The adaptor protein CrkII regulates IGF-1-induced biological behaviors of pancreatic ductal adenocarcinoma.

PubMed

Liu, Rui; Wang, Qing; Xu, Guangying; Li, Kexin; Zhou, Lingli; Xu, Baofeng

2016-01-01

Recently, the adaptor protein CrkII has been proved to function in initiating signals for proliferation and invasion in some malignancies. However, the specific mechanisms underlying insulin-like growth factor 1 (IGF-1)-CrkII signaling-induced proliferation of pancreatic ductal adenocarcinoma (PDAC) were not unraveled. In this work, PDAC tissues and cell lines were subjected to in vitro and in vivo assays. Our findings showed that CrkII was abundantly expressed in PDAC tissues and closely correlated with tumor-node-metastasis (TNM) stage and invasion. When cells were subjected to si-CrkII, si-CrkII inhibited IGF-1-mediated PDAC cell growth. In vitro, we demonstrated the upregulation of CrkII, p-Erk1/2, and p-Akt occurring in IGF-1-treated PDAC cells. Conversely, si-CrkII affected upregulation of CrkII, p-Erk1/2, and p-Akt. In addition, cell cycle and in vivo assay identified that knockdown of CrkII inhibited the entry of G1 into S phase and the increase of PDAC tumor weight. In conclusion, CrkII mediates IGF-1 signaling and further balanced PDAC biological behaviors via Erk1/2 and Akt pathway, which indicates that CrkII gene and protein may act as an effective target for the treatment of PDAC.

Takifugu rubripes cation independent mannose 6-phosphate receptor: Cloning, expression and functional characterization of the IGF-II binding domain.

PubMed

A, Ajith Kumar; Nadimpalli, Siva Kumar

2018-07-01

Mannose 6-phosphate/IGF-II receptor mediated lysosomal clearance of insulin-like growth factor-II is significantly associated with the evolution of placental mammals. The protein is also referred to as the IGF-II receptor. Earlier studies suggested relatively low binding affinity between the receptor and ligand in prototherian and metatherian mammals. In the present study, we cloned the IGF-II binding domain of the early vertebrate fugu fish and expressed it in bacteria. A 72000Da truncated receptor containing the IGF-II binding domain was obtained. Analysis of this protein (covering domains 11-13 of the CIMPR) for its affinity to fish and human IGF-II by ligand blot assays and ELISA showed that the expressed receptor can specifically bind to both fish and human IGF-II. Additionally, a peptide-specific antibody raised against the region of the IGF-II binding domain also was able to recognize the IGF-II binding regions of mammalian and non-mammalian cation independent MPR protein. These interactions were further characterized by Surface Plasma resonance support that the receptor binds to fish IGF-II, with a dissociation constant of 548nM. Preliminary analysis suggests that the binding mechanism as well as the affinity of the fish and human receptor for IGF-II may have varied according to different evolutionary pressures. Copyright © 2018. Published by Elsevier B.V.

Insulin-like growth factor-II regulates bone sialoprotein gene transcription.

PubMed

Choe, Jin; Sasaki, Yoko; Zhou, Liming; Takai, Hideki; Nakayama, Yohei; Ogata, Yorimasa

2016-09-01

Insulin-like growth factor-I and -II (IGF-I and IGF-II) have been found in bone extracts of several different species, and IGF-II is the most abundant growth factor stored in bone. Bone sialoprotein (BSP) is a noncollagenous extracellular matrix glycoprotein associated with mineralized connective tissues. In this study, we have investigated the regulation of BSP transcription by IGF-II in rat osteoblast-like ROS17/2.8 cells. IGF-II (50 ng/ml) increased BSP mRNA and protein levels after 6-h stimulation, and enhanced luciferase activities of the constructs pLUC3 (-116 to +60), pLUC4 (-425 to +60), pLUC5 (-801 to +60) and pLUC6 (-938 to +60). Effects of IGF-II were inhibited by tyrosine kinase, extracellular signal-regulated kinase1/2 and phosphatidylinositol 3-kinase inhibitors, and abrogated by 2-bp mutations in cAMP response element (CRE), FGF2 response element (FRE) and homeodomain protein-binding site (HOX). The results of gel shift assays showed that nuclear proteins binding to CRE, FRE and HOX sites were increased by IGF-II (50 ng/ml) at 3 and 6 h. CREB1, phospho-CREB1, c-Fos and c-Jun antibodies disrupted the formation of the CRE-protein complexes. Dlx5 and Runx2 antibodies disrupted the FRE- and HOX-protein complex formations. These studies therefore demonstrated that IGF-II increased BSP transcription by targeting CRE, FRE and HOX elements in the proximal promoter of the rat BSP gene. Moreover, phospho-CREB1, c-Fos, c-Jun, Dlx5 and Runx2 transcription factors appear to be key regulators of IGF-II effects on BSP transcription.

Association of tRNA methyltransferase NSUN2/IGF-II molecular signature with ovarian cancer survival.

PubMed

Yang, Jia-Cheng; Risch, Eric; Zhang, Meiqin; Huang, Chan; Huang, Huatian; Lu, Lingeng

2017-09-01

To investigate the association between NSUN2/IGF-II signature and ovarian cancer survival. Using a publicly accessible dataset of RNA sequencing and clinical follow-up data, we performed Classification and Regression Tree and survival analyses. Patients with NSUN2 high IGF-II low had significantly superior overall and disease progression-free survival, followed by NSUN2 low IGF-II low , NSUN2 high IGF-II high and NSUN2 low IGF-II high (p < 0.0001 for overall, p = 0.0024 for progression-free survival, respectively). The associations of NSUN2/IGF-II signature with the risks of death and relapse remained significant in multivariate Cox regression models. Random-effects meta-analyses show the upregulated NSUN2 and IGF-II expression in ovarian cancer versus normal tissues. The NSUN2/IGF-II signature associates with heterogeneous outcome and may have clinical implications in managing ovarian cancer.

Subcutaneous administration of insulin-like growth factor (IGF)-II/IGF binding protein-2 complex stimulates bone formation and prevents loss of bone mineral density in a rat model of disuse osteoporosis

NASA Technical Reports Server (NTRS)

Conover, Cheryl A.; Johnstone, Edward W.; Turner, Russell T.; Evans, Glenda L.; John Ballard, F. John; Doran, Patrick M.; Khosla, Sundeep

2002-01-01

Elevated serum levels of insulin-like growth factor binding protein-2 (IGFBP-2) and a precursor form of IGF-II are associated with marked increases in bone formation and skeletal mass in patients with hepatitis C-associated osteosclerosis. In vitro studies indicate that IGF-II in complex with IGFBP-2 has high affinity for bone matrix and is able to stimulate osteoblast proliferation. The purpose of this study was to determine the ability of the IGF-II/IGFBP-2 complex to increase bone mass in vivo. Osteopenia of the femur was induced by unilateral sciatic neurectomy in rats. At the time of surgery, 14-day osmotic minipumps containing vehicle or 2 microg IGF-II+9 microg IGFBP-2/100g body weight/day were implanted subcutaneously in the neck. Bone mineral density (BMD) measurements were taken the day of surgery and 14 days later using a PIXImus small animal densitometer. Neurectomy of the right hindlimb resulted in a 9% decrease in right femur BMD (P<0.05 vs. baseline). This loss in BMD was completely prevented by treatment with IGF-II/IGFBP-2. On the control limb, there was no loss of BMD over the 14 days and IGF-II/IGFBP-2 treatment resulted in a 9% increase in left femur BMD (P<0.05). Bone histomorphometry indicated increases in endocortical and cancellous bone formation rates and in trabecular thickness. These results demonstrate that short-term administration of the IGF-II/IGFBP-2 complex can prevent loss of BMD associated with disuse osteoporosis and stimulate bone formation in adult rats. Furthermore, they provide proof of concept for a novel anabolic approach to increasing bone mass in humans with osteoporosis.

Genetic variants in IGF-I, IGF-II, IGFBP-3, and adiponectin genes and colon cancer risk in African Americans and Whites

PubMed Central

Keku, Temitope O.; Vidal, Adriana; Oliver, Shannon; Hoyo, Catherine; Hall, Ingrid J.; Omofoye, Seun; McDoom, Maya; Worley, Kendra; Galanko, Joseph; Sandler, Robert S.; Millikan, Robert

2014-01-01

Purpose Evaluating genetic susceptibility may clarify effects of known environmental factors and also identify individuals at high risk. We evaluated the association of four insulin-related pathway gene polymorphisms in insulin-like growth factor-1 (IGF-I) (CA)n repeat, insulin-like growth factor-2 (IGF-II) (rs680), insulin-like growth factor binding protein-3 (IGFBP-3) (rs2854744), and adiponectin (APM1 rs1501299) with colon cancer risk, as well as relationships with circulating IGF-I, IGF-II, IGFBP-3, and C-peptide in a population-based study. Methods Participants were African Americans (231cases, 306 controls) and Whites (297 cases, 530 controls). Consenting subjects provided blood specimens, and lifestyle/diet information. Genotyping for all genes except IGF-I was performed by the 5′-exonuclease (Taqman) assay. The IGF-I (CA)n repeat was assayed by PCR, and fragment analysis. Circulating proteins were measured by enzyme immunoassays. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression. Results The IGF-I (CA)19 repeat was higher in White controls (50%) than African American controls (31%). Whites homozygous for the IGF-I (CA)19 repeat had a nearly two fold increase in risk of colon cancer (OR=1.77; 95%CI=1.15–2.73), but not African Americans (OR= 0.73, 95%CI 0.50–1.51). We observed an inverse association between the IGF-II Apa1 A-variant and colon cancer risk (OR= 0.49, 95%CI 0.28–0.88) in Whites only. Carrying the IGFBP-3 variant alleles was associated with lower IGFBP-3 protein levels, a difference most pronounced in Whites (p- trend < 0.05). Conclusions These results support an association between insulin pathway-related genes and elevated colon cancer risk in Whites but not in African Americans. PMID:22565227

Genetic variants in IGF-I, IGF-II, IGFBP-3, and adiponectin genes and colon cancer risk in African Americans and Whites.

PubMed

Keku, Temitope O; Vidal, Adriana; Oliver, Shannon; Hoyo, Catherine; Hall, Ingrid J; Omofoye, Oluwaseun; McDoom, Maya; Worley, Kendra; Galanko, Joseph; Sandler, Robert S; Millikan, Robert

2012-07-01

Evaluating genetic susceptibility may clarify effects of known environmental factors and also identify individuals at high risk. We evaluated the association of four insulin-related pathway gene polymorphisms in insulin-like growth factor-1 (IGF-I) (CA)( n ) repeat, insulin-like growth factor-2 (IGF-II) (rs680), insulin-like growth factor-binding protein-3 (IGFBP-3) (rs2854744), and adiponectin (APM1 rs1501299) with colon cancer risk, as well as relationships with circulating IGF-I, IGF-II, IGFBP-3, and C-peptide in a population-based study. Participants were African Americans (231 cases and 306 controls) and Whites (297 cases, 530 controls). Consenting subjects provided blood specimens and lifestyle/diet information. Genotyping for all genes except IGF-I was performed by the 5'-exonuclease (Taqman) assay. The IGF-I (CA)(n) repeat was assayed by PCR and fragment analysis. Circulating proteins were measured by enzyme immunoassays. Odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated by logistic regression. The IGF-I (CA)( 19 ) repeat was higher in White controls (50 %) than African American controls (31 %). Whites homozygous for the IGF-I (CA)(19) repeat had a nearly twofold increase in risk of colon cancer (OR = 1.77; 95 % CI = 1.15-2.73), but not African Americans (OR = 0.73, 95 % CI 0.50-1.51). We observed an inverse association between the IGF-II Apa1 A-variant and colon cancer risk (OR = 0.49, 95 % CI 0.28-0.88) in Whites only. Carrying the IGFBP-3 variant alleles was associated with lower IGFBP-3 protein levels, a difference most pronounced in Whites (p-trend <0.05). These results support an association between insulin pathway-related genes and elevated colon cancer risk in Whites but not in African Americans.

Heterogeneity for IGF-II production maintained by public goods dynamics in neuroendocrine pancreatic cancer.

PubMed

Archetti, Marco; Ferraro, Daniela A; Christofori, Gerhard

2015-02-10

The extensive intratumor heterogeneity revealed by sequencing cancer genomes is an essential determinant of tumor progression, diagnosis, and treatment. What maintains heterogeneity remains an open question because competition within a tumor leads to a strong selection for the fittest subclone. Cancer cells also cooperate by sharing molecules with paracrine effects, such as growth factors, and heterogeneity can be maintained if subclones depend on each other for survival. Without strict interdependence between subclones, however, nonproducer cells can free-ride on the growth factors produced by neighboring producer cells, a collective action problem known in game theory as the "tragedy of the commons," which has been observed in microbial cell populations. Here, we report that similar dynamics occur in cancer cell populations. Neuroendocrine pancreatic cancer (insulinoma) cells that do not produce insulin-like growth factor II (IGF-II) grow slowly in pure cultures but have a proliferation advantage in mixed cultures, where they can use the IGF-II provided by producer cells. We show that, as predicted by evolutionary game theory, producer cells do not go extinct because IGF-II acts as a nonlinear public good, creating negative frequency-dependent selection that leads to a stable coexistence of the two cell types. Intratumor cell heterogeneity can therefore be maintained even without strict interdependence between cell subclones. Reducing the amount of growth factors available within a tumor may lead to a reduction in growth followed by a new equilibrium, which may explain relapse in therapies that target growth factors.

Divergent mechanisms of insulin-like growth factor I and II on rat hepatocyte proliferation.

PubMed

Raper, S; Kothary, P; Ishoo, E; Dikin, M; Kokudo, N; Hashimoto, M; DeMatteo, R P

1995-07-21

Insulin-like growth factors I and II are peptides with a structural homology for proinsulin, and are involved in hepatocyte proliferation. IGF-I and IGF-II, however, have different metabolic roles, and their mechanisms of action are incompletely known. We hypothesized that IGF-I and IGF-II act by different signal transduction pathways. To test this hypothesis, hepatocytes from 200 g male Sprague-Dawley rats were isolated by a two-step collagenase perfusion technique and plated at a density of 10(5) cells/16 mm Primaria plate. Proliferation was measured by [3H]thymidine ([3H]thy) incorporation into DNA, and an autoradiographic nuclear labeling index (LI). To analyze signal transduction, cyclic AMP (cAMP) levels were measured 5 min after addition of reagents by a radioimmunoassay. Reagents (doses) used were: IGF-I (2 nM), IGF-II (2 nM), the inhibitory peptide somatostatin-14 (SS14) (10 nM), and the adenylyl cyclase antagonist dideoxyadenosine (DDA) (10 microM). A summary of the findings is as follows: (1) IGF-I stimulates [3H]thy, LI and cAMP accumulation. (2) IGF-II stimulates [3H]thy and LI but not cAMP; (3) IGF-I but not IGF-II effects are inhibited by SS14 and DDA. We conclude that the hepatotrophic effects of IGF-I and IGF-II occur by different mechanisms: IGF-I is cAMP-dependent, IGF-II is cAMP-independent.

IGF-II-mediated downregulation of peroxisome proliferator-activated receptor-γ coactivator-1α in myoblast cells involves PI3K/Akt/FoxO1 signaling pathway.

PubMed

Mu, Xiaoyu; Qi, Weihong; Liu, Yunzhang; Zhou, Jianfeng; Li, Yun; Rong, Xiaozhi; Lu, Ling

2017-08-01

Insulin-like growth factor II (IGF-II) can stimulate myogenesis and is critically involved in skeletal muscle differentiation. The presence of negative regulators of this process, however, is not well explored. Here, we showed that in myoblast cells, IGF-II negatively regulated peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) mRNA expression, while constitutive expression of PGC-1α induced myoblast differentiation. These results suggest that the negative regulation of PGC-1α by IGF-II may act as a negative feedback mechanism in IGF-II-induced myogenic differentiation. Reporter assays demonstrated that IGF-II suppresses the basal PGC-1α promoter activity. Blocking the IGF-II signaling pathway increased the endogenous PGC-1α levels. In addition, pharmacological inhibition of PI3 kinase activity prevented the downregulation of PGC-1α but the activation of mTOR was not required for this process. Importantly, further analysis showed that forkhead transcription factor FoxO1 contributes to mediating the effects of IGF-II on PGC-1 promoter activity. These findings indicate that IGF-II reduces PGC-1α expression in skeletal muscle cells through a mechanism involving PI3K-Akt-FoxO1 but not p38 MAPK or Erk1/2 MAPK pathways.

Genetic polymorphisms of the IGF-II gene intron 8 coding region and its association with growth and carcass traits in yak.

PubMed

Zeng, Y F; Ding, X Z; Cheng, S R; Yu, S J

2013-12-11

Insulin-like growth factor II (IGF-II) plays a key role in mammalian growth and is involved in stimulating fetal cell division, differentiation, and metabolic regulation. IGF-II is considered a candidate gene for genetic markers of growth and carcass traits. Therefore, in this study, the associations of single nucleotide polymorphisms (SNPs) in the IGF-II gene region with growth and carcass characteristics in five yak breeds were investigated. Two SNPs, G(330)C and A(358)G, were identified by sequencing intron 8 of the IGF-II gene in homozygotes. Two alleles, A and B, and three genotypes, AA, AB, and BB, were identified by polymerase chain reaction. Genotypic frequencies of IGF-II allele B were 0.8623, 0.8936, 0.8535, 0.8676, and 0.8300 for Datong yak, Gannan yak, Tianzhu white yak, Qinghai Plateau yak, and Xinjiang yak, respectively. Allele and the genotype of IGF-II were strongly associated with growth and carcass traits. Least square analysis revealed a significant effect (P < 0.01) of genotypes AA and AB compared with genotype BB on live-weight (at 12, 13-24, and 25-36 months of age), average daily weight gain (P < 0.01) and carcass weight (P < 0.05). Animals with genotype AB had a higher mean rib eye area, and a lower mean yield grade. The results indicated that the IGF-II gene acts by a primarily additive biological mechanism by adding weight independently of skeletal growth.

Using mass spectrometry to detect, differentiate, and semiquantitate closely related peptide hormones in complex milieu: measurement of IGF-II and vesiculin.

PubMed

Lee, Kate L; Middleditch, Martin J; Williams, Geoffrey M; Brimble, Margaret A; Cooper, Garth J S

2015-03-01

The search for an islet β-cell growth factor has been a key objective in recent diabetes research, because the ability to regenerate and/or protect the functioning β-cell population in patients could result in a great advancement for diabetes treatment. IGF-I and IGF-II are known to play crucial roles in fetal growth and prenatal development, and there is growing evidence that IGF-II increases β-cell proliferation and survival in vitro and in vivo. A search for the source of IGF-II-like immunoreactivity in isolated β-cell secretory granules from the murine cell line βTC6-F7 revealed a novel 2-chain IGF-II-derived peptide, which we named vesiculin and which has been shown to be a full insulin agonist. Here, we present a liquid chromatography-tandem mass spectrometry method that enables selective detection and semiquantitation of the highly related IGF-II and vesiculin molecules. We have used this method to measure these 2 peptides in conditioned media from 2 β-cell lines, produced under increasing glucose concentrations. This technique detected both IGF-II and vesiculin in media conditioned by MIN6 and βTC6-F7 cells at levels in the range of 0 to 6 μM (total insulin, 80-450 μM) and revealed a glucose-stimulated increase in insulin, IGF-II, and vesiculin. IGF-II was detected in adult human and neonatal mouse serum in high levels, but vesiculin was not present. The methodology we present herein has utility for detecting and differentiating active peptides that are highly related and of low abundance.

Platycodon grandiflorum (PG) reverses angiotensin II-induced apoptosis by repressing IGF-IIR expression.

PubMed

Lin, Yuan-Chuan; Lin, Chih-Hsueh; Yao, Hsien-Tsung; Kuo, Wei-Wen; Shen, Chia-Yao; Yeh, Yu-Lan; Ho, Tsung-Jung; Padma, V Vijaya; Lin, Yu-Chen; Huang, Chih-Yang; Huang, Chih-Yang

2017-06-09

Platycodon grandiflorum (PG) is a Chinese medical plant used for decades as a traditional prescription to eliminate phlegm, relieve cough, reduce inflammation and lower blood pressure. PG also has a significant effect on the cardiovascular systems. The aqueous extract of Platycodon grandiflorum (JACQ.) A. DC. root was screened for inhibiting Ang II-induced IGF-IIR activation and apoptosis pathway in H9c2 cardiomyocytes. The effects were also studied in spontaneously hypertensive rats (five groups, n=5) using low and high doses of PG for 50 days. The Ang II-induced IGF-IIR activation was analyzed by luciferase reporter, RT-PCR, western blot and surface IGF-IIR expression assay. Furthermore, the major active constituent of PG was carried out by high performance liquid chromatography-mass spectrometry (HPLC-MS). Our results indicate that a crude extract of PG significantly suppresses the Ang II-induced IGF-IIR signaling pathway to prevent cardiomyocyte apoptosis. PG extract inhibits Ang II-mediated JNK activation and SIRT1 degradation to reduce IGF-IIR activity. Moreover, PG maintains SIRT1 stability to enhance HSF1-mediated IGF-IIR suppression, which prevents cardiomyocyte apoptosis. In animal models, the administration of PG markedly reduced this apoptotic pathway in the heart of SHRs. Taken together, PG may be considered as an effective treatment for cardiac diseases in hypertensive patients. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Effects of different dietary intake on mRNA levels of MSTN, IGF-I, and IGF-II in the skeletal muscle of Dorper and Hu sheep hybrid F1 rams.

PubMed

Xing, H J; Wang, Z Y; Zhong, B S; Ying, S J; Nie, H T; Zhou, Z R; Fan, Y X; Wang, F

2014-07-24

MSTN, IGF-І(insulin-like growth factor-І) and IGF-II (insulin-like growth factor-II) regulate skeletal muscle growth. This study investigated the effects of different dietary intake levels on skeletal muscles. Sheep was randomly assigned to 3 feeding groups: 1) the maintenance diet (M), 2) 1.4 x the maintenance diet (1.4M), and 3) 2.15 x the maintenance diet (2.15M). Before slaughtering the animals, blood samples were collected to measure plasma urea, growth hormone, and insulin concentrations. After slaughtering, the longissimus dorsi, semitendinosus, semimembranosus, gastrocnemius, soleus, and chest muscle were removed to record various parameters, including the mRNA expression levels of MSTN and IGFs, in addition to skeletal muscle fiber diameter and cross-sectional area. The result showed that as dietary intake improved, the mRNA expression levels of MSTN and IGF-II decreased, whereas IGF-Іexpression increased. The mRNA expression levels of MSTN and IGFs were significantly different in the same skeletal muscle under different dietary intake. The skeletal muscle fiber diameter and cross-sectional area increased with greater dietary intake, as observed for the mRNA expression of IGF-І; however, it contrasted to that observed for the mRNA expression of MSTN and IGF-II. In conclusion, dietary intake levels have a certain influence on MSTN and IGFs mRNA expression levels, in addition to skeletal muscle fiber diameter and cross-sectional area. This study contributes valuable information for enhancing the molecular-based breeding of sheep.

Insulin-Like Growth Factor II Targets the mTOR Pathway to Reverse Autism-Like Phenotypes in Mice.

PubMed

Steinmetz, Adam B; Stern, Sarah A; Kohtz, Amy S; Descalzi, Giannina; Alberini, Cristina M

2018-01-24

Autism spectrum disorder (ASD) is a developmental disability characterized by impairments in social interaction and repetitive behavior, and is also associated with cognitive deficits. There is no current treatment that can ameliorate most of the ASD symptomatology; thus, identifying novel therapies is urgently needed. We used male BTBR T + Itpr3 tf /J (BTBR) mice, a model that reproduces most of the core behavioral phenotypes of ASD, to test the effects of systemic administration of insulin-like growth factor II (IGF-II), a polypeptide that crosses the blood-brain barrier and acts as a cognitive enhancer. We show that systemic IGF-II treatments reverse the typical defects in social interaction, cognitive/executive functions, and repetitive behaviors reflective of ASD-like phenotypes. In BTBR mice, IGF-II, via IGF-II receptor, but not via IGF-I receptor, reverses the abnormal levels of the AMPK-mTOR-S6K pathway and of active translation at synapses. Thus, IGF-II may represent a novel potential therapy for ASD. SIGNIFICANCE STATEMENT Currently, there is no effective treatment for autism spectrum disorder (ASD), a developmental disability affecting a high number of children. Using a mouse model that expresses most of the key core as well as associated behavioral deficits of ASD, that are, social, cognitive, and repetitive behaviors, we report that a systemic administration of the polypeptide insulin-like growth factor II (IGF-II) reverses all these deficits. The effects of IGF-II occur via IGF-II receptors, and not IGF-I receptors, and target both basal and learning-dependent molecular abnormalities found in several ASD mice models, including those of identified genetic mutations. We suggest that IGF-II represents a potential novel therapeutic target for ASD. Copyright © 2018 the authors 0270-6474/18/371015-15$15.00/0.

A high ratio of insulin-like growth factor II/insulin-like growth factor binding protein 2 messenger RNA as a marker for anaplasia in meningiomas.

PubMed

Nordqvist, A C; Peyrard, M; Pettersson, H; Mathiesen, T; Collins, V P; Dumanski, J P; Schalling, M

1997-07-01

Insulin-like growth factors (IGFs) I and II have been implicated as autocrine or paracrine growth promoters. These growth factors bind to specific receptors, and the response is modulated by interaction with IGF-binding proteins (IGFBPs). We observed a strong correlation between anaplastic/atypical histopathology and a high IGF-II/IGFBP-2 mRNA ratio in a set of 68 sporadic meningiomas. A strong correlation was also found between clinical outcome and IGF-II/IGFBP-2 ratio, whereas previously used histochemical markers were less correlated to outcome. We suggest that a high IGF-II/IGFBP-2 mRNA ratio may be a sign of biologically aggressive behavior in meningiomas that can influence treatment strategies. We propose that low IGFBP-2 levels in combination with increased levels of IGF-II would result in more free IGF-II and consequently greater stimulation of proliferation.

Higher Maternal Protein Intake during Pregnancy Is Associated with Lower Cord Blood Concentrations of Insulin-like Growth Factor (IGF)-II, IGF Binding Protein 3, and Insulin, but Not IGF-I, in a Cohort of Women with High Protein Intake.

PubMed

Switkowski, Karen M; Jacques, Paul F; Must, Aviva; Hivert, Marie-France; Fleisch, Abby; Gillman, Matthew W; Rifas-Shiman, Sheryl; Oken, Emily

2017-07-01

Background: Prenatal exposure to dietary protein may program growth-regulating hormones, consequently influencing early-life growth patterns and later risk of associated chronic diseases. The insulin-like growth factor (IGF) axis is of particular interest in this context given its influence on pre- and postnatal growth and its sensitivity to the early nutritional environment. Objective: Our objective was to examine associations of maternal protein intake during pregnancy with cord blood concentrations of IGF-I, IGF-II, IGF binding protein-3 (IGFBP-3), and insulin. Methods: We studied 938 mother-child pairs from early pregnancy through delivery in the Project Viva cohort. Using multivariable linear regression models adjusted for maternal race/ethnicity, education, income, smoking, parity, height, and gestational weight gain and for child sex, we examined associations of second-trimester maternal protein intake [grams per kilogram (weight before pregnancy) per day], as reported on a food frequency questionnaire, with IGF-I, IGF-II, IGFBP-3, and insulin concentrations in cord blood. We also examined how these associations may differ by child sex and parity. Results: Mothers were predominantly white (71%), college-educated (64%), and nonsmokers (67%). Mean ± SD protein intake was 1.35 ± 0.35 g ⋅ kg -1 ⋅ d -1 Each 1-SD increment in second-trimester protein intake corresponded to a change of -0.50 ng/mL (95% CI: -2.26, 1.26 ng/mL) in IGF-I and -0.91 μU/mL (95% CI: -1.45, -0.37 μU/mL) in insulin. Child sex and parity modified associations of maternal protein intake with IGF-II and IGFBP-3: protein intake was inversely associated with IGF-II in girls ( P -interaction = 0.04) and multiparous mothers ( P -interaction = 0.05), and with IGFBP-3 in multiparous mothers ( P -interaction = 0.04). Conclusions: In a cohort of pregnant women with relatively high mean protein intakes, higher intake was associated with lower concentrations of growth-promoting hormones in cord

Loss of insulin-like growth factor-II imprinting and the presence of screen-detected colorectal adenomas in women.

PubMed

Woodson, Karen; Flood, Andrew; Green, Lisa; Tangrea, Joseph A; Hanson, Jeffrey; Cash, Brooks; Schatzkin, Arthur; Schoenfeld, Phillip

2004-03-03

Loss of imprinting (LOI) of insulin-like growth factor-II (IGF-II) may be an inherited epigenetic trait that is polymorphic in the population, and its presence may predispose an individual to the development of colorectal cancer. We evaluated the association between LOI of IGF-II in normal colonic mucosal samples and adenomas in women participating in a colonoscopy screening study. Among 40 participants, 11 (27.5%) had LOI of IGF-II in their normal colonic mucosal tissue. After adjusting for body mass index and family history of colorectal cancer, LOI status was associated with a fivefold increased risk of adenoma formation (odds ratio = 5.2, 95% confidence interval = 1.0 to 26.7). On average, IGF-II expression was more than threefold higher among women with LOI of IGF-II than among women with normal imprinting status. Our findings support the hypothesis that LOI of IGF-II is an epigenetic trait polymorphic in the population and suggest that LOI of IGF-II may play a role in colorectal cancer. These findings are intriguing and need to be confirmed in larger studies.

The kangaroo cation-independent mannose 6-phosphate receptor binds insulin-like growth factor II with low affinity.

PubMed

Yandell, C A; Dunbar, A J; Wheldrake, J F; Upton, Z

1999-09-17

The mammalian cation-independent mannose 6-phosphate receptor (CI-MPR) binds mannose 6-phosphate-bearing glycoproteins and insulin-like growth factor (IGF)-II. However, the CI-MPR from the opossum has been reported to bind bovine IGF-II with low affinity (Dahms, N. M., Brzycki-Wessell, M. A., Ramanujam, K. S., and Seetharam, B. (1993) Endocrinology 133, 440-446). This may reflect the use of a heterologous ligand, or it may represent the intrinsic binding affinity of this receptor. To examine the binding of IGF-II to a marsupial CI-MPR in a homologous system, we have previously purified kangaroo IGF-II (Yandell, C. A., Francis, G. L., Wheldrake, J. F., and Upton, Z. (1998) J. Endocrinol. 156, 195-204), and we now report the purification and characterization of the CI-MPR from kangaroo liver. The interaction of the kangaroo CI-MPR with IGF-II has been examined by ligand blotting, radioreceptor assay, and real-time biomolecular interaction analysis. Using both a heterologous and homologous approach, we have demonstrated that the kangaroo CI-MPR has a lower binding affinity for IGF-II than its eutherian (placental mammal) counterparts. Furthermore, real-time biomolecular interaction analysis revealed that the kangaroo CI-MPR has a higher affinity for kangaroo IGF-II than for human IGF-II. The cDNA sequence of the kangaroo CI-MPR indicates that there is considerable divergence in the area corresponding to the IGF-II binding site of the eutherian receptor. Thus, the acquisition of a high-affinity binding site for regulating IGF-II appears to be a recent event specific to the eutherian lineage.

Insulin-like growth factors I and II in starry flounder (Platichthys stellatus): molecular cloning and differential expression during embryonic development.

PubMed

Xu, Yongjiang; Zang, Kun; Liu, Xuezhou; Shi, Bao; Li, Cunyu; Shi, Xueying

2015-02-01

In order to elucidate the possible roles of insulin-like growth factors I and II (IGF-I and IGF-II) in the embryonic development of Platichthys stellatus, their cDNAs were isolated and their spatial expression pattern in adult organs and temporal expression pattern throughout embryonic development were examined by quantitative real-time PCR assay. The IGF-I cDNA sequence was 1,268 bp in length and contained an open reading frame (ORF) of 558 bp, which encoded 185 amino acid residues. With respect to IGF-II, the full-length cDNA was 899 bp in length and contained a 648-bp ORF, which encoded 215 amino acid residues. The amino acid sequences of IGF-I and IGF-II exhibited high identities with their fish counterparts. The highest IGF-I mRNA level was found in the liver for both sexes, whereas the IGF-II gene was most abundantly expressed in female liver and male liver, gill, and brain. The sex-specific and spatial expression patterns of IGF-I and IGF-II mRNAs are thought to be related to the sexually dimorphic growth and development of starry flounder. Both IGF-I and IGF-II mRNAs were detected in unfertilized eggs, which indicated that IGF-I and IGF-II were parentally transmitted. Nineteen embryonic development stages were tested. IGF-I mRNA level remained high from unfertilized eggs to low blastula followed by a significant decrease at early gastrula and then maintained a lower level. In contrast, IGF-II mRNA level was low from unfertilized eggs to high blastula and peaked at low blastula followed by a gradual decrease. Moreover, higher levels of IGF-I mRNA than that of IGF-II were found from unfertilized eggs to high blastula, vice versa from low blastula to newly hatched larva, and the different expression pattern verified the differential roles of IGF-I and IGF-II in starry flounder embryonic development. These results could help in understanding the endocrine mechanism involved in the early development and growth of starry flounder.

IGF-1 prevents ANG II-induced skeletal muscle atrophy via Akt- and Foxo-dependent inhibition of the ubiquitin ligase atrogin-1 expression

PubMed Central

Yoshida, Tadashi; Semprun-Prieto, Laura; Sukhanov, Sergiy

2010-01-01

Congestive heart failure is associated with activation of the renin-angiotensin system and skeletal muscle wasting. Angiotensin II (ANG II) has been shown to increase muscle proteolysis and decrease circulating and skeletal muscle IGF-1. We have shown previously that skeletal muscle-specific overexpression of IGF-1 prevents proteolysis and apoptosis induced by ANG II. These findings indicated that downregulation of IGF-1 signaling in skeletal muscle played an important role in the wasting effect of ANG II. However, the signaling pathways and mechanisms whereby IGF-1 prevents ANG II-induced skeletal muscle atrophy are unknown. Here we show ANG II-induced transcriptional regulation of two ubiquitin ligases atrogin-1 and muscle ring finger-1 (MuRF-1) that precedes the reduction of skeletal muscle IGF-1 expression, suggesting that activation of atrogin-1 and MuRF-1 is an initial mechanism leading to skeletal muscle atrophy in response to ANG II. IGF-1 overexpression in skeletal muscle prevented ANG II-induced skeletal muscle wasting and the expression of atrogin-1, but not MuRF-1. Dominant-negative Akt and constitutively active Foxo-1 blocked the ability of IGF-1 to prevent ANG II-mediated upregulation of atrogin-1 and skeletal muscle wasting. Our findings demonstrate that the ability of IGF-1 to prevent ANG II-induced skeletal muscle wasting is mediated via an Akt- and Foxo-1-dependent signaling pathway that results in inhibition of atrogin-1 but not MuRF-1 expression. These data suggest strongly that atrogin-1 plays a critical role in mechanisms of ANG II-induced wasting in vivo. PMID:20228261

Gene therapy of murine teratocarcinoma: separate functions for insulin-like growth factors I and II in immunogenicity and differentiation.

PubMed Central

Trojan, J; Johnson, T R; Rudin, S D; Blossey, B K; Kelley, K M; Shevelev, A; Abdul-Karim, F W; Anthony, D D; Tykocinski, M L; Ilan, J

1994-01-01

Teratocarcinoma is a germ-line carcinoma giving rise to an embryoid tumor with structures derived from the three embryonic layers: mesoderm, endoderm, and ectoderm. Teratocarcinoma is widely used as an in vitro model system to study regulation of cell determination and differentiation during mammalian embryogenesis. Murine embryonic carcinoma (EC) PCC3 cells express insulin-like growth factor I(IGF-I) and its receptor, while all derivative tumor structures express IGF-I and IGF-II and their receptors. Therefore the system lends itself to dissect the role of these two growth factors during EC differentiation. With an episomal antisense strategy, we define a role for IGF-I in tumorigenicity and evasion of immune surveillance. Antisense IGF-I EC transfectants are shown to elicit a curative anti-tumor immune response with tumor regression at distal sites. In contrast, IGF-II is shown to drive determination and differentiation in EC cells. Since IGF-I and IGF-II bind to type I receptor and antisense sequence used for IGF-II cannot form duplex with endogenous IGF-I transcripts, it follows that this receptor is not involved in determination and differentiation. Images PMID:8016120

Effect of the association of IGF-I, IGF-II, bFGF, TGF-beta1, GM-CSF, and LIF on the development of bovine embryos produced in vitro.

PubMed

Neira, J A; Tainturier, D; Peña, M A; Martal, J

2010-03-15

This study examined the influence of the following growth factors and cytokines on early embryonic development: insulin-like growth factors I and II (IGF-I, IGF-II), basic fibroblast growth factor (bFGF), transforming growth factor (TGF-beta), granulocyte-macrophage colony-stimulating factor (GM-CSF), and leukemia inhibitory factor (LIF). Synthetic oviduct fluid (SOF) was used as the culture medium. We studied the development of bovine embryos produced in vitro and cultured until Day 9 after fertilization. TGF-beta1, bFGF, GM-CSF, and LIF used on their own significantly improved the yield of hatched blastocysts. IGF-I, bFGF, TGF-beta1, GM-CSF, and LIF significantly accelerated embryonic development, especially the change from the expanded blastocyst to hatched blastocyst stages. Use of a combination of these growth factors and cytokines (GF-CYK) in SOF medium produced higher percentages of blastocysts and hatched blastocysts than did use of SOF alone (45% and 22% vs. 24% and 12%; P<0.05) on Day 8 after in vitro fertilization and similar results to use of SOF+10% fetal calf serum (38% and 16%, at the same stages, respectively). The averages of total cells, inner cell mass cells, and trophectoderm cells of exclusively in vitro Day-8 blastocysts for pooled GF-CYK treatments were higher than those for SOF and similar to those for fetal calf serum. The presence of these growth factors and cytokines in the embryo culture medium therefore has a combined stimulatory action on embryonic development; in particular through an increase in hatching rate and in the number of cells of both the inner cell mass and trophoblast. These results are the first to demonstrate that use of a combination of recombinant growth factors and cytokine, as IGF-I, IGF-II, bFGF, TGF-beta1, LIF, and GM-CSF, produces similar results to 10% fetal calf serum for the development of in vitro-produced bovine embryos. This entirely synthetic method of embryo culture has undeniable advantages for the

Molecular Basis for the Recognition and Cleavages of IGF-II, TGF-[alpha], and Amylin by Human Insulin-Degrading Enzyme

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

Guo, Qing; Manolopoulou, Marika; Bian, Yao

2010-02-11

Insulin-degrading enzyme (IDE) is involved in the clearance of many bioactive peptide substrates, including insulin and amyloid-{beta}, peptides vital to the development of diabetes and Alzheimer's disease, respectively. IDE can also rapidly degrade hormones that are held together by intramolecular disulfide bond(s) without their reduction. Furthermore, IDE exhibits a remarkable ability to preferentially degrade structurally similar peptides such as the selective degradation of insulin-like growth factor (IGF)-II and transforming growth factor-{alpha} (TGF-{alpha}) over IGF-I and epidermal growth factor, respectively. Here, we used high-accuracy mass spectrometry to identify the cleavage sites of human IGF-II, TGF-{alpha}, amylin, reduced amylin, and amyloid-{beta} bymore » human IDE. We also determined the structures of human IDE-IGF-II and IDE-TGF-{alpha} at 2.3 {angstrom} and IDE-amylin at 2.9 {angstrom}. We found that IDE cleaves its substrates at multiple sites in a biased stochastic manner. Furthermore, the presence of a disulfide bond in amylin allows IDE to cut at an additional site in the middle of the peptide (amino acids 18-19). Our amylin-bound IDE structure offers insight into how the structural constraint from a disulfide bond in amylin can alter IDE cleavage sites. Together with NMR structures of amylin and the IGF and epidermal growth factor families, our work also reveals the structural basis of how the high dipole moment of substrates complements the charge distribution of the IDE catalytic chamber for the substrate selectivity. In addition, we show how the ability of substrates to properly anchor their N-terminus to the exosite of IDE and undergo a conformational switch upon binding to the catalytic chamber of IDE can also contribute to the selective degradation of structurally related growth factors.« less

Expression analysis of the insulin-like growth factors I and II during embryonic and early larval development of turbot ( Scophthalmus maximus)

NASA Astrophysics Data System (ADS)

Wen, Haishen; Qi, Qian; Hu, Jian; Si, Yufeng; He, Feng; Li, Jifang

2015-04-01

The insulin-like growth factors I and II (IGF-I and IGF-II) are important proteins involved in fish growth and development. Here, we report the isolation of IGF-II and expression analysis of IGFs in turbot Scophthalmus maximus, aiming to clarify their function in embryonic and larval development of fish. The deduced IGF-II gene is 808 bp in full length, which encodes a protein of 219 amino acids and is 93% similar with that of Paralichthys olicaceus in amino acid sequence. The tissue abundance and the expression pattern of IGFs in a turbot at early development stages were investigated via reverse transcription-polymer chain reaction. Result showed that the IGF-I and IGF-II genes were widely expressed in tissues of S. maximus. IGF-I was detected in all tissues except intestines with the highest level in liver, while IGF-II transcript presented in all tissues except muscle. At the stages of embryonic and larval development, the mRNA levels of IGFs sharply increased from the stage of unfertilized egg to post larva, followed by a decrease with larval development. However, there was an increase in IGF-I at the embryonic stage and IGF-II at the gastrula stage, respectively. These results suggested that IGFs play important roles in cell growth and division of the turbot. Our study provides reference data for further investigation of growth regulation in turbot, which can guarantee better understanding of the physiological role that IGFs play in fish.

Effect of iron deficiency on the expression of insulin-like growth factor-II and its receptor in neuronal and glial cells.

PubMed

Morales González, E; Contreras, I; Estrada, J A

2014-09-01

Many studies have demonstrated that iron deficiency modifies the normal function of the central nervous system and alters cognitive abilities. When cellular damage occurs in the central nervous system, neuroprotective mechanisms, such as the production of neurotrophic factors, are essential in order for nervous tissue to function correctly. Insulin-like growth factor II (IGF- II) is a neurotrophic factor that was recently shown to be involved in the normal functioning of cognitive processes in animal models. However, the impact of iron deficiency on the expression and function of this molecule has not yet been clarified. Mixed primary cell cultures from the central nervous system were collected to simulate iron deficiency using deferoxamine. The expression of IGF-I, IGF-II, IGF-IR, and IGF-IIR was determined with the western blot test. We observed increased expression of IGF-II, along with a corresponding decrease in the expression of IGF-IIR, in iron-deficient mixed primary cell cultures. We did not observe alterations in the expression of these proteins in isolated microglia or neuronal cultures under the same conditions. We did not detect differences in the expression of IGF-I and IGF-IR in iron-deficient cultures. In vitro iron deficiency increases the expression of IGF-II in mixed glial cell cultures, which may have a beneficial effect on brain tissue homeostasis in a situation in which iron availability is decreased. Copyright © 2013 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

Challenge with 17alpha-ethinylestradiol (EE2) during early development persistently impairs growth, differentiation, and local expression of IGF-I and IGF-II in immune organs of tilapia.

PubMed

Shved, Natallia; Berishvili, Giorgi; Häusermann, Eliane; D'Cotta, Helena; Baroiller, Jean-François; Eppler, Elisabeth

2009-03-01

The enormous expansion of world-wide aquaculture has led to increasing interest in the regulation of fish immune system. Estrogen has recently been shown to inhibit the endocrine (liver-derived) and autocrine/paracrine local insulin-like growth factor-I system in fish. In order to address the potential actions of estrogen on the IGF system in immune organs, tilapia were fed with 17alpha-ethinylestradiol (EE2)-enriched food from 10 to 40 days post fertilization (DPF) to induce functional feminization, an approach commonly used in aquaculture. EE2-treated and control fish were sampled at 75 and 165 DPF. The expression levels of ER-alpha, IGF-I, IGF-II and growth hormone receptor (GH-R) mRNA in spleen and head kidney were determined by real-time PCR and the expressing sites of IGF-I mRNA identified by in situ hybridisation. Ratios of spleen length and weight to body length and weight were determined. At 165 DPF, the length (4.9% vs. 7.6%) and weight (0.084% vs. 0.132%) ratios were significantly lowered in EE2-treated fish and number and size of the melanomacrophage centres were considerably reduced. At 75 DPF, both in spleen and head kidney of EE2-treated fish the expression levels of IGF-I and IGF-II mRNA were markedly diminished. The suppression was more pronounced for IGF-I (spleen: -12.071-fold; head kidney: -8.413-fold) than for IGF-II (spleen: -4.102-fold; head kidney: -1.342-fold). In agreement, clearly fewer leucocytes and macrophages in head kidney and spleen of EE2-treated fish contained IGF-I mRNA as shown by in situ hybridisation. ER-alpha mRNA expression in spleen was increased at 75 DPF but unchanged in head kidney. GH-R gene expression showed a mild upregulation at 165 DPF in both tissues. Thus, exposure to EE2 during early development affected distinctly the IGF system in tilapia immune organs. It led to lasting impairment of spleen growth and differentiation that can be attributed to an interaction of EE2 with IGF-I and, less pronouncedly, IGF-II

Relaxation of Insulin-Like Growth Factor II Imprinting in Prostate Cancer Development

DTIC Science & Technology

2005-01-01

in the Results in Senescence and Biallelic IGF2 Expression- Hypo - mouse and are putative ICRs (Fig. 3A). At MR2, located within methylation has been...elderly. In In mammals, reproduction is controlled by the hypo - the case of prostate cancer, the most commonly diagnosed thalamic--pituitary-gonadal... caloric the ligands IGF-I, IGF-II, cell-surface receptors and binding intake or hormonal exposure), loss of imprinting of IGF-II proteins. Epidemiological

Disruption of insulin-like growth factor-II imprinting during embryonic development rescues the dwarf phenotype of mice null for pregnancy-associated plasma protein-A.

PubMed

Bale, Laurie K; Conover, Cheryl A

2005-08-01

Pregnancy-associated plasma protein-A (PAPP-A), an insulin-like growth factor-binding protein (IGFBP) protease, increases insulin-like growth factor (IGF) activity through cleavage of inhibitory IGFBP-4 and the consequent release of IGF peptide for receptor activation. Mice homozygous for targeted disruption of the PAPP-A gene are born as proportional dwarfs and exhibit retarded bone ossification during fetal development. Phenotype and in vitro data support a model in which decreased IGF-II bioavailability during embryogenesis results in growth retardation and reduction in overall body size. To test the hypothesis that an increase in IGF-II during embryogenesis would overcome the growth deficiencies, PAPP-A-null mice were crossed with DeltaH19 mutant mice, which have increased IGF-II expression and fetal overgrowth due to disruption of IgfII imprinting. DeltaH19 mutant mice were 126% and PAPP-A-null mice were 74% the size of controls at birth. These size differences were evident at embryonic day 16.5. Importantly, double mutants were indistinguishable from controls both in terms of size and skeletal development. Body size programmed during embryo development persisted post-natally. Thus, disruption of IgfII imprinting and consequent elevation in IGF-II during fetal development was associated with rescue of the dwarf phenotype and ossification defects of PAPP-A-null mice. These data provide strong genetic evidence that PAPP-A plays an essential role in determining IGF-II bioavailability for optimal fetal growth and development.

Significance of abnormal serum binding of insulin-like growth factor II in the development of hypoglycemia in patients with non-islet-cell tumors

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

Daughaday, W.H.; Kapadia, M.

1989-09-01

The authors reported that serum and tumor from a hypoglycemic patient with a fibrosarcoma contained insulin-like growth factor II (IGF-II), mostly in a large molecular form designated big IGF-II. They now describe two additional patients with non-islet-cell tumor with hypoglycemia (NICTH) whose sera contained big IGF-II. Removal of the tumor eliminated most of the big IGF-II from the sera of two patients. Because specific IGF-binding proteins modify the bioactivity of IGFs, the sizes of the endogenous IGF-binding protein complexes were determined after neutral gel filtration through Sephadex G-200. Normally about 75% of IGFs are carried as a ternary complex ofmore » 150 kDa consisting of IGF, a growth hormone (GH)-dependent IGF-binding protein, and an acid-labile complexing component. The three patients with NICTH completely lacked the 150-kDa complex. IGF-II was present as a 60-kDa complex with variable contributions of smaller complexes. In the immediate postoperative period, a 110-kDa complex appeared rather than the expected 150-kDa complex. Abnormal IGF-II binding may be important in NICTH because the 150-kDa complexes cross the capillary membrane poorly. The smaller complexes present in our patients' sera would be expected to enter interstitial fluid readily, and a 4- to 5-fold increase in the fraction of IGFs reaching the target cells would result.« less

Hypoglycemia in a dog with a leiomyoma of the gastric wall producing an insulin-like growth factor II-like peptide.

PubMed

Boari, A; Barreca, A; Bestetti, G E; Minuto, F; Venturoli, M

1995-06-01

A 12-year-old mixed-breed male dog was referred to the Clinica Medica Veterinaria of Bologna University for recurrent episodes of seizures due to hypoglycemia with abnormally low plasma insulin levels (18 pmol/l). Resection of a large leiomyoma (780 g) of the gastric wall resulted in a permanent resolution of the hypoglycemic episodes. Insulin-like growth factors I and II (IGF-I and -II) were measured by RIA in serum before and after surgery and in tumor tissue. Results were compared to the serum concentration of 54 normal and to the tissue concentration observed in eight non-hypoglycemic dog gastric wall extracts. Before surgery, circulating immunoreactive IGF-I was 0.92 nmol/l, which is significantly lower than the control values (16.92 +/- 8.44 nmol/l, range 3.53-35.03), while IGF-II was 152 nmol/l, which is significantly higher than the control values (42.21 +/- 3.75, range 31.99-50.74). After surgery, IGF-I increased to 6.80 nmol/l while IGF-II decreased to 45.52 nmol/l. Tumor tissue IGF-II concentration was higher than normal (5.66 nmol/kg tissue as compared to a range in normal gastric wall tissue of 1.14-3.72 nmol/kg), while IGF-I was 0.08 nmol/kg tissue, which is close to the lowest normal value (range in controls, 0.08-1.18 nmol/kg). Partial characterization of IGF-II immunoreactivity extracted from tissue evidenced a molecular weight similar to that of mature IGF-II, thus excluding that peptide released by the tumor is a precursor molecule.(ABSTRACT TRUNCATED AT 250 WORDS)

Transgenic mice overexpressing insulin-like growth factor-II in β cells develop type 2 diabetes

PubMed Central

Devedjian, Jean-Christophe; George, Monica; Casellas, Alba; Pujol, Anna; Visa, Joana; Pelegrín, Mireia; Gros, Laurent; Bosch, Fatima

2000-01-01

During embryonic development, insulin-like growth factor-II (IGF-II) participates in the regulation of islet growth and differentiation. We generated transgenic mice (C57BL6/SJL) expressing IGF-II in β cells under control of the rat Insulin I promoter in order to study the role of islet hyperplasia and hyperinsulinemia in the development of type 2 diabetes. In contrast to islets from control mice, islets from transgenic mice displayed high levels of IGF-II mRNA and protein. Pancreases from transgenic mice showed an increase in β-cell mass (about 3-fold) and in insulin mRNA levels. However, the organization of cells within transgenic islets was disrupted, with glucagon-producing cells randomly distributed throughout the core. We also observed enhanced glucose-stimulated insulin secretion and glucose utilization in islets from transgenic mice. These mice displayed hyperinsulinemia, mild hyperglycemia, and altered glucose and insulin tolerance tests, and about 30% of these animals developed overt diabetes when fed a high-fat diet. Furthermore, transgenic mice obtained from the N1 backcross to C57KsJ mice showed high islet hyperplasia and insulin resistance, but they also developed fatty liver and obesity. These results indicate that local overexpression of IGF-II in islets might lead to type 2 diabetes and that islet hyperplasia and hypersecretion of insulin might occur early in the pathogenesis of this disease. PMID:10727441

Isolation of an inhibitory insulin-like growth factor (IGF) binding protein from bone cell-conditioned medium: A potential local regulator of IGF action

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

Mohan, S.; Bautista, C.M.; Wergedal, J.

1989-11-01

Inhibitory insulin-like growth factor binding protein (In-IGF-BP) has been purified to homogeneity from medium conditioned by TE89 human osteosarcoma cells by two different methods using Sephadex G-100 gel filtration, FPLC Mono Q ion-exchange, HPLC C{sub 4} reverse-phase, HPLC CN reverse-phase and affinity chromatographies. In-IGF-BP thus purified appeared to be homogeneous and unique by the following criteria. (i) N-terminal sequence analysis yielded a unique sequence (Asp-Glu-Ala-Ile-His-Cys-Pro-Pro-Glu-Ser-Glu-Ala-Lys-Leu-Ala). (ii) Amino acid composition of In-IGF-BP revealed marked differences with the amino acid compositions of other known PBs. (iii) In-IGF-BP exhibited a single band with molecular mass of 25 kDa under reducing conditions on sodiummore » dodecyl sulfate/polyacrylamide gels. IGF-I and IGF-II but not insulin displaced the binding of {sup 125}I-labeled IGF-I or {sup 125}I-labeled IGF-II binding to In-IGF-BP. In-IGF-BP inhibited basal, IGF-stimulated bone cell proliferation and serum-stimulated bone cell proliferation. Forskolin increases synthesis of In-IGF-BP in TE85 human osteosarcoma cells in a dose-dependent manner. Based on these findings, the authors conclude that In-IGF-BP is a protein that has a unique sequence and significant biological actions on bone cells.« less

Immunoassays for the measurement of IGF-II, IGFBP-2 and -3, and ICTP as indirect biomarkers of recombinant human growth hormone misuse in sport. Values in selected population of athletes.

PubMed

Abellan, Rosario; Ventura, Rosa; Palmi, Ilaria; di Carlo, Simonetta; Bacosi, Antonella; Bellver, Montse; Olive, Ramon; Pascual, Jose Antonio; Pacifici, Roberta; Segura, Jordi; Zuccaro, Piergiorgio; Pichini, Simona

2008-11-04

Insulin-like growth factor-II (IGF-II), insulin-like growth factor binding proteins (IGFBPs) -2 and -3 and C-terminal telopeptide of type I collagen (ICTP) have been proposed, among others, as indirect biomarkers of the recombinant human growth hormone misuse in sport. An extended intra- and inter-laboratory validation of commercially available immunoassays for biomarkers detection was performed. ELISA assays for total IGF-II, IGFBP-2 and IGFBP-3 (IGF-II/ELISA1: DSLabs, IGFBP-2/ELISA2: Biosource, and IGFBP-3/ELISA3: BioSource) and an EIA assay for ICTP (ICTP/EIA: Orion Diagnostica) were evaluated. The inter- and intra-laboratory precision values were acceptable for all evaluated assays (maximum imprecision of 30% and 66% were found only for the lowest quality control samples of IGF-II and IGFBP-3). Correct accuracy was obtained for all inter-laboratory immunoassays and for IGFBP-2 intra-laboratory immunoassay. The range of concentrations found in serum samples under investigation was always covered by the calibration curves of the studied immunoassays. However, 11% and 15% of the samples felt below the estimated LOQ for IGF-II and ICTP, respectively, in the zone where lower precision was obtained. Although the majority of evaluated assays showed an overall reliability not always suitable for antidoping control analysis, relatively high concordances between laboratory results were obtained for all assays. Evaluated immunoassays were used to measure serum concentrations of IGF-II, IGFBP-2 and -3 and ICTP in elite athletes of various sport disciplines at different moments of the training season; in recreational athletes at baseline conditions and finally in sedentary individuals. Serum IGF-II was statistically higher both in recreational and elite athletes compared to sedentary individuals. Elite athletes showed lower IGFBP-2 and higher IGFBP-3 concentration with respect to recreational athletes and sedentary people. Among elite athletes, serum IGFBP-3 (synchronized

Rapid molecular evolution across amniotes of the IIS/TOR network

PubMed Central

McGaugh, Suzanne E.; Bronikowski, Anne M.; Kuo, Chih-Horng; Reding, Dawn M.; Addis, Elizabeth A.; Flagel, Lex E.; Janzen, Fredric J.

2015-01-01

The insulin/insulin-like signaling and target of rapamycin (IIS/TOR) network regulates lifespan and reproduction, as well as metabolic diseases, cancer, and aging. Despite its vital role in health, comparative analyses of IIS/TOR have been limited to invertebrates and mammals. We conducted an extensive evolutionary analysis of the IIS/TOR network across 66 amniotes with 18 newly generated transcriptomes from nonavian reptiles and additional available genomes/transcriptomes. We uncovered rapid and extensive molecular evolution between reptiles (including birds) and mammals: (i) the IIS/TOR network, including the critical nodes insulin receptor substrate (IRS) and phosphatidylinositol 3-kinase (PI3K), exhibit divergent evolutionary rates between reptiles and mammals; (ii) compared with a proxy for the rest of the genome, genes of the IIS/TOR extracellular network exhibit exceptionally fast evolutionary rates; and (iii) signatures of positive selection and coevolution of the extracellular network suggest reptile- and mammal-specific interactions between members of the network. In reptiles, positively selected sites cluster on the binding surfaces of insulin-like growth factor 1 (IGF1), IGF1 receptor (IGF1R), and insulin receptor (INSR); whereas in mammals, positively selected sites clustered on the IGF2 binding surface, suggesting that these hormone-receptor binding affinities are targets of positive selection. Further, contrary to reports that IGF2R binds IGF2 only in marsupial and placental mammals, we found positively selected sites clustered on the hormone binding surface of reptile IGF2R that suggest that IGF2R binds to IGF hormones in diverse taxa and may have evolved in reptiles. These data suggest that key IIS/TOR paralogs have sub- or neofunctionalized between mammals and reptiles and that this network may underlie fundamental life history and physiological differences between these amniote sister clades. PMID:25991861

Rapid molecular evolution across amniotes of the IIS/TOR network.

PubMed

McGaugh, Suzanne E; Bronikowski, Anne M; Kuo, Chih-Horng; Reding, Dawn M; Addis, Elizabeth A; Flagel, Lex E; Janzen, Fredric J; Schwartz, Tonia S

2015-06-02

The insulin/insulin-like signaling and target of rapamycin (IIS/TOR) network regulates lifespan and reproduction, as well as metabolic diseases, cancer, and aging. Despite its vital role in health, comparative analyses of IIS/TOR have been limited to invertebrates and mammals. We conducted an extensive evolutionary analysis of the IIS/TOR network across 66 amniotes with 18 newly generated transcriptomes from nonavian reptiles and additional available genomes/transcriptomes. We uncovered rapid and extensive molecular evolution between reptiles (including birds) and mammals: (i) the IIS/TOR network, including the critical nodes insulin receptor substrate (IRS) and phosphatidylinositol 3-kinase (PI3K), exhibit divergent evolutionary rates between reptiles and mammals; (ii) compared with a proxy for the rest of the genome, genes of the IIS/TOR extracellular network exhibit exceptionally fast evolutionary rates; and (iii) signatures of positive selection and coevolution of the extracellular network suggest reptile- and mammal-specific interactions between members of the network. In reptiles, positively selected sites cluster on the binding surfaces of insulin-like growth factor 1 (IGF1), IGF1 receptor (IGF1R), and insulin receptor (INSR); whereas in mammals, positively selected sites clustered on the IGF2 binding surface, suggesting that these hormone-receptor binding affinities are targets of positive selection. Further, contrary to reports that IGF2R binds IGF2 only in marsupial and placental mammals, we found positively selected sites clustered on the hormone binding surface of reptile IGF2R that suggest that IGF2R binds to IGF hormones in diverse taxa and may have evolved in reptiles. These data suggest that key IIS/TOR paralogs have sub- or neofunctionalized between mammals and reptiles and that this network may underlie fundamental life history and physiological differences between these amniote sister clades.

Skeletal muscle hypertrophy and regeneration: interplay between the myogenic regulatory factors (MRFs) and insulin-like growth factors (IGFs) pathways.

