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Sample records for increases serum igf-i

  1. Short-term dietary concentrate supplementation during estrus synchronization treatment in beef cows increased IGF-I serum concentration but did not affect the reproductive response.

    PubMed

    Rosales-Torres, A M; López-Cedillo, Z B; Hernández-Coronado, C G; Rosete-Fernández, J V; Mendoza, G D; Guzmán, A

    2017-01-01

    The objective of this study was to evaluate if short-term dietary concentrate supplementation increased IGF-I serum concentration and resulted in a reproductive response during estrus synchronization treatment in non-lactating beef cows. Thirty non-lactating beef cows (Bos indicus × Bos taurus) were allocated to the same pastureland and fed native tropical grasses as a basal diet. Cows were synchronized using a 7-day CO-Synch plus controlled internal drug release (CIDR) protocol and received fixed time artificial insemination (FTAI). Cows were divided into two groups; the control group (n = 16) received 0.5 kg of concentrate/cow/day, whereas the supplemented group (n = 14) received 4.0 kg of concentrate/cow/day. The period of supplementation was 10 days from the day of CIDR insert to FTAI. The concentration of IGF-I increased (P < 0.05) in the supplemented group, while no significant changes were observed in the control group. Moreover, at the time of insemination, IGF-I serum concentrations were higher in supplemented cows compared with control cows (P < 0.05). Notably, metabolite and insulin concentrations did not differ (P > 0.05) between treatment groups or sampling day. The response to estrus induction, measured as estrus presentation, ovulation rate, and pregnancy rate, was similar between experimental groups (P > 0.05). In conclusion, our results indicated that supplementation with dietary concentrate for 10 days in non-lactating beef cows changed the endocrine milieu, specifically increasing IGF-I serum concentration. However, these endocrine changes did not affect response to estrous induction treatment.

  2. Serum insulin-like growth factor-I (IGF-I) levels during long-term IGF-I treatment of children and adults with primary GH resistance (Laron syndrome).

    PubMed

    Laron, Z; Klinger, B; Silbergeld, A

    1999-01-01

    Serum IGF-I levels were measured in 14 patients (9 children and 5 adults) with Laron syndrome (LS) during long-term treatment by IGF-I. Recombinant IGF-I (FK-780, Fujisawa Pharmaceutical Co. Ltd., Japan) was administered once daily subcutaneously before breakfast for 3-5 years to the children and for 9 months to the adults. The initial daily dose was 150 micrograms/kg for children and 120 micrograms/kg for adults. Before initiation of treatment the mean overnight fasting levels of serum IGF-I in the children was 3.2 +/- 0.8 nmol/l (mean +/- SEM), rising to 10 +/- 1.7 nmol/l during long-term treatment even on a dose of 120 micrograms/kg/day. The serum IGF-I levels 4 hours after injection rose from 31.2 +/- 3.5 to 48 +/- 2 nmol/l. In the adult patients, the initial basal IGF-I was 4.1 +/- 0.7 nmol/l, rising to 16.1 +/- 3.84 nmol/l after 8-9 months treatment. Serum IGF-I levels at 4 hours after injection rose in the adult patients from 24.1 +/- 5.8 up to 66.8 +/- 15.4 nmol/l. A progressively increasing half-life during long term exogenous administration of IGF-I to patients with Laron syndrome was demonstrated by following serum IGF-I dynamics after injection. Based on the fact that no antibodies to IGF-I were detected and on findings in previous studies, it is speculated that the increasing serum IGF-I levels during long-term IGF-I treatment are caused by an increase in serum IGFBP-3 induced by chronic IGF-I administration. It is concluded that treatment with IGF-I necessitates regular monitoring of serum IGF-I levels; in patients in whom the age adjusted maximal levels are exceeded, a reduction of the daily IGF-I dose is indicated to avoid undesirable effects.

  3. Effect of voluntary exercise on the expression of IGF-I and androgen receptor in three rat skeletal muscles and on serum IGF-I and testosterone levels.

    PubMed

    Matsakas, A; Nikolaidis, M G; Kokalas, N; Mougios, V; Diel, P

    2004-10-01

    The effects of anabolic agents and training on skeletal muscle are believed to be mediated by a variety of growth and transcription factors. Among these regulatory proteins, insulin-like growth factor-I (IGF-I) and androgen receptor (AR) play a crucial role. The purpose of this study was to investigate the effects of wheel running on IGF-I and AR mRNA expression in three distinct rat skeletal muscles (i.e., gastrocnemius, vastus lateralis, and soleus), as well as on the serum levels of IGF-I and testosterone. Twenty male Wistar rats were housed in cages with free access to running wheels for 12 weeks, while nine rats served as controls. Analysis of the mRNA expression of IGF-I and AR using real time RT-PCR revealed no significant differences between the trained and untrained rats in any of the muscles studied. Enzyme immunoassay showed significantly lower serum levels of IGF-I and testosterone in the trained compared to the untrained animals. These results suggest that chronic exercise in wheels does not affect IGF-I and AR mRNA levels in rat skeletal muscle, while decreasing the circulating levels of two anabolic factors, i.e., IGF-I and testosterone. It is concluded that IGF-I, AR and testosterone seem to play a marginal role during the adaptation process of rat skeletal muscle to long-term wheel running.

  4. [Changes in serum levels of IGF-I and its binding proteins and their relation to microcirculation in obese patients].

    PubMed

    Krsek, M; Prázný, M; Sucharda, P; Marek, J; Justová, V; Lacinová, Z

    2001-12-01

    The IGF-I system and its binding proteins participate in the pathogenesis of vascular affections under various pathological conditions. The mechanism and mode of its action were however not elucidated in details so far and views on its role are controversial. The objective of the study was to assess the relationship of this system and the blood flow in the microcirculation in obese patients. The authors examined 21 obese patients (BMI 39.7 +/- 7.3 kg/m2) and a group of healthy volunteers. They examined: serum concentrations of total IGF-I, free IGF-I, IGFBP-1,-2,-3, and -6, total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides as well as the intimomedial thickness of the common carotid arteries and parameters of blood flow in the microcirculation, evaluated by a laser-Doppler examination. In obese patients there were significantly lower serum concentrations of IGF-I and free-IGF I (p < 0.05) as compared with the control group. Comparison of the function of the microcirculation revealed in obese patients, as compared with the control group, a lower percentage increase of perfusion after occlusion (PORH%, p < 0.05) and after heating (TH%, p < 0.05) and a slower onset of thermal hyperaemia (THmax/t, p < 0.05). In the control group serum concentrations of free-IGF-I correlated inversely with the maximum perfusion after heat induced hyperaemia (THmax (r = -0.54, p < 0.02) and the rate of onset of hyperaemia after heating (THmax/t) (r = 0.51, p < 0.02). In the group of obese patients serum concentrations of free-IGF-I correlated inversely with the maximum perfusion after heat induced hyperaemia (THmax) (r = -0.55, p < 0.02), and IGFBP-3 concentrations correlated inversely with maximum hyperaemia after occlusion (PORGmax) (r = -0.57, p < 0.01). The results suggest that the function of the microcirculation in obese subjects is affected. The activity of the IGF-I system and its binding proteins is related to the affected function of the microcirculation and

  5. Validation of serum IGF-I as a biomarker to monitor the bioactivity of exogenous growth hormone agonists and antagonists in rabbits.

    PubMed

    Bielohuby, Maximilian; Zarkesh-Esfahani, Sayyed Hamid; Manolopoulou, Jenny; Wirthgen, Elisa; Walpurgis, Katja; Toghiany Khorasgani, Mohaddeseh; Aghili, Zahra Sadat; Wilkinson, Ian Robert; Hoeflich, Andreas; Thevis, Mario; Ross, Richard J; Bidlingmaier, Martin

    2014-11-01

    The development of new growth hormone (GH) agonists and growth hormone antagonists (GHAs) requires animal models for pre-clinical testing. Ideally, the effects of treatment are monitored using the same pharmacodynamic marker that is later used in clinical practice. However, intact rodents are of limited value for this purpose because serum IGF-I, the most sensitive pharmacodynamic marker for the action of GH in humans, shows no response to treatment with recombinant human GH and there is little evidence for the effects of GHAs, except when administered at very high doses or when overexpressed. As an alternative, more suitable model, we explored pharmacodynamic markers of GH action in intact rabbits. We performed the first validation of an IGF-I assay for the analysis of rabbit serum and tested precision, sensitivity, linearity and recovery using an automated human IGF-I assay (IDS-iSYS). Furthermore, IGF-I was measured in rabbits of different strains, age groups and sexes, and we monitored IGF-I response to treatment with recombinant human GH or the GHA Pegvisomant. For a subset of samples, we used LC-MS/MS to measure IGF-I, and quantitative western ligand blot to analyze IGF-binding proteins (IGFBPs). Although recovery of recombinant rabbit IGF-I was only 50% in the human IGF-I assay, our results show that the sensitivity, precision (1.7-3.3% coefficient of variation) and linearity (90.4-105.6%) were excellent in rabbit samples. As expected, sex, age and genetic background were major determinants of IGF-I concentration in rabbits. IGF-I and IGFBP-2 levels increased after single and multiple injections of recombinant human GH (IGF-I: 286±22 versus 434±26 ng/ml; P<0.01) and were highly correlated (P<0.0001). Treatment with the GHA lowered IGF-I levels from the fourth injection onwards (P<0.01). In summary, we demonstrated that the IDS-iSYS IGF-I immunoassay can be used in rabbits. Similar to rodents, rabbits display variations in IGF-I depending on sex, age and

  6. Long-term effects of insulin-like growth factor (IGF)-I on serum IGF-I, IGF-binding protein-3 and acid labile subunit in Laron syndrome patients with normal growth hormone binding protein.

    PubMed

    Kanety, H; Silbergeld, A; Klinger, B; Karasik, A; Baxter, R C; Laron, Z

    1997-12-01

    A minority of patients with Laron syndrome have normal serum GH binding protein (GHBP), indicating that the defect is elsewhere than in the extracellular domain of the GH receptor. We have evaluated the effect of long-term IGF-I treatment on serum IGF-binding protein (IGFBP)-3 and the acid-labile subunit (ALS) in three sibling with Laron syndrome caused by a GH post-receptor defect and with normal GHBP. The children (a boy aged 3 years, a girl aged 4 years and a boy aged 10 years) were treated by daily s.c. injection of IGF-I in a dose of 150 micrograms/kg. IGFBP-3 was measured by RIA and Western ligand blotting, ALS by RIA. Based values of IGFBP-3 and ALS were low. During IGF-I treatment, the IGFBP-3 concentrations in the girl gradually increased, whereas in the boys there was a 60% decrease during the first week, followed by gradual increase towards baseline. The ALS concentrations followed a similar pattern. We conclude that IGF-I treatment induces and initial suppression and then an increase in the IGFBP-3 and ALS concentrations, confirming data from animal experiments that IGFBP-3 synthesis is not solely under GH control. The differences in responsiveness between the female and male siblings may reflect genetic differences, or lower circulating concentrations of IGF-I in the boys compared with the girl.

  7. A Diet High in Meat Protein and Potential Renal Acid Load Increases Absorption and Urinary Excretion of Calcium, As Well As Serum IGF-I in Postmenopausal Women

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Objective: The objective was to determine the effect of increasing protein and potential renal acid load (PRAL) on Ca retention and markers of bone metabolism. Methods: In a randomized crossover design, twenty postmenopausal women consumed two diets: one low protein, low PRAL (LPLP) and one high pr...

  8. Relationships between serum IGF-I concentrations and piglet development or neonatal viability following porcine somatotropin (pST) and insulin administration to gestating gilts.

    PubMed

    Okere, C; Hacker, R R; Werchola, G

    1997-05-01

    This study was designed to evaluate the effects of exogenous treatment with pST, insulin and their combination on periparturient serum IGF-I levels, prenatal piglet development and viability. Pregnant Yorkshire gilts were injected daily with either 5 ml of saline (C), n = 23; 5 mg pST (P), n = 23; 0.50 IU/kg of insulin (I), n = 23; or pST plus insulin at the above dosage, according to 2 x 2 factorial design from Day 30 to 70 of gestation. All gilts were sacrificed on Day 113 of gestation. Peripartum IGF-I serum levels were determined by RIA following a 36 h incubation in 0.2 M gly-gly HCL. Recovery of human rIGF-I standard was > 95%, while the intra-assay CV was 5.74%. Measures of piglet viability were compared using Randall's adaptation of Apgar score for human neonates. Piglet weight and crown-to-rump length were determined prior to dissection. Treatments (P, I and P + I) elicited highly significant increases in maternal serum IGF-I concentrations (321.9, 337.0, 375.0 vs 247.6 ng/ml; P = 0.0001) on Day 113 of gestation. Nonsignificant differences were detected in piglet serum IGF-I (94.8, 102.6, 110.2 vs 92.2 ng/ml; P = 0.06). These results revealed no relationship between piglet weight and maternal (r = 0.03) or piglet serum IGF-I levels (r = 0.08). Only a weak association between gilt and piglet serum IGF-I concentrations (r = 0.26) was detected. Injections with pST and or insulin did not influence piglet viability scores (P = 0.74). Viability scores were highly correlated with piglet weight (r = 0.66), crown -rump length (r = 0.70), but not with IGF-I concentrations in gilt (r = 0.09) and piglet serum (r = 0.16). Body weights, crown -rump length and visceral organ weights of piglets did not differ between control and hormone -treated gilts (P >/= 0.05). These results indicate 1) that there was no direct treatment effects on in utero piglet development or neonatal viability; 2) that IGF-I production in gilt and piglet compartment is independent, suggesting

  9. Long-term IGF-I treatment of children with Laron syndrome increases adiposity.

    PubMed

    Laron, Zvi; Ginsberg, Shira; Lilos, Pnina; Arbiv, Mira; Vaisman, Nahum

    2006-02-01

    Laron syndrome (LS) is an autosomal recessive disease caused by deletions or mutations in the GH receptor gene leading to an inability of insulin-like growth factor I (IGF-I) generation. Among the major resulting body changes are dwarfism and obesity. The only effective treatment is daily administration of biosynthetic IGF-I. Body composition determination by DEXA (dual energy X-ray absorptiometry) of three girls with LS treated by IGF-I for 1, 3 and 11 1/2 years, respectively, revealed that concomitantly with the increase in growth there was a significant increase in body adipose tissue to double or triple the normal values. Due to the underdevelopment of the muscular and skeletal systems body mass index (BMI) did not accurately reflect the degree of obesity. In conclusion, IGF-I similar to insulin, exerts an adipogenic effect.

  10. Serum leptin in obese patients with Laron syndrome before and during IGF-I treatment.

    PubMed

    Laron, Z; Silbergeld, A; Lilos, P; Blum, F W

    1998-01-01

    Fifteen patients with primary GH resistance (Laron syndrome, LS) were studied before and during 6 months of daily replacement treatment with IGF-I. The main findings were that patients with LS and normal or high serum GH binding protein (GHBP) were less obese than those with a negative GHBP, and that serum leptin levels varied with body mass as in other types of obesity.

  11. Association between Serum IGF-I levels and Postoperative Delirium in Elderly Subjects Undergoing Elective Knee Arthroplasty.

    PubMed

    Yen, Timothy E; Allen, John C; Rivelli, Sarah K; Patterson, Stephanie C; Metcalf, Meredith R; Flink, Benjamin J; Mirrakhimov, Aibek E; Lagoo, Sandhya A; Vail, Thomas P; Young, Christopher C; Moon, Richard E; Trzepacz, Paula T; Kwatra, Madan M

    2016-02-05

    Evidence is mixed for an association between serum insulin-like growth factor-I (IGF-I) levels and postoperative delirium (POD). The current study assessed preoperative serum IGF-I levels as a predictor of incident delirium in non-demented elderly elective knee arthroplasty patients. Preoperative serum levels of total IGF-I were measured using a commercially available Human IGF-I ELISA kit. POD incidence and severity were determined using DSM-IV criteria and the Delirium Rating Scale-Revised-98 (DRS-R98), respectively. Median IGF-I levels in delirious (62.6 ng/ml) and non-delirious groups (65.9 ng/ml) were not significantly different (p = 0.141). The ratio (95% CI) of geometric means, D/ND, was 0.86 (0.70, 1.06). The Hodges-Lehmann median difference estimate was 7.23 ng/mL with 95% confidence interval (-2.32, 19.9). In multivariate logistic regression analysis IGF-I level was not a significant predictor of incident POD after correcting for medical comorbidities. IGF-I levels did not correlate with DRS-R98 scores for delirium severity. In conclusion, we report no evidence of association between serum IGF-I levels and incidence of POD, although the sample size was inadequate for a conclusive study. Further efforts to investigate IGF-I as a delirium risk factor in elderly should address comorbidities and confounders that influence IGF-I levels.

  12. IGF-I administration advances the decrease in hypersensitivity to oestradiol negative feedback inhibition of serum LH in adolescent female rhesus monkeys.

    PubMed

    Wilson, M E

    1995-04-01

    Developmental increases in serum LH were assessed in female rhesus monkeys to test the hypotheses that (1) the final stages of puberty are characterized by a decrease in hypersensitivity to oestradiol negative feedback of LH and (2) that increases in IGF-I secretion accelerate this decrease in hypersensitivity. In order to test the first hypothesis, serum LH in the absence of oestradiol and in response to three doses of oestradiol were compared between ovariectomized adult (n = 6) and adolescent female monkeys (control group; n = 6). The control females were not treated with oestradiol until serum LH had risen to within the 95% confidence interval of serum LH observed in ovariectomized adults. Doses of oestradiol achieved serum levels of approximately 80 ('low'), 160 ('intermediate'), and 250 ('high') pmol/l. For control group females, treatment with the next higher dose of oestradiol was not initiated until serum LH was no longer suppressed by the lower dose. Treatment with oestradiol produced a dose-dependent suppression in serum LH in adults. In contrast, low-dose oestradiol maximally suppressed serum LH throughout the initial treatment period in the control group compared with the adult females. The low oestradiol dose effectively suppressed serum LH throughout the study period in 4/6 of the control group and became ineffective at suppressing LH after 8 months of treatment in 2/6 control group females. Initiation of the intermediate dose of oestradiol to these females again maximally suppressed LH compared with adult females. In order to determine whether IGF-I regulates this change in hypersensitivity to oestradiol negative feedback, a second group of ovariectomized, adolescent monkeys (n = 6) were treated chronically with IGF-I to elevate serum IGF-I levels above those of control group females. Using the same protocol described for the control females, developmental changes in serum LH in the absence of oestradiol and in response to oestradiol negative

  13. Sleep extension increases IGF-I concentrations before and during sleep deprivation in healthy young men.

    PubMed

    Chennaoui, Mounir; Arnal, Pierrick J; Drogou, Catherine; Sauvet, Fabien; Gomez-Merino, Danielle

    2016-09-01

    Sleep deprivation is known to suppress circulating trophic factors such as insulin-like growth factor (IGF)-I and brain-derived neurotrophic factor (BDNF). This experiment examined the effect of an intervention involving 6 nights of extended sleep before total sleep deprivation on this catabolic profile. In a randomized crossover design, 14 young men (age range: 26-37 years) were either in an extended (EXT; time in bed: 2100-0700 h) or habitual (HAB: 2230-0700 h) sleep condition, followed by 3 days in the laboratory with blood sampling at baseline (B), after 24 h of sleep deprivation (24h-SD), and after 1 night of recovery sleep (R). In the EXT condition compared with the HAB condition, free IGF-I levels were significantly higher at B, 24h-SD, and R (P < 0.001), and those of total IGF-I at B and 24h-SD (P < 0.05). EXT did not influence growth hormone, IGF binding protein 3, BDNF, insulin, and glucose levels. The only effect of 24 h of sleep deprivation was for insulin levels, which were significantly higher after R compared with B. In a healthy adult, additional sleep over 1 week increased blood concentrations of the anabolic factor IGF-I before and during 24 h of sleep deprivation and after the subsequent recovery night without effects on BDNF. With further research, these findings may prove to be important in guiding effective lifestyle modifications to limit physical or cognitive deficits associated with IGF-I decrease with age.

  14. Effects of an endurance cycling competition on resting serum insulin-like growth factor I (IGF-I) and its binding proteins IGFBP-1 and IGFBP-3

    PubMed Central

    Chicharro, J; Lopez-Calderon, A; Hoyos, J; Martin-Velasco, A; Villa, G; Villanua, M; Lucia, A

    2001-01-01

    Objectives—To determine whether consecutive bouts of intense endurance exercise over a three week period alters serum concentrations of insulin-like growth factor I (IGF-I) and/or its binding proteins. Methods—Seventeen professional cyclists (mean (SEM) VO2MAX, 74.7 (2.1) ml/kg/min; age, 27 (1) years) competing in a three week tour race were selected as subjects. Blood samples were collected at each of the following time points: t0 (control, before the start of competition), t1 (end of first week), and t3 (end of third week). Serum levels of both total and free IGF-I and IGF binding proteins 1 and 3 (IGFBP-1 and IGFBP-3) were measured in each of the samples. Cortisol levels were measured in nine subjects. Results—A significant (p<0.01) increase was found in total IGF-I and IGFBP-1 at both t1 and t3 compared with to (IGF-I: 110.9 (17.7), 186.8 (12.0), 196.9 (14.7) ng/ml at t0, t1, and t3 respectively; IGFBP-1: 54.6 (6.6), 80.6 (8.0), and 89.2 (7.9) ng/ml at t0, t1, and t3 respectively). A significant (p<0.01) decrease was noted in free IGF-I at t3 compared with both to and t1 (t0: 0.9 (0.1) ng/ml; t1: 0.9 (0.1) ng/ml; t3: 0.7 (0.1) ng/ml); in contrast, IGFBP-3 levels remained stable throughout the race. Conclusions—It would appear that the increase in circulating levels of both IGF-I and its binding protein IGFBP-1 is a short term (one week) endocrine adaptation to endurance exercise. After three weeks of training, total IGF-I and IGFBP-1 remained stable, whereas free IGF-I fell below starting levels. Key Words: cycling; insulin-like growth factor; exercise; endurance; binding proteins PMID:11579061

  15. Serum IGF-I and C-reactive protein in healthy black and white young men: The CARDIA Male Hormone Study

    PubMed Central

    Colangelo, Laura A.; Chiu, Brian; Kopp, Peter; Liu, Kiang; Gapstur, Susan M.

    2009-01-01

    Objective Animal and human studies suggest that C-reactive protein (CRP) may be inversely associated with serum insulin-like growth factor-I (IGF-I) concentrations. However, most human studies have not controlled adequately for confounding factors, particularly nutritional intake. This population-based study examined whether CRP is inversely associated with IGF-I and IGFBP-3 concentrations. Methods In cross-sectional analysis, multivariable linear regression with adjustment for age, BMI, smoking status, alcohol intake, and nutritional factors was used to relate log CRP, the independent variable, to IGF-I and IGFBP-3 in a sample of black (n = 364) and white men (n = 486) separately by race. Results Only black men had positive findings: log CRP was significantly associated with IGF-I (β = −13.1 ng/ml, p = 0.02) and the difference in mean IGF-I concentrations between the highest and lowest quartiles of CRP was 26 ng/ml. There was a statistically significant interaction between log CRP and smoking status (p = 0.02); the regression coefficient for IGF-I predicted from log CRP was significant in smokers (β = −39.8 ng/ml, p = 0.0001), but not in non-smokers. The difference in mean IGF-I concentrations between highest and lowest quartiles of CRP was 100 ng/ml for black smokers. There were no associations for IGFBP-3. Conclusions In our study, CRP levels are inversely associated with IGF-I concentrations in black male smokers; however, the causal nature of the association is unclear and should be studied further. PMID:19138871

  16. A novel, noninvasive transdermal fluid sampling methodology: IGF-I measurement following exercise.

    PubMed

    Scofield, D E; McClung, H L; McClung, J P; Kraemer, W J; Rarick, K R; Pierce, J R; Cloutier, G J; Fielding, R A; Matheny, R W; Young, A J; Nindl, B C

    2011-06-01

    This study tested the hypothesis that transdermal fluid (TDF) provides a more sensitive and accurate measure of exercise-induced increases in insulin-like growth factor-I (IGF-I) than serum, and that these increases are detectable proximal, but not distal, to the exercising muscle. A novel, noninvasive methodology was used to collect TDF, followed by sampling of total IGF-I (tIGF-I) and free IGF-I (fIGF-I) in TDF and serum following an acute bout of exercise. Experiment 1: eight men (23 ± 3 yrs, 79 ± 7 kg) underwent two conditions (resting and 60 min of cycling exercise at 60% Vo(2)(peak)) in which serum and forearm TDF were collected for comparison. There were no significant changes in tIGF-I or fIGF-I in TDF obtained from the forearm or from serum following exercise (P > 0.05); however, the proportion of fIGF-I to tIGF-I in TDF was approximately fourfold greater than that of serum (P ≤ 0.05). These data suggest that changes in TDF IGF-I are not evident when TDF is sampled distal from the working tissue. To determine whether exercise-induced increases in local IGF-I could be detected when TDF was sampled directly over the active muscle group, we performed a second experiment. Experiment 2: fourteen subjects (22 ± 4 yr, 68 ± 11 kg) underwent an acute plyometric exercise condition consisting of 10 sets of 10 plyometric jumps with 2-min rest between sets. We observed a significant increase in TDF tIGF-I following exercise (P ≤ 0.05) but no change in serum tIGF-I (P > 0.05). Overall, these data suggest that TDF may provide a noninvasive means of monitoring acute exercise-induced changes in local IGF-I when sampled in proximity to exercising muscles. Moreover, our finding that the proportion of free to tIGF-I was greater in TDF than in serum suggests that changes in local IGF-I may be captured more readily using this system.

  17. Endogenous IGF-I and alpha v beta3 integrin ligands regulate increased smooth muscle growth in TNBS-induced colitis.

    PubMed

    Hazelgrove, Krystina B; Flynn, Robert S; Qiao, Li-Ya; Grider, John R; Kuemmerle, John F

    2009-06-01

    Endogenous insulin-like growth factor-I (IGF-I) regulates intestinal smooth muscle growth by concomitantly stimulating proliferation and inhibiting apoptosis. IGF-I-stimulated growth is augmented by the alpha(v)beta(3) integrin ligands vitronectin and fibronectin. IGF-I expression in smooth muscle is increased in both TNBS-induced colitis and Crohn's disease. We hypothesized that intestinal inflammation increased vitronectin and fibronectin expression by smooth muscle and, along with IGF-I upregulation, increased intestinal muscle growth. Intestinal smooth muscle cells were examined 7 days following the induction of TNBS-induced colitis. Although alpha(v)beta(3) integrin expression was not altered by TNBS-induced colitis, vitronectin and fibronectin levels were increased by 80 +/- 10% and 90 +/- 15%, above control levels, respectively. Basal IGF-I receptor phosphorylation in inflamed muscle from TNBS-treated rats was increased by 86 +/- 8% over vehicle-treated controls. Basal ERK1/2, p70S6 kinase, and GSK-3beta phosphorylation in muscle cells of TNBS-treated rats were also increased by 140-180%. TNBS treatment increased basal muscle cell proliferation by 130 +/- 15% and decreased apoptosis by 20 +/- 2% compared with that in vehicle-treated controls. The changes in proliferation and apoptosis were reversed by an IGF-I receptor tyrosine kinase inhibitor or an alpha(v)beta(3) integrin antagonist. The results suggest that smooth muscle hyperplasia in TNBS-induced colitis partly results from the upregulation of endogenous IGF-I and ligands of alpha(v)beta(3) integrin that mediate increased smooth muscle cell proliferation and decreased apoptosis. This paper has identified one mechanism regulating smooth muscle hyperplasia, a feature of stricture formation that occurs in the chronically inflamed intestine of TNBS-induced colitis and potentially Crohn's disease.

  18. A chimeric vitronectin: IGF-I protein supports feeder-cell-free and serum-free culture of human embryonic stem cells.

    PubMed

    Manton, Kerry J; Richards, Sean; Van Lonkhuyzen, Derek; Cormack, Luke; Leavesley, David; Upton, Zee

    2010-09-01

    The therapeutic use of human embryonic stem (hES) cells is severely limited by safety concerns regarding their culture in media containing animal-derived or nondefined factors and on animal-derived feeder cells. Thus, there is a pressing need to develop culture techniques that are xeno-free, fully defined, and synthetic. Our laboratory has discovered that insulin-like growth factor (IGF) and vitronectin (VN) bind to each other resulting in synergistic short-term functional effects in several cell types, including keratinocytes and breast epithelial cells. We have further refined this complex into a single chimeric VN:IGF-I protein that functionally mimics the effects obtained upon binding of IGF-I to VN. The aim of the current study was to determine whether hES cells can be serially propagated in feeder-cell-free and serum-free conditions using medium containing our novel chimeric VN:IGF-I protein. Here we demonstrate that hES cells can be serially propagated and retain their undifferentiated state in vitro for up to 35 passages in our feeder-cell-free, serum-free, chemically defined media. We have utilized real-time polymerase chain reaction (PCR), immunofluorescence, and fluorescence-activated cell sorter (FACS) analysis to show that the hES cells have maintained an undifferentiated phenotype. In vitro differentiation assays demonstrated that the hES cells retain their pluripotent potential and the karyotype of the hES cells remains unchanged. This study demonstrates that the novel, fully defined, synthetic VN:IGF-I chimera-containing medium described herein is a viable alternative to media containing serum, and that in conjunction with laminin-coated plates facilitates feeder-cell-free and serum-free growth of hES.

  19. IGF-I abuse in sport.

    PubMed

    Guha, Nishan; Dashwood, Alexander; Thomas, Nicholas J; Skingle, Alexander J; Sönksen, Peter H; Holt, Richard I G

    2009-09-01

    It is widely believed that growth hormone (GH) is abused by athletes for its anabolic and lipolytic effects. Many of the physiological effects of GH are mediated by the production of insulin-like growth factor-I (IGF-I). Both GH and IGF-I appear on the World Anti-Doping Agency list of prohibited substances. Little is known, however, about the prevalence of abuse with exogenous IGF-I. IGF-I has effects on carbohydrate, lipid and protein metabolism and some of these actions could prove beneficial to competitive athletes. No studies have demonstrated a positive effect of IGF-I on physical performance in healthy individuals but this has not yet been studied in appropriately designed trials. Two pharmaceutical preparations of IGF-I have recently become available for the treatment of growth disorders in children. This availability is likely to increase the prevalence of IGF-I abuse. Combining IGF-I with its binding protein IGFBP-3 in one preparation has the potential to reduce the side-effect profile but the adverse effects of long term IGF-I abuse are currently unknown. Detection of abuse with IGF-I is a major challenge for anti-doping authorities. It is extremely difficult to distinguish the exogenous recombinant form of the hormone from endogenously-produced IGF-I. One approach currently being investigated is based on measuring markers of GH and IGF-I action. This has already proved successful in the fight against GH abuse and, it is hoped, will subsequently lead to a similar test for detection of IGF-I abuse.

