicated due to complex fracture networks, the presence of tar mat and high heterogeneity of carbonate rocks of which the subsurface of Abu Dhabi is mainly composed. These complexities decrease signal-to-noise ratio and make attenuation estimation difficult. We obtained high-resolution attenuation profiles from vertical seismic profiling (VSP) and sonic waveform data. The VSP data were recorded in all four oilfields and the sonic data were acquired in the reservoir zones of oilfields I and IV. We found that the VSP scattering attenuation ({Q}{{S}{{c}}{{a}}{{t}}}-1) varies from -0.080 to 0.180 over a depth range of 400-3500 m. We attributed this significant scattering to the high heterogeneity of carbonate rocks. The scattering profiles seem to be sensitive to fractures, lithology heterogeneity and tar mat, but their effect is superimposed. The VSP intrinsic attenuation varies from -0.15 to 0.246 with high variation within each formation. Since intrinsic attenuation is closely related to fluids, we assumed that this variation is due to the non-uniform distribution of fluids caused by the complex porosity network of the subsurface. The sonic monopole attenuation ({Q}{{M}{{f}}}-1) in the reservoir zones ranges between 0.033-0.094 and dipole inline attenuation ({Q}{{I}{{n}}{{l}}}-1) ranges from 0.040-0.138. The sonic attenuation appears to be sensitive to the presence of fluid and type of fractures, where it shows high attenuation for open fractures and low attenuation for resistive fractures. The zones with high clay content display high sonic intrinsic attenuation in the reservoir of oilfield II. We explain this by the frictional movement between the clay and carbonates due to the elasticity contrast of these two materials. Therefore, the solid grain friction may be the dominant attenuation mechanism in those zones.

Effects of melting layer on Ku-band signal depolarization

NASA Astrophysics Data System (ADS)

Sarkar, Thumree; Das, Saurabh; Maitra, Animesh

2014-09-01

Propagation effects on Ku-band over an earth-space path is carried out at Kolkata, India, a tropical location, by receiving a Ku-band signal with horizontal plane polarization transmitted from the geostationary satellite NSS-6 (at 95°E). The amplitude of co-polar attenuation has been monitored along with the measurements of rain rate, rain drop size distribution and height profile of rain rate. The cross-polar enhancement of the signal is also monitored by receiving the same signal in orthogonal direction with another identical receiver. The experimental observations are used to study the effect of melting layer on both co-polar attenuation and cross-polar enhancement for the rain events observed during 2012-2013. Melting layer is indicated by the bright band signature in vertical profile of rain rate. The ground based drop size measurements indicate that the stratiform rain has more number of small drops whereas convective rain composed of large rain drops. The results indicate that the depolarization due to melting layer is more dominant compared to that due to the drop deformation mechanism at low rain rates.

Ultrasonic attenuation in pearlitic steel.

PubMed

Du, Hualong; Turner, Joseph A

2014-03-01

Expressions for the attenuation coefficients of longitudinal and transverse ultrasonic waves are developed for steel with pearlitic microstructure. This type of lamellar duplex microstructure influences attenuation because of the lamellar spacing. In addition, longitudinal attenuation measurements were conducted using an unfocused transducer with 10 MHz central frequency on the cross section of a quenched railroad wheel sample. The dependence of longitudinal attenuation on the pearlite microstructure is observed from the changes of longitudinal attenuation from the quenched tread surface to deeper locations. The results show that the attenuation value is lowest and relatively constant within the quench depth, then increases linearly. The experimental results demonstrate a reasonable agreement with results from the theoretical model. Ultrasonic attenuation provides an important non-destructive method to evaluate duplex microstructure within grains which can be implemented for quality control in conjunction with other manufacturing processes. Copyright © 2013 Elsevier B.V. All rights reserved.

High fructose-mediated attenuation of insulin receptor signaling does not affect PDGF-induced proliferative signaling in vascular smooth muscle cells.

PubMed

Osman, Islam; Poulose, Ninu; Ganapathy, Vadivel; Segar, Lakshman

2016-11-15

Insulin resistance is associated with accelerated atherosclerosis. Although high fructose is known to induce insulin resistance, it remains unclear as to how fructose regulates insulin receptor signaling and proliferative phenotype in vascular smooth muscle cells (VSMCs), which play a major role in atherosclerosis. Using human aortic VSMCs, we investigated the effects of high fructose treatment on insulin receptor substrate-1 (IRS-1) serine phosphorylation, insulin versus platelet-derived growth factor (PDGF)-induced phosphorylation of Akt, S6 ribosomal protein, and extracellular signal-regulated kinase (ERK), and cell cycle proteins. In comparison with PDGF (a potent mitogen), neither fructose nor insulin enhanced VSMC proliferation and cyclin D1 expression. d-[ 14 C(U)]fructose uptake studies revealed a progressive increase in fructose uptake in a time-dependent manner. Concentration-dependent studies with high fructose (5-25mM) showed marked increases in IRS-1 serine phosphorylation, a key adapter protein in insulin receptor signaling. Accordingly, high fructose treatment led to significant diminutions in insulin-induced phosphorylation of downstream signaling components including Akt and S6. In addition, high fructose significantly diminished insulin-induced ERK phosphorylation. Nevertheless, high fructose did not affect PDGF-induced key proliferative signaling events including phosphorylation of Akt, S6, and ERK and expression of cyclin D1 protein. Together, high fructose dysregulates IRS-1 phosphorylation state and proximal insulin receptor signaling in VSMCs, but does not affect PDGF-induced proliferative signaling. These findings suggest that systemic insulin resistance rather than VSMC-specific dysregulation of insulin receptor signaling by high fructose may play a major role in enhancing atherosclerosis and neointimal hyperplasia. Copyright © 2016 Elsevier B.V. All rights reserved.