PubMed

Zanou, Nadège; Gailly, Philippe

2013-11-01

Adult skeletal muscle can regenerate in response to muscle damage. This ability is conferred by the presence of myogenic stem cells called satellite cells. In response to stimuli such as injury or exercise, these cells become activated and express myogenic regulatory factors (MRFs), i.e., transcription factors of the myogenic lineage including Myf5, MyoD, myogenin, and Mrf4 to proliferate and differentiate into myofibers. The MRF family of proteins controls the transcription of important muscle-specific proteins such as myosin heavy chain and muscle creatine kinase. Different growth factors are secreted during muscle repair among which insulin-like growth factors (IGFs) are the only ones that promote both muscle cell proliferation and differentiation and that play a key role in muscle regeneration and hypertrophy. Different isoforms of IGFs are expressed during muscle repair: IGF-IEa, IGF-IEb, or IGF-IEc (also known as mechano growth factor, MGF) and IGF-II. MGF is expressed first and is observed in satellite cells and in proliferating myoblasts whereas IGF-Ia and IGF-II expression occurs at the state of muscle fiber formation. Interestingly, several studies report the induction of MRFs in response to IGFs stimulation. Inversely, IGFs expression may also be regulated by MRFs. Various mechanisms are proposed to support these interactions. In this review, we describe the general process of muscle hypertrophy and regeneration and decipher the interactions between the two groups of factors involved in the process.

Coordinate tropic hormone regulation of mRNAs for insulin-like growth factor II and the cholesterol side-chain-cleavage enzyme, P450scc [corrected], in human steroidogenic tissues.

PubMed Central

Voutilainen, R; Miller, W L

1987-01-01

Insulin-like growth factors (IGFs) are single-chain polypeptides important for cell proliferation and growth. IGFs are produced in several tissues, suggesting that they function in a paracrine or autocrine fashion as well as functioning as endocrine hormones. We studied the hormonal regulation of IGF-I and IGF-II mRNA in human steroidogenic tissues. In cultured human ovarian granulosa cells, follicle-stimulating hormone, human chorionic gonadotropin, and dibutyryl cAMP increased IGF-II mRNA, but corticotropin [adrenocorticotropic hormone (ACTH)], chorionic somatomammotropin, growth hormone, prolactin, dexamethasone, estradiol, and progesterone had no effect. In cultured human fetal adrenal cells, ACTH and dibutyryl cAMP increased IGF-II mRNA accumulation, but human chorionic gonadotropin and angiotensin II did not. The same five size species of IGF-II mRNA were detected in transfer blots of RNA from granulosa cells and fetal adrenal cells, and all of these increased after hormonal stimuli. Dibutyryl cAMP also increased IGF-II mRNA accumulation in cultured human placental cells. Accumulation of mRNA for the cholesterol side-chain-cleavage monooxygenase [P450scc [corrected]; cholesterol, reduced-adrenal-ferredoxin:oxygen oxidoreductase (side-chain-cleaving), EC 1.14.15.6] was regulated in parallel with IGF-II mRNA in all these steroidogenic tissues. IGF-I mRNA was not detected in transfer blots of these RNAs, and the minimal amounts detected in dot blots showed no detectable change after any of the hormonal stimuli studied. The data indicate that the IGF-II gene is expressed in human steroidogenic tissues and is regulated by cAMP. These data suggest that IGF-II may act in an autocrine or paracrine fashion to stimulate the adrenal and gonadal growth stimulated by ACTH and gonadotropins, respectively. Images PMID:3031644

Effects of Artesunate on the Expressions of Insulin-Like Growth Factor-1, Osteopontin and C-Telopeptides of Type II Collagen in a Rat Model of Osteoarthritis.

PubMed

Bai, Zhe; Guo, Xiao-Hui; Tang, Chi; Yue, Si-Tong; Shi, Long; Qiang, Bo

2018-01-01

The study aims to explore the effects of artesunate on insulin-like growth factor-1 (IGF-1), Osteopontin (OPN), and C-telopeptides of type II collagen (CTX-II) in serum, synovial fluid (SF), and cartilage tissues of rats with osteoarthritis (OA). OA models were established. Normal model, artesunate, and Viatril-S groups (20 rats respectively) were set. Enzyme-linked immunosorbent assay, IHC staining, and quantitative real-time polymerase chain reaction were conducted to calculate IGF-1, OPN, and CTX-II levels in serum, SF, and cartilage tissues of rats. The pathological changes in cartilage tissues were evaluated with Mankin score and Hematoxylin-Eosin staining. Compared with the normal group, the model group showed increased IGF-1 level; decreased OPN, CTX-II levels in the serum and SF; and contrary results were seen in the cartilage tissues. A gradual ascending IGF-1 level and descending OPN and CTX-II levels existed in the serum and SF in the artesunate and Viatril-S groups after 2 weeks. The model group showed the most obvious pathological changes and highest Mankin score compared with the other groups. Higher IGF-1 level and lower OPN, CTX-II levels were exhibited in the cartilage tissue in the artesunate and Viatril-S groups but not in the model group. Artesunate and Viatril-S inhibit OA development by elevating IGF-1 level and reducing OPN and CTX-II levels. © 2017 S. Karger AG, Basel.

Role of insulin-like growth factor-1 (IGF-1) in regulating cell cycle progression

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

Ma, Qi-lin; Yang, Tian-lun; Yin, Ji-ye

2009-11-06

Aims: Insulin-like growth factor-1 (IGF-1) is a polypeptide protein hormone, similar in molecular structure to insulin, which plays an important role in cell migration, cell cycle progression, cell survival and proliferation. In this study, we investigated the possible mechanisms of IGF-1 mediated cell cycle redistribution and apoptosis of vascular endothelial cells. Method: Human umbilical vein endothelial cells (HUVECs) were pretreated with 0.1, 0.5, or 2.5 {mu}g/mL of IGF-1 for 30 min before the addition of Ang II. Cell cycle redistribution and apoptosis were examined by flow cytometry. Expression of Ang II type 1 (AT{sub 1}) mRNA and cyclin E proteinmore » were determined by RT-PCR and Western blot, respectively. Results: Ang II (1 {mu}mol/L) induced HUVECs arrested at G{sub 0}/G{sub 1}, enhanced the expression level of AT{sub 1} mRNA in a time-dependent manner, reduced the enzymatic activity of nitric oxide synthase (NOS) and nitric oxide (NO) content as well as the expression level of cyclin E protein. However, IGF-1 enhanced NOS activity, NO content, and the expression level of cyclin E protein, and reduced the expression level of AT{sub 1} mRNA. L-NAME significantly counteracted these effects of IGF-1. Conclusions: Our data suggests that IGF-1 can reverse vascular endothelial cells arrested at G{sub 0}/G{sub 1} and apoptosis induced by Ang II, which might be mediated via a NOS-NO signaling pathway and is likely associated with the expression levels of AT1 mRNA and cyclin E proteins.« less

Insulin-like growth factor-I stimulates H{sub 4}II rat hepatoma cell proliferation: Dominant role of PI-3'K/Akt signaling

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

Alexia, Catherine; Fourmatgeat, Pascal; Delautier, Daniele

2006-04-15

Although hepatocytes are the primary source of endocrine IGF-I and -II in mammals, their autocrine/paracrine role in the dysregulation of proliferation and apoptosis during hepatocarcinogenesis and in hepatocarcinomas (HCC) remains to be elucidated. Indeed, IGF-II and type-I IGF receptors are overexpressed in HCC cells, and IGF-I is synthesized in adjacent non-tumoral liver tissue. In the present study, we have investigated the effects of type-I IGF receptor signaling on H{sub 4}II rat hepatoma cell proliferation, as estimated by {sup 3}H-thymidine incorporation into DNA. IGF-I stimulated the rate of DNA synthesis of serum-deprived H{sub 4}II cells, stimulation being maximal 3 h aftermore » the onset of IGF-I treatment and remaining elevated until at least 6 h. The IGF-I-induced increase in DNA replication was abolished by LY294002 and only partially inhibited by PD98059, suggesting that phosphoinositol-3' kinase (PI-3'K) and to a lesser extent MEK/Erk signaling were involved. Furthermore, the 3- to 19-fold activation of the Erks in the presence of LY294002 suggested a down-regulation of the MEK/Erk cascade by PI-3'K signaling. Finally, the effect of IGF-I on DNA replication was almost completely abolished in clones of H{sub 4}II cells expressing a dominant-negative form of Akt but was unaltered by rapamycin treatment of wild-type H{sub 4}II cells. Altogether, these data support the notion that the stimulation of H{sub 4}II rat hepatoma cell proliferation by IGF-I is especially dependent on Akt activation but independent on the Akt/mTOR signal0009i.« less

40 CFR Table II-1 to Subpart II of... - Emission Factors

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 21 2014-07-01 2014-07-01 false Emission Factors II Table II-1 to Subpart II of Part 98 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING Industrial Wastewater Treatment Pt. 98, Subpt. II, Table II-1...

40 CFR Table II-1 to Subpart II of... - Emission Factors

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 22 2013-07-01 2013-07-01 false Emission Factors II Table II-1 to Subpart II of Part 98 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING Industrial Wastewater Treatment Pt. 98, Subpt. II, Table II-1...

c-myb stimulates cell growth by regulation of insulin-like growth factor (IGF) and IGF-binding protein-3 in K562 leukemia cells

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

Kim, Min-Sun; Kim, Sun-Young; Arunachalam, Sankarganesh

2009-07-17

c-myb plays an important role in the regulation of cell growth and differentiation, and is highly expressed in immature hematopoietic cells. The human chronic myelogenous leukemia cell K562, highly expresses IGF-I, IGF-II, IGF-IR, and IGF-induced cellular proliferation is mediated by IGF-IR. To characterize the impact of c-myb on the IGF-IGFBP-3 axis in leukemia cells, we overexpressed c-myb using an adenovirus gene transfer system in K562 cells. The overexpression of c-myb induced cell proliferation, compared to control, and c-myb induced cell growth was inhibited by anti-IGF-IR antibodies. c-myb overexpression resulted in a significant increase in the expression of IGF-I, IGF-II, andmore » IGF-IR, and a decrease in IGFBP-3 expression. By contrast, disruption of c-myb function by DN-myb overexpression resulted in significant reduction of IGF-I, IGF-II, IGF-IR, and elevation of IGFBP-3 expression. In addition, exogenous IGFBP-3 inhibited the proliferation of K562 cells, and c-myb induced cell growth was blocked by IGFBP-3 overexpression in a dose-dependent manner. The growth-promoting effects of c-myb were mediated through two major intracellular signaling pathways, Akt and Erk. Activation of Akt and Erk by c-myb was completely blocked by IGF-IR and IGFBP-3 antibodies. These findings suggest that c-myb stimulates cell growth, in part, by regulating expression of the components of IGF-IGFBP axis in K562 cells. In addition, disruption of c-myb function by DN-myb may provide a useful strategy for treatment of leukemia.« less

Impact of angiotensin II on skeletal muscle metabolism and function in mice: contribution of IGF-1, Sirtuin-1 and PGC-1α.

PubMed

Kackstein, Katharina; Teren, Andrej; Matsumoto, Yasuharu; Mangner, Norman; Möbius-Winkler, Sven; Linke, Axel; Schuler, Gerhard; Punkt, Karla; Adams, Volker

2013-05-01

Activation of the renin-angiotensin-aldosterone system and increased levels of angiotensin II (Ang-II) occurs in numerous cardiovascular diseases such as chronic heart failure (CHF). Another hallmark in CHF is a reduced exercise tolerance with impaired skeletal muscle function. The aim of this study was to investigate in an animal model the impact of Ang-II on skeletal muscle function and concomitant molecular alterations. Mice were infused with Ang-II for 4 weeks. Subsequently, skeletal muscle function of the soleus muscle was assessed. Expression of selected proteins was quantified by qRT-PCR and Western blot. Infusion of Ang-II resulted in a 33% reduction of contractile force, despite a lack of changes in muscle weight. At the molecular level an increased expression of NAD(P)H oxidase and a reduced expression of Sirt1, PGC-1α and IGF-1 were noticed. No change was evident for the ubiquitin E3-ligases MuRF1 and MafBx and α-sarcomeric actin expression. Cytophotometrical analysis of the soleus muscle revealed a metabolic shift toward a glycolytic profile. This study provides direct evidence of Ang-II-mediated, metabolic deterioration of skeletal muscle function despite preserved muscle mass. One may speculate that the Ang-II-mediated loss of muscle force is due to an activation of NAD(P)H oxidase expression and a subsequent ROS-induced down regulation of IGF-1, PGC-1α and Sirt1. Copyright © 2012 Elsevier GmbH. All rights reserved.

Effect of recombinant insulin-like growth factor-1 treatment on short-term linear growth in a child with Majewski osteodysplastic primordial dwarfism type II and hepatic insufficiency.

PubMed

Faienza, Maria Felicia; Acquafredda, Angelo; D'Aniello, Mariangela; Soldano, Lucia; Marzano, Flaviana; Ventura, Annamaria; Cavallo, Luciano

2013-01-01

We report the case of a boy affected by severe intrauterine and postnatal growth retardation, microcephaly, facial dysmorphisms and postnecrotic cirrhosis, diagnosed at birth as having Seckel syndrome, and subsequently confirmed as Majewski osteodysplastic primordial dwarfism type II (MOPD II) on the basis of clinical and radiological features of skeletal dysplasia. At our observation (6 years 7 months) he presented height -10.3 standard deviation score (SDS), weight -22.1 SDS, head circumference -8 SDS, delayed bone age of 4 years with respect to chronological age. In consideration of the low levels of insulin-like growth factor-1 (IGF-1) as well as of hepatic insufficiency, we started the treatment with recombinant human IGF-1 (rhIGF-1) at the dose of 0.04 mg/kg in 2 doses/day, with an increase of 0.04 mg/kg after 1 week until the maximum dose of 0.12 mg/kg. We observed an early response to rhIGF-1 treatment, with a shift of height velocity from 1.8 cm/year (-4.6 SDS) at 4 cm/year (-1.9 SDS), and an increase in bone age of 1.5 years during the first 6 months. rhIGF-1 treatment does not seem to be able to replace the physiological action of IGF-1 in patients with MOPD II and hepatic insufficiency, however, it seems to preserve the typical growth pattern of MOPD II patients, avoiding a further widening of the growth deficiency in these subjects.

Partial IGF-1 deficiency is sufficient to reduce heart contractibility, angiotensin II sensibility, and alter gene expression of structural and functional cardiac proteins.

PubMed

González-Guerra, José Luis; Castilla-Cortazar, Inma; Aguirre, Gabriel A; Muñoz, Úrsula; Martín-Estal, Irene; Ávila-Gallego, Elena; Granado, Miriam; Puche, Juan E; García-Villalón, Ángel Luis

2017-01-01

Circulating levels of IGF-1 may decrease under several circumstances like ageing, metabolic syndrome, and advanced cirrhosis. This reduction is associated with insulin resistance, dyslipidemia, progression to type 2 diabetes, and increased risk for cardiovascular diseases. However, underlying mechanisms between IGF-1 deficiency and cardiovascular disease remain elusive. The specific aim of the present work was to study whether the partial IGF-1 deficiency influences heart and/or coronary circulation, comparing vasoactive factors before and after of ischemia-reperfusion (I/R). In addition, histology of the heart was performed together with cardiac gene expression for proteins involved in structure and function (extracellular matrix, contractile proteins, active peptides); carried out using microarrays, followed by RT-qPCR confirmation of the three experimental groups. IGF-1 partial deficiency is associated to a reduction in contractility and angiotensin II sensitivity, interstitial fibrosis as well as altered expression pattern of genes involved in extracellular matrix proteins, calcium dynamics, and cardiac structure and function. Although this work is descriptive, it provides a clear insight of the impact that partial IGF-1 deficiency on the heart and establishes this experimental model as suitable for studying cardiac disease mechanisms and exploring therapeutic options for patients under IGF-1 deficiency conditions.

Partial IGF-1 deficiency is sufficient to reduce heart contractibility, angiotensin II sensibility, and alter gene expression of structural and functional cardiac proteins

PubMed Central

Aguirre, Gabriel A.; Muñoz, Úrsula; Martín-Estal, Irene; Ávila-Gallego, Elena; Granado, Miriam; Puche, Juan E.; García-Villalón, Ángel Luis

2017-01-01

Circulating levels of IGF-1 may decrease under several circumstances like ageing, metabolic syndrome, and advanced cirrhosis. This reduction is associated with insulin resistance, dyslipidemia, progression to type 2 diabetes, and increased risk for cardiovascular diseases. However, underlying mechanisms between IGF-1 deficiency and cardiovascular disease remain elusive. The specific aim of the present work was to study whether the partial IGF-1 deficiency influences heart and/or coronary circulation, comparing vasoactive factors before and after of ischemia-reperfusion (I/R). In addition, histology of the heart was performed together with cardiac gene expression for proteins involved in structure and function (extracellular matrix, contractile proteins, active peptides); carried out using microarrays, followed by RT-qPCR confirmation of the three experimental groups. IGF-1 partial deficiency is associated to a reduction in contractility and angiotensin II sensitivity, interstitial fibrosis as well as altered expression pattern of genes involved in extracellular matrix proteins, calcium dynamics, and cardiac structure and function. Although this work is descriptive, it provides a clear insight of the impact that partial IGF-1 deficiency on the heart and establishes this experimental model as suitable for studying cardiac disease mechanisms and exploring therapeutic options for patients under IGF-1 deficiency conditions. PMID:28806738

Purification, amino acid sequence and characterisation of kangaroo IGF-I.

PubMed

Yandell, C A; Francis, G L; Wheldrake, J F; Upton, Z

1998-01-01

Insulin-like growth factor-I (IGF-I) and IGF-II have been purified to homogeneity from kangaroo (Macropus fuliginosus) serum, thus this represents the first report of the purification, sequencing and characterisation of marsupial IGFs. N-Terminal protein sequencing reveals that there are six amino acid differences between kangaroo and human IGF-I. Kangaroo IGF-II has been partially sequenced and no differences were found between human and kangaroo IGF-II in the 53 residues identified. Thus the IGFs appear to be remarkably structurally conserved during mammalian radiation. In addition, in vitro characterisation of kangaroo IGF-I demonstrated that the functional properties of human, kangaroo and chicken IGF-I are very similar. In an assay measuring the ability of the proteins to stimulate protein synthesis in rat L6 myoblasts, all IGF-I proteins were found to be equally potent. The ability of all three proteins to compete for binding with radiolabelled human IGF-I to type-1 IGF receptors in L6 myoblasts and in Sminthopsis crassicaudata transformed lung fibroblasts, a marsupial cell line, was comparable. Furthermore, kangaroo and human IGF-I react equally in a human IGF-I RIA using a human reference standard, radiolabelled human IGF-I and a polyclonal antibody raised against recombinant human IGF-I. This study indicates that not only is the primary structure of eutherian and metatherian IGF-I conserved, but also the proteins appear to be functionally similar.

Differential Expression of Glypican-3 and Insulin–Like Growth Factor-II mRNAs and Alpha-Fetoprotein and Ki-67 Markers in HCV Related Hepatocellular Carcinomas In Egyptian Patients

PubMed

Saber, Mohamed A; MM AbdelHafiz, Samah; Khorshed, Fatma E; Aboushousha, Tarek S; Hamdy, Hussam EM; Seleem, Mohamed I; Soliman, Amira H

2017-01-01

Background: Increasing evidence indicates that in hepatocellular carcinomas (HCCs) abnormal gene expression, for example of glypican-3 (GPC-3) and insulin-like growth factor-II (IGF-II), are associated with the occurrence and progression of HCC. The objective of this study was to evaluate the differential expression of GPC-3 and IGF-II mRNAs in HCC tissues with a background of chronic hepatitis C virus (HCV) genotype 4 cirrhosis, in relation to Ki-67 and alpha-feto protein (AFP) tissue markers. Methods: One hundred and five patients with HCCs who had undergone hepatectomy, were included, after obtaining informed consent. Total RNA was extracted from malignant and corresponding peri-malignant liver tissues, and GPC-3 and IGF-II mRNAs in addition to beta-actin mRNA as an internal control, were evaluated in all samples by reverse transcriptase-polymerase chain reactions (RT-PCR). Routine histopathological diagnosis as well as immunohistochemical (IHC) staining using monoclonal antibodies for Ki-67 and AFP were also performed. Result: Expression of GPC-3 mRNA was positive in all HCC malignant tissue, with overexpression in 86/105 (81.9%); in respect to the grade of the tumor (1-3 grades), while in peri-malignant tissue it was over expressed only in 20/105 (19%). The IGF-II mRNA was over expressed in only 10/105 (9.5%) malignant and peri-malignant samples. AFP was expressed in 33.3% of malignant samples but absent in peri-malignant tissues. Ki-67 expression was significantly increased in malignant compared to peri-malignant tissue. Conclusion: GPC-3 and IGF II mRNAs may be good molecular markers for HCC, especially with a background of cirrhosis due to chronic HCV infection. Significant correlations were noted with the pattern of AFP and Ki-67 expression. Creative Commons Attribution License

Angiotensin II Infusion Induces Marked Diaphragmatic Skeletal Muscle Atrophy

PubMed Central

Rezk, Bashir M.; Yoshida, Tadashi; Semprun-Prieto, Laura; Higashi, Yusuke; Sukhanov, Sergiy; Delafontaine, Patrice

2012-01-01

Advanced congestive heart failure (CHF) and chronic kidney disease (CKD) are characterized by increased angiotensin II (Ang II) levels and are often accompanied by significant skeletal muscle wasting that negatively impacts mortality and morbidity. Both CHF and CKD patients have respiratory muscle dysfunction, however the potential effects of Ang II on respiratory muscles are unknown. We investigated the effects of Ang II on diaphragm muscle in FVB mice. Ang II induced significant diaphragm muscle wasting (18.7±1.6% decrease in weight at one week) and reduction in fiber cross-sectional area. Expression of the E3 ubiquitin ligases atrogin-1 and muscle ring finger-1 (MuRF-1) and of the pro-apoptotic factor BAX was increased after 24 h of Ang II infusion (4.4±0.3 fold, 3.1±0.5 fold and 1.6±0.2 fold, respectively, compared to sham infused control) suggesting increased muscle protein degradation and apoptosis. In Ang II infused animals, there was significant regeneration of injured diaphragm muscles at 7 days as indicated by an increase in the number of myofibers with centralized nuclei and high expression of embryonic myosin heavy chain (E-MyHC, 11.2±3.3 fold increase) and of the satellite cell marker M-cadherin (59.2±22.2% increase). Furthermore, there was an increase in expression of insulin-like growth factor-1 (IGF-1, 1.8±0.3 fold increase) in Ang II infused diaphragm, suggesting the involvement of IGF-1 in diaphragm muscle regeneration. Bone-marrow transplantation experiments indicated that although there was recruitment of bone-marrow derived cells to the injured diaphragm in Ang II infused mice (267.0±74.6% increase), those cells did not express markers of muscle stem cells or regenerating myofibers. In conclusion, Ang II causes marked diaphragm muscle wasting, which may be important for the pathophysiology of respiratory muscle dysfunction and cachexia in conditions such as CHF and CKD. PMID:22276172

HSF1 phosphorylation by ERK/GSK3 suppresses RNF126 to sustain IGF-IIR expression for hypertension-induced cardiomyocyte hypertrophy.

PubMed

Huang, Chih-Yang; Lee, Fa-Lun; Peng, Shu-Fen; Lin, Kuan-Ho; Chen, Ray-Jade; Ho, Tsung-Jung; Tsai, Fu-Jen; Padma, Vijaya V; Kuo, Wei-Wen; Huang, Chih-Yang

2018-02-01

Hypertension-induced cardiac hypertrophy and apoptosis are major characteristics of early-stage heart failure (HF). Inhibition of extracellular signal-regulated kinases (ERK) efficaciously suppressed angiotensin II (ANG II)-induced cardiomyocyte hypertrophy and apoptosis by blocking insulin-like growth factor II receptor (IGF-IIR) signaling. However, the detailed mechanism by which ANG II induces ERK-mediated IGF-IIR signaling remains elusive. Here, we found that ANG II activated ERK to upregulate IGF-IIR expression via the angiotensin II type I receptor (AT 1 R). ERK activation subsequently phosphorylates HSF1 at serine 307, leading to a secondary phosphorylation by glycogen synthase kinase III (GSK3) at serine 303. Moreover, we found that ANG II mediated ERK/GSK3-induced IGF-IIR protein stability by downregulating the E3 ubiquitin ligase of IGF-IIR RING finger protein CXXVI (RNF126). The expression of RNF126 decreased following ANG II-induced HSF1 S303 phosphorylation, resulting in IGF-IIR protein stability and increased cardiomyocyte injury. Inhibition of GSK3 significantly alleviated ANG II-induced cardiac hypertrophy in vivo and in vitro. Taken together, these results suggest that HSF1 phosphorylation stabilizes IGF-IIR protein stability by downregulating RNF126 during cardiac hypertrophy. ANG II activates ERK/GSK3 to phosphorylate HSF1, resulting in RNF126 degradation, which stabilizes IGF-IIR protein expression and eventually results in cardiac hypertrophy. HSF1 could be a valuable therapeutic target for cardiac diseases among hypertensive patients. © 2017 Wiley Periodicals, Inc.

Impact of PTEN on the expression of insulin-like growth factors (IGFs) and IGF-binding proteins in human gastric adenocarcinoma cells

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

Yi, Ho-Keun; Kim, Sun-Young; Hwang, Pyoung-Han

2005-05-13

PTEN is a tumor suppressor gene that is frequently mutated or deleted in a variety of human cancers including human gastric cancer. PTEN functions primarily as a lipid phosphatase and plays a key role in the regulation of the PI3 kinase/Akt pathway, thereby modulating cell proliferation and cell survival. On the other hand, the IGF system plays an important role in cell proliferation and cell survival via the PI3 kinase/Akt and MAP kinase pathways in many cancer cells. To characterize the impact of PTEN on the IGF-IGFR-IGFBP axis in gastric cancer, we overexpressed PTEN using an adenovirus gene transfer systemmore » in human gastric adenocarcinoma cells, SNU-484 and SNU-663, which lack PTEN. Overexpression of PTEN inhibited serum-induced as well as IGF-I-induced cell proliferation as compared to control cells. PTEN overexpression resulted in a significant decrease in the expression of IGF-I, -II, and IGF-IR. Interestingly, amongst the six IGFBPs, only IGFBP-3 was upregulated by PTEN, whereas IGFBP-4 and -6 were reduced. The IGFBP-3 promoter activity assay and Western immunoblotting demonstrate that PTEN regulates IGFBP-3 at the transcriptional level. In addition, the PI3 kinase inhibitor, LY294002, upregulates IGFBP-3 expression but downregulates IGF-I and IGF-II, indicating that PTEN controls IGFBP-3 and IGFs by an Akt-dependent pathway. These findings suggest that PTEN may inhibit antiapoptotic IGF actions not only by blocking the IGF-IGFR-induced Akt activity, but also by regulating expression of components of the IGF system, in particular, upregulation of IGFBP-3, which is known to exert antiproliferative effects through IGF-dependent and IGF-independent mechanisms in cancer cells.« less

Factor II assay

MedlinePlus

... this page: //medlineplus.gov/ency/article/003674.htm Factor II assay To use the sharing features on ... M. is also a founding member of Hi-Ethics and subscribes to the principles of the Health ...

Associations of food and nutrient intakes with serum IGF-I, IGF-II, IGFBP-3, TGF-b1, total SOD activity and sFas levels among middle-aged Japanese: the Japan Collaborative Cohort study.

PubMed

Maruyama, Koutatsu; Iso, Hiroyasu; Ito, Yoshinori; Watanabe, Yoshiyuki; Inaba, Yutaka; Tajima, Kazuo; Nakachi, Kei; Tamakoshi, Akiko

2009-12-01

No observational study has examined whether cancer-related biomarkers are associated with diet in Japanese. We therefore assessed sex-specific food and nutrient intakes according to serum IGF-I, IGF-II, IGFBP-3, TGF-b1, total SOD activity and sFas levels, under a cross-sectional study of 10,350 control subjects who answered the food frequency questionnaire in the first-wave nested case-control study within the Japan Collaborative Cohort Study. For both men and women, IGF-I levels were associated with higher intakes of milk, fruits, green tea, calcium and vitamin C. IGF-II levels were associated with higher intakes of milk, yogurt, fruits and miso soup, and lower intakes of rice, coffee and carbohydrate. IGFBP-3 levels were associated with higher intakes of milk, yogurt, fruits and vitamin C, and lower intakes of rice, energy, protein, carbohydrate, sodium and polyunsaturated fatty acids. TGF-b1 levels were associated with lower intakes of coffee intakes, and higher intakes of miso soup and sodium. Total SOD activity levels were associated with lower intakes of most nutrients other than energy, carbohydrate, iron, copper, manganese, retinol equivalents, vitamin A, B2, B12, niacin, folic acid, vitamin C and fish fat. sFas levels were associated with higher intakes of manganese and folic acids. The results of the present study should help to account for findings on those biomarkers regarding risks of cancer and other lifestyle-related diseases in terms of dietary confounding as causality.

Rab9-dependent autophagy is required for the IGF-IIR triggering mitophagy to eliminate damaged mitochondria.

PubMed

Huang, Chih-Yang; Kuo, Wei-Wen; Ho, Tsung-Jung; Chiang, Shu-Fen; Pai, Pei-Ying; Lin, Jing-Ying; Lin, Ding-Yu; Kuo, Chia-Hua; Huang, Chih-Yang

2018-03-25

Mitochondria dysfunction is the major characteristic of mitophagy, which is essential in mitochondrial quality control. However, excessive mitophagy contributes to cell death in a number of diseases, including ischemic stroke and hepatotoxicity. Insulin-like growth factor II (IGF-II) and its receptor (IGF-IIR) play vital roles in the development of heart failure during hypertension. We found that IGF-II triggers IGF-IIR receptor activation, causing mitochondria dysfunction, resulting in mitophagy, and cardiomyocyte cell death. These results indicated that IGF-IIR activation triggers mitochondria fragmentation, leading to autophagosome formation, and loss of mitochondria content. These results are associated with Parkin-dependent mitophagy. Additionally, autophagic proteins Atg5, and Atg7 deficiency did not suppress IGF-IIR-induced mitophagy. However, Rab9 knockdown reduced mitophagy and maintained mitochondrial function. These constitutive mitophagies through IGF-IIR activation trigger mitochondria loss and mitochondrial ROS accumulation for cardiomyocyte viability decrease. Together, our results indicate that IGF-IIR predominantly induces mitophagy through the Rab9-dependent alternative autophagy. © 2018 Wiley Periodicals, Inc.

Insulin-like growth factor (IGF) binding protein from human decidua inhibits the binding and biological action of IGF-I in cultured choriocarcinoma cells

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

Ritvos, O.; Ranta, T.; Jalkanen, J.

1988-05-01

The placenta expresses genes for insulin-like growth factors (IGFs) and possesses IGF-receptors, suggesting that placental growth is regulated by IGFs in an autocrine manner. We have previously shown that human decidua, but not placenta, synthesizes and secretes a 34 K IGF-binding protein (34 K IGF-BP) called placental protein 12. We now used human choriocarcinoma JEG-3 cell monolayer cultures and recombinant (Thr59)IGF-I as a model to study whether the decidual 34 K IGF-BP is able to modulate the receptor binding and biological activity of IGFs in trophoblasts. JEG-3 cells, which possess type I IGF receptors, were unable to produce IGF-BPs. Purifiedmore » 34 K IGF-BP specifically bound (125I)iodo-(Thr59)IGF-I. Multiplication-stimulating activity had 2.5% the potency of (Thr59)IGF-I, and insulin had no effect on the binding of (125I) iodo-(Thr59)IGF-I. 34 K IGF-BP inhibited the binding of (125I) iodo-(Thr59)IGF-I to JEG-3 monolayers in a concentration-dependent manner by forming with the tracer a soluble complex that could not bind to the cell surface as demonstrated by competitive binding and cross-linking experiments. After incubating the cell monolayers with (125I)iodo-(Thr59)IGF-I in the presence of purified binding protein, followed by cross-linking, no affinity labeled bands were seen on autoradiography. In contrast, an intensely labeled band at 40 K was detected when the incubation medium was analyzed, suggesting that (Thr59)IGF-I and 34 K IGF-BP formed a complex in a 1:1 molar ratio. Also, 34 K IGF-BP inhibited both basal and IGF-I-stimulated uptake of alpha-(3H)aminoisobutyric acid in JEG-3 cells. RNA analysis revealed that IGF-II is expressed in JEG-3 cells.« less

Deficiency of liver-derived insulin-like growth factor-I (IGF-I) does not interfere with the skin wound healing rate.

PubMed

Botusan, Ileana Ruxandra; Zheng, Xiaowei; Narayanan, Sampath; Grünler, Jacob; Sunkari, Vivekananda Gupta; Calissendorff, Freja S; Ansurudeen, Ishrath; Illies, Christopher; Svensson, Johan; Jansson, John-Olov; Ohlsson, Claes; Brismar, Kerstin; Catrina, Sergiu-Bogdan

2018-01-01

IGF-I is a growth factor, which is expressed in virtually all tissues. The circulating IGF-I is however derived mainly from the liver. IGF-I promotes wound healing and its levels are decreased in wounds with low regenerative potential such as diabetic wounds. However, the contribution of circulating IGF-I to wound healing is unknown. Here we investigated the role of systemic IGF-I on wound healing rate in mice with deficiency of liver-derived IGF-I (LI-IGF-I-/- mice) during normal (normoglycemic) and impaired wound healing (diabetes). LI-IGF-I-/- mice with complete inactivation of the IGF-I gene in the hepatocytes were generated using the Cre/loxP recombination system. This resulted in a 75% reduction of circulating IGF-I. Diabetes was induced with streptozocin in both LI-IGF-I-/- and control mice. Wounds were made on the dorsum of the mice, and the wound healing rate and histology were evaluated. Serum IGF-I and GH were measured by RIA and ELISA respectively. The expression of IGF-I, IGF-II and the IGF-I receptor in the skin were evaluated by qRT-PCR. The local IGF-I protein expression in different cell types of the wounds during wound healing process was analyzed using immunohistochemistry. The wound healing rate was similar in LI-IGF-I-/- mice to that in controls. Diabetes significantly delayed the wound healing rate in both LI-IGF-I-/- and control mice. However, no significant difference was observed between diabetic animals with normal or reduced hepatic IGF-I production. The gene expression of IGF-I, IGF-II and IGF-I receptor in skin was not different between any group of animals tested. Local IGF-I levels in the wounds were similar between of LI-IGF-I-/- and WT mice although a transient reduction of IGF-I expression in leukocytes in the wounds of LI-IGF-I-/- was observed seven days post wounding. Deficiency in the liver-derived IGF-I does not affect wound healing in mice, neither in normoglycemic conditions nor in diabetes.

Effects of basic fibroblast growth factor and insulin-like growth factor on cultured cartilage cells from skate Raja porasa

NASA Astrophysics Data System (ADS)

Fan, Tingjun; Jin, Lingyun; Wang, Xiaofeng

2003-12-01

Effects of basic fibroblast growth factor (bFGF) and insulin-like growth factor II (IGF-II) on cartilage cells from proboscis of skate, Raja porasa Günther, were investigated in this study. The cartilage cells were cultured in 20% FBS-supplemented MEM medium at 24°C. Twelve hours after culture initiation, the cartilage cells were treated with bFGF and IGF-II at different concentration combinations. It was found that 20 ng/ml of bFGF or 80 ng/ml of IGF-II was enough to have obvious stimulating effect on the growth and division of skate cartilage cells. Test of bFGF and IGF-II together, revealed that 20 ng/ml of bFGF and 80 ng/ml of IGF-II together had the best stimulating effect on the growth and division of skate cartilage cells. The cartilage cells cultured could form a monolayer at day 7.

Over-stimulation of insulin/IGF-1 signaling by western diet may promote diseases of civilization: lessons learnt from laron syndrome.

PubMed

Melnik, Bodo C; John, Swen Malte; Schmitz, Gerd

2011-06-24

The insulin/insulin-like growth factor-1 (IGF-1) pathway drives an evolutionarily conserved network that regulates lifespan and longevity. Individuals with Laron syndrome who carry mutations in the growth hormone receptor (GHR) gene that lead to severe congenital IGF-1 deficiency with decreased insulin/IGF-1 signaling (IIS) exhibit reduced prevalence rates of acne, diabetes and cancer. Western diet with high intake of hyperglycemic carbohydrates and insulinotropic dairy over-stimulates IIS. The reduction of IIS in Laron subjects unmasks the potential role of persistent hyperactive IIS mediated by Western diet in the development of diseases of civilization and offers a rational perspective for dietary adjustments with less insulinotropic diets like the Paleolithic diet.

Over-stimulation of insulin/IGF-1 signaling by western diet may promote diseases of civilization: lessons learnt from laron syndrome

PubMed Central

2011-01-01

The insulin/insulin-like growth factor-1 (IGF-1) pathway drives an evolutionarily conserved network that regulates lifespan and longevity. Individuals with Laron syndrome who carry mutations in the growth hormone receptor (GHR) gene that lead to severe congenital IGF-1 deficiency with decreased insulin/IGF-1 signaling (IIS) exhibit reduced prevalence rates of acne, diabetes and cancer. Western diet with high intake of hyperglycemic carbohydrates and insulinotropic dairy over-stimulates IIS. The reduction of IIS in Laron subjects unmasks the potential role of persistent hyperactive IIS mediated by Western diet in the development of diseases of civilization and offers a rational perspective for dietary adjustments with less insulinotropic diets like the Paleolithic diet. PMID:21699736

The cAMP Response Element Binding protein (CREB) is activated by Insulin-like Growth Factor-1 (IGF-1) and regulates myostatin gene expression in skeletal myoblast

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

Zuloaga, R.; Fuentes, E.N.; Molina, A.

2013-10-18

Highlights: •IGF-1 induces the activation of CREB via IGF-1R/PI3K/PLC signaling pathway. •Calcium dependent signaling pathways regulate myostatin gene expression. •IGF-1 regulates myostatin gene expression via CREB transcription in skeletal myoblast. -- Abstract: Myostatin, a member of the Transforming Growth Factor beta (TGF-β) superfamily, plays an important role as a negative regulator of skeletal muscle growth and differentiation. We have previously reported that IGF-1 induces a transient myostatin mRNA expression, through the activation of the Nuclear Factor of Activated T cells (NFAT) in an IP{sub 3}/calcium-dependent manner. Here we examined the activation of CREB transcription factor as downstream targets of IGF-1more » during myoblast differentiation and its role as a regulator of myostatin gene expression. In cultured skeletal myoblast, IGF-1 induced the phosphorylation and transcriptional activation of CREB via IGF-1 Receptor/Phosphatidylinositol 3-Kinase (PI3K)/Phospholipase C gamma (PLC γ), signaling pathways. Also, IGF-1 induced calcium-dependent molecules such as Calmodulin Kinase II (CaMK II), Extracellular signal-regulated Kinases (ERK), Protein Kinase C (PKC). Additionally, we examined myostatin mRNA levels and myostatin promoter activity in differentiated myoblasts stimulated with IGF-1. We found a significant increase in mRNA contents of myostatin and its reporter activity after treatment with IGF-1. The expression of myostatin in differentiated myoblast was downregulated by the transfection of siRNA–CREB and by pharmacological inhibitors of the signaling pathways involved in CREB activation. By using pharmacological and genetic approaches together these data demonstrate that IGF-1 regulates the myostatin gene expression via CREB transcription factor during muscle cell differentiation.« less

Alveolar type II cell-fibroblast interactions, synthesis and secretion of surfactant and type I collagen.

PubMed

Griffin, M; Bhandari, R; Hamilton, G; Chan, Y C; Powell, J T

1993-06-01

contained low levels of IGF-1 and the stimulation of type I collagen secretion was abolished when the conditioned medium was pre-incubated with antibodies to insulin-like growth factor 1 (IGF-1). There are important reciprocal interactions between alveolar type II cells and fibroblasts in co-culture. Direct contacts between alveolar type II cells and fibroblasts appear to have a trophic effect on cultured alveolar type II cells, increasing the levels of mRNA for SP-A. Rat lung alveolar type II cells appear to release a factor (possibly IGF-1) that stimulates type I collagen secretion by fibroblasts.

Insulin-like signaling (IIS) responses to temperature, genetic background, and growth variation in garter snakes with divergent life histories.

PubMed

Reding, Dawn M; Addis, Elizabeth A; Palacios, Maria G; Schwartz, Tonia S; Bronikowski, Anne M

2016-07-01

The insulin/insulin-like signaling pathway (IIS) has been shown to mediate life history trade-offs in mammalian model organisms, but the function of this pathway in wild and non-mammalian organisms is understudied. Populations of western terrestrial garter snakes (Thamnophis elegans) around Eagle Lake, California, have evolved variation in growth and maturation rates, mortality senescence rates, and annual reproductive output that partition into two ecotypes: "fast-living" and "slow-living". Thus, genes associated with the IIS network are good candidates for investigating the mechanisms underlying ecological divergence in this system. We reared neonates from each ecotype for 1.5years under two thermal treatments. We then used qPCR to compare mRNA expression levels in three tissue types (brain, liver, skeletal muscle) for four genes (igf1, igf2, igf1r, igf2r), and we used radioimmunoassay to measure plasma IGF-1 and IGF-2 protein levels. Our results show that, in contrast to most mammalian model systems, igf2 mRNA and protein levels exceed those of igf1 and suggest an important role for igf2 in postnatal growth in reptiles. Thermal rearing treatment and recent growth had greater impacts on IGF levels than genetic background (i.e., ecotype), and the two ecotypes responded similarly. This suggests that observed ecotypic differences in field measures of IGFs may more strongly reflect plastic responses in different environments than evolutionary divergence. Future analyses of additional components of the IIS pathway and sequence divergence between the ecotypes will further illuminate how environmental and genetic factors influence the endocrine system and its role in mediating life history trade-offs. Copyright © 2016 Elsevier Inc. All rights reserved.

Deficiency of liver-derived insulin-like growth factor-I (IGF-I) does not interfere with the skin wound healing rate

PubMed Central

Narayanan, Sampath; Grünler, Jacob; Sunkari, Vivekananda Gupta; Calissendorff, Freja S.; Ansurudeen, Ishrath; Illies, Christopher; Svensson, Johan; Jansson, John-Olov; Ohlsson, Claes; Brismar, Kerstin; Catrina, Sergiu-Bogdan

2018-01-01

Objective IGF-I is a growth factor, which is expressed in virtually all tissues. The circulating IGF-I is however derived mainly from the liver. IGF-I promotes wound healing and its levels are decreased in wounds with low regenerative potential such as diabetic wounds. However, the contribution of circulating IGF-I to wound healing is unknown. Here we investigated the role of systemic IGF-I on wound healing rate in mice with deficiency of liver-derived IGF-I (LI-IGF-I-/- mice) during normal (normoglycemic) and impaired wound healing (diabetes). Methods LI-IGF-I-/- mice with complete inactivation of the IGF-I gene in the hepatocytes were generated using the Cre/loxP recombination system. This resulted in a 75% reduction of circulating IGF-I. Diabetes was induced with streptozocin in both LI-IGF-I-/- and control mice. Wounds were made on the dorsum of the mice, and the wound healing rate and histology were evaluated. Serum IGF-I and GH were measured by RIA and ELISA respectively. The expression of IGF-I, IGF-II and the IGF-I receptor in the skin were evaluated by qRT-PCR. The local IGF-I protein expression in different cell types of the wounds during wound healing process was analyzed using immunohistochemistry. Results The wound healing rate was similar in LI-IGF-I-/- mice to that in controls. Diabetes significantly delayed the wound healing rate in both LI-IGF-I-/- and control mice. However, no significant difference was observed between diabetic animals with normal or reduced hepatic IGF-I production. The gene expression of IGF-I, IGF-II and IGF-I receptor in skin was not different between any group of animals tested. Local IGF-I levels in the wounds were similar between of LI-IGF-I-/- and WT mice although a transient reduction of IGF-I expression in leukocytes in the wounds of LI-IGF-I-/- was observed seven days post wounding. Conclusion Deficiency in the liver-derived IGF-I does not affect wound healing in mice, neither in normoglycemic conditions nor in

Cytokines and growth factors which regulate bone cell function

NASA Astrophysics Data System (ADS)

Seino, Yoshiki

Everybody knows that growth factors are most important in making bone. Hormones enhance bone formation from a long distance. Growth factors promote bone formation as an autocrine or paracrine factor in nearby bone. BMP-2 through BMP-8 are in the TGF-β family. BMP makes bone by enchondral ossification. In bone, IGF-II is most abundant, second, TGF-β, and third IGF-I. TGF-β enhances bone formation mainly by intramembranous ossification in vivo. TGF-β affects both cell proliferation and differentiation, however, TGF-β mainly enhances bone formation by intramembranous ossification. Interestingly, TGF-β is increased by estrogen(E 2), androgen, vitamin D, TGF-β and FGF. IGF-I and IGF-II also enhance bone formation. At present it remains unclear why IGF-I is more active in bone formation than IGF-II, although IGF-II is more abundant in bone compared to IGF-I. However, if only type I receptor signal transduction promotes bone formation, the strong activity of IGF-I in bone formation is understandable. GH, PTH and E 2 promotes IGF-I production. Recent data suggest that hormones containing vitamin D or E 2 enhance bone formation through growth factors. Therefore, growth factors are the key to clarifying the mechanism of bone formation.

Nuclear IGF-1R interacts with regulatory regions of chromatin to promote RNA polymerase II recruitment and gene expression associated with advanced tumor stage.

PubMed

Aleksic, Tamara; Gray, Nicki E; Wu, Xiaoning; Rieunier, Guillaume; Osher, Eliot; Mills, Jack; Verrill, Clare; Bryant, Richard J; Han, Cheng; Hutchinson, Kathryn; Lambert, Adam; Kumar, Rajeev; Hamdy, Freddie C; Weyer-Czernilofsky, Ulrike; Sanderson, Michael; Bogenrieder, Thomas; Taylor, Stephen; Macaulay, Valentine M

2018-05-07

Internalization of ligand-activated type 1 IGF receptor (IGF-1R) is followed by recycling to the plasma membrane, degradation or nuclear translocation. Nuclear IGF-1R reportedly associates with clinical response to IGF-1R inhibitory drugs, yet its role in the nucleus is poorly characterized. Here we investigated the significance of nuclear IGF-1R in clinical cancers and cell line models. In prostate cancers, IGF-1R was predominantly membrane-localized in benign glands, while malignant epithelium contained prominent internalized (nuclear/cytoplasmic) IGF-1R, and nuclear IGF-1R associated significantly with advanced tumor stage. Using ChIP-seq to assess global chromatin occupancy, we identified IGF-1R binding sites at or near transcription start sites of genes including JUN and FAM21, most sites coinciding with occupancy by RNA polymerase II (RNAPol2) and histone marks of active enhancers/promoters. IGF-1R was inducibly recruited to chromatin, directly binding DNA and interacting with RNAPol2 to upregulate expression of JUN and FAM21, shown to mediate tumor cell survival and IGF-induced migration. IGF-1 also enriched RNAPol2 on promoters containing IGF-1R binding sites. These functions were inhibited by IGF-1/2 neutralizing antibody xentuzumab (BI 836845), or by blocking receptor internalization. We detected nuclear IGF-1R on JUN and FAM21 promoters in fresh prostate cancers that contained abundant nuclear IGF-1R, with evidence of correlation between nuclear IGF-1R content and JUN expression in malignant prostatic epithelium. Taken together, these data reveal previously unrecognized molecular mechanisms through which IGFs promote tumorigenesis, with implications for therapeutic evaluation of anti-IGF drugs. Copyright ©2018, American Association for Cancer Research.

IGF binding proteins in cancer: mechanistic and clinical insights.

PubMed

Baxter, Robert C

2014-05-01

The six members of the family of insulin-like growth factor (IGF) binding proteins (IGFBPs) were originally characterized as passive reservoirs of circulating IGFs, but they are now understood to have many actions beyond their endocrine role in IGF transport. IGFBPs also function in the pericellular and intracellular compartments to regulate cell growth and survival - they interact with many proteins, in addition to their canonical ligands IGF-I and IGF-II. Intranuclear roles of IGFBPs in transcriptional regulation, induction of apoptosis and DNA damage repair point to their intimate involvement in tumour development, progression and resistance to treatment. Tissue or circulating IGFBPs might also be useful as prognostic biomarkers.

Effects of methionine deficiencies on plasma levels of thyroid hormones, insulin-like growth factors-I and -II, liver and body weights, and feed intake in growing chickens.

PubMed

Carew, L B; McMurtry, J P; Alster, F A

2003-12-01

We showed previously that Met deficiency at 0.25% of the diet causes elevations in plasma triiodothyronine (T3) in broilers. In the present study, plasma levels of thyroid hormones as well as insulin-like growth factors (IGF)-I and -II were measured in chicks fed 3 deficient levels of total Met. Control (0.5%) and Met-deficient diets (0.4, 0.3, and 0.2%) were fed to male broilers from 8 to 22 d of age. Additional groups of control chicks were pair-fed with the Met-deficient ones. Chicks receiving 0.4% Met increased feed intake by 10% with no significant change in body weight. The more severe Met deficiencies of 0.3 and 0.2% caused graded reductions in feed intake and weight gain. However, corresponding pair-fed control chicks were significantly heavier. These changes suggest more marked alterations in metabolic processes with 0.3 and 0.2% Met than with 0.4% Met. Liver weights were heavier in chicks fed 0.3 and 0.2% Met but not 0.4%. Plasma T3 was higher in all deficient chicks compared with the free-fed control, which was significant only with 0.3% Met. However, with 0.3 and 0.2% Met, plasma T3 was significantly elevated compared to pair-fed controls. Plasma thyroxine (T4) was lower in all deficient groups, which was significant only with 0.2% Met, whereas no significant differences occurred between deficient chicks and their pair-fed controls. Plasma IGF-I levels were not significantly different, but they were consistently lower in deficient chicks and deserve further study. Plasma IGF-II was significantly less in chicks fed 0.2% Met compared to pair-fed controls suggesting that Met deficiency interferes with IGF-II metabolism. We concluded that a deficit of dietary Met altered plasma T3 and IGF-II levels, but the effect was dependent on the degree of deficiency.

Expression of the genes for insulin-like growth factors and their receptors in bone during skeletal growth

NASA Technical Reports Server (NTRS)

Bikle, D. D.; Harris, J.; Halloran, B. P.; Roberts, C. T.; Leroith, D.; Morey-Holton, E.

1994-01-01

Insulin-like growth factors (IGF) are important regulators of skeletal growth. To determine whether the capacity to produce and respond to these growth factors changes during skeletal development, we measured the protein and mRNA levels for IGF-I, IGF-II, and their receptors (IGF-IR and IGF-IIR, respectively) in the tibia and femur of rats before and up to 28 mo after birth. The mRNA levels remained high during fetal development but fell after birth, reaching a nadir by 3-6 wk. This fall was most pronounced for IGF-II and IGF-IIR mRNA and least pronounced for IGF-I mRNA. However, after 6 wk, both IGF-I and IGF-IR mRNA levels recovered toward the levels observed at birth. In the prenatal bones, the signals for the mRNAs of IGF-II and IGF-IIR were stronger than the signals for the mRNAs of IGF-I and IGF-IR, although the content of IGF-I was three- to fivefold greater than that of IGF-II. IGF-II levels fell postnatally, whereas the IGF-I content rose after birth such that the ratio IGF-I/IGF-II continued to increase with age. We conclude that, during development, rat bone changes its capacity to produce and respond to IGFs with a progressive trend toward the dominance of IGF-I.

Crosstalk between insulin-like growth factor-1 and angiotensin-II in dopaminergic neurons and glial cells: role in neuroinflammation and aging.

PubMed

Rodriguez-Perez, Ana I; Borrajo, Ana; Diaz-Ruiz, Carmen; Garrido-Gil, Pablo; Labandeira-Garcia, Jose L

2016-05-24

The local renin-angiotensin system (RAS) and insulin-like growth factor 1 (IGF-1) have been involved in longevity, neurodegeneration and aging-related dopaminergic degeneration. However, it is not known whether IGF-1 and angiotensin-II (AII) activate each other. In the present study, AII, via type 1 (AT1) receptors, exacerbated neuroinflammation and dopaminergic cell death. AII, via AT1 receptors, also increased the levels of IGF-1 and IGF-1 receptors in microglial cells. IGF-1 inhibited RAS activity in dopaminergic neurons and glial cells, and also inhibited the AII-induced increase in markers of the M1 microglial phenotype. Consistent with this, IGF-1 decreased dopaminergic neuron death induced by the neurotoxin MPP+ both in the presence and in the absence of glia. Intraventricular administration of AII to young rats induced a significant increase in IGF-1 expression in the nigral region. However, aged rats showed decreased levels of IGF-1 relative to young controls, even though RAS activity is known to be enhanced in aged animals. The study findings show that IGF-1 and the local RAS interact to inhibit or activate neuroinflammation (i.e. transition from the M1 to the M2 phenotype), oxidative stress and dopaminergic degeneration. The findings also show that this mechanism is impaired in aged animals.

Crosstalk between insulin-like growth factor-1 and angiotensin-II in dopaminergic neurons and glial cells: role in neuroinflammation and aging

PubMed Central

Rodriguez-Perez, Ana I.; Borrajo, Ana; Diaz-Ruiz, Carmen; Garrido-Gil, Pablo; Labandeira-Garcia, Jose L.

2016-01-01

The local renin-angiotensin system (RAS) and insulin-like growth factor 1 (IGF-1) have been involved in longevity, neurodegeneration and aging-related dopaminergic degeneration. However, it is not known whether IGF-1 and angiotensin-II (AII) activate each other. In the present study, AII, via type 1 (AT1) receptors, exacerbated neuroinflammation and dopaminergic cell death. AII, via AT1 receptors, also increased the levels of IGF-1 and IGF-1 receptors in microglial cells. IGF-1 inhibited RAS activity in dopaminergic neurons and glial cells, and also inhibited the AII-induced increase in markers of the M1 microglial phenotype. Consistent with this, IGF-1 decreased dopaminergic neuron death induced by the neurotoxin MPP+ both in the presence and in the absence of glia. Intraventricular administration of AII to young rats induced a significant increase in IGF-1 expression in the nigral region. However, aged rats showed decreased levels of IGF-1 relative to young controls, even though RAS activity is known to be enhanced in aged animals. The study findings show that IGF-1 and the local RAS interact to inhibit or activate neuroinflammation (i.e. transition from the M1 to the M2 phenotype), oxidative stress and dopaminergic degeneration. The findings also show that this mechanism is impaired in aged animals. PMID:27167199

Inhibition of HSF2 SUMOylation via MEL18 upregulates IGF-IIR and leads to hypertension-induced cardiac hypertrophy.

PubMed

Huang, Chih-Yang; Kuo, Chia-Hua; Pai, Pei-Ying; Ho, Tsung-Jung; Lin, Yueh-Min; Chen, Ray-Jade; Tsai, Fuu-Jen; Vijaya Padma, V; Kuo, Wei-Wen; Huang, Chih-Yang

2018-04-15

Cardiac hypertrophy is a major characteristic of early-stage hypertension-related heart failure. We have found that the insulin-like growth factor receptor II (IGF-IIR) signaling was critical for hypertensive angiotensin II-induced cardiomyocyte hypertrophy and apoptosis. Moreover, this IGF-IIR signaling was elegantly modulated by the heat shock transcription factors (HSFs) during heart failure. However, the detailed mechanism by which HSFs regulates IGF-IIR during hypertension-induced cardiac hypertrophy remains elusive. In this study, we found that heat shock transcription factor 2 (HSF2) activated IGF-IIR to induce cardiac hypertrophy for hypertension-induced heart failure. The transcriptional activity of HSF2 appeared to be primarily mediated by SUMOylation via conjugation with small ubiquitin-like modifier-1 (SUMO-1). The SUMOylation of HSF2 was severely attenuated by MEL18 (also known as polycomb group ring finger 2 or PCGF2) in the heart of spontaneously hypertensive rats (SHR). Inhibition of HSF2 SUMOylation severely induced cardiac hypertrophy via IGF-IIR-mediated signaling in hypertensive rats. Angiotensin II receptor type I blocker (ARB) treatment in spontaneously hypertensive rats restored HSF2 SUMOylation and alleviated the cardiac defects. Thus, our study uncovered a novel MEL18-SUMO-1-HSF2-IGF-IIR pathway in the heart that profoundly influences cardiac hypertrophy for hypertension-induced heart failure. Copyright © 2017 Elsevier B.V. All rights reserved.

Loss of insulin-like growth factor II imprinting is a hallmark associated with enhanced chemo/radiotherapy resistance in cancer stem cells.

PubMed

Zhao, Xin; Liu, Xiaoliang; Wang, Guanjun; Wen, Xue; Zhang, Xiaoying; Hoffman, Andrew R; Li, Wei; Hu, Ji-Fan; Cui, Jiuwei

2016-08-09

Insulin-like growth factor II (IGF2) is maternally imprinted in most tissues, but the epigenetic regulation of the gene in cancer stem cells (CSCs) has not been defined. To study the epigenetic mechanisms underlying self-renewal, we isolated CSCs and non-CSCs from colon cancer (HT29, HRT18, HCT116), hepatoma (Hep3B), breast cancer (MCF7) and prostate cancer (ASPC) cell lines. In HT29 and HRT18 cells that show loss of IGF2 imprinting (LOI), IGF2 was biallelically expressed in the isolated CSCs. Surprisingly, we also found loss of IGF2 imprinting in CSCs derived from cell lines HCT116 and ASPC that overall demonstrate maintenance of IGF2 imprinting. Using chromatin conformation capture (3C), we found that intrachromosomal looping between the IGF2 promoters and the imprinting control region (ICR) was abrogated in CSCs, in parallel with loss of IGF2 imprinting in these CSCs. Loss of imprinting led to increased IGF2 expression in CSCs, which have a higher rate of colony formation and greater resistance to chemotherapy and radiotherapy in vitro. These studies demonstrate that IGF2 LOI is a common feature in CSCs, even when the stem cells are derived from a cell line in which the general population of cells maintain IGF2 imprinting. This finding suggests that aberrant IGF2 imprinting may be an intrinsic epigenetic control mechanism that enhances stemness, self-renewal and chemo/radiotherapy resistance in cancer stem cells.

Local IGF-1 isoform protects cardiomyocytes from hypertrophic and oxidative stresses via SirT1 activity.

PubMed

Vinciguerra, Manlio; Santini, Maria Paola; Claycomb, William C; Ladurner, Andreas G; Rosenthal, Nadia

2009-12-10

Oxidative and hypertrophic stresses contribute to the pathogenesis of heart failure. Insulin-like growth factor-1 (IGF-1) is a peptide hormone with a complex post-transcriptional regulation, generating distinct isoforms. Locally acting IGF-1 isoform (mIGF-1) helps the heart to recover from toxic injury and from infarct. In the murine heart, moderate overexpression of the NAD(+)-dependent deacetylase SirT1 was reported to mitigate oxidative stress. SirT1 is known to promote lifespan extension and to protect from metabolic challenges. Circulating IGF-1 and SirT1 play antagonizing biological roles and share molecular targets in the heart, in turn affecting cardiomyocyte physiology. However, how different IGF-1 isoforms may impact SirT1 and affect cardiomyocyte function is unknown. Here we show that locally acting mIGF-1 increases SirT1 expression/activity, whereas circulating IGF-1 isoform does not affect it, in cultured HL-1 and neonatal cardiomyocytes. mIGF-1-induced SirT1 activity exerts protection against angiotensin II (Ang II)-triggered hypertrophy and against paraquat (PQ) and Ang II-induced oxidative stress. Conversely, circulating IGF-1 triggered itself oxidative stress and cardiomyocyte hypertrophy. Interestingly, potent cardio-protective genes (adiponectin, UCP-1 and MT-2) were increased specifically in mIGF-1-overexpressing cardiomyocytes, in a SirT1-dependent fashion. Thus, mIGF-1 protects cardiomyocytes from oxidative and hypertrophic stresses via SirT1 activity, and may represent a promising cardiac therapeutic.