  20. Mechanism of Action of Glucagon-Like Peptide-2 to Increase IGF-I mRNA in Intestinal Subepithelial Fibroblasts

    PubMed Central

    Leen, Jason L. S.; Izzo, Angelo; Upadhyay, Chandani; Rowland, Katherine J.; Dubé, Philip E.; Gu, Steven; Heximer, Scott P.; Rhodes, Christopher J.; Storm, Daniel R.; Lund, P. Kay

    2011-01-01

    IGF-I, a known secretory product of intestinal subepithelial myofibroblasts (ISEMFs), is essential for the intestinotropic effects of glucagon-like peptide-2 (GLP-2). Furthermore, GLP-2 increases IGF-I mRNA transcript levels in vitro in heterogeneous fetal rat intestinal cultures, as well as in vivo in the rodent small intestine. To determine the mechanism underlying the stimulatory effect of GLP-2 on intestinal IGF-I mRNA, murine ISEMF cells were placed into primary culture. Immunocytochemistry showed that the ISEMF cells appropriately expressed α-smooth muscle actin and vimentin but not desmin. The cells also expressed GLP-2 receptor and IGF-I mRNA transcripts. Treatment of ISEMF cells with (Gly2)GLP-2 induced IGF-I mRNA transcripts by up to 5-fold of basal levels after treatment with 10−8 m GLP-2 for 2 h (P < 0.05) but did not increase transcript levels for other intestinal growth factors, such as ErbB family members. Immunoblot revealed a 1.6-fold increase in phospho (p)-Akt/total-(t)Akt with 10−8 m GLP-2 treatment (P < 0.05) but no changes in cAMP, cAMP-dependent β-galactosidase expression, pcAMP response element-binding protein/tcAMP response element-binding protein, pErk1/2/tErk1/2, or intracellular calcium. Furthermore, pretreatment of ISEMF cells with the phosphatidylinositol 3 kinase (PI3K) inhibitors, LY294002 and wortmannin, abrogated the IGF-I mRNA response to GLP-2, as did overexpression of kinase-dead Akt. The role of PI3K/Akt in GLP-2-induced IGF-I mRNA levels in the murine jejunum was also confirmed in vivo. These findings implicate the PI3K/Akt pathway in the stimulatory effects of GLP-2 to enhance intestinal IGF-I mRNA transcript levels and provide further evidence in support of a role for IGF-I produced by the ISEMF cells in the intestinotropic effects of GLP-2. PMID:21159855

  1. Maternal nutrition affects the ability of treatment with IGF-I and IGF-II to increase growth of the placenta and fetus, in guinea pigs.

    PubMed

    Sohlström, A; Fernberg, P; Owens, J A; Owens, P C

    2001-12-01

    The aim of this study was to investigate how administration of IGF-I and IGF-II, during early to mid pregnancy, affects maternal growth and body composition as well as fetal and placental growth, in ad libitum fed, and in moderately, chronically food restricted guinea pigs. From day 20 of gestation, mothers (3-4 months old) were infused with IGF-I, IGF-II (565 microg/day) or vehicle for 17 days and then killed on day 40 of gestation. Maternal organ weights, fetal and placental weights were assessed. Treatment with IGFs did not alter body weight gain and had small effects on body composition in the mothers. Both IGF-I and IGF-II increased fetal and placental weights in ad libitum fed dams and IGF-I increased placental weight in food restricted dams. In conclusion, treatment with IGF-I during the first half of pregnancy stimulates placental growth in both ad libitum fed and food restricted guinea pigs without affecting maternal growth while fetal growth is stimulated by IGF treatment only in ad libitum fed animals.

  2. Liver-derived IGF-I regulates cortical bone mass but is dispensable for the osteogenic response to mechanical loading in female mice.

    PubMed

    Svensson, Johan; Windahl, Sara H; Saxon, Leanne; Sjögren, Klara; Koskela, Antti; Tuukkanen, Juha; Ohlsson, Claes

    2016-07-01

    Low circulating IGF-I is associated with increased fracture risk. Conditional depletion of IGF-I produced in osteoblasts or osteocytes inhibits the bone anabolic effect of mechanical loading. Here, we determined the role of endocrine IGF-I for the osteogenic response to mechanical loading in young adult and old female mice with adult, liver-specific IGF-I inactivation (LI-IGF-I(-/-) mice, serum IGF-I reduced by ≈70%) and control mice. The right tibia was subjected to short periods of axial cyclic compressive loading three times/wk for 2 wk, and measurements were performed using microcomputed tomography and mechanical testing by three-point bending. In the nonloaded left tibia, the LI-IGF-I(-/-) mice had lower cortical bone area and increased cortical porosity, resulting in reduced bone mechanical strength compared with the controls. Mechanical loading induced a similar response in LI-IGF-I(-/-) and control mice in terms of cortical bone area and trabecular bone volume fraction. In fact, mechanical loading produced a more marked increase in cortical bone mechanical strength, which was associated with a less marked increase in cortical porosity, in the LI-IGF-I(-/-) mice compared with the control mice. In conclusion, liver-derived IGF-I regulates cortical bone mass, cortical porosity, and mechanical strength under normal (nonloaded) conditions. However, despite an ∼70% reduction in circulating IGF-I, the osteogenic response to mechanical loading was not attenuated in the LI-IGF-I(-/-) mice.

  3. Failure of exogenous IGF-I to restore normal growth in rats submitted to dietary zinc deprivation.

    PubMed

    Ninh, N X; Maiter, D; Verniers, J; Lause, P; Ketelslegers, J M; Thissen, J P

    1998-11-01

    Dietary zinc deficiency in rats causes growth retardation associated with decreased circulating IGF-I concentrations. To investigate the potential role of low IGF-I in this condition, we attempted to reverse the growth failure by administration of exogenous IGF-I. Rats were fed for 4 weeks a zinc-deficient diet (ZD, Zn 0 ppm) or were pair-fed a zinc-normal diet (PF, Zn 75 ppm). We compared the anabolic action of recombinant human (rh) IGF-I infused at the dose of 120 microg/day for the last experimental week in ZD, PF and freely fed control (CTRL) rats. Zinc deficiency caused growth stunting (weight gain 47% of PF; P<0.001), decreased circulating IGF-I (52% of PF; P<0.01) and liver IGF-I mRNA (67% of PF; P<0.01). Serum insulin-like growth factor-binding protein-3 (IGFBP-3) assessed by ligand blot was also reduced in ZD rats (65% of PF; P<0. 01). While exogenous IGF-I increased body weight in CTRL (+12 g; P<0. 01) and PF (+7 g; not significant) animals, growth was not stimulated in ZD rats (-1.5 g) in comparison with the corresponding untreated groups. However, circulating IGF-I and IGFBP-3 levels were restored by IGF-I infusion to levels similar to those in untreated CTRL rats. In conclusion, restoration of normal circulating levels of IGF-I and IGFBP-3 by rhIGF-I infusion fails to reverse the growth retardation induced by zinc deficiency. These results suggest that growth retardation related to zinc deficiency is not only caused by low serum IGF-I concentrations, but also by inhibition of the anabolic actions of IGF-I.

  4. The dietary protein, IGF-I, skeletal health axis.

    PubMed

    Bonjour, Jean-Philippe

    2016-10-01

    Dietary protein represents an important nutrient for bone health and thereby for the prevention of osteoporosis. Besides its role as a brick provider for building the organic matrix of skeletal tissues, dietary protein stimulates the production of the anabolic bone trophic factor IGF-I (insulin-like growth factor I). The liver is the main source of circulating IGF-I. During growth, protein undernutrition results in reduced bone mass and strength. Genetic defect impairing the production of IGF-I markedly reduces bone development in both length and width. The serum level of IGF-I markedly increases and then decreases during pubertal maturation in parallel with the change in bone growth and standing height velocity. The impact of physical activity on bone structure and strength is enhanced by increased dietary protein consumption. This synergism between these two important environmental factors can be observed in prepubertal boys, thus modifying the genetically determined bone growth trajectory. In anorexia nervosa, IGF-I is low as well as bone mineral mass. In selective protein undernutrition, there is a resistance to the exogenous bone anabolic effect of IGF-I. A series of animal experiments and human clinical trials underscore the positive effect of increased dietary intake of protein on calcium-phosphate economy and bone balance. On the contrary, the dietary protein-induced acidosis hypothesis of osteoporosis is not supported by several experimental and clinical studies. There is a direct effect of amino acids on the local production of IGF-I by osteoblastic cells. IGF-I is likely the main mediator of the positive effect of parathyroid hormone (PTH) on bone formation, thus explaining the reduction in fragility fractures as observed in PTH-treated postmenopausal women. In elderly women and men, relatively high protein intake protects against spinal and femoral bone loss. In hip fracture patients, isocaloric correction of the relatively low protein intake results in

  5. IGF-I concentration and changes in critically ill patients

    PubMed Central

    Hajsadeghi, Shokoufeh; Khamseh, Mohammad Ebrahim; Gholami, Saeid; Kerman, Scott Reza Jafarian; Gohardehi, Golnar; Moghadam, Negar Seifi; Sabet, Azade Shafiee; Moradi, Masoud; Mollahoseini, Reza; Najafi, Mehri; Keramati, Mohammad Reza

    2011-01-01

    BACKGROUND: Insulin-like growth factor 1 (IGF-I) is an anabolic growth factor that affects nitrogen balance and its changing trend is not clearly understood in critically ill patients. This study was carried out to evaluate the association between serum IGF-I levels and its changing trend in critically ill patients. METHODS: In this nested case-control study, all consecutive patients admitted to the medical ICU of Rasoul-e-Akram and Firuzgar hospital (Tehran, Iran) from January through October 2008 were included. IGF1 concentration was measured within the first 24h of ICU admission and the fourth, seventh and tenth day since admission. Patients were followed until discharge from ICU or expiration. RESULTS: The study population consisted of 90 patients (mean age: 58.01 ± 22.56), 31 (34.4%) of who died and 59 (65.6%) were discharged. On admission, 43 patients (47.7%) had low IGF-I levels, whereas 47 (52.3%) had normal or high levels. The concentration of IGF-I was not significantly different in every 4 measurements between expired and discharged patients. Significant decrease was seen between first to fourth day IGF-I concentration (p = 0.005). Changing trend was not statistically different in two groups of patients. CONCLUSIONS: There was no relation between low IGF-I concentration on admission day and increased adverse outcome, but overall these patients had lower IGF1. No clear association was found between changing trend of IGF1 and mortality. Stress on admission time may cause decreasing pattern of IGF-I in the first 4 days of admission. PMID:22091227

  6. Nandrolone and stanozolol upregulate aromatase expression and further increase IGF-I-dependent effects on MCF-7 breast cancer cell proliferation.

    PubMed

    Sirianni, Rosa; Capparelli, Claudia; Chimento, Adele; Panza, Salvatore; Catalano, Stefania; Lanzino, Marilena; Pezzi, Vincenzo; Andò, Sebastiano

    2012-11-05

    Several doping agents, such as anabolic androgenic steroids (AAS) and peptide hormones like insulin-like growth factor-I (IGF-I), are employed without considering the potential deleterious effects that they can cause. In addition, androgens are used in postmenopausal women as replacement therapy. However, there are no clear guidelines regarding the optimal therapeutic doses of androgens or long-term safety data. In this study we aimed to determine if two commonly used AAS, nandrolone and stanozolol, alone or in combination with IGF-I, could activate signaling involved in breast cancer cell proliferation. Using a human breast cancer cell line, MCF-7, as an experimental model we found that both nandrolone and stanozolol caused a dose-dependent induction of aromatase expression and, consequently, estradiol production. Moreover, when nandrolone and stanozolol were combined with IGF-I, higher induction in aromatase expression was observed. This increase involved phosphatidylinositol 3-kinase (PI3K)/AKT and phospholipase C (PLC)/protein kinase C (PKC), which are part of IGF-I transductional pathways. Specifically, both AAS were able to activate membrane rapid signaling involving IGF-I receptor, extracellular regulated protein kinases 1/2 (ERK1/2) and AKT, after binding to estrogen receptor (ER), as confirmed by the ability of the ER antagonist ICI182, 780 to block such activation. The estrogenic activity of nandrolone and stanozolol was further confirmed by their capacity to induce the expression of the ER-regulated gene, CCND1 encoding for the cell cycle regulator cyclin D1, which represents a key protein for the control of breast cancer cell proliferation. In fact, when nandrolone and stanozolol were combined with IGF-I, they increased cell proliferation to levels higher than those elicited by the single factors. Taken together these data clearly indicate that the use of high doses of AAS, as occurs in doping practice, may increase the risk of breast cancer. This

  7. Oral IGF-I enhances nutrient and electrolyte absorption in neonatal piglet intestine.

    PubMed

    Alexander, A N; Carey, H V

    1999-09-01

    The effect of orally administered insulin-like growth factor-I (IGF-I) on small intestinal structure and function was studied in 5-day-old colostrum-deprived piglets. Human recombinant IGF-I (3.5 mg. kg(-1). day(-1)) or control vehicle was given orogastrically for 4 days. Body weights, jejunal and ileal mucosa wet and dry weights, and serum IGF-I levels were similar in the two groups. Small intestinal villus height and crypt depth and jejunal enterocyte microvillar dimensions were also similar between groups. Oral IGF-I produced higher rates of jejunal ion transport because of increased basal Na+ absorption. Short-circuit current responses to mucosal addition of D-glucose and L-alanine and net transepithelial absorption of 3-O-methylglucose were increased by IGF-I. Carrier-mediated uptake of D-glucose per milligram in everted jejunal sleeves was greater in IGF-I-treated piglets because of a significantly greater maximal rate of uptake. We conclude that rates of net Na+ and Na+-dependent nutrient absorption are enhanced in piglets treated with oral IGF-I, and this effect is independent of changes in mucosal mass or surface area.

  8. Conditional VHL Gene Deletion Causes Hypoglycemic Death Associated with Disproportionately Increased Glucose Uptake by Hepatocytes through an Upregulated IGF-I Receptor

    PubMed Central

    Kurabayashi, Atsushi; Kakinuma, Yoshihiko; Morita, Taku; Inoue, Keiji; Sato, Takayuki; Furihata, Mutsuo

    2013-01-01

    Our conditional VHL knockout (VHL-KO) mice, having VHL gene deletion induced by tamoxifen, developed severe hypoglycemia associated with disproportionately increased storage of PAS-positive substances in the liver and resulted in the death of these mice. This hypoglycemic state was neither due to impaired insulin secretion nor insulin receptor hypersensitivity. By focusing on insulin-like growth factor I (IGF-I), which has a similar effect on glucose metabolism as the insulin receptor, we demonstrated that IGF-I receptor (IGF-IR) protein expression in the liver was upregulated in VHL-KO mice compared to that in the mice without VHL deletion, as was the expression of glucose transporter (GLUT) 1. The interaction of the receptor for activated C kinase (RACK) 1, which predominantly binds to VHL, was enhanced in VHL-KO livers with IGF-IR, because VHL deletion increased free RACK1 and facilitated the IGF-IR-RACKI interaction. An IGF-IR antagonist retarded hypoglycemic progression and sustained an euglycemic state. These IGF-IR antagonist effects on restoring blood glucose levels also attenuated PAS-positive substance storage in the liver. Because the effect of IGF-I on HIF-1α protein synthesis is mediated by IGF-IR, our results indicated that VHL inactivation accelerated hepatic glucose storage through the upregulation of IGF-IR and GLUT1 and that IGF-IR was a key regulator in VHL-deficient hepatocytes. PMID:23874892

  9. Influence of alimentary zinc deficiency on the concentration of growth hormone (GH), insulin-like growth factor I (IGF-I) and insulin in the serum of force-fed rats.

    PubMed

    Roth, H P; Kirchgessner, M

    1994-09-01

    The study described here investigates the influence of a specific alimentary Zn deficiency on the concentration of growth hormone (GH), insulin-like growth factor I (IGF-I) and insulin in the serum of force-fed rats. For this purpose 24 male Sprague-Dawley rats with an average bodyweight of 108 g were divided into 2 groups of 12 animals each. The Zn-deficient group and the control group received for 12 days a semi-synthetic casein diet with a Zn content of 1.3 and 25 ppm respectively. In order to prevent the reduced feed intake which occurs in Zn deficiency and the associated energy and protein shortage from interfering with the experimental parameters, all animals were fed 4 times daily by gastric tube. This made it possible to supply all animals with adequate-nutrients and to synchronise the feed intake exactly. After 12 days the depleted rats were in a severe state of Zn deficiency, as demonstrated by the reduction of Zn in the serum and the femur by 62% and 44% respectively and the 70% lower serum activity of alkaline phosphatase. In the Zn-deficient rats the concentration of GH in the serum was significantly increased by 78%, while IGF-1 and insulin were significantly reduced by 28% and 25% respectively. It is thought that the growth depression observed in the Zn-deficient rats in this study despite their identical feed intake is probably due to a reduced concentration of IGF-I and insulin and that the biological activity or the binding of GH to receptors is impaired in specific alimentary Zn deficiency.

  10. Changes in the Growth Hormone-IGF-I Axis in Non-obese Diabetic Mice

    PubMed Central

    Segev, Yael; Eshet, Rina; Flyvbjerg, Allan; Phillip, Moshe

    2000-01-01

    We investigated the changes in GH-IGF-I axis in non-obese diabetic (NOD)-mice, a model of insulin dependent diabetes mellitus. Diabetic female NOD mice and their age- and sex-matched controls were sacrificed at 4, 14, 21 and 30 days (30d DM) after the onset of glycosuria. Serum GH levels increased and serum IGF-I levels decreased in the 30d DM group (182 ± 32% and 45 ± 24% of age-matched controls respectively, p < 0.05). Another group (30d DM + I) was given SC insulin, and its serum IGF-I levels remained decreased. Liver GH receptor (GHR) and GH binding protein (GHBP) mRNA levels, as well as liver membrane GH binding assays were deeply decreased in the 30d DM group in comparison to controls. GHR message and binding capacity remained decreased in the 30d DM + I group. Renal GHR mRNA was decreased at 21d DM but not at 14d DM, whereas GHBP mRNA remained unchanged throughout the experiment. In conclusion, increased serum GH levels are documented in NOD diabetic mice, similarly to the changes described in humans. The decrease in GHR levels and decreased serum IGF-I in spite of increased circulating GH suggest a state of GH resistance. PMID:11469393

  11. Cysteine induces longitudinal bone growth in mice by upregulating IGF-I.

    PubMed

    Moon, Phil-Dong; Kim, Min-Ho; Oh, Hyun-A; Nam, Sun-Young; Han, Na-Ra; Jeong, Hyun-Ja; Kim, Hyung-Min

    2015-08-01

    Cysteine (Cys) is known to exert various effects, such as antioxidant, antipancreatitic and antidiabetic effects. However, the effects of Cys on longitudinal bone growth have not been elucidate to date. Thus, the aim of the present study was to evaluate the effects of Cys on bone growth. Growth-plate thickness and bone parameters, such as bone volume/tissue volume (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), connectivity density (Conn.D) and total porosity were analyzed by means of micro-computed tomography (μCT). The levels of serum insulin-like growth factor-I (IGF-I) were measured by enzyme-linked immunosorbent assay (ELISA). Hepatic IGF-I mRNA expression was analyzed by quantitative polymerase chain reaction (qPCR). The phosphorylation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5) was investigated by western blot analysis. Our results revealed that Cys increased IGF-I mRNA expression in HepG2 cells. The thickness of the growth plates was increased following treatment with Cys. Moreover, BV/TV, Tb.Th, TbN, Conn.D and total porosity were improved following treatment with Cys. Hepatic IGF-I mRNA expression and serum IGF-I levels were increased by Cys. The levels of phosphorylated JAK2 and STAT5 were elevated by Cys. The findings of our study indicate that Cys increases the thickness of growth plates through the upregulation of IGF-I, which results from the phosphorylation of JAK2-STAT5. Thus, our data suggest that Cys may have potential for use as a growth-promoting agent.

  12. Reduction in Aβ-induced cell death in the hippocampus of 17β-estradiol-treated female rats is associated with an increase in IGF-I signaling and somatostatinergic tone.

    PubMed

    Perianes-Cachero, Aránzazu; Canelles, Sandra; Aguado-Llera, David; Frago, Laura M; Toledo-Lobo, María Val; Carrera, Iván; Cacabelos, Ramón; Chowen, Julie A; Argente, Jesús; Arilla-Ferreiro, Eduardo; Barrios, Vicente

    2015-12-01

    Several studies indicate that 17β-estradiol (E2) protects against amyloid β-peptide (Aβ)-induced cell death and activates factors associated with learning and memory, a function involving the hippocampal somatostatinergic system. As alterations in somatostatin have been demonstrated in Alzheimer's disease, we examined whether E2 prevents changes in the hippocampal somatostatinergic system induced by Aβ25-35 and cell death, as well as the possible involvement of leptin and insulin-like growth factor (IGF)-I signaling. We also measured the levels of Aβ proteases neprilysin and insulin-degrading-enzyme. Co-administration of E2 with Aβ25-35 reduced both its levels and cell death, in addition to preventing the Aβ-induced depletion of some somatostatinergic parameters. Activation of leptin and IGF-I pathways increased after E2 co-administration, and this correlated with changes in the somatostatinergic system. Changes in some components of this system were inversely related with Aβ levels and cell death. Moreover, neprilysin levels were increased only in Aβ plus E2-treated rats and E2 prevented the Aβ-induced insulin-degrading-enzyme reduction. Our results suggest that the E2-induced reduction in cell death is related to lower Aβ levels, probably because of IGF-I and somatostatin modulation of Aβ proteases. We asked how 17β-estradiol (E2) protects against β-amyloid (Aβ)-induced cell death. E2 co-administration prevents Aβ-produced depletion of hippocampal somatostatin (SRIF) by an IGF-I-mediated mechanism, being related this protective effect with an increase in Aβ proteases. Our results suggest that the E2-induced reduction in cell death is related to lower Aβ levels, probably because of SRIF modulation of Aβ proteases. CREB, cAMP response element-binding protein; IGF-I, insulin-like growth factor-I; STAT3, signal transducer and activator of transcription-3.

  13. Combined treatment with GH and IGF-I: additive effect on cortical bone mass but not on linear bone growth in female rats.

    PubMed

    Sundström, Katja; Cedervall, Therese; Ohlsson, Claes; Camacho-Hübner, Cecilia; Sävendahl, Lars

    2014-12-01

    The growth-promoting effect of combined therapy with GH and IGF-I in normal rats is not known. We therefore investigated the efficacy of treatment with recombinant human (rh)GH and/or rhIGF-I on longitudinal bone growth and bone mass in intact, prepubertal, female Sprague-Dawley rats. rhGH was injected twice daily sc (5 mg/kg·d) and rhIGF-I continuously infused sc (2.2 or 4.4 mg/kg·d) for 28 days. Longitudinal bone growth was monitored by weekly x-rays of tibiae and nose-anus length measurements, and tibial growth plate histomorphology was analyzed. Bone mass was evaluated by peripheral quantitative computed tomography. In addition, serum levels of IGF-I, rat GH, acid labile subunit, IGF binding protein-3, 150-kDa ternary complex formation, and markers of bone formation and degradation were measured. Monotherapy with rhGH was more effective than rhIGF-I (4.4 mg/kg·d) to increase tibia and nose-anus length, whereas combined therapy did not further increase tibia, or nose-anus, lengths or growth plate height. In contrast, combined rhGH and rhIGF-I (4.4 mg/kg·d) therapy had an additive stimulatory effect on cortical bone mass vs rhGH alone. Combined treatment with rhGH and rhIGF-I resulted in markedly higher serum IGF-I concentrations vs rhGH alone but did not compromise the endogenous secretion of GH. We conclude that rhIGF-I treatment augments cortical bone mass but does not further improve bone growth in rhGH-treated young, intact, female rats.

  14. Role of IGF-I in follistatin-induced skeletal muscle hypertrophy.

    PubMed

    Barbé, Caroline; Kalista, Stéphanie; Loumaye, Audrey; Ritvos, Olli; Lause, Pascale; Ferracin, Benjamin; Thissen, Jean-Paul

    2015-09-15

    Follistatin, a physiological inhibitor of myostatin, induces a dramatic increase in skeletal muscle mass, requiring the type 1 IGF-I receptor/Akt/mTOR pathway. The aim of the present study was to investigate the role of IGF-I and insulin, two ligands of the IGF-I receptor, in the follistatin hypertrophic action on skeletal muscle. In a first step, we showed that follistatin increases muscle mass while being associated with a downregulation of muscle IGF-I expression. In addition, follistatin retained its full hypertrophic effect toward muscle in hypophysectomized animals despite very low concentrations of circulating and muscle IGF-I. Furthermore, follistatin did not increase muscle sensitivity to IGF-I in stimulating phosphorylation of Akt but, surprisingly, decreased it once hypertrophy was present. Taken together, these observations indicate that increased muscle IGF-I production or sensitivity does not contribute to the muscle hypertrophy caused by follistatin. Unlike low IGF-I, low insulin, as obtained by streptozotocin injection, attenuated the hypertrophic action of follistatin on skeletal muscle. Moreover, the full anabolic response to follistatin was restored in this condition by insulin but also by IGF-I infusion. Therefore, follistatin-induced muscle hypertrophy requires the activation of the insulin/IGF-I pathway by either insulin or IGF-I. When insulin or IGF-I alone is missing, follistatin retains its full anabolic effect, but when both are deficient, as in streptozotocin-treated animals, follistatin fails to stimulate muscle growth.

  15. Transcriptional regulation of IGF-I expression in skeletal muscle

    NASA Technical Reports Server (NTRS)

    McCall, G. E.; Allen, D. L.; Haddad, F.; Baldwin, K. M.

    2003-01-01

    The present study investigated the role of transcription in the regulation of insulin-like growth factor (IGF)-I expression in skeletal muscle. RT-PCR was used to determine endogenous expression of IGF-I pre-mRNA and mRNA in control (Con) and functionally overloaded (FO) rat plantaris. The transcriptional activities of five different-length IGF-I promoter fragments controlling transcription of a firefly luciferase (FLuc) reporter gene were tested in vitro by transfection of myoblasts or in vivo during FO by direct gene transfer into the plantaris. Increased endogenous IGF-I gene transcription during 7 days of plantaris FO was evidenced by an approximately 140-160% increase (P < 0.0001) in IGF-I pre-mRNA (a transcriptional marker). IGF-I mRNA expression also increased by approximately 90% (P < 0.0001), and it was correlated (R = 0.93; P < 0.0001) with the pre-mRNA increases. The three longest IGF-I exon 1 promoters induced reporter gene expression in proliferating C2C12 and L6E9 myoblasts. In differentiated L6E9 myotubes, promoter activity increased approximately two- to threefold over myoblasts. Overexpression of calcineurin and MyoD increased the activity of the -852/+192 promoter in C2C12 myotubes by approximately 5- and approximately 18-fold, respectively. However, FO did not induce these exogenous promoter fragments. Nevertheless, the present findings are consistent with the hypothesis that the IGF-I gene is transcriptionally regulated during muscle hypertrophy in vivo as evidenced by the induction of the endogenous IGF-I pre-mRNA during plantaris FO. The exon 1 promoter region of the IGF-I gene is sufficient to direct inducible expression in vitro; however, an in vivo response to FO may require elements outside the -852/+346 region of the exon 1 IGF-I promoter or features inherent to the endogenous IGF-I gene.

  16. Recombinant bovine somatotropin stimulates short term increases in growth rate and insulin-like growth factor I (IGF-I) in chickens.

    PubMed

    Buonomo, F C; Baile, C A

    1988-07-01

    Recombinant bovine somatotropin (rbGH) was administered by subcutaneous injection at daily doses of 0.5 or 2.5 mg/kg for a two week period in female broiler chicks between 4 and 6 weeks of age. Half of the chicks received dietary corticosterone at a 1 ppm level. Growth rate was significantly increased 6.1% and 6.9% following one week of treatment with 0.5 or 2.5 mg/kg rbGH respectively. Treatment with the same respective doses of rbGH in the presence of 1 ppm corticosterone, supplied to suppress any possible immune response elicited by the heterologous somatotropin, resulted in an 8.0% and 7.8% increase (P less than .05) in growth rate during the first week of treatment. The rbGH-associated increase in growth rate was accompanied by a significant increase in food intake, higher circulating levels of IGF-I, and lower plasma T4 concentrations, while plasma T3 levels were unchanged. All effects were attenuated during the second week of treatment, concomitant with the development of high antibody titer against rbGH regardless of dietary corticosterone administration. Carcass parameters relating to bone, muscle and fat were not different between rbGH-treated and control chickens at the end of the two week treatment period. Thus rbGH is capable of stimulating a short-term improvement in growth rate, which is related to increased feed consumption and is of limited duration.

  17. 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.

  18. Thymic epithelial cells of human patients affected by myasthenia gravis overexpress IGF-I immunoreactivity.

    PubMed

    Marinova, Tsvetana T; Kuerten, Stefanie; Petrov, Danail B; Angelov, Doychin N

    2008-01-01

    Accumulating evidence shows that several kinds of thymic cells express insulin-like growth factor-I (IGF-I), which is known to play an important role in T cell ontogeny under both physiological and pathological conditions. Still, little is known about the mechanisms of IGF-I involvement in the pathological transformation of the thymocyte microenvironment. The present study focuses on a comparative analysis of the IGF-I immunoreactivity of thymic epithelial cells (EC) from human patients with hyperplasia-associated myasthenia gravis (MG) versus physiological thymic tissue from healthy controls using immunohistochemistry and immunoelectron microscopy. We show that myasthenic EC overexpress IGF-I in comparison to EC from control subjects. The IGF-I immunoreactivity in the medullary and cortical EC from MG patients was stronger than in the normal gland. The increased expression of IGF-I and more frequent distribution of IGF-I and IGF-I-receptor (IGF-IR) immunopositive EC correlated with modulation in the immunoreactivity of double (IGF-I/IGF-IR) positive EC. Our data provide new immunocytochemial evidence for alterations of IGF-I and IGF-IR immunoreactivity in EC from pathological thymi. The persisting expression of IGF-I and IGF-IR most likely indicates that the myasthenic thymus is still capable of governing IGF-I signaling pathways, which are involved in the local regulation of T cell development and plasticity.

  19. Combined growth hormone (GH) and insulin-like growth factor-I (IGF-I) treatment is more effective than GH or IGF-I alone at enhancing recovery from neonatal malnutrition in rats.