Mechanism of attenuation of a chimeric influenza A/B transfectant virus.

PubMed

Luo, G; Bergmann, M; Garcia-Sastre, A; Palese, P

1992-08-01

The ribonucleoprotein transfection system for influenza virus allowed us to construct an influenza A virus containing a chimeric neuraminidase (NA) gene in which the noncoding sequence is derived from the NS gene of influenza B virus (T. Muster, E. K. Subbarao, M. Enami, B. P. Murphy, and P. Palese, Proc. Natl. Acad. Sci. USA 88:5177-5181, 1991). This transfectant virus is attenuated in mice and grows to lower titers in tissue culture than wild-type virus. Since such a virus has characteristics desirable for a live attenuated vaccine strain, attempts were made to characterize this virus at the molecular level. Our analysis suggests that the attenuation of the virus is due to changes in the cis signal sequences, which resulted in a reduction of transcription and replication of the chimeric NA gene. The major finding concerns a sixfold reduction in NA-specific viral RNA in the virion, causing a reduction in the ratio of infectious particles to physical particles compared with the ratio in wild-type virus. Although the NA-specific mRNA level is also reduced in transfectant virus-infected cells, it does not appear to contribute to the attenuation characteristics of the virus. The levels of the other RNAs and their expression appear to be unchanged for the transfectant virus. It is suggested that downregulation of the synthesis of one viral RNA segment leads to the generation of defective viruses during each replication cycle. We believe that this represents a general principle for attenuation which may be applied to other segmented viruses containing either single-stranded or double-stranded RNA.

LINE-ABOVE-GROUND ATTENUATOR

DOEpatents

Wilds, R.B.; Ames, J.R.

1957-09-24

The line-above-ground attenuator provides a continuously variable microwave attenuator for a coaxial line that is capable of high attenuation and low insertion loss. The device consists of a short section of the line-above- ground plane type transmission lime, a pair of identical rectangular slabs of lossy material like polytron, whose longitudinal axes are parallel to and indentically spaced away from either side of the line, and a geared mechanism to adjust amd maintain this spaced relationship. This device permits optimum fineness and accuracy of attenuator control which heretofore has been difficult to achieve.

Ultrasonic correlator versus signal averager as a signal to noise enhancement instrument

NASA Technical Reports Server (NTRS)

Kishoni, Doron; Pietsch, Benjamin E.

1989-01-01

Ultrasonic inspection of thick and attenuating materials is hampered by the reduced amplitudes of the propagated waves to a degree that the noise is too high to enable meaningful interpretation of the data. In order to overcome the low Signal to Noise (S/N) ratio, a correlation technique has been developed. In this method, a continuous pseudo-random pattern generated digitally is transmitted and detected by piezoelectric transducers. A correlation is performed in the instrument between the received signal and a variable delayed image of the transmitted one. The result is shown to be proportional to the impulse response of the investigated material, analogous to a signal received from a pulsed system, with an improved S/N ratio. The degree of S/N enhancement depends on the sweep rate. This paper describes the correlator, and compares it to the method of enhancing S/N ratio by averaging the signals. The similarities and differences between the two are highlighted and the potential advantage of the correlator system is explained.

Ultrasonic correlator versus signal averager as a signal to noise enhancement instrument

NASA Technical Reports Server (NTRS)

Kishoni, Doron; Pietsch, Benjamin E.

1990-01-01

Ultrasonic inspection of thick and attenuating materials is hampered by the reduce amplitudes of the propagated waves to a degree that the noise is too high to enable meaningful interpretation of the data. In order to overcome the low signal to noise ratio (S/N), a correlation technique has been developed. In this method, a continuous pseudo-random pattern generated digitally is transmitted and detected by piezoelectric transducers. A correlation is performed in the instrument between the received signal and a variable delayed image of the transmitted one. The result is shown to be proportional to the impulse response of the investigated material, analogous to a signal received from a pulsed system, with an improved S/N ratio. The degree of S/N enhancement depends on the sweep rate. The correlator is described, and it is compared to the method of enhancing S/N ratio by averaging the signals. The similarities and differences between the two are highlighted and the potential advantage of the correlator system is explained.