Local IGF-1 isoform protects cardiomyocytes from hypertrophic and oxidative stresses via SirT1 activity

PubMed Central

Vinciguerra, Manlio; Santini, Maria Paola; Claycomb, William C.; Ladurner, Andreas G.; Rosenthal, Nadia

2010-01-01

Oxidative and hypertrophic stresses contribute to the pathogenesis of heart failure. Insulin-like growth factor-1 (IGF-1) is a peptide hormone with a complex post-transcriptional regulation, generating distinct isoforms. Locally acting IGF-1 isoform (mIGF-1) helps the heart to recover from toxic injury and from infarct. In the murine heart, moderate overexpression of the NAD+-dependent deacetylase SirT1 was reported to mitigate oxidative stress. SirT1 is known to promote lifespan extension and to protect from metabolic challenges. Circulating IGF-1 and SirT1 play antagonizing biological roles and share molecular targets in the heart, in turn affecting cardiomyocyte physiology. However, how different IGF-1 isoforms may impact SirT1 and affect cardiomyocyte function is unknown. Here we show that locally acting mIGF-1 increases SirT1 expression/activity, whereas circulating IGF-1 isoform does not affect it, in cultured HL-1 and neonatal cardiomyocytes. mIGF-1-induced SirT1 activity exerts protection against angiotensin II (Ang II)-triggered hypertrophy and against paraquat (PQ) and Ang II-induced oxidative stress. Conversely, circulating IGF-1 triggered itself oxidative stress and cardiomyocyte hypertrophy. Interestingly, potent cardio-protective genes (adiponectin, UCP-1 and MT-2) were increased specifically in mIGF-1-overexpressing cardiomyocytes, in a SirT1-dependent fashion. Thus, mIGF-1 protects cardiomyocytes from oxidative and hypertrophic stresses via SirT1 activity, and may represent a promising cardiac therapeutic. PMID:20228935

Regulation of insulin-like growth factor I receptors on vascular smooth muscle cells by growth factors and phorbol esters.

PubMed

Ververis, J J; Ku, L; Delafontaine, P

1993-06-01

Insulin-like growth factor I (IGF I) is an important mitogen for vascular smooth muscle cells. To characterize regulation of vascular IGF I receptors, we performed radioligand displacement experiments using rat aortic smooth muscle cells (RASMs). Serum deprivation for 48 hours caused a 40% decrease in IGF I receptor number. Exposure of quiescent RASMs to platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), or angiotensin II (Ang II) caused a 1.5-2.0-fold increase in IGF I receptors per cell. After FGF exposure, there was a marked increase in the mitogenic response to IGF I. IGF I downregulated its receptors in the presence of platelet-poor plasma. Stimulation of protein kinase C (PKC) by exposure of quiescent RASMs to phorbol 12-myristate 13-acetate caused a biphasic response in IGF I binding; there was a 42% decrease in receptor number at 45 minutes and a 238% increase at 24 hours. To determine the role of PKC in growth factor-induced regulation of IGF I receptors, we downregulated PKC by exposing RASMs to phorbol 12,13-dibutyrate (PDBu) for 48 hours. PDGF- and FGF- but not Ang II-mediated upregulation of IGF I receptors was completely inhibited in PDBu-treated cells. Thus, acute PKC activation by phorbol esters inhibits IGF I binding, whereas chronic PKC activation increases IGF I binding. PDGF and FGF but not Ang II regulate vascular IGF I receptors through a PKC-dependent pathway. These data provide new insights into the regulation of vascular smooth muscle cell IGF I receptors in vitro and are of potential importance in characterizing vascular proliferative responses in vivo.

IGF system targeted therapy: Therapeutic opportunities for ovarian cancer.

PubMed

Liefers-Visser, J A L; Meijering, R A M; Reyners, A K L; van der Zee, A G J; de Jong, S

2017-11-01

The insulin-like growth factor (IGF) system comprises multiple growth factor receptors, including insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (IR) -A and -B. These receptors are activated upon binding to their respective growth factor ligands, IGF-I, IGF-II and insulin, and play an important role in development, maintenance, progression, survival and chemotherapeutic response of ovarian cancer. In many pre-clinical studies anti-IGF-1R/IR targeted strategies proved effective in reducing growth of ovarian cancer models. In addition, anti-IGF-1R targeted strategies potentiated the efficacy of platinum based chemotherapy. Despite the vast amount of encouraging and promising pre-clinical data, anti-IGF-1R/IR targeted strategies lacked efficacy in the clinic. The question is whether targeting the IGF-1R/IR signaling pathway still holds therapeutic potential. In this review we address the complexity of the IGF-1R/IR signaling pathway, including receptor heterodimerization within and outside the IGF system and downstream signaling. Further, we discuss the implications of this complexity on current targeted strategies and indicate therapeutic opportunities for successful targeting of the IGF-1R/IR signaling pathway in ovarian cancer. Multiple-targeted approaches circumventing bidirectional receptor tyrosine kinase (RTK) compensation and prevention of system rewiring are expected to have more therapeutic potential. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Diabetic retinopathy in two patients with congenital IGF-I deficiency (Laron syndrome).

PubMed

Laron, Zvi; Weinberger, Dov

2004-07-01

Animal and clinical studies have shown that excessive amounts of growth hormone or insulin-like growth factor-I (IGF-I) promote the development of diabetes and diabetic retinopathy. Forthwith, we present two patients with congenital IGF-I deficiency who developed type II diabetes and subsequently retinopathy. Eighteen adult patients with classical Laron syndrome (8 males, 10 females, aged 20-62 years) were followed by us since childhood or underwent fundus photography with a Nikon NF 505 instrument. Three had been treated in childhood with IGF-I, the rest were never treated, including the two patients reported. Two never-treated patients were diagnosed with type II diabetes (DM) at ages 39 and 41 respectively. There was no diabetes in the families. Oral treatment was followed by insulin injections. Metabolic control was not optimal and one patient developed proliferative diabetic retinopathy, necessitating laser surgery. He also has nephropathy and severe neuropathy. The other patient has background diabetic retinopathy and has developed, progressively, exudates, microaneurisms, hemorrhages and clinically significant macular edema. He also has subacute ischemic heart disease. Our findings show that congenital IGF-I deficiency, similar to excess, causes vascular complications of DM, denoting also that vascular endothelial growth factor can induce neovascularization in the presence of congenital IGF-I deficiency.

Placental IGF-I, IGFBP-1, zinc, and iron, and maternal and infant anthropometry at birth.

PubMed

Akram, Shahzad K; Carlsson-Skwirut, Christine; Bhutta, Zulfiqar A; Söder, Olle

2011-11-01

To correlate placental protein levels of insulin-like growth factor (IGF)-I and insulin-like growth factor binding protein (IGFBP)-1, with previously determined levels of IGF-I and IGF-II mRNA expression, and the micronutrients zinc and iron, and maternal and newborn anthropometry. Placental samples were collected from rural field sites in Pakistan. Samples were divided into small and large for gestational age groups (SGA and LGA, respectively). IGFBP-1 levels were assessed using Western immunoblotting. IGF-I protein levels were assessed using ELISA techniques. IGF mRNA expression, zinc, and iron, were quantified as previously described and were used for comparative purposes only. Thirty-three subjects were included (SGA, n = 12; LGA n = 21). Higher levels of IGFBP-1 were seen in the SGA group (p < 0.01). IGFBP-1 correlated positively with maternal and infant triceps skin-fold thickness in the LGA and SGA groups, respectively (p < 0.05). Significantly lower IGF-I protein levels were seen in the SGA group. IGF-I levels correlated significantly with maternal and newborn anthropometry. IGFBP-1 correlated significantly with IGF-II mRNA expression (p < 0.05). Placental protein levels of IGF-I and IGFBP-1 appear to be associated with maternal anthropometry. Maternal anthropometry may thus influence IGFBP-1 and IGF-I levels and may possibly be used for screening of pregnancies, with the potential for timely identification of these high-risk pregnancies. © 2011 The Author(s)/Acta Paediatrica © 2011 Foundation Acta Paediatrica.

Insulin-Like Growth Factors and Metabolic Syndrome in Obese Children.

PubMed

Inzaghi, Elena; Baldini Ferroli, Barbara; Fintini, Danilo; Grossi, Armando; Nobili, Valerio; Cianfarani, Stefano

2017-01-01

Insulin-like growth factor (IGF)-I is related to cardiometabolic risk in adults, whereas the metabolic role of IGF-II is unclear. The aim of this study was to assess IGFs in obese children and correlate them with metabolic syndrome (MetS) components. This is a retrospective study including 574 obese children (11.34 ± 3.16 years). All subjects underwent complete anthropometry and biochemical assessment. In a subgroup of 136 subjects, body composition was evaluated. IGF-I was measured in 300 obese subjects and IGF-II in 77 obese and 15 lean children. 177 subjects were divided according to the presence of 1 or more MetS criteria: group 1, subjects with 1 MetS criterion; group 2, subjects with 2 components; and group 3, subjects with MetS diagnosis. IGF-I, IGF-II, and IGF-I/insulin-like growth factor-binding protein-3 ratio were not different among subjects with an increasing number of MetS criteria and were not associated with single components of MetS as well as with body composition parameters. In children younger than 10 years, IGF-I directly correlated with high-density lipoprotein cholesterol (p < 0.005) even after controlling for confounders. IGF-II was significantly higher in obese children and correlated with parameters of insulin sensitivity (p < 0.05). IGFs were neither related to MetS nor to body composition parameters in obese children. Further studies are needed to clarify the mechanisms underlying the relationship between IGF-II and insulin sensitivity. © 2017 S. Karger AG, Basel.

PAPP-A proteolytic activity enhances IGF bioactivity in ascites from women with ovarian carcinoma

PubMed Central

Thomsen, Jacob; Hjortebjerg, Rikke; Espelund, Ulrick; Ørtoft, Gitte; Vestergaard, Poul; Magnusson, Nils E.; Conover, Cheryl A.; Tramm, Trine; Hager, Henrik; Høgdall, Claus; Høgdall, Estrid; Oxvig, Claus; Frystyk, Jan

2015-01-01

Pregnancy-associated plasma protein-A (PAPP-A) stimulates insulin-like growth factor (IGF) action through proteolysis of IGF-binding protein (IGFBP)-4. In experimental animals, PAPP-A accelerates ovarian tumor growth by this mechanism. To investigate the effect of PAPP-A in humans, we compared serum and ascites from 22 women with ovarian carcinoma. We found that ascites contained 46-fold higher PAPP-A levels as compared to serum (P < 0.001). The majority (80%) of PAPP-A was enzymatically active. This is supported by the finding that ascites contained more cleaved than intact IGFBP-4 (P < 0.03). Ascites was more potent than serum in activating the IGF-I receptor (IGF-IR) in vitro (+31%, P < 0.05); in 8 of 22 patients by more than two-fold. In contrast, ascites contained similar levels of immunoreactive IGF-I, and lower levels of IGF-II (P < 0.001). Immunohistochemistry demonstrated the presence of IGF-IR in all but one tumor, whereas all tumors expressed PAPP-A, IGFBP-4, IGF-I and IGF-II. Addition of recombinant PAPP-A to ascites increased the cleavage of IGFBP-4 and enhanced IGF-IR activation (P < 0.05). In conclusion, human ovarian tumors express PAPP-A, IGFBP-4 and IGFs and these proteins are also present in ascites. We suggest that both soluble PAPP-A in ascites and tissue-associated PAPP-A serve to increase IGF bioactivity and, thereby, to stimulate IGF-IR-mediated tumor growth. PMID:26336825

The Factor Structure of the Beck Depression Inventory-II: An Evaluation

ERIC Educational Resources Information Center

Vanheule, Stijn; Desmet, Mattias; Groenvynck, Hans; Rosseel, Yves; Fontaine, Johnny

2008-01-01

The Beck Depression Inventory-II (BDI-II) is a frequently used scale for measuring depressive severity. BDI-II data (404 clinical; 695 nonclinical adults) were analyzed by means of confirmatory factor analysis to test whether the factor structure model with a somatic-affective and cognitive component of depression, formulated by Beck and…

Insulin-Like Growth Factor Regulates Peak Bone Mineral Density in Mice by Both Growth Hormone-Dependent and -Independent Mechanisms

PubMed Central

Mohan, Subburaman; Richman, Charmaine; Guo, Rongqing; Amaar, Yousef; Donahue, Leah Rea; Wergedal, Jon; Baylink, David J.

2010-01-01

To evaluate the relative contribution of the GH/IGF axis to the development of peak bone mineral density (BMD), we measured skeletal changes in IGF-I knockout (KO), IGF-II KO, and GH-deficient lit/lit mice and their corresponding control mice at d 23 (prepubertal), 31 (pubertal), and 56 (postpubertal) in the entire femur by dual energy x-ray absorptiometry and in the mid-diaphysis by peripheral quantitative computed tomography. Lack of growth factors resulted in different degrees of failure of skeletal growth depending on the growth period and the growth factor involved. At d 23, femoral length, size, and BMD were reduced by 25–40%, 15–17%, and 8–10%, respectively, in mice deficient in IGF-I, IGF-II, and GH compared with the control mice. During puberty, BMD increased by 40% in control mice and by 15% in IGF-II KO and GH-deficient mice, whereas it did not increase in the IGF-I KO mice. Disruption of IGF-I, but not IGF-II, completely prevented the periosteal expansion that occurs during puberty, whereas it was reduced by 50% in GH-deficient mice. At d 56, femoral length, size, and BMD were reduced by 40–55%, 11–18%, and 25–32%, respectively, in mice deficient in IGF-I, IGF-II, and GH compared with the control mice. Our data demonstrate that: 1) mice deficient in IGF-I exhibit a greater impairment in bone accretion than mice deficient in IGF-II or GH; 2) GH/IGF-I, but not IGF-II, is critical for puberty-induced bone growth; and 3) IGF-I effects on bone accretion during prepuberty are mediated predominantly via mechanisms independent of GH, whereas during puberty they are mediated via both GH-dependent and GH-independent mechanisms. PMID:12586770

Plasma insulin-like growth factors, insulin-like binding protein-3, and outcome in metastatic colorectal cancer: results from intergroup trial N9741.

PubMed

Fuchs, Charles S; Goldberg, Richard M; Sargent, Daniel J; Meyerhardt, Jeffrey A; Wolpin, Brian M; Green, Erin M; Pitot, Henry C; Pollak, Michael

2008-12-15

Insulin-like growth factor (IGF)-I and IGF-II stimulate neoplastic cell growth and inhibit apoptosis, whereas IGF-binding protein-3 (IGFBP-3) inhibits the bioavailability of IGF-I and has independent proapoptotic activity. We examined the influence of baseline plasma levels of IGF-I, IGF-II, IGFBP-3, and C-peptide on outcome among patients receiving first-line chemotherapy for metastatic colorectal cancer. The plasma levels of IGF-I, IGF-II, IGFBP-3, and C-peptide as well as data on prognostic factors and body size were measured at baseline among 527 patients participating in a randomized trial of first-line chemotherapy for metastatic colorectal cancer. Higher baseline plasma IGFBP-3 levels were associated with a significantly greater chemotherapy response rate (P = 0.03) after adjusting for other prognostic factors, whereas neither IGF-I nor IGF-II levels significantly predicted tumor response. Higher levels of IGF-I, IGF-II, and IGFBP-3 were all univariately associated with improved overall survival (P = 0.0001 for all). In a model that mutually adjusted for IGF-I and IGFBP-3, as well as other prognostic factors, increasing baseline-circulating IGFBP-3 was associated with a significantly longer time to tumor progression (P = 0.03), whereas circulating IGF-I was not associated with disease progression (P = 0.95). Levels of C-peptide were not associated with any measure of patient outcome. Among colorectal cancer patients receiving first-line chemotherapy, increasing levels of IGFBP-3, an endogenous antagonist to IGF-I, are associated with an improved objective treatment response and a prolonged time to cancer progression. The IGF pathway may represent an important target for future treatment strategies.

Type I and II Endometrial Cancers: Have They Different Risk Factors?

PubMed Central

Setiawan, Veronica Wendy; Yang, Hannah P.; Pike, Malcolm C.; McCann, Susan E.; Yu, Herbert; Xiang, Yong-Bing; Wolk, Alicja; Wentzensen, Nicolas; Weiss, Noel S.; Webb, Penelope M.; van den Brandt, Piet A.; van de Vijver, Koen; Thompson, Pamela J.; Strom, Brian L.; Spurdle, Amanda B.; Soslow, Robert A.; Shu, Xiao-ou; Schairer, Catherine; Sacerdote, Carlotta; Rohan, Thomas E.; Robien, Kim; Risch, Harvey A.; Ricceri, Fulvio; Rebbeck, Timothy R.; Rastogi, Radhai; Prescott, Jennifer; Polidoro, Silvia; Park, Yikyung; Olson, Sara H.; Moysich, Kirsten B.; Miller, Anthony B.; McCullough, Marjorie L.; Matsuno, Rayna K.; Magliocco, Anthony M.; Lurie, Galina; Lu, Lingeng; Lissowska, Jolanta; Liang, Xiaolin; Lacey, James V.; Kolonel, Laurence N.; Henderson, Brian E.; Hankinson, Susan E.; Håkansson, Niclas; Goodman, Marc T.; Gaudet, Mia M.; Garcia-Closas, Montserrat; Friedenreich, Christine M.; Freudenheim, Jo L.; Doherty, Jennifer; De Vivo, Immaculata; Courneya, Kerry S.; Cook, Linda S.; Chen, Chu; Cerhan, James R.; Cai, Hui; Brinton, Louise A.; Bernstein, Leslie; Anderson, Kristin E.; Anton-Culver, Hoda; Schouten, Leo J.; Horn-Ross, Pamela L.

2013-01-01

Purpose Endometrial cancers have long been divided into estrogen-dependent type I and the less common clinically aggressive estrogen-independent type II. Little is known about risk factors for type II tumors because most studies lack sufficient cases to study these much less common tumors separately. We examined whether so-called classical endometrial cancer risk factors also influence the risk of type II tumors. Patients and Methods Individual-level data from 10 cohort and 14 case-control studies from the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 14,069 endometrial cancer cases and 35,312 controls were included. We classified endometrioid (n = 7,246), adenocarcinoma not otherwise specified (n = 4,830), and adenocarcinoma with squamous differentiation (n = 777) as type I tumors and serous (n = 508) and mixed cell (n = 346) as type II tumors. Results Parity, oral contraceptive use, cigarette smoking, age at menarche, and diabetes were associated with type I and type II tumors to similar extents. Body mass index, however, had a greater effect on type I tumors than on type II tumors: odds ratio (OR) per 2 kg/m2 increase was 1.20 (95% CI, 1.19 to 1.21) for type I and 1.12 (95% CI, 1.09 to 1.14) for type II tumors (Pheterogeneity < .0001). Risk factor patterns for high-grade endometrioid tumors and type II tumors were similar. Conclusion The results of this pooled analysis suggest that the two endometrial cancer types share many common etiologic factors. The etiology of type II tumors may, therefore, not be completely estrogen independent, as previously believed. PMID:23733771

Modulation of GH/IGF-1 axis: potential strategies to counteract sarcopenia in older adults.

PubMed

Giovannini, Silvia; Marzetti, Emanuele; Borst, Stephen E; Leeuwenburgh, Christiaan

2008-10-01

Aging is associated with progressive decline of skeletal muscle mass and function. This condition, termed sarcopenia, is associated with several adverse outcomes, including loss of autonomy and mortality. Due to the high prevalence of sarcopenia, a deeper understanding of its pathophysiology and possible remedies represents a high public health priority. Evidence suggests the existence of a relationship between declining growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels and age-related changes in body composition and physical function. Therefore, the age-dependent decline of GH and IGF-1 serum levels may promote frailty by contributing to the loss of muscle mass and strength. Preclinical studies showed that infusion of angiotensin II produced a marked reduction in body weight, accompanied by decreased serum and muscle levels of IGF-1. Conversely, overexpression of muscle-specific isoform of IGF-1 mitigates angiotensin II-induced muscle loss. Moreover, IGF-1 serum levels have been shown to increase following angiotensin converting enzyme inhibitors (ACEIs) treatment. Here we will review the most recent evidence regarding age-related changes of the GH/IGF-1 axis and its modulation by several interventions, including ACEIs which might represent a potential novel strategy to delay the onset and impede the progression of sarcopenia.

A meta-analysis of individual participant data reveals an association between circulating levels of IGF-I and prostate cancer risk

PubMed Central

Travis, Ruth C.; Appleby, Paul N.; Martin, Richard M.; Holly, Jeff M.P.; Albanes, Demetrius; Black, Amanda; Bueno-de-Mesquita, H.B(as).; Chan, June M.; Chen, Chu; Chirlaque, Maria-Dolores; Cook, Michael B.; Deschasaux, Mélanie; Donovan, Jenny L.; Ferrucci, Luigi; Galan, Pilar; Giles, Graham G.; Giovannucci, Edward L.; Gunter, Marc J.; Habel, Laurel A.; Hamdy, Freddie C.; Helzlsouer, Kathy J.; Hercberg, Serge; Hoover, Robert N.; Janssen, Joseph A.M.J.L.; Kaaks, Rudolf; Kubo, Tatsuhiko; Le Marchand, Loic; Metter, E. Jeffrey; Mikami, Kazuya; Morris, Joan K.; Neal, David E.; Neuhouser, Marian L.; Ozasa, Kotaro; Palli, Domenico; Platz, Elizabeth A.; Pollak, Michael; Price, Alison J.; Roobol, Monique J.; Schaefer, Catherine; Schenk, Jeannette M.; Severi, Gianluca; Stampfer, Meir J.; Stattin, Pär; Tamakoshi, Akiko; Tangen, Catherine M.; Touvier, Mathilde; Wald, Nicholas J.; Weiss, Noel S.; Ziegler, Regina G.

2016-01-01

The role of insulin-like growth factors (IGFs) in prostate cancer development is not fully understood. To investigate the association between circulating concentrations of IGFs (IGF-I, IGF-II, IGFBP-1, IGFBP-2, IGFBP-3) and prostate cancer risk, we pooled individual participant data from 17 prospective and two cross-sectional studies, including up to 10,554 prostate cancer cases and 13,618 control participants. Conditional logistic regression was used to estimate the odds ratios (ORs) for prostate cancer based on the study-specific fifth of each analyte. Overall, IGF-I, IGF-II, IGFBP-2, and IGFBP-3 concentrations were positively associated with prostate cancer risk (Ptrend all ≤ 0.005), and IGFBP-1 was weakly inversely associated with risk (Ptrend = 0.05). However, heterogeneity between the prospective and cross-sectional studies was evident (Pheterogeneity = 0.03), unless the analyses were restricted to prospective studies (with the exception of IGF-II, Pheterogeneity = 0.02). For prospective studies, the OR for men in the highest versus the lowest fifth of each analyte was 1.29 (95% confidence interval=1.16-1.43) for IGF-I, 0.81 (0.68-0.96) for IGFBP-1, and 1.25 (1.12-1.40) for IGFBP-3. These associations did not differ significantly by time-to-diagnosis or tumor stage or grade. After mutual adjustment for each of the other analytes, only IGF-I remained associated with risk. Our collaborative study represents the largest pooled analysis of the relationship between prostate cancer risk and circulating concentrations of IGF-I, providing strong evidence that IGF-I is highly likely to be involved in prostate cancer development. PMID:26921328

Proteomic Screening and Lasso Regression Reveal Differential Signaling in Insulin and Insulin-like Growth Factor I (IGF1) Pathways *

PubMed Central

Erdem, Cemal; Nagle, Alison M.; Casa, Angelo J.; Litzenburger, Beate C.; Wang, Yu-fen; Taylor, D. Lansing; Lee, Adrian V.; Lezon, Timothy R.

2016-01-01

Insulin and insulin-like growth factor I (IGF1) influence cancer risk and progression through poorly understood mechanisms. To better understand the roles of insulin and IGF1 signaling in breast cancer, we combined proteomic screening with computational network inference to uncover differences in IGF1 and insulin induced signaling. Using reverse phase protein array, we measured the levels of 134 proteins in 21 breast cancer cell lines stimulated with IGF1 or insulin for up to 48 h. We then constructed directed protein expression networks using three separate methods: (i) lasso regression, (ii) conventional matrix inversion, and (iii) entropy maximization. These networks, named here as the time translation models, were analyzed and the inferred interactions were ranked by differential magnitude to identify pathway differences. The two top candidates, chosen for experimental validation, were shown to regulate IGF1/insulin induced phosphorylation events. First, acetyl-CoA carboxylase (ACC) knock-down was shown to increase the level of mitogen-activated protein kinase (MAPK) phosphorylation. Second, stable knock-down of E-Cadherin increased the phospho-Akt protein levels. Both of the knock-down perturbations incurred phosphorylation responses stronger in IGF1 stimulated cells compared with insulin. Overall, the time-translation modeling coupled to wet-lab experiments has proven to be powerful in inferring differential interactions downstream of IGF1 and insulin signaling, in vitro. PMID:27364358

Oligomeric state regulated trafficking of human platelet-activating factor acetylhydrolase type-II.

PubMed

Monillas, Elizabeth S; Caplan, Jeffrey L; Thévenin, Anastasia F; Bahnson, Brian J

2015-05-01

The intracellular enzyme platelet-activating factor acetylhydrolase type-II (PAFAH-II) hydrolyzes platelet-activating factor and oxidatively fragmented phospholipids. PAFAH-II in its resting state is mainly cytoplasmic, and it responds to oxidative stress by becoming increasingly bound to endoplasmic reticulum and Golgi membranes. Numerous studies have indicated that this enzyme is essential for protecting cells from oxidative stress induced apoptosis. However, the regulatory mechanism of the oxidative stress response by PAFAH-II has not been fully resolved. Here, changes to the oligomeric state of human PAFAH-II were investigated as a potential regulatory mechanism toward enzyme trafficking. Native PAGE analysis in vitro and photon counting histogram within live cells showed that PAFAH-II is both monomeric and dimeric. A Gly-2-Ala site-directed mutation of PAFAH-II demonstrated that the N-terminal myristoyl group is required for homodimerization. Additionally, the distribution of oligomeric PAFAH-II is distinct within the cell; homodimers of PAFAH-II were localized to the cytoplasm while monomers were associated to the membranes of the endoplasmic reticulum and Golgi. We propose that the oligomeric state of PAFAH-II drives functional protein trafficking. PAFAH-II localization to the membrane is critical for substrate acquisition and effective oxidative stress protection. It is hypothesized that the balance between monomer and dimer serves as a regulatory mechanism of a PAFAH-II oxidative stress response. Copyright © 2015 Elsevier B.V. All rights reserved.

Relationship of serum insulin-like growth factor I (IGF-I) with nutritional status in pediatric patients with malignant diseases--a single Romanian center experience.

PubMed

Chinceşan, Mihaela Ioana; Mărginean, Oana; Pitea, Ana-Maria; Dobreanu, Minodora

2013-10-01

The aim of this study was to analyze insulin-like growth factor I (IGF-I) serum level in pediatric patients with cancer compared with pediatric patients with nononcological diseases and to assess the relationship between IGF-I and nutritional status of oncological patients. From January 2009 to July 2012, we assessed 151 consecutively hospitalized patients in a tertiary emergency pediatric hospital. The patients were divided into two groups: group I, consisting of patients with malignant diseases (64 patients), and group II, the control group, consisting of 87 age- and gender-matched patients with different pediatric diseases. The anthropometric parameters (weight, height, body mass index, middle upper arm circumference (MUAC), and tricipital skinfold thickness (TST) and biochemical parameters (proteins, albumin, and total IGF-I) were comparatively evaluated at the diagnosis and after intensive chemotherapy in the malignant group. Anthropometric and biochemical parameters in group I were significantly different from those in group II for height, MUAC, TST, total proteins, and albumin (p < 0.05). Twenty-five out of 64 patients with malignant diseases and 5 out of 87 patients in the control group had malnutrition. IGF-I in patients with cancer was much lower than in the control group (median 48.3 ng/ml, range 25.00-662.00 ng/ml vs 129.00 ng/ml, range 25.00-745.00 ng/ml) (p = 0.014). We found a positive correlation between IGF-I, MUAC, and TST at the diagnosis of the malignant disease. Also, we identified positive correlations between IGF-I, protein, and albumin. Serum IGF-I levels in cancer patients were significantly lower at diagnosis than after chemotherapy (48.3 ng/ml, range 25.00-662.00 ng/ml vs 110.0 ng/ml, range 25.00-573.00 ng/ml; p = 0.04). IGF-I seems to be an accurate biochemical parameter used in malnutrition assessment of children with cancer. IGF-I correlated with the anthropometric parameters of the arm, serum protein, and albumin. These parameters

Salinity and temperature variations reflecting on cellular PCNA, IGF-I and II expressions, body growth and muscle cellularity of a freshwater fish larvae.

PubMed

Martins, Y S; Melo, R M C; Campos-Junior, P H A; Santos, J C E; Luz, R K; Rizzo, E; Bazzoli, N

2014-06-01

The present study assessed the influence of salinity and temperature on body growth and on muscle cellularity of Lophiosilurus alexaxdri vitelinic larvae. Slightly salted environments negatively influenced body growth of freshwater fish larvae and we observed that those conditions notably act as an environmental influencer on muscle growth and on local expression of hypertrophia and hypeplasia markers (IGFs and PCNA). Furthermore, we could see that salinity tolerance for NaCl 4gl(-)(1) diminishes with increasing temperature, evidenced by variation in body and muscle growth, and by irregular morphology of the lateral skeletal muscle of larvae. We saw that an increase of both PCNA and autocrine IGF-II are correlated to an increase in fibre numbers and fibre diameter as the temperature increases and salinity diminishes. On the other hand, autocrine IGF-I follows the opposite way to the other biological parameters assessed, increasing as salinity increases and temperature diminishes, showing that this protein did not participate in muscle cellularity, but participating in molecular/cellular repair. Therefore, slightly salted environments may provide adverse conditions that cause some obstacles to somatic growth of this species, suggesting some osmotic expenditure with a salinity increment. Copyright © 2014 Elsevier Inc. All rights reserved.

Examination of the Beck Depression Inventory-II Factor Structure Among Bariatric Surgery Candidates.

PubMed

Hayes, Sharon; Stoeckel, Nina; Napolitano, Melissa A; Collins, Charlotte; Wood, G Craig; Seiler, Jamie; Grunwald, Heidi E; Foster, Gary D; Still, Christopher D

2015-07-01

The Beck Depression Inventory-II (BDI-II) is frequently used to evaluate bariatric patients in clinical and research settings; yet, there are limited data regarding the factor structure of the BDI-II with a bariatric surgery population. Exploratory factor analysis (EFA) using principal axis factoring with oblimin rotation was employed with data from 1228 consecutive presurgical bariatric candidates. Independent t tests were used to examine potential differences between sexes. Confirmatory factor analysis (CFA) was conducted with the next 383 consecutive presurgical patients to evaluate the proposed model based on EFA results. EFA revealed three factors: negative perceptions, diminished vigor, and cognitive dysregulation, each with adequate internal consistency. Six BDI-II items did not load significantly on any of the three factors. CFA results largely supported the proposed model. Results suggest that dimensions of depression for presurgical bariatric candidates vary from other populations and raise important caveats regarding the utility of the BDI-II in bariatric research.

Dual sphingosine kinase inhibitor SKI-II enhances sensitivity to 5-fluorouracil in hepatocellular carcinoma cells via suppression of osteopontin and FAK/IGF-1R signalling

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

Grbčić, Petra; Tomljanović, Ivana; Klobučar, Marko

Hepatocellular carcinoma (HCC) represents the third leading cause of cancer-related deaths globally. Although 5-Fluorouracil (5-FU) is used as the first choice treatment for advanced HCC, it exerts poor efficacy and is associated with acquired and intrinsic resistance. Sphingosine kinases (Sphk) 1 and 2 play tumour-promoting roles in different cancer types including HCC and thus represent promising pharmacological targets. In the present study, we have investigated for the first time the anticancer efficacy and underlying molecular mechanisms of combined administration of 5-FU and dual Sphk1/Sphk2 inhibitor SKI-II (4-[[4-(4-chlorophenyl)-1,3-thiazol-2-yl]amino]phenol) in HepG2 hepatocellular carcinoma cells. Here, we report that co-administration of 5-FU andmore » SKI-II at low sub-toxic concentrations of 20 μM and 5 μM, respectively, synergistically inhibit cell proliferation, markedly reduce cell migration and the clonogenic survival, and increase apoptosis induction in HepG2 cells. Additional Western blot analyses have shown that possible mechanisms underlying enhanced sensitivity to 5-FU induced by dual Sphk 1/2 inhibition could include abrogation of FAK-regulated IGF-1R activity and down-regulation of osteopontin expression culminating in the inhibition of NF-κB activity and its downstream signalling mediated by sirtuin 1 and p38 MAPK. Our results clearly show that pharmacological blockade of both Sphk isoforms represents a promising strategy to boost the anti-tumour efficacy of 5-FU and provide a rationale for further in vivo studies into the possible use of SKI-II inhibitor as an adjunct to 5-FU treatment in HCC. - Highlights: • Pharmacological inhibition of sphingosine kinase 1/2 augments cytotoxic effects of 5-FU in HepG2 cells. • Co-administration of 5-FU and SKI-II synergistically inhibits cell proliferation, reduces cell migration and clonogenic survival and increases apoptosis induction in HepG2 cells. • The mechanism underlying

Proteomic Screening and Lasso Regression Reveal Differential Signaling in Insulin and Insulin-like Growth Factor I (IGF1) Pathways.

PubMed

Erdem, Cemal; Nagle, Alison M; Casa, Angelo J; Litzenburger, Beate C; Wang, Yu-Fen; Taylor, D Lansing; Lee, Adrian V; Lezon, Timothy R

2016-09-01

Insulin and insulin-like growth factor I (IGF1) influence cancer risk and progression through poorly understood mechanisms. To better understand the roles of insulin and IGF1 signaling in breast cancer, we combined proteomic screening with computational network inference to uncover differences in IGF1 and insulin induced signaling. Using reverse phase protein array, we measured the levels of 134 proteins in 21 breast cancer cell lines stimulated with IGF1 or insulin for up to 48 h. We then constructed directed protein expression networks using three separate methods: (i) lasso regression, (ii) conventional matrix inversion, and (iii) entropy maximization. These networks, named here as the time translation models, were analyzed and the inferred interactions were ranked by differential magnitude to identify pathway differences. The two top candidates, chosen for experimental validation, were shown to regulate IGF1/insulin induced phosphorylation events. First, acetyl-CoA carboxylase (ACC) knock-down was shown to increase the level of mitogen-activated protein kinase (MAPK) phosphorylation. Second, stable knock-down of E-Cadherin increased the phospho-Akt protein levels. Both of the knock-down perturbations incurred phosphorylation responses stronger in IGF1 stimulated cells compared with insulin. Overall, the time-translation modeling coupled to wet-lab experiments has proven to be powerful in inferring differential interactions downstream of IGF1 and insulin signaling, in vitro. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

IGF-1 as a Drug for Preterm Infants: A Step-Wise Clinical Development.

PubMed

Hellstrom, Ann; Ley, David; Hallberg, Boubou; Lofqvist, Chatarina; Hansen-Pupp, Ingrid; Ramenghi, Luca A; Borg, Jan; Smith, Lois E H; Hard, Anna-Lena

2017-01-01

Insulin-like growth factor 1 (IGF-1) is a mitogenic hormone involved in many processes such as growth, metabolism, angiogenesis and differentiation. After very preterm birth, energy demands increase while maternal supplies of nutrients and other factors are lost and the infant may become dependent on parenteral nutrition for weeks. Low postnatal IGF-1 concentrations in preterm infants are associated with poor weight gain, retinopathy of prematurity (ROP) and other morbidities. We will describe the process by which we aim to develop supplementation with recombinant human (rh) IGF-1 and its binding protein rhIGFBP-3 as a possible therapy to promote growth and maturation and reduce morbidities in extremely preterm infants. In order to calculate a dose of IGF-1 tolerated by neonates, a pharmacokinetic study of transfusion with fresh frozen plasma was performed, which provided a relatively low dose of IGF-1, (on average 1.4 µg/kg), that increased serum IGF-1 to levels close to those observed in fetuses and preterm infants of similar GAs. Thereafter, a Phase I 3 hours IV infusion of rhIGF-1/rhIGFBP-3 was conducted in 5 infants, followed by a Phase II study with four sections (A-D). In the Phase II, sections A-D studies, time on infusion increased and younger gestational ages were included. IV infusion increased IGF-1 but with short half-life (0.5h) implying a need for continuous infusion. In order to obtain in utero levels of IGF-I, the dose was increased from 100 to 250 µg/kg/24 h and the infusion was prolonged from 3 weeks postnatal age until a postmenstrual age of 29 weeks and 6 days. The purpose has been to ensure high-quality research into the development of a new drug for preterm infants. We hope that our work will help to establish a new standard for the testing of medications for preterm infants. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Negative energy balance in dairy cows is associated with specific changes in IGF-binding protein expression in the oviduct

PubMed Central

Fenwick, M A; Llewellyn, S; Fitzpatrick, R; Kenny, D A; Murphy, J J; Patton, J; Wathes, D C

2008-01-01

Negative energy balance (NEB) during early lactation in dairy cows leads to an altered metabolic state that has major effects on the production of IGF family members. Low IGF-I concentrations are associated with poor fertility and therefore we aimed to determine whether NEB exerts a direct effect on IGF expression in the postpartum oviduct. Multiparous Holstein cows were allocated to two treatments (each n=6) designed using differential feeding and milking regimes to produce either mild NEB (MNEB) or severe NEB (SNEB). Animals were slaughtered in week 2 of lactation when divergent metabolic profiles were evident. Oviducts were collected for RNA analysis by real-time RT-PCR and in situ hybridisation. Quantitative measures in oviduct gene expression were obtained for all members of the IGF family (IGF-I/II, IGF-binding proteins (IGFBP) 1–6 and receptors for IGF types 1 and 2), insulin A/B, GH, glucocorticoid and oestrogen α/β. Expression of IGFBP-2 and IGFBP-6 (both of which have a high affinity for IGF-II) was decreased in SNEB relative to MNEB (P<0.05). No other gene was altered by NEB, but IGF-II, IGFBP-3, IGFBP-5 and IGFBP-6 all showed differential expression in different regions of the oviduct. These results indicate that, in addition to low circulating IGF-I after calving, NEB may also influence IGF availability in the oviduct indirectly through changes in specific IGFBP expression. It is possible that the predicted increased signalling by IGF-II may perturb embryo development, contributing to the high rates of embryonic mortality in dairy cows. PMID:18159084

Adsorption of Pb(II), Cu(II), Cd(II), Zn(II), Ni(II), Fe(II), and As(V) on bacterially produced metal sulfides.

PubMed

Jong, Tony; Parry, David L

2004-07-01

The adsorption of Pb(II), Cu(II), Cd(II), Zn(II), Ni(II), Fe(II) and As(V) onto bacterially produced metal sulfide (BPMS) material was investigated using a batch equilibrium method. It was found that the sulfide material had adsorptive properties comparable with those of other adsorbents with respect to the specific uptake of a range of metals and, the levels to which dissolved metal concentrations in solution can be reduced. The percentage of adsorption increased with increasing pH and adsorbent dose, but decreased with increasing initial dissolved metal concentration. The pH of the solution was the most important parameter controlling adsorption of Cd(II), Cu(II), Fe(II), Ni(II), Pb(II), Zn(II), and As(V) by BPMS. The adsorption data were successfully modeled using the Langmuir adsorption isotherm. Desorption experiments showed that the reversibility of adsorption was low, suggesting high-affinity adsorption governed by chemisorption. The mechanism of adsorption for the divalent metals was thought to be the formation of strong, inner-sphere complexes involving surface hydroxyl groups. However, the mechanism for the adsorption of As(V) by BPMS appears to be distinct from that of surface hydroxyl exchange. These results have important implications to the management of metal sulfide sludge produced by bacterial sulfate reduction.

Insulin-like growth factor-I (IGF-1), IGF-binding protein-3 (IGFBP-3) and mammographic features.

PubMed

Izzo, L; Meggiorini, M L; Nofroni, I; Pala, A; De Felice, C; Meloni, P; Simari, T; Izzo, S; Pugliese, F; Impara, L; Merlini, G; Di Cello, P; Cipolla, V; Forcione, A R; Paliotta, A; Domenici, L; Bolognese, A

2012-05-01

The IGF system has recently been shown to play an important role in the regulation of breast tumor cell proliferation. However, also breast density is currently considered as the strongest breast cancer risk factor. It is not yet clear whether these factors are interrelated and if and how they are influenced by menopausal status. The purpose of this study was to examine the possible effects of IGF-1 and IGFBP-3 and IGF-1/IGFBP-3 molar ratio on mammographic density stratified by menopausal status. A group of 341 Italian women were interviewed to collect the following data: family history of breast cancer, reproductive and menstrual factors, breast biopsies, previous administration of hormonal contraceptive therapy, hormone replacement therapy (HRT) in menopause and lifestyle information. A blood sample was drawn for determination of IGF-1, IGFBP-3 levels. IGF-1/ IGFBP-3 molar ratio was then calculated. On the basis of recent mammograms the women were divided into two groups: dense breast (DB) and non-dense breast (NDB). Student's t-test was employed to assess the association between breast density and plasma level of IGF-1, IGFBP-3 and molar ratio. To assess if this relationship was similar in subgroups of pre- and postmenopausal women, the study population was stratified by menopausal status and Student's t-test was performed. Finally, multivariate analysis was employed to evaluate if there were confounding factors that might influence the relationship between growth factors and breast density. The analysis of the relationship between mammographic density and plasma level of IGF-1, IGFBP-3 and IGF-1/ IGFBP-3 molar ratio showed that IGF-1 levels and molar ratio varied in the two groups resulting in higher mean values in the DB group (IGF-1: 109.6 versus 96.6 ng/ml; p= 0.001 and molar ratio 29.4 versus 25.5 ng/ml; p= 0.001) whereas IGFBP-3 showed similar values in both groups (DB and NDB). Analysis of plasma level of IGF-1, IGFBP-3 and IGF-1/IGFBP-3 molar ratio

The IGF-1 Receptor Identifies a Pool of Human Cardiac Stem Cells with Superior Therapeutic Potential for Myocardial Regeneration

PubMed Central

D’Amario, Domenico; Cabral-Da-Silva, Mauricio; Zheng, Hanqiao; Fiorini, Claudia; Goichberg, Polina; Steadman, Elisabeth; Ferreira-Martins, João; Sanada, Fumihiro; Piccoli, Marco; Cappetta, Donato; D’Alessandro, David A.; Michler, Robert E.; Hosoda, Toru; Anastasia, Luigi; Rota, Marcello; Leri, Annarosa; Anversa, Piero; Kajstura, Jan

2012-01-01

Rationale Age and coronary artery disease may negatively affect the function of human cardiac stem cells (hCSCs) and their potential therapeutic efficacy for autologous cell transplantation in the failing heart. Objective Insulin-like growth factor 1 (IGF-1) and 2 (IGF-2), and angiotensin II (Ang II) and their receptors, IGF-1R, IGF-2R and AT1R, were characterized in c-kit-positive-hCSCs to establish whether these systems would allow us to separate hCSC classes with different growth reserve in the aging and diseased myocardium. Methods and Results C-kit-positive-hCSCs were collected from myocardial samples obtained from 24 patients, 48 to 86 years of age, undergoing elective cardiac surgery for coronary artery disease. The expression of IGF-1R in hCSCs recognized a young cell phenotype defined by long telomeres, high telomerase activity, enhanced cell proliferation and attenuated apoptosis. In addition to IGF-1, IGF-1R-positive-hCSCs secreted IGF-2 that promoted myocyte differentiation. Conversely, the presence of IGF-2R and AT1R, in the absence of IGF-1R, identified senescent hCSCs with impaired growth reserve and increased susceptibility to apoptosis. The ability of IGF-1R-positive-hCSCs to regenerate infarcted myocardium was then compared with that of unselected c-kit-positive-hCSCs. IGF-1R-positive-hCSCs improved cardiomyogenesis and vasculogenesis. Pretreatment of IGF-1R-positive-hCSCs with IGF-2 resulted in the formation of more mature myocytes and superior recovery of ventricular structure. Conclusions hCSCs expressing only IGF-1R synthesize both IGF-1 and IGF-2, which are potent modulators of stem cell replication, commitment to the myocyte lineage and myocyte differentiation, pointing to this hCSC subset as the ideal candidate cell for the management of human heart failure. PMID:21546606

RISK FACTORS FOR HTLV-II INFECTION IN PERUVIAN MEN WHO HAVE SEX WITH MEN

PubMed Central

ZUNT, JOSEPH R.; LA ROSA, ALBERTO M.; PEINADO, JESÚS; LAMA, JAVIER R.; SUAREZ, LUIS; PUN, MONICA; CABEZAS, CESAR; SANCHEZ, JORGE

2009-01-01

Human T-cell lymphotropic virus type-II (HTLV-II) infection is endemic in indigenous groups in the Americas and injection drug users (IDUs) worldwide. In Peru, HTLV-II infection was previously identified in two indigenous Amazonians. We examined risk factors for HTLV-II infection in 2,703 Peruvian men who have sex with men (MSM): 35 (1.3%) were HTLV-II positive. HTLV-II infection was associated with syphilis, HSV-2 infection, unprotected receptive anal intercourse, and older age. This is the first report of HTLV-II in a non-indigenous non-IDU population in Peru. Additional studies are needed to determine if HTLV-II is a sexually transmitted infection in this and other sexually active populations. PMID:16687704

Effect of Cu(II), Cd(II) and Zn(II) on Pb(II) biosorption by algae Gelidium-derived materials.

PubMed

Vilar, Vítor J P; Botelho, Cidália M S; Boaventura, Rui A R

2008-06-15

Biosorption of Pb(II), Cu(II), Cd(II) and Zn(II) from binary metal solutions onto the algae Gelidium sesquipedale, an algal industrial waste and a waste-based composite material was investigated at pH 5.3, in a batch system. Binary Pb(II)/Cu(II), Pb(II)/Cd(II) and Pb(II)/Zn(II) solutions have been tested. For the same equilibrium concentrations of both metal ions (1 mmol l(-1)), approximately 66, 85 and 86% of the total uptake capacity of the biosorbents is taken by lead ions in the systems Pb(II)/Cu(II), Pb(II)/Cd(II) and Pb(II)/Zn(II), respectively. Two-metal results were fitted to a discrete and a continuous model, showing the inhibition of the primary metal biosorption by the co-cation. The model parameters suggest that Cd(II) and Zn(II) have the same decreasing effect on the Pb(II) uptake capacity. The uptake of Pb(II) was highly sensitive to the presence of Cu(II). From the discrete model it was possible to obtain the Langmuir affinity constant for Pb(II) biosorption. The presence of the co-cations decreases the apparent affinity of Pb(II). The experimental results were successfully fitted by the continuous model, at different pH values, for each biosorbent. The following sequence for the equilibrium affinity constants was found: Pb>Cu>Cd approximately Zn.

IGF-1 deficiency impairs cerebral myogenic autoregulation in hypertensive mice.

PubMed

Toth, Peter; Tucsek, Zsuzsanna; Tarantini, Stefano; Sosnowska, Danuta; Gautam, Tripti; Mitschelen, Matthew; Koller, Akos; Sonntag, William E; Csiszar, Anna; Ungvari, Zoltan

2014-12-01

Aging impairs autoregulatory protection in the brain, exacerbating hypertension-induced cerebromicrovascular injury, neuroinflammation, and development of vascular cognitive impairment. Despite the importance of the age-related decline in circulating insulin-like growth factor-1 (IGF-1) levels in cerebrovascular aging, the effects of IGF-1 deficiency on functional adaptation of cerebral arteries to high blood pressure remain elusive. To determine whether IGF-1 deficiency impairs autoregulatory protection, hypertension was induced in control and IGF-1-deficient mice (Igf1(f/f)+TBG-iCre-AAV8) by chronic infusion of angiotensin-II. In hypertensive control mice, cerebral blood flow (CBF) autoregulation was extended to higher pressure values and the pressure-induced tone of middle cerebral arteries (MCAs) was increased. In hypertensive IGF-1-deficient mice, autoregulation was markedly disrupted, and MCAs did not show adaptive increases in myogenic tone. In control mice, the mechanism of adaptation to hypertension involved upregulation of TRPC channels in MCAs and this mechanism was impaired in hypertensive IGF-1-deficient mice. Likely downstream consequences of cerebrovascular autoregulatory dysfunction in hypertensive IGF-1-deficient mice included exacerbated disruption of the blood-brain barrier and neuroinflammation (microglia activation and upregulation of proinflammatory cytokines and chemokines), which were associated with impaired hippocampal cognitive function. Collectively, IGF-1 deficiency impairs autoregulatory protection in the brain of hypertensive mice, potentially exacerbating cerebromicrovascular injury and neuroinflammation mimicking the aging phenotype.

Free metal ion depletion by "Good's" buffers. III. N-(2-acetamido)iminodiacetic acid, 2:1 complexes with zinc(II), cobalt(II), nickel(II), and copper(II); amide deprotonation by Zn(II), Co(II), and Cu(II).

PubMed

Lance, E A; Rhodes, C W; Nakon, R

1983-09-01

Potentiometric, visible, infrared, electron spin, and nuclear magnetic resonance studies of the complexation of N-(2-acetamido)iminodiacetic acid (H2ADA) by Ca(II), Mg(II), Mn(II), Zn(II), Co(II), Ni(II), and Cu(II) are reported. Ca(II) and Mg(II) were found not to form 2:1 ADA2- to M(II) complexes, while Mn(II), Cu(II), Ni(II), Zn(II), and Co(II) did form 2:1 metal chelates at or below physiological pH values. Co(II) and Zn(II), but not Cu(II), were found to induce stepwise deprotonation of the amide groups to form [M(H-1ADA)4-(2)]. Formation (affinity) constants for the various metal complexes are reported, and the probable structures of the various metal chelates in solution are discussed on the basis of various spectral data.

Dinuclear complexes containing linear M-F-M [M = Mn(II), Fe(II), Co(II), Ni(II), Cu(II), Zn(II), Cd(II)] bridges: trends in structures, antiferromagnetic superexchange interactions, and spectroscopic properties.

PubMed

Reger, Daniel L; Pascui, Andrea E; Smith, Mark D; Jezierska, Julia; Ozarowski, Andrew

2012-11-05

The reaction of M(BF(4))(2)·xH(2)O, where M is Fe(II), Co(II), Ni(II), Cu(II), Zn(II), and Cd(II), with the new ditopic ligand m-bis[bis(3,5-dimethyl-1-pyrazolyl)methyl]benzene (L(m)*) leads to the formation of monofluoride-bridged dinuclear metallacycles of the formula [M(2)(μ-F)(μ-L(m)*)(2)](BF(4))(3). The analogous manganese(II) species, [Mn(2)(μ-F)(μ-L(m)*)(2)](ClO(4))(3), was isolated starting with Mn(ClO(4))(2)·6H(2)O using NaBF(4) as the source of the bridging fluoride. In all of these complexes, the geometry around the metal centers is trigonal bipyramidal, and the fluoride bridges are linear. The (1)H, (13)C, and (19)F NMR spectra of the zinc(II) and cadmium(II) compounds and the (113)Cd NMR of the cadmium(II) compound indicate that the metallacycles retain their structure in acetonitrile and acetone solution. The compounds with M = Mn(II), Fe(II), Co(II), Ni(II), and Cu(II) are antiferromagnetically coupled, although the magnitude of the coupling increases dramatically with the metal as one moves to the right across the periodic table: Mn(II) (-6.7 cm(-1)) < Fe(II) (-16.3 cm(-1)) < Co(II) (-24.1 cm(-1)) < Ni(II) (-39.0 cm(-1)) ≪ Cu(II) (-322 cm(-1)). High-field EPR spectra of the copper(II) complexes were interpreted using the coupled-spin Hamiltonian with g(x) = 2.150, g(y) = 2.329, g(z) = 2.010, D = 0.173 cm(-1), and E = 0.089 cm(-1). Interpretation of the EPR spectra of the iron(II) and manganese(II) complexes required the spin Hamiltonian using the noncoupled spin operators of two metal ions. The values g(x) = 2.26, g(y) = 2.29, g(z) = 1.99, J = -16.0 cm(-1), D(1) = -9.89 cm(-1), and D(12) = -0.065 cm(-1) were obtained for the iron(II) complex and g(x) = g(y) = g(z) = 2.00, D(1) = -0.3254 cm(-1), E(1) = -0.0153, J = -6.7 cm(-1), and D(12) = 0.0302 cm(-1) were found for the manganese(II) complex. Density functional theory (DFT) calculations of the exchange integrals and the zero-field splitting on manganese(II) and iron(II) ions were performed

IGF-1 deficiency causes atrophic changes associated with upregulation of VGluT1 and downregulation of MEF2 transcription factors in the mouse cochlear nuclei.

PubMed

Fuentes-Santamaría, V; Alvarado, J C; Rodríguez-de la Rosa, L; Murillo-Cuesta, S; Contreras, J; Juiz, J M; Varela-Nieto, I

2016-03-01

Insulin-like growth factor 1 (IGF-1) is a neurotrophic protein that plays a crucial role in modulating neuronal function and synaptic plasticity in the adult brain. Mice lacking the Igf1 gene exhibit profound deafness and multiple anomalies in the inner ear and spiral ganglion. An issue that remains unknown is whether, in addition to these peripheral abnormalities, IGF-1 deficiency also results in structural changes along the central auditory pathway that may contribute to an imbalance between excitation and inhibition, which might be reflected in abnormal auditory brainstem responses (ABR). To assess such a possibility, we evaluated the morphological and physiological alterations in the cochlear nucleus complex of the adult mouse. The expression and distribution of the vesicular glutamate transporter 1 (VGluT1) and the vesicular inhibitory transporter (VGAT), which were used as specific markers for labeling excitatory and inhibitory terminals, and the involvement of the activity-dependent myocyte enhancer factor 2 (MEF2) transcription factors in regulating excitatory synapses were assessed in a 4-month-old mouse model of IGF-1 deficiency and neurosensorial deafness (Igf1 (-/-) homozygous null mice). The results demonstrate decreases in the cochlear nucleus area and cell size along with cell loss in the cochlear nuclei of the deficient mouse. Additionally, our results demonstrate that there is upregulation of VGluT1, but not VGAT, immunostaining and downregulation of MEF2 transcription factors together with increased wave II amplitude in the ABR recording. Our observations provide evidence of an abnormal neuronal cytoarchitecture in the cochlear nuclei of Igf1 (-/-) null mice and suggest that the increased efficacy of glutamatergic synapses might be mediated by MEF2 transcription factors.

Alpinate Oxyphyllae Fructus Inhibits IGFII-Related Signaling Pathway to Attenuate Ang II-Induced Pathological Hypertrophy in H9c2 Cardiomyoblasts.

PubMed

Tsai, Chuan-Te; Chang, Yung-Ming; Lin, Shu-Luan; Chen, Yueh-Sheng; Yeh, Yu-Lan; Padma, Viswanadha Vijaya; Tsai, Chin-Chuan; Chen, Ray-Jade; Ho, Tsung-Jung; Huang, Chih-Yang

2016-03-01

Angiotensin II (Ang II) is a very important cardiovascular disease inducer and may cause cardiac pathological hypertrophy and remodeling. We evaluated a Chinese traditional medicine, alpinate oxyphyllae fructus (AOF), for therapeutic efficacy for treating Ang II-induced cardiac hypertrophy. AOF has been used to treat patients with various symptoms accompanying hypertension and cerebrovascular disorders in Korea. We investigated its protective effect against Ang II-induced cytoskeletal change and hypertrophy in H9c2 cells. The results showed that treating cells with Ang II resulted in pathological hypertrophy, such as increased expression of transcription factors NFAT-3/p-NFAT-3, hypertrophic response genes (atrial natriuretic peptide [ANP] and b-type natriuretic peptide [BNP]), and Gαq down-stream effectors (PLCβ3 and calcineurin). Pretreatment with AOF (60-100 μg/mL) led to significantly reduced hypertrophy. We also found that AOF pretreatment significantly suppressed the cardiac remodeling proteins, metalloproteinase (MMP9 and MMP2), and tissue plasminogen activator (tPA), induced by Ang II challenge. In conclusion, we provide evidence that AOF protects against Ang II-induced pathological hypertrophy by specifically inhibiting the insulin-like growth factor (IGF) II/IIR-related signaling pathway in H9c2 cells. AOF might be a candidate for cardiac hypertrophy and ventricular remodeling prevention in chronic cardiovascular diseases.

Patient-related barriers to pain management: the Barriers Questionnaire II (BQ-II).

PubMed

Gunnarsdottir, Sigridur; Donovan, Heidi S; Serlin, Ronald C; Voge, Catherine; Ward, Sandra

2002-10-01

Patients' beliefs can act as barriers to optimal management of cancer pain. The Barriers Questionnaire (BQ) is a tool used to evaluate such barriers. Here, the BQ has been revised to reflect changes in pain management practices, resulting in the Barriers Questionnaire-II (BQ-II), a 27-item, self report instrument. This paper presents the results from two studies where the psychometric properties of the BQ-II were evaluated. In the first study, the responses of 27 nurses trained in pain management were compared to responses of a convenience sample of 12 patients with cancer. The results indicated that patients with cancer had higher mean scores on the BQ-II than did nurses trained in pain management. In the second study, a convenience sample of 172 patients with cancer responded to the BQ-II and a set of pain and quality of life (QOL) measures. A factor analysis supported four factors. Factor one, physiological effects, consists of 12 items addressing the beliefs that side effects of analgesics are inevitable and unmanageable, concerns about tolerance, and concerns about not being able to monitor changes in one's body when taking strong pain medications. Factor two, Fatalism, consists of three items addressing fatalistic beliefs about cancer pain and its management. Factor three, Communication, consists of six items addressing the concern that reports of pain distract the physician from treating the underlying disease, and the belief that 'good' patients do not complain of pain. The fourth and final factor, harmful effects, consists of six items addressing fear of becoming addicted to pain medication and the belief that pain medications harm the immune system. The BQ-II total had an internal consistency of 0.89, and alpha for the subscales ranged from 0.75 to 0.85. Mean (SD) scores on the total scale was 1.52 (0.73). BQ-II scores were related to measures of pain intensity and duration, mood, and QOL. Patients who used adequate analgesics for their levels of pain had

Binding Selectivity of Methanobactin from Methylosinus trichosporium OB3b for Copper(I), Silver(I), Zinc(II), Nickel(II), Cobalt(II), Manganese(II), Lead(II), and Iron(II).

PubMed

McCabe, Jacob W; Vangala, Rajpal; Angel, Laurence A

2017-12-01

Methanobactin (Mb) from Methylosinus trichosporium OB3b is a member of a class of metal binding peptides identified in methanotrophic bacteria. Mb will selectively bind and reduce Cu(II) to Cu(I), and is thought to mediate the acquisition of the copper cofactor for the enzyme methane monooxygenase. These copper chelating properties of Mb make it potentially useful as a chelating agent for treatment of diseases where copper plays a role including Wilson's disease, cancers, and neurodegenerative diseases. Utilizing traveling wave ion mobility-mass spectrometry (TWIMS), the competition for the Mb copper binding site from Ag(I), Pb(II), Co(II), Fe(II), Mn(II), Ni(II), and Zn(II) has been determined by a series of metal ion titrations, pH titrations, and metal ion displacement titrations. The TWIMS analyses allowed for the explicit identification and quantification of all the individual Mb species present during the titrations and measured their collision cross-sections and collision-induced dissociation patterns. The results showed Ag(I) and Ni(II) could irreversibly bind to Mb and not be effectively displaced by Cu(I), whereas Ag(I) could also partially displace Cu(I) from the Mb complex. At pH ≈ 6.5, the Mb binding selectivity follows the order Ag(I)≈Cu(I)>Ni(II)≈Zn(II)>Co(II)>Mn(II)≈Pb(II)>Fe(II), and at pH 7.5 to 10.4 the order is Ag(I)>Cu(I)>Ni(II)>Co(II)>Zn(II)>Mn(II)≈Pb(II)>Fe(II). Breakdown curves of the disulfide reduced Cu(I) and Ag(I) complexes showed a correlation existed between their relative stability and their compact folded structure indicated by their CCS. Fluorescence spectroscopy, which allowed the determination of the binding constant, compared well with the TWIMS analyses, with the exception of the Ni(II) complex. Graphical abstract ᅟ.