    PubMed

    Zhao, X; Donovan, S M

    1995-11-01

    The effect of hormonal therapy on enhancing recovery from neonatal malnutrition was assessed in rats. Malnutrition was induced by maternal food restriction (60% control intake) during lactation. On d 16 postpartum, restricted pups were refed by cross-fostering to control dams and were subcutaneously administered growth hormone (GH), insulin-like growth factor-I (IGF-I), GH + IGF-I or saline. At d 21, pups were weaned and continued hormonal treatments until d 39 postpartum. By d 39, body weight of GH (96% control) and GH + IGF-I- (98%) treated animals were normal, whereas IGF-I (88%) and saline- (85%) treated animals were still stunted. Hormone effectiveness was age dependent, with growth rates of GH + IGF-I-, IGF-I- and GH-treated pups being greatest between d 16 and 30, d 16 and 21 and after d 30, respectively. Protein accretion by d 39 was higher (P < 0.01) in GH and GH + IGF-I groups than saline- or IGF-I-treated groups. On d 39, serum IGF-I concentrations were as follows: GH + IGF-I > IGF-I > GH = saline (placebo), indicating that an elevated serum IGF-I was not required for GH-stimulated growth. Of the three hormonal treatments, GH + IGF-I therapy was most efficacious at promoting rapid and complete body weight recovery and supporting lean body mass accretion.

  20. IGF-I/IGFBP-3 equilibrates ratios of pro- to anti-inflammatory cytokines, which are predictors for organ function in severely burned pediatric patients.

    PubMed Central

    Jeschke, Marc G.; Barrow, Robert E.; Suzuki, Fujiyo; Rai, Jyoti; Benjamin, Deb; Herndon, David N.

    2002-01-01

    BACKGROUND: We hypothesized that ratios of pro- to anti-inflammatory cytokines can be associated with hepatic, cardiac, and renal function after a severe trauma and can be used as predictors for clinical outcome. Furthermore, insulin-like growth factor-I (IGF-I) in combination with its principle binding protein (IGFBP-3) equilibrates pro- to anti-inflammatory cytokine ratios and improves homeostasis of severely burned pediatric patients. MATERIALS AND METHODS: Seventeen severely burned children were given a continuous infusion of IGF-I/BP-3 for 5 days after wound excision and grafting; seven were given saline during the same time period to serve as controls. Patient demographics and mortality were determined. Five days after excision and grafting, cardiac function was determined and blood samples were taken for serum levels of IGF-I, IGFBP-3, creatinine, pre-albumin, cholinesterase, pro-inflammatory cytokines (IL-1beta, IL-6, and TNF), and anti-inflammatory cytokines (IL-2, IL-4, IL-10 and IFN-gamma). RESULTS: There were no differences between IGF-I/BP-3 and controls in age, gender, burn size, or mortality. Serum IGF-I in burned children given the IGF-I/BP-3 complex increased from 102 + 15 to 433 + 33 microg/ml and IGFBP-3 increased from 1.5 + 0.2 to 3.0 + 0.2 microg/ml (p < 0.05). Serum pre-albumin and cholinesterase increased with IGF-I/BP-3, whereas serum creatinine decreased when compared to controls (p < 0.05). IGF-I/BP-3 increased cardiac index by 16% and stroke volume index by 15% (p < 0.05). These improvements in organ homeostasis were associated with decreased ratios of pro- to anti-inflammatory cytokines in the IGF-I/BP-3 group when compared to controls (p < 0.05). CONCLUSIONS: Increased ratios of pro- to anti-inflammatory cytokines may indicate a higher risk for the incidence of multi-organ failure. We therefore suggest that ratios of pro-inflammatory to anti-inflammatory cytokines can be used to predict organ function. We further conclude that IGF-I

  1. Antidepressant-like behavioral effects of IGF-I produced by enhanced serotonin transmission.

    PubMed

    Hoshaw, Brian A; Hill, Tiffany I; Crowley, James J; Malberg, Jessica E; Khawaja, Xavier; Rosenzweig-Lipson, Sharon; Schechter, Lee E; Lucki, Irwin

    2008-10-10

    Previous research has suggested that mobilization of neurotrophic factors, such as insulin-like growth factor I (IGF-I), can be involved in the effects of antidepressant treatments. The current experiments showed that IGF-I leads to antidepressant-like effects in the modified rat forced swim test when tested 3 days, but not 1 day, after i.c.v. administration. These effects were sustained longer than the antidepressants paroxetine and desipramine. In addition, blockade of the IGF-I receptor with the IGF-I antagonist JB1 30 min before IGF-I administration prevented the antidepressant-like effects of IGF-I. However, when JB1 was administered 3 days after IGF-I administration and 30 min prior to testing, the antidepressant-like effects of IGF-I were still present suggesting that IGF-1 produces a long-term activation of neural systems involved in the antidepressant response. Because the pattern of antidepressant-like effects of IGF-I resembled those of selective serotonin reuptake inhibitors, the role of serotonin in the behavioral effects of IGF-I was studied. Depletion of serotonin, by the tryptophan hydroxylase inhibitor para-chlorophenylalanine, blocked the antidepressant-like effects of IGF-I. Administration of IGF-I increased basal serotonin levels in the ventral hippocampus and altered the effects of acute citalopram. IGF-I administration did not change hippocampal cell proliferation at the 3-day timepoint when behavioral effects were seen. In addition, IGF-I did not alter the expression of mRNA levels of tryptophan hydroxylase or SERT in the brain stem, or [3H] citalopram binding in the hippocampus or cortex. Thus, IGF-I administration initiates a long-lasting cascade of neurochemical effects involving increased serotonin levels that results in antidepressant-like behavioral effects.

  2. IGF-I, GH, and sex steroid effects in normal mammary gland development.

    PubMed

    Kleinberg, David L; Ruan, Weifeng

    2008-12-01

    Although the pubertal surge of estrogen is the immediate stimulus to mammary development, the action of estrogen depends upon the presence of pituitary growth hormone and the ability of GH to stimulate production of IGF-I in the mammary gland. Growth hormone binds to its receptor in the mammary fat pad, after which production of IGF-I mRNA and IGF-I protein occurs. It is likely that IGF-I then works through paracrine means to stimulate formation of TEBs, which then form ducts by bifurcating or trifurcating and extending through the mammary fat pad. By the time pubertal development is complete a tree-like structure of branching ducts fills the rodent mammary fat pad. In addition to requiring IGF-I in order to act, estradiol also directly synergizes with IGF-I to enhance formation of TEBs and ductal morphogenesis. Together they increase IRS-1 phosphorylation and cell proliferation, and inhibit apoptosis. In fact, the entire process of ductal morphogenesis, in oophorectomized IGF-I(-/-) knockout female mice, can occur as a result of the combined actions of estradiol and IGF-I. IGF-I also permits progesterone action in the mammary gland. Together they have been shown to stimulate a form of ductal morphogenesis, which is anatomically different from the kind induced by IGF-I and estradiol. Although both progesterone and estradiol synergize with IGF-I by increasing IGF-I action parameters, there must be other, as yet unknown mechanisms that account for the anatomical differences in the different forms of ductal morphogenesis observed (hyperplasia in response to IGF-I plus estradiol and single layered ducts in response to IGF-I plus progesterone).

  3. An examination of the association of serum IGF-I concentration, potential candidate genes, and fiber type composition with variation in residual feed intake in progeny of Red Angus sires divergent for maintenance energy EPD.

    PubMed

    Welch, C M; Thornton, K J; Murdoch, G K; Chapalamadugu, K C; Schneider, C S; Ahola, J K; Hall, J B; Price, W J; Hill, R A

    2013-12-01

    Investigating the genetic and physiological drivers of postweaning residual feed intake (RFI) and finishing phase feed efficiency (FE) may identify underlying mechanisms that are responsible for the variation in these complex FE traits. The objectives were 1) to evaluate the relationship of serum IGF-I concentration and muscle gene expression with postweaning RFI and sire maintenance energy (MEM) EPD and 2) to determine fiber type composition as it relates to postweaning RFI and finishing phase FE. Results indicate that RFI and serum IGF-I concentration were not associated (P > 0.05); however, negative correlations (P < 0.05) between sire MEM EPD and serum IGF-I concentration were observed. Gene expression differences between high- and low-RFI animals were observed in cohort 1, where IGFBP5 expression was greater (P < 0.05) in high-RFI animals. When animals were grouped according to sire MEM EPD, the low MEM EPD group of cohort 1 showed greater muscle mRNA expression (P < 0.01) of fatty acid synthase (FASN) and marginally (P < 0.10) greater expression of IGFBP5 and C/EBP alpha (C/EBPα) whereas the high MEM EPD group of cohort 2 had greater muscle mRNA expression of IGFBP2 (P < 0.05) and C/EBPα (P ≤ 0.01) and marginally (P < 0.10) greater expression of IGFBP3. Biopsy tissue samples collected at harvest revealed that the percentage of type IIa fibers was lower (P ≤ 0.05) in high-RFI steers, with a similar trend (P < 0.10) being observed in high finishing phase FE steers. The percentage of type IIb fibers was higher (P < 0.05) in high-RFI (and finishing phase FE) steers than in low-RFI (and finishing phase FE) steers. There was a marginal, negative correlation between RFI and type I (r = -0.36, P = 0.08) and IIa (r = -0.37, P = 0.07) fiber percentages and a positive correlation (r = 0.48, P = 0.01) between RFI and type IIb fiber percentage whereas finishing phase FE was negatively correlated (r = -0.43, P = 0.03) with type I fiber percentage and positively

  4. IGF-I abuse in sport: current knowledge and future prospects for detection.

    PubMed

    Guha, Nishan; Sönksen, Peter H; Holt, Richard I G

    2009-08-01

    As the tests for detecting growth hormone (GH) abuse develop further, it is likely that athletes will turn to doping with insulin-like growth factor-I (IGF-I). IGF-I mediates many of the anabolic actions of growth hormone. It stimulates muscle protein synthesis, promotes glycogen storage and enhances lipolysis, all of which make IGF-I attractive as a potential performance-enhancing agent. Pharmaceutical companies have developed commercial preparations of recombinant human IGF-I (rhIGF-I) for use in disorders of growth. The increased availability of rhIGF-I increases the opportunity for athletes to acquire supplies of the drug on the black market. The long-term effects of IGF-I administration are currently unknown but it is likely that these will be similar to the adverse effects of chronic GH abuse. The detection of IGF-I abuse is a challenge for anti-doping organisations. Research has commenced into the development of a test for IGF-I abuse based on the measurement of markers of GH action. Simultaneously, the effects of rhIGF-I on physical fitness, body composition and substrate utilisation in healthy volunteers are being investigated.

  5. Long-Term IGF-I Exposure Decreases Autophagy and Cell Viability

    PubMed Central

    Bitto, Alessandro; Lerner, Chad; Torres, Claudio; Roell, Michaela; Malaguti, Marco; Perez, Viviana; Lorenzini, Antonello; Hrelia, Silvana; Ikeno, Yuji; Matzko, Michelle Elizabeth; McCarter, Roger; Sell, Christian

    2010-01-01

    A reduction in IGF-I signaling has been found to increase lifespan in multiple organisms despite the fact that IGF-I is a trophic factor for many cell types and has been found to have protective effects against multiple forms of damage in acute settings. The increase in longevity seen in response to reduced IGF-I signaling suggests that there may be differences between the acute and chronic impact of IGF-I signaling. We have examined the possibility that long-term stimulation with IGF-I may have a negative impact at the cellular level using quiescent human fibroblasts. We find that fibroblast cells exposed to IGF-I for 14 days have reduced long-term viability as judged by colony forming assays, which is accompanied by an accumulation of senescent cells. In addition we observe an accumulation of cells with depolarized mitochondria and a reduction in autophagy in the long-term IGF-I treated cultures. An examination of mice with reduced IGF-I levels reveals evidence of enhanced autophagy and fibroblast cells derived from these mice have a larger mitochondrial mass relative to controls indicating that changes in mitochondrial turnover occurs in animals with reduced IGF-I. The results indicate that chronic IGF-I stimulation leads to mitochondrial dysfunction and reduced cell viability. PMID:20830296

  6. Plasma GH, IGF-I, and conception rate in cattle treated with low doses of recombinant bovine GH.

    PubMed

    Bilby, C R; Bader, J F; Salfen, B E; Youngquist, R S; Murphy, C N; Garverick, H A; Crooker, B A; Lucy, M C

    1999-05-01

    Blood and uterine concentrations of GH and insulin-like growth factor (IGF)-I are correlated with improved fertility in cattle. We tested incremental doses of a 14-d sustained release recombinant bovine GH (rbGH) to increase blood GH and IGF-I (Experiments 1 and 2). Conception rate after administration of an optimized rbGH dose was also tested (Experiment 3). In Experiment 1, lactating Holstein cows (n = 18) were randomly assigned to receive 0 (n = 5), 100 (n = 5), 200 (n = 5), or 500 (n = 3) mg sc rbGH. Increasing the doses of rbGH was associated with increased serum concentrations of GH and IGF-I. The 100- and 200-mg doses caused an IGF-I release that was below and above, respectively, the perceived optimum response. Therefore, Experiment 2 was designed to test a rbGH dose (167 mg), which was intermediate to the doses tested in Experiment 1. Lactating and nonlactating postpartum beef cows were treated with 0 (n = 9) or 167 (n = 9) mg rbGH at insemination. Plasma concentrations of GH and IGF-I were greater in rbGH-treated cows than in controls. Lactating cows had initial IGF-I concentrations that were lower than nonlactating cows. The 167-mg dose of rbGH increased plasma IGF-I concentrations in lactating cows to the levels of those of nonlactating cows. In Experiment 3, cows and heifers were administered either 0 or 167 mg rbGH at insemination. The conception rate for rbGH-treated and control cows was 54.4 and 49.5% (n = 617), and 46.0 and 46.3% for heifers (n = 1123), respectively. Herd (P<0.01) and parity (P<0.01) affected conception rate, but conception rates for rbGH and control cattle were similar. In summary, low doses of rbGH increased blood GH and restored blood IGF-I concentrations in lactating cows to those of nonlactating cows, but the conception rate in cows and heifers was not affected by administration of 14-d sustained-release rbGH at insemination.

  7. GH/IGF-I axis and matrix adaptation of the musculotendinous tissue to exercise in humans.

    PubMed

    Heinemeier, K M; Mackey, A L; Doessing, S; Hansen, M; Bayer, M L; Nielsen, R H; Herchenhan, A; Malmgaard-Clausen, N M; Kjaer, M

    2012-08-01

    Exercise is not only associated with adaptive responses within skeletal muscle fibers but also with induction of collagen synthesis both in muscle and adjacent connective tissue. Additionally, exercise and training leads to activation of the systemic growth hormone/insulin-like growth factor I axis (GH/IGF-I), as well as increased local IGF-I expression. Studies in humans with pathologically high levels of GH/IGF-I, and in healthy humans who receive either weeks of GH administration or acute injection of IGF-I into connective tissue, demonstrate increased expression and synthesis of collagen in muscle and tendon. These observations support a stimulatory effect of GH/IGF-I on the connective tissue in muscle and tendon, which appears far more potent than the effect on contractile proteins of skeletal muscle. However, GH/IGF-I may play an additional role in skeletal muscle by regulation of stem cells (satellite cells), as increased satellite cell numbers are found in human muscle with increased GH/IGF-I levels, despite no change in myofibrillar protein synthesis. Although advanced age is associated with both a reduction in the GH/IGF-I axis activity, and in skeletal muscle mass (sarcopenia) as well as in tendon connective tissue, there is no direct proof linking age-related changes in the musculotendinous tissue to an impaired GH/IGF-I axis.

  8. IGF-I enhances cellular senescence via the reactive oxygen species-p53 pathway

    SciTech Connect

    Handayaningsih, Anastasia-Evi; Takahashi, Michiko; Fukuoka, Hidenori; Iguchi, Genzo; Nishizawa, Hitoshi; Yamamoto, Masaaki; Suda, Kentaro; Takahashi, Yutaka

    2012-08-24

    Highlights: Black-Right-Pointing-Pointer Cellular senescence plays an important role in tumorigenesis and aging process. Black-Right-Pointing-Pointer We demonstrated IGF-I enhanced cellular senescence in primary confluent cells. Black-Right-Pointing-Pointer IGF-I enhanced cellular senescence in the ROS and p53-dependent manner. Black-Right-Pointing-Pointer These results may explain the underlying mechanisms of IGF-I involvement in tumorigenesis and in regulation of aging. -- Abstract: Cellular senescence is characterized by growth arrest, enlarged and flattened cell morphology, the expression of senescence-associated {beta}-galactosidase (SA-{beta}-gal), and by activation of tumor suppressor networks. Insulin-like growth factor-I (IGF-I) plays a critical role in cellular growth, proliferation, tumorigenesis, and regulation of aging. In the present study, we show that IGF-I enhances cellular senescence in mouse, rat, and human primary cells in the confluent state. IGF-I induced expression of a DNA damage marker, {gamma}H2AX, the increased levels of p53 and p21 proteins, and activated SA-{beta}-gal. In the confluent state, an altered downstream signaling of IGF-I receptor was observed. Treatment with a reactive oxygen species (ROS) scavenger, N-acetylcystein (NAC) significantly suppressed induction of these markers, indicating that ROS are involved in the induction of cellular senescence by IGF-I. In p53-null mouse embryonic fibroblasts, the IGF-I-induced augmentation of SA-{beta}-gal and p21 was inhibited, demonstrating that p53 is required for cellular senescence induced by IGF-I. Thus, these data reveal a novel pathway whereby IGF-I enhances cellular senescence in the ROS and p53-dependent manner and may explain the underlying mechanisms of IGF-I involvement in tumorigenesis and in regulation of aging.

  9. Differential responses of IGF-I molecular complexes to military operational field training.

    PubMed

    Nindl, Bradley C; Castellani, John W; Young, Andrew J; Patton, John F; Khosravi, M Javad; Diamandi, Anastasia; Montain, Scott J

    2003-09-01

    Insulin-like growth factor (IGF) I and IGF binding proteins (IGFBPs) modulate metabolic activity and tissue repair and are influenced by nutritional status. IGF-I circulates in free, ternary [IGF-I + IGFBP-3 + acid labile subunit (ALS)], and binary (IGF-I + IGFBP) molecular complexes, and the relative proportions regulate IGF-I extravascular shifting and bioavailability. This study examined the hypothesis that sustained physical activity and sleep deprivation superimposed on a short-term energy deficit would alter the IGFBP concentrations and alter the proportions of IGF-I circulating in ternary vs. binary molecular complexes. Components of the IGF-I system (total and free IGF-I; IGFBP-1, -3, and ALS; nonternary IGF-I and IGFBP-3), biomarkers of metabolic and nutritional status (transferrin, ferritin, prealbumin, glucose, free fatty acids, glycerol, beta-hydroxybutyrate), and body composition were measured in 12 men (22 +/- 3 yr, 87 +/- 8 kg, 183 +/- 7 cm, 20 +/- 5% body fat) on days 1, 3, and 4 during a control and experimental (Exp) period. During Exp, subjects performed prolonged work (energy expenditure of approximately 4500 kcal/day) with caloric (1600 kcal/day) and sleep (6.2 h total) restriction. IGF-I and IGFBP-3 were measured by immunoassay before and after immunoaffinity depletion of ALS-based complexes (i.e., ternary complex removal). Exp produced losses in body mass (-3.0%), lowered total IGF-I (-24%), free IGF-I (-42%), IGFBP-3 (-6%), nonternary IGF-I (-27%), and IGFBP-3 (-16%), and increased IGFBP-1 (256%). No Exp effects were observed for ALS. No changes were observed in the proportion of IGF-I circulating in free ( approximately 1.2%), ternary ( approximately 87.4%), or nonternary ( approximately 11.4%) molecular complexes. During Exp, glucose concentrations were lower on day 3, but days 1 and 4 were statistically similar. In conclusion, during a short-term energy deficit in young, healthy men, 1). IGF-I system components differentially respond

  10. Assessment of serum IGF-I and ß-hydroxybutyrate concentrations on reproductive performance prior to calving and breeding in young beef cows grazing native range

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Metabolites involved in the metabolic adaptation to negative energy balance may have the potential to regulate timing of reproductive success. Therefore, the objective of this 4-yr study was to determine the association of serum metabolites, cow BW, BCS, and calf performance on conception date in 2...

  11. Effects of Moderate Aerobic Exercise Combined with Caloric Restriction on Circulating Estrogens and IGF-I in Premenopausal Women

    DTIC Science & Technology

    2005-08-01

    in plasma, T3, IGF-I and leptin . Recently, dried blood spot (DBS) sample collection techniques have allowed for endocrine based population studies...partially validated for some hormonal assays, it has not yet been properly validated for T3, IGF-I, and leptin , and it is unclear whether the...6, 8, 10, 12, 14 , 16, 19, 22, & 25): Serum &DBS (FP): IGF-I, IGFBP-1, Insulin, T3, leptin Menses 3-Day Diet Record (FP & LP

  12. 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

  13. Regulation of muscle mass by growth hormone and IGF-I

    PubMed Central

    Velloso, C P

    2008-01-01

    Growth hormone (GH) is widely used as a performance-enhancing drug. One of its best-characterized effects is increasing levels of circulating insulin-like growth factor I (IGF-I), which is primarily of hepatic origin. It also induces synthesis of IGF-I in most non-hepatic tissues. The effects of GH in promoting postnatal body growth are IGF-I dependent, but IGF-I-independent functions are beginning to be elucidated. Although benefits of GH administration have been reported for those who suffer from GH deficiency, there is currently very little evidence to support an anabolic role for supraphysiological levels of systemic GH or IGF-I in skeletal muscle of healthy individuals. There may be other performance-enhancing effects of GH. In contrast, the hypertrophic effects of muscle-specific IGF-I infusion are well documented in animal models and muscle cell culture systems. Studies examining the molecular responses to hypertrophic stimuli in animals and humans frequently cite upregulation of IGF-I messenger RNA or immunoreactivity. The circulatory/systemic (endocrine) and local (autocrine/paracrine) effects of GH and IGF-I may have distinct effects on muscle mass regulation. PMID:18500379

  14. The Effect of Skeletal Unloading on Bone Formation: Role of IGF-I

    NASA Technical Reports Server (NTRS)

    Bikle, D. D.; Kostenuik, P.; Holton, E. M.; Halloran, B. P.

    1999-01-01

    skeletal unloading. We have focussed on the role of IGF- 1 as the local factor mediating the effects of skeletal unloading on bone formation. IGF-I is produced by bone cells and chondrocytes; these cells have receptors for IGF-I, and respond to IGF-I with an increase in proliferation and function (e.g. collagen, and glycosaminoglycan production, respectively). IGF-I production by bone is under hormonal control, principally by GH and PTH, and IGF-I is thought to mediate some if not all of the effects of GH and PTH on bone growth. Thus, systemic changes in hormones such as GH and PTH may still have effects which vary from bone to bone depending on the loading history.

  15. IGF-I redirects doublecortin-positive cell migration in the normal adult rat brain.

    PubMed

    Maucksch, C; McGregor, A L; Yang, M; Gordon, R J; Yang, M; Connor, B

    2013-06-25

    The migration of subventricular zone (SVZ)-derived neural precursor cells through the rostral migratory stream (RMS) to the olfactory bulb is tightly regulated by local micro-environmental cues. Insulin-like Growth Factor-I (IGF-I) can stimulate the migration of several neuronal cell types and acts as a 'departure' factor in the avian SVZ. To establish whether IGF-I can also act as a migratory factor for adult neuronal precursor cells in vivo, in addition to its well established role in precursor cell proliferation and differentiation, we used AAV2-mediated gene transfer to produce ectopic expression of IGF-I in the normal adult rat striatum. We then assessed whether the expression of IGF-I would recruit SVZ-derived neuronal precursor cells from the RMS into the striatum. Ectopic expression of IGF-I in the normal adult rat brain significantly increased the number of doublecortin (Dcx)-positive cells and the extent of their migration into the striatum 4 and 8 weeks after AAV2-IGF-I injection but did not promote neuronal differentiation. In vitro migration assays confirmed that IGF-I is an inducer of migration and directs SVZ-derived adult neuronal precursor cell migration by both chemotaxis and chemokinesis. These results demonstrate that overexpression of IGF-I in the normal adult rat brain can override the normal cues directing precursor cell migration along the RMS and can redirect precursor cell migration into a non-neurogenic region. Enhanced expression of IGF-I following brain injury may therefore act as a diffusible factor mediating precursor cell migration to areas of neuronal cell damage.

  16. GH/IGF-I Transgene Expression on Muscle Homeostasis

    NASA Technical Reports Server (NTRS)

    Schwartz, Robert J.

    1999-01-01

    We propose to test the hypothesis that the growth hormone/ insulin like growth factor-I axis through autocrine/paracrine mechanisms may provide long term muscle homeostasis under conditions of prolonged weightlessness. As a key alternative to hormone replacement therapy, ectopic production of hGH, growth hormone releasing hormone (GHRH), and IGF-I will be studied for its potential on muscle mass impact in transgenic mice under simulated microgravity. Expression of either hGH or IGF-I would provide a chronic source of a growth-promoting protein whose biosynthesis or secretion is shut down in space. Muscle expression of the IGF-I transgene has demonstrated about a 20% increase in hind limb muscle mass over control nontransgenic litter mates. These recent experiments, also establish the utility of hind-limb suspension in mice as a workable model to study atrophy in weight bearing muscles. Thus, transgenic mice will be used in hind-limb suspension models to determine the role of GH/IGF-I on maintenance of muscle mass and whether concentric exercises might act in synergy with hormone treatment. As a means to engineer and ensure long-term protein production that would be workable in humans, gene therapy technology will be used by to monitor muscle mass preservation during hind-limb suspension, after direct intramuscular injection of a genetically engineered muscle-specific vector expressing GHRH. Effects of this gene-based therapy will be assessed in both fast twitch (medial gastrocnemius) and slow twitch muscle (soleus). End-points include muscle size, ultrastructure, fiber type, and contractile function, in normal animals, hind limb suspension, and reambutation.

  17. Regulation of cell proliferation and estrogen synthesis by ovine LH, IGF-I, and EGF in theca interstitial cells of the domestic hen cultured in defined media.

    PubMed

    Onagbesan, O M; Peddie, M J; Williams, J

    1994-05-01

    There is relatively little information on the factors which regulate the proliferation and alterations in the steroidogenic capacity of avian theca cells during follicular maturation. The development of culture conditions for these cells to determine the effects of gonadotrophin (LH) and the growth factors epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I) on DNA synthesis and estrogen production is reported. Cultures were established in serum-supplemented (with fetal calf serum or chicken serum) or ITS+ (insulin, transferrin, and selenium plus additives) supplemented serum-free media. Cell replication occurred throughout the 72-hr culture period as indicated by a linear increase in the DNA content of the culture dishes. Aromatase activity of the cells as defined by conversion of androstenedione to estrogen was best maintained in serum-free medium while sera inhibited this activity. Ovine LH enhanced the aromatase activity of cultured cells from medium and small-sized follicles, while IGF-I and EGF inhibited both basal and LH-stimulated aromatase activity. LH, IGF-I, and EGF all stimulated cell proliferation as reflected by increased DNA. The responses of cells to these peptides varied with the size of the follicle, with the greatest effects on cells from F4/5.

  18. In vivo actions of insulin-like growth factor-I (IGF-I) on brain myelination: studies of IGF-I and IGF binding protein-1 (IGFBP-1) transgenic mice.

    PubMed

    Ye, P; Carson, J; D'Ercole, A J

    1995-11-01

    To study the effects and mechanisms of insulin-like growth factor I (IGF-I) on brain myelination in vivo, the morphology of myelinated axons and the expression of myelin specific protein genes have been examined in transgenic (Tg) mice that overexpress IGF-I and that those ectopically express IGF binding protein-1 (IGFBP-1), a protein that inhibits IGF-I actions when present in molar excess. Our data show that the percentage of myelinated axons and the thickness of myelin sheaths are significantly increased in IGF-I Tg and decreased in the IGFBP-1 mice. Cerebral cortical proteolipid protein (PLP) and myelin basic protein (MBP) mRNAs consistently exhibit approximately 200% increases in IGF-I Tg mice and approximately 50% decreases in IGFBP-1 Tg mice. The percentage of oligodendrocytes labeled with a PLP cRNA probe in the corpus callosum and cerebral cortex also is increased in IGF-I Tg mice and reduced in IGFBP-1 Tg mice, suggesting that IGF-I promotes oligodendrocyte survival and/or proliferation. The alterations in the number of oligodendrocytes, however, can not completely account for the changes in myelin gene expression. These results strongly indicate that IGF-I increases myelination by increasing the number of myelinated axons and the thickness of myelin sheaths, the latter by mechanisms that involve stimulation of the expression of myelin protein genes and increase of oligodendrocyte number.

  19. Increased cardiac alpha-myosin heavy chain in left atria and decreased myocardial insulin-like growth factor (Igf-I) expression accompany low heart rate in hibernating grizzly bears.

    PubMed

    Barrows, N D; Nelson, O L; Robbins, C T; Rourke, B C

    2011-01-01

    Grizzly bears (Ursus arctos horribilis) tolerate extended periods of extremely low heart rate during hibernation without developing congestive heart failure or cardiac chamber dilation. Left ventricular atrophy and decreased left ventricular compliance have been reported in this species during hibernation. We evaluated the myocardial response to significantly reduced heart rate during hibernation by measuring relative myosin heavy-chain (MyHC) isoform expression and expression of a set of genes important to muscle plasticity and mass regulation in the left atria and left ventricles of active and hibernating bears. We supplemented these data with measurements of systolic and diastolic function via echocardiography in unanesthetized grizzly bears. Atrial strain imaging revealed decreased atrial contractility, decreased expansion/reservoir function (increased atrial stiffness), and decreased passive-filling function (increased ventricular stiffness) in hibernating bears. Relative MyHC-α protein expression increased significantly in the atrium during hibernation. The left ventricle expressed 100% MyHC-β protein in both groups. Insulin-like growth factor (IGF-I) mRNA expression was reduced by ∼50% in both chambers during hibernation, consistent with the ventricular atrophy observed in these bears. Interestingly, mRNA expression of the atrophy-related ubiquitin ligases Muscle Atrophy F-box (MAFBx) and Muscle Ring Finger 1 did not increase, nor did expression of myostatin or hypoxia-inducible factor 1α (HIF-1α). We report atrium-specific decreases of 40% and 50%, respectively, in MAFBx and creatine kinase mRNA expression during hibernation. Decreased creatine kinase expression is consistent with lowered energy requirements and could relate to reduced atrial emptying function during hibernation. Taken together with our hemodynamic assessment, these data suggest a potential downregulation of atrial chamber function during hibernation to prevent fatigue and dilation

  20. Administration of growth hormone (GH), but not insulin-like growth factor-I (IGF-I), by continuous infusion can induce the formation of the 150-kilodalton IGF-binding protein-3 complex in GH-deficient rats.

    PubMed

    Gargosky, S E; Tapanainen, P; Rosenfeld, R G

    1994-05-01

    In the adult circulation, 70-90% of the serum insulin-like growth factors (IGFs) are carried by IGF-binding protein-3 (IGFBP-3), which exists as part of a 150-kilodalton (kDa) ternary complex including IGF and an acid-labile subunit (ALS). We have examined the hormonal regulation and molecular distribution of IGFBP-3 in the circulation of a uniquely GH-deficient (GHD) rat model. For 7 days, GHD rats were given GH by either twice daily injections (1 mg/kg) or continuous infusion (2.4 mg/kg.day) or IGF-I by continuous infusion (1.4 mg/kg.day). Each day, weight and feed and water intake were monitored, and on day 7, liver, kidney, spleen, heart, and lung were weighted, and sera were collected. Serum IGF-I was analyzed by immunoassay, and the molecular distribution of the IGFBPs was determined by neutral size-exclusion chromatography combined with Western ligand blot and Western immunoblot. The GHD rats were 40-60% lighter than their normal littermates, and all organs examined were proportionately smaller. Serum IGF-I and IGFBP-3 levels were less than 10% of those in normal rats. Incubation of serum from GHD rats with [125I]IGF-II showed that radiolabel was incorporated only into a 44-kDa IGFBP region that contained the smaller IGFBPs. IGFBP-3 eluted around 60 kDa. No 150-kDa IGFBP region was detected. The administration of GH or IGF-I to GHD rats resulted in significant increases in weight gained, although food and water intake remained unaltered. Weight gain was observed in all three treatments groups. Both GH treatment regimens significantly increased liver, spleen, and lung weight, whereas IGF-I therapy increased spleen, kidney, and heart. Administration of GH twice daily did not increase serum IGF-I or IGFBP-3 concentrations, and the molecular distribution of IGFBP-3 remained unchanged. In contrast, continuous infusion of GH resulted in 5-fold increases in serum IGF-I and increases in IGFBP-3 levels. Size-exclusion chromatography combined with Western ligand blot

  1. Insulin and insulin-like growth factor-I (IGF-I) receptor phosphorylation in µ-calpain knockout mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Numerous cellular processes are controlled by insulin and IGF-I signaling pathways. Due to previous work in our laboratories, we hypothesized that insulin (IR) and type 1 IGF-I (IGF-IR) receptor signaling is decreased due to increased protein tyrosine phosphatase 1B (PTP1B) activity. C57BL/6J mice...

  2. Concentrations of IGF-I and IGFBP-3 and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition

    PubMed Central

    Rohrmann, S; Grote, V A; Becker, S; Rinaldi, S; Tjønneland, A; Roswall, N; Grønbæk, H; Overvad, K; Boutron-Ruault, M C; Clavel-Chapelon, F; Racine, A; Teucher, B; Boeing, H; Drogan, D; Dilis, V; Lagiou, P; Trichopoulou, A; Palli, D; Tagliabue, G; Tumino, R; Vineis, P; Mattiello, A; Rodríguez, L; Duell, E J; Molina-Montes, E; Dorronsoro, M; Huerta, J-M; Ardanaz, E; Jeurnink, S; Peeters, P H M; Lindkvist, B; Johansen, D; Sund, M; Ye, W; Khaw, K-T; Wareham, N J; Allen, N E; Crowe, F L; Fedirko, V; Jenab, M; Michaud, D S; Norat, T; Riboli, E; Bueno-de-Mesquita, H B; Kaaks, R

    2012-01-01

    Background: Insulin-like growth factors (IGFs) and their binding proteins (BPs) regulate cell differentiation, proliferation and apoptosis, and may have a role in the aetiology of various cancers. Information on their role in pancreatic cancer is limited and was examined here in a case–control study nested within the European Prospective Investigation into Cancer and Nutrition. Methods: Serum concentrations of IGF-I and IGFBP-3 were measured using enzyme-linked immunosorbent assays in 422 cases and 422 controls matched on age, sex, study centre, recruitment date, and time since last meal. Conditional logistic regression was used to compute odds ratios (OR) and 95% confidence intervals (CI) adjusted for confounding variables. Results: Neither circulating levels of IGF-I (OR=1.21, 95% CI 0.75–1.93 for top vs bottom quartile, P-trend 0.301), IGFBP-3 (OR=1.00, 95% CI 0.66–1.51, P-trend 0.79), nor the molar IGF-I/IGFBP-3 ratio, an indicator of free IGF-I level (OR=1.22, 95% CI 0.75–1.97, P-trend 0.27), were statistically significantly associated with the risk of pancreatic cancer. In a cross-classification, however, a high concentration of IGF-I with concurrently low levels of IGFBP-3 was related to an increased risk of pancreatic cancer (OR=1.72, 95% CI 1.05–2.83; P-interaction=0.154). Conclusion: On the basis of these results, circulating levels of components of the IGF axis do not appear to be the risk factors for pancreatic cancer. However, on the basis of the results of a subanalysis, it cannot be excluded that a relatively large amount of IGF-1 together with very low levels of IGFBP-3 might still be associated with an increase in pancreatic cancer risk. PMID:22315049

  3. IGF-I and IGF-I receptor polymorphisms among elite swimmers.

    PubMed

    Ben Zaken, Sigal; Meckel, Yoav; Dror, Nitzan; Nemet, Dan; Eliakim, Alon

    2014-11-01

    In recent years several genetic polymorphisms related to the GH-IGF-I axis were suggested to promote athletic excellence in endurance and power sports. We studied the presence of the C-1245T SNP (rs35767), a nucleotide substitution in the promoter region of the IGF-I gene, and the presence of the 275124A > C SNP (rs1464430), a common nucleotide substitution in the intron region of the IGF-I receptor (IGF-IR) gene in elite long and short-distance swimmers compared with nonphysically active controls. The rare T/T IGF-I polymorphism was found only in 5.3% of the long-distance swimmers, and was not found at all in the short-distance swimmers or among the control group participants. The prevalence of the IGF-I receptor AA genotype was significantly lower in the swimming group as a whole (35%) compared with the control group (46%), in particularly due to reduced frequency of the AA genotype among short-distance swimmers (26%). In contrast to previous reports in elite endurance and power track and field athletes, single nucleotide polymorphisms of the IGF-I and the IGF-IR were not frequent among elite Israeli short- and long-distance swimmers emphasizing the importance of other factors for excellence in swimming. The results also suggest that despite seemingly similar metabolic characteristics different sports disciplines may have different genetic polymorphisms. Thus, combining different disciplines for sports genetic research purposes should be done with extreme caution.

  4. Localized infusion of IGF-I results in skeletal muscle hypertrophy in rats

    NASA Technical Reports Server (NTRS)

    Adams, G. R.; McCue, S. A.

    1998-01-01

    Insulin-like growth factor I (IGF-I) peptide levels have been shown to increase in overloaded skeletal muscles (G. R. Adams and F. Haddad. J. Appl. Physiol. 81: 2509-2516, 1996). In that study, the increase in IGF-I was found to precede measurable increases in muscle protein and was correlated with an increase in muscle DNA content. The present study was undertaken to test the hypothesis that direct IGF-I infusion would result in an increase in muscle DNA as well as in various measurements of muscle size. Either 0.9% saline or nonsystemic doses of IGF-I were infused directly into a non-weight-bearing muscle of rats, the tibialis anterior (TA), via a fenestrated catheter attached to a subcutaneous miniosmotic pump. Saline infusion had no effect on the mass, protein content, or DNA content of TA muscles. Local IGF-I infusion had no effect on body or heart weight. The absolute weight of the infused TA muscles was approximately 9% greater (P < 0.05) than that of the contralateral TA muscles. IGF-I infusion resulted in significant increases in the total protein and DNA content of TA muscles (P < 0.05). As a result of these coordinated changes, the DNA-to-protein ratio of the hypertrophied TA was similar to that of the contralateral muscles. These results suggest that IGF-I may be acting to directly stimulate processes such as protein synthesis and satellite cell proliferation, which result in skeletal muscle hypertrophy.

  5. Elevated GH/IGF-I promotes mammary tumors in high-fat, but not low-fat, fed mice.

    PubMed

    Gahete, Manuel D; Córdoba-Chacón, José; Lantvit, Daniel D; Ortega-Salas, Rosa; Sanchez-Sanchez, Rafael; Pérez-Jiménez, Francisco; López-Miranda, José; Swanson, Steven M; Castaño, Justo P; Luque, Raúl M; Kineman, Rhonda D

    2014-11-01

    Growth hormone (GH) and/or insulin-like growth factor I (IGF-I) are thought to promote breast cancer based on reports showing circulating IGF-I levels correlate, in epidemiological studies, with breast cancer risk. Also, mouse models with developmental GH/IGF-I deficiency/resistance are less susceptible to genetic- or chemical-induced mammary tumorigenesis. However, given the metabolic properties of GH, medical strategies have been considered to raise GH to improve body composition and metabolic function in elderly and obese patients. Since hyperlipidemia, inflammation, insulin resistance and obesity increase breast cancer risk, elevating GH may serve to exacerbate cancer progression. To better understand the role GH/IGF-I plays in tumor formation, this study used unique mouse models to determine if reducing GH/IGF-I in adults protects against 7,12-dimethylbenz[α]anthracene (DMBA)-induced mammary tumor development, and if moderate elevations in endogenous GH/IGF-I alter DMBA-induced tumorigenesis in mice fed a standard-chow diet or in mice with altered metabolic function due to high-fat feeding. We observed that adult-onset isolated GH-deficient mice, which also have reduced IGF-I levels, were less susceptible to DMBA-treatment. Specifically, fewer adult-onset isolated GH-deficient mice developed mammary tumors compared with GH-replete controls. In contrast, chow-fed mice with elevated endogenous GH/IGF-I (HiGH mice) were not more susceptible to DMBA-treatment. However, high-fat-fed, HiGH mice showed reduced tumor latency and increased tumor incidence compared with diet-matched controls. These results further support a role of GH/IGF-I in regulating mammary tumorigenesis but suggest the ultimate consequences of GH/IGF-I on breast tumor development are dependent on the diet and/or metabolic status.

  6. Elevated GH/IGF-I promotes mammary tumors in high-fat, but not low-fat, fed mice

    PubMed Central

    Gahete, Manuel D.; Córdoba-Chacón, José; Lantvit, Daniel D.; Ortega-Salas, Rosa; Sanchez-Sanchez, Rafael; Pérez-Jiménez, Francisco; López-Miranda, José; Swanson, Steven M.; Castaño, Justo P.; Luque, Raúl M.; Kineman, Rhonda D.

    2014-01-01

    Growth hormone (GH) and/or insulin-like growth factor I (IGF-I) are thought to promote breast cancer based on reports showing circulating IGF-I levels correlate, in epidemiological studies, with breast cancer risk. Also, mouse models with developmental GH/IGF-I deficiency/resistance are less susceptible to genetic- or chemical-induced mammary tumorigenesis. However, given the metabolic properties of GH, medical strategies have been considered to raise GH to improve body composition and metabolic function in elderly and obese patients. Since hyperlipidemia, inflammation, insulin resistance and obesity increase breast cancer risk, elevating GH may serve to exacerbate cancer progression. To better understand the role GH/IGF-I plays in tumor formation, this study used unique mouse models to determine if reducing GH/IGF-I in adults protects against 7,12-dimethylbenz[α]anthracene (DMBA)-induced mammary tumor development, and if moderate elevations in endogenous GH/IGF-I alter DMBA-induced tumorigenesis in mice fed a standard-chow diet or in mice with altered metabolic function due to high-fat feeding. We observed that adult-onset isolated GH-deficient mice, which also have reduced IGF-I levels, were less susceptible to DMBA-treatment. Specifically, fewer adult-onset isolated GH-deficient mice developed mammary tumors compared with GH-replete controls. In contrast, chow-fed mice with elevated endogenous GH/IGF-I (HiGH mice) were not more susceptible to DMBA-treatment. However, high-fat-fed, HiGH mice showed reduced tumor latency and increased tumor incidence compared with diet-matched controls. These results further support a role of GH/IGF-I in regulating mammary tumorigenesis but suggest the ultimate consequences of GH/IGF-I on breast tumor development are dependent on the diet and/or metabolic status. PMID:25085903

  7. Accelerated Telomere Shortening in Acromegaly; IGF-I Induces Telomere Shortening and Cellular Senescence

    PubMed Central

    Matsumoto, Ryusaku; Fukuoka, Hidenori; Iguchi, Genzo; Odake, Yukiko; Yoshida, Kenichi; Bando, Hironori; Suda, Kentaro; Nishizawa, Hitoshi; Takahashi, Michiko; Yamada, Shozo; Ogawa, Wataru; Takahashi, Yutaka

    2015-01-01

    Objective Patients with acromegaly exhibit reduced life expectancy and increased prevalence of age-related diseases, such as diabetes, hypertension, and cardiovascular disease. However, the underlying mechanism has not been fully elucidated. Telomere shortening is reportedly associated with reduced life expectancy and increased prevalence of these age-related diseases. Methods We measured telomere length in patients with acromegaly using quantitative PCR method. The effect of GH and IGF-I on telomere length and cellular senescence was examined in human skin fibroblasts. Results Patients with acromegaly exhibited shorter telomere length than age-, sex-, smoking-, and diabetes-matched control patients with non-functioning pituitary adenoma (0.62 ± 0.23 vs. 0.75 ± 0.35, respectively, P = 0.047). In addition, telomere length in acromegaly was negatively correlated with the disease duration (R2 = 0.210, P = 0.003). In vitro analysis revealed that not GH but IGF-I induced telomere shortening in human skin fibroblasts. Furthermore, IGF-I-treated cells showed increased senescence-associated β-galactosidase activity and expression of p53 and p21 protein. IGF-I-treated cells reached the Hayflick limit earlier than GH- or vehicle-treated cells, indicating that IGF-I induces cellular senescence. Conclusion Shortened telomeres in acromegaly and cellular senescence induced by IGF-I can explain, in part, the underlying mechanisms by which acromegaly exhibits an increased morbidity and mortality in association with the excess secretion of IGF-I. PMID:26448623

  8. Development and validation of a radioimmunoassay for fish insulin-like growth factor I (IGF-I) and the effect of aquaculture related stressors on circulating IGF-I levels.

    PubMed

    Dyer, Anthony R; Upton, Zee; Stone, David; Thomas, Philip M; Soole, Kathleen L; Higgs, Naomi; Quinn, Kirsty; Carragher, John F

    2004-02-01

    This paper describes the development and validation of a commercially available radioimmunoassay (RIA) for the detection of fish insulin-like growth factor-I (IGF-I). The assay was developed using recombinant barramundi IGF-I as antigen and recombinant tuna IGF-I as radiolabelled tracer and standard. Assay sensitivity was 0.15 ng/ml, inter-assay variation was 16% (n = 9) and intra-assay variation was 3% (n = 10). Cross reactivity of less than 0.01% was found with salmon insulin, salmon IGF-II and barramundi IGF-II, less than 0.5% with human IGF-I and less than 1% with human IGF-II. Parallel dose-response inhibition curves were shown for barramundi (Lates calcarifer), coho salmon (Oncorhynchus kisutch), Southern Bluefin tuna (Thunnus maccoyii), tilapia (Oreochromis mossambicus), and seabream (Pagrus auratus) IGF-I. The assay was then used to measure stress related changes in different aquacultured fish species. Salt water acclimated Atlantic salmon smolts (Salmo salar) bathed for 2 h in fresh water showed significantly lower IGF-I concentrations than control smolts two days after the bath (53.1 compared to 32.1 ng/ml), with levels of IGF-I also lower in smolts exhibiting stunted growth (stunts). Capture and confinement of wild tuna in sea-cages resulted in a significant decrease in IGF-I levels (28 ng/ml) when compared to tuna captured and sampled immediately (48 ng/ml), but had recovered to starting levels after 3 weeks (43 ng/ml). Handling and isolation in silver perch (Bidyanus bidyanus) led to a gradual decline in IGF-I over a 12 h period (36-19 ng/ml) but showed signs of recovery by 24 h (24 ng/ml) and had recovered fully 72 h after treatment (40 ng/ml). A similar trial in black bream (Acanthopagrus butcherii) showed comparable results with IGF-I levels gradually decreasing (40-26 ng/ml) over 24 h, results that were mirrored by cortisol concentrations which increased during this time (1-26 ng/ml). In the studies presented here changes in IGF-I levels were not

  9. Coordinate expression of IGF-I and its receptor during limb outgrowth.

    PubMed

    Geduspan, J S; Padanilam, B J; Solursh, M

    1992-09-01

    The morphogenetic mechanisms involved in shaping the embyro are largely unknown. Previous studies from this laboratory suggest that the mesonephros promotes limb outgrowth in ovo in the chicken embryo and might be involved in early limb morphogenesis, since damage to the mesonephros results in truncated limbs. In limb bud organ cultures, the presence of the mesonephros promotes cartilage formation. This effect can be reproduced by exogenous IGF-I or prevented by blocking antibody to IGF-I. In order to examine the hypothesis that mesonephros-derived IGF-I is involved in the early morphogenesis of the limb, we examined the spatial and temporal expression of IGF-I and type I receptor for IGF by in situ hybridization at stages when the onset of limb development occurs. The results show that neither transcript is detected at stage 13, prior to the appearance of the limb bud; but both transcripts are detected in the mesonephros at stage 14, an early stage in limb outgrowth. The hybridization signal in the mesonephros for both transcripts increases with development and signal was codistributed as well. At stage 18 the level of receptor transcripts detected in the flank relative to the limb decreased. Thus, the temporal and spatial patterns of expression of IGF-I and its receptor are consistent with their involvement in the initiation of limb outgrowth and support the model that localized expression of a growth factor and its receptor can be involved in shaping the embryo.

  10. Subcutaneous administration of rhIGF-I post irradiation exposure enhances hematopoietic recovery and survival in BALB/c mice

    PubMed Central

    Chen, Shilei; Xu, Yang; Wang, Song; Shen, Mingqiang; Chen, Fang; Chen, Mo; Wang, Aiping; Cheng, Tianmin; Su, Yongping; Wang, Junping

    2012-01-01

    It is unclear how to effectively mitigate against irradiation injury. In this study, we studied the capacity of recombinant human insulin-like growth factor-I (rhIGF-I) on hematologic recovery in irradiated BALB/c mice and its possible mechanism. BALB/c mice were injected with rhIGF-I subcutaneously at a dose of 100 μg/kg twice daily for 7 days after total body irradiation. Compared with a saline control group, treatment with rhIGF-I significantly improved the survival of mice after lethal irradiation (7.5 Gy). It was found that treatment with rhIGF-I not only could increase the frequency of Sca-1+ cells in bone marrow harvested at Day 14 after irradiation, but also it could decrease the apoptosis of mononuclear cells induced by irradiation as measured by flow cytometry, suggesting that rhIGF-I may mediate its effects primarily through promoting hematopoietic stem cell/progenitor survival and protecting mononuclear cells from apoptosis after irradiation exposure. Moreover, we have found that rhIGF-I might facilitate thrombopoiesis in an indirect way. Our data demonstrated that rhIGF-I could promote overall hematopoietic recovery after ionizing radiation and reduce the mortality when administered immediately post lethal irradiation exposure. PMID:22843623

  11. IGF-I activity may be a key determinant of stroke risk--a cautionary lesson for vegans.

    PubMed

    McCarty, M F

    2003-09-01

    IGF-I acts on vascular endothelium to activate nitric oxide synthase, thereby promoting vascular health; there is reason to believe that this protection is especially crucial to the cerebral vasculature, helping to ward off thrombotic strokes. IGF-I may also promote the structural integrity of cerebral arteries, thereby offering protection from hemorrhagic stroke. These considerations may help to explain why tallness is associated with low stroke risk, whereas growth hormone deficiency increases stroke risk--and why age-adjusted stroke mortality has been exceptionally high in rural Asians eating quasi-vegan diets, but has been declining steadily in Asia as diets have become progressively higher in animal products. There is good reason to suspect that low-fat vegan diets tend to down-regulate systemic IGF-I activity; this effect would be expected to increase stroke risk in vegans. Furthermore, epidemiology suggests that low serum cholesterol, and possibly also a low dietary intake of saturated fat--both characteristic of those adopting low-fat vegan diets--may also increase stroke risk. Vegans are thus well advised to adopt practical countermeasures to minimize stroke risk--the most definitive of which may be salt restriction. A high potassium intake, aerobic exercise training, whole grains, moderate alcohol consumption, low-dose aspirin, statin or policosanol therapy, green tea, and supplementation with fish oil, taurine, arginine, and B vitamins--as well as pharmacotherapy of hypertension if warranted--are other practical measures for lowering stroke risk. Although low-fat vegan diets may markedly reduce risk for coronary disease, diabetes, and many common types of cancer, an increased risk for stroke may represent an 'Achilles heel'. Nonetheless, vegans have the potential to achieve a truly exceptional 'healthspan' if they face this problem forthrightly by restricting salt intake and taking other practical measures that promote cerebrovascular health.

  12. A low-fat, whole-food vegan diet, as well as other strategies that down-regulate IGF-I activity, may slow the human aging process.

    PubMed

    McCarty, Mark F

    2003-06-01

    A considerable amount of evidence is consistent with the proposition that systemic IGF-I activity acts as pacesetter in the aging process. A reduction in IGF-I activity is the common characteristic of rodents whose maximal lifespan has been increased by a wide range of genetic or dietary measures, including caloric restriction. The lifespans of breeds of dogs and strains of rats tend to be inversely proportional to their mature weight and IGF-I levels. The link between IGF-I and aging appears to be evolutionarily conserved; in worms and flies, lifespan is increased by reduction-of-function mutations in signaling intermediates homologous to those which mediate insulin/IGF-I activity in mammals. The fact that an increase in IGF-I activity plays a key role in the induction of sexual maturity, is consistent with a broader role for-IGF-I in aging regulation. If down-regulation of IGF-I activity could indeed slow aging in humans, a range of practical measures for achieving this may be at hand. These include a low-fat, whole-food, vegan diet, exercise training, soluble fiber, insulin sensitizers, appetite suppressants, and agents such as flax lignans, oral estrogen, or tamoxifen that decrease hepatic synthesis of IGF-I. Many of these measures would also be expected to decrease risk for common age-related diseases. Regimens combining several of these approaches might have a sufficient impact on IGF-I activity to achieve a useful retardation of the aging process. However, in light of the fact that IGF-I promotes endothelial production of nitric oxide and may be of especial importance to cerebrovascular health, additional measures for stroke prevention-most notably salt restriction-may be advisable when attempting to down-regulate IGF-I activity as a pro-longevity strategy.

  13. Exogenous GLP-2 and IGF-I induce a differential intestinal response in IGF binding protein-3 and -5 double knockout mice

    PubMed Central

    Murali, Sangita G.; Brinkman, Adam S.; Solverson, Patrick; Pun, Wing; Pintar, John E.

    2012-01-01

    Glucagon-like peptide-2 (GLP-2) action is dependent on intestinal expression of IGF-I, and IGF-I action is modulated by IGF binding proteins (IGFBP). Our objective was to evaluate whether the intestinal response to GLP-2 or IGF-I is dependent on expression of IGFBP-3 and -5. Male, adult mice in six treatment groups, three wild-type (WT) and three double IGFBP-3/-5 knockout (KO), received twice daily intraperitoneal injections of GLP-2 (0.5 μg/g body wt), IGF-I (4 μg/g body wt), or PBS (vehicle) for 7 days. IGFBP-3/-5 KO mice showed a phenotype of lower plasma IGF-I concentration, but greater body weight and relative mass of visceral organs, compared with WT mice (P < 0.001). WT mice showed jejunal growth with either IGF-I or GLP-2 treatment. In KO mice, IGF-I did not stimulate jejunal growth, crypt mitosis, sucrase activity, and IGF-I receptor (IGF-IR) expression, suggesting that the intestinotrophic actions of IGF-I are dependent on expression of IGFBP-3 and -5. In KO mice, GLP-2 induced significant increases in jejunal mucosal cellularity, crypt mitosis, villus height, and crypt depth that was associated with increased expression of the ErbB ligand epiregulin and decreased expression of IGF-I and IGF-IR. This suggests that in KO mice, GLP-2 action in jejunal mucosa is independent of the IGF-I system and linked with ErbB ligands. In summary, the intestinotrophic actions of IGF-I, but not GLP-2, in mucosa are dependent on IGFBP-3 and -5. These findings support the role of multiple downstream mediators for the mucosal growth induced by GLP-2. PMID:22281475

  14. The effects of recombinant bovine somatotropin (rbST) on tissue IGF-I, IGF-I receptor, and GH mRNA levels in rainbow trout, Oncorhynchus mykiss.

    PubMed

    Biga, Peggy R; Schelling, Gerald T; Hardy, Ronald W; Cain, Kenneth D; Overturf, Kenneth; Ott, Troy L

    2004-02-01

    Numerous studies demonstrated that rbST increased growth rates in several fish species, and several species exhibit GH production in tissues other than the pituitary. The role of tissue GH and IGF-I in regulating fish growth is poorly understood. Therefore an experiment was conducted to examine the effects of rbST treatment on tissue GH, IGF-I, and IGF-I receptor-A (rA) expression in rainbow trout. Rainbow trout (550 +/- 10 g) received either intra-peritoneal injections of rbST (120 microg/g body weight) or vehicle on days 0 and 21, and tissue samples were collected on days 0, 0.5, 1, 3, 7, and 28 (n = 6/day/trt). Total RNA was isolated and assayed for steady-state levels of IGF-I, IGF-IrA, and GH mRNA using quantitative RT-PCR. Insulin-like growth factor-I mRNA levels increased in liver, gill, gonad, muscle, brain, and intestine in response to rbST treatment (P < 0.10). Liver IGF-I mRNA increased (P < 0.01) 0.5 day after treatment and remained elevated throughout the trial. Intestine IGF-I mRNA increased (P < 0.05) in treated fish from day 1 to day 3, then decreased to day 7 and increased again at day 28, and remained elevated above control levels throughout the trial. Gill IGF-I mRNA levels increased (P < 0.05) 1 day after treatment and remained elevated throughout the trial. Heart IGF-IrA mRNA levels decreased (P < 0.05) while gonad GH mRNA levels increased (P < 0.10) following rbST treatment. These results demonstrate that rbST treatment increased IGF-I mRNA levels in extra-hepatic tissues, and decreased heart IGF-IrA and increased gonad GH mRNA levels. Because the primary source for endocrine IGF-I is liver, the increased IGF-I mRNA reported in extra-hepatic tissues may indicate local paracrine/autocrine actions for IGF-I for local physiological functions.

  15. Phex cDNA cloning from rat bone and studies on phex mRNA expression: tissue-specificity, age-dependency, and regulation by insulin-like growth factor (IGF) I in vivo.

    PubMed

    Zoidis, E; Zapf, J; Schmid, C

    2000-10-25

    Phosphate regulating gene with homology to endopeptidases on the X chromosome (Phex) inactivating mutations cause X-linked hypophosphatemia (XLH). The disorder is characterized by decreased renal phosphate (Pi) reabsorption in both humans and mice, in the latter shown to be due to a reduction in mRNA and protein of type II sodium-dependent phosphate cotransporter (NadPi-II). To gain insight into the physiological role of Phex, we cloned the rat cDNA and examined tissue-specific and age-dependent mRNA expression. The rat full-length cDNA (2247 nucleotides) shares 96 and 90% identity with the mouse and human cDNA, respectively. We found 6.6 kb Phex transcripts in calvarial bone and lungs, and a weaker signal in liver of newborn rats. In adult animals, Phex mRNA signals were weaker in bone and lungs and absent in liver. Phex mRNA expression in bones and NadPi-I and -II cotransporter mRNA expression in kidney were also determined in hypophysectomized rats. These rats, which lack GH and IGF I, stop growing and exhibit decreased serum Pi levels. Treatment during 6 days with IGF I stimulated growth and increased serum Pi. Phex and NadPi-II cotransporter mRNA levels were higher in IGF I than in vehicle-treated animals, while mRNA expression of NadPi-I, 1alpha-hydroxylase and 24-hydroxylase and serum levels of calcitriol remained unaffected. Age-dependency of Phex expression suggests a role for Phex in Pi retention during growth. Moreover, our findings indicate that an increase in Phex expression in bones under the influence of IGF I may contribute to increased serum Pi by enhancing renal phosphate reabsorption. Because IGF I treatment increased NadPi-II mRNA expression and serum Pi, IGF I appears to act at least partially at pretranslational levels to increase NadPi-II mediated renal Pi retention in growing rats.

  16. Maintenance of myonuclear domain size in rat soleus after overload and growth hormone/IGF-I treatment

    NASA Technical Reports Server (NTRS)

    McCall, G. E.; Allen, D. L.; Linderman, J. K.; Grindeland, R. E.; Roy, R. R.; Mukku, V. R.; Edgerton, V. R.

    1998-01-01

    The purpose of this study was to determine the effects of functional overload (FO) combined with growth hormone/insulin-like growth factor I (GH/IGF-I) administration on myonuclear number and domain size in rat soleus muscle fibers. Adult female rats underwent bilateral ablation of the plantaris and gastrocnemius muscles and, after 7 days of recovery, were injected three times daily for 14 days with GH/IGF-I (1 mg/kg each; FO + GH/IGF-I group) or saline vehicle (FO group). Intact rats receiving saline vehicle served as controls (Con group). Muscle wet weight was 32% greater in the FO than in the Con group: 162 +/- 8 vs. 123 +/- 16 mg. Muscle weight in the FO + GH/IGF-I group (196 +/- 14 mg) was 59 and 21% larger than in the Con and FO groups, respectively. Mean soleus fiber cross-sectional area of the FO + GH/IGF-I group (2,826 +/- 445 microm2) was increased compared with the Con (2,044 +/- 108 microm2) and FO (2,267 +/- 301 microm2) groups. The difference in fiber size between the FO and Con groups was not significant. Mean myonuclear number increased in FO (187 +/- 15 myonuclei/mm) and FO + GH/IGF-I (217 +/- 23 myonuclei/mm) rats compared with Con (155 +/- 12 myonuclei/mm) rats, although the difference between FO and FO + GH/IGF-I animals was not significant. The mean cytoplasmic volume per myonucleus (myonuclear domain) was similar across groups. These results demonstrate that the larger mean muscle weight and fiber cross-sectional area occurred when FO was combined with GH/IGF-I administration and that myonuclear number increased concomitantly with fiber volume. Thus there appears to be some mechanism(s) that maintains the myonuclear domain when a fiber hypertrophies.

  17. Insulin-like growth factor (IGF)-I and -II and IGF-binding proteins-1, -2, and -3 in children and adolescents with diabetes mellitus: correlation with metabolic control and height attainment.