RNA Polymerase II Elongation Control

PubMed Central

Zhou, Qiang; Li, Tiandao; Price, David H.

2014-01-01

Regulation of the elongation phase of transcription by RNA Polymerase II (Pol II) is utilized extensively to generate the pattern of mRNAs needed to specify cell types and to respond to environmental changes. After Pol II initiates, negative elongation factors cause it to pause in a promoter proximal position. These polymerases are poised to respond to the positive transcription elongation factor, P-TEFb, and then enter productive elongation only under the appropriate set of signals to generate full length properly processed mRNAs. Recent global analyses of Pol II and elongation factors, mechanisms that regulate P-TEFb involving the 7SK snRNP, factors that control both the negative and positive elongation properties of Pol II and the mRNA processing events that are coupled with elongation are discussed. PMID:22404626

Binding Selectivity of Methanobactin from Methylosinus trichosporium OB3b for Copper(I), Silver(I), Zinc(II), Nickel(II), Cobalt(II), Manganese(II), Lead(II), and Iron(II)

NASA Astrophysics Data System (ADS)

McCabe, Jacob W.; Vangala, Rajpal; Angel, Laurence A.

2017-12-01

Methanobactin (Mb) from Methylosinus trichosporium OB3b is a member of a class of metal binding peptides identified in methanotrophic bacteria. Mb will selectively bind and reduce Cu(II) to Cu(I), and is thought to mediate the acquisition of the copper cofactor for the enzyme methane monooxygenase. These copper chelating properties of Mb make it potentially useful as a chelating agent for treatment of diseases where copper plays a role including Wilson's disease, cancers, and neurodegenerative diseases. Utilizing traveling wave ion mobility-mass spectrometry (TWIMS), the competition for the Mb copper binding site from Ag(I), Pb(II), Co(II), Fe(II), Mn(II), Ni(II), and Zn(II) has been determined by a series of metal ion titrations, pH titrations, and metal ion displacement titrations. The TWIMS analyses allowed for the explicit identification and quantification of all the individual Mb species present during the titrations and measured their collision cross-sections and collision-induced dissociation patterns. The results showed Ag(I) and Ni(II) could irreversibly bind to Mb and not be effectively displaced by Cu(I), whereas Ag(I) could also partially displace Cu(I) from the Mb complex. At pH ≈ 6.5, the Mb binding selectivity follows the order Ag(I)≈Cu(I)>Ni(II)≈Zn(II)>Co(II)>>Mn(II)≈Pb(II)>Fe(II), and at pH 7.5 to 10.4 the order is Ag(I)>Cu(I)>Ni(II)>Co(II)>Zn(II)>Mn(II)≈Pb(II)>Fe(II). Breakdown curves of the disulfide reduced Cu(I) and Ag(I) complexes showed a correlation existed between their relative stability and their compact folded structure indicated by their CCS. Fluorescence spectroscopy, which allowed the determination of the binding constant, compared well with the TWIMS analyses, with the exception of the Ni(II) complex. [Figure not available: see fulltext.

Temporal requirements of insulin/IGF-1 signaling for proteotoxicity protection.

PubMed

Cohen, Ehud; Du, Deguo; Joyce, Derek; Kapernick, Erik A; Volovik, Yuli; Kelly, Jeffery W; Dillin, Andrew

2010-04-01

Toxic protein aggregation (proteotoxicity) is a unifying feature in the development of late-onset human neurodegenerative disorders. Reduction of insulin/IGF-1 signaling (IIS), a prominent lifespan, developmental and reproductive regulatory pathway, protects worms from proteotoxicity associated with the aggregation of the Alzheimer's disease-linked Abeta peptide. We utilized transgenic nematodes that express human Abeta and found that late life IIS reduction efficiently protects from Abeta toxicity without affecting development, reproduction or lifespan. To alleviate proteotoxic stress in the animal, the IIS requires heat shock factor (HSF)-1 to modulate a protein disaggregase, while DAF-16 regulates a presumptive active aggregase, raising the question of how these opposing activities could be co-regulated. One possibility is that HSF-1 and DAF-16 have distinct temporal requirements for protection from proteotoxicity. Using a conditional RNAi approach, we found an early requirement for HSF-1 that is distinct from the adult functions of DAF-16 for protection from proteotoxicity. Our data also indicate that late life IIS reduction can protect from proteotoxicity when it can no longer promote longevity, strengthening the prospect that IIS reduction might be a promising strategy for the treatment of neurodegenerative disorders caused by proteotoxicity.

Insulin-like growth factor-I and growth differentiation factor-5 promote the formation of tissue-engineered human nasal septal cartilage.

PubMed

Alexander, Thomas H; Sage, August B; Chen, Albert C; Schumacher, Barbara L; Shelton, Elliot; Masuda, Koichi; Sah, Robert L; Watson, Deborah

2010-10-01

Tissue engineering of human nasal septal chondrocytes offers the potential to create large quantities of autologous material for use in reconstructive surgery of the head and neck. Culture with recombinant human growth factors may improve the biochemical and biomechanical properties of engineered tissue. The objectives of this study were to (1) perform a high-throughput screen to assess multiple combinations of growth factors and (2) perform more detailed testing of candidates identified in part I. In part I, human nasal septal chondrocytes from three donors were expanded in monolayer with pooled human serum (HS). Cells were then embedded in alginate beads for 2 weeks of culture in medium supplemented with 2% or 10% HS and 1 of 90 different growth factor combinations. Combinations of insulin-like growth factor-I (IGF-1), bone morphogenetic protein (BMP)-2, BMP-7, BMP-13, growth differentiation factor-5 (GDF-5), transforming growth factor β (TGFβ)-2, insulin, and dexamethasone were evaluated. Glycosaminoglycan (GAG) accumulation was measured. A combination of IGF-1 and GDF-5 was selected for further testing based on the results of part I. Chondrocytes from four donors underwent expansion followed by three-dimensional alginate culture for 2 weeks in medium supplemented with 2% or 10% HS with or without IGF-1 and GDF-5. Chondrocytes and their associated matrix were then recovered and cultured for 4 weeks in 12 mm transwells in medium supplemented with 2% or 10% HS with or without IGF-1 and GDF-5 (the same medium used for alginate culture). Biochemical and biomechanical properties of the neocartilage were measured. In part I, GAG accumulation was highest for growth factor combinations including both IGF-1 and GDF-5. In part II, the addition of IGF-1 and GDF-5 to 2% HS resulted in a 12-fold increase in construct thickness compared with 2% HS alone (p < 0.0001). GAG and type II collagen accumulation was significantly higher with IGF-1 and GDF-5. Confined compression

Longitudinal infusion of a complex of insulin-like growth factor-I and IGF-binding protein-3 in five preterm infants: pharmacokinetics and short-term safety.

PubMed

Ley, David; Hansen-Pupp, Ingrid; Niklasson, Aimon; Domellöf, Magnus; Friberg, Lena E; Borg, Jan; Löfqvist, Chatarina; Hellgren, Gunnel; Smith, Lois E H; Hård, Anna-Lena; Hellström, Ann

2013-01-01

In preterm infants, low levels of insulin-like growth factor-I (IGF-I) and IGF binding protein 3 (IGFBP-3) are associated with impaired brain growth and retinopathy of prematurity (ROP). Treatment with IGF-I/IGFBP-3 may be beneficial for brain development and may decrease the prevalence of ROP. In a phase II pharmacokinetics and safety study, five infants (three girls) with a median (range) gestational age (GA) of 26 wk + 6 d (26 wk + 0 d to 27 wk + 2 d) and birth weight of 990 (900-1,212) g received continuous intravenous infusion of recombinant human (rh)IGF-I/rhIGFBP-3. Treatment was initiated during the first postnatal day and continued for a median (range) duration of 168 (47-168) h in dosages between 21 and 111 µg/kg/24 h. Treatment with rhIGF-I/rhIGFBP-3 was associated with higher serum IGF-I and IGFBP-3 concentrations (P < 0.001) than model-predicted endogenous levels. Of 74 IGF-I samples measured during study drug infusion, 37 (50%) were within the target range, 4 (5%) were above, and 33 (45%) were below. The predicted dose of rhIGF-I/rhIGFBP-3 required to establish circulating levels of IGF-I within the intrauterine range in a 1,000 g infant was 75-100 µg/kg/24 h. No hypoglycemia or other adverse effects were recorded. In this study, continuous intravenous infusion of rhIGF-I/rhIGFBP-3 was effective in increasing serum concentrations of IGF-I and IGFBP-3, and was found to be safe.

On the Factor Structure of the Beck Depression Inventory-II: G Is the Key

ERIC Educational Resources Information Center

Brouwer, Danny; Meijer, Rob R.; Zevalkink, Jolien

2013-01-01

The Beck Depression Inventory-II (BDI-II; Beck, Steer, & Brown, 1996) is intended to measure severity of depression, and because items represent a broad range of depressive symptoms, some multidimensionality exists. In recent factor-analytic studies, there has been a debate about whether the BDI-II can be considered as one scale or whether…

Can insulin-like growth factor 1 (IGF-1), IGF-1 receptor connective tissue growth factor and Ki-67 labelling index have a prognostic role in pulmonary carcinoids?

PubMed

Kanakis, Georgios A; Grimelius, Lars; Papaioannou, Dimitrios; Kaltsas, Gregory; Tsolakis, Apostolos V

2018-04-27

Altered expression of Insulin-like Growth Factor-1 (IGF-1), its receptor (IGF-1R), Connective Tissue Growth Factor (CTGF) and Hypoxia Inducible Factor-1 (HIF-1), has been implicated in tumorigenesis. So far, these factors have not been studied systematically in Pulmonary Carcinoids (PCs). To examine IGF-1, IGF-1R, CTGF and HIF-1 expression in PCs, and assess their prognostic value over established factors. Retrospective study of 121 PCs (104 Typical and 17 Atypical). The expression of growth factors was studied immunohistochemically and tumors were considered positive if immunoreactivity appeared in >50% of cells. All studied parameters were expressed in the majority of tumors (IGF-1, IGF-1R, CTGF and HIF-1, in 78.5%, 67%, 72% and 78%, respectively). Their expression tended to be more frequent in TCs and in tumors with Ki-67≤2% (significant only for HIF-1; 82 vs. 53%; p=0.023 and 83 vs. 63%; p=0.025 respectively). CTGF was the only factor correlated with more extensive disease (larger size; presence of lymph node and distant metastases). According to logistic regression analysis, only advanced age, Ki-67≥3.4% and lymph node involvement could predict the development of distant metastases. IGF-1, IGF-1R, CTGF and HIF-1 are avidly expressed in PCs; however, their presence did not appear to be of statistically significant value over established prognostic factors.

The effects of EGF and IGF-1 on FSH-mediated in vitro maturation of domestic cat oocytes derived from follicular and luteal stages.

PubMed

Yıldırım, Koray; Vural, M Rıfat; Küplülü, Sükrü; Ozcan, Ziya; Polat, I Mert

2014-04-01

The objective of this study was to evaluate the influence of epidermal growth factor (EGF) and insulin like growth factor-I (IGF-1) on the in vitro maturation of cat oocytes recovered from follicular and luteal stage ovaries. Oocytes from follicular (n=580) and luteal (n=209) stages were harvested and divided into four groups, which were cultured in FSH-mediated maturation medium supplemented with: (1) EGF alone (25ng/mL); (2) IGF-1 alone (100ng/mL); (3) EGF+IGF-1 (25ng/mL EGF+100ng/mL IGF-I); or (4) no growth factor (control). The proportion of follicular stage oocytes reaching the metaphase II stage was significantly higher than that of oocytes obtained at the luteal stage in both control and study groups (p<0.001). The percentages of oocytes reaching the metaphase II stage during the follicular period were 62.6% in control; 70.9% in EGF; 72.8% in IGF-1, and 78.1% in EGF+IGF-1 groups, whereas the respective values for gametes collected from luteal stage ovaries were 12.5%, 17.5%, 12.5%, and 16.9%. Additionally, the differences between the study and control groups were significant in the case of follicular stage oocytes. Finally, supplementing the maturation medium with EGF and/or IGF-1 significantly enhanced the meiotic maturation of oocytes recovered from follicular stage ovaries. The present study also demonstrated that the combination of EGF and IGF-I provides an additional or synergic effect on meiotic maturation of oocytes recovered from the follicular stage. Copyright © 2014 Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish Academy of Sciences in Olsztyn. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Postpartum IGF-I and IGFBP-2 levels are prospectively associated with the development of type 2 diabetes in women with previous gestational diabetes mellitus.

PubMed

Lappas, M; Jinks, D; Shub, A; Willcox, J C; Georgiou, H M; Permezel, M

2016-12-01

Women with previous gestational diabetes mellitus (GDM) are at greater risk of developing type 2 diabetes. In the general population, the insulin-like growth factor (IGF) system has been implicated in the development of type 2 diabetes. The aim of this study was to determine if circulating IGF-I, IGF-II, IGFBP-1 and IGFBP-2 levels 12weeks following a GDM pregnancy are associated with an increased risk of developing type 2 diabetes. IGF-I, IGF-II, IGFBP-1 and IGFBP-2 levels were measured in 98 normal glucose tolerant women, 12weeks following an index GDM pregnancy using enzyme immunoassay. Women were assessed for up to 10years for the development of overt type 2 diabetes. Among the 98 women with previous GDM, 21 (21%) developed diabetes during the median follow-up period of 8.5years. After adjusting for age and BMI, IGF-I and IGFBP-2 were significantly associated with the development of type 2 diabetes. In a clinical model of prediction of type 2 diabetes that included age, BMI, pregnancy fasting glucose and postnatal fasting glucose, the addition of IGF-I and IGFBP-2 resulted in an improvement in the net reclassification index of 17.8%. High postpartum IGF-I and low postpartum IGFBP-2 levels are a significant risk factor for the development of type 2 diabetes in women with a previous history of GDM. This is the first report that identifies IGF-I and IGFBP-2 as a potential biomarker for the prediction of type 2 diabetes in women with a history of GDM. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Insulin-like growth factor-I receptor activity is essential for Kaposi's sarcoma growth and survival.

PubMed

Catrina, S-B; Lewitt, M; Massambu, C; Dricu, A; Grünler, J; Axelson, M; Biberfeld, P; Brismar, K

2005-04-25

Kaposi's sarcoma (KS) is a highly vascular tumour and is the most common neoplasm associated with human immunodeficiency virus (HIV-1) infection. Growth factors, in particular vascular endothelial growth factor (VEGF), have been shown to play an important role in its development. The role of insulin-like growth factors (IGFs) in the pathophysiology of different tumours led us to evaluate the role of IGF system in KS. The IGF-I receptors (IGF-IR) were identified by immunohistochemistry in biopsies taken from patients with different AIDS/HIV-related KS stages and on KSIMM cells (an established KS-derived cell line). Insulin-like growth factor-I is a growth factor for KSIMM cells with a maximum increase of 3H-thymidine incorporation of 130 +/- 27.6% (P < 0.05) similar to that induced by VEGF and with which it is additive (281 +/- 13%) (P < 0.05). Moreover, specific blockade of the receptor (either by alpha IR3 antibody or by picropodophyllin, a recently described selective IGF-IR tyrosine phosphorylation inhibitor) induced KSIMM apoptosis, suggesting that IGF-IR agonists (IGF-I and -II) mediate antiapoptotic signals for these cells. We were able to identify an autocrine loop essential for KSIMM cell survival in which IGF-II is the IGF-IR agonist secreted by the cells. In conclusion, IGF-I pathway inhibition is a promising therapeutical approach for KS tumours.

Longitudinal infusion of a complex of insulin-like growth factor-I and IGF-binding protein-3 in five preterm infants: pharmacokinetics and short-term safety

PubMed Central

Ley, David; Hansen-Pupp, Ingrid; Niklasson, Aimon; Domellöf, Magnus; Friberg, Lena E.; Borg, Jan; Löfqvist, Chatarina; Hellgren, Gunnel; Smith, Lois E.H.; Hård, Anna-Lena; Hellström, Ann

2014-01-01

BACKGROUND In preterm infants, low levels of insulin-like growth factor-I (IGF-I) and IGF binding protein 3 (IGFBP-3) are associated with impaired brain growth and retinopathy of prematurity (ROP). Treatment with IGF-I/IGFBP-3 may be beneficial for brain development and may decrease the prevalence of ROP. METHODS In a phase II pharmacokinetics and safety study, five infants (three girls) with a median (range) gestational age (GA) of 26 wk + 6 d (26 wk + 0 d to 27 wk + 2 d) and birth weight of 990 (900–1,212) g received continuous intravenous infusion of recombinant human (rh)IGF-I/rhIGFBP-3. Treatment was initiated during the first postnatal day and continued for a median (range) duration of 168 (47–168) h in dosages between 21 and 111 µg/kg/24 h. RESULTS Treatment with rhIGF-I/rhIGFBP-3 was associated with higher serum IGF-I and IGFBP-3 concentrations (P < 0.001) than model-predicted endogenous levels. Of 74 IGF-I samples measured during study drug infusion, 37 (50%) were within the target range, 4 (5%) were above, and 33 (45%) were below. The predicted dose of rhIGF-I/rhIGFBP-3 required to establish circulating levels of IGF-I within the intrauterine range in a 1,000 g infant was 75–100 µg/kg/24 h. No hypoglycemia or other adverse effects were recorded. CONCLUSION In this study, continuous intravenous infusion of rhIGF-I/rhIGFBP-3 was effective in increasing serum concentrations of IGF-I and IGFBP-3, and was found to be safe. PMID:23095978

Recombinant bovine growth hormone (rBGH) enhances somatic growth by regulating the GH-IGF axis in fingerlings of gilthead sea bream (Sparus aurata).

PubMed

Vélez, Emilio J; Perelló, Miquel; Azizi, Sheida; Moya, Alberto; Lutfi, Esmail; Pérez-Sánchez, Jaume; Calduch-Giner, Josep A; Navarro, Isabel; Blasco, Josefina; Fernández-Borràs, Jaume; Capilla, Encarnación; Gutiérrez, Joaquim

2018-02-01

The growth hormone (GH)/insulin-like growth factors (IGFs) endocrine axis is the main growth-regulator system in vertebrates. Some authors have demonstrated the positive effects on growth of a sustained-release formulation of a recombinant bovine GH (rBGH) in different fish species. The aim of this work was to characterize the effects of a single injection of rBGH in fingerlings of gilthead sea bream on growth, GH-IGF axis, and both myogenic and osteogenic processes. Thus, body weight and specific growth rate were significantly increased in rBGH-treated fish respect to control fish at 6weeks post-injection, whereas the hepatosomatic index was decreased and the condition factor and mesenteric fat index were unchanged, altogether indicating enhanced somatic growth. Moreover, rBGH injection increased the plasma IGF-I levels in parallel with a rise of hepatic mRNA from total IGF-I, IGF-Ic and IGF-II, the binding proteins IGFBP-1a and IGFBP-2b, and also the receptors IGF-IRb, GHR-I and GHR-II. In skeletal muscle, the expression of IGF-Ib and GHR-I was significantly increased but that of IGF-IRb was reduced; the mRNA levels of myogenic regulatory factors, proliferation and differentiation markers (PCNA and MHC, respectively), or that of different molecules of the signaling pathway (TOR/AKT) were unaltered. Besides, the growth inhibitor myostatin (MSTN1 and MSTN2) and the hypertrophic marker (MLC2B) expression resulted significantly enhanced, suggesting altogether that the muscle is in a non-proliferative stage of development. Contrarily in bone, although the expression of most molecules of the GH/IGF axis was decreased, the mRNA levels of several osteogenic genes were increased. The histology analysis showed a GH induced lipolytic effect with a clear decrease in the subcutaneous fat layer. Overall, these results reveal that a better growth potential can be achieved on this species and supports the possibility to improve growth and quality through the optimization of its

Production of insulin-like growth factor binding proteins by small-cell lung cancer cell lines

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

Jaques, G.; Kiefer, P.; Rotsch, M.

1989-10-01

Conditioned serum-free media (CM) from small-cell lung cancer (SCLC) cell lines were examined for the presence of insulin-like growth-factor-binding proteins (IGF-BP). 6/9 SCLC cell lines secreted binding proteins with high affinity for IGFs. When ({sup 125}I)IGF-1 or ({sup 125}I)IGF-II was incubated with the CMs, complexes of tracer with proteins could be demonstrated by gel filtration, by precipitation with polyethylenglycol, and after adsorption of unbound tracer with activated charcoal. Analysis of binding data according to the method of Scatchard resulted in linear plots for IGF-I and IGF-II. Cross-linking of ({sup 125}I)IGF-I or ({sup 125}I)IGF-II to the CMs followed by sodium dodecylmore » sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) under nonreducing conditions revealed the presence of IGF-BPs with molecular masses in the range of 24-32 kDa. Northern blot hybridization with an IGF-BP cDNA probe encoding a low-molecular-weight IGF-BP from a human placenta cDNA library and Western blot analysis with a corresponding polyclonal antibody showed no expression of this gene. These data demonstrate that SCLC cell lines release IGF-BPs in culture supernatants, which differ from IGF-BPs detected in liver and placenta. These IGF-BPs might be important mediators in the autocrine/paracrine growth regulation of IGFs in SCLC.« less

Untangling Longevity, Dauer, and Healthspan in Caenorhabditis elegans Insulin/IGF-1-Signalling.

PubMed

Ewald, Collin Yvès; Castillo-Quan, Jorge Iván; Blackwell, T Keith

2018-01-01

The groundbreaking discovery that lower levels of insulin/IGF-1 signaling (IIS) can induce lifespan extension was reported 24 years ago in the nematode Caenorhabditis elegans. In this organism, mutations in the insulin/IGF-1 receptor gene daf-2 or other genes in this pathway can double lifespan. Subsequent work has revealed that reduced IIS (rIIS) extends lifespan across diverse species, possibly including humans. In C. elegans, IIS also regulates development into the diapause state known as dauer, a quiescent larval form that enables C. elegans to endure harsh environments through morphological adaptation, improved cellular repair, and slowed metabolism. Considerable progress has been made uncovering mechanisms that are affected by C. elegans rIIS. However, from the beginning it has remained unclear to what extent rIIS extends C. elegans lifespan by mobilizing dauer-associated mechanisms in adults. As we discuss, recent work has shed light on this question by determining that rIIS can extend C. elegans lifespan comparably through downstream processes that are either dauer-related or -independent. Importantly, these two lifespan extension programs can be distinguished genetically. It will now be critical to tease apart these programs, because each may involve different longevity-promoting mechanisms that may be relevant to higher organisms. A recent analysis of organismal "healthspan" has questioned the value of C. elegans rIIS as a paradigm for understanding healthy aging, as opposed to simply extending life. We discuss other work that argues strongly that C. elegans rIIS is indeed an invaluable model and consider the likely possibility that dauer-related processes affect parameters associated with health under rIIS conditions. Together, these studies indicate that C. elegans and analyses of rIIS in this organism will continue to provide unexpected and exciting results, and new paradigms that will be valuable for understanding healthy aging in humans. © 2017 S

The mannose 6-phosphate-binding sites of M6P/IGF2R determine its capacity to suppress matrix invasion by squamous cell carcinoma cells

PubMed Central

Probst, Olivia C.; Karayel, Evren; Schida, Nicole; Nimmerfall, Elisabeth; Hehenberger, Elisabeth; Puxbaum, Verena; Mach, Lukas

2013-01-01

The M6P (mannose 6-phosphate)/IGF2R (insulin-like growth factor II receptor) interacts with a variety of factors that impinge on tumour invasion and metastasis. It has been shown that expression of wild-type M6P/IGF2R reduces the tumorigenic and invasive properties of receptor-deficient SCC-VII squamous cell carcinoma cells. We have now used mutant forms of M6P/IGF2R to assess the relevance of the different ligand-binding sites of the receptor for its biological activities in this cellular system. The results of the present study demonstrate that M6P/IGF2R does not require a functional binding site for insulin-like growth factor II for inhibition of anchorage-independent growth and matrix invasion by SCC-VII cells. In contrast, the simultaneous mutation of both M6P-binding sites is sufficient to impair all cellular functions of the receptor tested. These findings highlight that the interaction between M6P/IGF2R and M6P-modified ligands is not only important for intracellular accumulation of lysosomal enzymes and formation of dense lysosomes, but is also crucial for the ability of the receptor to suppress SCC-VII growth and invasion. The present study also shows that some of the biological activities of M6P/IGF2R in SCC-VII cells strongly depend on a functional M6P-binding site within domain 3, thus providing further evidence for the non-redundant cellular functions of the individual carbohydrate-binding domains of the receptor. PMID:23347038

Dauer-independent insulin/IGF-1-signalling implicates collagen remodelling in longevity.

PubMed

Ewald, Collin Y; Landis, Jess N; Porter Abate, Jess; Murphy, Coleen T; Blackwell, T Keith

2015-03-05

Interventions that delay ageing mobilize mechanisms that protect and repair cellular components, but it is unknown how these interventions might slow the functional decline of extracellular matrices, which are also damaged during ageing. Reduced insulin/IGF-1 signalling (rIIS) extends lifespan across the evolutionary spectrum, and in juvenile Caenorhabditis elegans also allows the transcription factor DAF-16/FOXO to induce development into dauer, a diapause that withstands harsh conditions. It has been suggested that rIIS delays C. elegans ageing through activation of dauer-related processes during adulthood, but some rIIS conditions confer robust lifespan extension unaccompanied by any dauer-like traits. Here we show that rIIS can promote C. elegans longevity through a program that is genetically distinct from the dauer pathway, and requires the Nrf (NF-E2-related factor) orthologue SKN-1 acting in parallel to DAF-16. SKN-1 is inhibited by IIS and has been broadly implicated in longevity, but is rendered dispensable for rIIS lifespan extension by even mild activity of dauer-related processes. When IIS is decreased under conditions that do not induce dauer traits, SKN-1 most prominently increases expression of collagens and other extracellular matrix genes. Diverse genetic, nutritional, and pharmacological pro-longevity interventions delay an age-related decline in collagen expression. These collagens mediate adulthood extracellular matrix remodelling, and are needed for ageing to be delayed by interventions that do not involve dauer traits. By genetically delineating a dauer-independent rIIS ageing pathway, our results show that IIS controls a broad set of protective mechanisms during C. elegans adulthood, and may facilitate elucidation of processes of general importance for longevity. The importance of collagen production in diverse anti-ageing interventions implies that extracellular matrix remodelling is a generally essential signature of longevity assurance

p53-mediated miR-18 repression activates HSF2 for IGF-IIR-dependent myocyte hypertrophy in hypertension-induced heart failure.

PubMed

Huang, Chih-Yang; Pai, Pei-Ying; Kuo, Chia-Hua; Ho, Tsung-Jung; Lin, Jing-Ying; Lin, Ding-Yu; Tsai, Fu-Jen; Padma, V Vijaya; Kuo, Wei-Wen; Huang, Chih-Yang

2017-08-10

Hypertension-induced cardiac hypertrophy and attenuated cardiac function are the major characteristics of early stage heart failure. Cardiomyocyte death in pathological cardiac conditions is the primary cause of heart failure and mortality. Our previous studies found that heat shock factor 1 (HSF1) protected cardiomyocytes from death by suppressing the IGF-IIR signaling pathway, which is critical for hypertensive angiotensin II-induced cardiomyocyte apoptosis. However, the role of heat shock factor 2 (HSF2) in hypertension-induced cardiac hypertrophy is unknown. We identified HSF2 as a miR-18 target for cardiac hypertrophy. p53 activation in angiotensin II (ANG II)-stimulated NRVMs is responsible for miR-18 downregulation both in vitro and in vivo, which triggers HSF2 expression and the activation of IGF-IIR-induced cardiomyocyte hypertrophy. Finally, we provide genetic evidence that miR-18 is required for cardiomyocyte functions in the heart based on the gene transfer of cardiac-specific miR-18 via adenovirus-associated virus 2 (AAV2). Transgenic overexpression of miR-18 in cardiomyocytes is sufficient to protect against dilated cardiomyopathy during hypertension-induced heart failure. Our results demonstrated that the p53-miR-18-HSF2-IGF-IIR axis was a critical regulatory pathway of cardiomyocyte hypertrophy in vitro and in vivo, suggesting that miR-18 could be a therapeutic target for the control of cardiac functions and the alleviation of cardiomyopathy during hypertension-induced heart failure.

CCAAT/enhancer binding protein Beta-2 is involved in growth hormone-regulated insulin-like growth factor-II gene expression in the liver of rainbow trout (Oncorhynchus mykiss)

USDA-ARS?s Scientific Manuscript database

Previously, we showed that levels of different CCAAT/enhancer binding protein (C/EBP) mRNAs in the liver of rainbow trout were modulated by GH and suggested that C/EBPs might be involved in GH induced IGF-II gene expression. As a step toward further investigation, we have developed monospecific poly...

An investigation of the factor structure of the beck depression inventory-II in anorexia nervosa.

PubMed

Fuss, Samantha; Trottier, Kathryn; Carter, Jacqueline

2015-01-01

Symptoms of depression frequently co-occur with eating disorders and have been associated with negative outcomes. Self-report measures such as the Beck Depression Inventory-II (BDI-II) are commonly used to assess for the presence of depressive symptoms in eating disorders, but the instrument's factor structure in this population has not been examined. The purposes of this study were to explore the factor structure of the BDI-II in a sample of individuals (N = 437) with anorexia nervosa undergoing inpatient treatment and to examine changes in depressive symptoms on each of the identified factors following a course of treatment for anorexia nervosa in order to provide evidence supporting the construct validity of the measure. Exploratory factor analysis revealed that a three-factor model reflected the best fit for the data. Confirmatory factor analysis was used to validate this model against competing models and the three-factor model exhibited strong model fit characteristics. BDI-II scores were significantly reduced on all three factors following inpatient treatment, which supported the construct validity of the scale. The BDI-II appears to be reliable in this population, and the factor structure identified through this analysis may offer predictive utility for identifying individuals who may have more difficulty achieving weight restoration in the context of inpatient treatment. Copyright © 2014 John Wiley & Sons, Ltd and Eating Disorders Association. Copyright © 2014 John Wiley & Sons, Ltd and Eating Disorders Association.

TAF(II)250: a transcription toolbox.

PubMed

Wassarman, D A; Sauer, F

2001-08-01

Activation of RNA-polymerase-II-dependent transcription involves conversion of signals provided by gene-specific activator proteins into the synthesis of messenger RNA. This conversion requires dynamic structural changes in chromatin and assembly of general transcription factors (GTFs) and RNA polymerase II at core promoter sequence elements surrounding the transcription start site of genes. One hallmark of transcriptional activation is the interaction of DNA-bound activators with coactivators such as the TATA-box binding protein (TBP)-associated factors (TAF(II)s) within the GTF TFIID. TAF(II)250 possesses a variety of activities that are likely to contribute to the initial steps of RNA polymerase II transcription. TAF(II)250 is a scaffold for assembly of other TAF(II)s and TBP into TFIID, TAF(II)250 binds activators to recruit TFIID to particular promoters, TAF(II)250 regulates binding of TBP to DNA, TAF(II)250 binds core promoter initiator elements, TAF(II)250 binds acetylated lysine residues in core histones, and TAF(II)250 possesses protein kinase, ubiquitin-activating/conjugating and acetylase activities that modify histones and GTFs. We speculate that these activities achieve two goals--(1) they aid in positioning and stabilizing TFIID at particular promoters, and (2) they alter chromatin structure at the promoter to allow assembly of GTFs--and we propose a model for how TAF(II)250 converts activation signals into active transcription.

Manganese(II), iron(II), cobalt(II), and copper(II) complexes of an extended inherently chiral tris-bipyridyl cage.

PubMed

Perkins, David F; Lindoy, Leonard F; McAuley, Alexander; Meehan, George V; Turner, Peter

2006-01-17

Manganese(II), iron(II), cobalt(II), and copper(II) derivatives of two inherently chiral, Tris(bipyridyl) cages (L and L') of type [ML]-(PF(6))(2)(solvent)(n) and [FeL'](ClO(4))(2) are reported, where L is the hexa-tertiary butyl-substituted derivative of L'. These products were obtained by using the free cage and metal template procedures; the latter involved the reductive amination of the respective Tris-dialdehyde precursor complexes of iron(II), cobalt(II), or nickel(II). Electrochemical, EPR, and NMR studies have been used to probe the nature of the individual complexes. X-ray structures of the manganese(II), iron(II), and copper(II) complexes of L and the iron(II) complex of L' are presented; these are compared with the previously reported structures of the corresponding nickel(II) complex and metal-free cage (L). In each complex the metal cation occupies the cage's central cavity and is coordinated to six nitrogens from the three bipyridyl groups. The cations [MnL](2+) and [FeL](2+) are isostructural but both exhibit a different arrangement of the bound cage to that observed in the corresponding nickel(II) and copper(II) complexes. The latter have an exo-exo arrangement of the bridgehead nitrogen lone pairs, with the metal inducing a triple helical twist that extends approximately 22 A along the axial length of each complex. In contrast, [MnL](2+) and [FeL](2+) have their terminal nitrogen lone pairs directed endo, causing a significant change in the configuration of the bound ligand. In [FeL'](2+), the cage has both bridgehead nitrogen lone pairs orientated exo. Semiempirical calculations indicate that the observed endo-endo and exo-exo arrangements are of comparable energy.

Essential roles of angiotensin II in vascular endothelial growth factor expression in sleep apnea syndrome.

PubMed

Takahashi, Susumu; Nakamura, Yutaka; Nishijima, Tsuguo; Sakurai, Shigeru; Inoue, Hiroshi

2005-09-01

Hypoxia-induced endothelial cell dysfunction has been implicated in increased cardiovascular disease associated with obstructive sleep apnea syndrome (OSAS). OSAS mediates hypertension by stimulating angiotensin II (Ang II) production. Hypoxia and Ang II are the major stimuli of vascular endothelial growth factor (VEGF), which is a potent angiogenic cytokine and also contributes to the atherogenic process itself. We observed serum Ang II and VEGF levels and peripheral blood mononuclear cell (PBMC) and neutrophil VEGF expression. Compared to controls, subjects with OSAS had significantly increased levels of serum Ang II and VEGF and VEGF mRNA expression in their leukocytes. To examine whether Ang II stimulates VEGF expression in OSAS, we treated PBMCs obtained from control subjects with Ang II and with an Ang II receptor type 1 (AT(1)) blocker, olmesartan. We observed an increased expression of VEGF in the Ang II-stimulated PBMCs and decreased in VEGF mRNA and protein expression in the PBMCs treated with olmesartan. These findings suggest that the Ang II-AT(1) receptors pathway potentially are involved in OSAS and VEGF-induced vascularity and that endothelial dysfunction might be linked to this change in Ang II activity within leukocytes of OSAS patients.

Competitive adsorption of copper(II), cadmium(II), lead(II) and zinc(II) onto basic oxygen furnace slag.

PubMed

Xue, Yongjie; Hou, Haobo; Zhu, Shujing

2009-02-15

Polluted and contaminated water can often contain more than one heavy metal species. It is possible that the behavior of a particular metal species in a solution system will be affected by the presence of other metals. In this study, we have investigated the adsorption of Cd(II), Cu(II), Pb(II), and Zn(II) onto basic oxygen furnace slag (BOF slag) in single- and multi-element solution systems as a function of pH and concentration, in a background solution of 0.01M NaNO(3). In adsorption edge experiments, the pH was varied from 2.0 to 13.0 with total metal concentration 0.84mM in the single element system and 0.21mM each of Cd(II), Cu(II), Pb(II), and Zn(II) in the multi-element system. The value of pH(50) (the pH at which 50% adsorption occurs) was found to follow the sequence Zn>Cu>Pb>Cd in single-element systems, but Pb>Cu>Zn>Cd in the multi-element system. Adsorption isotherms at pH 6.0 in the multi-element systems showed that there is competition among various metals for adsorption sites on BOF slag. The adsorption and potentiometric titrations data for various slag-metal systems were modeled using an extended constant-capacitance surface complexation model that assumed an ion-exchange process below pH 6.5 and the formation of inner-sphere surface complexes at higher pH. Inner-sphere complexation was more dominant for the Cu(II), Pb(II) and Zn(II) systems.

Green tea component EGCG, insulin and IGF-1 promote nuclear efflux of atrophy-associated transcription factor Foxo1 in skeletal muscle fibers.

PubMed

Wimmer, Robert J; Russell, Sarah J; Schneider, Martin F

2015-12-01

Prevention and slowing of skeletal muscle atrophy with nutritional approaches offers the potential to provide far-reaching improvements in the quality of life for our increasingly aging population. Here we show that polyphenol flavonoid epigallocatechin 3-gallate (EGCG), found in the popular beverage green tea (Camellia sinensis), demonstrates similar effects to the endogenous hormones insulin-like growth factor 1 (IGF-1) and insulin in the ability to suppress action of the atrophy-promoting transcription factor Foxo1 through a net translocation of Foxo1 out of the nucleus as monitored by nucleo-cytoplasmic movement of Foxo1-green fluorescent protein (GFP) in live skeletal muscle fibers. Foxo1-GFP nuclear efflux is rapid in IGF-1 or insulin, but delayed by an additional 30 min for EGCG. Once activated, kinetic analysis with a simple mathematical model shows EGCG, IGF-1 and insulin all produce similar apparent rate constants for Foxo1-GFP unidirectional nuclear influx and efflux. Interestingly, EGCG appears to have its effect at least partially via parallel signaling pathways that are independent of IGF-1's (and insulin's) downstream PI3K/Akt/Foxo1 signaling axis. Using the live fiber model system, we also determine the dose-response curve for both IGF-1 and insulin on Foxo1 nucleo-cytoplasmic distribution. The continued understanding of the activation mechanisms of EGCG could allow for nutritional promotion of green tea's antiatrophy skeletal muscle benefits and have implications in the development of a clinically significant parallel pathway for new drugs to target muscle wasting and the reduced insulin receptor sensitivity which causes type II diabetes mellitus. Copyright © 2015 Elsevier Inc. All rights reserved.

Evidences for involvement of growth hormone and insulin-like growth factor in ovarian development of starry flounder (Platichthys stellatus).

PubMed

Xu, Yongjiang; Wang, Bin; Liu, Xuezhou; Shi, Bao; Zang, Kun

2017-04-01

Although gonadotrophins are major regulators of ovarian function in teleosts and other vertebrates, accumulating evidence indicates that the growth hormone (GH)-insulin-like growth factor (IGF) axis also plays an important role in fish reproduction. As a first step to understand the physiological role of the GH-IGF system in the ovarian development of starry flounder (Platichthys stellatus), the expression profiles of GH and IGF messenger RNAs (mRNAs) and plasma GH, IGF-I, estradiol-17β (E2), and testosterone (T) levels during the ovarian development were investigated. The developmental stages of ovaries were divided into five stages (II, III, IV, V, and VI) by histological analysis. The hepatosomatic index (HSI) and gonadosomatic index (GSI) values increased and peaked at stage IV and stage V, respectively, and then declined at stage VI. Pituitary GH mRNA levels decreased sharply at stage III and raised to top level at stage VI. The hepatic IGF-I mRNA levels ascended to maximum value at stage V and then declined significantly at stage VI. However, the hepatic IGF-II mRNA levels remained stable and increased significantly at stage VI. In contrast, the ovarian IGF-I mRNA levels increased gradually and peaked at stage VI. The ovarian IGF-II mRNA levels were initially stable and increased significantly at stage V until the top level at stage VI. Consistent with the pituitary GH mRNA levels, plasma GH levels reduced sharply at stage III and remained depressed until stage V and then raised remarkably at stage VI. Plasma IGF-I level peaked at stage V and then declined to initial level. Plasma E2 level peaked at stage IV and then dramatically descended to the basal level. Plasma T level peaked at stage V and then declined significantly back to the basal level. Based on statistical analysis, significant positive correlations between hepatic IGF-I mRNA and GSI, ovarian IGF-II mRNA and hepatic IGF-II mRNA, ovarian IGF-I mRNA and ovarian IGF-II mRNA, and plasma IGF-I and

Ionization correction factors for H II regions in blue compact dwarf galaxies

NASA Astrophysics Data System (ADS)

Holovatyi, V. V.; Melekh, B. Ya.

2002-08-01

Energy distributions in the spectra of the ionizing nuclei of H II regions beyond λ <= 91.2 nm were calculated. A grid of photoionization models of 270 H II regions was constructed. The free parameters of the model grid are the hydrogen density nH in the nebular gas, filling factor, energy Lc-spectrum of ionizing nuclei, and metallicity. The chemical composition from the studies of Izotov et al. were used for model grid initialization. The integral linear spectra calculated for the photoionization models were used to determine the concentration ne, temperatures Te of electrons, and ionic concentrations n(A+i)/n(H+) by the nebular gas diagnostic method. The averaged relative ionic abundances n(A+i)/n(H+) thus calculated were used to determine new expressions for ionization correction factors which we recommend for the determination of abundances in the H II regions of blue compact dwarf galaxies.

The TFIID components human TAF(II)140 and Drosophila BIP2 (TAF(II)155) are novel metazoan homologues of yeast TAF(II)47 containing a histone fold and a PHD finger.

PubMed

Gangloff, Y G; Pointud, J C; Thuault, S; Carré, L; Romier, C; Muratoglu, S; Brand, M; Tora, L; Couderc, J L; Davidson, I

2001-08-01

The RNA polymerase II transcription factor TFIID comprises the TATA binding protein (TBP) and a set of TBP-associated factors (TAF(II)s). TFIID has been extensively characterized for yeast, Drosophila, and humans, demonstrating a high degree of conservation of both the amino acid sequences of the constituent TAF(II)s and overall molecular organization. In recent years, it has been assumed that all the metazoan TAF(II)s have been identified, yet no metazoan homologues of yeast TAF(II)47 (yTAF(II)47) and yTAF(II)65 are known. Both of these yTAF(II)s contain a histone fold domain (HFD) which selectively heterodimerizes with that of yTAF(II)25. We have cloned a novel mouse protein, TAF(II)140, containing an HFD and a plant homeodomain (PHD) finger, which we demonstrated by immunoprecipitation to be a mammalian TFIID component. TAF(II)140 shows extensive sequence similarity to Drosophila BIP2 (dBIP2) (dTAF(II)155), which we also show to be a component of Drosophila TFIID. These proteins are metazoan homologues of yTAF(II)47 as their HFDs selectively heterodimerize with dTAF(II)24 and human TAF(II)30, metazoan homologues of yTAF(II)25. We further show that yTAF(II)65 shares two domains with the Drosophila Prodos protein, a recently described potential dTAF(II). These conserved domains are critical for yTAF(II)65 function in vivo. Our results therefore identify metazoan homologues of yTAF(II)47 and yTAF(II)65.

The Factor Structure of the CIBS-II-Readiness Assessment

ERIC Educational Resources Information Center

Gotch, Chad M.; French, Brian F.

2011-01-01

The Brigance Comprehensive Inventory of Basic Skills-II (CIBS-II)-Readiness form is a diagnostic battery intended for children aged 5 and 6 years. The CIBS-II-Readiness is a new version of the CIBS-Revised-Readiness and includes updated normative information on a larger representative sample in comparison to the CIBS-Revised-Readiness. Empirical…

Genetic and Dietary Determinants of Insulin-Like Growth Factor (IGF)-1 and IGF Binding Protein (BP)-3 Levels among Chinese Women

PubMed Central

Li, Hui; McCullough, Lauren E.; Qi, Ya-na; Li, Jia-yuan; Zhang, Jing; Miller, Erline; Yang, Chun-xia; Smith, Jennifer S.

2014-01-01

Background Higher insulin-like growth factor (IGF)-1 and lower IGF binding protein (BP)-3 levels have been associated with higher commoncancer risk, including breast cancer. Dietary factors, genetic polymorphisms, and the combination of both may influence circulating IGF-1 and IGFBP-3 serum concentrations. Methods From September 2011 to July 2012, we collected demographic, reproductive and dietary data on 143 women (≥40 years). We genotyped IGF-1 rs1520220 and IGFBP-3 rs2854744 and measured circulating IGF-1 and IGFBP-3 levels in serum. Covariance analyses were used to estimate the associations of serum levels of IGF-1 and IGFBP-3, and the molar ratio of IGF-1to IGFBP-3 with IGF-1 rs1520220 and IGFBP-3 rs2854744 genotypes. We subsequently assessed the combined influence of genetics and diet (daily intake of protein, fat and soy isoflavones) on IGF-1 and IGFBP-3 levels. Results Among women aged less than 50 years, circulating IGF-1 serum levels were significantly lower for those with CC genotype for IGF-1 rs1520220 than levels for those with the GC or GG genotypes (in recessive model: P = 0.007).In gene-diet analyses among these women, we found carrying CC genotype for IGF-1 rs1520220 and high soy isoflavone intake tend to be associated with lower circulating IGF-1 levels synthetically (P = 0.002). Women with GG or GC genotypes for IGF-1 rs1520220 and with low intake of soy isoflavones had the highest levels of circulating IGF-1 (geometric mean [95% CI]: 195 [37, 1021] µg/L). Comparatively, women with both the CC genotype and high soy intake had the lowest levels of circulating IGF-1 (geometric mean [95% CI]: 120 [38,378] µg/L). Conclusions IGF-1 serum levels are significantly lower among women with the CC genotype for IGF-1-rs1520220. High soy isoflavone intake may interact with carrying CC genotype for IGF-1-rs1520220 to lower women's serum IGF-1 levels more. PMID:25285521

Effects of an acute bout of resistance exercise on fiber-type specific to GLUT4 and IGF-1R expression.

PubMed

Gallagher, Philip M; Touchberry, Chad D; Teson, Kelli; McCabe, Everlee; Tehel, Michelle; Wacker, Michael J

2013-05-01

The effects of resistance exercise on fiber-type-specific expression of insulin-like growth factor I receptor (IGF-1R) and glucose transporter 4 (GLUT4) was determined in 6 healthy males. The expression of both genes increased in Type I fibers (p < 0.05), but only GLUT4 increased (p < 0.05) in Type II fibers. These data demonstrates that an acute bout of resistance exercise can up-regulate mechanisms of glucose uptake in slow and fast-twitch fibers, but the IGF signaling axis may not be as effective in fast-twitch fibers.

Angiotensin II induces tumor necrosis factor biosynthesis in the adult mammalian heart through a protein kinase C-dependent pathway.

PubMed

Kalra, Dinesh; Sivasubramanian, Natarajan; Mann, Douglas L

2002-05-07

Previous studies suggest that angiotensin II (Ang II) upregulates the expression of tumor necrosis factor (TNF) in nonmyocyte cell types; however, the effect of Ang II on TNF expression in the adult mammalian heart is not known. To determine whether Ang II was sufficient to provoke TNF biosynthesis in the adult heart, we examined the effects of Ang II in isolated buffer-perfused Langendorff feline hearts. Ang II (10(-7) mol/L) treatment resulted in a time- and dose-dependent increase in myocardial TNF mRNA and protein biosynthesis in the heart as well as in cultured adult cardiac myocytes. The effects of Ang II on myocardial TNF mRNA and protein synthesis were mediated through the angiotensin type 1 receptor (AT1R), insofar as an AT1R antagonist (AT1a) blocked the effects of Ang II, whereas an angiotensin type 2 receptor (AT2R) antagonist (AT2a) had no effect. Stimulation with Ang II led to the activation of nuclear factor-kappaB and activator protein-1 (AP-1), two transcription factors that are important for TNF gene expression. Nuclear factor-kappaB activation was accompanied by phosphorylation of IkappaBalpha on serine 32 as well as degradation of IkappaBalpha, suggesting that the effects of Ang II were mediated through an IkappaBalpha-dependent pathway. The important role of protein kinase C (PKC) was suggested by studies in which a phorbol ester triggered TNF biosynthesis, and a PKC inhibitor abrogated Ang II-induced TNF biosynthesis. These studies suggest that Ang II provokes TNF biosynthesis in the adult mammalian heart through a PKC-dependent pathway.

A magnetostructural study of linear NiII MnIII NiII, NiII CrIII NiII and triangular Ni(II)3 species containing (pyridine-2-aldoximato)nickel(II) unit as a building block.

PubMed

Weyhermüller, Thomas; Wagner, Rita; Khanra, Sumit; Chaudhuri, Phalguni

2005-08-07

Three trinuclear complexes, NiII MnIII NiII, NiII CrIII NiII and Ni(II)3 based on (pyridine-2-aldoximato)nickel(II) units are described. Two of them, and , contain metal-centers in linear arrangement, as is revealed by X-ray diffraction. Complex is a homonuclear complex in which the three nickel(II) centers are disposed in a triangular fashion. The compounds were characterized by various physical methods including cyclic voltammetric and variable-temperature (2-290 K) susceptibility measurements. Complexes and display antiferromagnetic exchange coupling of the neighbouring metal centers, while weak ferromagnetic spin exchange between the adjacent Ni II and Cr III ions in is observed. The experimental magnetic data were simulated by using appropriate models.

Average [O II] nebular emission associated with Mg II absorbers: dependence on Fe II absorption

NASA Astrophysics Data System (ADS)

Joshi, Ravi; Srianand, Raghunathan; Petitjean, Patrick; Noterdaeme, Pasquier

2018-05-01

We investigate the effect of Fe II equivalent width (W2600) and fibre size on the average luminosity of [O II] λλ3727, 3729 nebular emission associated with Mg II absorbers (at 0.55 ≤ z ≤ 1.3) in the composite spectra of quasars obtained with 3 and 2 arcsec fibres in the Sloan Digital Sky Survey. We confirm the presence of strong correlations between [O II] luminosity (L_{[O II]}) and equivalent width (W2796) and redshift of Mg II absorbers. However, we show L_{[O II]} and average luminosity surface density suffer from fibre size effects. More importantly, for a given fibre size, the average L_{[O II]} strongly depends on the equivalent width of Fe II absorption lines and found to be higher for Mg II absorbers with R ≡W2600/W2796 ≥ 0.5. In fact, we show the observed strong correlations of L_{[O II]} with W2796 and z of Mg II absorbers are mainly driven by such systems. Direct [O II] detections also confirm the link between L_{[O II]} and R. Therefore, one has to pay attention to the fibre losses and dependence of redshift evolution of Mg II absorbers on W2600 before using them as a luminosity unbiased probe of global star formation rate density. We show that the [O II] nebular emission detected in the stacked spectrum is not dominated by few direct detections (i.e. detections ≥3σ significant level). On an average, the systems with R ≥ 0.5 and W2796 ≥ 2 Å are more reddened, showing colour excess E(B - V) ˜ 0.02, with respect to the systems with R < 0.5 and most likely trace the high H I column density systems.

Insulin-like Growth Factor (IGF) Signaling Requires αvβ3-IGF1-IGF Type 1 Receptor (IGF1R) Ternary Complex Formation in Anchorage Independence, and the Complex Formation Does Not Require IGF1R and Src Activation

PubMed Central

Fujita, Masaaki; Takada, Yoko K.; Takada, Yoshikazu

2013-01-01

Integrin αvβ3 plays a role in insulin-like growth factor 1 (IGF1) signaling (integrin-IGF1 receptor (IGF1R) cross-talk) in non-transformed cells in anchorage-dependent conditions. We reported previously that IGF1 directly binds to αvβ3 and induces αvβ3-IGF1-IGF1R ternary complex formation in these conditions. The integrin-binding defective IGF1 mutant (R36E/R37E) is defective in inducing ternary complex formation and IGF signaling, whereas it still binds to IGF1R. We studied if IGF1 can induce signaling in anchorage-independent conditions in transformed Chinese hamster ovary cells that express αvβ3 (β3-CHO) cells. Here we describe that IGF1 signals were more clearly detectable in anchorage-independent conditions (polyHEMA-coated plates) than in anchorage-dependent conditions. This suggests that IGF signaling is masked by signals from cell-matrix interaction in anchorage-dependent conditions. IGF signaling required αvβ3 expression, and R36E/R37E was defective in inducing signals in polyHEMA-coated plates. These results suggest that αvβ3-IGF1 interaction, not αvβ3-extracellular matrix interaction, is essential for IGF signaling. Inhibitors of IGF1R, Src, AKT, and ERK1/2 did not suppress αvβ3-IGF-IGF1R ternary complex formation, suggesting that activation of these kinases are not required for ternary complex formation. Also, mutations of the β3 cytoplasmic tail (Y747F and Y759F) that block β3 tyrosine phosphorylation did not affect IGF1R phosphorylation or AKT activation. We propose a model in which IGF1 binding to IGF1R induces recruitment of integrin αvβ3 to the IGF-IGF1R complex and then β3 and IGF1R are phosphorylated. It is likely that αvβ3 should be together with the IGF1-IGF1R complex for triggering IGF signaling. PMID:23243309

Dynamics of liver GH/IGF axis and selected stress markers in juvenile gilthead sea bream (Sparus aurata) exposed to acute confinement: differential stress response of growth hormone receptors.

PubMed

Saera-Vila, Alfonso; Calduch-Giner, Josep Alvar; Prunet, Patrick; Pérez-Sánchez, Jaume

2009-10-01

The time courses of liver GH/IGF axis and selected stress markers were analyzed in juvenile gilthead sea bream (Sparus aurata) sampled at zero time and at fixed intervals (1.5, 3, 6, 24, 72 and 120 h) after acute confinement (120 kg/m(3)). Fish remained unfed throughout the course of the confinement study, and the fasting-induced increases in plasma growth hormone (GH) levels were partially masked by the GH-stress inhibitory tone. Hepatic mRNA levels of growth hormone receptor-I (GHR-I) were not significantly altered by confinement, but a persistent 2-fold decrease in GHR-II transcripts was found at 24 and 120 h. A consistent decrease in circulating levels of insulin-like growth factor-I (IGF-I) was also found through most of the experimental period, and the down-regulated expression of GHR-II was positively correlated with changes in hepatic IGF-I and IGF-II transcripts. This stress-specific response was concurrent with plasma increases in cortisol and glucose levels, reflecting the cortisol peak (60-70 ng/mL), the intensity and duration of the stressor when data found in the literature were compared. Adaptive responses against oxidative damage were also found, and a rapid enhanced expression was reported in the liver tissue for mitochondrial heat-shock proteins (glucose regulated protein 75). At the same time, the down-regulated expression of proinflammatory cytokines (tumour necrosis factor-alpha) and detoxifying enzymes (cytochrome P450 1A1) might dictate the hepatic depletion of potential sources of reactive oxygen species. These results provide suitable evidence for a functional partitioning of hepatic GHRs under states of reduced IGF production and changing cellular environment resulting from acute confinement.

Macrocyclic receptor showing extremely high Sr(II)/Ca(II) and Pb(II)/Ca(II) selectivities with potential application in chelation treatment of metal intoxication.

PubMed

Ferreirós-Martínez, Raquel; Esteban-Gómez, David; Tóth, Éva; de Blas, Andrés; Platas-Iglesias, Carlos; Rodríguez-Blas, Teresa

2011-04-18

Herein we report a detailed investigation of the complexation properties of the macrocyclic decadentate receptor N,N'-Bis[(6-carboxy-2-pyridil)methyl]-4,13-diaza-18-crown-6 (H(2)bp18c6) toward different divalent metal ions [Zn(II), Cd(II), Pb(II), Sr(II), and Ca(II)] in aqueous solution. We have found that this ligand is especially suited for the complexation of large metal ions such as Sr(II) and Pb(II), which results in very high Pb(II)/Ca(II) and Pb(II)/Zn(II) selectivities (in fact, higher than those found for ligands widely used for the treatment of lead poisoning such as ethylenediaminetetraacetic acid (edta)), as well as in the highest Sr(II)/Ca(II) selectivity reported so far. These results have been rationalized on the basis of the structure of the complexes. X-ray crystal diffraction, (1)H and (13)C NMR spectroscopy, as well as theoretical calculations at the density functional theory (B3LYP) level have been performed. Our results indicate that for large metal ions such as Pb(II) and Sr(II) the most stable conformation is Δ(δλδ)(δλδ), while for Ca(II) our calculations predict the Δ(λδλ)(λδλ) form being the most stable one. The selectivity that bp18c6(2-) shows for Sr(II) over Ca(II) can be attributed to a better fit between the large Sr(II) ions and the relatively large crown fragment of the ligand. The X-ray crystal structure of the Pb(II) complex shows that the Δ(δλδ)(δλδ) conformation observed in solution is also maintained in the solid state. The Pb(II) ion is endocyclically coordinated, being directly bound to the 10 donor atoms of the ligand. The bond distances to the donor atoms of the pendant arms (2.55-2.60 Å) are substantially shorter than those between the metal ion and the donor atoms of the crown moiety (2.92-3.04 Å). This is a typical situation observed for the so-called hemidirected compounds, in which the Pb(II) lone pair is stereochemically active. The X-ray structures of the Zn(II) and Cd(II) complexes show that

Vascular Induction of a Disintegrin and Metalloprotease 17 by Angiotensin II Through Hypoxia Inducible Factor 1α

PubMed Central

Obama, Takashi; Takayanagi, Takehiko; Kobayashi, Tomonori; Bourne, Allison M.; Elliott, Katherine J.; Charbonneau, Martine; Dubois, Claire M.

2015-01-01

BACKGROUND A disintegrin and metalloprotease 17 (ADAM17) is a membrane-spanning metalloprotease overexpressed in various cardiovascular diseases such as hypertension and atherosclerosis. However, little is known regarding the regulation of ADAM17 expression in the cardiovascular system. Here, we test our hypothesis that angiotensin II induces ADAM17 expression in the vasculature. METHODS Cultured vascular smooth muscle cells were stimulated with 100nM angiotensin II. Mice were infused with 1 μg/kg/minute angiotensin II for 2 weeks. ADAM17 expression was evaluated by a promoter–reporter construct, quantitative polymerase chain reaction, immunoblotting, and immunohistochemistry. RESULTS In vascular smooth muscle cells, angiotensin II increased ADAM17 protein expression, mRNA, and promoter activity. We determined that the angiotensin II response involves hypoxia inducible factor 1α and a hypoxia responsive element. In angiotensin II–infused mice, marked induction of ADAM17 and hypoxia inducible factor 1α was seen in vasculatures in heart and kidney, as well as in aortae, by immunohistochemistry. CONCLUSIONS Angiotensin II induces ADAM17 expression in the vasculatures through a hypoxia inducible factor 1α–dependent transcriptional upregulation, potentially contributing to end-organ damage in the cardiovascular system. PMID:24871629

Structural, spectroscopic and thermal characterization of 2-tert-butylaminomethylpyridine-6-carboxylic acid methylester and its Fe(III), Co(II), Ni(II), Cu(II), Zn(II) and UO(2)(II) complexes.

PubMed

Mohamed, Gehad G; El-Gamel, Nadia E A

2005-04-01

Fe(III), Co(II), Ni(II), Cu(II), Zn(II) and UO(2)(II) complexes with the ligand 2-tert-butylaminomethylpyridine-6-carboxylic acid methylester (HL(2)) have been prepared and characterized by elemental analyses, molar conductance, magnetic moment, thermal analysis and spectral data. 1:1 M:HL(2) complexes, with the general formula [M(HL(2))X(2)].nH(2)O (where M = Co(II) (X = Cl, n = 0), Ni(II) (X = Cl, n = 3), Cu(II) (grey colour, X = AcO, n = 1), Cu(II) (yellow colour, X = Cl, n = 0) and Zn(II) (X = Br, n = 0). In addition, the Fe(III) and UO(2)(II) complexes of the type 1:2 M:HL(2) and with the formulae [Fe(L(2))(2)]Cl and [UO(2)(HL(2))(2)](NO(3))(2) are prepared. From the IR data, it is seen that HL(2) ligand behaves as a terdentate ligand coordinated to the metal ions via the pyridyl N, carboxylate O and protonated NH group; except the Fe(III) complex, it coordinates via the deprotonated NH group. This is supported by the molar conductance data, which show that all the complexes are non-electrolytes, while the Fe(III) and UO(2)(II) complexes are 1:1 electrolytes. IR and H1-NMR spectral studies suggest a similar behaviour of the Zn(II) complex in solid and solution states. From the solid reflectance spectral data and magnetic moment measurements, the complexes have a trigonal bipyramidal (Co(II), Ni(II), Cu(II) and Zn(II) complexes) and octahedral (Fe(III), UO(2)(II) complexes) geometrical structures. The thermal behaviour of the complexes is studied and the different dynamic parameters are calculated applying Coats-Redfern equation.