    PubMed

    Strasser-Vogel, B; Blum, W F; Past, R; Kessler, U; Hoeflich, A; Meiler, B; Kiess, W

    1995-04-01

    The putative effects of diabetes and metabolic control on circulating levels of insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) remain controversial. In the present study, serum levels of IGF-I and IGF-II and IGFBP-1, -2, and -3 were measured in 58 patients (age, 0.8-17 yr) with treated (51 subjects) or untreated (7 subjects) insulin-dependent diabetes mellitus (IDDM) and were compared with the levels in normal subjects. In the untreated patients IGF-I and IGF-II were decreased as compared with the healthy controls. In the treated diabetics IGF-I and IGF-II were reduced; IGFBP-2 (only in prepubertal subjects) and IGFBP-3 were increased. Furthermore, age-adjusted values of IGF-I, IGF-II, and IGFBP-3 were lower in prepubertal than in pubertal patients. Regression analysis revealed a negative correlation between hemoglobin (Hb)A1c and standard deviation scores (SDS) of IGF-I and a positive association between HbA1c and IGFBP-1 SDS or IGFBP-2 SDS. In the treated patients HbA1c was positively related to IGFBP-1 SDS and IGFBP-2 SDS when applying simple regression analysis and to IGFBP-2 SDS when using a multiple regression model. Strong correlations were observed between height SDS and IGF-I SDS, IGF-II SDS, and IGFBP-3 SDS in prepubertal subjects who had had IDDM for at least 2 yr, but not in adolescents. Such correlations have also been found in healthy children and adolescents. In conclusion; 1) IDDM is associated with alterations of the IGF-IGFBP system, which are partially accounted for by differences in metabolic control and pubertal status; 2) the lower plasma concentrations of serum IGF-I may play a role in the pathogenesis of growth impairment of poorly controlled prepubertal, but not pubertal, children and adolescents with IDDM; and 3) in addition, a potential role of the altered IGF-IGFBP system for the development of diabetic late complications is hypothesized.

  18. Mechanical properties and structure-function relationships in articular cartilage repaired using IGF-I gene-enhanced chondrocytes.

    PubMed

    Griffin, Darvin J; Ortved, Kyla F; Nixon, Alan J; Bonassar, Lawrence J

    2016-01-01

    Several studies have demonstrated the benefits of IGF-I gene therapy in enhancing the histologic and biochemical content of cartilage repaired by chondrocyte transplantation. However, there is little to no data on the mechanical performance of IGF-I augmented cartilage grafts. This study evaluated the compressive properties of full-thickness chondral defects in the equine femur repaired with and without IGF-I gene therapy. Animals were randomly assigned to one of three study cohorts based on chondrocyte treatment provided in each defect: (i) IGF-I gene delivered by recombinant adeno-associated virus (rAAV)-5; (ii) AAV-5 delivering GFP as a reporter; (iii) naïve cells without virus. In each case, the opposite limb was implanted with a fibrin carrier without cells. Samples were prepared for confined compression testing to measure the aggregate modulus and hydraulic permeability. All treatment groups, regardless of cell content or transduction, had mechanical properties inferior to native cartilage. Overexpression of IGF-I increased modulus and lowered permeability relative to other treatments. Investigation of structure-property relationships revealed that Ha and k were linearly correlated with GAG content but logarithmically correlated with collagen content. This provides evidence that IGF-I gene therapy can improve healing of articular cartilage and can greatly increase the mechanical properties of repaired grafts.

  19. Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability.

    PubMed

    Dauber, Andrew; Muñoz-Calvo, María T; Barrios, Vicente; Domené, Horacio M; Kloverpris, Soren; Serra-Juhé, Clara; Desikan, Vardhini; Pozo, Jesús; Muzumdar, Radhika; Martos-Moreno, Gabriel Á; Hawkins, Federico; Jasper, Héctor G; Conover, Cheryl A; Frystyk, Jan; Yakar, Shoshana; Hwa, Vivian; Chowen, Julie A; Oxvig, Claus; Rosenfeld, Ron G; Pérez-Jurado, Luis A; Argente, Jesús

    2016-04-01

    Mutations in multiple genes of the growth hormone/IGF-I axis have been identified in syndromes marked by growth failure. However, no pathogenic human mutations have been reported in the six high-affinity IGF-binding proteins (IGFBPs) or their regulators, such as the metalloproteinase pregnancy-associated plasma protein A2 (PAPP-A2) that is hypothesized to increase IGF-I bioactivity by specific proteolytic cleavage of IGFBP-3 and -5. Multiple members of two unrelated families presented with progressive growth failure, moderate microcephaly, thin long bones, mildly decreased bone density and elevated circulating total IGF-I, IGFBP-3, and -5, acid labile subunit, and IGF-II concentrations. Two different homozygous mutations in PAPPA2, p.D643fs25* and p.Ala1033Val, were associated with this novel syndrome of growth failure. In vitro analysis of IGFBP cleavage demonstrated that both mutations cause a complete absence of PAPP-A2 proteolytic activity. Size-exclusion chromatography showed a significant increase in IGF-I bound in its ternary complex. Free IGF-I concentrations were decreased. These patients provide important insights into the regulation of longitudinal growth in humans, documenting the critical role of PAPP-A2 in releasing IGF-I from its BPs.

  20. Growth hormone, IGF-I, and exercise effects on non-weight-bearing fast muscles of hypophysectomized rats

    NASA Technical Reports Server (NTRS)

    Grossman, E. J.; Grindeland, R. E.; Roy, R. R.; Talmadge, R. J.; Evans, J.; Edgerton, V. R.

    1997-01-01

    The effects of growth hormone (GH) or insulin-like growth factor I (IGF-I) with or without exercise (ladder climbing) in countering the effects of unweighting on fast muscles of hypophysectomized rats during 10 days of hindlimb suspension were determined. Compared with untreated suspended rats, muscle weights were 16-29% larger in GH-treated and 5-15% larger in IGF-I-treated suspended rats. Exercise alone had no effect on muscle weights. Compared with ambulatory control, the medial gastrocnemius weight in suspended, exercised rats was larger after GH treatment and maintained with IGF-I treatment. The combination of GH or IGF-I plus exercise in suspended rats resulted in an increase in size of each predominant fiber type, i.e., types I, I + IIa and IIa + IIx, in the medial gastrocnemius compared with untreated suspended rats. Normal ambulation or exercise during suspension increased the proportion of fibers expressing embryonic myosin heavy chain in hypophysectomized rats. The phenotype of the medial gastrocnemius was minimally affected by GH, IGF-I, and/or exercise. These results show that there is an IGF-I, as well as a GH, and exercise interactive effect in maintaining medial gastrocnemius fiber size in suspended hypophysectomized rats.

  1. Upper airway loading induces growth retardation and change in local chondrocyte IGF-I expression is reversed by stimulation of GH release in juvenile rats.

    PubMed

    Segev, Yael; Berdugo-Boura, Nilly; Porati, Orit; Tarasiuk, Ariel

    2008-11-01

    Chronic resistive airway loading (CAL) impairs growth in juvenile rats. The effects of CAL on epiphyseal growth plate (EGP) structure and insulin-like growth factor (IGF)-I gene expression have not been explored. Little is known about whether stimulants of endogenous growth hormone (GH) secretion can normalize this growth impairment. This study explored the effect of CAL on circulating and EGP GH/IGF-I pathway GH and the effect of ritanserin (endogenous GH stimulant) on somatic growth and the GH/IGF-I axis. We hypothesized that CAL would lead to a decrease in body temperature (Tb) and alterations of GH/IGF-I pathways, consequently leading to growth retardation. The tracheae of 22-day-old male rats were obstructed by tracheal banding (38 sham-operated control, 42 CAL). Tibial EGP morphometry, liver and EGP IGF mRNA, and serum GH and IGF-I levels were analyzed with quantitative real-time PCR and ELISA. Tb and locomotion activity (MA) were measured with telemetric transmitters inserted into the abdominal cavity. CAL animals had lower Tb and MA despite preserved food consumption. CAL impaired both tibial and tail length gains. Tail and tibial length gains inversely correlated with tracheal resistance. Circulating GH and IGF-I, liver and EGP IGF-I mRNA, and EGP width were decreased in the CAL group. Ritanserin administration to CAL animals normalized circulating and local EGP GH and IGF-I levels and minimized the longitudinal growth impairment. We conclude that CAL causes growth delay associated with alterations in the GH/IGF-I axis. Stimulation of GH release by ritanserin restored both global and local GH/IGF-I pathways, yet growth parameters were only partially restored.

  2. Liver-spleen axis, insulin-like growth factor-(IGF)-I axis and fat mass in overweight/obese females

    PubMed Central

    2011-01-01

    Background Fat mass (FM) in overweight/obese subjects has a primary role in determining low-grade chronic inflammation and, in turn, insulin resistance (IR) and ectopic lipid storage within the liver. Obesity, aging, and FM influence the growth hormone/insulin-like growth factor (IGF)-I axis, and chronic inflammation might reduce IGF-I signaling. Altered IGF-I axis is frequently observed in patients with Hepatic steatosis (HS). We tested the hypothesis that FM, or spleen volume and C-reactive protein (CRP)--all indexes of chronic inflammation--could affect the IGF-I axis status in overweight/obese, independently of HS. Methods The study population included 48 overweight/obese women (age 41 ± 13 years; BMI: 35.8 ± 5.8 kg/m2; range: 25.3-53.7), who underwent assessment of fasting plasma glucose and insulin, homeostasis model assessment of insulin resistance (HOMA), cholesterol and triglycerides, HDL-cholesterol, transaminases, high-sensitive CRP, uric acid, IGF-I, IGF binding protein (BP)-1, IGFBP-3, and IGF-I/IGFBP-3 ratio. Standard deviation score of IGF-I according to age (zSDS) were also calculated. FM was determined by bioelectrical impedance analysis. HS severity grading (score 0-4 according liver hyperechogenicity) and spleen longitudinal diameter (SLD) were evaluated by ultrasound. Results Metabolic syndrome (MS) and HS were present in 33% and 85% of subjects, respectively. MS prevalence was 43% in subjects with increased SLD. IGF-I values, but not IGF-I zSDS, and IGF-I/IGFBP-3 ratio were significantly lower, while FM%, FPI, HOMA, ALT, CRP, were significantly higher in patients with severe HS than in those with mild HS. IGF-I zSDS (r = -0.42, r = -0.54, respectively; p < 0.05), and IGFBP-1 (r = -0.38, r = -0.42, respectively; p < 0.05) correlated negatively with HS severity and FM%. IGF-I/IGFBP-3 ratio correlated negatively with CRP, HS severity, and SLD (r = -0.30, r = -0.33, r = -0.43, respectively; p < 0.05). At multivariate analysis the best

  3. Insulin and IGF-I inhibit GH synthesis and release in vitro and in vivo by separate mechanisms.

    PubMed

    Gahete, Manuel D; Córdoba-Chacón, José; Lin, Qing; Brüning, Jens C; Kahn, C Ronald; Castaño, Justo P; Christian, Helen; Luque, Raúl M; Kineman, Rhonda D

    2013-07-01

    IGF-I is considered a primary inhibitor of GH secretion. Insulin may also play an important role in regulating GH levels because insulin, like IGF-I, can suppress GH synthesis and release in primary pituitary cell cultures and insulin is negatively correlated with GH levels in vivo. However, understanding the relative contribution insulin and IGF-I exert on controlling GH secretion has been hampered by the fact that circulating insulin and IGF-I are regulated in parallel and insulin (INSR) and IGF-I (IGFIR) receptors are structurally/functionally related and ubiquitously expressed. To evaluate the separate roles of insulin and IGF-I in directly regulating GH secretion, we used the Cre/loxP system to knock down the INSR and IGFIR in primary mouse pituitary cell cultures and found insulin-mediated suppression of GH is independent of the IGFIR. In addition, pharmacological blockade of intracellular signals in both mouse and baboon cultures revealed insulin requires different pathways from IGF-I to exert a maximal inhibitory effect on GH expression/release. In vivo, somatotrope-specific knockout of INSR (SIRKO) or IGFIR (SIGFRKO) increased GH levels. However, comparison of the pattern of GH release, GH expression, somatotrope morphometry, and pituitary explant sensitivity to acute GHRH challenge in lean SIRKO and SIGFRKO mice strongly suggests the primary role of insulin in vivo is to suppress GH release, whereas IGF-I serves to regulate GH synthesis. Finally, SIRKO and/or SIGFRKO could not prevent high-fat, diet-induced suppression of pituitary GH expression, indicating other factors/tissues are involved in the decline of GH observed with weight gain.

  4. Alterations in tumorigenicity of embryonal carcinoma cells by IGF-I triple-helix induced changes in immunogenicity and apoptosis.

    PubMed

    Ly, A; Francois, J C; Upegui-Gonzalez, L C; Swiercz, B; Bedel, C; Duc, H T; Bout, D; Trojan, J

    2000-12-08

    IGF-I antisense gene therapy has been applied successfully to animal models of glioma, hepatoma and teratocarcinoma. The antisense strategy has shown that tumor cells transfected with vectors encoding IGF-I antisense RNA lose tumorigenicity, become immunogenic and are associated with tumor specific immune response involving CD8+ lymphocytes. An IGF-I triple helix approach to gene therapy for glioma was recently described. The approach we have taken is to establish parameters of change using the IGF-I triple helix strategy. PCC-3 embryonal carcinoma cells derived from murine teratocarcinoma which express IGF-I were used as a model. The cells were transfected with vector which encodes an oligoribonucleotide that forms RNA-IGF-I DNA triple-helix structure. The triple-helix stops the production of IGF-I. Cells transfected in this manner underwent changes in phenotype and an increase in MHC-I and B-7 cell surface molecules. They also showed enhancement in the production of apoptotic cells (60-70%). The "triple helix" transfected cells lost the ability to induce tumor when injected subcutaneously in syngeneic 129 Sv mice. When co-transfected in vitro with expression vectors encoding both MHC-I and B-7 cDNA in antisense orientation, the "triple-helix" transfected cells were down-regulated in expression of MHC-I and B-7 and the number of apoptotic cells was significantly decreased. Injection of the doubly co-transfected cells into 129 Sv mice was associated with induction of teratocarcinoma. Comparison between antisense and triple-helix transfected cells strategies showed similar immunogenic and apoptotic changes. The findings suggest that triple-helix technology may offer a new clinical approach to treatement of tumors expressing IGF-I.

  5. [Differences in dynamics of insulin and insulin-like growth I (IGF-I) receptors internalization in isolated rat hepatocytes].

    PubMed

    Kolychev, A P; Ternovskaya, E E; Arsenieva, A V; Shapkina, E V

    2013-01-01

    Insulin and IGF-I are two related peptides performing in the mammalian body functionally different roles of the metabolic and growth hormones, respectively. Internalization of the insulin-receptor complex (IRC) is the most important chain of mechanism of the action of hormone. To elucidate differences in the main stages of internalization of the two related hormones, the internalization dynamics of 125I-insulin and 125I-IGF-I was traced in isolated rat hepatocytes at 37 and 12 degrees C. There were established marked differences in the process of internalization of labeled hormones, which is stimulated by insulin and IGF-I. At 37 degrees C the insulin-stimulated internalization, unlike the process initiated by IGF-I, did not reach the maximal level for 1 h of incubation. However, essential differences in the internalization course of these two related peptide were obvious at the temperature of 12 degrees C. The internalization level of insulin receptors at 12 degrees C decreased by one third in spite of a significant increase of the insulin receptor binding on the hepatocytes plasma membrane. At 12 degrees C a slight decrease of the proportion of intracellular 125I-IGF-I correlated with a decrease in the 125I-IGF-I binding to receptors on the cell membrane. Internalization of IGF-I receptors was not affected by low temperature, as neither its level, nor the rate changed at 12 degrees C. The paradoxical decrease of the insulin-stimulated internalization at low temperature seems to represent a peculiar "inhibition mechanism" of immersion of IRC into the cell, which leads to accumulation of the complexes on the cell surface and possibly to a readjustment of the insulin biological activity. The resistance of internalization of the IGF-I receptor to cold seems to be related to the more ancient origin of this mechanism in the poikilothermal vertebrates.

  6. Muscle RING finger-1 attenuates IGF-I-dependent cardiomyocyte hypertrophy by inhibiting JNK signaling.

    PubMed

    Wadosky, Kristine M; Rodríguez, Jessica E; Hite, Rebecca L; Min, Jin-na; Walton, Bethany L; Willis, Monte S

    2014-04-01

    Recent studies implicate the muscle-specific ubiquitin ligase muscle RING finger-1 (MuRF1) in inhibiting pathological cardiomyocyte growth in vivo by inhibiting the transcription factor SRF. These studies led us to hypothesize that MuRF1 similarly inhibits insulin-like growth factor-I (IGF-I)-mediated physiological cardiomyocyte growth. We identified two lines of evidence to support this hypothesis: IGF-I stimulation of cardiac-derived cells with MuRF1 knockdown 1) exhibited an exaggerated hypertrophy and, 2) conversely, increased MuRF1 expression-abolished IGF-I-dependent cardiomyocyte growth. Enhanced hypertrophy with MuRF1 knockdown was accompanied by increases in Akt-regulated gene expression. Unexpectedly, MuRF1 inhibition of this gene expression profile was not a result of differences in p-Akt. Instead, we found that MuRF1 inhibits total protein levels of Akt, GSK-3β (downstream of Akt), and mTOR while limiting c-Jun protein expression, a mechanism recently shown to govern Akt, GSK-3β, and mTOR activities and expression. These findings establish that MuRF1 inhibits IGF-I signaling by restricting c-Jun activity, a novel mechanism recently identified in the context of ischemia-reperfusion injury. Since IGF-I regulates exercise-mediated physiological cardiac growth, we challenged MuRF1(-/-) and MuRF1-Tg+ mice and their wild-type sibling controls to 5 wk of voluntary wheel running. MuRF1(-/-) cardiac growth was increased significantly over wild-type control; conversely, the enhanced exercise-induced cardiac growth was lost in MuRF1-Tg+ animals. These studies demonstrate that MuRF1-dependent attenuation of IGF-I signaling via c-Jun is applicable in vivo and establish that further understanding of this novel mechanism may be crucial in the development of therapies targeting IGF-I signaling.

  7. Effects of type IV collagen on myogenic characteristics of IGF-I gene-engineered myoblasts.

    PubMed

    Ito, Akira; Yamamoto, Masahiro; Ikeda, Kazushi; Sato, Masanori; Kawabe, Yoshinori; Kamihira, Masamichi

    2015-05-01

    Skeletal muscle regeneration requires migration, proliferation and fusion of myoblasts to form multinucleated myotubes. In our previous study, we showed that insulin-like growth factor (IGF)-I gene delivery stimulates the proliferation and differentiation of mouse myoblast C2C12 cells and promotes the contractile force generated by tissue-engineered skeletal muscles. The aim of this study was to investigate the effects of the extracellular matrix on IGF-I gene-engineered C2C12 cells in vitro. Retroviral vectors for doxycycline (Dox)-inducible expression of the IGF-I gene were transduced into C2C12 cells. When cultured on a type IV collagen-coated surface, we observed significant increases in the migration speed and number of IGF-I gene-engineered C2C12 cells with Dox addition, designated as C2C12/IGF (+) cells. Co-culture of C2C12/IGF (+) cells and parental C2C12 cells, which had been cultured in differentiation medium for 3 days, greatly enhanced myotube formation. Moreover, type IV collagen supplementation promoted the fusion of C2C12/IGF (+) cells with differentiated C2C12 cells and increased the number of myotubes with striations. Myotubes formed by C2C12/IGF (+) cells cultured on type IV collagen showed a dynamic contractile activity in response to electrical pulse stimulation. These findings indicate that type IV collagen promotes skeletal muscle regeneration mediated by IGF-I-expressing myoblasts, which may have important clinical implications in the design of myoblast-based therapies.

  8. Effects of exogenous cortisol on the GH/IGF-I/IGFBP network in channel catfish.

    PubMed

    Peterson, Brian C; Small, Brian C

    2005-05-01

    Glucocorticoids are known to hinder somatic growth in a number of vertebrate species. In order to better understand the mechanisms through which they may act in channel catfish, we examined the effects of feeding cortisol on the growth hormone (GH)/insulin-like growth factor-I (IGF-I)/IGF-binding protein (IGFBP) network. Fish (30.6+/-3.0 g) were fed once daily for 4 weeks and treatments included: (1) High-cortisol (dietary cortisol provided at 400 mg/kg feed), (2) Low-cortisol (dietary cortisol provided at 200 mg/kg feed), and (3) Control (commercial catfish feed). Fish fed diets with cortisol weighed approximately 50% less than Controls. Feed intake was reduced by approximately 30% in both treatments of cortisol fed fish compared to Controls. A approximately 20-kDa IGFBP was observed in plasma from High- and Low-treated fish while it was not detected in Control fish plasma. High-cortisol treatment increased pituitary GH mRNA expression approximately 10-fold while liver IGF-I mRNA expression was not different between cortisol-treated fish and Controls. Cortisol treatments decreased plasma levels of IGF-I. These data indicate that feeding cortisol for 4 weeks reduces weight gain, feed intake, and plasma levels of IGF-I and induces a approximately 20-kDa IGFBP. One mechanism through which cortisol may impede growth of catfish is through an increase in a low molecular weight IGFBP which may lead to inhibitory effects on the action of IGF-I.

  9. Synergistic stimulation of myogenesis by glucocorticoid and IGF-I signaling.

    PubMed

    Pansters, N A; Langen, R C; Wouters, E F; Schols, A M

    2013-05-01

    Muscle wasting is associated with poor prognosis in chronic obstructive pulmonary disease (COPD). Exercise stimulates muscle recovery, but its efficacy is variable, depending on the clinical condition and medical treatment. Systemic glucocorticoids, commonly administered in high doses during acute disease exacerbations or as maintenance treatment in end-stage disease, are known to contribute to muscle wasting. As muscle mass recovery involves insulin-like growth factor (IGF)-I signaling, which can be stimulated by anabolic steroids, the impact of glucocorticoids and the effect of simultaneous IGF-I stimulation by anabolic steroids on muscle recovery and growth were investigated. The effects of, and interactions between, glucocorticoid and IGF-I signaling on skeletal muscle growth were assessed in differentiating C2C12 myocytes. As proof of principle, we performed a post hoc analysis stratifying patients by glucocorticoid use of a clinical trial investigating the efficacy of anabolic steroid supplementation on muscle recovery in muscle-wasted patients with COPD. Glucocorticoids strongly impaired protein synthesis signaling, myotube formation, and muscle-specific protein expression. In contrast, in the presence of glucocorticoids, IGF-I synergistically stimulated myotube fusion and myofibrillar protein expression, which corresponded with restored protein synthesis signaling by IGF-I and increased transcriptional activation of muscle-specific genes by glucocorticoids. In COPD patients on maintenance glucocorticoid treatment, the clinical trial also revealed an enhanced effect of anabolic steroids on muscle mass and respiratory muscle strength. In conclusion, synergistic effects of anabolic steroids and glucocorticoids on muscle recovery may be caused by relief of the glucocorticoid-imposed blockade on protein synthesis signaling, allowing effective translation of glucocorticoid-induced accumulation of muscle-specific gene transcripts.

  10. PKC{eta} is a negative regulator of AKT inhibiting the IGF-I induced proliferation

    SciTech Connect

    Shahaf, Galit; Rotem-Dai, Noa; Koifman, Gabriela; Raveh-Amit, Hadas; Frost, Sigal A.; Livneh, Etta

    2012-04-15

    The PI3K-AKT pathway is frequently activated in human cancers, including breast cancer, and its activation appears to be critical for tumor maintenance. Some malignant cells are dependent on activated AKT for their survival; tumors exhibiting elevated AKT activity show sensitivity to its inhibition, providing an Achilles heel for their treatment. Here we show that the PKC{eta} isoform is a negative regulator of the AKT signaling pathway. The IGF-I induced phosphorylation on Ser473 of AKT was inhibited by the PKC{eta}-induced expression in MCF-7 breast adenocarcinoma cancer cells. This was further confirmed in shRNA PKC{eta}-knocked-down MCF-7 cells, demonstrating elevated phosphorylation on AKT Ser473. While PKC{eta} exhibited negative regulation on AKT phosphorylation it did not alter the IGF-I induced ERK phosphorylation. However, it enhanced ERK phosphorylation when stimulated by PDGF. Moreover, its effects on IGF-I/AKT and PDGF/ERK pathways were in correlation with cell proliferation. We further show that both PKC{eta} and IGF-I confer protection against UV-induced apoptosis and cell death having additive effects. Although the protective effect of IGF-I involved activation of AKT, it was not affected by PKC{eta} expression, suggesting that PKC{eta} acts through a different route to increase cell survival. Hence, our studies show that PKC{eta} provides negative control on AKT pathway leading to reduced cell proliferation, and further suggest that its presence/absence in breast cancer cells will affect cell death, which could be of therapeutic value.

  11. IGF-I and amino acids effects through TOR signaling on proliferation and differentiation of gilthead sea bream cultured myocytes.

    PubMed

    Vélez, Emilio J; Lutfi, Esmail; Jiménez-Amilburu, Vanesa; Riera-Codina, Miquel; Capilla, Encarnación; Navarro, Isabel; Gutiérrez, Joaquim

    2014-09-01

    Skeletal muscle growth and development is controlled by nutritional (amino acids, AA) as well as hormonal factors (insulin-like growth factor, IGF-I); however, how its interaction modulates muscle mass in fish is not clearly elucidated. The purpose of this study was to analyze the development of gilthead sea bream cultured myocytes to describe the effects of AA and IGF-I on proliferating cell nuclear antigen (PCNA) and myogenic regulatory factors (MRFs) expression, as well as on the transduction pathways involved in its signaling (TOR/AKT). Our results showed that AA and IGF-I separately increased the number of PCNA-positive cells and, together produced a synergistic effect. Furthermore, AA and IGF-I, combined or separately, increased significantly Myogenin protein expression, whereas MyoD was not affected. These results indicate a role for these factors in myocyte proliferation and differentiation. At the mRNA level, AA significantly enhanced PCNA expression, but no effects were observed on the expression of the MRFs or AKT2 and FOXO3 upon treatment. Nonetheless, we demonstrated for the first time in gilthead sea bream that AA significantly increased the gene expression of TOR and its downstream effectors 4EBP1 and 70S6K, with IGF-I having a supporting role on 4EBP1 up-regulation. Moreover, AA and IGF-I also activated TOR and AKT by phosphorylation, respectively, being this activation decreased by specific inhibitors. In summary, the present study demonstrates the importance of TOR signaling on the stimulatory role of AA and IGF-I in gilthead sea bream myogenesis and contributes to better understand the potential regulation of muscle growth and development in fish.

  12. IGF-I slightly improves nuclear maturation and cleavage rate of bovine oocytes exposed to acute heat shock in vitro.

    PubMed

    Meiyu, Qi; Liu, Di; Roth, Zvi

    2015-08-01

    An in vitro model of embryo production was used to examine the effects of insulin-like growth factor (IGF)-I on maturation and developmental competence of oocytes exposed to heat shock. Cumulus-oocyte complexes were matured at 38.5°C or exposed to acute heat shock (HS; 41.5°C), with or without 100 ng/ml IGF-I, for 22 h through in vitro maturation. The experimental groups were control (C), C + IGF-I, HS, and HS + IGF-I. Oocytes were fertilized at the end of maturation, and the proportion of cleaved embryos was recorded 44 h later. HS during maturation increased the proportion of TUNEL-positive oocytes (P < 0.05). HS did not have any effect on cortical granule translocation but impaired resumption of meiosis, expressed as a decreased proportion of oocytes with nuclei in metaphase I (P < 0.05) and metaphase II (MII; P < 0.05). HS decreased the proportion of oocytes that cleaved (P < 0.05), in particular those oocytes that further developed to 4-cell-stage embryos (P < 0.05). IGF-I alleviated, to some extent, the deleterious effects of HS on the oocytes as reflected by a reduced proportion of TUNEL-positive oocytes (P < 0.03). While not significant, IGF-I tended to increase the proportion of MII-stage oocytes (P < 0.08) and 4-cell-stage cleaved embryos (P < 0.06). Further examination is required to explore whether IGF-I also affects the developmental competence of oocytes exposed to HS.

  13. Circulating bioactive and immunoreactive IGF-I remain stable in women, despite physical fitness improvements after 8 weeks of resistance, aerobic, and combined exercise training.

    PubMed

    Nindl, Bradley C; Alemany, Joseph A; Tuckow, Alexander P; Rarick, Kevin R; Staab, Jeffery S; Kraemer, William J; Maresh, Carl M; Spiering, Barry A; Hatfield, Disa L; Flyvbjerg, Allan; Frystyk, Jan

    2010-07-01

    Insulin-like growth factor-I (IGF-I) is regulated by a number of IGF-binding proteins (IGFBPs) and proteases that influence IGF-I bioactivity. A specific IGF-I kinase receptor activation assay (KIRA) has been developed that determines the ability of IGF-I to activate the IGF-I receptor by quantification of intracellular receptor autophosphorylation on IGF-I binding. KIRA-assessed IGF-I bioactivity has not been utilized within the context of chronic exercise training paradigms. This study measured total and free immunoreactive IGF-I, bioactive IGF-I, and IGFBP-1, -2, and -3 before (Pre), during (Mid), and after (Post) 8 wk of exercise training in young, healthy women, who were randomized into one of four groups: control (n = 10), resistance (n = 18), aerobic (n = 13), and combined (n = 15) exercise training. The training programs were effective in improving physical fitness specific to the exercise mode engaged in: increases were observed for lean mass ( approximately 2%), aerobic fitness (6-7%), and upper (20-24%) and lower (15-48%) body strength (all P values < 0.05). By contrast, no time, group, or interaction effects were observed for the circulating IGF-I system, as immunoreactive total (Pre = 264 +/- 16 microg/l; Mid = 268 +/- 17 microg/l; Post = 271 +/- 17 microg/l), free (Pre = 0.70 +/- 0.1 microg/l; Mid = 0.63 +/- 0.1 microg/l; Post = 0.63 +/- 0.2 microg/l) and bioactive (Pre = 2.35 +/- 0.3 microg/l; Mid = 2.25 +/- 0.3 microg/l; Post = 2.33 +/- 0.3 microg/l) IGF-I were unchanged throughout the study. All IGFBP measures were also unchanged. We conclude that increased lean mass, aerobic fitness, and upper and lower body strength resulting from an 8-wk exercise training programs can occur without concomitant increases in either circulating bioactive or immunoreactive IGF-I, as well as associated IGFBPs. In terms of reflecting positive anabolic neuromuscular outcomes, these data do not support a role for endocrine-derived IGF-I.

  14. Polymorphism of the IGF-I System and Sports Performance.

    PubMed

    Ben-Zaken, Sigal; Meckel, Yoav; Nemet, Dan; Dror, Nitzan; Eliakim, Alon

    2016-06-01

    The potential use genetic polymorphism, and in particularly polymorphism of hormone genes, as tool to predict athletic performance is currently very challenging. Recent studies suggest that single nucleotide polymorphisms in IGF-I and myostatin may be beneficial for endurance and short distance running, and may even be associated with elite performance. Polymorphism in IGF-I receptor may differentiate between the two edges of the endurance-power athletic performance running spectrum suggesting beneficial effects for endurance and prevent from success in power events. In contrast, and despite similar metabolic demands, the myostatin-IGF-I-IGF-IR system seems not to play an important role in swimming excellence. This suggests that combining different sport disciplines for sports genetic research purposes should be done with extreme caution. Finally, since any phenotype reflects a complex relationship between genes, environment, epigenetic factors, and the interactions between them, consulting the young athlete regarding future success cannot be based solely on genetic polymorphism.

  15. Effects of Growth Hormone/IGF-I and Exercise on Unloaded Bones

    NASA Technical Reports Server (NTRS)

    Harper, J. S.; Arnaud, S. B.; Gosselink, K. L.; Grindeland, R. E.

    1994-01-01

    Growth hormone (GH) and insulin-like growth factor-I (IGF-I) in combination with exercise prevent muscle atrophy induced by unloading in the tail-suspension rat model for space flight (Gosselink et al, FASEB J 1994). This study evaluated the effects of these treatments on bone. Hypophysectomized rats were suspended (S) and treated with 1mg/kg/day CH plus IGF-I (H) or vehicle (Sal) daily by injection and exercised (Ex) by 3 climbs up a 1m ladder carrying a load equal to 30% the initial body weight (BW) 3x/day for 10 days. Tibial epiphysis (Epi) widths were measured by micrometry and femoral Bone Mineral Content (fBMC) in excised femurs by DEXA (Lunar DPX-L). Serum calcium (Ca) and phosphorus (Pi) were measured by COBAS Autoanalyzer (Roche Diag.). Ambulatory (Amb)-H treated rats showed growth rates of 6.6+-0.9 g/day, similar to S-H-Ex and higher than S-H (3.210.6, p less than 0.05) and S-Sal (-0.711.0, p less than 0.05). Epi widths were 10% lower in S-Sal, and S-Sal-Ex, and increased 100% in all H groups. fBMC was less in S than Amb, only when all S groups are compared to both Amb groups (p less than 0.03). H treatment increased fBMC (p less than 0.05) but reduced fBMC/100g BW in all H groups (p less than 0.001). The reduced density of H bone cannot be attributed to low circulating Ca. and Pi since they were higher in H than Sal (p less than 0.001). H treatment for 10 days in doses sufficient to support normal growth in BW failed to produce normal Epi widths or fBMC, even when combined with exercise. The suspension effect observed in Epi widths was not corrected by H or Ex alone, but was improved by H plus a This regimen. although effective in preventing muscle atrophy, failed to return bone measures, Epi widths and fBMC, to normal.

  16. The therapeutic potential of IGF-I in skeletal muscle repair.

    PubMed

    Song, Yao-Hua; Song, Jenny L; Delafontaine, Patrice; Godard, Michael P

    2013-06-01

    Skeletal muscle loss due to aging, motor-neuron degeneration, cancer, heart failure, and ischemia is a serious condition for which currently there is no effective treatment. Insulin-like growth factor 1 (IGF-I) plays an important role in muscle maintenance and repair. Preclinical studies have shown that IGF-I is involved in increasing muscle mass and strength, reducing degeneration, inhibiting the prolonged and excessive inflammatory process due to toxin injury, and increasing the proliferation potential of satellite cells. However, clinical trials have not been successful due to ineffective delivery methods. Choosing the appropriate isoforms or peptides and developing targeted delivery techniques can resolve this issue. Here we discuss the latest development in the field with special emphasis on novel therapeutic approaches.

  17. The therapeutic potential of IGF-I in skeletal muscle repair

    PubMed Central

    Song, Yao-Hua; Song, Jenny L.; Delafontaine, Patrice; Godard, Michael P.

    2013-01-01

    Skeletal muscle loss due to aging, motor neuron degeneration, cancer, heart failure and ischemia is a serious condition for which currently there is no effective treatment. Insulin-like growth factor 1 (IGF-I) plays an important role in muscle maintenance and repair. Preclinical studies have shown that IGF-I is involved in increasing muscle mass and strength, reducing degeneration, inhibiting the prolonged and excessive inflammatory process due to toxin injury and increasing the proliferation potential of satellite cells. However, clinical trials have not been successful due to ineffective delivery method. Choosing the appropriate isoforms or peptides and developing targeted delivery techniques can resolve this issue. Here we discuss the latest development in the field with special emphasis on novel therapeutic approaches. PMID:23628587

  18. The somatotropic axis in neonatal calves can be modulated by nutrition, growth hormone, and Long-R3-IGF-I.

    PubMed

    Hammon, H; Blum, J W

    1997-07-01

    Effects on the somatotropic axis [plasma levels of insulin-like growth factors (IGFs) I and II, IGF-binding proteins (IGFBPs), and growth hormone (GH)] of feeding different amounts of colostrum or milk replacer, of Long-R3-IGF-I (administered subcutaneously or orally; 50 micrograms.kg body wt-1.day-1 for 7 days), and of subcutaneously injected recombinant bovine GH (rbGH; 1 mg.kg body wt-1.day-1 for 7 days) were evaluated in calves during the 1st wk of life. Plasma Long-R3-IGF-I increased after subcutaneous application but not with the oral dose. Endogenous IGF-I was higher in calves fed colostrum six times compared with those fed only milk replacer. Native IGF-I was highest in rbGH-injected calves but was lowered by the subcutaneous injection of Long-R3-IGF-I. IGF-II concentrations were not modified by any of the treatments. IGFBP-2 increased in calves fed only milk replacer and those receiving subcutaneous Long-R3-IGF-I. GH was not modulated by differences in nutrition but increased after rbGH administration and similarly in all groups after intravenous injection of GH-releasing factor analog GRF-(1-29). Parenteral administration of Long-R3-IGF-I decreased GH concentration but did not affect the secretory pattern. The data demonstrate that the somatotrophic axis is basically functioning in neonatal calves and is influenced by nutrition, GH, and Long-R3-IGF-I.

  19. Decreased Serum Insulin-like Growth Factor-I is a Risk Factor for Non-vertebral Fractures in Diabetic Postmenopausal Women.

    PubMed

    Miyake, Hitomi; Kanazawa, Ippei; Sugimoto, Toshitsugu

    2017-01-01

    Objective Previous studies have shown that serum insulin-like growth factor-I (IGF-I) is involved in diabetes-related bone fragility. Although lower serum levels of IGF-I are reported to be associated with a higher risk of vertebral fractures in patients with type 2 diabetes, it is unknown whether or not the serum level of IGF-I is associated with the incidence of non-vertebral fractures. Methods We investigated the relationships between the serum levels of IGF-I and the incidence of non-vertebral osteoporotic fractures in 188 men and 168 postmenopausal women with type 2 diabetes. Results A multiple logistic regression analysis adjusted for age, duration of diabetes, observation period, body mass index, HbA1c, serum creatinine, and the bone mineral density at the lumbar spine showed that the serum IGF-I level was significantly and inversely associated with the incidence of non-vertebral osteoporotic fractures in postmenopausal women (odds ratio =0.48, 95% confidential interval [CI] 0.23-0.99 per SD increase; p=0.047), but not in men. Moreover, the inverse association between the serum IGF-I level and the incidence of non-vertebral fractures remained significant after additional adjustment for insulin use, and the serum calcium and phosphate levels (odds ratio =0.48, 95% CI 0.23-0.99 per SD increase; p=0.046). Conclusion This is the first study to show that decreased serum IGF-I levels are associated with a higher risk of non-vertebral osteoporotic fractures in postmenopausal women with type 2 diabetes. Serum IGF-I could be a useful marker for assessing the incidence of osteoporotic fractures.

  20. Decreased Serum Insulin-like Growth Factor-I is a Risk Factor for Non-vertebral Fractures in Diabetic Postmenopausal Women

    PubMed Central

    Miyake, Hitomi; Kanazawa, Ippei; Sugimoto, Toshitsugu

    2017-01-01

    Objective Previous studies have shown that serum insulin-like growth factor-I (IGF-I) is involved in diabetes-related bone fragility. Although lower serum levels of IGF-I are reported to be associated with a higher risk of vertebral fractures in patients with type 2 diabetes, it is unknown whether or not the serum level of IGF-I is associated with the incidence of non-vertebral fractures. Methods We investigated the relationships between the serum levels of IGF-I and the incidence of non-vertebral osteoporotic fractures in 188 men and 168 postmenopausal women with type 2 diabetes. Results A multiple logistic regression analysis adjusted for age, duration of diabetes, observation period, body mass index, HbA1c, serum creatinine, and the bone mineral density at the lumbar spine showed that the serum IGF-I level was significantly and inversely associated with the incidence of non-vertebral osteoporotic fractures in postmenopausal women (odds ratio =0.48, 95% confidential interval [CI] 0.23-0.99 per SD increase; p=0.047), but not in men. Moreover, the inverse association between the serum IGF-I level and the incidence of non-vertebral fractures remained significant after additional adjustment for insulin use, and the serum calcium and phosphate levels (odds ratio =0.48, 95% CI 0.23-0.99 per SD increase; p=0.046). Conclusion This is the first study to show that decreased serum IGF-I levels are associated with a higher risk of non-vertebral osteoporotic fractures in postmenopausal women with type 2 diabetes. Serum IGF-I could be a useful marker for assessing the incidence of osteoporotic fractures. PMID:28154269

  1. USP15 attenuates IGF-I signaling by antagonizing Nedd4-induced IRS-2 ubiquitination.

    PubMed

    Fukushima, Toshiaki; Yoshihara, Hidehito; Furuta, Haruka; Hakuno, Fumihiko; Iemura, Shun-Ichiro; Natsume, Tohru; Nakatsu, Yusuke; Kamata, Hideaki; Asano, Tomoichiro; Komada, Masayuki; Takahashi, Shin-Ichiro

    2017-03-11

    Insulin receptor substrates (IRSs) are phosphorylated by IGF-I receptor tyrosine kinase in a ligand-dependent manner. In turn, they bind to and activate effector proteins such as PI3K, leading to various cell responses including cell proliferation. We had reported that ubiquitin ligase Nedd4 induces mono-ubiquitination of IRS-2, thereby enhancing IRS-2 tyrosine phosphorylation, leading to increased IGF signaling and mitogenic activity. Here we show that ubiquitin-specific protease 15 (USP15) antagonizes the effect of Nedd4 on IRS-2. We identified USP15 as a protein that preferentially bound to IRS-2 when IRS-2 was conjugated with ubiquitin. In HEK293 cells, Nedd4 overexpression induced IRS-2 ubiquitination, which was decreased by USP15 co-expression while increased by USP15 knockdown. Nedd4 overexpression enhanced IGF-I-dependent IRS-2 tyrosine phosphorylation, and USP15 co-expression suppressed it. Conversely, USP15 knockdown increased IRS-2 tyrosine phosphorylation and downstream signaling in prostate cancer PC-3 cells. We concluded that USP15 attenuates IGF-I signaling by antagonizing Nedd4-induced IRS-2 ubiquitination.

  2. Selective osteoblast overexpression of IGF-I in mice prevents low protein-induced deterioration of bone strength and material level properties.

    PubMed

    Brennan-Speranza, Tara C; Rizzoli, René; Kream, Barbara E; Rosen, Clifford; Ammann, Patrick

    2011-11-01

    Protein deficiency is frequently observed in elderly osteoporotic patients. Undernutrition leads to decreased levels of IGF-I, an important factor in regulating bone homeostasis throughout life. IGF-I is produced in the liver and locally in the skeleton. We hypothesized that increasing IGF-I expression in the osteoblasts, the bone forming cells, would protect the skeleton from the negative effects of a low-protein diet. To test our hypothesis, we employed a mouse model in which IGF-I was overexpressed exclusively in osteoblasts and fed either a 15% (normal) or a 2.5% (low) protein isocaloric diet to the transgenic (TG) mice and their wild-type (WT) littermates for 8 weeks. Blood was collected for biochemical determinations and weight was monitored weekly. Bones were excised for microstructural analysis (μCT), as well as biomechanical and material level properties. Histomorphometric analysis was performed for bone formation parameters. A low protein diet decreased body weight, circulating IGF-I and osteocalcin levels regardless of genotype. Overexpression of IGF-I in the osteoblasts was, however, able to protect the negative effects of low protein diet on microstructure including tibia cortical thickness and volumetric density, and on bone strength. Overexpression of IGF-I in osteoblasts in these mice protected the vertebrae from the substantial negative effects of low protein on the material level properties as measured my nanoindentation. TG mice also had larger overall geometric properties than WT mice regardless of diet. This study provides evidence that while a low protein diet leads to decreased circulating IGF-I, altered microstructure and decreased bone strength, these negative effects can be prevented with IGF-I overexpression exclusively in bone cells.

  3. IGF-I maintains calpastatin expression and attenuates apoptosis in several models of photoreceptor cell death.

    PubMed

    Arroba, Ana I; Wallace, Deborah; Mackey, Ashley; de la Rosa, Enrique J; Cotter, Thomas G

    2009-09-01

    Retinitis pigmentosa is a heterogeneous group of inherited retinal dystrophies in which the loss of photoreceptor cells via apoptosis leads to blindness. In this study we have experimentally mimicked this condition by treating 661W cells and wild-type mouse retinal explants with a Ca(2+) ionophore. Ca(2+) overload induced apoptosis, which was correlated with calpain-2 activation, loss of calpastatin, its endogenous inhibitor, as well as the loss of its transcriptional activator, phospho-cAMP response element binding (CREB). All are similar changes to those observed in the rd1 mouse model of retinitis pigmentosa. Insulin like-growth factor-I (IGF-I) attenuated this Ca(2+)-induced apoptosis, as well as decreased the activation of calpain-2 and maintained calpastatin levels through the activation of the Akt-CREB pathway. Similarly, IGF-I decreased photoreceptor apoptosis in rd1 mouse retinal explants in parallel with reduced activation of calpain-2 and increased levels of calpastatin and activation of phospho-CREB. In conclusion, IGF-I seems to protect neural cells following a physiopathological or an experimental increase in intracellular Ca(2+), an observation that may have therapeutic consequences in neurodegenerative diseases such as retinitis pigmentosa.

  4. β cell expression of IGF-I leads to recovery from type 1 diabetes

    PubMed Central

    George, Mónica; Ayuso, Eduard; Casellas, Alba; Costa, Cristina; Devedjian, Jean Christophe; Bosch, Fatima

    2002-01-01

    Patients with type 1 diabetes are identified after the onset of the disease, when β cell destruction is almost complete. β cell regeneration from islet cell precursors might reverse this disease, but factors that can induce β cell neogenesis and replication and prevent a new round of autoimmune destruction remain to be identified. Here we show that expression of IGF-I in β cells of transgenic mice (in both C57BL/6–SJL and CD-1 genetic backgrounds) counteracts cytotoxicity and insulitis after treatment with multiple low doses of streptozotocin (STZ). STZ-treated nontransgenic mice developed high hyperglycemia and hypoinsulinemia, lost body weight, and died. In contrast, STZ-treated C57BL/6–SJL transgenic mice showed mild hyperglycemia for about 1 month, after which they normalized glycemia and survived. After STZ treatment, all CD-1 mice developed high hyperglycemia, hypoinsulinemia, polydipsia, and polyphagia. However, STZ-treated CD-1 transgenic mice gradually normalized all metabolic parameters and survived. β cell mass increased in parallel as a result of neogenesis and β cell replication. Thus, our results indicate that local expression of IGF-I in β cells regenerates pancreatic islets and counteracts type 1 diabetes, suggesting that IGF-I gene transfer to the pancreas might be a suitable therapy for this disease. PMID:11994404

  5. IGF-I/EGF and E2 signaling crosstalk through IGF-IR conduit point affects breast cancer cell adhesion.

    PubMed

    Voudouri, Kallirroi; Nikitovic, Dragana; Berdiaki, Aikaterini; Kletsas, Dimitris; Karamanos, Nikos K; Tzanakakis, George N

    2016-12-01

    Epidermal growth factor (EGF)/insulin like growth factor-I (IGF-I) and Estradiol (E2) can regulate biological functions of hormone-dependent tumor cells. Fibronectin (FN) is a large glycoprotein abundantly expressed in breast cancer extracellular matrices (ECMs) postulated to be a marker of aggressiveness during cancer pathogenesis. In this study we demonstrate that IGF-I/EGF as well E2 strongly increase the adhesion of the MCF-7 breast cancer cells onto FN. Moreover, IGF-IR is necessary for the IGF-I-/EGF- and E2-induced cell adhesion. Erk1/2 inhibition abolished the IGF-I-/EGF-/E2-induced MCF-7 cell adhesion, suggesting that this regulation of cell adhesion is perpetrated through Erk1/2 downstream signaling. Erk1/2 signaling was shown to modulate IGF-IR status as its' inhibition attenuates both IGF-IR expression and activation. Notably, EGF and E2 enhanced the mRNA as well as protein expression of IGF-IR in MCF-7 cells. Confocal microscopy demonstrated that treatment of MCF-7 cells with IGF-I or EGF induced actin reorganization, which was attenuated with Erk1/2 inhibition. Interestingly, IGF-I treatment induced a co-localization of IGF-IR and FAK, which was evident mostly at the cell membranes of MCF-7 cells. In summary, IGF-IR was shown to be a convergence point for the IGF-/EGF- and E2-dependent MCF-7 cell adhesion onto FN.

  6. Association of serum retinol and carotenoids with insulin-like growth factors and insulin-like growth factor binding protein-3 among control subjects of a nested case-control study in the Japan Collaborative Cohort Study.

    PubMed

    Suzuki, Koji; Ito, Yoshinori; Hashimoto, Shuji; Kawado, Miyuki; Inoue, Takashi; Ando, Masahiko; Watanabe, Yoshiyuki; Inaba, Yutaka; Tajima, Kazuo; Nakachi, Kei; Tamakoshi, Akiko

    2009-12-01

    Insulin-like growth factor (IGF)-I and its main binding protein, IGFBP-3, modulate cell growth and survival, and thus are thought to be important for tumor development. Carotenoids and retinol have been linked to the prevention of several cancers. We here evaluated associations of serum levels of carotenoids and retinol with IGF-I, IGF-II, and IGFBP-3 within the context of the JACC Study. The study subjects were 924 controls (578 men and 346 women) of a nested case-control study of lung and colorectal cancer risk. Using frozen-stored sera, serum levels of a-carotene, b-carotene, lycopene, b-cryptoxanthin, zeaxanthin/lutein, and retinol were separately determined using high-performance liquid chromatography. Serum levels of IGF-I, IGF-II, and IGFBP-3 were measured by immuno-radiometric assay. Confounding factors-adjusted least squares mean levels of serum IGF-I, IGF-II, and IGFBP-3 for each quartile of serum levels of carotenoids and retinol were estimated. Serum IGF-I, IGF-II, and IGFBP-3 levels increased with increasing serum retinol levels. Moreover, serum IGF-I levels were significantly higher in highest quartile of serum provitamin A, such as a-carotene, b-carotene, and b-cryptoxanthin, among women. Serum IGFBP-3 levels decreased with increasing serum lycopene levels in women and with increasing serum zeaxanthin/lutein levels in men. The current study indicates that positive associations exist for serum retinol levels with serum levels of IGF-I, IGF-II, and IGFBP-3 independent of age, BMI, smoking habits, drinking habits, and intake of energy and protein among Japanese healthy men and women.

  7. Responses of insulin-like growth factor (IGF)-I and two IGF-binding protein-1 subtypes to fasting and re-feeding, and their relationships with individual growth rates in yearling masu salmon (Oncorhynchus masou).

    PubMed

    Kawaguchi, Kohei; Kaneko, Nobuto; Fukuda, Miki; Nakano, Yusuke; Kimura, Shizuo; Hara, Akihiko; Shimizu, Munetaka

    2013-06-01

    Two subtypes of insulin-like growth factor binding protein (IGFBP)-1 are present in salmon blood and they are both up-regulated under catabolic conditions such as stress. The present study examined effects of fasting and re-feeding on IGFBP-1a (28-kDa form) and IGFBP-1b (22-kDa form) both at mRNA and protein levels along with IGF-I and RNA/DNA ratio in yearling masu salmon. Fish were individually tagged and assigned to one of three treatments: Fed, Fasted or Re-fed. Circulating IGF-I levels significantly decreased after fasting for 5 weeks and were positively correlated with individual growth rates. Liver igf-1 mRNA levels were not affected by the treatment. Muscle RNA/DNA ratio did not respond to fasting nor showed correlations with growth rates. Circulating IGFBP-1a and IGFBP-1b increased during fasting and decreased after re-feeding. Both serum levels were inversely correlated with growth rates, while IGFBP-1b had consistent negative relationships with growth rates. Fasting/re-feeding also affected their mRNA levels in the liver. These results suggest that circulating IGF-I and IGFBP-1b could serve as positive and negative indices of growth, respectively, in masu salmon. Different sensitivities of IGBP-1a and IGFBP-1b may be useful to assess a broad range of catabolic conditions when they are combined.

  8. Bone Growth, Mechanical Stimulus and IGF-I

    DTIC Science & Technology

    2007-10-01

    in the elderly. 15. SUBJECT TERMS Mechanical Intervention, Fractures, IGF-I, Teenagers , Low Bone Mass 16. SECURITY CLASSIFICATION OF: 17...for low bone mass is present early in life, the amount of bone gained during adolescence is a main contributor to peak bone mass in the young adult...reversing osteoporosis in the elderly, these data from children, adolescents and young adults indicate that enhancing bone health early in life represents a

  9. Bone Growth, Mechanical Stimulus and IGF-I

    DTIC Science & Technology

    2005-10-01

    genetic susceptibility for low bone mass is present very early in life. The aim of this project is to establish whether bone acquisition in teenagers who...twelve-month interventions on musculoskeletal development will be studied and the results will be compared to matched teenagers undergoing no...3, and IGF-I genotypes, and between bone acquisition induced by interventions and insulin-like growth factors, in teenagers ages 15 to 20 years old

  10. Fasting modulates GH/IGF-I axis and its regulatory systems in the mammary gland of female mice: Influence of endogenous cortistatin.

    PubMed

    Villa-Osaba, Alicia; Gahete, Manuel D; Cordoba-Chacon, José; de Lecea, Luis; Castaño, Justo P; Luque, Raúl M

    2016-10-15

    Growth hormone (GH) and insulin-like growth factor-I (IGF-I) are essential factors in mammary-gland (MG) development and are altered during fasting. However, no studies have investigated the alterations in the expression of GH/IGF-I and its regulatory systems (somatostatin/cortistatin and ghrelin) in MG during fasting. Therefore, this study was aimed at characterizing the regulation of GH/IGF-I/somatostatin/cortistatin/ghrelin-systems expression in MG of fasted female-mice (compared to fed-controls) and the influence of endogenous-cortistatin (using cortistatin-knockouts). Fasting decreased IGF-I while increased IGF-I/Insulin-receptors expression in MGs. Fasting provoked an increase in GH expression that might be associated to enhanced ghrelin-variants/ghrelin-O-acyl-transferase enzyme expression, while an upregulation of somatostatin-receptors was observed. However, cortistatin-knockouts mice showed a decrease in GH and somatostatin receptor-subtypes expression. Altogether, we demonstrate that GH/IGF-I, somatostatin/cortistatin and ghrelin systems expression is altered in MG during fasting, suggesting a relevant role in coordinating its response to metabolic stress, wherein endogenous cortistatin might be essential for an appropriate response.

  11. IGF-I and IGF Binding Protein-3 Generation Tests and Response to Growth Hormone in Children with Silver-Russell Syndrome

    PubMed Central

    Beserra, Izabel C. R.; Ribeiro, Márcia G.; Collett-Solberg, Paulo F.; Vaisman, Mário; Guimarães, Marília M.

    2010-01-01

    Objectives. To evaluate, in children with Silver-Russell Syndrome, the response to the IGF-I and IGFBP-3 generation test and compare results to the growth response after 6 months of rhGH. Methods. Eight children (6 males), with a mean age of 5.71 ± 2.48 years and height SDS of −3.88 ± 1.28 received rhGH for 6 months. IGF-I and IGFBP-3 were analyzed before and after 4 doses of rhGH. Results. The mean growth velocity (GV) before treatment was 5.28 ± 1.9 cm/year. GV increased after rhGH in five children to a mean GV of 10.3 ± 3.64 cm/year. Six children had normal basal IGF-I levels and two low levels. After 4 doses of rhGH, the IGF-I levels were normal in seven. There was no correlation between the growth response and the IGF-I generation test. Conclusions. Children with SRS have normal IGF-I generation test. There is no correlation between the generation test and the growth velocity after 6 months of rhGH. PMID:21234390

  12. Growth hormone (GH) activity is associated with increased serum oestradiol and reduced anti-Müllerian hormone in healthy male volunteers treated with GH and a GH antagonist.

    PubMed

    Andreassen, M; Frystyk, J; Faber, J; Kristensen, L Ø; Juul, A

    2013-07-01

    Growth hormone (GH) and insulin-like growth factor I (IGF-I) receptors are present on pituitary gonadotrophs and on testicular Leydig and Sertoli cells. Thus, the GH/IGF-I system may modulate the pituitary-gonadal axis in males. This is a randomized cross-over study. Eight healthy male volunteers (mean age 35, range 29-46 years) were treated with GH for 3 weeks (1st week 0.01, 2nd week 0.02, 3rd week 0.03 mg/day/kg) or a GH receptor antagonist (Pegvisomant) (1st week 10, last 2 weeks 15 mg/day), separated by 8 weeks of washout. Before and after the two treatment periods, concentrations of luteinizing hormone (LH), follicle-stimulating hormone, testosterone, oestradiol, sex hormone-binding globulin, inhibin B and Anti-Müllerian Hormone (AMH) were measured. During GH treatment, IGF-I increased [(median (IQR)] 166 (162-235) vs. 702 (572-875) μg/L, p < 0.001) together with oestradiol [(mean ± SD) 78 ± 23 vs. 111 ± 30 pm, p = 0.019], and the oestradiol/testosterone ratio (p = 0.003). By contrast, AMH (42 ± 14 vs. 32 ± 7 pm, p = 0.018), Inhibin B (211 (146-226) vs. 176 (129-204) ng/L, p = 0.059) and LH (3.8 ± 1.5 vs. 3.2 ± 1.2 U/L, p = 0.096) decreased. During pegvisomant treatment IGF-I (204 (160-290) vs. 106 (97-157) μg/L, p = 0.001) and oestradiol (86 ± 28 vs. 79 ± 25 pm, p = 0.060) decreased. No significant changes or trends in the other reproductive hormones occurred during the two treatment regimens. GH/IGF-I activity was positively associated with serum oestradiol, suggesting that GH/IGF-I stimulates aromatase activity in vivo. As a novel observation, we found that high GH activity was associated with reduced levels of the Sertoli cell marker AMH. Further studies are needed to evaluate possible effects of GH on Sertoli cell function and/or spermatogenesis.

  13. Associations of serum insulin-like growth factor-I and insulin-like growth factor-binding protein 3 levels with biomarker-calibrated protein, dairy product and milk intake in the Women's Health Initiative.

    PubMed

    Beasley, Jeannette M; Gunter, Marc J; LaCroix, Andrea Z; Prentice, Ross L; Neuhouser, Marian L; Tinker, Lesley F; Vitolins, Mara Z; Strickler, Howard D

    2014-03-14

    It is well established that protein-energy malnutrition decreases serum insulin-like growth factor (IGF)-I levels, and supplementation of 30 g of whey protein daily has been shown to increase serum IGF-I levels by 8 % after 2 years in a clinical trial. Cohort studies provide the opportunity to assess associations between dietary protein intake and IGF axis protein levels under more typical eating conditions. In the present study, we assessed the associations of circulating IGF axis protein levels (ELISA, Diagnostic Systems Laboratories) with total biomarker-calibrated protein intake, as well as with dairy product and milk intake, among postmenopausal women enrolled in the Women's Health Initiative (n 747). Analyses were carried out using multivariate linear regression models that adjusted for age, BMI, race/ethnicity, education, biomarker-calibrated energy intake, alcohol intake, smoking, physical activity and hormone therapy use. There was a positive association between milk intake and free IGF-I levels. A three-serving increase in milk intake per d (approximately 30 g of protein) was associated with an estimated average 18·6 % higher increase in free IGF-I levels (95 % CI 0·9, 39·3 %). However, total IGF-I and insulin-like growth factor-binding protein 3 (IGFBP-3) levels were not associated with milk consumption and nor were there associations between biomarker-calibrated protein intake, biomarker-calibrated energy intake, and free IGF-I, total IGF-I or IGFBP-3 levels. The findings of the present study carried out in postmenopausal women are consistent with clinical trial data suggesting a specific relationship between milk consumption and serum IGF-I levels, although in the present study this association was only statistically significant for free, but not total, IGF-I or IGFBP-3 levels.