Solid Phase Extraction of Trace Al(III), Fe(II), Co(II), Cu(II), Cd(II) and Pb(II) Ions in Beverages on Functionalized Polymer Microspheres Prior to Flame Atomic Absorption Spectrometric Determinations.

PubMed

Berber, Hale; Alpdogan, Güzin

2017-01-01

In this study, poly(glycidyl methacrylate-methyl methacrylate-divinylbenzene) was synthesized in the form of microspheres, and then functionalized by 2-aminobenzothiazole ligand. The sorption properties of these functionalized microspheres were investigated for separation, preconcentration and determination of Al(III), Fe(II), Co(II), Cu(II), Cd(II) and Pb(II) ions using flame atomic absorption spectrometry. The optimum pH values for quantitative sorption were 2 - 4, 5 - 8, 6 - 8, 4 - 6, 2 - 6 and 2 - 3 for Al(III), Fe(II), Co(II), Cu(II), Cd(II) and Pb(II), respectively, and also the highest sorption capacity of the functionalized microspheres was found to be for Cu(II) with the value of 1.87 mmol g -1 . The detection limits (3σ; N = 6) obtained for the studied metals in the optimal conditions were observed in the range of 0.26 - 2.20 μg L -1 . The proposed method was successfully applied to different beverage samples for the determination of Al(III), Fe(II), Co(II), Cu(II), Cd(II) and Pb(II) ions, with the relative standard deviation of <3.7%.

Gastric cancer: the role of insulin-like growth factor 2 (IGF 2) and its receptors (IGF 1R and M6-P/IGF 2R).

PubMed

Pavelić, Kresimir; Kolak, Toni; Kapitanović, Sanja; Radosević, Senka; Spaventi, Sime; Kruslin, Bozo; Pavelić, Jasminka

2003-11-01

Insulin-like growth factor 2 (IGF 2) appears to be involved in the progression of many tumours. It binds to at least two different types of receptor: IGF type 1 (IGF 1R) and mannose 6-phosphate/IGF type 2 (M6-P/IGF 2R). Ligand binding to IGF 1R provokes mitogenic and anti-apoptotic effects. M6-P/IGF 2R has a tumour suppressor function--it mediates IGF 2 degradation. Mutation of M6-P/IGF 2R causes both diminished growth suppression and augmented growth stimulation. The aim of this study was to investigate the role of IGF 2 and its receptors (IGF 1R and IGF 2R) in human gastric cancer. The expression of IGF 2 and its receptors was measured in order to analyse the possible correlation between the activity of these genes and cell proliferation in two different gastric tumour types: diffuse and intestinal. The effect of IGF 1 receptor blockage on cell proliferation and anchorage-independent cell growth was also examined. Increased expression of IGF 2 and IGF 1R genes (at the mRNA and protein level) was found in gastric cancer when compared with non-tumour tissue. Furthermore, there was a significant difference between IGF 2 expression in the more aggressive diffuse type and that in the intestinal type of gastric cancer. Moreover, the IGF 2 peptide level in the culture media obtained from the diffuse type of cancer cells was significantly higher when compared with the intestinal type. The level of IGF 2 peptide in the conditioned media strongly correlated with [3H]thymidine incorporation and cell proliferation. On the contrary, IGF 2R mRNA expression was much higher in the intestinal type of cancer than in the diffuse type. In addition, IGF 2R protein expression was substantially lower with progression of the diffuse cancer type to a higher stage. The alphaIR3 monoclonal antibody strongly inhibited [3H]thymidine incorporation and decreased the number of colonies in soft agar of cells overexpressing IGF 2. These findings suggest that members of the IGF family are involved

Identification and Characterization of Novel Immunomodulatory Bursal-derived Pentapeptide-II (BPP-II)*

PubMed Central

Feng, Xiu-Li; Liu, Qing-Tao; Cao, Rui-Bing; Zhou, Bin; Ma, Zhi-Yong; Deng, Wen-Lei; Wei, Jian-Chao; Qiu, Ya-Feng; Wang, Fang-Quan; Gu, Jin-Yan; Wang, Feng-Juan; Zheng, Qi-Sheng; Ishag, Hassan; Chen, Pu-Yan

2012-01-01

The bursa of Fabricius, the acknowledged central humoral immune organ, plays a vital role in B lymphocyte differentiation. However, there are few reports of the molecular basis of the mechanism on immune induction and potential antitumor activity of bursal-derived peptides. In this paper, a novel bursal-derived pentapeptide-II (BPP-II, MTLTG) was isolated and exerted immunomodulatory functions on antibody responses in vitro. Gene microarray analyses demonstrated that BPP-II regulated expression of 2478 genes in a mouse-derived hybridoma cell line. Immune-related gene ontology functional procedures were employed for further functional analysis. Furthermore, the majority of BPP-II-regulated pathways were associated with immune responses and tumor processes. Moreover, BPP-II exhibited immunomodulatory effects on antigen-specific immune responses in vivo, including enhancement of avian influenza virus (H9N2 subtype)-specific antibody and cytokine production and modification of T cell immunophenotypes and lymphocyte proliferation. Finally, BPP-II triggered p53 expression and stabilization and selectively inhibited tumor cell proliferation. These data identified the multifunctional factor, BPP-II, as a novel biomaterial representing an important linking between the humoral central immune system and immune induction, including antitumor. Information generated in this study elucidates further the mechanisms involved in humoral immune system and represents the potential basis of effective immunotherapeutic strategies for treating human tumors and immune improvement. PMID:22184121

Identification and characterization of novel immunomodulatory bursal-derived pentapeptide-II (BPP-II).

PubMed

Feng, Xiu-Li; Liu, Qing-Tao; Cao, Rui-Bing; Zhou, Bin; Ma, Zhi-Yong; Deng, Wen-Lei; Wei, Jian-Chao; Qiu, Ya-Feng; Wang, Fang-Quan; Gu, Jin-Yan; Wang, Feng-Juan; Zheng, Qi-Sheng; Ishag, Hassan; Chen, Pu-Yan

2012-02-03

The bursa of Fabricius, the acknowledged central humoral immune organ, plays a vital role in B lymphocyte differentiation. However, there are few reports of the molecular basis of the mechanism on immune induction and potential antitumor activity of bursal-derived peptides. In this paper, a novel bursal-derived pentapeptide-II (BPP-II, MTLTG) was isolated and exerted immunomodulatory functions on antibody responses in vitro. Gene microarray analyses demonstrated that BPP-II regulated expression of 2478 genes in a mouse-derived hybridoma cell line. Immune-related gene ontology functional procedures were employed for further functional analysis. Furthermore, the majority of BPP-II-regulated pathways were associated with immune responses and tumor processes. Moreover, BPP-II exhibited immunomodulatory effects on antigen-specific immune responses in vivo, including enhancement of avian influenza virus (H9N2 subtype)-specific antibody and cytokine production and modification of T cell immunophenotypes and lymphocyte proliferation. Finally, BPP-II triggered p53 expression and stabilization and selectively inhibited tumor cell proliferation. These data identified the multifunctional factor, BPP-II, as a novel biomaterial representing an important linking between the humoral central immune system and immune induction, including antitumor. Information generated in this study elucidates further the mechanisms involved in humoral immune system and represents the potential basis of effective immunotherapeutic strategies for treating human tumors and immune improvement.

Validation of the Sexual Assault Symptom Scale II (SASS II) Using a Panel Research Design

ERIC Educational Resources Information Center

Ruch, Libby O.; Wang, Chang-Hwai

2006-01-01

To examine the utility of a self-report scale of sexual assault trauma, 223 female victims were interviewed with the 43-item Sexual Assault Symptom Scale II (SASS II) at 1, 3, 7, 11, and 15 months postassault. Factor analyses using principal-components extraction with an oblimin rotation yielded 7 common factors with 31 items. The internal…

The transcription factor MEF2C mediates cardiomyocyte hypertrophy induced by IGF-1 signaling

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

Munoz, Juan Pablo; Collao, Andres; Chiong, Mario

2009-10-09

Myocyte enhancer factor 2C (MEF2C) plays an important role in cardiovascular development and is a key transcription factor for cardiac hypertrophy. Here, we describe MEF2C regulation by insulin-like growth factor-1 (IGF-1) and its role in IGF-1-induced cardiac hypertrophy. We found that IGF-1 addition to cultured rat cardiomyocytes activated MEF2C, as evidenced by its increased nuclear localization and DNA binding activity. IGF-1 stimulated MEF2 dependent-gene transcription in a time-dependent manner, as indicated by increased MEF2 promoter-driven reporter gene activity; IGF-1 also induced p38-MAPK phosphorylation, while an inhibitor of p38-MAPK decreased both effects. Additionally, inhibitors of phosphatidylinositol 3-kinase and calcineurin prevented IGF-1-inducedmore » MEF2 transcriptional activity. Via MEF2C-dependent signaling, IGF-1 also stimulated transcription of atrial natriuretic factor and skeletal {alpha}-actin but not of fos-lux reporter genes. These novel data suggest that MEF2C activation by IGF-1 mediates the pro-hypertrophic effects of IGF-1 on cardiac gene expression.« less

Role of heterotrimeric G protein and calcium in cardiomyocyte hypertrophy induced by IGF-1.

PubMed

Carrasco, Loreto; Cea, Paola; Rocco, Paola; Peña-Oyarzún, Daniel; Rivera-Mejias, Pablo; Sotomayor-Flores, Cristian; Quiroga, Clara; Criollo, Alfredo; Ibarra, Cristian; Chiong, Mario; Lavandero, Sergio

2014-04-01

In the heart, insulin-like growth factor-1 (IGF-1) is a peptide with pro-hypertrophic and anti-apoptotic actions. The pro-hypertrophic properties of IGF-1 have been attributed to the extracellular regulated kinase (ERK) pathway. Recently, we reported that IGF-1 also increases intracellular Ca(2+) levels through a pertussis toxin (PTX)-sensitive G protein. Here we investigate whether this Ca(2+) signal is involved in IGF-1-induced cardiomyocyte hypertrophy. Our results show that the IGF-1-induced increase in Ca(2+) level is abolished by the IGF-1 receptor tyrosine kinase inhibitor AG538, PTX and the peptide inhibitor of Gβγ signaling, βARKct. Increases in the activities of Ca(2+) -dependent enzymes calcineurin, calmodulin kinase II (CaMKII), and protein kinase Cα (PKCα) were observed at 5 min after IGF-1 exposure. AG538, PTX, βARKct, and the dominant negative PKCα prevented the IGF-1-dependent phosphorylation of ERK1/2. Participation of calcineurin and CaMKII in ERK phosphorylation was discounted. IGF-1-induced cardiomyocyte hypertrophy, determined by cell size and β-myosin heavy chain (β-MHC), was prevented by AG538, PTX, βARKct, dominant negative PKCα, and the MEK1/2 inhibitor PD98059. Inhibition of calcineurin with CAIN did not abolish IGF-1-induced cardiac hypertrophy. We conclude that IGF-1 induces hypertrophy in cultured cardiomyocytes by activation of the receptor tyrosine kinase activity/βγ-subunits of a PTX-sensitive G protein/Ca(2+) /PKCα/ERK pathway without the participation of calcineurin. © 2013 Wiley Periodicals, Inc.

The transcription factor ETS-1 regulates angiotensin II-stimulated fibronectin production in mesangial cells.

PubMed

Hua, Ping; Feng, Wenguang; Rezonzew, Gabriel; Chumley, Phillip; Jaimes, Edgar A

2012-06-01

Angiotensin II (ANG II) produced as result of activation of the renin-angiotensin system (RAS) plays a critical role in the pathogenesis of chronic kidney disease via its hemodynamic effects on the renal microcirculation as well as by its nonhemodynamic actions including the production of extracellular matrix proteins such as fibronectin, a multifunctional extracellular matrix protein that plays a major role in cell adhesion and migration as well as in the development of glomerulosclerosis. ETS-1 is an important transcription factor essential for normal kidney development and glomerular integrity. We previously showed that ANG II increases ETS-1 expression and is required for fibronectin production in mesangial cells. In these studies, we determined that ANG II induces phosphorylation of ETS-1 via activation of the type 1 ANG II receptor and that Erk1/2 and Akt/PKB phosphorylation are required for these effects. In addition, we characterized the role of ETS-1 on the transcriptional activation of fibronectin production in mesangial cells. We determined that ETS-1 directly activates the fibronectin promoter and by utilizing gel shift assays and chromatin immunoprecipitation assays identified two different ETS-1 binding sites that promote the transcriptional activation of fibronectin in response to ANG II. In addition, we identified the essential role of CREB and its coactivator p300 on the transcriptional activation of fibronectin by ETS-1. These studies unveil novel mechanisms involved in RAS-induced production of the extracellular matrix protein fibronectin in mesangial cells and establish the role of the transcription factor ETS-1 as a direct mediator of these effects.

The IGF-system is not affected by a twofold change in protein intake in patients with type 1 diabetes.

PubMed

Hedman, Christina A; Frystyk, Jan; Fridell, Karin; Jönsson, Anna; Flyvbjerg, Allan; Lindström, Torbjörn; Arnqvist, Hans J

2005-08-01

In type 1 diabetes the circulating IGF-system is altered with low IGF-I and changes in levels of IGF-binding proteins (IGFBPs) which may be of importance for the development of diabetes complications. Our aim was to study if IGF-I, as supported by experimental data in animals, can be affected by dietary protein intake. Twelve patients with type 1 diabetes, age 37.5+/-10.0 years (mean+/-SD), diabetes duration 20.1+/-9.3 years and HbA1c 6.3+/-0.6% were allocated to isocaloric diets with either low normal protein content (LNP), (10 E%; 0.9 g protein/kg body weight) or high normal protein content (HNP) (20 E%; 1.8 g protein/kg body weight) in an open randomised cross-over study. Each diet was taken for 10 days with a wash-out period of 11 days in between. Circulating levels of total and free IGF-I and -II, IGFBP-1, -2 and -3 and GH-binding protein (GHBP) as well as ghrelin were measured with validated in-house immunoassays. At day 10, urinary urea excretion was 320+/-75 mmol/24h during LNP diet compared with 654+/-159 mmol/24h during HNP diet (p<0.001). There were no changes in body weight or glycaemic control between the diets. Fasting levels of total IGF-I were 121+/-33 microg/L after LNP and 117+/-28 microg/L after HNP diet (ns) and the corresponding concentrations of IGFBP-1 were 142(141) and 132(157)mug/L [median (IQR)] (ns). There were no differences in plasma concentrations of total IGF-II, free IGF-I and -II, IGFBP-3, GHBP and ghrelin, whereas a small difference was found for IGFBP-2 (302+/-97 vs. 263+/-66 microg/L; LNP vs. HNP; p<0.04). A twofold change of the dietary protein intake does not influence the altered circulating IGF-system in type 1 diabetes. In order to affect the IGF-system other interventions must be used.

Composition, Characterization and Antibacterial activity of Mn(II), Co(II),Ni(II), Cu(II) Zn(II) and Cd(II) mixed ligand complexes Schiff base derived from Trimethoprim with 8-Hydroxy quinoline

NASA Astrophysics Data System (ADS)

Numan, Ahmed T.; Atiyah, Eman M.; Al-Shemary, Rehab K.; Ulrazzaq, Sahira S. Abd

2018-05-01

New Schiff base ligand 2-((4-amino-5-(3, 4, 5-trimethoxybenzyl) pyrimidin-2-ylimino) (phenyl)methyl)benzoic acid] = [HL] was synthesized using microwave irradiation trimethoprim and 2-benzoyl benzoic acid. Mixed ligand complexes of Mn((II), Co(II), Ni(II), Cu(II), Zn(II) and Cd(II) are reacted in ethanol with Schiff base ligand [HL] and 8-hydroxyquinoline [HQ] then reacted with metal salts in ethanol as a solvent in (1:1:1) ratio. The ligand [HL] is characterized by FTIR, UV-Vis, melting point, elemental microanalysis (C.H.N), 1H-NMR, 13C-NMR, and mass spectra. The mixed ligand complexes are characterized by infrared spectra, electronic spectra, (C.H.N), melting point, atomic absorption, molar conductance and magnetic moment measurements. These measurements indicate that the ligand [HL] coordinates with metal (II) ion in a tridentate manner through the oxygen and nitrogen atoms of the ligand, octahedral structures are suggested for these complexes. Antibacterial activity of the ligands [HL], [HQ] and their complexes are studied against (gram positive) and (gram negative) bacteria.

Small Diameter Bomb Increment II (SDB II)

DTIC Science & Technology

2015-12-01

Selected Acquisition Report ( SAR ) RCS: DD-A&T(Q&A)823-439 Small Diameter Bomb Increment II (SDB II) As of FY 2017 President’s Budget Defense...Acquisition Management Information Retrieval (DAMIR) March 23, 2016 16:19:13 UNCLASSIFIED SDB II December 2015 SAR March 23, 2016 16:19:13 UNCLASSIFIED...Document OSD - Office of the Secretary of Defense O&S - Operating and Support PAUC - Program Acquisition Unit Cost SDB II December 2015 SAR March 23

Body shape throughout life and correlations with IGFs and GH.

PubMed

Schernhammer, Eva S; Tworoger, Shelley S; Eliassen, A Heather; Missmer, Stacey A; Holly, Jeff M; Pollak, Michael N; Hankinson, Susan E

2007-09-01

Both insulin-like growth factors (IGF) and body size have been linked to premenopausal breast cancer risk. However, observational studies of IGF have not been consistent, and they suggest that perhaps earlier levels of IGF might be more strongly related to breast cancer than those measured at mid-age. We therefore sought to explore associations between several measures of body size throughout life and IGF levels in premenopausal women. We examined cross-sectional associations of birth weight, body shape (or somatotype) at ages 5 and 10, body mass index (BMI) at age 18 and adulthood, bra cup size at age 20, adult waist circumference and waist-to-hip ratio (WHR), and attained height with plasma levels of IGF-I, IGF binding protein 3 (IGFBP-3), IGFBP-1, and GH. Participants were 592 healthy premenopausal women aged 34-52 from the Nurses' Health Study II. Using multiple linear regression, we computed least-square mean hormone levels across the categories of early life anthropometric factors. We observed consistent and strong inverse associations between body shape at various stages in life and IGF levels. Somatotype at ages 5 and 10 was inversely associated with IGF-I (P for difference, < 0.01) and positively with IGFBP-3 measured later in adulthood. Further, comparing women with a BMI > or = 25 kg/m(2) at age 18 vs < 19 kg/m(2), similar associations were observed for IGF-I (P for trend, 0.005) and IGFBP-3 (P for trend, 0.01), which were even stronger for BMI at blood collection (BMI< 20 versus BMI > or = 30, mean IGF-I 254 ng/ml, 95% CI, 239-271 vs 208 ng/ml, 95% CI, 195-222). Both waist circumference and WHR were strongly and inversely related to IGFBP-1 levels (top versus bottom quartile of waist circumference: 14.5 vs 40.0 ng/ml, P for trend 0.0005; WHR: 18.3 vs 39.4 ng/ml, P for trend 0.002), with similar results for bra cup size at age 20 although they did not reach statistical significance. There was no association between height and IGF or GH levels. Birth

Confirmatory Factor Analysis of the KABC-II in Preschool Children

ERIC Educational Resources Information Center

Morgan, Kimberly E.; Rothlisberg, Barbara A.; McIntosh, David E.; Hunt, Madeline S.

2009-01-01

The present study assessed the Kaufman Assessment Battery for Children, Second Edition (KABC-II) in relation to the synthesized Cattell-Horn-Carroll (CHC) theory of intelligence with a preschool sample. Participants were 200 preschool children between four and five years of age. A confirmatory factor analysis (CFA) was conducted, and different…

Neuroprotective Effects and Mechanisms of Curcumin-Cu(II) and -Zn(II) Complexes Systems and Their Pharmacological Implications.

PubMed

Yan, Fa-Shun; Sun, Jian-Long; Xie, Wen-Hai; Shen, Liang; Ji, Hong-Fang

2017-12-28

Alzheimer's disease (AD) is the main form of dementia and has a steadily increasing prevalence. As both oxidative stress and metal homeostasis are involved in the pathogenesis of AD, it would be interesting to develop a dual function agent, targeting the two factors. Curcumin, a natural compound isolated from the rhizome of Curcuma longa , is an antioxidant and can also chelate metal ions. Whether the complexes of curcumin with metal ions possess neuroprotective effects has not been evaluated. Therefore, the present study was designed to investigate the protective effects of the complexes of curcumin with Cu(II) or Zn(II) on hydrogen peroxide (H₂O₂)-induced injury and the underlying molecular mechanisms. The use of rat pheochromocytoma (PC12) cells, a widely used neuronal cell model system, was adopted. It was revealed that curcumin-Cu(II) complexes systems possessed enhanced O₂ ·- -scavenging activities compared to unchelated curcumin. In comparison with unchelated curcumin, the protective effects of curcumin-Cu(II) complexes systems were stronger than curcumin-Zn(II) system. Curcumin-Cu(II) or -Zn(II) complexes systems significantly enhanced the superoxide dismutase, catalase, and glutathione peroxidase activities and attenuated the increase of malondialdehyde levels and caspase-3 and caspase-9 activities, in a dose-dependent manner. The curcumin-Cu(II) complex system with a 2:1 ratio exhibited the most significant effect. Further mechanistic study demonstrated that curcumin-Cu(II) or -Zn(II) complexes systems inhibited cell apoptosis via downregulating the nuclear factor κB (NF-κB) pathway and upregulating Bcl-2/Bax pathway. In summary, the present study found that curcumin-Cu(II) or -Zn(II) complexes systems, especially the former, possess significant neuroprotective effects, which indicates the potential advantage of curcumin as a promising agent against AD and deserves further study.

DNA methyltransferase inhibitor CDA-II inhibits myogenic differentiation

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

Chen, Zirong; Department of Molecular Genetics and Microbiology, Shands Cancer Center, University of Florida, Gainesville, FL 32610; Jin, Guorong

2012-06-08

Highlights: Black-Right-Pointing-Pointer CDA-II inhibits myogenic differentiation in a dose-dependent manner. Black-Right-Pointing-Pointer CDA-II repressed expression of muscle transcription factors and structural proteins. Black-Right-Pointing-Pointer CDA-II inhibited proliferation and migration of C2C12 myoblasts. -- Abstract: CDA-II (cell differentiation agent II), isolated from healthy human urine, is a DNA methyltransferase inhibitor. Previous studies indicated that CDA-II played important roles in the regulation of cell growth and certain differentiation processes. However, it has not been determined whether CDA-II affects skeletal myogenesis. In this study, we investigated effects of CDA-II treatment on skeletal muscle progenitor cell differentiation, migration and proliferation. We found that CDA-II blocked differentiationmore » of murine myoblasts C2C12 in a dose-dependent manner. CDA-II repressed expression of muscle transcription factors, such as Myogenin and Mef2c, and structural proteins, such as myosin heavy chain (Myh3), light chain (Mylpf) and MCK. Moreover, CDA-II inhibited C1C12 cell migration and proliferation. Thus, our data provide the first evidence that CDA-II inhibits growth and differentiation of muscle progenitor cells, suggesting that the use of CDA-II might affect skeletal muscle functions.« less

Synthesis, investigation and spectroscopic characterization of piroxicam ternary complexes of Fe(II), Fe(III), Co(II), Ni(II), Cu(II) and Zn(II) with glycine and DL-phenylalanine.

PubMed

Mohamed, Gehad G; El-Gamel, Nadia E A

2004-11-01

The ternary piroxicam (Pir; 4-hydroxy-2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide) complexes of Fe(II), Fe(III), Co(II), Ni(II), Cu(II) and Zn(II) with various amino acids (AA) such as glycine (Gly) or DL-phenylalanine (PhA) were prepared and characterized by elemental analyses, molar conductance, IR, UV-Vis, magnetic moment, diffuse reflectance and X-ray powder diffraction. The UV-Vis spectra of Pir and the effect of metal chelation on the different interligand transitions are discussed in detailed manner. IR and UV-Vis spectra confirm that Pir behaves as a neutral bidentate ligand coordinated to the metal ions via the pyridine-N and carbonyl group of the amide moiety. Gly molecule acted as a uninegatively monodentate ligand and coordinate to the metal ions through its carboxylic group, in addition PhA acted as a uninegatively bidentate ligand and coordinate to the metal ions through its carboxylic and amino groups. All the chelates have octahedral geometrical structures while Cu(II)- and Zn(II)-ternary chelates with PhA have square planar geometrical structures. The molar conductance data reveal that most of these chelates are non electrolytes, while Fe(III)-Pir-Gly, Co(II)-, Ni(II)-, Cu(II)- and Zn(II)-Pir-PhA chelates were 1:1 electrolytes. X-ray powder diffraction is used as a new tool to estimate the crystallinity of chelates as well as to elucidate their geometrical structures.

Synthesis, investigation and spectroscopic characterization of piroxicam ternary complexes of Fe(II), Fe(III), Co(II), Ni(II), Cu(II) and Zn(II) with glycine and DL-phenylalanine

NASA Astrophysics Data System (ADS)

Mohamed, Gehad G.; El-Gamel, Nadia E. A.

2004-11-01

The ternary piroxicam (Pir; 4-hydroxy-2-methyl- N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide) complexes of Fe(II), Fe(III), Co(II), Ni(II), Cu(II) and Zn(II) with various amino acids (AA) such as glycine (Gly) or DL-phenylalanine (PhA) were prepared and characterized by elemental analyses, molar conductance, IR, UV-Vis, magnetic moment, diffuse reflectance and X-ray powder diffraction. The UV-Vis spectra of Pir and the effect of metal chelation on the different interligand transitions are discussed in detailed manner. IR and UV-Vis spectra confirm that Pir behaves as a neutral bidentate ligand coordinated to the metal ions via the pyridine- N and carbonyl group of the amide moiety. Gly molecule acted as a uninegatively monodentate ligand and coordinate to the metal ions through its carboxylic group, in addition PhA acted as a uninegatively bidentate ligand and coordinate to the metal ions through its carboxylic and amino groups. All the chelates have octahedral geometrical structures while Cu(II)- and Zn(II)-ternary chelates with PhA have square planar geometrical structures. The molar conductance data reveal that most of these chelates are non electrolytes, while Fe(III)-Pir-Gly, Co(II)-, Ni(II)-, Cu(II)- and Zn(II)-Pir-PhA cheletes were 1:1 electrolytes. X-ray powder diffraction is used as a new tool to estimate the crystallinity of chelates as well as to elucidate their geometrical structures.

Synthesis, spectroscopic characterization, thermal analysis and electrical conductivity studies of Mg(II), Ca(II), Sr(II) and Ba(II) vitamin B2 complexes

NASA Astrophysics Data System (ADS)

Refat, Moamen S.; Moussa, Mohamed A. A.; Mohamed, Soha F.

2011-05-01

Riboflavin (RF) complexes of Mg(II), Ca(II), Sr(II) and Ba(II) were successfully synthesized. Structures of metal complexes obtained were confirmed and characterized by elemental analysis, molar conductance, and infrared spectra. DC electrical conductivity measurements indicated that the alkaline earth metal (II) complexes of RF ligand are non-electrolytes. Elemental analysis of chelates suggest that the metal(II) ligand ratio is 1:2 with structure formula as [M(RF) 2( X) 2]· nH 2O. Infrared assignments clearly show that RF ligand coordinated as a bidentate feature through azomethine nitrogen of pyrazine ring and C dbnd O of pyrimidine-2,4-dione. Thermal analyses of Mg(II), Ca(II), Sr(II) and Ba(II) complexes were investigated using (TG/DSC) under atmospheric nitrogen between 30 and 800 °C. The surface morphology of the complexes was studied by SEM. The electrical conductivities of RF and its metal complexes were also measured with DC electrical conductivity in the temperature range from room to 483 K.

PPAR-γ Agonists As Antineoplastic Agents in Cancers with Dysregulated IGF Axis

PubMed Central

Vella, Veronica; Nicolosi, Maria Luisa; Giuliano, Stefania; Bellomo, Maria; Belfiore, Antonino; Malaguarnera, Roberta

2017-01-01

It is now widely accepted that insulin resistance and compensatory hyperinsulinemia are associated to increased cancer incidence and mortality. Moreover, cancer development and progression as well as cancer resistance to traditional anticancer therapies are often linked to a deregulation/overactivation of the insulin-like growth factor (IGF) axis, which involves the autocrine/paracrine production of IGFs (IGF-I and IGF-II) and overexpression of their cognate receptors [IGF-I receptor, IGF-insulin receptor (IR), and IR]. Recently, new drugs targeting various IGF axis components have been developed. However, these drugs have several limitations including the occurrence of insulin resistance and compensatory hyperinsulinemia, which, in turn, may affect cancer cell growth and survival. Therefore, new therapeutic approaches are needed. In this regard, the pleiotropic effects of peroxisome proliferator activated receptor (PPAR)-γ agonists may have promising applications in cancer prevention and therapy. Indeed, activation of PPAR-γ by thiazolidinediones (TZDs) or other agonists may inhibit cell growth and proliferation by lowering circulating insulin and affecting key pathways of the Insulin/IGF axis, such as PI3K/mTOR, MAPK, and GSK3-β/Wnt/β-catenin cascades, which regulate cancer cell survival, cell reprogramming, and differentiation. In light of these evidences, TZDs and other PPAR-γ agonists may be exploited as potential preventive and therapeutic agents in tumors addicted to the activation of IGF axis or occurring in hyperinsulinemic patients. Unfortunately, clinical trials using PPAR-γ agonists as antineoplastic agents have reached conflicting results, possibly because they have not selected tumors with overactivated insulin/IGF-I axis or occurring in hyperinsulinemic patients. In conclusion, the use of PPAR-γ agonists in combined therapies of IGF-driven malignancies looks promising but requires future developments. PMID:28275367

Signal transduction by beta1 integrin receptors in human chondrocytes in vitro: collaboration with the insulin-like growth factor-I receptor.

PubMed

Shakibaei, M; John, T; De Souza, P; Rahmanzadeh, R; Merker, H J

1999-09-15

We have examined the mechanism by which collagen-binding integrins co-operate with insulin-like growth factor-I (IGF-I) receptors (IGF-IR) to regulate chondrocyte phenotype and differentiation. Adhesion of chondrocytes to anti-beta1 integrin antibodies or collagen type II leads to phosphorylation of cytoskeletal and signalling proteins localized at focal adhesions, including alpha-actinin, vinculin, paxillin and focal adhesion kinase (FAK). These stimulate docking proteins such as Shc (Src-homology collagen). Moreover, exposure of collagen type II-cultured chondrocytes to IGF-I leads to co-immunoprecipitation of Shc protein with the IGF-IR and with beta1, alpha1 and alpha5 integrins, but not with alpha3 integrin. Shc then associates with growth factor receptor-bound protein 2 (Grb2), an adaptor protein and extracellular signal-regulated kinase. The expression of the docking protein Shc occurs only when chondrocytes are bound to collagen type II or integrin antibodies and increases when IGF-I is added, suggesting a collaboration between integrins and growth factors in a common/shared biochemical signalling pathway. Furthermore, these results indicate that focal adhesion assembly may facilitate signalling via Shc, a potential common target for signal integration between integrin and growth-factor signalling regulatory pathways. Thus, the collagen-binding integrins and IGF-IR co-operate to regulate focal adhesion components and these signalling pathways have common targets (Shc-Grb2 complex) in subcellular compartments, thereby linking to the Ras-mitogen-activated protein kinase signalling pathway. These events may play a role during chondrocyte differentiation.

Resveratrol prevents angiotensin II-induced hypertrophy of vascular smooth muscle cells through the transactivation of growth factor receptors.

PubMed

Hossain, Ekhtear; Anand-Srivastava, Madhu B

2017-08-01

We previously showed that augmented levels of endogenous angiotensin II (AngII) contribute to vascular smooth muscle cell (VSMC) hypertrophy through the transactivation of growth factor receptors in spontaneously hypertensive rats. Resveratrol (RV), a polyphenolic component of red wine, has also been shown to attenuate AngII-evoked VSMC hypertrophy; however, the molecular mechanism mediating this response is obscure. The present study was therefore undertaken to examine whether RV could prevent AngII-induced VSMC hypertrophy through the transactivation of growth factor receptor and associated signaling pathways. AngII treatment of VSMC enhanced the protein synthesis that was attenuated towards control levels by RV pretreatment as well as by the inhibitors of NADPH oxidase, c-Src, and growth factor receptors. Furthermore, RV pretreatment also inhibited enhanced levels of superoxide anion, NADPH oxidase activity, increased expression of NADPH oxidase subunits, and phosphorylation of c-Src, EGF-R, PDGE-R, ERK1/2, and AKT1/2. In conclusion, these results indicate that RV attenuates AngII-induced VSMC hypertrophy through the inhibition of enhanced oxidative stress and activation of c-Src, growth factor receptors, and MAPK/AKT signaling. We suggest that RV could be used as a therapeutic agent in the treatment of vascular complications associated with hypertension and hypertrophy.

The Beck Depression Inventory-II: Testing for Measurement Equivalence and Factor Mean Differences across Hong Kong and American Adolescents

ERIC Educational Resources Information Center

Byrne, Barbara M.; Stewart, Sunita M.; Kennard, Betsy D.; Lee, Peter W. H.

2007-01-01

Working within the framework of a confirmatory factor analytic (CFA) model, this study adds another dimension to construct validation of both the Beck Depression Inventory-II (BDI-II; Beck, Steer, & Brown, 1996) and a Chinese version of the BDI-II (C-BDI-II; Chinese Behavioral Sciences Society, 2000). Specifically, we tested for measurement…

Small-Molecule Inhibition and Activation-Loop Trans-Phosphorylation of the IGF1 Receptor

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

Wu,J.; Li, W.; Craddock, B.

2008-01-01

The insulin-like growth factor-1 receptor (IGF1R) is a receptor tyrosine kinase (RTK) that has a critical role in mitogenic signalling during embryogenesis and an antiapoptotic role in the survival and progression of many human tumours. Here, we present the crystal structure of the tyrosine kinase domain of IGF1R (IGF1RK), in its unphosphorylated state, in complex with a novel compound, cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo[1, 5-a]pyrazin-8-ylamine (PQIP), which we show is a potent inhibitor of both the unphosphorylated (basal) and phosphorylated (activated) states of the kinase. PQIP interacts with residues in the ATP-binding pocket and in the activation loop, which confers specificity for IGF1RK andmore » the highly related insulin receptor (IR) kinase. In this crystal structure, the IGF1RK active site is occupied by Tyr1135 from the activation loop of an symmetry (two-fold)-related molecule. This dimeric arrangement affords, for the first time, a visualization of the initial trans-phosphorylation event in the activation loop of an RTK, and provides a molecular rationale for a naturally occurring mutation in the activation loop of the IR that causes type II diabetes mellitus.« less

Chitosan film loaded with silver nanoparticles-sorbent for solid phase extraction of Al(III), Cd(II), Cu(II), Co(II), Fe(III), Ni(II), Pb(II) and Zn(II).

PubMed

Djerahov, Lubomir; Vasileva, Penka; Karadjova, Irina; Kurakalva, Rama Mohan; Aradhi, Keshav Krishna

2016-08-20

The present study describes the ecofriendly method for the preparation of chitosan film loaded with silver nanoparticles (CS-AgNPs) and application of this film as efficient sorbent for separation and enrichment of Al(III), Cd(II), Cu(II), Co(II), Fe(III), Ni(II), Pb(II) and Zn(II). The stable CS-AgNPs colloid was prepared by dispersing the AgNPs sol in chitosan solution at appropriate ratio and further used to obtain a cast film with very good stability under storage and good mechanical strength for easy handling in aqueous medium. The incorporation of AgNPs in the structure of CS film and interaction between the polymer matrix and nanoparticles were confirmed by UV-vis and FTIR spectroscopy. The homogeneously embedded AgNPs (average diameter 29nm, TEM analysis) were clearly observed throughout the film by SEM. The CS-AgNPs nanocomposite film shows high sorption activity toward trace metals under optimized chemical conditions. The results suggest that the CS-AgNPs nanocomposite film can be feasibly used as a novel sorbent material for solid-phase extraction of metal pollutants from surface waters. Copyright © 2016 Elsevier Ltd. All rights reserved.

Class II ADP-ribosylation factors are required for efficient secretion of dengue viruses.

PubMed

Kudelko, Mateusz; Brault, Jean-Baptiste; Kwok, Kevin; Li, Ming Yuan; Pardigon, Nathalie; Peiris, J S Malik; Bruzzone, Roberto; Desprès, Philippe; Nal, Béatrice; Wang, Pei Gang

2012-01-02

Identification and characterization of virus-host interactions are very important steps toward a better understanding of the molecular mechanisms responsible for disease progression and pathogenesis. To date, very few cellular factors involved in the life cycle of flaviviruses, which are important human pathogens, have been described. In this study, we demonstrate a crucial role for class II Arf proteins (Arf4 and Arf5) in the dengue flavivirus life cycle. We show that simultaneous depletion of Arf4 and Arf5 blocks recombinant subviral particle secretion for all four dengue serotypes. Immunostaining analysis suggests that class II Arf proteins are required at an early pre-Golgi step for dengue virus secretion. Using a horseradish peroxidase protein fused to a signal peptide, we show that class II Arfs act specifically on dengue virus secretion without altering the secretion of proteins through the constitutive secretory pathway. Co-immunoprecipitation data demonstrate that the dengue prM glycoprotein interacts with class II Arf proteins but not through its C-terminal VXPX motif. Finally, experiments performed with replication-competent dengue and yellow fever viruses demonstrate that the depletion of class II Arfs inhibits virus secretion, thus confirming their implication in the virus life cycle, although data obtained with West Nile virus pointed out the differences in virus-host interactions among flaviviruses. Our findings shed new light on a molecular mechanism used by dengue viruses during the late stages of the life cycle and demonstrate a novel function for class II Arf proteins.

Collaborative Research to Optimize Warfighter Nutrition II (CROWN II)

DTIC Science & Technology

2016-09-01

Award Number: W81XWH-14-1-0335 TITLE: Collaborative Research to Optimize Warfighter Nutrition II (CROWN II) PRINCIPAL INVESTIGATOR: Jennifer C...2016 4. TITLE AND SUBTITLE Collaborative Research to Optimize Warfighter Nutrition II (CROWN II) 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-14-1...has been forged between USARIEM and Pennington Biomedical Research Center (PBRC) since 1988. Objective: CROWN II conducts research in nutrition

The quantitative and functional relation between insulin-like growth factor-I (IGF) and IGF-binding proteins during human osteoarthritis.

PubMed

Morales, Teresa I

2008-04-01

A previous hypothesis stated that during osteoarthritis (OA) increased insulin-like growth factor (IGF) binding proteins (IGFBPs) sequester IGFs and limit their access to the cell. The objective of this article was to test this by: (1) quantifying IGF and IGFBP-3 as well as their ratios in human OA cartilages, and (2) measuring the metabolic responses of diseased cartilage to IGF-I and its IGFBP-insensitive analogs. Knee or hip OA cartilages were staged for OA by histology. Cartilage slices were either extracted for assays of IGF proteins, or maintained intact as organ cultures. Proteoglycan (PG) metabolism +/- IGFs was measured by use of the (35)S-sulfate precursor. IGFBP-3 (ng/mg protein) was weakly correlated with OA score by regression analysis (R(2) = 0.122; p = 0.040; n = 35). IGF-I (ng/mg protein) was constant across all OA groups (ANOVA; p = .428, n = 18) and the IGF-I/IGFBP-3 ratios were > 1 in most samples. All OA cartilages responded to hrIGF-I by increasing PG synthesis [average 2.29-fold +/- 0.55 (+/-SD) at saturation, n = 12] irrespective of OA score. The des (1-3) IGF-I analog (which lacks the three N-terminal amino acids) had similar maximal effects (average 2.23-fold stimulation +/- 0.71, n = 10), but it was more effective in two out of three samples at suboptimal doses. The effect of hrIGF-I, des (1-3) IGF-I, or the B-chain analog on degradation was minimal. In summary, catabolism was insensitive to IGF-I, and this was probably not due to IGFBPs. By contrast, IGF-I exerted a robust stimulation of anabolism at sufficiently high doses, even though IGFBPs could tone down the ligand effect at low doses. (c) 2007 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Coordination behavior of tetraaza [N4] ligand towards Co(II), Ni(II), Cu(II), Cu(I) and Pd(II) complexes: Synthesis, spectroscopic characterization and anticancer activity

NASA Astrophysics Data System (ADS)

El-Boraey, Hanaa A.

2012-11-01

Novel eight Co(II), Ni(II), Cu(II), Cu(I) and Pd(II) complexes with [N4] ligand (L) i.e. 2-amino-N-{2-[(2-aminobenzoyl)amino]ethyl}benzamide have been synthesized and structurally characterized by elemental analysis, spectral, thermal (TG/DTG), magnetic, and molar conductivity measurements. On the basis of IR, mass, electronic and EPR spectral studies an octahedral geometry has been proposed for Co(II), Ni(II) complexes and Cu(II) chloride complex, square-pyramidal for Cu(I) bromide complex. For Cu(II) nitrate complex (6), Pd(II) complex (8) square planar geometry was proposed. The EPR data of Cu(II) complexes in powdered form indicate dx2-y2 ground state of Cu(II) ion. The antitumor activity of the synthesized ligand and some selected metal complexes has been studied. The palladium(II) complex (8) was found to display cytotoxicity (IC50 = 25.6 and 41 μM) against human breast cancer cell line MCF-7 and human hepatocarcinoma HEPG2 cell line.

The pro-Forms of Insulin-Like Growth Factor I (IGF-I) Are Predominant in Skeletal Muscle and Alter IGF-I Receptor Activation

PubMed Central

Durzyńska, Julia; Philippou, Anastassios; Brisson, Becky K.; Nguyen-McCarty, Michelle

2013-01-01

IGF-I is a key regulator of muscle development and growth. The pre-pro-peptide produced by the Igf1gene undergoes several posttranslational processing steps to result in a secreted mature protein, which is thought to be the obligate ligand for the IGF-I receptor (IGF-IR). The goals of this study were to determine what forms of IGF-I exist in skeletal muscle, and whether the mature IGF-I protein was the only form able to activate the IGF-IR. We measured the proportion of IGF-I species in murine skeletal muscle and found that the predominant forms were nonglycosylated pro-IGF-I and glycosylated pro-IGF-I, which retained the C-terminal E peptide extension, instead of mature IGF-I. These forms were validated using samples subjected to viral expression of IGF-I combined with furin and glycosidase digestion. To determine whether the larger molecular weight IGF-I forms were also ligands for the IGF-IR, we generated each specific form through transient transfection of 3T3 cells and used the enriched media to perform kinase receptor activation assays. Compared with mature IGF-I, nonglycosylated pro-IGF-I had similar ability to activate the IGF-IR, whereas glycosylation of pro-IGF-I significantly reduced receptor activation. Thus, it is important to understand not only the quantity, but also the proportion of IGF-I forms produced, to evaluate the true biological activity of this growth factor. PMID:23407451

Predictive value of the APACHE II, SAPS II, SOFA and GCS scoring systems in patients with severe purulent bacterial meningitis.

PubMed

Pietraszek-Grzywaczewska, Iwona; Bernas, Szymon; Łojko, Piotr; Piechota, Anna; Piechota, Mariusz

2016-01-01

Scoring systems in critical care patients are essential for predicting of the patient outcome and evaluating the therapy. In this study, we determined the value of the Acute Physiology and Chronic Health Evaluation II (APACHE II), Simplified Acute Physiology Score II (SAPS II), Sequential Organ Failure Assessment (SOFA) and Glasgow Coma Scale (GCS) scoring systems in the prediction of mortality in adult patients admitted to the intensive care unit (ICU) with severe purulent bacterial meningitis. We retrospectively analysed data from 98 adult patients with severe purulent bacterial meningitis who were admitted to the single ICU between March 2006 and September 2015. Univariate logistic regression identified the following risk factors of death in patients with severe purulent bacterial meningitis: APACHE II, SAPS II, SOFA, and GCS scores, and the lengths of ICU stay and hospital stay. The independent risk factors of patient death in multivariate analysis were the SAPS II score, the length of ICU stay and the length of hospital stay. In the prediction of mortality according to the area under the curve, the SAPS II score had the highest accuracy followed by the APACHE II, GCS and SOFA scores. For the prediction of mortality in a patient with severe purulent bacterial meningitis, SAPS II had the highest accuracy.

Synthesis, characterization and anti-microbial evaluation of Cu(II), Ni(II), Pt(II) and Pd(II) sulfonylhydrazone complexes; 2D-QSAR analysis of Ni(II) complexes of sulfonylhydrazone derivatives

NASA Astrophysics Data System (ADS)

Özbek, Neslihan; Alyar, Saliha; Alyar, Hamit; Şahin, Ertan; Karacan, Nurcan

2013-05-01

Copper(II), nickel(II), platinum(II) and palladium(II) complexes with 2-hydroxy-1-naphthaldehyde-N-methylpropanesulfonylhydrazone (nafpsmh) derived from propanesulfonic acid-1-methylhydrazide (psmh) were synthesized, their structure were identified, and antimicrobial activity of the compounds was screened against three Gram-positive and three Gram-negative bacteria. The results of antimicrobial studies indicate that Pt(II) and Pd(II) complexes showed the most activity against all bacteria. The crystal structure of 2-hydroxy-1-naphthaldehyde-N-methylpropanesulfonylhydrazone (nafpsmh) was also investigated by X-ray analysis. A series of Ni(II) sulfonyl hydrazone complexes (1-33) was synthesized and tested in vitro against Escherichia coli and Staphylococcus aureus. Their antimicrobial activities were used in the QSAR analysis. Four-parameter QSAR models revealed that nucleophilic reaction index for Ni and O atoms, and HOMO-LUMO energy gap play key roles in the antimicrobial activity.

Neurodevelopmental effects of insulin-like growth factor signaling

PubMed Central

O’Kusky, John; Ye, Ping

2012-01-01

Insulin-like growth factor (IGF) signaling greatly impacts the development and growth of the central nervous system (CNS). IGF-I and IGF-II, two ligands of the IGF system, exert a wide variety of actions both during development and in adulthood, promoting the survival and proliferation of neural cells. The IGFs also influence the growth and maturation of neural cells, augmenting dendritic growth and spine formation, axon outgrowth, synaptogenesis, and myelination. Specific IGF actions, however, likely depend on cell type, developmental stage, and local microenvironmental milieu within the brain. Emerging research also indicates that alterations in IGF signaling likely contribute to the pathogenesis of some neurological disorders. This review summarizes experimental studies and shed light on the critical roles of IGF signaling, as well as its mechanisms, during CNS development. PMID:22710100

c-Jun binds the N terminus of human TAF(II)250 to derepress RNA polymerase II transcription in vitro.

PubMed

Lively, T N; Ferguson, H A; Galasinski, S K; Seto, A G; Goodrich, J A

2001-07-06

c-Jun is an oncoprotein that activates transcription of many genes involved in cell growth and proliferation. We studied the mechanism of transcriptional activation by human c-Jun in a human RNA polymerase II transcription system composed of highly purified recombinant and native transcription factors. Transcriptional activation by c-Jun depends on the TATA-binding protein (TBP)-associated factor (TAF) subunits of transcription factor IID (TFIID). Protein-protein interaction assays revealed that c-Jun binds with high specificity to the largest subunit of human TFIID, TAF(II)250. The region of TAF(II)250 bound by c-Jun lies in the N-terminal 163 amino acids. This same region of TAF(II)250 binds to TBP and represses its interaction with TATA boxes, thereby decreasing DNA binding by TFIID. We hypothesized that c-Jun is capable of derepressing the effect of the TAF(II)250 N terminus on TFIID-driven transcription. In support of this hypothesis, we found that c-Jun increased levels of TFIID-driven transcription in vitro when added at high concentrations to a DNA template lacking activator protein 1 (AP-1) sites. Moreover, c-Jun blocked the repression of TBP DNA binding caused by the N terminus of TAF(II)250. In addition to revealing a mechanism by which c-Jun activates transcription, our studies provide the first evidence that an activator can bind directly to the N terminus of TAF(II)250 to derepress RNA polymerase II transcription in vitro.

Bipolar II disorder as a risk factor for postpartum depression.

PubMed

Mandelli, Laura; Souery, Daniel; Bartova, Lucie; Kasper, Siegfried; Montgomery, Stuart; Zohar, Joseph; Mendlewicz, Julien; Serretti, Alessandro

2016-11-01

There is evidence for a bipolar diathesis in postpartum depression (PPD) and women presenting with a first PPD frequently receive a diagnosis of bipolar type II disorder (BD-II). However formal evidence for an association between BD-II and PPD has not yet been reported. In the present study we tested a potential association between BD-II and PPD. Parous women with a diagnosis of bipolar type I disorder (BD-I) (n=93), BD-II (n=36) or major depressive disorder (MDD) (n=444) were considered in the present study. All women were retrospectively evaluated for history of PPD (DSM-IV criteria) and other clinical and socio-demographic features. Women with a history of PDD (n=139, 24%) were younger, younger at illness onset and had more family history for BD compared to women without history of PPD (n=436, 75.9%). Half of BD-II women reported PPD (50%), compared to less than one-third of BD-I and MDD women (respectively 27.5% and 21.6%) (p=0.004). Limitations include the retrospective assessment of PPD and no available data about the timing of postpartum episodes, illness onset or psychiatric care before or after childbirth, and the number of postpartum episodes. BD-II may confer a remarkable risk for PPD, which may be even higher than that of women affected by BD-I disorder. Careful monitoring of BD-II women during the pregnancy and postpartum period, as well as assessment of bipolar features in women with a PPD without a current diagnosis of BD are recommended. Copyright © 2016 Elsevier B.V. All rights reserved.

Expression of serum insulin-like growth factors, insulin-like growth factor-binding proteins, and the growth hormone-binding protein in heterozygote relatives of Ecuadorian growth hormone receptor deficient patients.

PubMed

Fielder, P J; Guevara-Aguirre, J; Rosenbloom, A L; Carlsson, L; Hintz, R L; Rosenfeld, R G

1992-04-01

Recently, an isolated population of apparent GH-receptor deficient (GHRD) patients has been identified in the Loja province of southern Ecuador. These individuals presented many of the physical and biochemical phenotypes characteristic of Laron-Syndrome and are believed to have a defect in the GH-receptor gene. In this study, we have compared the biochemical phenotypes between the affected individuals and their parents, considered to be obligate heterozygotes for the disorder. Serum GH, insulin-like growth factor I and II (IGF-I and IGF-II) levels were measured by RIA Insulin-like growth factor binding proteins. (IGFBPs) were measured by Western ligand blotting (WLB) of serum samples, following separation by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and relative quantitation of serum IGFBPs was performed with a scanning laser densitometer. Serum GH-binding protein (GHBP) levels were measured with a ligand-mediated immunofunctional assay using a monoclonal antibody raised against the GHBP. These values were then compared to values obtained from normal, sex-matched adult Ecuadorian controls, to determine if the above parameters were abnormal in the heterozygotes. The serum IGF-I levels of the GHRD patients were less than 13% of control values for adults and 2% for children. However, the IGF-I levels of both the mothers and fathers were not significantly different from that of the control population. The serum IGF-II levels of the GHRD patients were approximately 20% of control values for adults and 12% for the children. The IGF-II levels of the mothers were reduced, but were not significantly different from that of the control population. However, IGF-II levels of the fathers were significantly lower than those of controls (64% of control male levels). WLB analysis of serum IGFBP levels of the affected subjects demonstrated increased IGFBP-2 and decreased IGFBP-3, suggesting an inverse relationship between these IGFBPs. The GHRD patients who had the

Synthesis, spectroscopic characterization, first order nonlinear optical properties and DFT calculations of novel Mn(II), Co(II), Ni(II), Cu(II) and Zn(II) complexes with 1,3-diphenyl-4-phenylazo-5-pyrazolone ligand

NASA Astrophysics Data System (ADS)

Abdel-Latif, Samir A.; Mohamed, Adel A.

2018-02-01

Novel Mn(II), Co(II), Ni(II), Cu(II) and Zn(II) metal ions with 1,3-diphenyl-4-phenylazo-5-pyrazolone (L) have been prepared and characterized using different analytical and spectroscopic techniques. 1:1 Complexes of Mn(II), Co(II) and Zn(II) are distorted octahedral whereas Ni(II) complex is square planar and Cu(II) is distorted trigonal bipyramid. 1:2 Complexes of Mn(II), Co(II), Cu(II) and Zn(II) are distorted trigonal bipyramid whereas Ni(II) complex is distorted tetrahedral. All complexes behave as non-ionic in dimethyl formamide (DMF). The electronic structure and nonlinear optical parameters (NLO) of the complexes were investigated theoretically at the B3LYP/GEN level of theory. Molecular stability and bond strengths have been investigated by applying natural bond orbital (NBO) analysis. The geometries of the studied complexes are non-planner. DFT calculations have been also carried out to calculate the global properties; hardness (η), global softness (S) and electronegativity (χ). The calculated small energy gap between HOMO and LUMO energies shows that the charge transfer occurs within the complexes. The total static dipole moment (μtot), the mean polarizability (<α>), the anisotropy of the polarizability (Δα) and the mean first-order hyperpolarizability (<β>) were calculated and compared with urea as a reference material. The complexes show implying optical properties.

Zn(II) stimulation of Fe(II)-activated repression in the iron-dependent repressor from Mycobacterium tuberculosis.

PubMed

Stapleton, Brian; Walker, Lawrence R; Logan, Timothy M

2013-03-19

Thermodynamic measurements of Fe(II) binding and activation of repressor function in the iron-dependent repressor from Mycobacterium tuberculosis (IdeR) are reported. IdeR, a member of the diphtheria toxin repressor family of proteins, regulates iron homeostasis and contributes to the virulence response in M. tuberculosis. Although iron is the physiological ligand, this is the first detailed analysis of iron binding and activation in this protein. The results showed that IdeR binds 2 equiv of Fe(II) with dissociation constants that differ by a factor of 25. The high- and low-affinity iron binding sites were assigned to physical binding sites I and II, respectively, using metal binding site mutants. IdeR was also found to contain a high-affinity Zn(II) binding site that was assigned to physical metal binding site II through the use of binding site mutants and metal competition assays. Fe(II) binding was modestly weaker in the presence of Zn(II), but the coupled metal binding-DNA binding affinity was significantly stronger, requiring 30-fold less Fe(II) to activate DNA binding compared to Fe(II) alone. Together, these results suggest that IdeR is a mixed-metal repressor, where Zn(II) acts as a structural metal and Fe(II) acts to trigger the physiologically relevant promoter binding. This new model for IdeR activation provides a better understanding of IdeR and the biology of iron homeostasis in M. tuberculosis.

Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels.

PubMed

Bonilla, Carolina; Lewis, Sarah J; Rowlands, Mari-Anne; Gaunt, Tom R; Davey Smith, George; Gunnell, David; Palmer, Tom; Donovan, Jenny L; Hamdy, Freddie C; Neal, David E; Eeles, Rosalind; Easton, Doug; Kote-Jarai, Zsofia; Al Olama, Ali Amin; Benlloch, Sara; Muir, Kenneth; Giles, Graham G; Wiklund, Fredrik; Grönberg, Henrik; Haiman, Christopher A; Schleutker, Johanna; Nordestgaard, Børge G; Travis, Ruth C; Pashayan, Nora; Khaw, Kay-Tee; Stanford, Janet L; Blot, William J; Thibodeau, Stephen; Maier, Christiane; Kibel, Adam S; Cybulski, Cezary; Cannon-Albright, Lisa; Brenner, Hermann; Park, Jong; Kaneva, Radka; Batra, Jyotsna; Teixeira, Manuel R; Pandha, Hardev; Lathrop, Mark; Martin, Richard M; Holly, Jeff M P

2016-10-01

Circulating insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are associated with prostate cancer. Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. We identified from the literature 56 single nucleotide polymorphisms (SNPs) in the IGF axis previously associated with biomarker levels (8 from a genome-wide association study [GWAS] and 48 in reported candidate genes). In ∼700 men without prostate cancer and two replication cohorts (N ∼ 900 and ∼9,000), we examined the properties of these SNPS as instrumental variables (IVs) for IGF-I, IGF-II, IGFBP-2 and IGFBP-3. Those confirmed as strong IVs were tested for association with prostate cancer risk, low (< 7) vs. high (≥ 7) Gleason grade, localised vs. advanced stage, and mortality, in 22,936 controls and 22,992 cases. IV analysis was used in an attempt to estimate the causal effect of circulating IGF peptides on prostate cancer. Published SNPs in the IGFBP1/IGFBP3 gene region, particularly rs11977526, were strong instruments for IGF-II and IGFBP-3, less so for IGF-I. Rs11977526 was associated with high (vs. low) Gleason grade (OR per IGF-II/IGFBP-3 level-raising allele 1.05; 95% CI: 1.00, 1.10). Using rs11977526 as an IV we estimated the causal effect of a one SD increase in IGF-II (∼265 ng/mL) on risk of high vs. low grade disease as 1.14 (95% CI: 1.00, 1.31). Because of the potential for pleiotropy of the genetic instruments, these findings can only causally implicate the IGF pathway in general, not any one specific biomarker. © 2016 UICC.

Clinical Evaluation of Insulin like Growth Factor-I and Vascular Endothelial Growth Factor with Alloplastic Bone Graft Material in the Management of Human Two Wall Intra-Osseous Defects

PubMed Central

Dixit, Jaya

2016-01-01

Introduction In recent years, emphasis on the use of growth factors for periodontal healing is gaining great momentum. Several growth factors showed promising results in periodontal regeneration. Aim This study was designed to compare the clinical outcomes of 0.8μg recombinant human Vascular Endothelial Growth Factor (rh-VEGF) and 10μg recombinant human Insulin Like Growth Factor-I (rh-IGF-I) with β-Tricalcium Phosphate (β-TCP) and Polylactide-Polyglycolide Acid (PLGA) membrane in two wall intra-osseous defects. Materials and Methods A total of 29 intra-osseous defects in 27 subjects were randomly divided into 3 test and 1 control group. Test group I (n=8) received rh-VEGF+ rh-IGF-I, Test group II (n=7) rh-VEGF, Test group III (n=7) rh-IGF-I and control group (n=7) with no growth factor, β-TCP and PLGA membrane was used in all the groups. Baseline soft tissue parameters including Probing Pocket Depth (PPD), Clinical Attachment Level (CAL), and Gingival Recession (GR) at selected sites were recorded at baseline and at 6 months. Intrasurgically, intra-osseous component was calculated as a) Cemento-Enamel Junction to Bone Crest (CEJ to BC), b) Bone Crest to Base of the Defect (BC to BD) at baseline and at re-entry. The mean changes at baseline and after 6 months within each group were compared using Wilcoxon Signed Rank Test. The mean changes for each parameter between groups were compared using Mann-Whitney U test. Results After 6 months, maximum mean PPD reduction occurred in test group I followed by test group II, III and control group. Similar trend was observed in CAL gain. Non-significant GR was present in test group I and control group whereas in test group II and III GR was absent. The use of rh-VEGF+ rhIGF-I exhibited 95.8% osseous fill as compared to 54.8% in test group II, 52.7% in test group III and 41.1 % in the control group. Conclusion Within the limitations of this study, it can be concluded that, rh-IGF-I+rh-VEGF treated sites resulted in greater

The growth hormone-insulin-like growth factor axis in glycogen storage disease type 1: evidence of different growth patterns and insulin-like growth factor levels in patients with glycogen storage disease type 1a and 1b.