  14. Role of ghrelin in regulating rabbit ovarian function and the response to LH and IGF-I.

    PubMed

    Sirotkin, Alexander V; Rafay, Ján; Kotwica, Ján; Darlak, Krzysztof; Valenzuela, Francisco

    2009-04-01

    The aim of these in vivo and in vitro studies was to examine the role of ghrelin in the control of plasma hormone concentrations, the proliferation, apoptosis and secretory activity of ovarian granulosa cells and the response of these cells to hormonal treatments. Female rabbits were injected with ghrelin (10 microg/animal/day for one week before ovulation induced by 25IU PMSG and 0.25IU LHRH). On the day of ovulation, blood samples were collected and analyzed for concentrations of progesterone (P(4)), testosterone (T), estradiol (E(2)), estrone-sulphate (ES), insulin-like growth factor I (IGF-I) and leptin (L) by RIA. Some control and ghrelin-treated animals were killed in the periovulatory period, their ovaries were weighed and granulosa cells were isolated and cultured for 2d. Cell proliferation (expression of PCNA) and apoptosis (expression of TdT) were evaluated by immunocytochemistry and TUNEL respectively. Secretion of P(4), T, E(2), IGF-I, and prostaglandin F (PGF) by granulosa cells cultured with and without LH or IGF-I (1, 10 or 100 ng/ml medium) was assessed by RIA. The remaining control and treated animals were kept until parturition, while the number, viability and body weight of pups were recorded. Ghrelin treatment increased rabbit plasma T and decreased ES concentrations but did not influence P(4), E(2), IGF-I or L. Granulosa cells from ghrelin-treated animals showed higher expression of PCNA and lower expression of TdT, than those from control animals. They also secreted less P(4), T, E(2), IGF-I and PGF than granulosa cells from untreated animals. Treatment of cultured granulosa cells with ghrelin (1, 10 or 100 ng/ml medium) either increased (at 1 ng/ml) or decreased (at 10 ng/ml) P(4) secretion, increased (at 100 ng/ml) or decreased (at 10 ng/ml) IGF-I secretion, decreased T (at 1 and 10 ng/ml) and OT (at 1 ng/ml) secretion, and increased (at 100 ng/ml) PGF secretion. LH treatment of cells from control animals stimulated P(4) (at 1 and 10 ng

  15. Evolution of insulin-like growth factor-I (IGF-I) action: in vitro characterization of vertebrate IGF-I proteins.

    PubMed

    Upton, Z; Yandell, C A; Degger, B G; Chan, S J; Moriyama, S; Francis, G L; Ballard, F J

    1998-09-01

    While there is considerable structural evidence that IGFs share a long evolutionary history, less is known about the conservation of IGF action. These studies have primarily been hampered by the small amounts of purified IGFs that have been available for testing. More recently, however, we have adopted recombinant strategies to produce milligram quantities of IGFs for biological studies. Thus we have been able to compare the properties of rat, kangaroo, chicken, salmon and barramundi IGF-I, proteins that differ from human IGF-I by 3, 6, 8, 14 and 16 amino acids respectively. While we have found that the IGF-I proteins exhibit similar biological activities and type-I IGF receptor binding affinities, regardless of whether mammalian, avian or piscine cell lines are used, there was a trend suggesting that the fish proteins at least, were most effective in studies using homologous systems. Thus, salmon IGF-I was not as potent as human IGF-I in bioassays in mammalian cells, but was as effective as human IGF-I in piscine cells. As expected, the IGF-I proteins competed poorly for binding to type-2 receptors present on ovine placental membranes. Interestingly however, the two fish IGF-I proteins exhibited greater affinity for this receptor than the other IGF-I proteins, hence reminiscent of the results previously found with recombinant hagfish IGF. Despite these small differences, these results taken together indicate that the IGF-I proteins appear to have been remarkably conserved in both structure and in vitro action during vertebrate radiation.

  16. Extracellular matrix contains insulin-like growth factor binding protein-5: potentiation of the effects of IGF-I

    PubMed Central

    1993-01-01

    Insulin-like growth factor binding proteins (IGFBPs) have been shown to serve as carrier proteins for the insulin-like growth factors (IGFs) and to modulate their biologic effects. Since extracellular matrix (ECM) has been shown to be a reservoir for IGF-I and IGF-II, we examined the ECM of cultured human fetal fibroblasts and found that IGFBP-5 was incorporated intact into ECM, while mostly inert proteolytic fragments were found in the medium. In contrast, two other forms of IGFBP that are secreted by these cells were either present in ECM in minimal amounts (IGFBP-3) or not detected (IGFBP-4). Likewise, when purified IGFBPs were incubated with ECM, IGFBP-5 bound preferentially. IGFBP-5 was found to bind to types III and IV collagen, laminin, and fibronectin. Increasing salt concentrations inhibited the binding of IGFBP-5 to ECM and accelerated the release of IGFBP-5 from ECM, suggesting an ionic basis for this interaction. ECM-associated IGFBP-5 had a sevenfold decrease in affinity for IGF-I compared to IGFBP-5 in solution. Furthermore, when IGFBP-5 was present in cell culture substrata, it potentiated the growth stimulatory effects of IGF- I on fibroblasts. When IGFBP-5 was present only in the medium, it was degraded to a 22-kD fragment and had no effect on IGF-I-stimulated growth. We conclude that IGFBP-5 is present in fibroblast ECM, where it is protected from degradation and can potentiate the biologic actions of IGF-I. These findings provide a molecular explanation for the association of the IGF's with the extracellular matrix, and suggest that the binding of the IGF's to matrix, via IGFBP-5, may be important in mediating the cellular growth response to these growth factors. PMID:7683690

  17. Effect of insulin-like growth factor-I treatment on serum androgens and testicular and penile size in males with Laron syndrome (primary growth hormone resistance).

    PubMed

    Laron, Z; Klinger, B

    1998-02-01

    Serum gonadotrophins. androgens, insulin and insulin-like growth factor-I (IGF-I) were determined before and during long-term treatment with recombinant IGF-I of seven males with Laron syndrome, and the changes correlated with changes in testicular volume and penile size. The subjects were four boys below the age of 5, two boys aged 10 and 14 but prepubertal and one 28-year-old fully sexually developed adult. IGF-I was administered by a once daily subcutaneous injection of 150 microg/kg per day to the boys and 120 microg/kg per day to the adult patient. In the very young boys no change in serum gonadotrophins, androgens, gonads or genitals was registered. In the two older boys and the adult patient, there was a progressive rise in luteinizing hormone, follicle-stimulating hormone and testosterone. Concomitantly, there was an increase in size of the testes and penile length. The two boys started puberty. As very high serum IGF-I levels were registered in the adult patient, the daily dose was progressively decreased to 70 microg/kg per day. Stopping the IGF-I administration in this patient, according to the protocol, led to a return to pretreatment serum levels and testicular and penile size. This report shows for the first time a direct effect of IGF-I on sex hormones and sex organs in the male.

  18. Evolution of insulin-like growth factor I (IGF-I): structure and expression of an IGF-I precursor from Xenopus laevis.

    PubMed

    Kajimoto, Y; Rotwein, P

    1990-02-01

    By means of a cloning strategy employing the polymerase chain reaction, we have isolated and characterized cDNAs for Xenopus laevis insulin-like growth factor I (IGF-I). These cDNAs encode a primary IGF-I translation product of 153 residues that demonstrates considerable amino acid sequence similarity with IGF-IA peptides from other species. Fifty-seven of 70 residues of the mature protein are identical among human, rat, chicken, and Xenopus IGF-I, while less amino acid conservation is found at the COOH-terminus (25/35 identities) or at the NH2-terminus (24/48 identities) of the precursor protein. Despite the lower degree of structural similarity at the NH2-terminus, in vitro studies of IGF-I biosynthesis and proteolytic processing support a conserved function for the atypically long 48 residue NH2-terminal signal sequence in directing the nascent IGF-I peptide through the secretory pathway. The 5'-untranslated region of Xenopus IGF-I mRNA matches the human, rat, and chicken sequences in greater than 90% of 279 nucleotides. IGF-I mRNAs from all four species encode a conserved upstream open reading frame of 14 amino acids starting 240-250 nucleotides 5' to the translation start site, suggesting a possible role for this region in modulating IGF-I gene expression. The X. laevis IGF-I gene is transcribed and processed into three mRNAs of 1.6, 2.1, and 3.0 kilobases in liver, and IGF-I mRNAs can be detected in liver, lung, heart, kidney, and peritoneal fat of adult animals. These studies demonstrate that both the IGF-I protein precursor and potential regulatory regions of IGF-I mRNA have been conserved during vertebrate evolution, and indicate that like several other polypeptide growth factors, IGF-I may be of fundamental importance in regulating specific aspects of growth and development in all vertebrates.

  19. Nandrolone and stanozolol induce Leydig cell tumor proliferation through an estrogen-dependent mechanism involving IGF-I system.

    PubMed

    Chimento, Adele; Sirianni, Rosa; Zolea, Fabiana; De Luca, Arianna; Lanzino, Marilena; Catalano, Stefania; Andò, Sebastiano; Pezzi, Vincenzo

    2012-05-01

    Several substances such as anabolic androgenic steroids (AAS), peptide hormones like insulin-like growth factor-I (IGF-I), aromatase inhibitors and estrogen antagonists are offered via the Internet, and are assumed without considering the potential deleterious effects that can be caused by their administration. In this study we aimed to determine if nandrolone and stanozolol, two commonly used AAS, could have an effect on Leydig cell tumor proliferation and if their effects could be potentiated by the concomitant use of IGF-I. Using a rat Leydig tumor cell line, R2C cells, as experimental model we found that nandrolone and stanozolol caused a dose-dependent induction of aromatase expression and estradiol (E2) production. When used in combination with IGF-I they were more effective than single molecules in inducing aromatase expression. AAS exhibited estrogenic activity and induced rapid estrogen receptor (ER)-dependent pathways involving IGF1R, AKT, and ERK1/2 phosphorylation. Inhibitors for these kinases decreased AAS-dependent aromatase expression. Up-regulated aromatase levels and related E2 production increased cell proliferation as a consequence of increased cyclin E expression. The observation that ER antagonist ICI182,780 was also able to significantly reduce ASS- and AAS + IGF-induced cell proliferation, confirmed a role for estrogens in AAS-dependent proliferative effects. Taken together these data clearly indicate that the use of high doses of AAS, as it occurs in doping practice, enhances Leydig cell proliferation, increasing the risk of tumor development. This risk is higher when AAS are used in association with IGF-I. To our knowledge this is the first report directly associating AAS and testicular cancer.

  20. IGF-I modulation of GH and LH secretion in the pig

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Three experiments (EXP) were conducted to determine the role of IGF-I in modulating GH and LH secretion. In EXP I, prepuberal gilts, 65 ± 6 kg body weight (BW) and 140 days of age received intracerebroventricular (ICV) injections of saline (n = 4), 25µg (n = 4) or 75µg (n = 4) IGF-I and jugular blo...

  1. Autocrine/paracrine proliferative effect of ovarian GH and IGF-I in chicken granulosa cell cultures.

    PubMed

    Ahumada-Solórzano, S Marisela; Martínez-Moreno, Carlos G; Carranza, Martha; Ávila-Mendoza, José; Luna-Acosta, José Luis; Harvey, Steve; Luna, Maricela; Arámburo, Carlos

    2016-08-01

    It is known that growth hormone (GH) and its receptor (GHR) are expressed in granulosa cells (GC) and thecal cells during the follicular development in the hen ovary, which suggests GH is involved in autocrine/paracrine actions in the female reproductive system. In this work, we show that the knockdown of local ovarian GH with a specific cGH siRNA in GC cultures significantly decreased both cGH mRNA expression and GH secretion to the media, and also reduced their proliferative rate. Thus, we analyzed the effect of ovarian GH and recombinant chicken GH (rcGH) on the proliferation of pre-hierarchical GCs in primary cultures. Incubation of GCs with either rcGH or conditioned media, containing predominantly a 15-kDa GH isoform, showed that both significantly increased proliferation as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, proliferating cell nuclear antigen (PCNA) quantification and ((3)H)-thymidine incorporation ((3)H-T) assays in a dose response fashion. Both, locally produced GH and rcGH also induced the phosphorylation of Erk1/2 in GC cultures. Furthermore, GH increased IGF-I synthesis and its release into the GC culture incubation media. These results suggest that GH may act through local IGF-I to induce GC proliferation, since IGF-I immunoneutralization completely abolished the GH-induced proliferative effect. These data suggest that GH and IGF-I may play a role as autocrine/paracrine regulators during the follicular development in the hen ovary at the pre-hierarchical stage.

  2. Effect of nutrition during calfhood and peripubertal period on serum metabolic hormones, gonadotropins and testosterone concentrations, and on sexual development in bulls.

    PubMed

    Brito, Leonardo F C; Barth, Albert D; Rawlings, Norm C; Wilde, Randal E; Crews, Denny H; Mir, Priya S; Kastelic, John P

    2007-07-01

    The objective of the present study was to characterize the effects of nutrition on circulating concentrations of metabolic hormones, gonadotropins, and testosterone during sexual development in bulls. Nutrition regulated the hypothalamus-pituitary-testes axis through effects on the GnRH pulse generator in the hypothalamus and through direct effects on the testes. Pituitary function (gonadotropin secretion after GnRH challenge) was not affected by nutrition. However, nutrition affected LH pulse frequency and basal LH concentration during the early gonadotropin rise (10-26 weeks of age). There were close temporal associations between changes in insulin-like growth factor-I (IGF-I) concentrations and changes in LH pulse frequency, suggesting a role for IGF-I in regulating the early gonadotropin rise in bulls. The peripubertal increase in testosterone concentration was delayed in bulls with lesser serum IGF-I concentrations (low nutrition), suggesting a role for IGF-I in regulating Leydig cell function. Serum IGF-I concentrations accounted for 72 and 67% of the variation in scrotal circumference and paired-testes volume, respectively (at any given age), indicating that IGF-I may regulate testicular growth. Bulls with a more sustained elevated LH pulse frequency during the early gonadotropin rise (high nutrition) had greater testicular mass at 70 weeks of age relative to the control group (medium nutrition), despite no differences in metabolic hormone concentrations after 26 weeks of age. Therefore, gonadotropin-independent mechanism regulating testicular growth might be dependent on previous gonadotropin milieu.

  3. In Vitro and In Vivo Effects of IGF-I on Adiposity in HIV-associated Metabolic Disease: A Pilot Study

    PubMed Central

    Kim, Roy J.; Vaghani, Sumit; Zifchak, Larisa M.; Quinn, Joseph H.; He, Weimian; Tebas, Pablo; Frank, Ian

    2013-01-01

    Background and Aims We tested the effects of recombinant insulin-like growth factor-I (IGF-I) in an adipocyte model of HIV lipodystrophy and in an open label study on body composition and metabolism in patients with HIV lipodystrophy. Methods The effects of IGF-I on ritonavir-induced adipocyte cell death were studied in vitro. We assessed lipid accumulation, IGF signaling, apoptosis, and gene expression. We conducted a 24-week open label trial of recombinant IGF-I in ten adults with HIV associated lipoatrophy. Laboratory assessments included glucose, insulin, lipids, and IGF-I. At weeks 0 and 24, body composition studies were performed including skinfold measurement, dual-energy x-ray absorptiometry, and computed tomography of the abdomen and thigh. Results In vitro, ritonavir increased delipidation and apoptosis of adipocytes, whereas co-treatment with IGF-I attenuated the effect. In the clinical study, subcutaneous adipose tissue did not increase in patients after treatment with IGF-I; however, there was a decrease in the proportion of abdominal fat (39.8 ± 7% vs. 34.6 ± 7%, p = 0.007). IGF-I levels increased with treatment (143 ± 28 µg/L at week 0 vs. 453 ± 212 µg/L at week 24, p = 0.002), whereas IGFBP-3 levels declined (3.554 ± 1.146 mg/L vs. 3.235 ± 1.151 mg/L, p = 0.02). Insulin at week 12 week decreased significantly (90.1 ± 39.8 pmol/L vs. 33.2 ± 19.6 pmol/L, p = 0.002). There was a nonsignificant decrease in visceral adipose tissue (155.2 ± 68 cm2 at week 0 vs. 140.6 ± 70 cm2 at week 24, p = 0.08). Conclusions Use of recombinant IGF-I may lower fasting insulin and abdominal fat in patients with lipoatrophy associated with HIV infection. Further evaluation of this agent for treatment of HIV-associated lipodystrophy may be warranted. PMID:23867790

  4. Expression and regulation by thyroid hormone (TH) of zebrafish IGF-I gene and amphioxus IGFl gene with implication of the origin of TH/IGF signaling pathway.

    PubMed

    Wang, Yanfeng; Zhang, Shicui

    2011-12-01

    Thyroid hormone (TH)/insulin-like growth factor (IGF) signaling pathway has been identified in all the vertebrates, but its evolutionary origin remains elusive. In this study we examined the expression profiles in vitro as well as in vivo of the IGF-I gene of fish Danio rerio (vertebrate) and the IGF-like gene (IGFl) of amphioxus Branchiostoma japonicum (protochordate) following T(3) treatment. Our results showed that T(3) was able to enhance hepatic IGF-I/IGFl gene expression in vitro in both zebrafish and amphioxus in a dose-dependent manner. This T(3)-induced hepatic expression of IGF-I/IGFl genes in both species was significantly inhibited by the T(3)-specific inhibitor DEA, indicating the specificity of IGF-I/IGFl gene regulation by T(3). At 100nM T(3), in both the long (42h) and short (8h) time course experiments, the IGF-I/IGFl gene expression profiles following T(3) treatment in the tissue cultures of both species exhibited closely similar pattern and trend. Moreover, exposure of zebrafish and amphioxus to T(3)in vivo for 72h induced a significant increase in the expression of IGF-I/IGFl genes in both the liver and the hepatic caecum. These data together suggest that amphioxus and zebrafish both share a similar regulatory mechanism of IGF gene expression in response to T(3), providing an evidence for the presence of a vertebrate-like TH/IGF signaling pathway in the protochordate amphioxus.

  5. The effects of dairy processes and storage on insulin-like growth factor-I (IGF-I) content in milk and in model IGF-I-fortified dairy products.

    PubMed

    Kang, S H; Kim, J U; Imm, J Y; Oh, S; Kim, S H

    2006-02-01

    The effects of several dairy processes on insulin-like growth factor-I (IGF-I) concentrations in milk and the storage stability of IGF-I-fortified dairy products were examined. The IGF-I content in raw milk determined by radioimmunoassay was significantly changed by the strength of heat treatments. In commercial manufacture of whole milk dry powder, IGF-I concentration was not significantly changed. A significant reduction in IGF-I content was found as the result of fermentation with a commercial starter culture. The IGF-I content in fortified milk and dried milk powder exhibited no significant changes over the tested storage periods (12 d for milk, 4 wk for dried milk powder), but the IGF-I content in the yogurt decreased significantly during storage. The use of IGF-I was varied by lactic strains and was apparent in the viable cells. When IGF-I was encapsulated using the surface-reforming process, the remaining IGF-I content after fermentation was significantly higher compared with that of the untreated control. Therefore, enteric coating of IGF-I before fermentation might be an effective method for the prevention of IGF-I degradation during fermentation.

  6. Large scale, in situ isolation of periplasmic IGF-I from E. coli.

    PubMed

    Hart, R A; Lester, P M; Reifsnyder, D H; Ogez, J R; Builder, S E

    1994-11-01

    Human insulin-like growth factor I (IGF-I) accumulates in both folded and aggregated forms in the fermentation medium and cellular periplasmic space when expressed in E. coli with an endogenous secretory signal sequence. Due to its heterogeneity in form and location, low yield of IGF-I was obtained using a typical refractile body recovery strategy. To enhance recovery yield, a new procedure was developed to solubilize and extract IGF-I from cells while in fermentation broth. This method, called in situ solubilization, involves addition of chaotrope and reductant to alkaline fermentation broth and provides recovery of about 90% of all IGF-I in an isolated supernatant. To further enhance recovery, a new aqueous two-phase extraction procedure was developed which partitions soluble non-native IGF-I and biomass solids into separate liquid phases. This two-phase extraction procedure involves addition of polymer and salt to the solubilization mixture and provides about 90% recovery of solubilized IGF-I in the light phase. The performance of the solubilization and aqueous extraction procedures is reproducible at scales ranging from 10 to 1000 liters and provides a 70% cumulative recovery yield of IGF-I in the isolated light phase. The procedure provides significant initial IGF-I purification since most host proteins remain cell associated during solubilization and are enriched in heavy phase. ELISA analysis for E. coli proteins indicates that 97% of the protein in the light phase is IGF-I. Together, the techniques of in situ solubilization and aqueous two-phase extraction provide a new, high yield approach for isolating recombinant protein which is accumulated in more than one form during fermentation.

  7. Endocrine and Local IGF-I in the Bony Fish Immune System

    PubMed Central

    Franz, Anne-Constance; Faass, Oliver; Köllner, Bernd; Shved, Natallia; Link, Karl; Casanova, Ayako; Wenger, Michael; D’Cotta, Helena; Baroiller, Jean-François; Ullrich, Oliver; Reinecke, Manfred; Eppler, Elisabeth

    2016-01-01

    A role for GH and IGF-I in the modulation of the immune system has been under discussion for decades. Generally, GH is considered a stimulator of innate immune parameters in mammals and teleost fish. The stimulatory effects in humans as well as in bony fish often appear to be correlated with elevated endocrine IGF-I (liver-derived), which has also been shown to be suppressed during infection in some studies. Nevertheless, data are still fragmentary. Some studies point to an important role of GH and IGF-I particularly during immune organ development and constitution. Even less is known about the potential relevance of local (autocrine/paracrine) IGF-I within adult and developing immune organs, and the distinct localization of IGF-I in immune cells and tissues of mammals and fish has not been systematically defined. Thus far, IGF-I has been localized in different mammalian immune cell types, particularly macrophages and granulocytes, and in supporting cells, but not in T-lymphocytes. In the present study, we detected IGF-I in phagocytic cells isolated from rainbow trout head kidney and, in contrast to some findings in mammals, in T-cells of a channel catfish cell line. Thus, although numerous analogies among mammals and teleosts exist not only for the GH/IGF-system, but also for the immune system, there are differences that should be further investigated. For instance, it is unclear whether the primarily reported role of GH/IGF-I in the innate immune response is due to the lack of studies focusing on the adaptive immune system, or whether it truly preferentially concerns innate immune parameters. Infectious challenges in combination with GH/IGF-I manipulations are another important topic that has not been sufficiently addressed to date, particularly with respect to developmental and environmental influences on fish growth and health. PMID:26821056

  8. Endocrine and Local IGF-I in the Bony Fish Immune System.

    PubMed

    Franz, Anne-Constance; Faass, Oliver; Köllner, Bernd; Shved, Natallia; Link, Karl; Casanova, Ayako; Wenger, Michael; D'Cotta, Helena; Baroiller, Jean-François; Ullrich, Oliver; Reinecke, Manfred; Eppler, Elisabeth

    2016-01-26

    A role for GH and IGF-I in the modulation of the immune system has been under discussion for decades. Generally, GH is considered a stimulator of innate immune parameters in mammals and teleost fish. The stimulatory effects in humans as well as in bony fish often appear to be correlated with elevated endocrine IGF-I (liver-derived), which has also been shown to be suppressed during infection in some studies. Nevertheless, data are still fragmentary. Some studies point to an important role of GH and IGF-I particularly during immune organ development and constitution. Even less is known about the potential relevance of local (autocrine/paracrine) IGF-I within adult and developing immune organs, and the distinct localization of IGF-I in immune cells and tissues of mammals and fish has not been systematically defined. Thus far, IGF-I has been localized in different mammalian immune cell types, particularly macrophages and granulocytes, and in supporting cells, but not in T-lymphocytes. In the present study, we detected IGF-I in phagocytic cells isolated from rainbow trout head kidney and, in contrast to some findings in mammals, in T-cells of a channel catfish cell line. Thus, although numerous analogies among mammals and teleosts exist not only for the GH/IGF-system, but also for the immune system, there are differences that should be further investigated. For instance, it is unclear whether the primarily reported role of GH/IGF-I in the innate immune response is due to the lack of studies focusing on the adaptive immune system, or whether it truly preferentially concerns innate immune parameters. Infectious challenges in combination with GH/IGF-I manipulations are another important topic that has not been sufficiently addressed to date, particularly with respect to developmental and environmental influences on fish growth and health.

  9. Effects of eccentric cycling exercise on IGF-I splice variant expression in the muscles of young and elderly people.

    PubMed

    Hameed, M; Toft, A D; Pedersen, B K; Harridge, S D R; Goldspink, G

    2008-08-01

    Recovery from micro damage resulting from intensive exercise has been shown to take longer in older muscles. To investigate the factors that may contribute to muscle repair, we have studied the expression of two splice variants of the insulin-like growth factor-I (IGF-I) gene. IGF-IEa and mechano growth factor (MGF) were studied in response to 1 h of eccentric cycling exercise in young and old individuals. Subjects (nine young, aged 20-27 years and eight elderly, aged 67-75 years) completed an eccentric exercise protocol that consisted of 60 min of reverse pedal cycling. Workloads were chosen to give the same relative increases in oxygen uptake (VO2max) and heart rate in young and old subjects. Muscle biopsy samples were obtained from the quadriceps muscle before and 2 1/4 h after completion of the exercise bout and were analyzed for IGF-IEa and MGF mRNA levels using real-time quantitative PCR. No difference was observed between the baseline levels of the two splice variants between the two subject groups. Eccentric cycling exercise resulted in a significant increase in the mean MGF mRNA in both young and old subjects but did not alter IGF-IEa mRNA levels in either age group. As reported previously (Toft et al., 2002), the levels of serum creatine kinase and myoglobin, markers of muscle damage, were increased significantly from baseline and to 5 days after exercise in both young and old subjects. This supports previous research in suggesting that the MGF splice variant is sensitive to muscle damage-inducing exercise and is differentially regulated compared with IGF-IEa.

  10. Cotransfected human chondrocytes: over-expression of IGF-I and SOX9 enhances the synthesis of cartilage matrix components collagen-II and glycosaminoglycans.

    PubMed

    Simental-Mendía, M; Lara-Arias, J; Álvarez-Lozano, E; Said-Fernández, S; Soto-Domínguez, A; Padilla-Rivas, G R; Martínez-Rodríguez, H G

    2015-12-01

    Damage to cartilage causes a loss of type II collagen (Col-II) and glycosaminoglycans (GAG). To restore the original cartilage architecture, cell factors that stimulate Col-II and GAG production are needed. Insulin-like growth factor I (IGF-I) and transcription factor SOX9are essential for the synthesis of cartilage matrix, chondrocyte proliferation, and phenotype maintenance. We evaluated the combined effect of IGF-I and SOX9 transgene expression on Col-II and GAG production by cultured human articular chondrocytes. Transient transfection and cotransfection were performed using two mammalian expression plasmids (pCMV-SPORT6), one for each transgene. At day 9 post-transfection, the chondrocytes that were over-expressing IGF-I/SOX9 showed 2-fold increased mRNA expression of the Col-II gene, as well as a 57% increase in Col-II protein, whereas type I collagen expression (Col-I) was decreased by 59.3% compared with controls. The production of GAG by these cells increased significantly compared with the controls at day 9 (3.3- vs 1.8-times, an increase of almost 83%). Thus, IGF-I/SOX9 cotransfected chondrocytes may be useful for cell-based articular cartilage therapies.

  11. Overexpression of IGF-I in skeletal muscle of transgenic mice does not prevent unloading-induced atrophy

    NASA Technical Reports Server (NTRS)

    Criswell, D. S.; Booth, F. W.; DeMayo, F.; Schwartz, R. J.; Gordon, S. E.; Fiorotto, M. L.

    1998-01-01

    This study examined the association between local insulin-like growth factor I (IGF-I) overexpression and atrophy in skeletal muscle. We hypothesized that endogenous skeletal muscle IGF-I mRNA expression would decrease with hindlimb unloading (HU) in mice, and that transgenic mice overexpressing human IGF-I (hIGF-I) specifically in skeletal muscle would exhibit less atrophy after HU. Male transgenic mice and nontransgenic mice from the parent strain (FVB) were divided into four groups (n = 10/group): 1) transgenic, weight-bearing (IGF-I/WB); 2) transgenic, hindlimb unloaded (IGF-I/HU); 3) nontransgenic, weight-bearing (FVB/WB); and 4) nontransgenic, hindlimb unloaded (FVB/HU). HU groups were hindlimb unloaded for 14 days. Body mass was reduced (P < 0.05) after HU in both IGF-I (-9%) and FVB mice (-13%). Contrary to our hypothesis, we found that the relative abundance of mRNA for the endogenous rodent IGF-I (rIGF-I) was unaltered by HU in the gastrocnemius (GAST) muscle of wild-type FVB mice. High-level expression of hIGF-I peptide and mRNA was confirmed in the GAST and tibialis anterior (TA) muscles of the transgenic mice. Nevertheless, masses of the GAST and TA muscles were reduced (P < 0.05) in both FVB/HU and IGF-I/HU groups compared with FVB/WB and IGF-I/WB groups, respectively, and the percent atrophy in mass of these muscles did not differ between FVB and IGF-I mice. Therefore, skeletal muscle atrophy may not be associated with a reduction of endogenous rIGF-I mRNA level in 14-day HU mice. We conclude that high local expression of hIGF-I mRNA and peptide in skeletal muscle alone cannot attenuate unloading-induced atrophy of fast-twitch muscle in mice.

  12. Potency of Full- Length MGF to Induce Maximal Activation of the IGF-I R Is Similar to Recombinant Human IGF-I at High Equimolar Concentrations

    PubMed Central

    Janssen, Joseph A. M. J. L.; Hofland, Leo J.; Strasburger, Christian J.; van den Dungen, Elisabeth S. R.; Thevis, Mario

    2016-01-01

    Aims To compare full-length mechano growth factor (full-length MGF) with human recombinant insulin-like growth factor-I (IGF-I) and human recombinant insulin (HI) in their ability to activate the human IGF-I receptor (IGF-IR), the human insulin receptor (IR-A) and the human insulin receptor-B (IR-B), respectively. In addition, we tested the stimulatory activity of human MGF and its stabilized analog Goldspink-MGF on the IGF-IR. Methods The effects of full-length MGF, IGF-I, human mechano growth factor (MGF), Goldspink-MGF and HI were compared using kinase specific receptor activation (KIRA) bioassays specific for IGF-I, IR-A or IR-B, respectively. These assays quantify activity by measuring auto-phosphorylation of the receptor upon ligand binding. Results IGF-IR: At high equimolar concentrations maximal IGF-IR stimulating effects generated by full-length MGF were similar to that of IGF-I (89-fold vs. 77-fold, respectively). However, EC50 values of IGF-I and full-length MGF for the IGF-I receptor were 0.86 nmol/L (95% CI 0.69–1.07) and 7.83 nmol/L (95% CI: 4.87–12.58), respectively. No IGF-IR activation was observed by human MGF and Goldspink-MGF, respectively. IR-A/IR-B: At high equimolar concentrations similar maximal IR-A stimulating effects were observed for full -length MGF and HI, but maximal IR-B stimulation achieved by full -length MGF was stronger than that by HI (292-fold vs. 98-fold). EC50 values of HI and full-length MGF for the IR-A were 1.13 nmol/L (95% CI 0.69–1.84) and 73.11 nmol/L (42.87–124.69), respectively; for IR-B these values were 1.28 nmol/L (95% CI 0.64–2.57) and 35.10 nmol/L (95% 17.52–70.33), respectively. Conclusions Full-length MGF directly stimulates the IGF-IR. Despite a higher EC50 concentration, at high equimolar concentrations full-length MGF showed a similar maximal potency to activate the IGF-IR as compared to IGF-I. Further research is needed to understand the actions of full-length MGF in vivo and to define the

  13. Divergent responses of serum insulin-like growth factor-I and liver growth hormone (GH) receptors to exogenous GH in protein-restricted rats.