PubMed

Melis, Daniela; Pivonello, Rosario; Parenti, Giancarlo; Della Casa, Roberto; Salerno, Mariacarolina; Balivo, Francesca; Piccolo, Pasquale; Di Somma, Carolina; Colao, Annamaria; Andria, Generoso

2010-04-01

To investigate the growth hormone (GH)-insulin-like growth factor (IGF) system in patients with glycogen storage disease type 1 (GSD1). This was a prospective, case-control study. Ten patients with GSD1a and 7 patients with GSD1b who were given dietary treatment and 34 sex-, age-, body mass index-, and pubertal stage-matched control subjects entered the study. Auxological parameters were correlated with circulating GH, either at basal or after growth hormone releasing hormone plus arginine test, insulin-like growth factors (IGF-I and IGF-II), and anti-pituitary antibodies (APA). Short stature was detected in 10.0% of patients with GSD1a, 42.9% of patients with GSD1b (P = .02), and none of the control subjects. Serum IGF-I levels were lower in patients with GSD1b (P = .0001). An impaired GH secretion was found in 40% of patients with GSD1a (P = .008), 57.1% of patients with GSD1b (P = .006), and none of the control subjects. Short stature was demonstrated in 3 of 4 patients with GSD1b and GH deficiency. The prevalence of APA was significantly higher in patients with GSD1b than in patients with GSD1a (P = .02) and control subjects (P = .03). The GH response to the provocative test inversely correlated with the presence of APA (P = .003). Compared with levels in control subjects, serum IGF-II and insulin levels were higher in both groups of patients, in whom IGF-II levels directly correlated with height SD scores (P = .003). Patients with GSD1a have an impaired GH secretion associated with reference range serum IGF-I levels and normal stature, whereas in patients with GSD1b, the impaired GH secretion, probably because of the presence of APA, was associated with reduced IGF-I levels and increased prevalence of short stature. The increased IGF-II levels, probably caused by increased insulin levels, in patients with GSD1 are presumably responsible for the improved growth pattern observed in patients receiving strict dietary treatment. Copyright 2010 Mosby, Inc. All

Class II ADP-ribosylation Factors Are Required for Efficient Secretion of Dengue Viruses*

PubMed Central

Kudelko, Mateusz; Brault, Jean-Baptiste; Kwok, Kevin; Li, Ming Yuan; Pardigon, Nathalie; Peiris, J. S. Malik; Bruzzone, Roberto; Desprès, Philippe; Nal, Béatrice; Wang, Pei Gang

2012-01-01

Identification and characterization of virus-host interactions are very important steps toward a better understanding of the molecular mechanisms responsible for disease progression and pathogenesis. To date, very few cellular factors involved in the life cycle of flaviviruses, which are important human pathogens, have been described. In this study, we demonstrate a crucial role for class II Arf proteins (Arf4 and Arf5) in the dengue flavivirus life cycle. We show that simultaneous depletion of Arf4 and Arf5 blocks recombinant subviral particle secretion for all four dengue serotypes. Immunostaining analysis suggests that class II Arf proteins are required at an early pre-Golgi step for dengue virus secretion. Using a horseradish peroxidase protein fused to a signal peptide, we show that class II Arfs act specifically on dengue virus secretion without altering the secretion of proteins through the constitutive secretory pathway. Co-immunoprecipitation data demonstrate that the dengue prM glycoprotein interacts with class II Arf proteins but not through its C-terminal VXPX motif. Finally, experiments performed with replication-competent dengue and yellow fever viruses demonstrate that the depletion of class II Arfs inhibits virus secretion, thus confirming their implication in the virus life cycle, although data obtained with West Nile virus pointed out the differences in virus-host interactions among flaviviruses. Our findings shed new light on a molecular mechanism used by dengue viruses during the late stages of the life cycle and demonstrate a novel function for class II Arf proteins. PMID:22105072

The inhibition of IGF-1 signaling promotes proteostasis by enhancing protein aggregation and deposition.

PubMed

Moll, Lorna; Ben-Gedalya, Tziona; Reuveni, Hadas; Cohen, Ehud

2016-04-01

The discovery that the alteration of aging by reducing the activity of the insulin/IGF-1 signaling (IIS) cascade protects nematodes and mice from neurodegeneration-linked, toxic protein aggregation (proteotoxicity) raises the prospect that IIS inhibitors bear therapeutic potential to counter neurodegenerative diseases. Recently, we reported that NT219, a highly efficient IGF-1 signaling inhibitor, protects model worms from the aggregation of amyloid β peptide and polyglutamine peptides that are linked to the manifestation of Alzheimer's and Huntington's diseases, respectively. Here, we employed cultured cell systems to investigate whether NT219 promotes protein homeostasis (proteostasis) in mammalian cells and to explore its underlying mechanisms. We found that NT219 enhances the aggregation of misfolded prion protein and promotes its deposition in quality control compartments known as "aggresomes." NT219 also elevates the levels of certain molecular chaperones but, surprisingly, reduces proteasome activity and impairs autophagy. Our findings show that IGF-1 signaling inhibitors in general and NT219 in particular can promote proteostasis in mammalian cells by hyperaggregating hazardous proteins, thereby bearing the potential to postpone the onset and slow the progression of neurodegenerative illnesses in the elderly.-Moll, L., Ben-Gedalya, T., Reuveni, H., Cohen, E. The inhibition of IGF-1 signaling promotes proteostasis by enhancing protein aggregation and deposition. © FASEB.

Human transcription factor hTAF(II)150 (CIF150) is involved in transcriptional regulation of cell cycle progression.

PubMed

Martin, J; Halenbeck, R; Kaufmann, J

1999-08-01

Here we present evidence that CIF150 (hTAF(II)150), the human homolog of Drosophila TAF(II)150, plays an important and selective role in establishing gene expression patterns necessary for progression through the cell cycle. Gel filtration experiments demonstrate that CIF150 (hTAF(II)150) seems to be less tightly associated with human transcription factor IID than hTAF(II)130 is associated with hTAF(II)250. The transient functional knockout of CIF150 (hTAF(II)150) protein led to cell cycle arrest at the G(2)/M transition in mammalian cell lines. PCR display analysis with the RNA derived from CIF150-depleted cells indicated that CIF150 (hTAF(II)150) is required for the transcription of only a subset of RNA polymerase II genes. CIF150 (hTAF(II)150) directly stimulated cyclin B1 and cyclin A transcription in cotransfection assays and in vitro assays, suggesting that the expression of these genes is dependent on CIF150 (hTAF(II)150) function. We defined a CIF150 (hTAF(II)150) consensus binding site and demonstrated that a CIF150-responsive cis element is present in the cyclin B1 core promoter. These results suggest that one function of CIF150 (hTAF(II)150) is to select specific RNA polymerase II core promoter elements involved in cell cycle progression.

Human conditions of insulin-like growth factor-I (IGF-I) deficiency

PubMed Central

2012-01-01

Insulin-like growth factor I (IGF-I) is a polypeptide hormone produced mainly by the liver in response to the endocrine GH stimulus, but it is also secreted by multiple tissues for autocrine/paracrine purposes. IGF-I is partly responsible for systemic GH activities although it possesses a wide number of own properties (anabolic, antioxidant, anti-inflammatory and cytoprotective actions). IGF-I is a closely regulated hormone. Consequently, its logical therapeutical applications seems to be limited to restore physiological circulating levels in order to recover the clinical consequences of IGF-I deficiency, conditions where, despite continuous discrepancies, IGF-I treatment has never been related to oncogenesis. Currently the best characterized conditions of IGF-I deficiency are Laron Syndrome, in children; liver cirrhosis, in adults; aging including age-related-cardiovascular and neurological diseases; and more recently, intrauterine growth restriction. The aim of this review is to summarize the increasing list of roles of IGF-I, both in physiological and pathological conditions, underlying that its potential therapeutical options seem to be limited to those proven states of local or systemic IGF-I deficiency as a replacement treatment, rather than increasing its level upper the normal range. PMID:23148873

Chelation of Cu(II), Zn(II), and Fe(II) by tannin constituents of selected edible nuts.

PubMed

Karamać, Magdalena

2009-12-22

The tannin fractions isolated from hazelnuts, walnuts and almonds were characterised by colorimetric assays and by an SE-HPLC technique. The complexation of Cu(II) and Zn(II) was determined by the reaction with tetramethylmurexide, whereas for Fe(II), ferrozine was employed. The walnut tannins exhibited a significantly weaker reaction with the vanillin/HCl reagent than hazelnut and almond tannins, but the protein precipitation capacity of the walnut fraction was high. The SE-HPLC chromatogram of the tannin fraction from hazelnuts revealed the presence of oligomers with higher molecular weights compared to that of almonds. Copper ions were most effectively chelated by the constituents of the tannin fractions of hazelnuts, walnuts and almonds. At a 0.2 mg/assay addition level, the walnut tannins complexed almost 100% Cu(II). The Fe(II) complexation capacities of the tannin fractions of walnuts and hazelnuts were weaker in comparison to that of the almond tannin fraction, which at a 2.5 mg/assay addition level, bound Fe(II) by approximately 90%. The capacity to chelate Zn(II) was quite varied for the different nut tannin fractions: almond tannins bound as much as 84% Zn(II), whereas the value for walnut tannins was only 8.7%; and for hazelnut tannins, no Zn(II) chelation took place at the levels tested.

Chelation of Cu(II), Zn(II), and Fe(II) by Tannin Constituents of Selected Edible Nuts

PubMed Central

Karamać, Magdalena

2009-01-01

The tannin fractions isolated from hazelnuts, walnuts and almonds were characterised by colorimetric assays and by an SE-HPLC technique. The complexation of Cu(II) and Zn(II) was determined by the reaction with tetramethylmurexide, whereas for Fe(II), ferrozine was employed. The walnut tannins exhibited a significantly weaker reaction with the vanillin/HCl reagent than hazelnut and almond tannins, but the protein precipitation capacity of the walnut fraction was high. The SE-HPLC chromatogram of the tannin fraction from hazelnuts revealed the presence of oligomers with higher molecular weights compared to that of almonds. Copper ions were most effectively chelated by the constituents of the tannin fractions of hazelnuts, walnuts and almonds. At a 0.2 mg/assay addition level, the walnut tannins complexed almost 100% Cu(II). The Fe(II) complexation capacities of the tannin fractions of walnuts and hazelnuts were weaker in comparison to that of the almond tannin fraction, which at a 2.5 mg/assay addition level, bound Fe(II) by ~90%. The capacity to chelate Zn(II) was quite varied for the different nut tannin fractions: almond tannins bound as much as 84% Zn(II), whereas the value for walnut tannins was only 8.7%; and for hazelnut tannins, no Zn(II) chelation took place at the levels tested. PMID:20054482

Nonmuscle Myosin II Is Required for Internalization of the Epidermal Growth Factor Receptor and Modulation of Downstream Signaling*

PubMed Central

Kim, Jong Hyun; Wang, Aibing; Conti, Mary Anne; Adelstein, Robert S.

2012-01-01

Ligand-induced internalization of the epidermal growth factor receptor (EGFR) is an important process for regulating signal transduction, cellular dynamics, and cell-cell communication. Here, we demonstrate that nonmuscle myosin II (NM II) is required for the internalization of the EGFR and to trigger the EGFR-dependent activation of ERK and AKT. The EGFR was identified as a protein that interacts with NM II by co-immunoprecipitation and mass spectrometry analysis. This interaction requires both the regulatory light chain 20 (RLC20) of NM II and the kinase domain of the EGFR. Two paralogs of NM II, NM II-A, and NM II-B can act to internalize the EGFR, depending on the cell type and paralog content of the cell line. Loss (siRNA) or inhibition (25 μm blebbistatin) of NM II attenuates the internalization of the EGFR and impairs EGFR-dependent activation of ERK and AKT. Both internalization of the EGFR and downstream signaling to ERK and AKT can be partially restored in siRNA-treated cells by introduction of wild type (WT) GFP-NM II, but cannot be restored by motor mutant NM II. Taken together, these results suggest that NM II plays a role in the internalization of the EGFR and EGFR-mediated signaling pathways. PMID:22718763

Roles of insulin-like growth factors in metamorphic development of turbot (Scophthalmus maximus).

PubMed

Jia, Yudong

2018-01-31

Larval turbot (Scophthalmus maximus) undergo metamorphosis, a late post-embryonic developmental event that precedes juvenile transition. Insulin-like growth factors (IGFs) are important endocrine/autocrine/paracrine factors that provide essential signals to control of the embryonic and postnatal development of vertebrate species, including fish. Accumulating evidence suggests that IGFs are involved in regulating the metamorphic development of flatfish. This mini review focus on the functions of all known IGFs (IGF-I and IGF-II) during the metamorphic development of turbot. Information about IGFs and insulin-like growth factors binding proteins (IGFBPs) from other teleosts is also included in this review to provide an overview of IGFs functions in the metamorphic development of turbot. These findings may enhance our understanding of the potential roles of the IGFs system in controlling of flatfish metamorphosis and contributing to the improvement of broodstock management strategies for larval turbot. Copyright © 2018 Elsevier Inc. All rights reserved.

Synthesis, characterization, nucleic acid interactions and photoluminescent properties of methaniminium hydrazone Schiff base and its Mn(II), Co(II), Ni(II), Cu(II), Zn(II) and Cd(II) complexes

NASA Astrophysics Data System (ADS)

Sennappan, M.; Murali Krishna, P.; Hosamani, Amar A.; Hari Krishna, R.

2018-07-01

An environmental benign and efficient reaction was carried out via amine exchange and condensation reaction in water and methanol mixture (3:1) and absence of catalyst between 1-[3-(2-hydroxy benzylidene)amine)phenyl]ethanone and benzhydrazide yields methaniminium hydrazone Schiff base in high yield. The prepared ligand was structurally characterized by using single crystal XRD, elemental analysis and spectroscopy (UV-Vis, FT-IR, LC-MS and NMR) techniques. The crystal data indicates the ligand crystallizes in orthorhombic system with Pna21 space group. Further, the ligand was used in synthesis of mononuclear Mn(II), Co(II), Ni(II), Cu(II), Zn(II) and Cd(II) complexes and were characterized by elemental analysis, magnetic moment and spectroscopy (UV-Vis, FT-IR and ESR) studies. The spectral data showed that ligand is coordinated to the metal ion through azomethine nitrogen and methaniminium nitrogen. The DNA binding absorption titrations reveals that, ligand, L and its metal complexes, 1-6 are avid binders to CT- DNA. The apparent binding constant values of compounds are in the order of 106 M-1. The nuclease activity of ligand, L and its metal complexes, 1-6 were investigated by gel electrophoresis method using pUC18 DNA. The photoluminescent properties of the methaniminium hydrazone ligand, L and its various metal complexes, 1-6 were investigated. The emission spectra of both ligand (L) and metal complexes (1-6) exhibits emission in the range of blue to red.

Spectroscopic and mycological studies of Co(II), Ni(II) and Cu(II) complexes with 4-aminoantipyrine derivative

NASA Astrophysics Data System (ADS)

Sharma, Amit Kumar; Chandra, Sulekh

2011-10-01

Complexes of the type [M(L)X 2], where M = Co(II), Ni(II) and Cu(II), have been synthesized with novel NO-donor Schiff's base ligand, 1,4-diformylpiperazine bis(4-imino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one) which is obtained by the acid catalyzed condensation of 1,4-diformylpiperazine with 4-aminoantipyrine. The elemental analyses, molar conductance measurements, magnetic susceptibility measurements, IR, UV, NMR, mass and EPR studies of the compounds led to the conclusion that the ligand acts as tetradentate chelate. The Schiff's base ligand forms hexacoordinated complexes having octahedral geometry for Ni(II) and tetragonal geometry for Co(II) and Cu(II) complexes. The mycological studies of the compounds were examined against the several opportunistic pathogens, i.e., Alternaria brassicae, Aspergillus niger and Fusarium oxysporum. The Cu(II) complexes were found to have most fungicidal behavior.

Activity of insulin growth factors and shrimp neurosecretory organ extracts on a lepidopteran cell line.

PubMed

Hatt, P J; Liebon, C; Morinière, M; Oberlander, H; Porcheron, P

1997-01-01

Ecdysteroids, or molting hormones, have been proven to be key differentiation regulators for epidermal cells in the postembryonic development of arthropods. Regulators of cell proliferation, however, remain largely unknown. To date, no diffusible insect peptidic growth factors have been characterized. Molecules structurally related to insulin have been discovered in insects, as in other eucaryotes. We developed in vitro tests for the preliminary characterization of potential growth factors in arthropods by adapting the procedures designed to detect such factors in vertebrates to an insect cell line (IAL-PID2) established from imaginal discs of the Indian meal moth. We verified the ability of these tests to measure the proliferation of IAL-PID2 cells. We tested mammalian insulin and insulin-like growth factors (IGF-I, IGF-II). Following an arrest of cell proliferation by serum deprivation, IGF-I and IGF-II caused partial resumption of the cell cycle, evidenced by DNA synthesis. In contrast, the addition of 20-hydroxyecdysone arrested the proliferation of the IAL-PID2 cells. The cell line was then used in a test for functional characterization of potential growth factors originating from the penaeid shrimp, Penaeus vannamei. Crude extracts of neurosecretory and nervous tissues, eyestalks, and ventral neural chain compensated for serum deprivation and stimulated completion of mitosis. Arch.

Insulin growth factor-1 (IGF-1) enhances hippocampal excitatory and seizure activity through IGF-1 receptor-mediated mechanisms in the epileptic brain.

PubMed

Jiang, Guohui; Wang, Wei; Cao, Qingqing; Gu, Juan; Mi, Xiujuan; Wang, Kewei; Chen, Guojun; Wang, Xuefeng

2015-12-01

Insulin-like growth factor-1 (IGF-1) is known to promote neurogenesis and survival. However, recent studies have suggested that IGF-1 regulates neuronal firing and excitatory neurotransmission. In the present study, focusing on temporal lobe epilepsy, we found that IGF-1 levels and IGF-1 receptor activation are increased in human epileptogenic tissues, and pilocarpine- and pentylenetetrazole-treated rat models. Using an acute model of seizures, we showed that lateral cerebroventricular infusion of IGF-1 elevates IGF-1 receptor (IGF-1R) signalling before pilocarpine application had proconvulsant effects. In vivo electroencephalogram recordings and power spectrogram analysis of local field potential revealed that IGF-1 promotes epileptiform activities. This effect is diminished by co-application of an IGF-1R inhibitor. In an in vitro electrophysiological study, we demonstrated that IGF-1 enhancement of excitatory neurotransmission and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor- and N-methyl-D-aspartate receptor-mediated currents is inhibited by IGF-1R inhibitor. Finally, activation of extracellular signal-related kinase (ERK)-1/2 and protein kinase B (Akt) in seizures in rats is increased by exogenous IGF-1 and diminished by picropodophyllin. A behavioural study reveals that the ERK1/2 or Akt inhibitor attenuates seizure activity. These results indicate that increased IGF-1 levels after recurrent hippocampal neuronal firings might, in turn, promote seizure activity via IGF-1R-dependent mechanisms. The present study presents a previously unappreciated role of IGF-1R in the development of seizure activity. © 2015 Authors; published by Portland Press Limited.

Evidence for growth hormone/insulin-like growth factor I axis regulation of seawater acclimation in the euryhaline teleost Fundulus heteroclitus

USGS Publications Warehouse

Mancera, J.M.; McCormick, S.D.

1998-01-01

The ability of ovine growth hormone (oGH), recombinant bovine insulin- like growth factor I (rbIGF-I), recombinant human insulin-like growth factor II (rhIGF-II), and bovine insulin to increase hypoosmoregulatory capacity in the euryhaline teleost Fundulus heteroclitus was examined. Fish acclimated to brackish water (BW, 10 ppt salinity, 320 mOsm/kg H2O) were injected with a single dose of hormone and transferred to seawater (SW, 35 ppt salinity, 1120 mOsm/kg H2O) 2 days later. Fish were sampled 24 h after transfer and plasma osmolality, plasma glucose, and gill Na+,K+-ATPase activity were examined. Transfer from BW to SW increased plasma osmolality and gill Na+,K+-ATPase activity. Transfer from BW to BW had no effect on these parameters. rbIGF-I (0.05, 0.1, and 0.2 ??g/g) improved the ability to maintain plasma osmolality and to increase gill Na+, K+-ATPase activity in a dose-dependent manner. oGH (0.5, 1, and 2 ??g/g) also increased hypoosmoregulatory ability but only the higher doses (2 ??g/g) significantly increased gill Na+,K+-ATPase activity. oGH (1 ??g/g) and rbIGF-I (0.1 ??g/g) had a significantly greater effect on plasma osmolality and gill Na+,K+-ATPase activity than either hormone alone. rhIGF-II (0.05, 0.1, and 0.2 ??g/g) and bovine insulin (0.01 and 0.05 ??g/g) were without effect. The results suggest a role of GH and insulin-like growth factor I (IGF-I) in seawater acclimation of E heteroclitus. Based on these findings and previous studies, it is concluded that the capacity of the GH/IGF-I axis to increase hypoosmoregulatory ability may be a common feature of euryhalinity in teleosts.

Multi-metals column adsorption of lead(II), cadmium(II) and manganese(II) onto natural bentonite clay.

PubMed

Alexander, Jock Asanja; Surajudeen, Abdulsalam; Aliyu, El-Nafaty Usman; Omeiza, Aroke Umar; Zaini, Muhammad Abbas Ahmad

2017-10-01

The present work was aimed at evaluating the multi-metals column adsorption of lead(II), cadmium(II) and manganese(II) ions onto natural bentonite. The bentonite clay adsorbent was characterized for physical and chemical properties using X-ray diffraction, X-ray fluorescence, Brunauer-Emmett-Teller surface area and cation exchange capacity. The column performance was evaluated using adsorbent bed height of 5.0 cm, with varying influent concentrations (10 mg/L and 50 mg/L) and flow rates (1.4 mL/min and 2.4 mL/min). The result shows that the breakthrough time for all metal ions ranged from 50 to 480 minutes. The maximum adsorption capacity was obtained at initial concentration of 10 mg/L and flow rate of 1.4 mL/min, with 2.22 mg/g of lead(II), 1.71 mg/g of cadmium(II) and 0.37 mg/g of manganese(II). The order of metal ions removal by natural bentonite is lead(II) > cadmium(II) > manganese(II). The sorption performance and the dynamic behaviour of the column were predicted using Adams-Bohart, Thomas, and Yoon-Nelson models. The linear regression analysis demonstrated that the Thomas and Yoon-Nelson models fitted well with the column adsorption data for all metal ions. The natural bentonite was effective for the treatment of wastewater laden with multi-metals, and the process parameters obtained from this work can be used at the industrial scale.

Culture of prostate epithelial cells of the rhesus monkey on extracellular matrix substrate: influence of steroids and insulin-like growth factors.

PubMed

Udayakumar, T S; Jeyaraj, D A; Rajalakshmi, M; Sharma, R S

1999-09-01

Rhesus monkey prostate epithelial cells from the cranial lobe were isolated and cultured in flasks coated either with collagen IV or laminin. The effects of stromal cell medium, androgens and growth factors on cell number, thymidine incorporation and secretory activity were assessed. The results indicate that dihydrotestosterone (DHT) and androstenedione have stimulatory influences on cell proliferation and secretion in coated flasks. DHT was more effective in increasing cell number but the induction of secretory activity was similar with both steroids. The combination of IGF-I and -II resulted in inducing better cell proliferation and secretory activity than the individual IGFs but, of the two IGFs, IGF-I was more effective than IGF-II. DHT with IGFs was more potent in inducing proliferation, differentiation and secretion than androstenedione. Even in the absence of steroids or growth factors, colony formation and confluence occurred in coated flasks but cell differentiation and secretion only to a limited extent. In conclusion, we were able to establish an in vitro primary culture of prostate epithelial cells from rhesus monkey using extracellular matrix proteins, steroids and growth factors as additional supplements. This culture system may be useful to study prostate cell physiology and to identify drugs that can inhibit cell proliferation.

Fe (III), Co(II), Ni(II), Cu(II) and Zn(II) complexes of schiff bases based-on glycine and phenylalanine: Synthesis, magnetic/thermal properties and antimicrobial activity

NASA Astrophysics Data System (ADS)

Sevgi, Fatih; Bagkesici, Ugur; Kursunlu, Ahmed Nuri; Guler, Ersin

2018-02-01

Zinc (II), copper (II), nickel (II), cobalt (II) and iron (III) complexes of Schiff bases (LG, LP) derived from 2-hydroxynaphthaldehyde with glycine and phenylalanine were reported and characterized by 1H NMR, 13C NMR, elemental analyses, melting point, FT-IR, magnetic susceptibility and thermal analyses (TGA). TGA data show that iron and cobalt include to the coordinated water and metal:ligand ratio is 1:2 while the complex stoichiometry for Ni (II), Cu (II) and Zn (II) complexes is 1:1. As expected, Ni (II) and Zn (II) complexes are diamagnetic; Cu (II), Co (II) and Fe (III) complexes are paramagnetic character due to a strong ligand of LG and LP. The LG, LP and their metal complexes were screened for their antimicrobial activities against five Gram-positive (Staphylococcus aureus, Methicillin resistant Staphylococcus aureus (MRSA), Bacillus cereus, Streptococcus mutans and Enterococcus faecalis) and three Gram-negative (Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa) and one fungi (Candida albicans) by using broth microdilution techniques. The activity data show that ligands and their metal complexes exhibited moderate to good activity against Gram-positive bacteria and fungi.

[Correlation of insulin-like growth factor-1 (IGF-1) to angiogenesis of breast cancer in IGF-1-deficient mice].

PubMed

Tang, Hong-Bo; Ren, Yu-Ping; Zhang, Jun; Ma, Shi-Hui; Gao, Feng; Wu, Yi-Ping

2007-11-01

Insulin-like growth factors (IGFs) play important roles in the development and progression of tumors. But the mechanism of tumorigenesis in relation to IGF-1 is unclear yet. This study was to explore the correlation of circulating IGF-1 level to the angiogenesis of breast cancer in IGF-1-deficient mice. The liver-specific IGF-1-deficient (LID) mice and control mice were injected with 7,12-dimethybenz(a)anthracene (DMBA) to develop breast cancer. Ginsenoside Rg3 was used to intervene tumor growth. The occurrence rates of breast cancer were compared. The expression of vascular endothelial growth factor (VEGF) and microvessel density (MVD) was detected by immunohistochemistry. The occurrence rate of breast cancer was 66.67% in untreated control mice, 33.33% in untreated LID mice, 36.00% in Rg3-treated control mice, and 12.00% in Rg3-treated LID mice. The tumor size was (0.79+/-0.20) cm in untreated control mice, (0.37+/-0.08) cm in untreated LID mice, (0.32+/-0.08) cm in Rg3-treated control mice, and (0.15+/-0.05) cm in Rg3-treated LID mice. The average light density and positive rate of VEGF were the highest in untreated control mice (0.34+/-0.10 and 0.04+/-0.02, P<0.05), and the lowest in Rg3-treated LID mice (0.13+/-0.03 and 0.01+/-0.00, P<0.05). The MVD was 31.9+/-5.3 in untreated control mice, 26.8+/-4.9 in untreated LID mice, 20.1+/-4.9 in Rg3-treated control mice, and 14.4+/-4.9 in Rg3-treated LID mice. Circulating IGF-1 plays a role in the onset and development of breast cancer. Degrading serum IGF-1 level could inhibit angiogenesis and growth of breast cancer. Rg3 could promote this effect.

Chemical speciation and bioavailability of Cu(II). Study of the ionic copper(II) and bis(glycinate)-copper(II) accumulation by Lemna species

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

Benda, F.; Kouba, J.

1991-03-01

In this paper, the authors examined the accumulation of copper(II) in, and its toxic effect on, duckweed, a plant which exhibits extremely high concentration factors. The effect of copper(II) was investigated by adding it to the minimal medium in two forms: CuSO{sub 4} and (Cu(Gly){sub 2}). The neutral (2:1) tetracoordinated bis(glycinate)-copper(II) complex is constituted by two five-membered rings bonded to the central copper atom with the cis configuration. This complex was chosen to model the function of a neutral species (eliminating the charge effect) involving a nontoxic ligand, for which - in contrast to the hydrated Cu{sup 2+} species -more » direct permeation through the cell wall is conceivable.« less

Synthesis, characterization and biological activity of complexes of 2-hydroxy-3,5-dimethylacetophenoneoxime (HDMAOX) with copper(II), cobalt(II), nickel(II) and palladium(II)

NASA Astrophysics Data System (ADS)

Singh, Bibhesh K.; Jetley, Umesh K.; Sharma, Rakesh K.; Garg, Bhagwan S.

2007-09-01

A new series of complexes of 2-hydroxy-3,5-dimethyl acetophenone oxime (HDMAOX) with Cu(II), Co(II), Ni(II) and Pd(II) have been prepared and characterized by different physical techniques. Infrared spectra of the complexes indicate deprotonation and coordination of the phenolic OH. It also confirms that nitrogen atom of the oximino group contributes to the complexation. Electronic spectra and magnetic susceptibility measurements reveal square planar geometry for Cu(II), Ni(II) and Pd(II) complexes and tetrahedral geometry for Co(II) complex. The elemental analyses and mass spectral data have justified the ML 2 composition of complexes. Kinetic and thermodynamic parameters were computed from the thermal decomposition data using Coats and Redfern method. The geometry of the metal complexes has been optimized with the help of molecular modeling. The free ligand (HDMAOX) and its metal complexes have been tested in vitro against Alternarie alternate, Aspergillus flavus, Aspergillus nidulans and Aspergillus niger fungi and Streptococcus, Staph, Staphylococcus and Escherchia coli bacteria in order to assess their antimicrobial potential. The results indicate that the ligand and its metal complexes possess antimicrobial properties.

Synthesis, characterization and biological activity of complexes of 2-hydroxy-3,5-dimethylacetophenoneoxime (HDMAOX) with copper(II), cobalt(II), nickel(II) and palladium(II).

PubMed

Singh, Bibhesh K; Jetley, Umesh K; Sharma, Rakesh K; Garg, Bhagwan S

2007-09-01

A new series of complexes of 2-hydroxy-3,5-dimethyl acetophenone oxime (HDMAOX) with Cu(II), Co(II), Ni(II) and Pd(II) have been prepared and characterized by different physical techniques. Infrared spectra of the complexes indicate deprotonation and coordination of the phenolic OH. It also confirms that nitrogen atom of the oximino group contributes to the complexation. Electronic spectra and magnetic susceptibility measurements reveal square planar geometry for Cu(II), Ni(II) and Pd(II) complexes and tetrahedral geometry for Co(II) complex. The elemental analyses and mass spectral data have justified the ML(2) composition of complexes. Kinetic and thermodynamic parameters were computed from the thermal decomposition data using Coats and Redfern method. The geometry of the metal complexes has been optimized with the help of molecular modeling. The free ligand (HDMAOX) and its metal complexes have been tested in vitro against Alternarie alternate, Aspergillus flavus, Aspergillus nidulans and Aspergillus niger fungi and Streptococcus, Staph, Staphylococcus and Escherchia coli bacteria in order to assess their antimicrobial potential. The results indicate that the ligand and its metal complexes possess antimicrobial properties.

Solar Type II Radio Bursts and IP Type II Events

NASA Technical Reports Server (NTRS)

Cane, H. V.; Erickson, W. C.

2005-01-01

We have examined radio data from the WAVES experiment on the Wind spacecraft in conjunction with ground-based data in order to investigate the relationship between the shocks responsible for metric type II radio bursts and the shocks in front of coronal mass ejections (CMEs). The bow shocks of fast, large CMEs are strong interplanetary (IP) shocks, and the associated radio emissions often consist of single broad bands starting below approx. 4 MHz; such emissions were previously called IP type II events. In contrast, metric type II bursts are usually narrowbanded and display two harmonically related bands. In addition to displaying complete dynamic spectra for a number of events, we also analyze the 135 WAVES 1 - 14 MHz slow-drift time periods in 2001-2003. We find that most of the periods contain multiple phenomena, which we divide into three groups: metric type II extensions, IP type II events, and blobs and bands. About half of the WAVES listings include probable extensions of metric type II radio bursts, but in more than half of these events, there were also other slow-drift features. In the 3 yr study period, there were 31 IP type II events; these were associated with the very fastest CMEs. The most common form of activity in the WAVES events, blobs and bands in the frequency range between 1 and 8 MHz, fall below an envelope consistent with the early signatures of an IP type II event. However, most of this activity lasts only a few tens of minutes, whereas IP type II events last for many hours. In this study we find many examples in the radio data of two shock-like phenomena with different characteristics that occur simultaneously in the metric and decametric/hectometric bands, and no clear example of a metric type II burst that extends continuously down in frequency to become an IP type II event. The simplest interpretation is that metric type II bursts, unlike IP type II events, are not caused by shocks driven in front of CMEs.

Phosphate effects on copper(II) and lead(II) sorption to ferrihydrite

NASA Astrophysics Data System (ADS)

Tiberg, Charlotta; Sjöstedt, Carin; Persson, Ingmar; Gustafsson, Jon Petter

2013-11-01

Transport of lead(II) and copper(II) ions in soil is affected by the soil phosphorus status. Part of the explanation may be that phosphate increases the adsorption of copper(II) and lead(II) to iron (hydr)oxides in soil, but the details of these interactions are poorly known. Knowledge about such mechanisms is important, for example, in risk assessments of contaminated sites and development of remediation methods. We used a combination of batch experiments, extended X-ray absorption fine structure (EXAFS) spectroscopy and surface complexation modeling with the three-plane CD-MUSIC model to study the effect of phosphate on sorption of copper(II) and lead(II) to ferrihydrite. The aim was to identify the surface complexes formed and to derive constants for the surface complexation reactions. In the batch experiments phosphate greatly enhanced the adsorption of copper(II) and lead(II) to ferrihydrite at pH < 6. The largest effects were seen for lead(II).

Insulin-Like Growth Factor 1 (IGF-1) in Parkinson's Disease: Potential as Trait-, Progression- and Prediction Marker and Confounding Factors.

PubMed

Bernhard, Felix P; Heinzel, Sebastian; Binder, Gerhard; Weber, Karin; Apel, Anja; Roeben, Benjamin; Deuschle, Christian; Maechtel, Mirjam; Heger, Tanja; Nussbaum, Susanne; Gasser, Thomas; Maetzler, Walter; Berg, Daniela

2016-01-01

Biomarkers indicating trait, progression and prediction of pathology and symptoms in Parkinson's disease (PD) often lack specificity or reliability. Investigating biomarker variance between individuals and over time and the effect of confounding factors is essential for the evaluation of biomarkers in PD, such as insulin-like growth factor 1 (IGF-1). IGF-1 serum levels were investigated in up to 8 biannual visits in 37 PD patients and 22 healthy controls (HC) in the longitudinal MODEP study. IGF-1 baseline levels and annual changes in IGF-1 were compared between PD patients and HC while accounting for baseline disease duration (19 early stage: ≤3.5 years; 18 moderate stage: >4 years), age, sex, body mass index (BMI) and common medical factors putatively modulating IGF-1. In addition, associations of baseline IGF-1 with annual changes of motor, cognitive and depressive symptoms and medication dose were investigated. PD patients in moderate (130±26 ng/mL; p = .004), but not early stages (115±19, p>.1), showed significantly increased baseline IGF-1 levels compared with HC (106±24 ng/mL; p = .017). Age had a significant negative correlation with IGF-1 levels in HC (r = -.47, p = .028) and no correlation in PD patients (r = -.06, p>.1). BMI was negatively correlated in the overall group (r = -.28, p = .034). The annual changes in IGF-1 did not differ significantly between groups and were not correlated with disease duration. Baseline IGF-1 levels were not associated with annual changes of clinical parameters. Elevated IGF-1 in serum might differentiate between patients in moderate PD stages and HC. However, the value of serum IGF-1 as a trait-, progression- and prediction marker in PD is limited as IGF-1 showed large inter- and intraindividual variability and may be modulated by several confounders.

Overexpressed connective tissue growth factor in cardiomyocytes attenuates left ventricular remodeling induced by angiotensin II perfusion.

PubMed

Zhang, Ying; Yan, Hua; Guang, Gong-Chang; Deng, Zheng-Rong

2017-01-01

To evaluate the improving effects of specifically overexpressed connective tissue growth factor (CTGF) in cardiomyocytes on mice with hypertension induced by angiotensin II (AngII) perfusion, 24 transgenic mice with cardiac-restricted overexpression of CTGF (Tg-CTGF) were divided into two equal groups that were perfused with acetic acid and AngII, respectively, for 7 days. Another 24 cage-control wild-type C57BL/6 mice (NLC) were divided and treated identically. Blood pressure was detected by caudal artery cannulation. Cardiac structural and functional changes were observed by echocardiography. Cardiac fibrosis was detected by Masson staining. After AngII perfusion, blood pressures of NLC and Tg-CTGF mice, especially those of the formers, significantly increased. Compared with NLC + AngII group, Tg-CTGF + AngII group had significantly lower left ventricular posterior wall thickness at end-diastole and left ventricular posterior wall thickness at end-systole as well as significantly higher left ventricular end-systolic diameter and left ventricular end-diastolic diameter (P < 0.05). Reverse transcription-polymerase chain reaction (RT-PCR) showed that Tg-CTGF + AngII group had significantly lower collagen I, α-SMA, and TGF-β mRNA expressions in cardiac tissues (P < 0.05). Tg-CTGF can protect AngII-induced cardiac remodeling of mice with hypertension by mitigating inflammatory response. CTGF may be a therapy target for hypertension-induced myocardial fibrosis, but the detailed mechanism still needs in-depth studies.

Porous cellulosic adsorbent for the removal of Cd (II), Pb(II) and Cu(II) ions from aqueous media

NASA Astrophysics Data System (ADS)

Barsbay, Murat; Kavaklı, Pınar Akkaş; Tilki, Serhad; Kavaklı, Cengiz; Güven, Olgun

2018-01-01

The main objective of this work is to prepare a renewable cellulosic adsorbent by γ-initiated grafting of poly(glycidyl methacrylate) (PGMA) from cellulose substrate and subsequent modification of PGMA with chelating species, iminodiacetic acid (IDA), for Cd (II), Pb(II) and Cu(II) removal from aqueous media. Modification of PGMA grafted cellulose with IDA in aqueous solution under mild conditions has proceeded efficiently to yield a natural-based and effective porous adsorbent with well-defined properties as provided by the controlled polymerization technique, namely RAFT, applied during the radiation-induced graft copolymerization step and with sufficient degree of IDA immobilization as confirmed by XPS, FTIR, contact angle measurements and elemental analysis. In order to examine the Cd (II), Pb(II) and Cu(II) removing performance of the resulting adsorbent, batch experiments were carried out by ICP-MS. The adsorption capacities were determined as 53.4 mg Cd(II)/g polymer, 52.0 mg Pb(II)/g polymer and 69.6 mg Cu(II)/g polymer at initial feed concentration of 250 ppm, showing the promising potential of the natural-based adsorbent to steadily and efficiently chemisorb toxic metal ions.

Redundant role of tissue-selective TAF(II)105 in B lymphocytes.

PubMed

Freiman, Richard N; Albright, Shane R; Chu, Leslie E; Zheng, Shuang; Liang, Hong-Erh; Sha, William C; Tjian, Robert

2002-09-01

Regulated gene expression is a complex process achieved through the function of multiple protein factors acting in concert at a given promoter. The transcription factor TFIID is a central component of the machinery regulating mRNA synthesis by RNA polymerase II. This large multiprotein complex is composed of the TATA box binding protein (TBP) and several TBP-associated factors (TAF(II)s). The recent discovery of multiple TBP-related factors and tissue-specific TAF(II)s suggests the existence of specialized TFIID complexes that likely play a critical role in regulating transcription in a gene- and tissue-specific manner. The tissue-selective factor TAF(II)105 was originally identified as a component of TFIID derived from a human B-cell line. In this report we demonstrate the specific induction of TAF(II)105 in cultured B cells in response to bacterial lipopolysaccharide (LPS). To examine the in vivo role of TAF(II)105, we have generated TAF(II)105-null mice by homologous recombination. Here we show that B-lymphocyte development is largely unaffected by the absence of TAF(II)105. TAF(II)105-null B cells can proliferate in response to LPS, produce relatively normal levels of resting antibodies, and can mount an immune response by producing antigen-specific antibodies in response to immunization. Taken together, we conclude that the function of TAF(II)105 in B cells is likely redundant with the function of other TAF(II)105-related cellular proteins.

Effect of insulin-like growth factor-1 (IGF-1) plus alendronate on bone density during puberty in IGF-1-deficient MIDI mice.

PubMed

Stabnov, L; Kasukawa, Y; Guo, R; Amaar, Y; Wergedal, J E; Baylink, D J; Mohan, S

2002-06-01

Insulin-like growth factor-1 (IGF-1) increases both bone formation and bone resorption processes. To test the hypothesis that treatment with an antiresorber along with IGF-1, during the pubertal growth phase, would be more effective than IGF-1 alone to increase peak bone mass, we used an IGF-1 MIDI mouse model, which exhibits a >60% reduction in circulating IGF-1 levels. We first determined an optimal IGF-1 delivery by evaluating IGF-1 administration (2 mg/kg body weight/day) by either a single daily injection, three daily injections, or by continuous delivery via a minipump during puberty. Of the three regimens, the three daily IGF-1 injections and IGF-1 through a minipump produced a significant increase in total body bone mineral density (BMD) (6.0% and 4.4%, respectively) and in femoral BMD (4.3% and 6.2%, respectively) compared with the control group. Single subcutaneous (s.c.) administration did not increase BMD. We chose IGF-1 administration three times daily for testing the combined effects of IGF-1 and alendronate (100 microg/kg per day). The treatment of IGF-1 + alendronate for a period of 2 weeks increased total body BMD at 1 week and 3 weeks after treatment (21.1% and 20.5%, respectively) and femoral BMD by 29% at 3 weeks after treatment. These increases were significantly greater than those produced by IGF-1 alone. IGF-1, but not alendronate, increased bone length. IGF-1 and/or alendronate increased both periosteal and endosteal circumference. Combined treatment caused a greater increase in the total body bone mineral content (BMC) and periosteal circumference compared with individual treatment with IGF-1 or alendronate. Our data demonstrate that: (1) inhibition of bone turnover during puberty increases net bone density; and (2) combined treatment with IGF-1 and alendronate is more effective than IGF-1 or alendronate alone in increasing peak bone mass in an IGF-1-deficient MIDI mouse model.

Extraction and separation of Co(II) and Ni(II) from acidic sulfate solutions using Aliquat 336.

PubMed

Nayl, A A

2010-01-15

Extraction and separation of Co(II) and Ni(II) from acidic sulfate solutions by solvent extraction technique were studied using different forms of Aliquat 336 diluted with kerosene. The extraction percent of each metal ion was found to increase with increasing pH and extractant concentration. Co(II) was preferentially extracted by different forms of Aliquat 336 over Ni(II) under the same extraction conditions. From analysis of the experimental results, the extraction mechanism of R(4)N-forms was proposed with Co(II). It was found that the highest separation factor (S(Co/Ni)) value of 606.7 was obtained with 0.36 M R(4)N-SCN in kerosene from 2.0M H(2)SO(4) solution at pH 4.8 and shaking time of 20 min. Stripping of the two metal ions from the organic phase was also investigated. Based on the experimental results, a separation method was developed and tested to separate high purity Co(II), Ni(II) and Ln(III) from Ni-MH batteries leached by 2.0M H(2)SO(4). Based on the experimental results, a flow sheet was developed and tested and 0.34 g Co, 1.39 g Ln and 5.2g Ni were obtained from the leaching process.

Pecan nutshell as biosorbent to remove Cu(II), Mn(II) and Pb(II) from aqueous solutions.

PubMed

Vaghetti, Julio C P; Lima, Eder C; Royer, Betina; da Cunha, Bruna M; Cardoso, Natali F; Brasil, Jorge L; Dias, Silvio L P

2009-02-15

In the present study we reported for the first time the feasibility of pecan nutshell (PNS, Carya illinoensis) as an alternative biosorbent to remove Cu(II), Mn(II) and Pb(II) metallic ions from aqueous solutions. The ability of PNS to remove the metallic ions was investigated by using batch biosorption procedure. The effects such as, pH, biosorbent dosage on the adsorption capacities of PNS were studied. Four kinetic models were tested, being the adsorption kinetics better fitted to fractionary-order kinetic model. Besides that, the kinetic data were also fitted to intra-particle diffusion model, presenting three linear regions, indicating that the kinetics of adsorption should follow multiple sorption rates. The equilibrium data were fitted to Langmuir, Freundlich, Sips and Redlich-Peterson isotherm models. Taking into account a statistical error function, the data were best fitted to Sips isotherm model. The maximum biosorption capacities of PNS were 1.35, 1.78 and 0.946mmolg(-1) for Cu(II), Mn(II) and Pb(II), respectively.

The association of plasma IGF-I with dietary, lifestyle, anthropometric, and early life factors in postmenopausal women.

PubMed

Bradbury, Kathryn E; Balkwill, Angela; Tipper, Sarah J; Crowe, Francesca L; Reeves, Gillian K; Green, Jane; Beral, Valerie; Key, Timothy J

2015-04-01

Higher circulating concentrations of insulin like growth factor (IGF-I) are associated with an increased risk of breast cancer. The objective of this study was to investigate associations between circulating IGF-I concentrations and dietary factors (intakes of protein, dairy protein, and alcohol), lifestyle factors (smoking and HT use), anthropometric indices (height and adiposity) and factors in early life (birth weight, having been breastfed, body size at age 10, and at age 20) in postmenopausal women in the UK. An analysis of plasma IGF-I concentrations (measured by immunoassay) in 1883 postmenopausal women. Multivariate analysis was used to examine correlates of plasma IGF-I concentrations. Women in the highest quintile of total protein and dairy protein intakes had, respectively, 7.6% and 5.5% higher plasma IGF-I concentrations than women in the lowest quintile (p trend <0.05 for both). Other factors significantly (p<0.05) associated with reduced IGF-I concentrations were: consuming 14 or more vs 3-7 alcoholic drinks per week (8.8% lower IGF-I); current vs non-current HT users (9.9% lower IGF-I); current use of oestrogen alone vs oestrogen+progestagen (16.9% lower IGF-I); obese vs overweight (6.8% lower IGF-I); and women who reported wearing larger vs smaller clothes sizes at age 20 (4.9% lower IGF-I). This study in post-menopausal women identified several potentially modifiable determinants of circulating IGF-I concentrations. There is now strong evidence from this and other studies that IGF-I concentrations are associated with dietary protein intakes. Copyright © 2015 Elsevier Ltd. All rights reserved.

Nucleoside-2',3'/3',5'-bis(thio)phosphate antioxidants are also capable of disassembly of amyloid beta42-Zn(ii)/Cu(ii) aggregates via Zn(ii)/Cu(ii)-chelation.

PubMed

Hevroni, Bosmat Levi; Major, Dan Thomas; Dixit, Mudit; Mhashal, Anil Ranu; Das, Susanta; Fischer, Bilha

2016-05-18

Currently, there is an urgent need for biocompatible metal-ion chelators capable of antioxidant activity and disassembly of amyloid beta (Aβ)-aggregates as potential therapeutics for Alzheimer's disease (AD). We recently demonstrated the promising antioxidant activity of adenine/guanine 2',3' or 3',5'-bis(thio)phosphate analogues, 2'-dA/G3'5'PO/S and A2'3'PO/S, and their affinity to Zn(ii)-ions. These findings encouraged us to evaluate them as agents for the dissolution of Aβ42-Zn(ii)/Cu(ii) aggregates. Specifically, we explored their ability to bind Cu(ii)/Zn(ii)-ions, the geometry and stoichiometry of these complexes, Cu(ii)/Zn(ii)-binding-sites and binding mode, and the ability of these analogues to dissolve Aβ42-Zn(ii)/Cu(ii) aggregates, as well as their effect on the secondary structure of those aggregates. Finally, we identified the most promising agents for dissolution of Aβ42-Zn(ii)/Cu(ii) aggregates. Specifically, we observed the formation of a 1 : 1 complex between 2'-dG3'5'PO and Cu(ii), involving O4 ligands. Zn(ii) was coordinated by both thiophosphate groups of 2'-dA3'5'PS and A2'3'PS involving O2S2 ligands in a 1 : 1 stoichiometry. A2'3'PS dissolves Aβ42-Zn(ii) and Aβ42-Cu(ii) aggregates as effectively as, and 2.5-fold more effectively than EDTA, respectively. Furthermore, 2'-dG3'5'PS and A2'3'PS reverted the Aβ42-M(ii) structure, back to that of the free Aβ42. Finally, cryo-TEM and TEM images confirmed the disassembly of Aβ42 and Aβ42-M(ii) aggregates by A2'3'PS. Hence, 2'-dG3'5'PS and A2'3'PS may serve as promising scaffolds for new AD therapeutics, acting as both effective antioxidants and agents for solubilization of Aβ42-Cu(ii)/Zn(ii) aggregates.

Genotype-dependent activation or repression of HBV enhancer II by transcription factor COUP-TF1

PubMed Central

Fischer, Silke F; Schmidt, Katja; Fiedler, Nicola; Glebe, Dieter; Schüttler, Christian; Sun, Jianguang; Gerlich, Wolfram H; Repp, Reinald; Schaefer, Stephan

2006-01-01

AIM: To study the expression of HBV enhancer II by transcription factor COUP-TF1. METHODS: In order to study the regulation of HBV variants in the vicinity of the NRRE we cloned luciferase constructs containing the HBV enhancer II from variants and from HBV genotypes A and D and cotransfected them together with expression vectors for COUP-TF1 into HepG2 cells. RESULTS: Our findings show that enhancer II of HBV genotype A is also repressed by COUP-TF1. In contrast, two different enhancer II constructs of HBV genotype D were activated by COUP-TF1. The activation was independent of the NRRE because a natural variant with a deletion of nt 1763-1770 was still activated by COUP-TF1. CONCLUSION: Regulation of transcription of the HBV genome seems to differ among HBV genomes derived from different genotypes. These differences in transcriptional control among HBV genotypes may be the molecular basis for differences in the clinical course among HBV genotypes. PMID:17009409

Genotype-dependent activation or repression of HBV enhancer II by transcription factor COUP-TF1.

PubMed

Fischer, Silke F; Schmidt, Katja; Fiedler, Nicola; Glebe, Dieter; Schüttler, Christian; Sun, Jianguang; Gerlich, Wolfram H; Repp, Reinald; Schaefer, Stephan

2006-10-07

To study the expression of HBV enhancer II by transcription factor COUP-TF1. In order to study the regulation of HBV variants in the vicinity of the NRRE we cloned luciferase constructs containing the HBV enhancer II from variants and from HBV genotypes A and D and cotransfected them together with expression vectors for COUP-TF1 into HepG2 cells. Our findings show that enhancer II of HBV genotype A is also repressed by COUP-TF1. In contrast, two different enhancer II constructs of HBV genotype D were activated by COUP-TF1. The activation was independent of the NRRE because a natural variant with a deletion of nt 1763-1770 was still activated by COUP-TF1. Regulation of transcription of the HBV genome seems to differ among HBV genomes derived from different genotypes. These differences in transcriptional control among HBV genotypes may be the molecular basis for differences in the clinical course among HBV genotypes.

Synthesis, spectral, thermal and antimicrobial studies on cobalt(II), nickel(II), copper(II), zinc(II) and palladium(II) complexes containing thiosemicarbazone ligand

NASA Astrophysics Data System (ADS)

El-Sawaf, Ayman K.; El-Essawy, Farag; Nassar, Amal A.; El-Samanody, El-Sayed A.

2018-04-01

The coordination characteristic of new N4-morpholinyl isatin-3-thiosemicarbazone (HL) towards Co(II), Ni(II), Cu(II), Zn(II) and Pd(II) has been studies. The structures of the complexes were described by elemental analyses, molar conductivity, magnetic, thermal and spectral (IR, UV-Vis, 1H and 13C NMR and ESR) studies. On the basis of analytical and spectral studies the ligand behaves as monobasic tridentate ONS donor forming two five membered rings towards cobalt, copper and palladium and afforded complexes of the kind [M(L)X], (Mdbnd Co, Cu or Pd; Xdbnd Cl, Br or OAc). Whereas the ligand bound to NiCl2 as neutral tridentate ONS donor and with ZnCl2 as neutral bidentate NS donor. The newly synthesized thiosemicarbazone ligand and some of its complexes were examined for antimicrobial activity against 2 gram negative bacterial strains (Escherichia coli Pseudomonas and aeruginosa), 2 gram positive bacterial strains (Streptococcus pneumoniae and Staphylococcus aureus)} and two Pathogenic fungi (Aspergillus fumigatus and Candida albicans). All metal complexes possess higher antimicrobial activity comparing with the free thiosemicarbazone ligand. The high potent activities of the complexes may arise from the coordination and chelation, which tends to make metal complexes act as more controlling and potent antimicrobial agents, thus hindering the growing of the microorganisms. The antimicrobial results also show that copper bromide complex is better antimicrobial agent as compared to the Schiff base and its metal complexes.

Synthesis, characterization, DFT calculations and biological studies of Mn(II), Fe(II), Co(II) and Cd(II) complexes based on a tetradentate ONNO donor Schiff base ligand

NASA Astrophysics Data System (ADS)

Abdel-Rahman, Laila H.; Ismail, Nabawia M.; Ismael, Mohamed; Abu-Dief, Ahmed M.; Ahmed, Ebtehal Abdel-Hameed

2017-04-01

This study highlights synthesis and characterization of a tetradentate ONNO Schiff base ligand namely (1, 1‧- (pyridine-2, 3-dimethyliminomethyl) naphthalene-2, 2‧-diol) and hereafter denotes as "HNDAP″ and selected metal complexes including Mn(II), Fe(II), Co(II) and Cd(II) as a central metal. HNDAP was synthesized from 1:2 M ratio condensation of 2, 3-diaminopyridine and 2- hydroxy-1-naphthaldhyde, respectively. The stoichiometric ratios of the prepared complexes were estimated using complementary techniques such as; elemental analyses (-C, H, N), FT-IR, magnetic measurements and molar conductivity. Furthermore, their physicochemical studies were carried out using thermal TGA, DTA and kinetic-thermodynamic studies along with DFT calculations. The results of elemental analyses showed that these complexes are present in a 1:1 metal-to- ligand molar ratio. Moreover, the magnetic susceptibilities values at room temperature revealed that Mn(II), Fe(II) and Co(II) complexes are paramagnetic in nature and have an octahedral (Oh) geometry. In contrast, Cd(II) is diamagnetic and stabilizes in square planar sites. The molar conductivity measurements indicated that all complexes are nonelectrolytes in dimethyl formamide. Spectral data suggested that the ligand is as tetradentate and coordinated with Co(II) ion through two phenolic OH and two azomethine nitrogen. However, for Mn(II), Fe(II) and Cd(II) complexes, the coordination occurred through two phenolic oxygen and two azomethine nitrogen with deprotonation of OH groups. The proposed chemical structures have been validated by quantum mechanics calculations. Antimicrobial activities of both the HNDAP Schiff base ligand and its metal complexes were tested against strains of Gram (-ve) E. coli and Gram (+ve) B. subtilis and S. aureus bacteria and C. albicans, A. flavus and T. rubrum fungi. All the prepared compounds showed good results of inhibition against the selected pathogenic microorganisms. The investigated

Phosphatidylinositol 3-Kinase (PI3K) Activity Bound to Insulin-like Growth Factor-I (IGF-I) Receptor, which Is Continuously Sustained by IGF-I Stimulation, Is Required for IGF-I-induced Cell Proliferation*

PubMed Central

Fukushima, Toshiaki; Nakamura, Yusaku; Yamanaka, Daisuke; Shibano, Takashi; Chida, Kazuhiro; Minami, Shiro; Asano, Tomoichiro; Hakuno, Fumihiko; Takahashi, Shin-Ichiro

2012-01-01

Continuous stimulation of cells with insulin-like growth factors (IGFs) in G1 phase is a well established requirement for IGF-induced cell proliferation; however, the molecular components of this prolonged signaling pathway that is essential for cell cycle progression from G1 to S phase are unclear. IGF-I activates IGF-I receptor (IGF-IR) tyrosine kinase, followed by phosphorylation of substrates such as insulin receptor substrates (IRS) leading to binding of signaling molecules containing SH2 domains, including phosphatidylinositol 3-kinase (PI3K) to IRS and activation of the downstream signaling pathways. In this study, we found prolonged (>9 h) association of PI3K with IGF-IR induced by IGF-I stimulation. PI3K activity was present in this complex in thyrocytes and fibroblasts, although tyrosine phosphorylation of IRS was not yet evident after 9 h of IGF-I stimulation. IGF-I withdrawal in mid-G1 phase impaired the association of PI3K with IGF-IR and suppressed DNA synthesis the same as when PI3K inhibitor was added. Furthermore, we demonstrated that Tyr1316-X-X-Met of IGF-IR functioned as a PI3K binding sequence when this tyrosine is phosphorylated. We then analyzed IGF signaling and proliferation of IGF-IR−/− fibroblasts expressing exogenous mutant IGF-IR in which Tyr1316 was substituted with Phe (Y1316F). In these cells, IGF-I stimulation induced tyrosine phosphorylation of IGF-IR and IRS-1/2, but mutated IGF-IR failed to bind PI3K and to induce maximal phosphorylation of GSK3β and cell proliferation in response to IGF-I. Based on these results, we concluded that PI3K activity bound to IGF-IR, which is continuously sustained by IGF-I stimulation, is required for IGF-I-induced cell proliferation. PMID:22767591

[Relationship between the expression levels of PAPP-A metalloproteinase and growth and transcriptional factors in endometrial cancer].

PubMed

Iunusova, N V; Spirina, L V; Kondakova, L A; Kolomiets, A L; Chernyshova, A L; Koval', V D; Nedosekov, V V; Savenkova, O V

2013-01-01

We have examined for the first time the relationship between the expression of PAPP-A metalloproteinase and insulin-like growth factors (IGF-I, IGF-II, VEGF) and transcription factors (NF-kappaB, HIF-1) playing an important role in pathogenesis of cancer. We also demonstrated a positive association between the level of PAPP-A metalloproteinase and the level of growth (VEGF and IGF-I) and transcription factors (NF-kappaB p50, NF-kappaB p65, HIF-1alpha). The current findings suggest an important role of PAPP-A in regulation of bioavailability of IGF-I, VEGF, activated forms of NF-kappaB, and alpha-subunits of HIF-1 in endometrial tumors.

Spectroscopic (FT-IR, FT-Raman, 1H, 13C NMR, UV/VIS), thermogravimetric and antimicrobial studies of Ca(II), Mn(II), Cu(II), Zn(II) and Cd(II) complexes of ferulic acid

NASA Astrophysics Data System (ADS)

Kalinowska, M.; Piekut, J.; Bruss, A.; Follet, C.; Sienkiewicz-Gromiuk, J.; Świsłocka, R.; Rzączyńska, Z.; Lewandowski, W.

2014-03-01

The molecular structure of Mn(II), Cu(II), Zn(II), Cd(II) and Ca(II) ferulates (4-hydroxy-3-methoxycinnamates) was studied. The selected metal ferulates were synthesized. Their composition was established by means of elementary and thermogravimetric analysis. The following spectroscopic methods were used: infrared (FT-IR), Raman (FT-Raman), nuclear magnetic resonance (13C, 1H NMR) and ultraviolet-visible (UV/VIS). On the basis of obtained results the electronic charge distribution in studied metal complexes in comparison with ferulic acid molecule was discussed. The microbiological study of ferulic acid and ferulates toward Escherichia coli, Bacillus subtilis, Candida albicans, Pseudomonas aeruginosa, Staphylococcus aureus and Proteus vulgaris was done.

Insulin-like growth factor 1 (IGF-1): a growth hormone

PubMed Central

Laron, Z

2001-01-01

Aim—To contribute to the debate about whether growth hormone (GH) and insulin-like growth factor 1 (IGF-1) act independently on the growth process. Methods—To describe growth in human and animal models of isolated IGF-1 deficiency (IGHD), such as in Laron syndrome (LS; primary IGF-1 deficiency and GH resistance) and IGF-1 gene or GH receptor gene knockout (KO) mice. Results—Since the description of LS in 1966, 51 patients were followed, many since infancy. Newborns with LS are shorter (42–47 cm) than healthy babies (49–52 cm), suggesting that IGF-1 has some influence on intrauterine growth. Newborn mice with IGF-1 gene KO are 30% smaller. The postnatal growth rate of patients with LS is very slow, the distance from the lowest normal centile increasing progressively. If untreated, the final height is 100–136 cm for female and 109–138 cm for male patients. They have acromicia, organomicria including the brain, heart, gonads, genitalia, and retardation of skeletal maturation. The availability of biosynthetic IGF-1 since 1988 has enabled it to be administered to children with LS. It accelerated linear growth rates to 8–9 cm in the first year of treatment, compared with 10–12 cm/year during GH treatment of IGHD. The growth rate in following years was 5–6.5 cm/year. Conclusion—IGF-1 is an important growth hormone, mediating the protein anabolic and linear growth promoting effect of pituitary GH. It has a GH independent growth stimulating effect, which with respect to cartilage cells is possibly optimised by the synergistic action with GH. PMID:11577173

Competitive adsorption of Pb(II), Cu(II), and Zn(II) ions onto hydroxyapatite-biochar nanocomposite in aqueous solutions

NASA Astrophysics Data System (ADS)

Wang, Yu-Ying; Liu, Yu-Xue; Lu, Hao-Hao; Yang, Rui-Qin; Yang, Sheng-Mao

2018-05-01

A hydroxyapatite-biochar nanocomposite (HAP-BC) was successfully fabricated and its physicochemical properties characterized. The analyses showed that HAP nanoparticles were successfully loaded on the biochar surface. The adsorption of Pb(II), Cu(II), and Zn(II) by HAP-BC was systematically studied in single and ternary metal systems. The results demonstrated that pH affects the adsorption of heavy metals onto HAP-BC. Regarding the adsorption kinetics, the pseudo-second-order model showed the best fit for all three heavy metal ions on HAP-BC. In both single and ternary metal ion systems, the adsorption isotherm of Pb(II) by HAP-BC followed Langmuir model, while those of Cu(II) and Zn(II) fitted well with Freundlich model. The maximum adsorption capacity for each tested metal by HAP-BC was higher than that of pristine rice straw biochar (especially for Pb(II)) or those of other reported adsorbents. Therefore, HAP-BC could explore as a new material for future application in heavy metal removal.

Biosorption characteristics of copper (II), chromium (III), nickel (II), and lead (II) from aqueous solutions by Chara sp. and Cladophora sp.

PubMed

Elmaci, Ayşe; Yonar, Taner; Ozengin, Nihan

2007-09-01

The aim of this research was to expose individual removals of copper, chromium, nickel, and lead from aqueous solutions via biosorption using nonliving algae species, Chara sp. and Cladophora sp. Optimum pH values for biosorption of copper (II), chromium (III), nickel (II), and lead (II) from aqueous solutions were determined to be 6, 7, 7, and 3 for Cladophora sp. and 5, 3, 5, and 4 for Chara sp. respectively. Maximum adsorption capacities of Chara sp. [10.54 for chromium (III) and 61.72 for lead (II)] and Cladophora sp. [6.59 for chromium (III) and 16.75 and 23.25 for lead (II)] for chromium (III) and lead (II) are similar. On the other hand, copper (II) and nickel (II) biosorption capacity of Cladophora sp. [14.28 for copper (II) and 16.75 for nickel (II)] is greater than Chara sp. [6.506 for copper (II) and 11.76 for nickel (II)]. Significantly high correlation coefficients indicated for the Langmuir adsorption isotherm models can be used to describe the equilibrium behavior of copper, chromium, nickel, and lead adsorption onto Cladophora sp. and Chara sp.

Role of epidermal growth factor receptor and endoplasmic reticulum stress in vascular remodeling induced by angiotensin II.

PubMed

Takayanagi, Takehiko; Kawai, Tatsuo; Forrester, Steven J; Obama, Takashi; Tsuji, Toshiyuki; Fukuda, Yamato; Elliott, Katherine J; Tilley, Douglas G; Davisson, Robin L; Park, Joon-Young; Eguchi, Satoru

2015-06-01

The mechanisms by which angiotensin II (AngII) elevates blood pressure and enhances end-organ damage seem to be distinct. However, the signal transduction cascade by which AngII specifically mediates vascular remodeling such as medial hypertrophy and perivascular fibrosis remains incomplete. We have previously shown that AngII-induced epidermal growth factor receptor (EGFR) transactivation is mediated by disintegrin and metalloproteinase domain 17 (ADAM17), and that this signaling is required for vascular smooth muscle cell hypertrophy but not for contractile signaling in response to AngII. Recent studies have implicated endoplasmic reticulum (ER) stress in hypertension. Interestingly, EGFR is capable of inducing ER stress. The aim of this study was to test the hypothesis that activation of EGFR and ER stress are critical components required for vascular remodeling but not hypertension induced by AngII. Mice were infused with AngII for 2 weeks with or without treatment of EGFR inhibitor, erlotinib, or ER chaperone, 4-phenylbutyrate. AngII infusion induced vascular medial hypertrophy in the heart, kidney and aorta, and perivascular fibrosis in heart and kidney, cardiac hypertrophy, and hypertension. Treatment with erlotinib as well as 4-phenylbutyrate attenuated vascular remodeling and cardiac hypertrophy but not hypertension. In addition, AngII infusion enhanced ADAM17 expression, EGFR activation, and ER/oxidative stress in the vasculature, which were diminished in both erlotinib-treated and 4-phenylbutyrate-treated mice. ADAM17 induction and EGFR activation by AngII in vascular cells were also prevented by inhibition of EGFR or ER stress. In conclusion, AngII induces vascular remodeling by EGFR activation and ER stress via a signaling mechanism involving ADAM17 induction independent of hypertension. © 2015 American Heart Association, Inc.

Removal of Pb(II), Cd(II), Cu(II), and Zn(II) by hematite nanoparticles: effect of sorbent concentration, pH, temperature, and exhaustion.

PubMed

Shipley, Heather J; Engates, Karen E; Grover, Valerie A

2013-03-01

Nanoparticles offer the potential to improve environmental treatment technologies due to their unique properties. Adsorption of metal ions (Pb(II), Cd(II), Cu(II), Zn(II)) to nanohematite was examined as a function of sorbent concentration, pH, temperature, and exhaustion. Adsorption experiments were conducted with 0.05, 0.1, and 0.5 g/L nanoparticles in a pH 8 solution and in spiked San Antonio tap water. The adsorption data showed the ability of nanohematite to remove Pb, Cd, Cu, and Zn species from solution with adsorption increasing as the nanoparticle concentration increased. At 0.5 g/L nanohematite, 100 % Pb species adsorbed, 94 % Cd species adsorbed, 89 % Cu species adsorbed and 100 % Zn species adsorbed. Adsorption kinetics for all metals tested was described by a pseudo second-order rate equation with lead having the fastest rate of adsorption. The effect of temperature on adsorption showed that Pb(II), Cu(II), and Cd(II) underwent an endothermic reaction, while Zn(II) underwent an exothermic reaction. The nanoparticles were able to simultaneously remove multiple metals species (Zn, Cd, Pb, and Cu) from both a pH 8 solution and spiked San Antonio tap water. Exhaustion experiments showed that at pH 8, exhaustion did not occur for the nanoparticles but adsorption does decrease for Cd, Cu, and Zn species but not Pb species. The strong adsorption coupled with the ability to simultaneously remove multiple metal ions offers a potential remediation method for the removal of metals from water.

New Rh 2 (II,II) Architecture for the Catalytic Reduction of H +

DOE PAGES

White, Travis A.; Witt, Suzanne E.; Li, Zhanyong; ...

2015-09-25

Formamidinate-bridged Rh 2 II,II complexes containing diimine ligands of the formula cis-[Rh 2 II,II(μ-DTolF) 2(NN) 2] 2+ (Rh 2-NN 2), where DTolF = p-ditolylformamidinate and NN = dppn (benzo[i]dipyrido[3,2-a:2',3'-h]quinoxaline), dppz (dipyrido[3,2-a:2',3'-c]phenazine), and phen (1,10-phenanthroline), electrocatalytically reduce H + to H 2 in DMF solutions containing CH 3COOH at a glassy carbon electrode. Cathodic scans in the absence of acid display a Rh III,II/II,II reduction at -0.90 V vs Fc +/Fc followed by NN 0/– reduction at -1.13, -1.36, and -1.65 V for Rh 2-dppn 2, Rh 2-dppz 2, and Rh 2-phen 2, respectively. Upon the addition of acid, Rh 2-dppnmore » 2 and Rh 2-dppz 2 undergo reduction–protonation–reduction at each pyrazine-containing NN ligand prior to the Rh 2 II,II/II,I reduction. The Rh 2 II,I species is thus protonated at one of the metal centers, resulting in the formation of the corresponding Rh 2 II,III-hydride. In the case of Rh 2-phen 2, the reduction of the phen ligand is followed by intramolecular electron transfer to the Rh 2 II,II core in the presence of protons to form a Rh 2 II,III-hydride species. Further reduction and protonation at the Rh 2 core for all three complexes rapidly catalyzes H 2 formation with varied calculated turnover frequencies (TOF) and overpotential values (η): 2.6 × 10 4 s –1 and 0.56 V for Rh 2-dppn, 2.8 × 10 4 s –1 and 0.50 V for Rh 2-dppz 2, and 5.9 × 10 4 s –1 and 0.64 V for Rh 2-phen 2. Bulk electrolysis confirmed H 2 formation, and further CH 3COOH addition regenerates H 2 production, attesting to the robust nature of the architecture. The cis-[Rh 2 II,II(μ-DTolF) 2(NN) 2] 2+ architecture benefits by combining electron-rich formamidinate bridges, a redox-active Rh 2 II,II core, and electron-accepting NN diimine ligands to allow for the electrocatalysis of H + substrate to H 2 fuel.« less

Insulin-Like Growth Factor 1 (IGF-1) in Parkinson's Disease: Potential as Trait-, Progression- and Prediction Marker and Confounding Factors

PubMed Central

Binder, Gerhard; Weber, Karin; Apel, Anja; Roeben, Benjamin; Deuschle, Christian; Maechtel, Mirjam; Heger, Tanja; Nussbaum, Susanne; Gasser, Thomas; Maetzler, Walter; Berg, Daniela

2016-01-01

Introduction Biomarkers indicating trait, progression and prediction of pathology and symptoms in Parkinson's disease (PD) often lack specificity or reliability. Investigating biomarker variance between individuals and over time and the effect of confounding factors is essential for the evaluation of biomarkers in PD, such as insulin-like growth factor 1 (IGF-1). Materials and Methods IGF-1 serum levels were investigated in up to 8 biannual visits in 37 PD patients and 22 healthy controls (HC) in the longitudinal MODEP study. IGF-1 baseline levels and annual changes in IGF-1 were compared between PD patients and HC while accounting for baseline disease duration (19 early stage: ≤3.5 years; 18 moderate stage: >4 years), age, sex, body mass index (BMI) and common medical factors putatively modulating IGF-1. In addition, associations of baseline IGF-1 with annual changes of motor, cognitive and depressive symptoms and medication dose were investigated. Results PD patients in moderate (130±26 ng/mL; p = .004), but not early stages (115±19, p>.1), showed significantly increased baseline IGF-1 levels compared with HC (106±24 ng/mL; p = .017). Age had a significant negative correlation with IGF-1 levels in HC (r = -.47, p = .028) and no correlation in PD patients (r = -.06, p>.1). BMI was negatively correlated in the overall group (r = -.28, p = .034). The annual changes in IGF-1 did not differ significantly between groups and were not correlated with disease duration. Baseline IGF-1 levels were not associated with annual changes of clinical parameters. Discussion Elevated IGF-1 in serum might differentiate between patients in moderate PD stages and HC. However, the value of serum IGF-1 as a trait-, progression- and prediction marker in PD is limited as IGF-1 showed large inter- and intraindividual variability and may be modulated by several confounders. PMID:26967642

Syntheses, structures, and properties of trinuclear complexes [M(bpca)(2)(M'(hfac)(2))(2)], constructed with the complexed bridging ligand [M(bpca)(2)] [M, M' = Ni(II), Mn(II); Cu(II), Mn(II); Fe(II), Mn(II); Ni(II), Fe(II); and Fe(II), Fe(II); Hbpca = Bis(2-pyridylcarbonyl)amine, Hhfac = Hexafluoroacetylacetone].

PubMed

Kamiyama, Asako; Noguchi, Tomoko; Kajiwara, Takashi; Ito, Tasuku

2002-02-11

Five trinuclear complexes [M(bpca)(2)(M'(hfac)(2))(2)] (where MM'(2) = NiMn(2), CuMn(2), FeMn(2), NiFe(2), and FeFe(2); Hbpca = bis(2-pyridylcarbonyl)amine; and Hhfac = hexafluoroacetylacetone) were synthesized almost quantitatively by the reaction of [M(bpca)(2)] and [M'(hfac)(2)] in 1:2 molar ratio, and their structures and magnetic properties were investigated. Three complexes, with M' = Mn, crystallize in the same space group, Pna2(1), whereas two complexes, with M' = Fe, crystallize in P4(1), and complexes within each set are isostructural to one another. In all complexes, [M(bpca)(2)] acts as a bis-bidentate bridging ligand to form a linear trinuclear complex in which three metal ions are arranged in the manner M'-M-M'. The central metal ion is in a strong ligand field created by the N(6) donor set, and hence the Fe(II) in the [Fe(bpca)(2)] moiety is in a low-spin state. The terminal metal ions (M') are surrounded by O(6) donor sets with a moderate ligand field, which leads to the high-spin configuration of Fe(II). Three metal ions in all complexes are almost collinear, and metal-metal distances are ca. 5.5 A. The magnetic behavior of NiMn(2) and NiFe(2) shows a weak ferromagnetic interaction between the central Ni(II) ion and the terminal Mn(II) or Fe(II) ions. In these complexes, sigma-spin orbitals of the central Ni(II) ion and those of terminal metal ions have different symmetry about a 2-fold rotation axis through the Ni-N(amide)-M'(terminal) atoms, and this results in orthogonality between the neighboring sigma-spin orbitals and thus ferromagnetic interactions.

Structural alteration of hexagonal birnessite by aqueous Mn(II): Impacts on Ni(II) sorption

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

Lefkowitz, Joshua P.; Elzinga, Evert J.

We studied the impacts of aqueous Mn(II) (1 mM) on the sorption of Ni(II) (200 μM) by hexagonal birnessite (0.1 g L- 1) at pH 6.5 and 7.5 with batch experiments and XRD, ATR-FTIR and Ni K-edge EXAFS analyses. In the absence of Mn(II)aq, sorbed Ni(II) was coordinated predominantly as triple corner-sharing complexes at layer vacancies at both pH values. Introduction of Mn(II)aq into Ni(II)-birnessite suspensions at pH 6.5 caused Ni(II) desorption and led to the formation of edge-sharing Ni(II) complexes. This was attributed to competitive displacement of Ni(II) from layer vacancies by either Mn(II) or by Mn(III) formed throughmore » interfacial Mn(II)-Mn(IV) comproportionation, and/or incorporation of Ni(II) into the birnessite lattice promoted by Mn(II)-catalyzed recrystallization of the sorbent. Similar to Mn(II)aq, the presence of HEPES or MES caused the formation of edge-sharing Ni(II) sorption complexes in Ni(II)-birnessite suspensions, which was attributed to partial reduction of the sorbent by the buffers. At pH 7.5, interaction with aqueous Mn(II) caused reductive transformation of birnessite into secondary feitknechtite that incorporated Ni(II), enhancing removal of Ni(II) from solution. These results demonstrate that reductive alteration of phyllomanganates may significantly affect the speciation and solubility of Ni(II) in anoxic and suboxic environments.« less

Phase I/II Trial and Pharmacokinetic Study of Cixutumumab in Pediatric Patients With Refractory Solid Tumors and Ewing Sarcoma: A Report From the Children's Oncology Group

PubMed Central

Malempati, Suman; Weigel, Brenda; Ingle, Ashish M.; Ahern, Charlotte H.; Carroll, Julie M.; Roberts, Charles T.; Reid, Joel M.; Schmechel, Stephen; Voss, Stephan D.; Cho, Steven Y.; Chen, Helen X.; Krailo, Mark D.; Adamson, Peter C.; Blaney, Susan M.

2012-01-01

Purpose A phase I/II study of cixutumumab (IMC-A12) in children with refractory solid tumors was conducted. This study was designed to assess the toxicities, pharmacokinetics, and pharmacodynamics of cixutumumab in children to determine a recommended phase II dose and to assess antitumor activity in Ewing sarcoma (ES). Patients and Methods Pediatric patients with relapsed or refractory solid tumors were treated with cixutumumab as a 1-hour intravenous infusion once per week. Two dose levels—6 and 9 mg/kg—were evaluated using a standard three-plus-three cohort design. Patients with refractory ES were treated in an expanded phase II cohort at each dose level. Results Forty-seven eligible patients with a median age of 15 years (range, 4 to 28 years) were enrolled. Twelve patients were treated in the dose-finding phase. Hematologic and nonhematologic toxicities were generally mild and infrequent. Dose-limiting toxicities included grade 4 thrombocytopenia at 6 mg/kg and grade 3 dehydration at 9 mg/kg. Mean trough concentration (± standard deviation) at 9 mg/kg was 106 ± 57 μg/mL, which exceeded the effective trough concentration of 60 μg/mL observed in xenograft models. Three patients with ES had confirmed partial responses: one of 10 at 6 mg/kg and two of 20 at 9 mg/kg. Serum insulin-like growth factor I (IGF-I) levels consistently increased after one dose of cixutumumab. Tumor IGF-I receptor expression by immunohistochemistry did not correlate with response in patients with ES. Conclusion Cixutumumab is well tolerated in children with refractory solid tumors. The recommended phase II dose is 9 mg/kg. Limited single-agent activity of cixutumumab was seen in ES. PMID:22184397

Synthesis, spectroscopic characterization and biological activities of N4O2 Schiff base ligand and its metal complexes of Co(II), Ni(II), Cu(II) and Zn(II)

NASA Astrophysics Data System (ADS)

Al-Resayes, Saud I.; Shakir, Mohammad; Abbasi, Ambreen; Amin, Kr. Mohammad Yusuf; Lateef, Abdul

The Schiff base ligand, bis(indoline-2-one)triethylenetetramine (L) obtained from condensation of triethylenetetramine and isatin was used to synthesize the complexes of type, [ML]Cl2 [M = Co(II), Ni(II), Cu(II) and Zn(II)]. L was characterized on the basis of the results of elemental analysis, FT-IR, 1H and 13C NMR, mass spectroscopic studies. The stoichiometry, bonding and stereochemistries of complexes were ascertained on the basis of results of elemental analysis, magnetic susceptibility values, molar conductance and various spectroscopic studies. EPR, UV-vis and magnetic moments revealed an octahedral geometry for complexes. L and its Cu(II) and Zn(II) complexes were screened for their antibacterial activity. Analgesic activity of Cu(II) and Zn(II) complexes was also tested in rats by tail flick method. Both complexes were found to possess good antibacterial and moderate analgesic activity.

Elaboration of a Highly Porous RuII,II Analogue of HKUST-1.

PubMed

Zhang, Wenhua; Freitag, Kerstin; Wannapaiboon, Suttipong; Schneider, Christian; Epp, Konstantin; Kieslich, Gregor; Fischer, Roland A

2016-12-19

When the dinuclear Ru II,II precursor [Ru 2 (OOCCH 3 ) 4 ] is employed under redox-inert conditions, a Ru II,II analogue of HKUST-1 was successfully prepared and characterized as a phase-pure microcrystalline powder. X-ray absorption near-edge spectroscopy confirms the oxidation state of the Ru centers of the paddle-wheel nodes in the framework. The porosity of 1371 m 2 /mmol of Ru II,II -HKUST-1 exceeds that of the parent compound HKUST1 (1049 m 2 / mmol).

Dynamic adsorption of mixtures of Rhodamine B, Pb (II), Cu (II) and Zn(II) ions on composites chitosan-silica-polyethylene glycol membrane

NASA Astrophysics Data System (ADS)

Mahatmanti, F. W.; Rengga, W. D. P.; Kusumastuti, E.; Nuryono

2018-04-01

The adsorption of a solution mixture of Rhodamine B, Pb (II), Cu (II) and Zn(II) was studied using dynamic methods employing chitosan-silica-polyethylene glycol (Ch/Si/P) composite membrane as an adsorptive membrane. The composite Ch/Si/P membrane was prepared by mixing a chitosan-based membrane with silica isolated from rice husk ash (ASP) and polyethylene glycol (PEG) as a plasticizer. The resultant composite membrane was a stronger and more flexible membrane than the original chitosan-based membrane as indicated by the maximum percentage of elongation (20.5 %) and minimum Young’s Modulus (80.5 MPa). The composite membrane also showed increased mechanical and hydrophilic properties compared to the chitosan membranes. The membrane was used as adsorption membrane for Pb (II), Cu (II), Cd (II) ions and Rhodamine B dyes in a dynamic system where the permeation and selectivity were determined. The permeation of the components was observed to be in the following order: Rhodamine B > Cd (II) > Pb (II) > Cu (II) whereas the selectivity was shown to decrease the order of Cu (II) > Pb (II) > Cd (II) > Rhodamine B.

Combined administration of mesenchymal stem cells overexpressing IGF-1 and HGF enhances neovascularization but moderately improves cardiac regeneration in a porcine model.

PubMed

Gómez-Mauricio, Guadalupe; Moscoso, Isabel; Martín-Cancho, María-Fernanda; Crisóstomo, Verónica; Prat-Vidal, Cristina; Báez-Díaz, Claudia; Sánchez-Margallo, Francisco M; Bernad, Antonio

2016-07-16

Insulin-like growth factor 1 (IGF-1) and hepatocyte growth factor (HGF) are among the most promising growth factors for promoting cardiorepair. Here, we evaluated the combination of cell- and gene-based therapy using mesenchymal stem cells (MSC) genetically modified to overexpress IGF-1 or HGF to treat acute myocardial infarction (AMI) in a porcine model. Pig MSC from adipose tissue (paMSC) were genetically modified for evaluation of different therapeutic strategies to improve AMI treatment. Three groups of infarcted Large White pigs were compared (I, control, non-transplanted; II, transplanted with paMSC-GFP (green fluorescent protein); III, transplanted with paMSC-IGF-1/HGF). Cardiac function was evaluated non-invasively using magnetic resonance imaging (MRI) for 1 month. After euthanasia and sampling of the animal, infarcted areas were studied by histology and immunohistochemistry. Intramyocardial transplant in a porcine infarct model demonstrated the safety of paMSC in short-term treatments. Treatment with paMSC-IGF-1/HGF (1:1) compared with the other groups showed a clear reduction in inflammation in some sections analyzed and promoted angiogenic processes in ischemic tissue. Although cardiac function parameters were not significantly improved, cell retention and IGF-1 overexpression was confirmed within the myocardium. The simultaneous administration of IGF-1- and HGF-overexpressing paMSC appears not to promote a synergistic effect or effective repair. The combined enhancement of neovascularization and fibrosis in paMSC-IGF-1/HGF-treated animals nonetheless suggests that sustained exposure to high IGF-1 + HGF levels promotes beneficial as well as deleterious effects that do not improve overall cardiac regeneration.

Arginase-II Promotes Tumor Necrosis Factor-α Release From Pancreatic Acinar Cells Causing β-Cell Apoptosis in Aging.

PubMed

Xiong, Yuyan; Yepuri, Gautham; Necetin, Sevil; Montani, Jean-Pierre; Ming, Xiu-Fen; Yang, Zhihong

2017-06-01

Aging is associated with glucose intolerance. Arginase-II (Arg-II), the type-II L -arginine-ureahydrolase, is highly expressed in pancreas. However, its role in regulation of pancreatic β-cell function is not known. Here we show that female (not male) mice deficient in Arg-II (Arg-II -/- ) are protected from age-associated glucose intolerance and reveal greater glucose induced-insulin release, larger islet size and β-cell mass, and more proliferative and less apoptotic β-cells compared with the age-matched wild-type (WT) controls. Moreover, Arg-II is mainly expressed in acinar cells and is upregulated with aging, which enhances p38 mitogen-activated protein kinase (p38 MAPK) activation and release of tumor necrosis factor-α (TNF-α). Accordingly, conditioned medium of isolated acinar cells from old WT (not Arg-II -/- ) mice contains higher TNF-α levels than the young mice and stimulates β-cell apoptosis and dysfunction, which are prevented by a neutralizing anti-TNF-α antibody. In acinar cells, our study demonstrates an age-associated Arg-II upregulation, which promotes TNF-α release through p38 MAPK leading to β-cell apoptosis, insufficient insulin secretion, and glucose intolerance in female rather than male mice. © 2017 by the American Diabetes Association.

Prenatal stress affects insulin-like growth factor-1 (IGF-1) level and IGF-1 receptor phosphorylation in the brain of adult rats.

PubMed

Basta-Kaim, Agnieszka; Szczesny, Ewa; Glombik, Katarzyna; Stachowicz, Katarzyna; Slusarczyk, Joanna; Nalepa, Irena; Zelek-Molik, Agnieszka; Rafa-Zablocka, Katarzyna; Budziszewska, Boguslawa; Kubera, Marta; Leskiewicz, Monika; Lason, Wladyslaw

2014-09-01

It has been shown that stressful events occurring in early life have a powerful influence on the development of the central nervous system. Insulin-like growth factor-1 (IGF-1) promotes the growth, differentiation and survival of both neurons and glial cells and is thought to exert antidepressant-like activity. Thus, it is possible that disturbances in the function of the IGF-1 system may be responsible for disturbances observed over the course of depression. Prenatal stress was used as a valid model of depression. Adult male offspring of control and stressed rat dams were subjected to behavioural testing (forced swim test). The level of IGF-1 in the blood and the expression of IGF-1, IGF-1R, and IRS-1/2 in the hippocampus and frontal cortex using RT-PCR, ELISA and western blotting were measured. In addition the effect of intracerebroventricularly administered IGF-1 and/or the IGF-1R receptor antagonist JB1 in the forced swim test was studied. Prenatally stressed rats showed depressive like behaviour, including increased immobility time as well as decreased mobility and climbing. Intracerebroventricular administration of IGF-1 reversed these effects in stressed animals, whereas concomitant administration of the IGF-1R antagonist JB1 completely blocked the effects. Biochemical analysis of homogenates from the hippocampus and frontal cortex revealed decreases in IGF-1 level and IGF-1R phosphorylation along with disturbances in IRS-1 phosphorylation. These findings reveal that prenatal stress alters IGF-1 signalling, which may contribute to the behavioural changes observed in depression. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

Validation of the Parental Facilitation of Mastery Scale-II.

PubMed

Zalta, Alyson K; Allred, Kelly M; Jayawickreme, Eranda; Blackie, Laura E R; Chambless, Dianne L

2017-10-01

To develop a more reliable and comprehensive version of the Parental Facilitation of Mastery Scale (PFMS) METHOD: In Study 1, 387 undergraduates completed an expanded PFMS (PFMS-II) and measures of parenting, perceived control, responses to early life challenges, and psychopathology. In Study 2, 182 trauma-exposed community participants completed the PFMS-II and measures of perceived control, psychopathology, and well-being RESULTS: In Study 1, exploratory factor analysis of the PFMS-II revealed two factors. These factors replicated in Study 2; one item was removed to achieve measurement invariance across race. The final PFMS-II comprised a 10-item overprotection scale and a 7-item challenge scale. In both samples, this measure demonstrated good convergent and discriminant validity and was more reliable than the original PFMS. Parental challenge was a unique predictor of perceived control in both samples CONCLUSION: The PFMS-II is a valid measure of important parenting behaviors not fully captured in other measures. © 2016 Wiley Periodicals, Inc.

BASS-II Experiment

NASA Image and Video Library

2014-08-02

Image taken on card 8 during BASS-II flame test session with reduced O2 partial pressure. Session conducted on GMT 213. The Burning and Suppression of Solids - II (BASS-II) investigation examines the burning and extinction characteristics of a wide variety of fuel samples in microgravity. The BASS-II experiment will guide strategies for materials flammability screening for use in spacecraft as well as provide valuable data on solid fuel burning behavior in microgravity. BASS-II results contribute to the combustion computational models used in the design of fire detection and suppression systems in microgravity and on Earth.

Electrochemical studies of DNA interaction and antimicrobial activities of MnII, FeIII, CoII and NiII Schiff base tetraazamacrocyclic complexes

NASA Astrophysics Data System (ADS)

Kumar, Anuj; Vashistha, Vinod Kumar; Tevatia, Prashant; Singh, Randhir

2017-04-01

Tetraazamacrocyclic complexes of MnII, FeIII, CoII and NiII have been synthesized by template method. These tetraazamacrocycles have been analyzed with various techniques like molar conductance, IR, UV-vis, mass spectral and cyclic voltammetric studies. On the basis of all these studies, octahedral geometry has been assigned to these tetraazamacrocyclic complexes. The DNA binding properties of these macrocyclic complexes have been investigated by electronic absorption spectra, fluorescence spectra, cyclic voltammetric and differential pulse voltammetric studies. The cyclic voltammetric data showed that ipc and ipa were effectively decreased in the presence of calf thymus DNA, which is a strong evidence for the interaction of these macrocyclic complexes with the calf thymus DNA (ct-DNA). The heterogeneous electron transfer rate constant found in the order: KCoII > KNiII > KMnII which indicates that CoII macrocyclic complex has formed a strong intercalated intermediate. The Stern-Volmer quenching constant (KSV) and voltammetric binding constant were found in the order KSV(CoII) > KSV(NiII) > KSV(MnII) and K+(CoII) > K+(NiII) > K+(MnII) which shows that CoII macrocyclic complex exhibits the high interaction affinity towards ct-DNA by the intercalation binding. Biological studies of the macrocyclic complexes compared with the standard drug like Gentamycin, have shown antibacterial activities against E. coli, P. aeruginosa, B. cereus, S. aureus and antifungal activity against C. albicans.

Comparative study on kinetic adsorption of Cu(II), Cd(II) and Ni(II) ions from aqueous solutions using activated sludge and dried sludge

NASA Astrophysics Data System (ADS)

Ong, Soon-An; Toorisaka, Eiichi; Hirata, Makoto; Hano, Tadashi

2013-03-01

The adsorption of Cu(II), Cd(II) and Ni(II) ions from aqueous solutions by activated sludge and dried sludge was investigated under laboratory conditions to assess its potential in removing metal ions. The adsorption behavior of metal ions onto activated sludge and dried sludge was analyzed with Weber-Morris intra-particle diffusion model, Lagergren first-order model and pseudo second-order model. The rate constant of intra-particle diffusion on activated sludge and dried sludge increased in the sequence of Cu(II) > Ni(II) > Cd(II). According to the regression coefficients, it was observed that the kinetic adsorption data can fit better by the pseudo second-order model compared to the first-order Lagergren model with R 2 > 0.997. The adsorption capacities of metal ions onto activated sludge and dried sludge followed the sequence Ni(II) ≈ Cu(II) > Cd(II) and Cu(II) > Ni(II) > Cd(II).

Kinetics of homogeneous and surface-catalyzed mercury(II) reduction by iron(II)

USGS Publications Warehouse

Amirbahman, Aria; Kent, Douglas B.; Curtis, Gary P.; Marvin-DiPasquale, Mark C.

2013-01-01

Production of elemental mercury, Hg(0), via Hg(II) reduction is an important pathway that should be considered when studying Hg fate in environment. We conducted a kinetic study of abiotic homogeneous and surface-catalyzed Hg(0) production by Fe(II) under dark anoxic conditions. Hg(0) production rate, from initial 50 pM Hg(II) concentration, increased with increasing pH (5.5–8.1) and aqueous Fe(II) concentration (0.1–1 mM). The homogeneous rate was best described by the expression, rhom = khom [FeOH+] [Hg(OH)2]; khom = 7.19 × 10+3 L (mol min)−1. Compared to the homogeneous case, goethite (α-FeOOH) and hematite (α-Fe2O3) increased and γ-alumina (γ-Al2O3) decreased the Hg(0) production rate. Heterogeneous Hg(0) production rates were well described by a model incorporating equilibrium Fe(II) adsorption, rate-limited Hg(II) reduction by dissolved and adsorbed Fe(II), and rate-limited Hg(II) adsorption. Equilibrium Fe(II) adsorption was described using a surface complexation model calibrated with previously published experimental data. The Hg(0) production rate was well described by the expression rhet = khet [>SOFe(II)] [Hg(OH)2], where >SOFe(II) is the total adsorbed Fe(II) concentration; khet values were 5.36 × 10+3, 4.69 × 10+3, and 1.08 × 10+2 L (mol min)−1 for hematite, goethite, and γ-alumina, respectively. Hg(0) production coupled to reduction by Fe(II) may be an important process to consider in ecosystem Hg studies.

Ontogeny and nutritional programming of the hepatic growth hormone-insulin-like growth factor-prolactin axis in the sheep.

PubMed

Hyatt, Melanie A; Budge, Helen; Walker, David; Stephenson, Terence; Symonds, Michael E

2007-10-01

The liver is an important metabolic and endocrine organ in the fetus, but the extent to which its hormone receptor sensitivity is developmentally regulated in early life is not fully established. Therefore, we examined developmental changes in mRNA abundance for the GH receptor (GHR) and prolactin receptor (PRLR) plus IGF-I and -II and their receptors. Fetal and postnatal sheep were sampled at either 80 or 140 d gestation, 1 or 30 d, or 6 months of age. The effect of maternal nutrient restriction between early gestation to midgestation (i.e. 28-80 d gestation, the time of early liver growth) on gene expression was also examined in the fetus and juvenile offspring. Gene expression for the GHR, PRLR, and IGF-I receptor increased through gestation peaking at birth, whereas IGF-I was maximal near to term. In contrast, IGF-II mRNA decreased between midgestation and late gestation to increase after birth, whereas IGF-II receptor remained unchanged. A substantial decline in mRNA abundance for GHR, PRLR, and IGF-I receptor then occurred up to 6 months. Maternal nutrient restriction reduced GHR and IGF-II receptor mRNA abundance in the fetus, but caused a precocious increase in the PRLR. Gene expression for IGF-I and -II were increased in juvenile offspring born to nutrient-restricted mothers. In conclusion, there are marked differences in the ontogeny and nutritional programming of specific hormones and their receptors involved in hepatic growth and development in the fetus. These could contribute to changes in liver function during adult life.

Insulin-like growth factor-1, insulin-like growth factor binding protein-3 and lobule type in the Nurses' Health Study II.

PubMed

Rice, Megan S; Tamimi, Rulla M; Connolly, James L; Collins, Laura C; Shen, Dejun; Pollak, Michael N; Rosner, Bernard; Hankinson, Susan E; Tworoger, Shelley S

2012-03-13

Previous research in the Nurses' Health Study (NHS) and the NHSII observed that, among women diagnosed with benign breast disease (BBD), those with predominant type 1/no type 3 lobules (a marker of complete involution) versus other lobule types were at lower risk of subsequent breast cancer. Studies in animal models suggest that insulin-like growth factor-1 (IGF-1) may inhibit involution of lobules in the breast; however, this has not been studied in humans. We conducted a cross-sectional study among 472 women in the NHSII who were diagnosed with biopsy-confirmed proliferative BBD between 1991 and 2002 and provided blood samples between 1996 and 1999. A pathologist, blinded to exposure status, classified lobule type in normal adjacent tissue on available biopsy slides according to the number of acini per lobule. For each participant, the pathologist determined the predominant lobule type (that is, type 1, type 2, or type 3) and whether any type 1 or any type 3 lobules were present. Lobule type was then classified as: predominant type 1/no type 3 lobules, which is suggestive of complete involution; or other lobule types. Multivariate logistic models were used to assess the associations between plasma IGF-1, insulin-like growth factor binding protein-3 (IGFBP-3), and the ratio of IGF-1:IGFBP-3 levels with lobule type. In univariate analyses, greater age, higher body mass index, postmenopausal status, nulliparity, and lower IGF-1 levels were associated with predominant type 1/no type 3 lobules (P < 0.05). In multivariate models adjusting for age and assay batch, higher IGF-1 levels were associated with decreased odds of predominant type 1/no type 3 lobules (odds ratio quartile 4 vs. quartile 1 = 0.37, 95% confidence interval = 0.15 to 0.89). Greater ratios of IGF-1:IGFBP-3 levels were also associated with decreased odds of predominant type 1/no type 3 lobules (odds ratio quartile 4 vs. quartile 1 = 0.26, 95% confidence interval = 0.11 to 0.64). These results were

Differential neuronal vulnerability identifies IGF-2 as a protective factor in ALS

PubMed Central

Allodi, Ilary; Comley, Laura; Nichterwitz, Susanne; Nizzardo, Monica; Simone, Chiara; Benitez, Julio Aguila; Cao, Ming; Corti, Stefania; Hedlund, Eva

2016-01-01

The fatal disease amyotrophic lateral sclerosis (ALS) is characterized by the loss of somatic motor neurons leading to muscle wasting and paralysis. However, motor neurons in the oculomotor nucleus, controlling eye movement, are for unknown reasons spared. We found that insulin-like growth factor 2 (IGF-2) was maintained in oculomotor neurons in ALS and thus could play a role in oculomotor resistance in this disease. We also showed that IGF-1 receptor (IGF-1R), which mediates survival pathways upon IGF binding, was highly expressed in oculomotor neurons and on extraocular muscle endplate. The addition of IGF-2 induced Akt phosphorylation, glycogen synthase kinase-3β phosphorylation and β-catenin levels while protecting ALS patient motor neurons. IGF-2 also rescued motor neurons derived from spinal muscular atrophy (SMA) patients from degeneration. Finally, AAV9::IGF-2 delivery to muscles of SOD1G93A ALS mice extended life-span by 10%, while preserving motor neurons and inducing motor axon regeneration. Thus, our studies demonstrate that oculomotor-specific expression can be utilized to identify candidates that protect vulnerable motor neurons from degeneration. PMID:27180807

Anti-inflammatory drugs interacting with Zn(II), Cd(II) and Pt(II) metal ions.

PubMed

Dendrinou-Samara, C; Tsotsou, G; Ekateriniadou, L V; Kortsaris, A H; Raptopoulou, C P; Terzis, A; Kyriakidis, D A; Kessissoglou, D P

1998-09-01

Complexes of Zn(II), Cd(II) and Pt(II) metal ions with the anti-inflammatory drugs, 1-methyl-5-(p-toluoyl)-1H-pyrrole-2-acetic acid (Tolmetin), alpha-methyl-4-(2-methylpropyl)benzeneacetic acid (Ibuprofen), 6-methoxy-alpha-methylnaphthalene-2-acetic acid (Naproxen) and 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid (indomethacin) have been synthesized and characterized. In the structurally characterized Cd(naproxen)2 complex the anti-inflammatory drugs acts as bidentate chelate ligand coordinatively bound to metal ions through the deprotonated carboxylate group. Crystal data for 1: [C32H26O8Cd], orthorhombic, space group P22(1)2(1), a = 5.693(2) (A), b = 8.760(3) (A), c = 30.74(1) (A), V = 1533(1) A3, Z = 2. Antibacterial and growth inhibitory activity is higher than that of the parent ligands or the platinum(II) diamine compounds.

Simultaneous Stripping Detection of Pb(II), Cd(II) and Zn(II) Using a Bimetallic Hg-Bi/Single-Walled Carbon Nanotubes Composite Electrode

PubMed Central

Ouyang, Ruizhuo; Zhu, Zhenqian; Tatum, Clarissa E.; Chambers, James Q.; Xue, Zi-Ling

2011-01-01

A new, sensitive platform for the simultaneous electrochemical assay of Zn(II), Cd(II) and Pb(II) in aqueous solution has been developed. The platform is based on a new bimetallic Hg-Bi/single-walled carbon nanotubes (SWNTs) composite modified glassy carbon electrode (GCE), demonstrating remarkably improved performance for the anodic stripping assay of Zn(II), Cd(II) and Pb(II). The synergistic effect of Hg and Bi as well as the enlarged, activated surface and good electrical conductivity of SWNTs on GCE contribute to the enhanced activity of the proposed electrode. The analytical curves for Zn(II), Cd(II) an Pb(II) cover two linear ranges varying from 0.5 to 11 μg L-1 and 10 to 130 μg L-1 with correlation coefficients higher than 0.992. The limits of detection for Zn(II), Cd(II) are lower than 2 μg L-1 (S/N = 3). For Pb(II), moreover, there is another lower, linear range from 5 to 1100 ng L-1 with a coefficient of 0.987 and a detection limit of 0.12 ng L-1. By using the standard addition method, Zn(II), Cd(II) and Pb(II) ions in river samples were successfully determined. These results suggest that the proposed method can be applied as a simple, efficient alternative for the simultaneous monitoring of heavy metals in water samples. In addition, this method demonstrates the powerful application of carbon nanotubes in electrochemical analysis of heavy metals. PMID:21660117

Exploratory Factor Analysis of the Beck Anxiety Inventory and the Beck Depression Inventory-II in a Psychiatric Outpatient Population

PubMed Central

2018-01-01

Background To further understand the relationship between anxiety and depression, this study examined the factor structure of the combined items from two validated measures for anxiety and depression. Methods The participants were 406 patients with mixed psychiatric diagnoses including anxiety and depressive disorders from a psychiatric outpatient unit at a university-affiliated medical center. Responses of the Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI)-II, and Symptom Checklist-90-Revised (SCL-90-R) were analyzed. We conducted an exploratory factor analysis of 42 items from the BAI and BDI-II. Correlational analyses were performed between subscale scores of the SCL-90-R and factors derived from the factor analysis. Scores of individual items of the BAI and BDI-II were also compared between groups of anxiety disorder (n = 185) and depressive disorder (n = 123). Results Exploratory factor analysis revealed the following five factors explaining 56.2% of the total variance: somatic anxiety (factor 1), cognitive depression (factor 2), somatic depression (factor 3), subjective anxiety (factor 4), and autonomic anxiety (factor 5). The depression group had significantly higher scores for 12 items on the BDI while the anxiety group demonstrated higher scores for six items on the BAI. Conclusion Our results suggest that anxiety and depressive symptoms as measured by the BAI and BDI-II can be empirically differentiated and that particularly items of the cognitive domain in depression and those of physical domain in anxiety are noteworthy. PMID:29651821

Validation of Arabic and English versions of the ARSMA-II Acculturation Rating Scale.

PubMed

Jadalla, Ahlam; Lee, Jerry

2015-02-01

To translate and adapt the Acculturation Rating Scale of Mexican-Americans II (ARSMA-II) for Arab Americans. A multistage translation process followed by a pilot and a large study. The translated and adapted versions, Acculturation Rating Scale for Arabic Americans-II Arabic and English (ARSAA-IIA, ARSAA-IIE), were validated in a sample of 297 Arab Americans. Factor analyses with principal axis factoring extractions and direct oblimin rotations were used to identify the underlying structure of ARSAA-II. Factor analysis confirmed the underlying structure of ARSAA-II and produced two interpretable factors labeled as 'Attraction to American Culture' (AAmC) and 'Attraction to Arabic Culture' (AArC). The Cronbach's alphas of AAmC and AArC were .89 and .85 respectively. Findings support ARSAA-II A & E to assess acculturation among Arab Americans. The emergent factors of ARSAA-II support the theoretical structure of the original ARSMA-II tool and show high internal consistency.

[Evaluation of serum PIVKA-II by Lumipulse PrestoII assay].

PubMed

Hiramatsu, Kumiko; Tanaka, Yasuhito; Takagi, Kazumi; Kani, Satomi; Goto, Takaaki; Takasaka, Yoshimitsu; Matsuura, Kentaro; Sugauchi, Fuminaka; Moriyama, Kazushige; Murakami, Hiroshi; Kitajima, Sachiko; Mizokami, Masashi

2009-03-01

Measurements of serum concentrations of Des-gamma-carboxy Prothrombin (PIVKA-II) are widely used for diagnosing hepatocellular carcinoma (HCC). Recently, in Lumipulsef assay, it was reported that antibodies against alkaline phosphatase (ALP) derived from anti bleeding sheets led false high values of PIVKA-II in the patients with HCC resection. To improve the previous issue, newly developed Lumipulse PrestoII assay was examined. (1) The assay was reliable and positively correlated with the previous assays (Lumipulse f and Picolumi, R = 0.997 and 0.994 (n=115), respectively). (2) Eleven cases, which had false high values of PIVKA-II by the Lumipulsef assay, were examined by the PrestoII assay with excess of inactive ALP. The false high values of 10 cases were improved, but only one was still high. False reactivity of this case was stronger than other cases, more effective adsorption was required. (3) Comparing the absorbent activity of inactive ALP among 6 different kinds, we found inactive ALP with much higher adsorbent activity. When this inactive ALP was applied to assay, false high values of PIVKA-II were improved in all 11 cases. In conclusion, the PrestoII assay, which applies the inactive ALP with high activity, is reliable and useful for clinical screening.

Impact of a commercial glyphosate formulation on adsorption of Cd(II) and Pb(II) ions on paddy soil.

PubMed

Divisekara, T; Navaratne, A N; Abeysekara, A S K

2018-05-01

Use of glyphosate as a weedicide on rice cultivation has been a controversial issue in Sri Lanka, due to the hypothesis that the metal complexes of commercial glyphosate is one of the causative factors of Chronic Kidney Disease of unknown aetiology (CKDu) prevalent in some parts of Sri Lanka. The effect of commercial glyphosate on the adsorption and desorption of Cd(II) and Pb(II) ions on selective paddy soil studied using batch experiments, over a wide concentration range, indicates that the Langmuir adsorption isotherm model is obeyed at low initial metal ion concentrations while the Freundlich adsorption isotherm model obeys at high metal ion concentrations in the presence and absence of glyphosate. For all cases, adsorption of both Cd(II) and Pb(II) ions obeys pseudo second order kinetics, suggesting that initial adsorption is a chemisorption process. In the presence of glyphosate formulation, the extent of adsorption of Cd(II) and Pb(II) ions on soil is decreased, while their desorption is increased at high concentrations of glyphosate. Low concentrations of glyphosate formulation do not significantly affect the desorption of metal ions from soil. Reduction of adsorption leads to enhance the concentration of Cd(II) and Pb(II) ions in the aqueous phase when in contact with soil. Copyright © 2018 Elsevier Ltd. All rights reserved.

[RNA polymerase II and pre-mRNA splicing factors in diplotene oocyte nuclei of the giant African gastropod Achatina fulica].

PubMed

Stepanova, I S; Bogoliubov, D S

2003-01-01

The nuclear distribution of pre-mRNA splicing factors (snRNPs and SR-protein SC35) and unphosphorylated from of RNA polymerase II (Pol II) was studied using fluorescent and immunoelectron cytochemistry in diplotene oocytes of the gastropod Achatina fulica. Association of Pol II and splicing factors with oocyte nuclear structures was analysed. The antibodies against splicing factors and Pol II were shown to label perichromatin fibrils at the periphery of condensed chromatin blocks as well as those in interchromatin regions of nucleoplasm. The revealed character of distribution of snRNPs, SC35 protein, and Pol II, together with the decondensed chromatin and absence of karyosphere, enable us to suggest that oocyte chromosomes maintain their transcriptional activity at the diplotene stage of oogenesis. In A. fulica oocytes, sparse nuclear bodies (NBs) of a complex morphological structure were revealed. These NBs contain snRNPs rather than SC35 protein. NBs are associated with a fibrogranular material (FGM), which contains SC35 protein. No snRNPs were revealed in this material. Homology of A. fulica oocyte nuclear structures to Cajal bodies and interchromatin granule clusters is discussed.

Synthesis and studies on Cu(II), Co(II), Ni(II) complexes of Knoevenagel β-diketone ligands.

PubMed

Sumathi, S; Tharmaraj, P; Sheela, C D; Anitha, C

2012-11-01

Transition metal complexes of various acetylacetone based ligands of the type ML [where M=Cu(II), Ni(II), Co(II); L=3-(aryl)-pentane-2,4-dione] have been synthesized. The structural features have been derived from their elemental analysis, magnetic susceptibility, molar conductance, IR, UV-Vis, (1)H NMR, Mass and ESR spectral studies. Conductivity measurements reveal that all the complexes are non-electrolytic in nature. Spectroscopic and other analytical data of the complexes suggest octahedral geometry for other metal(II) complexes. The redox behavior of the copper(II) complexes have been studied by cyclic voltammetry. The free ligands and their metal complexes have been screened for their in vitro biological activities against the bacteria Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus as well as the fungus Candida albicans by well diffusion method. The zone of inhibition value indicates that the most of the metal(II) complexes are found to possess increased activities compared to those of the free ligands. All synthesized compounds may serve as potential photoactive materials as indicated from their characteristic fluorescence properties. The second harmonic generation (SHG) efficiency of the ligands (L1-L3) was found to be considerable effect than that of urea and KDP (potassium dihydrogen phosphate). Copyright © 2012 Elsevier B.V. All rights reserved.

Synthesis and studies on Cu(II), Co(II), Ni(II) complexes of Knoevenagel β-diketone ligands

NASA Astrophysics Data System (ADS)

Sumathi, S.; Tharmaraj, P.; Sheela, C. D.; Anitha, C.

2012-11-01

Transition metal complexes of various acetylacetone based ligands of the type ML [where M = Cu(II), Ni(II), Co(II); L = 3-(aryl)-pentane-2,4-dione] have been synthesized. The structural features have been derived from their elemental analysis, magnetic susceptibility, molar conductance, IR, UV-Vis, 1H NMR, Mass and ESR spectral studies. Conductivity measurements reveal that all the complexes are non-electrolytic in nature. Spectroscopic and other analytical data of the complexes suggest octahedral geometry for other metal(II) complexes. The redox behavior of the copper(II) complexes have been studied by cyclic voltammetry. The free ligands and their metal complexes have been screened for their in vitro biological activities against the bacteria Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus as well as the fungus Candida albicans by well diffusion method. The zone of inhibition value indicates that the most of the metal(II) complexes are found to possess increased activities compared to those of the free ligands. All synthesized compounds may serve as potential photoactive materials as indicated from their characteristic fluorescence properties. The second harmonic generation (SHG) efficiency of the ligands (L1-L3) was found to be considerable effect than that of urea and KDP (potassium dihydrogen phosphate).

SP70-alpha-benzoin oxime chelating resin for preconcentration-separation of Pb(II), Cd(II), Co(II) and Cr(III) in environmental samples.

PubMed

Narin, Ibrahim; Surme, Yavuz; Bercin, Erdogan; Soylak, Mustafa

2007-06-25

In the presented work, alpha-benzoin oxime immobilized SP70 chelating resin was synthesized for separation and preconcentration of Pb(II), Cd(II), Co(II) and Cr(III). The optimization procedure for analytical parameters including pH, eluent type, flow rate, etc. was examined in order to gain quantitative recoveries of analyte ions. The effects of foreign ions on the recoveries of studied metal ions were also investigated. The detection limits (3sigma) were found to be 16.0, 4.2, 1.3, 2.4microgL(-1) for Pb, Cd, Co and Cr, respectively. The preconcentration factor was 75 for Pb, 100 for Cd, Co and Cr. The optimized method was validated with certified reference materials and successfully applied to the waters, crops and pharmaceutical samples with good results (recoveries greater than 95%, R.S.D. lower than 10%).

Better prognostic marker in ICU - APACHE II, SOFA or SAP II!

PubMed

Naqvi, Iftikhar Haider; Mahmood, Khalid; Ziaullaha, Syed; Kashif, Syed Mohammad; Sharif, Asim

2016-01-01

This study was designed to determine the comparative efficacy of different scoring system in assessing the prognosis of critically ill patients. This was a retrospective study conducted in medical intensive care unit (MICU) and high dependency unit (HDU) Medical Unit III, Civil Hospital, from April 2012 to August 2012. All patients over age 16 years old who have fulfilled the criteria for MICU admission were included. Predictive mortality of APACHE II, SAP II and SOFA were calculated. Calibration and discrimination were used for validity of each scoring model. A total of 96 patients with equal gender distribution were enrolled. The average APACHE II score in non-survivors (27.97+8.53) was higher than survivors (15.82+8.79) with statistically significant p value (<0.001). The average SOFA score in non-survivors (9.68+4.88) was higher than survivors (5.63+3.63) with statistically significant p value (<0.001). SAP II average score in non-survivors (53.71+19.05) was higher than survivors (30.18+16.24) with statistically significant p value (<0.001). All three tested scoring models (APACHE II, SAP II and SOFA) would be accurate enough for a general description of our ICU patients. APACHE II has showed better calibration and discrimination power than SAP II and SOFA.

Genetic modification of chondrocytes with insulin-like growth factor-1 enhances cartilage healing in an equine model.

PubMed

Goodrich, L R; Hidaka, C; Robbins, P D; Evans, C H; Nixon, A J

2007-05-01

Gene therapy with insulin-like growth factor-1 (IGF-1) increases matrix production and enhances chondrocyte proliferation and survival in vitro. The purpose of this study was to determine whether arthroscopically-grafted chondrocytes genetically modified by an adenovirus vector encoding equine IGF-1 (AdIGF-1) would have a beneficial effect on cartilage healing in an equine femoropatellar joint model. A total of 16 horses underwent arthroscopic repair of a single 15 mm cartilage defect in each femoropatellar joint. One joint received 2 x 10(7) AdIGF-1 modified chondrocytes and the contralateral joint received 2 x 10(7) naive (unmodified) chondrocytes. Repairs were analysed at four weeks, nine weeks and eight months after surgery. Morphological and histological appearance, IGF-1 and collagen type II gene expression (polymerase chain reaction, in situ hybridisation and immunohistochemistry), collagen type II content (cyanogen bromide and sodium dodecyl sulphate-polyacrylamide gel electrophoresis), proteoglycan content (dimethylmethylene blue assay), and gene expression for collagen type I, matrix metalloproteinase (MMP)-1, MMP-3, MMP-13, aggrecanase-1, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and TIMP-3 were evaluated. Genetic modification of chondrocytes significantly increased IGF-1 mRNA and ligand production in repair tissue for up to nine weeks following transplantation. The gross and histological appearance of IGF-1 modified repair tissue was improved over control defects. Gross filling of defects was significantly improved at four weeks, and a more hyaline-like tissue covered the lesions at eight months. Histological outcome at four and nine weeks post-transplantation revealed greater tissue filling of defects transplanted with genetically modified chondrocytes, whereas repair tissue in control defects was thin and irregular and more fibrous. Collagen type II expression in IGF-1 gene-transduced defects was increased 100-fold at four weeks and

Insulin-like growth factor I (IGF-1) Ec/Mechano Growth factor--a splice variant of IGF-1 within the growth plate.

PubMed

Schlegel, Werner; Raimann, Adalbert; Halbauer, Daniel; Scharmer, Daniela; Sagmeister, Susanne; Wessner, Barbara; Helmreich, Magdalena; Haeusler, Gabriele; Egerbacher, Monika

2013-01-01

Human insulin-like growth factor 1 Ec (IGF-1Ec), also called mechano growth factor (MGF), is a splice variant of insulin-like growth factor 1 (IGF-1), which has been shown in vitro as well as in vivo to induce growth and hypertrophy in mechanically stimulated or damaged muscle. Growth, hypertrophy and responses to mechanical stimulation are important reactions of cartilaginous tissues, especially those in growth plates. Therefore, we wanted to ascertain if MGF is expressed in growth plate cartilage and if it influences proliferation of chondrocytes, as it does in musculoskeletal tissues. MGF expression was analyzed in growth plate and control tissue samples from piglets aged 3 to 6 weeks. Furthermore, growth plate chondrocyte cell culture was used to evaluate the effects of the MGF peptide on proliferation. We showed that MGF is expressed in considerable amounts in the tissues evaluated. We found the MGF peptide to be primarily located in the cytoplasm, and in some instances, it was also found in the nucleus of the cells. Addition of MGF peptides was not associated with growth plate chondrocyte proliferation.

The group II intron maturase: a reverse transcriptase and splicing factor go hand in hand.

PubMed

Zhao, Chen; Pyle, Anna Marie

2017-12-01

The splicing of group II introns in vivo requires the assistance of a multifunctional intron encoded protein (IEP, or maturase). Each IEP is also a reverse-transcriptase enzyme that enables group II introns to behave as mobile genetic elements. During splicing or retro-transposition, each group II intron forms a tight, specific complex with its own encoded IEP, resulting in a highly reactive holoenzyme. This review focuses on the structural basis for IEP function, as revealed by recent crystal structures of an IEP reverse transcriptase domain and cryo-EM structures of an IEP-intron complex. These structures explain how the same IEP scaffold is utilized for intron recognition, splicing and reverse transcription, while providing a physical basis for understanding the evolutionary transformation of the IEP into the eukaryotic splicing factor Prp8. Copyright © 2017 Elsevier Ltd. All rights reserved.

Synthesis, Characterization and Antibacterial Activity of 1,4-di[ aminomethylene carboxyl] phenylene (H2L) and its Complexes Co(II), Cu (II), Zn(II) and Cd (II)

NASA Astrophysics Data System (ADS)

Sultan, J. S.; Fezea, S. M.; Mousa, F. H.

2018-05-01

A binucleating tetradentate Schiff base ligand, 1,4- di[amino methylene carboxylic] phenylene (H2L) and its forth new binuclear complexes [Co(II), Cu(II), Zn(II) and Cd(II)] were prepared via reaction metal (II) chloride with ligand (H2L) using 2:1 (M:L) in ethanol solvent. The new ligand (H2L) and its complexes were characterized by elemental microanalysis (C.H.N), atomic absorption, chloride content, molar conductance’s magnetic susceptibility, FTIR UV- Vis spectral and, 1H, 13 C- NMR (for H2L). The antibacterial activity with bacteria activity with bacteria, Staphylococcus aureus, Bacillus and Esccherichia Coli were studied.

Central sympathoexcitatory actions of angiotensin II: role of type 1 angiotensin II receptors.

PubMed

DiBona, G F

1999-01-01

The role of the renin-angiotensin system in the control of sympathetic nerve activity is reviewed. Two general mechanisms are considered, one that involves the effects of circulating angiotensin II (AngII) on the central nervous system and a second that involves the central nervous system effects of AngII that originates within the central nervous system. The role of type 1 AngII receptors in discrete brain sites that mediate the sympathoexcitatory actions of AngII of either circulating or central nervous system origin is examined. AngII of circulating origin has ready access to the subfornical organ and area postrema, where it can bind to type 1 AngII receptors on neurons whose connections to the nucleus tractus solitarius and rostral ventrolateral medulla result in sympathoexcitation. In the rostral ventrolateral medulla, angiotensin peptides of central nervous system origin, likely involving angiotensin species in addition to AngII and binding to receptors other than type 1 or 2 AngII receptors, tonically support sympathetic nerve activity.

Adsorption of Pb(II) and Cd(II) by Squid Ommastrephes bartrami Melanin

PubMed Central

Chen, Shiguo; Xue, Changhu; Wang, Jingfeng; Feng, Hui; Wang, Yuming; Ma, Qin; Wang, Dongfeng

2009-01-01

The adsorption of Cd(II) and Pb(II) by squid melanin was investigated. At a metal ion concentration of 2 mM/L, the biosorption efficiency of melanin reached 95% for Cd(II) and Pb(II). The maximum content of bound Cd(II) and Pb(II) was 0.93 mM/g and 0.65 mM/g, respectively. Temperature had no obvious effect on the adsorption of the metals, and in a pH range of 4.0–7.0, the adsorption yield was high and stable. Macrosalts such as NaCl, MgCl2, and CaCl2 had no obvious effect on the binding of Pb(II) but greatly diminished the adsorption of Cd(II), which indicated that different functional groups in squid melanin are responsible for their adsorption. IR analysis of metal ion-enriched squid melanin demonstrated that the possible functional groups responsible for metal binding were phenolic hydroxyl (OH), carboxyl (COOH), and amine groups (NH). This study reports a new material for the removal of heavy metals from low-strength wastewater. PMID:20148082

Synthesis, spectral characterization, structural investigation and antimicrobial studies of mononuclear Cu(II), Ni(II), Co(II), Zn(II) and Cd(II) complexes of a new potentially hexadentate N2O4 Schiff base ligand derived from salicylaldehyde

NASA Astrophysics Data System (ADS)

Keypour, Hassan; Shayesteh, Maryam; Rezaeivala, Majid; Chalabian, Firoozeh; Elerman, Yalcin; Buyukgungor, Orhan

2013-01-01

A new potentially hexadentate N2O4 Schiff base ligand, H2L derived from condensation reaction of an aromatic diamine and salicylaldehyde, and its metal complexes were characterized by elemental analyses, IR, UV-Vis, EI-MS, 1H and 13C NMR spectra, as well as conductance measurements. It has been originated that the Schiff base ligand with Cu(II), Ni(II), Co(II), Cd(II) and Zn(II) ions form mononuclear complexes on 1:1 (metal:ligand) stoichiometry. The conductivity data confirm the non-electrolytic nature of the complexes. Also the crystal structures of the complexes [ZnL] and [CoL] have also been determined by using X-ray crystallographic technique. The Zn(II) and Co(II) complexes show a tetrahedral configuration. Electronic absorption spectra of the Cu(II) and Ni(II) complexes suggest a square-planar geometry around the central metal ion. The synthesized compounds have antibacterial activity against the three Gram-positive bacteria: Bacillus cereus, Enterococcus faecalis and Listeria monocytogenes and also against the three Gram-negative bacteria: Salmonella paraB, Citrobacter freundii and Enterobacter aerogenes. The results showed that in some cases the antibacterial activity of complexes were more than nalidixic acid and amoxicillin as standards.

Motility screen identifies Drosophila IGF-II mRNA-binding protein--zipcode-binding protein acting in oogenesis and synaptogenesis.

PubMed

Boylan, Kristin L M; Mische, Sarah; Li, Mingang; Marqués, Guillermo; Morin, Xavier; Chia, William; Hays, Thomas S

2008-02-01

The localization of specific mRNAs can establish local protein gradients that generate and control the development of cellular asymmetries. While all evidence underscores the importance of the cytoskeleton in the transport and localization of RNAs, we have limited knowledge of how these events are regulated. Using a visual screen for motile proteins in a collection of GFP protein trap lines, we identified the Drosophila IGF-II mRNA-binding protein (Imp), an ortholog of Xenopus Vg1 RNA binding protein and chicken zipcode-binding protein. In Drosophila, Imp is part of a large, RNase-sensitive complex that is enriched in two polarized cell types, the developing oocyte and the neuron. Using time-lapse confocal microscopy, we establish that both dynein and kinesin contribute to the transport of GFP-Imp particles, and that regulation of transport in egg chambers appears to differ from that in neurons. In Drosophila, loss-of-function Imp mutations are zygotic lethal, and mutants die late as pharate adults. Imp has a function in Drosophila oogenesis that is not essential, as well as functions that are essential during embryogenesis and later development. Germline clones of Imp mutations do not block maternal mRNA localization or oocyte development, but overexpression of a specific Imp isoform disrupts dorsal/ventral polarity. We report here that loss-of-function Imp mutations, as well as Imp overexpression, can alter synaptic terminal growth. Our data show that Imp is transported to the neuromuscular junction, where it may modulate the translation of mRNA targets. In oocytes, where Imp function is not essential, we implicate a specific Imp domain in the establishment of dorsoventral polarity.

Changes in photochemically significant solar UV spectral irradiance as estimated by the composite Mg II index and scale factors

NASA Technical Reports Server (NTRS)

Deland, Matthew T.; Cebula, Richard P.

1994-01-01

Quantitative assessment of the impact of solar ultraviolet irradiance variations on stratospheric ozone abundances currently requires the use of proxy indicators. The Mg II core-to-wing index has been developed as an indicator of solar UV activity between 175-400 nm that is independent of most instrument artifacts, and measures solar variability on both rotational and solar cycle time scales. Linear regression fits have been used to merge the individual Mg II index data sets from the Nimbus-7, NOAA-9, and NOAA-11 instruments onto a single reference scale. The change in 27-dayrunning average of the composite Mg II index from solar maximum to solar minimum is approximately 8 percent for solar cycle 21, and approximately 9 percent for solar cycle 22 through January 1992. Scaling factors based on the short-term variations in the Mg II index and solar irradiance data sets have been developed to estimate solar variability at mid-UV and near-UV wavelengths. Near 205 nm, where solar irradiance variations are important for stratospheric photo-chemistry and dynamics, the estimated change in irradiance during solar cycle 22 is approximately 10 percent using the composite Mg II index and scale factors.

Syntheses, structures, and properties of imidazolate-bridged Cu(II)-Cu(II) and Cu(II)-Zn(II) dinuclear complexes of a single macrocyclic ligand with two hydroxyethyl pendants.

PubMed

Li, Dongfeng; Li, Shuan; Yang, Dexi; Yu, Jiuhong; Huang, Jin; Li, Yizhi; Tang, Wenxia

2003-09-22

The imidazolate-bridged homodinuclear Cu(II)-Cu(II) complex, [(CuimCu)L]ClO(4).0.5H(2)O (1), and heterodinuclear Cu(II)-Zn(II) complex, [(CuimZnL(-)(2H))(CuimZnL(-)(H))](ClO(4))(3) (2), of a single macrocyclic ligand with two hydroxyethyl pendants, L (L = 3,6,9,16,19,22-hexaaza-6,19-bis(2-hydroxyethyl)tricyclo[22,2,2,2(11,14)]triaconta-1,11,13,24,27,29-hexaene), have been synthesized as possible models for copper-zinc superoxide dismutase (Cu(2),Zn(2)-SOD). Their crystal structures analyzed by X-ray diffraction methods have shown that the structures of the two complexes are markedly different. Complex 1 crystallizes in the orthorhombic system, containing an imidazolate-bridged dicopper(II) [Cu-im-Cu](3+) core, in which the two copper(II) ions are pentacoordinated by virtue of an N4O environment with a Cu.Cu distance of 5.999(2) A, adopting the geometry of distorted trigonal bipyramid and tetragonal pyramid, respectively. Complex 2 crystallizes in the triclinic system, containing two similar Cu-im-Zn cores in the asymmetric unit, in which both the Cu(II) and Zn(II) ions are pentacoordinated in a distorted trigonal bipyramid geometry, with the Cu.Zn distance of 5.950(1)/5.939(1) A, respectively. Interestingly, the macrocyclic ligand with two arms possesses a chairlike (anti) conformation in complex 1, but a boatlike (syn) conformation in complex 2. Magnetic measurements and ESR spectroscopy of complex 1 have revealed the presence of an antiferromagnetic exchange interaction between the two Cu(II) ions. The ESR spectrum of the Cu(II)-Zn(II) heterodinuclear complex 2 displayed a typical signal for mononuclear trigonal bipyramidal Cu(II) complexes. From pH-dependent ESR and electronic spectroscopic studies, the imidazolate bridges in the two complexes have been found to be stable over broad pH ranges. The cyclic voltammograms of the two complexes have been investigated. Both of the two complexes can catalyze the dismutation of superoxide and show rather high activity.

The IGF2 Locus

USDA-ARS?s Scientific Manuscript database

Insulin-like growth factor 2 (IGF2) is a peptide hormone regulating various cellular processes such as proliferation and apoptosis. IGF2 is vital to embryo development. The IGF2 locus covers approximately 150-kb genomic region on human chromosome 11, containing two imprinted genes, IGF2 and H19, sha...

Co(II), Ni(II), Cu(II) and Zn(II) complexes of tridentate ONO donor Schiff base ligand: Synthesis, characterization, thermal, non-isothermal kinetics and DFT calculations

NASA Astrophysics Data System (ADS)

Kusmariya, Brajendra S.; Mishra, A. P.

2017-02-01

We report here four mononuclear Co(II), Ni(II), Cu(II) and Zn(II) coordination compounds of general formula [M(L)2] {L = dcp; M = CoII, CuII & ZnII} and [M(L)(H2O)]·H2O {L = dcp; M = NiII} derived from tridentate 2,4-dichloro-6-{[(3-chloro-2-hydroxy-5-nitrophenyl)imino]methyl}phenol (dcp) ligand. These compounds were synthesized and characterized by elemental analysis, FT-IR, uv-vis, 1H NMR, molar conductance, magnetic moment, thermal, PXRD and SEM-EDX. The Powder X-ray Diffraction patterns and SEM analyses showed the crystalline nature of synthesized compounds. The peak broadening was explained in terms of crystallite size and the lattice strain using Scherrer and Williamson-Hall method. Thermogravimetric analysis was performed to determine the thermal stability of synthesized compounds under nitrogen atmosphere up to 820 K at 10 Kmin-1 heating rate. The kinetic and thermodynamic parameters of thermal decomposition were calculated using Coats-Redfern (C-R), Piloyan-Novikova (P-N) and Horowitz-Metzger (H-M) methods assuming first order degradation. The calculated optical band gap values of complexes were found to be in semiconducting range. To support the experimental findings, and derive some fruitful information viz. frequency calculations, HOMO-LUMO, energy gap (ΔE), molecular electrostatic potential (MEP), spin density, absorption spectra etc.; theoretical calculations by means of DFT and TD-DFT at B3LYP level were incorporated.

Characterization and biological studies on Co(II), Ni(II) and Cu(II) complexes of carbohydrazones ending by pyridyl ring.

PubMed

Abu El-Reash, G M; El-Gammal, O A; Ghazy, S E; Radwan, A H

2013-03-01

The chelating behavior of ligands based on carbohydrazone core modified with pyridine end towards Co(II), Ni(II) and Cu(II) ions have been examined. The ligands derived from the condensation of carbohydrazide with 2-acetylpyridine (H(2)APC) and 4-acetylpyridine (H(2)APEC). The (1)H NMR, IR data and the binding energy calculations of H(2)APC revealed the presence of two stereoisomers syn and anti in the solid state and in the solution. The (1)H NMR, IR data and the binding energy calculations confirmed the presence of H(2)APEC in one keto form only in the solid state and in the solution. The spectroscopic data confirmed that H(2)APC behaves as a monobasic pentadentate in Co(II) and Cu(II) complexes and as mononegative tetradentate in Ni(II) complex. On the other hand, H(2)APEC acts as a mononegative tridentate in Co(II) complex, neutral tridentate in Ni(II) complex and neutral bidentate in Cu(II) complex. The electronic spectra and the magnetic measurements of complexes as well as the ESR of the copper complexes suggested the octahedral geometry. The bond length and bond angles were evaluated by DFT method using material studio program. The thermal behavior and the kinetic parameters of degradation were determined using Coats-Redfern and Horowitz-Metzger methods. The antioxidant (DDPH and ABTS methods), anti-hemolytic and in vitro Ehrlich ascites of the compounds have been screened. Copyright © 2012 Elsevier B.V. All rights reserved.

Insulin-like growth factor and fibroblast growth factor expression profiles in growth-restricted fetal sheep pancreas.

PubMed

Chen, Xiaochuan; Rozance, Paul J; Hay, William W; Limesand, Sean W

2012-05-01

Placental insufficiency results in intrauterine growth restriction (IUGR), impaired fetal insulin secretion and less fetal pancreatic β-cell mass, partly due to lower β-cell proliferation rates. Insulin-like growth factors (IGFs) and fibroblast growth factors (FGFs) regulate fetal β-cell proliferation and pancreas development, along with transcription factors, such as pancreatic and duodenal homeobox 1 (PDX-1). We determined expression levels for these growth factors, their receptors and IGF binding proteins in ovine fetal pancreas and isolated islets. In the IUGR pancreas, relative mRNA expression levels of IGF-I, PDX-1, FGF7 and FGFR2IIIb were 64% (P < 0.01), 76% (P < 0.05), 76% (P < 0.05) and 52% (P < 0.01) lower, respectively, compared with control fetuses. Conversely, insulin-like growth factor binding protein 2 (IGFBP-2) mRNA and protein concentrations were 2.25- and 1.2-fold greater (P < 0.05) in the IUGR pancreas compared with controls. In isolated islets from IUGR fetuses, IGF-II and IGFBP-2 mRNA concentrations were 1.5- and 3.7-fold greater (P < 0.05), and insulin mRNA was 56% less (P < 0.05) than control islets. The growth factor expression profiles for IGF and FGF signaling pathways indicate that declines in β-cell mass are due to decreased growth factor signals for both pancreatic progenitor epithelial cell and mature β-cell replication.

Production and Isomeric Distribution of Xanthylium Cation Pigments and Their Precursors in Wine-like Conditions: Impact of Cu(II), Fe(II), Fe(III), Mn(II), Zn(II), and Al(III).

PubMed

Guo, Anque; Kontoudakis, Nikolaos; Scollary, Geoffrey R; Clark, Andrew C

2017-03-22

This study establishes the influence of Cu(II), Fe(II), Fe(III), Zn(II), Al(III), and Mn(II) on the oxidative production of xanthylium cations from (+)-catechin and either tartaric acid or glyoxylic acid in model wine systems. The reaction was studied at 25 °C using UHPLC and LC-HRMS for the analysis of phenolic products and their isomeric distribution. In addition to the expected products, a colorless product, tentatively assigned as a lactone, was detected for the first time. The results show the importance of Fe ions and a synergistic influence of Mn(II) in degrading tartaric acid to glyoxylic acid, whereas the other metal ions had minimal activity in this mechanistic step. Fe(II) and Fe(III) were shown to mediate the (+)-catechin-glyoxylic acid addition reaction, a role previously attributed to only Cu(II). Importantly, the study demonstrates that C-8 addition products of (+)-catechin are promoted by Cu(II), whereas C-6 addition products are promoted by Fe ions.

AIM-9X Block II Sidewinder (AIM-9X Blk II)

DTIC Science & Technology

2015-12-01

Selected Acquisition Report (SAR) RCS: DD- A &T(Q& A )823-442 AIM-9X Block II Sidewinder (AIM-9X Blk II) As of FY 2017 President’s Budget Defense...MDAP - Major Defense Acquisition Program MILCON - Military Construction N/ A - Not Applicable O&M - Operations and Maintenance ORD - Operational...15:14:10 UNCLASSIFIED 5 Mission and Description The AIM-9X Block II Sidewinder (AIM-9X Blk II) short-range air-to-air missile is a long term

Histone deacetylase and GATA-binding factor 6 regulate arterial remodeling in angiotensin II-induced hypertension.

PubMed

Kim, Gwi Ran; Cho, Soo-Na; Kim, Hyung-Seok; Yu, Seon Young; Choi, Sin Young; Ryu, Yuhee; Lin, Ming Quan; Jin, Li; Kee, Hae Jin; Jeong, Myung Ho

2016-11-01

Histone deacetylase (HDAC) inhibitors have been reported to improve essential and secondary hypertension. However, the specific HDAC that might serve as a therapeutic target and the associated upstream and downstream molecules involved in regulating hypertension remain unknown. Our study was aimed at investigating whether a selective inhibitor of class II HDAC (MC1568) modulates hypertension, elucidating the underlying mechanism. Hypertension was established by administering angiotensin II (Ang II) to mice before treatment with MC1568. SBP was measured. Treatment with MC1568 reduced elevated SBP; attenuated arterial remodeling in the kidney's small arteries and thoracic aorta; and inhibited cell cycle regulatory gene expression, vascular smooth muscle cell (VSMC) proliferation, DNA synthesis, and VSMC hypertrophy in vivo and in vitro. Ang II enhanced the expression of phosphorylated HDAC4 and GATA-binding factor 6 (GATA6) proteins, which were specifically localized in the cytoplasm of cells in the arteries of kidneys and in aortas. Forced expression and knockdown of HDAC4 increased and decreased, respectively, the proliferation and expression of cell cycle genes in VSMCs. GATA6, a newly described binding partner of HDAC4, markedly enhanced the size and number of VSMCs. Calcium/calmodulin-dependent kinase IIα (CaMKIIα), but not HDAC4, translocated from the nucleus to the cytoplasm in response to Ang II. CaMKIIα and protein kinase D1 were associated with VSMC hypertrophy and hyperplasia via direct interaction with HDAC4. MC1568 treatment weakened the association between HDAC4 and CaMKIIα. These results suggest that class II HDAC inhibition attenuates hypertension by negatively regulating VSMC hypertrophy and hyperplasia via the CaMKIIα/protein kinase D1/HDAC4/GATA6 pathway.

Effects of the Insulin-like Growth Factor Pathway on the Regulation of Mammary Gland Development.

PubMed

Ha, Woo Tae; Jeong, Ha Yeon; Lee, Seung Yoon; Song, Hyuk

2016-09-01

The insulin-like growth factor (IGF) pathway is a key signal transduction pathway involved in cell proliferation, migration, and apoptosis. In dairy cows, IGF family proteins and binding receptors, including their intracellular binding partners, regulate mammary gland development. IGFs and IGF receptor interactions in mammary glands influence the early stages of mammogenesis, i.e., mammary ductal genesis until puberty. The IGF pathway includes three major components, IGFs (such as IGF-I, IGF-II, and insulin), their specific receptors, and their high-affinity binding partners (IGF binding proteins [IGFBPs]; i.e., IGFBP1-6), including specific proteases for each IGFBP. Additionally, IGFs and IGFBP interactions are critical for the bioactivities of various intracellular mechanisms, including cell proliferation, migration, and apoptosis. Notably, the interactions between IGFs and IGFBPs in the IGF pathway have been difficult to characterize during specific stages of bovine mammary gland development. In this review, we aim to describe the role of the interaction between IGFs and IGFBPs in overall mammary gland development in dairy cows.

Endothelium-derived contracting factors mediate the Ang II-induced endothelial dysfunction in the rat aorta: preventive effect of red wine polyphenols.

PubMed

Kane, Modou O; Etienne-Selloum, Nelly; Madeira, Soccoro V F; Sarr, Mamadou; Walter, Allison; Dal-Ros, Stéphanie; Schott, Christa; Chataigneau, Thierry; Schini-Kerth, Valérie B

2010-04-01

Angiotensin II (Ang II)-induced hypertension is associated with vascular oxidative stress and an endothelial dysfunction. This study examined the role of reactive oxygen species (ROS) and endothelium-derived contracting factors in Ang II-induced endothelial dysfunction and whether these effects are prevented by red wine polyphenols (RWPs), a rich source of natural antioxidants. Rats were infused with Ang II for 14 days. RWPs were administered in the drinking water 1 week before and during the Ang II infusion. Arterial pressure was measured in conscious rats. Vascular reactivity was assessed in organ chambers and cyclooxygenase-1 (COX-1) and COX-2 expression by Western blot and immunofluorescence analyses. Ang II-induced hypertension was associated with blunted endothelium-dependent relaxations and induction of endothelium-dependent contractions in the presence of nitro-L-arginine in response to acetylcholine (Ach). These effects were not affected by the combination of membrane permeant analogs of superoxide dismutase and catalase but were abolished by the thromboxane A(2) (TP) receptor antagonist GR32191B and the COX-2 inhibitor NS-398. The COX-1 inhibitor SC-560 also prevented contractile responses to Ach. Ang II increased the expression of COX-1 and COX-2 in the aortic wall. RWPs prevented Ang II-induced hypertension, endothelial dysfunction, and upregulation of COX-1 and COX-2. Thus, Ang II-induced endothelial dysfunction cannot be explained by an acute formation of ROS reducing the bioavailability of nitric oxide but rather by COX-dependent formation of contracting factors acting on TP receptors. RWPs are able to prevent the Ang II-induced endothelial dysfunction mostly due to their antioxidant properties.

Central insulin-like growth factor-1 (IGF-1) restores whole-body insulin action in a model of age-related insulin resistance and IGF-1 decline.

PubMed

Huffman, Derek M; Farias Quipildor, Gabriela; Mao, Kai; Zhang, Xueying; Wan, Junxiang; Apontes, Pasha; Cohen, Pinchas; Barzilai, Nir

2016-02-01

Low insulin-like growth factor-1 (IGF-1) signaling is associated with improved longevity, but is paradoxically linked with several age-related diseases in humans. Insulin-like growth factor-1 has proven to be particularly beneficial to the brain, where it confers protection against features of neuronal and cognitive decline. While aging is characterized by central insulin resistance in the face of hyperinsulinemia, the somatotropic axis markedly declines in older humans. Thus, we hypothesized that increasing IGF-1 in the brain may prove to be a novel therapeutic alternative to overcome central insulin resistance and restore whole-body insulin action in aging. Utilizing hyperinsulinemic-euglycemic clamps, we show that old insulin-resistant rats with age-related declines in IGF-1 level demonstrate markedly improved whole-body insulin action, when treated with central IGF-1, as compared to central vehicle or insulin (P < 0.05). Furthermore, central IGF-1, but not insulin, suppressed hepatic glucose production and increased glucose disposal rates in aging rats (P < 0.05). Taken together, IGF-1 action in the brain and periphery provides a 'balance' between its beneficial and detrimental actions. Therefore, we propose that strategies aimed at 'tipping the balance' of IGF-1 action centrally are the optimal approach to achieve healthy aging and longevity in humans. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

MHC class II is an important genetic risk factor for canine systemic lupus erythematosus (SLE)-related disease: implications for reproductive success.

PubMed

Wilbe, M; Andersson, G

2012-01-01

Major histocompatibility complex (MHC) class II genes are important genetic risk factors for development of immune-mediated diseases in mammals. Recently, the dog (Canis lupus familiaris) has emerged as a useful model organism to identify critical MHC class II genotypes that contribute to development of these diseases. Therefore, a study aimed to evaluate a potential genetic association between the dog leukocyte antigen (DLA) class II region and an immune-mediated disease complex in dogs of the Nova Scotia duck tolling retriever breed was performed. We show that DLA is one of several genetic risk factors for this disease complex and that homozygosity of the risk haplotype is disadvantageous. Importantly, the disease is complex and has many genetic risk factors and therefore we cannot provide recommendations for breeders exclusively on the basis of genetic testing for DLA class II genotype. © 2012 Blackwell Verlag GmbH.

Cd(II) and Pb(II) complexes of the polyether ionophorous antibiotic salinomycin

PubMed Central

2011-01-01

Background The natural polyether ionophorous antibiotics are used for the treatment of coccidiosis in poultry and ruminants. They are effective agents against infections caused by Gram-positive microorganisms. On the other hand, it was found that some of these compounds selectively bind lead(II) ions in in vivo experiments, despite so far no Pb(II)-containing compounds of defined composition have been isolated and characterized. To assess the potential of polyether ionophores as possible antidotes in the agriculture, a detailed study on their in vitro complexation with toxic metal ions is required. In the present paper we report for the first time the preparation and the structure elucidation of salinomycin complexes with ions of cadmium(II) and lead(II). Results New metal(II) complexes of the polyether ionophorous antibiotic salinomycin with Cd(II) and Pb(II) ions were prepared and structurally characterized by IR, FAB-MS and NMR techniques. The spectroscopic information and elemental analysis data reveal that sodium salinomycin (SalNa) undergoes a reaction with heavy metal(II) ions to form [Cd(Sal)2(H2O)2] (1) and [Pb(Sal)(NO3)] (2), respectively. Abstraction of sodium ions from the cavity of the antibiotic is occurring during the complexation reaction. Salinomycin coordinates with cadmium(II) ions as a bidentate monoanionic ligand through the deprotonated carboxylic moiety and one of the hydroxyl groups to yield 1. Two salinomycin anions occupy the equatorial plane of the Cd(II) center, while two water molecules take the axial positions of the inner coordination sphere of the metal(II) cation. Complex 2 consists of monoanionic salinomycin acting in polydentate coordination mode in a molar ratio of 1: 1 to the metal ion with one nitrate ion for charge compensation. Conclusion The formation of the salinomycin heavy metal(II) complexes indicates a possible antidote activity of the ligand in case of chronic/acute intoxications likely to occur in the stock farming

Selective adsorption of Pb(II), Cd(II), and Ni(II) ions from aqueous solution using chitosan-MAA nanoparticles.

PubMed

Heidari, Aghdas; Younesi, Habibollah; Mehraban, Zahra; Heikkinen, Harri

2013-10-01

Chitosan-MAA nanoparticles (CS-MAA) with an average size of 10-70 nm were prepared by polymerizing chitosan with methacrylic acid in aqueous solution. The physicochemical properties of nanoparticles were investigated using Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), dynamic light scattering (DLS) and nuclear magnetic resonance (NMR). The adsorption of Pb(II), Cd(II) and Ni(II) from aqueous solution on CS-MAA was studied in a batch system. The effects of the solution pH, initial metal concentration, contact time, and dosage of the adsorbent on the adsorption process were examined. The experimental data were analyzed using the pseudo-second-order kinetic equations and the Langmuir, Freundlich and Redlish-Peterson isotherms. The maximum adsorption capacity was 11.30, 1.84, and 0.87 mg/g for Pb(II), Cd(II) and Ni(II) ions, respectively, obtained by the Langmuir isotherm. However, the adsorption isotherm was better explained by the Freundlich rather than by the Langmuir model, as the high correlation coefficients (R(2)>0.99) were obtained at a higher confidence level. Copyright © 2013 Elsevier B.V. All rights reserved.

The Genocidal Mentality: Philip II of Spain and Sultan Abdul Hamid II.

ERIC Educational Resources Information Center

Kuttner, Robert E.

1986-01-01

Historical comparison of Sultan Abdul Hamid of Turkey and King Philip II of Spain with Adolph Hitler revealed similar personality traits, possibly characteristic determinants of individuals prone to undertake genocidal measures. Commitment to bureaucratic detail coupled with opportunistic belief in Messianic destiny are key factors in these…

Adsorption of Cu(II), Hg(II), and Ni(II) ions by modified natural wool chelating fibers.

PubMed

Monier, M; Ayad, D M; Sarhan, A A

2010-04-15

The graft copolymerization of ethyl acrylate (EA) onto natural wool fibers initiated by potassium persulphate and Mohr's salt redox initiator system in limited aqueous medium was carried out in heterogeneous media. Ester groups of the grafted copolymers were partially converted into hydrazide function groups followed by hydrazone formation through reaction with isatin. Also the application of the modified fibers for metal ion uptake was studied using Cu(II), Hg(II) and Ni(II). The modified chelating fibers were characterized using FTIR spectroscopy, SEM and X-ray diffraction. 2009 Elsevier B.V. All rights reserved.

Insulin-Like Growth Factor I (IGF-1) Ec/Mechano Growth Factor – A Splice Variant of IGF-1 within the Growth Plate

PubMed Central

Schlegel, Werner; Raimann, Adalbert; Halbauer, Daniel; Scharmer, Daniela; Sagmeister, Susanne; Wessner, Barbara; Helmreich, Magdalena; Haeusler, Gabriele; Egerbacher, Monika

2013-01-01

Human insulin-like growth factor 1 Ec (IGF-1Ec), also called mechano growth factor (MGF), is a splice variant of insulin-like growth factor 1 (IGF-1), which has been shown in vitro as well as in vivo to induce growth and hypertrophy in mechanically stimulated or damaged muscle. Growth, hypertrophy and responses to mechanical stimulation are important reactions of cartilaginous tissues, especially those in growth plates. Therefore, we wanted to ascertain if MGF is expressed in growth plate cartilage and if it influences proliferation of chondrocytes, as it does in musculoskeletal tissues. MGF expression was analyzed in growth plate and control tissue samples from piglets aged 3 to 6 weeks. Furthermore, growth plate chondrocyte cell culture was used to evaluate the effects of the MGF peptide on proliferation. We showed that MGF is expressed in considerable amounts in the tissues evaluated. We found the MGF peptide to be primarily located in the cytoplasm, and in some instances, it was also found in the nucleus of the cells. Addition of MGF peptides was not associated with growth plate chondrocyte proliferation. PMID:24146828

[Examination of diagnosis procedure combination survey data that influence function evaluation coefficient II].

PubMed

Nakajima, Hisato; Yano, Kouya; Nagasawa, Kaoko; Kobayashi, Eiji; Yokota, Kuninobu

2015-01-01

On the basis of Diagnosis Procedure Combination (DPC) survey data, the factors that increase the value of function evaluation coefficient II were considered. A total of 1,505 hospitals were divided into groups I, II, and III, and the following items were considered. 1. Significant differences in function evaluation coefficient II and DPC survey data. 2. Examination of using the Mahalanobis-Taguchi (MT) method. 3. Correlation between function evaluation coefficient II and each DPC survey data item. 1. Function evaluation coefficient II was highest in group II. Group I hospitals showed the highest bed capacity, and numbers of hospitalization days, operations, chemotherapies, radiotherapies and general anesthesia procedures. 2. Using the MT method, we found that the number of ambulance conveyances was effective factor in group I hospitals, the number of general anesthesia procedures was effective factor in group II hospitals, and the bed capacity was effective factor in group III hospitals. 3. In group I hospitals, function evaluation coefficient II significantly correlated to the numbers of ambulance conveyances and chemotherapies. In group II hospitals, function evaluation coefficient II significantly correlated to bed capacity, the numbers of ambulance conveyances, hospitalization days, operations, general anesthesia procedures, and mean hospitalization days. In group III hospitals, function evaluation coefficient II significantly correlated to all items. The factors that improve the value of function evaluation coefficient II were the increases in the numbers of ambulance conveyances, chemotherapies and radiotherapies in group I hospitals, increases in the numbers of hospitalization days, operations, ambulance conveyances and general anesthesia procedures in group II hospitals, and increases in the numbers of hospitalization days, operations and ambulance conveyances. These results indicate that the profit of a hospital will increase, which will lead to medical

Synthesis and characterization of hydroxyapatite nanoparticles impregnated on apple pomace to enhanced adsorption of Pb(II), Cd(II), and Ni(II) ions from aqueous solution.

PubMed

Chand, Piar; Pakade, Yogesh B

2015-07-01

Hydroxyapatite nanoparticles were synthesized, characterized, and impregnated onto apple pomace surface (HANP@AP) for efficient removal of Pb(II), Cd(II), and Ni(II) ions from water. HANP@AP was characterized by Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), energy-dispersive spectroscopy (EDS), transmission electron microscope (TEM), X-ray diffraction (XRD), and surface area analysis. Batch sorption studies were carried out to investigate the influence of different parameters as amount of dose (g), pH, time (min), and initial concentration (mg L(-1)) on adsorption process. Experimental kinetic data followed pseudo-second-order model and equilibrium data well fitted to Langmuir adsorption model with maximum adsorption capacities of 303, 250, and 100 mg g(-1) for Pb(II), Cd(II), and Ni(II) ions, respectively. Competitive adsorption of Pb(II), Cd(II), and Ni(II) ions in presences of each other was studied to evaluate the removal efficiency of HANP@AP against multi metal-loaded water. HANP@AP was successfully applied to real industrial wastewater with 100 % removal of all three metal ions even at high concentration. HANP@AP could be recycled for four, four, and three cycles in case of Pb(II), Cd(II) and Ni(II), respectively. The study showed that HANP@AP is fast, cost effective, and environmental friendly adsorbent for removal of Pb(II), Cd(II), and Ni(II) ions from real industrial wastewater.

Suckling induced insulin-like growth factor-1 (IGF-1) release in mother rats.

PubMed

Lékó, András H; Cservenák, Melinda; Dobolyi, Árpád

2017-12-01

Lactation involves significant neuroendocrine changes. The elevated prolactin (PRL) release from the pituitary, induced markedly by suckling, is the most relevant example. Suckling also causes a significant and rapid elevation in growth hormone (GH) levels. GH is necessary for milk synthesis as milk yield is stopped completely in the absence of PRL and GH, while the absence of PRL alone causes only a 50% reduction. Insulin-like growth factor-1 (IGF-1) plays an important role in the GH axis. GH exerts its effects through IGF-1 in the periphery, for example in the mammary gland. In addition, IGF-1 is responsible for the long-loop feedback control of GH secretion. IGF-1 secretion has not been established yet in mothers. Therefore, in the present study, we investigated the effect of suckling on serum IGF-1 level in rat mothers and correlated it with serum PRL levels. We examined a potential mechanism of the regulation of IGF-1 level during suckling by administering IGF-1 into the lateral ventricle of rat mothers continuously for 12days, or acutely, right before the start of suckling. We described that suckling affected IGF-1 release based on one-way repeated measures ANOVA (F=10.8 and p<0.001) and caused a marked increase of IGF-1 level 30min after the start of suckling (p<0.001). We demonstrated a significant (p<0.05; the correlation coefficient was 0.29) correlation to PRL level during suckling which supports that PRL could induce IGF-1 release. The prolonged central IGF-1 administration diminished the suckling-induced IGF-1 surge (F=9.19 and p<0.001) while the acute treatment did not have any effect compared to artificial cerebrospinal fluid injection, analysed with two-way repeated measures ANOVA. In conclusion, suckling induces IGF-1 release either by elevating PRL or GH. Long-loop feedback via IGF-1 in the GH axis can diminish this action. Copyright © 2017 Elsevier Ltd. All rights reserved.

Spectroscopic characterization, antioxidant and antitumour studies of novel bromo substituted thiosemicarbazone and its copper(II), nickel(II) and palladium(II) complexes

NASA Astrophysics Data System (ADS)

Jagadeesh, M.; Lavanya, M.; Kalangi, Suresh K.; Sarala, Y.; Ramachandraiah, C.; Varada Reddy, A.

2015-01-01

A new, slightly distorted octahedral complex of copper(II), square planar complexes of nickel(II) and palladium(II) with 2,4‧-dibromoacetophenone thiosemicarbazone (DBAPTSC) are synthesized. The ligand and the complexes are characterized by FT-IR, FT-Raman, powder X-ray diffraction studies. The IR and Raman data are correlated for the presence of the functional groups which specifically helped in the confirmation of the compounds. In addition, the free ligand is unambiguously characterized by 1H and 13C NMR spectroscopy while the copper(II) complex is characterized by electron paramagnetic resonance spectroscopy (EPR). The g values for the same are found to be 2.246 (g1), 2.012 (g2) and 2.005 (g3) which suggested rhombic distortions. The HOMO-LUMO band gap calculations for these compounds are found to be in between 0.5 and 4.0 eV and these compounds are identified as semiconducting materials. The synthesized ligand and its copper(II), nickel(II) and palladium(II) complexes are subjected to antitumour activity against the HepG2 human hepatoblastoma cell lines. Among all the compounds, nickel(II) complex is found to exert better antitumour activity with 57.6% of cytotoxicity.

Confirmatory Factor Analysis of the Beck Depression Inventory-II in Bariatric Surgery Candidates

ERIC Educational Resources Information Center

Hall, Brian J.; Hood, Megan M.; Nackers, Lisa M.; Azarbad, Leila; Ivan, Iulia; Corsica, Joyce

2013-01-01

Screening for depression is an integral part of psychological evaluations conducted prior to bariatric surgery. The Beck Depression Inventory-II (BDI-II) is the most commonly used measure of depression in these treatment evaluations. The reliability and validity of the BDI-II has not yet been evaluated within bariatric surgery-seeking samples,…

Cadmium(II) and lead(II) adsorption onto hetero-atom functional mesoporous silica and activated carbon

NASA Astrophysics Data System (ADS)

Machida, Motoi; Fotoohi, Babak; Amamo, Yoshimasa; Mercier, Louis

2012-07-01

Adsorption of cadmium(II) and lead(II) on amino-, mercapto-functionalized mesoporous silica (HMS) and carboxylic-functionalized activated carbon (AC) were examined. The resultant isotherms fitted the Langmuir model and amino-functionalized HMS exhibited the highest adsorption capacity for both cadmium(II) and lead(II). Adsorption affinities for cadmium(II) were always greater than those for lead(II) in all three adsorbent types, while the difference between the two values was the largest for mercapto-functionalized HMS indicating a selective adsorption of cadmium(II). Influence of equilibrium solution pH on adsorption of cadmium(II), lead(II) and their binary mixtures was also studied. Carboxylic-functionalized AC adsorbed cadmium(II) and lead(II) in a wide pH range than conditions for the mercapto-functionalized HMS. It was concluded that each functional group had its own characteristics and advantages for adsorption of heavy metal ions; amino-groups showed high adsorption capacity, while mercapto-groups had good selectivity toward cadmium(II) adsorption and a wide solution pH in adsorption by carboxylic-groups were established in this study.

Thermodynamic Analysis of Nickel(II) and Zinc(II) Adsorption to Biochar.

PubMed

Alam, Md Samrat; Gorman-Lewis, Drew; Chen, Ning; Flynn, Shannon L; Ok, Yong Sik; Konhauser, Kurt O; Alessi, Daniel S

2018-05-21

While numerous studies have investigated metal uptake from solution by biochar, few of these have developed a mechanistic understanding of the adsorption reactions that occur at the biochar surface. In this study, we explore a combined modeling and spectroscopic approach for the first time to describe the molecular level adsorption of Ni(II) and Zn(II) to five types of biochar. Following thorough characterization, potentiometric titrations were carried out to measure the proton (H + ) reactivity of each biochar, and the data was used to develop protonation models. Surface complexation modeling (SCM) supported by synchrotron-based extended X-ray absorption fine structure (EXAFS) was then used to gain insights into the molecular scale metal-biochar surface reactions. The SCM approach was combined with isothermal titration calorimetry (ITC) data to determine the thermodynamic driving forces of metal adsorption. Our results show that the reactivity of biochar toward Ni(II) and Zn(II) directly relates to the site densities of biochar. EXAFS along with FT-IR analyses, suggest that Ni(II) and Zn(II) adsorption occurred primarily through proton-active carboxyl (-COOH) and hydroxyl (-OH) functional groups on the biochar surface. SCM-ITC analyses revealed that the enthalpies of protonation are exothermic and Ni(II) and Zn(II) complexes with biochar surface are slightly exothermic to slightly endothermic. The results obtained from these combined approaches contribute to the better understanding of molecular scale metal adsorption onto the biochar surface, and will facilitate the further development of thermodynamics-based, predictive approaches to biochar removal of metals from contaminated water.

TSH Compensates Thyroid-Specific IGF-I Receptor Knockout and Causes Papillary Thyroid Hyperplasia

PubMed Central

Müller, Kathrin; Führer, Dagmar; Mittag, Jens; Klöting, Nora; Blüher, Matthias; Weiss, Roy E.; Many, Marie-Christine; Schmid, Kurt Werner

2011-01-01

Although TSH stimulates all aspects of thyroid physiology IGF-I signaling through a tyrosine kinase-containing transmembrane receptor exhibits a permissive impact on TSH action. To better understand the importance of the IGF-I receptor in the thyroid in vivo, we inactivated the Igf1r with a Tg promoter-driven Cre-lox system in mice. We studied male and female mice with thyroidal wild-type, Igf1r+/−, and Igf1r−/− genotypes. Targeted Igf1r inactivation did transiently reduce thyroid hormone levels and significantly increased TSH levels in both heterozygous and homozygous mice without affecting thyroid weight. Histological analysis of thyroid tissue with Igf1r inactivation revealed hyperplasia and heterogeneous follicle structure. From 4 months of age, we detected papillary thyroid architecture in heterozygous and homozygous mice. We also noted increased body weight of male mice with a homozygous thyroidal null mutation in the Igf1r locus, compared with wild-type mice, respectively. A decrease of mRNA and protein for thyroid peroxidase and increased mRNA and protein for IGF-II receptor but no significant mRNA changes for the insulin receptor, the TSH receptor, and the sodium-iodide-symporter in both Igf1r+/− and Igf1r−/− mice were detected. Our results suggest that the strong increase of TSH benefits papillary thyroid hyperplasia and completely compensates the loss of IGF-I receptor signaling at the level of thyroid hormones without significant increase in thyroid weight. This could indicate that the IGF-I receptor signaling is less essential for thyroid hormone synthesis but maintains homeostasis and normal thyroid morphogenesis. PMID:21980075

PTB-associated splicing factor inhibits IGF-1-induced VEGF upregulation in a mouse model of oxygen-induced retinopathy.

PubMed

Dong, Lijie; Nian, Hong; Shao, Yan; Zhang, Yan; Li, Qiutang; Yi, Yue; Tian, Fang; Li, Wenbo; Zhang, Hong; Zhang, Xiaomin; Wang, Fei; Li, Xiaorong

2015-05-01

Pathological retinal neovascularization, including retinopathy of prematurity and age-related macular degeneration, is the most common cause of blindness worldwide. Insulin-like growth factor-1 (IGF-1) has a direct mitogenic effect on endothelial cells, which is the basis of angiogenesis. Vascular endothelial growth factor (VEGF) activation in response to IGF-1 is well documented; however, the molecular mechanisms responsible for the termination of IGF-1 signaling are still not completely elucidated. Here, we show that the polypyrimidine tract-binding protein-associated splicing factor (PSF) is a potential negative regulator of VEGF expression induced by IGF stimulation. Functional analysis demonstrated that ectopic expression of PSF inhibits IGF-1-stimulated transcriptional activation and mRNA expression of the VEGF gene, whereas knockdown of PSF increased IGF-1-stimulated responses. PSF recruited Hakai to the VEGF transcription complex, resulting in inhibition of IGF-1-mediated transcription. Transfection with Hakai siRNA reversed the PSF-mediated transcriptional repression of VEGF gene transcription. In summary, these results show that PSF can repress the transcriptional activation of VEGF stimulated by IGF-1 via recruitment of the Hakai complex and delineate a novel regulatory mechanism of IGF-1/VEGF signaling that may have implications in the pathogenesis of neovascularization in ocular diseases.

Electrochemical, spectroscopic, and photophysical properties of structurally diverse polyazine-bridged Ru(II),Pt(II) and Os(II),Ru(II),Pt(II) supramolecular motifs.

PubMed

Knoll, Jessica D; Arachchige, Shamindri M; Wang, Guangbin; Rangan, Krishnan; Miao, Ran; Higgins, Samantha L H; Okyere, Benjamin; Zhao, Meihua; Croasdale, Paul; Magruder, Katherine; Sinclair, Brian; Wall, Candace; Brewer, Karen J

2011-09-19

Five new tetrametallic supramolecules of the motif [{(TL)(2)M(dpp)}(2)Ru(BL)PtCl(2)](6+) and three new trimetallic light absorbers [{(TL)(2)M(dpp)}(2)Ru(BL)](6+) (TL = bpy = 2,2'-bipyridine or phen = 1,10-phenanthroline; M = Ru(II) or Os(II); BL = dpp = 2,3-bis(2-pyridyl)pyrazine, dpq = 2,3-bis(2-pyridyl)quinoxaline, or bpm = 2,2'-bipyrimidine) were synthesized and their redox, spectroscopic, and photophysical properties investigated. The tetrametallic complexes couple a Pt(II)-based reactive metal center to Ru and/or Os light absorbers through two different polyazine BL to provide structural diversity and interesting resultant properties. The redox potential of the M(II/III) couple is modulated by M variation, with the terminal Ru(II/III) occurring at 1.58-1.61 V and terminal Os(II/III) couples at 1.07-1.18 V versus Ag/AgCl. [{(TL)(2)M(dpp)}(2)Ru(BL)](PF(6))(6) display terminal M(dπ)-based highest occupied molecular orbitals (HOMOs) with the dpp(π*)-based lowest unoccupied molecular orbital (LUMO) energy relatively unaffected by the nature of BL. The coupling of Pt to the BL results in orbital inversion with localization of the LUMO on the remote BL in the tetrametallic complexes, providing a lowest energy charge separated (CS) state with an oxidized terminal Ru or Os and spatially separated reduced BL. The complexes [{(TL)(2)M(dpp)}(2)Ru(BL)](6+) and [{(TL)(2)M(dpp)}(2)Ru(BL)PtCl(2)](6+) efficiently absorb light throughout the UV and visible regions with intense metal-to-ligand charge transfer (MLCT) transitions in the visible at about 540 nm (M = Ru) and 560 nm (M = Os) (ε ≈ 33,000-42,000 M(-1) cm(-1)) and direct excitation to the spin-forbidden (3)MLCT excited state in the Os complexes about 720 nm. All the trimetallic and tetrametallic Ru-based supramolecular systems emit from the terminal Ru(dπ)→dpp(π*) (3)MLCT state, λ(max)(em) ≈ 750 nm. The tetrametallic systems display complex excited state dynamics with quenching of the (3)MLCT emission at

Insulin growth factor (IGF) 1, IGF-binding proteins and ovarian cancer risk: A systematic review and meta-analysis.

PubMed

Gianuzzi, Ximena; Palma-Ardiles, Gabriela; Hernandez-Fernandez, Wendy; Pasupuleti, Vinay; Hernandez, Adrian V; Perez-Lopez, Faustino R

2016-12-01

Insulin resistance (IR) has been implicated in carcinogenesis, but there is no consensus regarding its involvement in ovarian cancer. We performed a systematic review and meta-analysis to evaluate the association between IR and ovarian cancer. Searches were conducted in five databases for studies evaluating IR markers (levels of serum insulin, C peptide, insulin growth factor [IGF] 1 and IGF-binding proteins [IGFBPs], homeostatic model assessment insulin resistance, and quantitative insulin-sensitivity check index) and ovarian cancer risk. Study selection, data extraction and an assessment of risk of bias were performed independently by three researchers. The associations between IR markers and ovarian cancer were quantified as mean differences (MDs) or standardized MDs (SMDs) and their 95% CIs using random-effects models. Fourteen case-control studies satisfied our inclusion criteria (n=8130). There was little information on IR markers with the exception of the IGF system. Ovarian cancer was associated with lower IGF-1 levels (SMD -0.43ng/mL, 95% CI -0.67 to -0.18; p=0.0006), and lower IGFBP-3 levels (SMD -0.11ng/mL, 95% CI -0.21 to -0.00; p=0.04). However, ovarian cancer was associated with higher levels of IGFBP-2 and IGFBP-1 (MD 527.3ng/mL, 95%CI 473.6, 581.0; p<0.00001, and MD 3.47ng/mL, 95%CI 1.42, 5.52; p=0.0009 respectively). Subgroup analyses by menopausal status and age (≤55 vs >55y) for IGF-1 and IGFBP-3 showed the subgroups were similar, although heterogeneity remained high. The evidence suggests that levels of IGF-1 and IGFBP-3 are lower in patients with ovarian cancer. In contrast, higher levels of IGBP-2 and IGBP-1 are found in patients with ovarian cancer. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Epidermal growth factor stimulates mouse placental lactogen I but inhibits mouse placental lactogen II secretion in vitro.

PubMed Central

Yamaguchi, M; Ogren, L; Endo, H; Thordarson, G; Kensinger, R; Talamantes, F

1992-01-01

This study was undertaken to determine whether epidermal growth factor (EGF) regulates the secretion of mouse placental lactogen (mPL)-I and mPL-II. Primary cell cultures were prepared from placentas from days 7, 9, and 11 of pregnancy and cultured for up to 5 days. Addition of EGF (20 ng/ml) to the medium resulted in significant stimulation of mPL-I secretion by the second day of culture in cells from days 7 and 9 of pregnancy and significant inhibition of mPL-II secretion by the third or fourth day of culture in cells from days 7, 9, and 11. Dose-response studies carried out with cells from day 7 of pregnancy demonstrated that the minimum concentration of EGF that stimulated mPL-I secretion and inhibited mPL-II secretion was 1.0 ng/ml. EGF did not affect the DNA content of the cells or cell viability, assessed by trypan blue exclusion, nor did it have a general effect on protein synthesis. There are three types of PL-containing giant cells in mouse placental cell cultures: cells that contain either mPL-I or mPL-II and cells that contain both hormones. Immunocytochemical analysis and the reverse hemolytic plaque assay indicated that EGF treatment was accompanied by a significant increase in the number of cells that produce mPL-I, but among the PL cells that contained mPL-I, there was no change in the fraction of cells that contained only mPL-I or the fraction that contained both mPL-I and mPL-II. In contrast, EGF treatment did affect the distribution of mPL-II among PL cells. In control cultures, about 75% of the cells that contained mPL-II also contained mPL-I, but in EGF-treated cultures, all of the cells that contained mPL-II also contained mPL-I. These data suggest that EGF regulates mPL-I and mPL-II secretion at least partly by regulating PL cell differentiation. PMID:1454826

Relationships Between RNA Polymerase II Activity and Spt Elongation Factors to Spt- Phenotype and Growth in Saccharomyces cerevisiae

PubMed Central

Cui, Ping; Jin, Huiyan; Vutukuru, Manjula Ramya; Kaplan, Craig D.

2016-01-01

The interplay between adjacent transcription units can result in transcription-dependent alterations in chromatin structure or recruitment of factors that determine transcription outcomes, including the generation of intragenic or other cryptic transcripts derived from cryptic promoters. Mutations in a number of genes in Saccharomyces cerevisiae confer both cryptic intragenic transcription and the Suppressor of Ty (Spt-) phenotype for the lys2-128∂ allele of the LYS2 gene. Mutants that suppress lys2-128∂ allow transcription from a normally inactive Ty1 ∂ promoter, conferring a LYS+ phenotype. The arrangement of transcription units at lys2-128∂ is reminiscent of genes containing cryptic promoters within their open reading frames. We set out to examine the relationship between RNA Polymerase II (Pol II) activity, functions of Spt elongation factors, and cryptic transcription because of the previous observation that increased-activity Pol II alleles confer an Spt- phenotype. We identify both cooperating and antagonistic genetic interactions between Pol II alleles and alleles of elongation factors SPT4, SPT5, and SPT6. We find that cryptic transcription at FLO8 and STE11 is distinct from that at lys2-128∂, though all show sensitivity to reduction in Pol II activity, especially the expression of lys2-128∂ found in Spt- mutants. We determine that the lys2-128∂ Spt- phenotypes for spt6-1004 and increased activity rpo21/rpb1 alleles each require transcription from the LYS2 promoter. Furthermore, we identify the Ty1 transcription start site (TSS) within the ∂ element as the position of Spt- transcription in tested Spt- mutants. PMID:27261007

Randomized Phase Ib/II Trial of Rilotumumab or Ganitumab with Panitumumab versus Panitumumab Alone in Patients with Wild-type KRAS Metastatic Colorectal Cancer

PubMed Central

Cutsem, Eric Van; Eng, Cathy; Nowara, Elzbieta; Świeboda-Sadlej, Anna; Tebbutt, Niall C.; Mitchell, Edith; Davidenko, Irina; Stephenson, Joe; Elez, Elena; Prenen, Hans; Deng, Hongjie; Tang, Rui; McCaffery, Ian; Oliner, Kelly S.; Chen, Lisa; Gansert, Jennifer; Loh, Elwyn; Smethurst, Dominic; Tabernero, Josep

2015-01-01

Purpose Panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody (mAb), has demonstrated efficacy in patients with wild-type KRAS metastatic colorectal cancer (mCRC). Rilotumumab and ganitumab are investigational, fully human mAbs against hepatocyte growth factor (HGF)/scatter factor and IGF1R, respectively. Here we evaluate combining rilotumumab or ganitumab with panitumumab in previously treated patients with wild-type KRAS mCRC. Experimental Design Part 1 was a phase Ib dose-finding study of panitumumab plus rilotumumab. The primary endpoint was the incidence of dose-limiting toxicities (DLT). Part 2 was a randomized phase II trial of panitumumab in combination with rilotumumab, ganitumab, or placebo. The primary endpoint was objective response rate (ORR); safety, progression-free survival (PFS), and overall survival (OS) were secondary endpoints. Archival tissue specimens were collected for exploratory correlative work. Results In part 1, no DLTs were reported. A recommended phase II dose of 10 mg/kg rilotumumab was selected. In part 2, for the panitumumab plus rilotumumab (n = 48), panitumumab plus ganitumab (n = 46), and panitumumab plus placebo arms (n = 48), the ORRs were 31%, 22%, and 21%, respectively. The median PFS was 5.2, 5.3, and 3.7 months and median OS 13.8,10.6, and 11.6 months, respectively. Adverse events were tolerable. Exploratory biomarker analyses, including MET and IGF-related protein expression, failed to indicate conclusive predictive evidence on efficacy endpoints. Conclusions Panitumumab plus rilotumumab met the prespecified criterion for improvement in ORR whereas ganitumab did not. This is the first study to suggest a benefit for combining an HGF inhibitor (rilotumumab) with panitumumab in previously treated patients with wild-type KRAS mCRC. PMID:24919569

Combination of two insulin-like growth factor-I receptor inhibitory antibodies targeting distinct epitopes leads to an enhanced antitumor response.

PubMed

Dong, Jianying; Demarest, Stephen J; Sereno, Arlene; Tamraz, Susan; Langley, Emma; Doern, Adam; Snipas, Tracey; Perron, Keli; Joseph, Ingrid; Glaser, Scott M; Ho, Steffan N; Reff, Mitchell E; Hariharan, Kandasamy

2010-09-01

The insulin-like growth factor-I receptor (IGF-IR) is a cell surface receptor tyrosine kinase that mediates cell survival signaling and supports tumor progression in multiple tumor types. We identified a spectrum of inhibitory IGF-IR antibodies with diverse binding epitopes and ligand-blocking properties. By binding distinct inhibitory epitopes, two of these antibodies, BIIB4 and BIIB5, block both IGF-I and IGF-II binding to IGF-IR using competitive and allosteric mechanisms, respectively. Here, we explored the inhibitory effects of combining BIIB4 and BIIB5. In biochemical assays, the combination of BIIB4 and BIIB5 improved both the potency and extent of IGF-I and IGF-II blockade compared with either antibody alone. In tumor cells, the combination of BIIB4 and BIIB5 accelerated IGF-IR downregulation and more efficiently inhibited IGF-IR activation as well as downstream signaling, particularly AKT phosphorylation. In several carcinoma cell lines, the antibody combination more effectively inhibited ligand-driven cell growth than either BIIB4 or BIIB5 alone. Notably, the enhanced tumor growth-inhibitory activity of the BIIB4 and BIIB5 combination was much more pronounced at high ligand concentrations, where the individual antibodies exhibited substantially reduced activity. Compared with single antibodies, the BIIB4 and BIIB5 combination also significantly further enhanced the antitumor activity of the epidermal growth factor receptor inhibitor erlotinib and the mTOR inhibitor rapamycin. Moreover, in osteosarcoma and hepatocellular carcinoma xenograft models, the BIIB4 and BIIB5 combination significantly reduced tumor growth to a greater degree than each single antibody. Taken together, our results suggest that targeting multiple distinct inhibitory epitopes on IGF-IR may be a more effective strategy of affecting the IGF-IR pathway in cancer.

Interplay of HD-Zip II and III transcription factors in auxin-regulated plant development.

PubMed

Turchi, L; Baima, S; Morelli, G; Ruberti, I

2015-08-01

The homeodomain-leucine zipper (HD-Zip) class of transcription factors is unique to plants. HD-Zip proteins bind to DNA exclusively as dimers recognizing dyad symmetric sequences and act as positive or negative regulators of gene expression. On the basis of sequence homology in the HD-Zip DNA-binding domain, HD-Zip proteins have been grouped into four families (HD-Zip I-IV). Each HD-Zip family can be further divided into subfamilies containing paralogous genes that have arisen through genome duplication. Remarkably, all the members of the HD-Zip IIγ and -δ clades are regulated by light quality changes that induce in the majority of the angiosperms the shade-avoidance response, a process regulated at multiple levels by auxin. Intriguingly, it has recently emerged that, apart from their function in shade avoidance, the HD-Zip IIγ and -δ transcription factors control several auxin-regulated developmental processes, including apical embryo patterning, lateral organ polarity, and gynoecium development, in a white-light environment. This review presents recent advances in our understanding of HD-Zip II protein function in plant development, with particular emphasis on the impact of loss-of-function HD-Zip II mutations on auxin distribution and response. The review also describes evidence demonstrating that HD-Zip IIγ and -δ genes are directly and positively regulated by HD-Zip III transcription factors, primary determinants of apical shoot development, known to control the expression of several auxin biosynthesis, transport, and response genes. Finally, the interplay between HD-Zip II and III transcription factors in embryo apical patterning and organ polarity is discussed. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Determining skeletal maturation using insulin-like growth factor I (IGF-I) test.

PubMed

Gupta, Shreya; Jain, Sandhya; Gupta, Puneet; Deoskar, Anuradha

2012-11-01

To investigate the validity of Insulin like Growth Factor -1(IGF-1) as a skeletal maturity indicator by comparing serum IGF-1 levels with the stages in cervical vertebral maturation (CVM) and in the middle phalanx of the third finger (MP3). The study population was selected by using simple random sampling technique and consisted of 30 female subjects in the age range of 8-23 years who had blood sample, cephalometric and MP3 radiographs taken on the same day. Serum IGF-I estimation was carried out on the blood samples using chemiluminescence immunoassay (CLIA) method. CVM was evaluated using method by Baccetti et al and MP3 staging was done using Rajagopal & Kansal method. Mean IGF-1 level between the stages was compared by Kruskal-Wallis and Mann Whitney test. Serum IGF-1 levels in females correlate well with skeletal maturity determined by CVM and MP3 stages and increase sharply during early pubertal stages followed by a decrease in late puberty. In addition we hypothesis that serum IGF-1 testing can be undertaken as a preliminary screening test in patients in whom the orthodontist predicts the possibility of using myofunctional appliance but in whom the chronologic age is not suggestive for a growth modification therapy. The finding of the study highlights the fact that the serum IGF-1 estimation can be a valuable tool in assessing skeletal maturation. Copyright © 2012 Società Italiana di Ortodonzia SIDO. Published by Elsevier Srl. All rights reserved.

Growth factors and cytokines in patients with long bone fractures and associated spinal cord injury.

PubMed

Khallaf, Fathy G; Kehinde, Elijah O; Mostafa, Ahmed

2016-06-01

The aim of the study was to test the effect of acute traumatic spinal cord injury of quadriplegia or paraplegia on bone healing in patients with associated long bone fractures and to investigate the molecular and cellular events of the underlying mechanism for a possible acceleration. Healing indicators of long bone fractures and growth factors, IGF-II, platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), Activin-A, and cytokine I-L-1, in the patients' blood were calculated and measured for 21 patients with spinal cord injuries and associated long bone fractures in prospective controlled study and compared to 20 patients with only spinal cord injuries, 30 patients with only long bone fractures, and 30 healthy volunteers. The study results showed that long bone fractures in patients with associated acute traumatic spinal cord injury of quadriplegia or paraplegia heal more expectedly, faster, and with exuberant florid union callus (P > 0.001) and show statistically significant higher levels of growth factors like PDGF, VEGF, Activin-A, and cytokine I-L-1, along the 3 weeks of follow-up (P > 0.005). I-IGF-II showed statistically significant subnormal level along the whole follow-up period in the same patients (P > 0.005). We concluded that long bone fractures in spinal cord injury patients heal more expectedly, faster, and with exuberant and florid callus formation; growth factors like IGF-II, PDGF, VEGF, Activin-A, and cytokine I-L-I have roles as mediators, in molecular events and as byproducts of the subtle mechanism of accelerated osteogenesis in these patients and may represent therapeutic potentials to serve as agents to enhance bone repair.

Insulin/IGF and sex hormone axes in human endometrium and associations with endometrial cancer risk factors.

PubMed

Merritt, Melissa A; Strickler, Howard D; Einstein, Mark H; Yang, Hannah P; Sherman, Mark E; Wentzensen, Nicolas; Brouwer-Visser, Jurriaan; Cossio, Maria Jose; Whitney, Kathleen D; Yu, Herbert; Gunter, Marc J; Huang, Gloria S

2016-06-01

Experimental and observational data link insulin, insulin-like growth factor (IGF), and estrogens to endometrial tumorigenesis. However, there are limited data regarding insulin/IGF and sex hormone axes protein and gene expression in normal endometrial tissues, and very few studies have examined the impact of endometrial cancer risk factors on endometrial tissue biology. We evaluated endometrial tissues from 77 premenopausal and 30 postmenopausal women who underwent hysterectomy for benign indications and had provided epidemiological data. Endometrial tissue mRNA and protein levels were measured using quantitative real-time PCR and immunohistochemistry, respectively. In postmenopausal women, we observed higher levels of phosphorylated IGF-I/insulin receptor (pIGF1R/pIR) in diabetic versus non-diabetic women (p value =0.02), while women who reported regular nonsteroidal anti-inflammatory drug use versus no use had higher levels of insulin and progesterone receptors (both p values ≤0.03). We also noted differences in pIGF1R/pIR staining with OC use (postmenopausal women only), and the proportion of estrogen receptor-positive tissues varied by the number of live births and PTEN status (premenopausal only) (p values ≤0.04). Compared to premenopausal proliferative phase women, postmenopausal women exhibited lower mRNA levels of IGF1, but higher IGFBP1 and IGFBP3 expression (all p values ≤0.004), and higher protein levels of the receptors for estrogen, insulin, and IGF-I (all p values ≤0.02). Conversely, pIGF1R/pIR levels were higher in premenopausal proliferative phase versus postmenopausal endometrium (p value =0.01). These results highlight links between endometrial cancer risk factors and mechanistic factors that may contribute to early events in the multistage process of endometrial carcinogenesis.

Born to run: control of transcription elongation by RNA polymerase II.

PubMed