    PubMed

    Thissen, J P; Triest, S; Underwood, L E; Maes, M; Ketelslegers, J M

    1990-02-01

    Protein deprivation in young rats retards growth and decreases serum insulin-like growth factor-I (IGF-I) concentrations, neither of which is prevented by injections of GH once daily. Since four time daily injections of GH in hypophysectomized rats increase serum IGF-I concentrations more efficiently than single daily injections, we assessed whether this mode of GH delivery could overcome the GH resistance of protein malnutrition. Also, we evaluated whether continuous GH infusion could override this GH resistance. We fed 4-week-old female Wistar rats a low (5%) protein diet (P5) or a normal (15%) protein diet (P15) for 7 days. In a first experiment, rats fed a P5 diet received 40 or 400 micrograms/100 g BW.day rat GH (rGH) in four daily sc injections, while control P5 rats were injected at the same frequency with vehicle. In a second experiment, rats fed a P5 diet received 200 micrograms rGH/100 g BW.day by continuous infusion, while P5 sham-operated rats served as controls. IGF-I was measured by RIA on extracted serum, and free and total liver GH binding were determined by incubation of [125I]bovine GH with water- or MgCl2-treated homogenates, respectively. Neither continuous infusion nor repeated injections of rGH normalized the indices of growth or restored the serum IGF-I level to P15 control values. Injections of 400 micrograms rGH increased serum IGF-I 2-fold (P less than 0.01), but did not promote growth. Continuous GH infusion increased total and free liver GH binding to P15 control values, but had no effect on serum IGF-I. The discordance between liver GH binding and IGF-I confirms that a postreceptor defect is responsible for the GH resistance in protein restriction. These observations demonstrate that the consequences of protein restriction on growth are not overridden by intermittent or continuous administration of GH. The increase in IGF-I in response to 400 micrograms GH given intermittently in the absence of growth-promoting effects suggests that

  14. Insulin-like Growth Factor I (IGF-I)-induced Chronic Gliosis and Retinal Stress Lead to Neurodegeneration in a Mouse Model of Retinopathy*

    PubMed Central

    Villacampa, Pilar; Ribera, Albert; Motas, Sandra; Ramírez, Laura; García, Miquel; de la Villa, Pedro; Haurigot, Virginia; Bosch, Fatima

    2013-01-01

    Insulin-like growth factor I (IGF-I) exerts multiple effects on different retinal cell types in both physiological and pathological conditions. Despite the growth factor's extensively described neuroprotective actions, transgenic mice with increased intraocular levels of IGF-I showed progressive impairment of electroretinographic amplitudes up to complete loss of response, with loss of photoreceptors and bipolar, ganglion, and amacrine neurons. Neurodegeneration was preceded by the overexpression of genes related to retinal stress, acute-phase response, and gliosis, suggesting that IGF-I altered normal retinal homeostasis. Indeed, gliosis and microgliosis were present from an early age in transgenic mice, before other alterations occurred, and were accompanied by signs of oxidative stress and impaired glutamate recycling. Older mice also showed overproduction of pro-inflammatory cytokines. Our results suggest that, when chronically increased, intraocular IGF-I is responsible for the induction of deleterious cellular processes that can lead to neurodegeneration, and they highlight the importance that this growth factor may have in the pathogenesis of conditions such as ischemic or diabetic retinopathy. PMID:23620587

  15. PfIRR Interacts with HrIGF-I and Activates the MAP-kinase and PI3-kinase Signaling Pathways to Regulate Glycogen Metabolism in Pinctada fucata

    PubMed Central

    Shi, Yu; He, Mao-xian

    2016-01-01

    The insulin-induced mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways are major intracellular signaling modules and conserved among eukaryotes that are known to regulate diverse cellular processes. However, they have not been investigated in the mollusk species Pinctada fucata. Here, we demonstrate that insulin-related peptide receptor of P. fucata (pfIRR) interacts with human recombinant insulin-like growth factor I (hrIGF-I), and stimulates the MAPK and PI3K signaling pathways in P. fucata oocytes. We also show that inhibition of pfIRR by the inhibitor PQ401 significantly attenuates the basal and hrIGF-I-induced phosphorylation of MAPK and PI3K/Akt at amino acid residues threonine 308 and serine 473. Furthermore, our experiments show that there is cross-talk between the MAPK and PI3K/Akt pathways, in which MAPK kinase positively regulates the PI3K pathway, and PI3K positively regulates the MAPK cascade. Intramuscular injection of hrIGF-I stimulates the PI3K and MAPK pathways to increase the expression of pfirr, protein phosphatase 1, glucokinase, and the phosphorylation of glycogen synthase, decreases the mRNA expression of glycogen synthase kinase-3 beta, decreases glucose levels in hemocytes, and increases glycogen levels in digestive glands. These results suggest that the MAPK and PI3K pathways in P. fucata transmit the hrIGF-I signal to regulate glycogen metabolism. PMID:26911653

  16. Structural analogs of human insulin-like growth factor I with reduced affinity for serum binding proteins and the type 2 insulin-like growth factor receptor

    SciTech Connect

    Bayne, M.L.; Applebaum, J.; Chicchi, G.G.; Hayes, N.S.; Green, B.G.; Cascieri, M.A.

    1988-05-05

    Four structural analogs of human insulin-like growth factor I (hIGF-I) have been prepared by site-directed mutagenesis of a synthetic IGF-I gene and subsequent expression and purification of the mutant protein from the conditioned media of transformed yeast. (Phe/sup -1/, Val/sup 1/, Asn/sup 2/, Gln/sup 3/, His/sup 4/, Ser/sup 8/, His/sup 9/, Glu/sup 12/, Tyr/sup 15/, Leu/sup 16/)IGF-I (B-chain mutant), in which the first 16 amino acids of hIGF-I were replaced with the first 17 amino acids of the B-chain of insulin, has >1000-, 100-, and 2-fold reduced potency for human serum binding proteins, the rat liver type 2 IGF receptor, and the human placental type 1 IGF receptor, respectively. The B-chain mutant also has 4-fold increased affinity for the human placental insulin receptor. (Gln/sup 3/, Ala/sup 4/) IGF-I has 4-fold reduced affinity for human serum binding proteins, but is equipotent to hIGF-I at the types 1 and 2 IGF and insulin receptors. (Tyr/sup 15/, Leu/sup 16/) IGH-I has 4-fold reduced affinity for human serum binding proteins and 10-fold increased affinity for the insulin receptor. The peptide in which these four-point mutations are combined, (Gln/sup 3/, Ala/sup 4/, Tyr/sup 15/,Leu/sup 16/)IGF-I, has 600-fold reduced affinity for the serum binding proteins. All four of these mutants stimulate DNA synthesis in the rat vascular smooth muscle cell line A10 with potencies reflecting their potency at the type 1 IGF receptor. These studies identify some of the domains of hIGF-I which are responsible for maintaining high affinity binding with the serum binding protein and the type 2 IGF receptor. In addition, These peptides will be useful in defining the role of the type 2 IGF receptor and serum binding proteins in the physiological actions of hIGF-I.

  17. Effect of dietary supplementation of chitosan and galacto-mannan-oligosaccharide on serum parameters and the insulin-like growth factor-I mRNA expression in early-weaned piglets.

    PubMed

    Tang, Zhi-Ru; Yin, Yu-Long; Nyachoti, Charles M; Huang, Rui-Lin; Li, Tie-Jun; Yang, Chengbo; Yang, Xiao-Jian; Gong, Joshua; Peng, Jiang; Qi, De-Sheng; Xing, Jian-Jun; Sun, Zhi-Hong; Fan, Ming Z

    2005-05-01

    The study was to determine effects of dietary supplementation of chitosan (COS) and galacto-mannan-oligosaccharides (GMOS) on some serum biochemical indices, serum growth hormone (GH) and insulin-like growth factor-I (IGF-I) levels, and hepatic and long gissimus muscle IGF-I mRNA expression in early-weaned piglets. Twenty six Duroc x Landrace x Yorkshire piglets at the age of 15 days were used. The piglets had access to creep feed during the suckling. Six piglets were sacrificed for sampling at the beginning of the study. The other 20 piglets were individually housed in metabolic cages and randomly allotted to four corn and soybean meal-based diets including the control group, the antibiotic group with 110 mg lincomycin/kg diet, the COS group containing 0.025% COS, and the GMOS group with 0.20% GMOS, respectively, in a 2-week feeding experiment. Blood urea nitrogen (BUN) level was reduced whereas serum total protein concentration was increased (P<0.05) in responses to the COS and GMOS supplementation. Dietary supplementation of COS and GMOS also increased (P<0.05) the serum GH and IGF-I levels along with enhanced hepatic and the muscle IGF-I mRNA abundance. Dietary supplementation of oligosaccharides such as COS and GMOS may improve growth and feed conversion efficiency by increasing plasma GH and IGF-I levels, in the early-weaned piglets.

  18. IGF-I treatment in adults with type 1 diabetes: effects on glucose and protein metabolism in the fasting state and during a hyperinsulinemic-euglycemic amino acid clamp.

    PubMed

    Carroll, P V; Christ, E R; Umpleby, A M; Gowrie, I; Jackson, N; Bowes, S B; Hovorka, R; Croos, P; Sönksen, P H; Russell-Jones, D L

    2000-05-01

    Type 1 diabetes is associated with abnormalities of the growth hormone (GH)-IGF-I axis. Such abnormalities include decreased circulating levels of IGF-I. We studied the effects of IGF-I therapy (40 microg x kg(-1) x day(-1)) on protein and glucose metabolism in adults with type 1 diabetes in a randomized placebo-controlled trial. A total of 12 subjects participated, and each subject was studied at baseline and after 7 days of treatment, both in the fasting state and during a hyperinsulinemic-euglycemic amino acid clamp. Protein and glucose metabolism were assessed using infusions of [1-13C]leucine and [6-6-2H2]glucose. IGF-I administration resulted in a 51% rise in circulating IGF-I levels (P < 0.005) and a 56% decrease in the mean overnight GH concentration (P < 0.05). After IGF-I treatment, a decrease in the overnight insulin requirement (0.26+/-0.07 vs. 0.17+/-0.06 U/kg, P < 0.05) and an increase in the glucose infusion requirement were observed during the hyperinsulinemic clamp (approximately 67%, P < 0.05). Basal glucose kinetics were unchanged, but an increase in insulin-stimulated peripheral glucose disposal was observed after IGF-I therapy (37+/-6 vs. 52+/-10 micromol x kg(-1) x min(-1), P < 0.05). IGF-I administration increased the basal metabolic clearance rate for leucine (approximately 28%, P < 0.05) and resulted in a net increase in leucine balance, both in the basal state and during the hyperinsulinemic amino acid clamp (-0.17+/-0.03 vs. -0.10+/-0.02, P < 0.01, and 0.25+/-0.08 vs. 0.40+/-0.06, P < 0.05, respectively). No changes in these variables were recorded in the subjects after administration of placebo. These findings demonstrated that IGF-I replacement resulted in significant alterations in glucose and protein metabolism in the basal and insulin-stimulated states. These effects were associated with increased insulin sensitivity, and they underline the major role of IGF-I in protein and glucose metabolism in type 1 diabetes.

  19. Effect of recombinant growth hormone on expression of growth hormone receptor, insulin-like growth factor mRNA and serum level of leptin in growing pigs.

    PubMed

    Xu, Qingfu; Zhao, Zhihui; Ni, Yingdong; Zhao, Ruqian; Chen, Jie

    2003-04-01

    Sixteen Large White x Landrace castrated male pigs were allotted into treatment and control group. The treatment group was injected intramuscularly with recombinant porcine growth hormone (rpGH, 4 mg d(-1)) and the control group with vehicle for 28 days. Animals were slaughtered 4 h after final injection for liver, longissimus dorsi (LD) muscle and blood sampling. Serum concentration of insulin-like growth factor 1 (IGF-I) and leptin were determined by RIA. The total RNA was extracted from tissues to measure the abundance of growth hormone receptor (GHR), IGF-I mRNA by RT-PCR with 18S rRNA internal standard. Results showed that rpGH enhanced the average daily weight gain by 26.1% (P < 0.05), the serum IGF-I concentration by 70.94% (P < 0.01), decreased serum leptin by 34.8% (P < 0.01). The relative abundance of GHR and IGF-I mRNA in liver were increased by 24.45% (P < 0.05) and 45.30% (P < 0.01), respectively, but no difference of GHR (P > 0.05) and IGF-I mRNA (P > 0.05) in LD between GH treated and control group was found. These results suggest that rpGH can up-regulate hepatic GHR and IGF-I gene expression and improve animal growth. However the effect of rpGH on GHR and IGF-I gene expression are tissue-specific.

  20. Insulin receptor isoform A confers a higher proliferative capability to pancreatic beta cells enabling glucose availability and IGF-I signaling.

    PubMed

    Escribano, Oscar; Gómez-Hernández, Almudena; Díaz-Castroverde, Sabela; Nevado, Carmen; García, Gema; Otero, Yolanda F; Perdomo, Liliana; Beneit, Nuria; Benito, Manuel

    2015-07-05

    The main compensatory response to insulin resistance is the pancreatic beta cell hyperplasia to account for increased insulin secretion. In fact, in a previous work we proposed a liver-pancreas endocrine axis with IGF-I (insulin-like growth factor type I) secreted by the liver acting on IRA insulin receptor in beta cells from iLIRKO mice (inducible Liver Insulin Receptor KnockOut) that showed a high IRA/IRB ratio. However, the role of insulin receptor isoforms in the IGF-I-induced beta cell proliferation as well as the underlying molecular mechanisms remain poorly understood. For this purpose, we have used four immortalized mouse beta cell lines: bearing IR (IRLoxP), lacking IR (IRKO), expressing exclusively IRA (IRA), or alternatively expressing IRB (IRB). Pancreatic beta cell proliferation studies showed that IRA cells are more sensitive than those expressing IRB to the mitogenic response induced by IGF-I, acting through the pathway IRA/IRS-1/2/αp85/Akt/mTORC1/p70S6K. More importantly, IRA beta cells, but not IRB, showed an increased glucose uptake as compared with IRLoxP cells, this effect being likely owing to an enhanced association between Glut-1 and Glut-2 with IRA. Overall, our results strongly suggest a prevalent role of IRA in glucose availability and IGF-I-induced beta cell proliferation mainly through mTORC1. These results could explain, at least partially, the role played by the liver-secreted IGF-I in the compensatory beta cell hyperplasia observed in response to severe hepatic insulin resistance in iLIRKO mice.

  1. Insulin-like growth factor-I (IGF-I) misuse in athletes and potential methods for detection.

    PubMed

    Guha, Nishan; Cowan, David A; Sönksen, Peter H; Holt, Richard I G

    2013-12-01

    To athletes, insulin-like growth factor-I (IGF-I) is an attractive performance-enhancing drug, particularly as an alternative to growth hormone (GH) because IGF-I mediates many of the anabolic actions of GH. IGF-I has beneficial effects on muscle protein synthesis and glycogen storage that could enhance performance in several sporting disciplines. Recombinant human IGF-I (rhIGF-I) is used in clinical practice, but a variety of IGF-I compounds and IGF-I analogues are also advertised on the internet and many have been available on the black market for several years. Although methods for detecting GH misuse are now well established and there have been several cases in which athletes have tested positive for GH, no test is yet in place for detecting IGF-I misuse. The GH-2004 research group has been investigating methods for detection of IGF-I misuse and a test is being developed on the basis of the principles of the successful GH-2000 marker method, in which markers from the IGF axis and markers of collagen and bone turnover are used to detect GH misuse. Commercial immunoassays for these markers have been validated for anti-doping purposes but new methods, including IGF-I measurement by use of mass spectrometry, should improve the performance of the tests and help in the detection of athletes who are doping with these peptide hormones.

  2. Differences in the GH-IGF-I axis in children of different weight and fitness status

    PubMed Central

    Hosick, Peter A.; McMurray, Robert G.; Hackney, A.C.; Battaglini, Claudio L.; Combs, Terry P.; Harrell, Joanne S.

    2012-01-01

    Objective To determine if differences in the GH-IGF-I axis exist between children of high and low aerobic fitness who are obese or of normal weight. Design 124 children (ages 8–11) divided into four groups based on BMI and VO2max (mL O2/kg fat free mass(FFM)/min): normal weight — high-fit (NH), normal weight — low-fit (NL), obese — high-fit (OH), and obese — low-fit (OL). Height, weight, skinfolds, body mass index (BMI), body fat percentage and predicted VO2max (both ml/kg/min and ml/kgFFM/min) were assessed. Resting growth hormone (GH), total insulin-like growth factor 1 (total IGF-I), free insulin-like growth factor 1(free IGF-I), and insulin were measured using morning fasting blood samples. Results GH was greater in the NH group compared to the OL group only (p<0.01). No group differences existed for either total IGF-I (p=0.53) or free IGF-I (p=0.189). Insulin was greater in the OH and OL groups than the NH and NL groups (p<0.01). With groups combined (or overall), insulin and free IGF-I were related to fitness (insulin — ml/kg/min: r=−0.226, p<0.05 and ml/kgFFM/min: r= −0.212, p < 0.05; free IGF-I — ml/kg/min: r=−0.219, p<0.01 and ml/kgFFM/min: r= −0.272, p < 0.05). Conclusions Fitness may contribute to the obesity related reduction of GH that may be involved with weight gain. PMID:22436514

  3. Effects of dietary genistein on GH/IGF-I axis of Nile tilapia Oreochromis niloticus

    NASA Astrophysics Data System (ADS)

    Chen, Dong; Wang, Wei; Ru, Shaoguo

    2016-09-01

    There is considerable concern that isoflavones, such as genistein in fish feed composed of soybean protein, aff ects somatic growth in fish. Our previous works demonstrated that 30 and 300 μg/g dietary genistein had no significant eff ect on growth performance in Nile tilapia ( Oreochromis niloticus), but the higher level of genistein (3 000 μg/g) significantly depressed growth. This study was conducted to further examine the eff ects of dietary genistein on the endocrine disruption on growth hormone/insulin-like growth factor-I (GH/IGF-I) axis in Nile tilapia ( O. niloticus). Juvenile fish were fed by hand twice daily to satiation with one of four isonitrogenous and isoenergetic diets, each containing either 0, 30, 300 or 3 000 μg/g genistein. Following an 8-week feeding period, plasma GH and IGF-I levels were investigated by radioimmunoassay and gene expression levels of gh, ghrelin, gnrhs, ghr, npy, npyrs, pacap, ghrs, i gf-I, igf-Ir, and igfbp3 were examined by real-time PCR. The results show that no significant change in plasma GH and IGF-I levels in fish fed with diets containing 30 μg/g and 300 μg/g genistein. mRNA expression of genes along the GH/IGF-I axis remained unaff ected, except for igf-Ir, which was stimulated by the 300 μg/g genistein diet. While in fish fed the 3 000 μg/g genistein diet, the plasma GH and IGF-I levels decreased, and mRNA expression of gh, ghr2, npyr1, igf-I, and igf-Ir were also significantly depressed. In contrast, npy and igfbp3 mRNA expression were enhanced. This study provides convincing evidence for growth impediment by genistein by disturbing the GH/IGF-I axis in Nile tilapia O. niloticus.

  4. Membrane receptor cross talk in gonadotropin-, IGF-I-, and insulin-mediated steroidogenesis in fish ovary: An overview.

    PubMed

    Mukherjee, Dilip; Majumder, Suravi; Roy Moulik, Sujata; Pal, Puja; Gupta, Shreyasi; Guha, Payel; Kumar, Dhynendra

    2017-01-01

    Gonadal steroidogenesis is critical for survival and reproduction of all animals. The pathways that regulate gonadal steroidogenesis are therefore conserved among animals from the steroidogenic enzymes to the intracellular signaling molecules and G protein-coupled receptors (GPCRs) that mediate the activity of these enzymes. Regulation of fish ovarian steroidogenesis in vitro by gonadotropin (GtH) and GPCRs revealed interaction between adenylate cyclase and calcium/calmodulin-dependent protein kinases (CaMKs) and also MAP kinase pathway. Recent studies revealed another important pathway in GtH-induced fish ovarian steroidogenesis: cross talk between GPCRs and membrane receptor tyrosine kinases. Gonadotropin binding to Gαs-coupled membrane receptor in fish ovary leads to production of cAMP which in turn trans-activate the membrane-bound epidermal growth factor receptor (EGFR). This is followed by activation of ERK1/2 signaling that promotes steroid production. Interestingly, GtH-induced trans-activation of EGFR in the fish ovary uniquely requires matrix-metalloproteinase-mediated release of EGF. Inhibition of these proteases blocks GtH-induced steroidogenesis. Increased cAMP production in fish ovarian follicle upregulate follicular cyp19a1a mRNA expression and aromatase activity leading to increased biosynthesis of 17β-estradiol (E2). Evidence for involvement of SF-1 protein in inducing cyp19a1a mRNA and aromatase activity has also been demonstrated. In addition to GtH, insulin-like growth factor (IGF-I) and bovine insulin can alone induced steroidogenesis in fish ovary. In intact follicles and isolated theca cells, IGF-I and insulin had no effect on GtH-induced testosterone and 17a,hydroxysprogeaterone production. GtH-stimulated E2 and 17,20bdihydroxy-4-pregnane 3-one production in granulosa cells however, was significantly increased by IGF-I and insulin. Both IGF-I and insulin mediates their signaling via receptor tyrosine kinases leading to activation of PI3

  5. Co-induction of hepatic IGF-I and progranulin mRNA by growth hormone in tilapia, Oreochromis mossambiccus.

    PubMed

    Chen, Mark Hung-Chih; Li, Yen-Hsing; Chang, Yvonne; Hu, Shao-Yang; Gong, Hong-Yi; Lin, Gen-Hwa; Chen, Thomas T; Wu, Jen-Leih

    2007-01-15

    Like IGF-I, progranulin (pgrn) is a growth factor involved in tumorigenesis and wound healing. We report here the identification and characterization of pgrn cDNA in tilapia and the regulation of its expression by growth hormone (GH). The tilapia pgrn cDNA was cloned by RT-PCR amplification, using gene specific oligonucleotides as amplification primers. The cDNA contains an open reading frame encoding a peptide of 206 amino acid residues (aa) that contains a presumptive signal peptide (23 aa) and two repeat units of granulin (grn, 51 and 52 aa, respectively) franked by a GAP of 49 aa and the carboxyl terminus with 31 aa. The two predicted grn peptides are arranged in tandem repeats interrupted by a GAP peptide. RT-PCR analysis revealed that high levels of prgn mRNA were present in several tissues such as spleen, gastric cecum, intestine, fat tissue, gill, kidney, eye and pancreas, and lower levels in liver, muscle, heart, brain, skin and stomach. Administration of a single dose (500 ng/g body weight) of recombinant seabream growth hormone (rbGH) by intraperitoneal (ip) injection into one-month-old tilapia resulted in an obvious increase of IGF-I and pgrn mRNA (2.7-fold and 2.5-fold, respectively) in the liver at three hours post-GH treatment. The peptide levels of pgrn in the liver of GH-treated fish also were substantially induced over controls at 12h post-GH treatment as detected by western immuno-blot analysis. The co-induction of IGF-I and pgrn following GH treatment may suggest the involvement of pgrn in GH regulated growth in tilapia.

  6. [Growth Hormone-Insulin Growth Factor I (GH-IGF-I) axis and growth].

    PubMed

    Castell, A-L; Sadoul, J-L; Bouvattier, C

    2013-10-01

    Normal human linear growth results from an evolutionary process expressing the sum effect of multiple genes. The growth hormone (GH) - insulin like growth factor (IGF)-I axis is one of the main actors in the growth process. Defects in this axis can be responsible for short or tall stature. Short stature is defined as smaller than - 2 standard deviations (SD). It is a very common reason for consultation in pediatrics; indeed, 2.5 % of children are concerned. Multiple causes make diagnosis difficult. In this article, we detail the most common constitutional causes of small size, including those related to a defect in the GH-IGF-I axis. Then, we report, the first results of the clinical and genetic study conducted on 213 patients with gigantism. Tall stature is defined by a height superior to 2 SD. Finally, recent work linking epigenetics and growth - via signaling pathways of GH-IGF-I axis - will be presented.

  7. Growth hormone, IGF-I and insulin and their abuse in sport

    PubMed Central

    Holt, R I G; Sönksen, P H

    2008-01-01

    There is widespread anecdotal evidence that growth hormone (GH) is used by athletes for its anabolic and lipolytic properties. Although there is little evidence that GH improves performance in young healthy adults, randomized controlled studies carried out so far are inadequately designed to demonstrate this, not least because GH is often abused in combination with anabolic steroids and insulin. Some of the anabolic actions of GH are mediated through the generation of insulin-like growth factor-I (IGF-I), and it is believed that this is also being abused. Athletes are exposing themselves to potential harm by self-administering large doses of GH, IGF-I and insulin. The effects of excess GH are exemplified by acromegaly. IGF-I may mediate and cause some of these changes, but in addition, IGF-I may lead to profound hypoglycaemia, as indeed can insulin. Although GH is on the World Anti-doping Agency list of banned substances, the detection of abuse with GH is challenging. Two approaches have been developed to detect GH abuse. The first is based on an assessment of the effect of exogenous recombinant human GH on pituitary GH isoforms and the second is based on the measurement of markers of GH action. As a result, GH abuse can be detected with reasonable sensitivity and specificity. Testing for IGF-I and insulin is in its infancy, but the measurement of markers of GH action may also detect IGF-I usage, while urine mass spectroscopy has begun to identify the use of insulin analogues. PMID:18376417

  8. Insulin-like growth factor (IGF)-I, IGF-II, IGF binding protein-3, and risk of colorectal cancer: a nested case-control study in the Japan Collaborative Cohort study.

    PubMed

    Suzuki, Sadao; Kojima, Masayo; Tokudome, Shinkan; Suzuki, Koji; Ozasa, Kotaro; Ito, Yoshinori; Inaba, Yutaka; Tajima, Kazuo; Nakachi, Kei; Watanabe, Yoshiyuki; Tamakoshi, Akiko

    2009-12-01

    Insulin-like growth factor (IGF)-I and IGF-II are important mitogen and IGF binding protein-3 (IGFBP-3) exerts opposite effects. However, the results of epidemiological studies on cancer influence are somewhat controversial, and mainly from Western countries. In the present study, we therefore examined associations of serum IGF-I, IGF-II and IGFBP-3 with colorectal cancer risk among participants in the JACC Study in Japan. After matching 3 controls to cases by sex, age, and study area, a total 101 risk sets were examined using a conditional logistic regression model adjusted for body mass index, smoking habit, alcohol consumption and family history of colorectal cancer. The odds ratios (and 95% CIs) for colorectal cancer mortality among the highest tertiles of IGF-I, IGF-II, and IGFBP-3, compared to the lowest tertiles were 1.01 (0.49-2.10), 1.02 (0.55- 1.91), and 1.22 (0.63-2.38), respectively. No linear trends were observed. The lack of any association was not altered after additional adjustment for mutual markers of IGF-I/IGF-II or IGFBP-3, 0.76 (0.34-1.71) for IGF-I, 0.66 (0.30-1.45) for IGF-II, and 1.11 (0.47-2.66) for IGFBP-3. Our prospective data thus indicated that there is no association of IGF-I, IGF-II, and IGFBP-3 with colorectal cancer risk in the Japanese population. Although these markers might be etiologically significant in relation to colorectal cancer, we did not obtain evidence supporting this hypothesis.

  9. Statement by the Growth Hormone Research Society on the GH/IGF-I axis in extending health span.

    PubMed

    Thorner, Michael O

    2009-10-01

    Despite the fact that growth hormone (GH) has not been approved for antiaging purposes, its use for this indication is widespread and increasing. The Growth Hormone Research Society (GRS) convened an international workshop to critically review and debate the available evidence related to the use of GH in the older adults and the relationship between the GH/insulin-like growth factor I (IGF-I) axis and the aging process. This statement presents the conclusions reached and gives recommendations for future studies in this research field regarding the use of GH and growth hormone secretagogues (GHS) for promoting health span. The participants concluded that, until future clinical research in this area is conducted, in particular carefully designed, long-term studies, using validated outcome parameters, the clinical use of GH or GHS in older adults, alone or in combination with testosterone, cannot be recommended. In addition, future basic studies in model systems, to continue to unravel GH/IGF-I effects related to human life span and health span, were advocated.

  10. 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

  11. Whole body cortisol and expression of HSP70, IGF-I and MSTN in early development of sea bass subjected to heat shock.

    PubMed

    Bertotto, Daniela; Poltronieri, Carlo; Negrato, Elena; Richard, Jacopo; Pascoli, Francesco; Simontacchi, Claudia; Radaelli, Giuseppe

    2011-10-01

    Whole body cortisol levels were determined during early larval developmental stages of sea bass (Dicentrarchus labrax) subjected to a heat shock with the aim to investigate the correlation between the stress event and the activation of the hypothalamic-pituitary-interrenal axis. Moreover, the mRNA expression of inducible heat shock protein 70 (HSP70), insulin-like growth factor I (IGF-I) and myostatin (MSTN) was also detected. Whole body cortisol was determined by a radio-immunoassay (RIA) technique whereas the expression of HSP70, IGF-I and MSTN mRNAs was quantified by Real-Time PCR. Cortisol was detectable in all the larvae from hatching but its level increased significantly in larvae submitted to heat shock from 2-day post hatching onwards. An effect of the sole transfer on cortisol levels was detectable at day 10, indicating an increase of the hypothalamic-pituitary-interrenal axis sensitivity from this stage of sea bass development. In animals exposed to heat shock, the expression of inducible HSP70 resulted in a marked increase of mRNA levels already at hatching. This increase was significantly higher from 6 days onwards if compared to controls. Moreover, heat shock resulted in a decrease (although not significant) in IGF-I mRNA expression of stressed larvae if compared to controls. On the contrary, heat shock did not influence the expression of MSTN mRNA in all groups. The results indicate a very early activation of the hypothalamic-pituitary-interrenal axis and in general of the stress response during the development of European sea bass. Moreover, these results suggest the importance of cortisol and inducible HSP70 as bioindicators of stress in aquaculture and confirm the role of IGF-I and MSTN as regulatory factors during development and growth of fish.

  12. Acute regulation of IGF-I by alterations in post-exercise macronutrients

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This investigation sought to examine the contributions of exercise and nutrient replenishment on in vivo regulation of the insulin-like growth factor-I (IGF-I) axis components. Eight college-aged males completed three high-intensity interval training (HIIT) protocols followed by three post-exercise ...

  13. IGF-I induces senescence of hepatic stellate cells and limits fibrosis in a p53-dependent manner

    PubMed Central

    Nishizawa, Hitoshi; Iguchi, Genzo; Fukuoka, Hidenori; Takahashi, Michiko; Suda, Kentaro; Bando, Hironori; Matsumoto, Ryusaku; Yoshida, Kenichi; Odake, Yukiko; Ogawa, Wataru; Takahashi, Yutaka

    2016-01-01

    Hepatic fibrosis in nonalcoholic steatohepatitis (NASH) and cirrhosis determines patient prognosis; however, effective treatment for fibrosis has not been established. Oxidative stress and inflammation activate hepatic stellate cells (HSCs) and promote fibrosis. In contrast, cellular senescence inhibits HSCs’ activity and limits fibrosis. The aim of this study was to explore the effect of IGF-I on NASH and cirrhotic models and to clarify the underlying mechanisms. We demonstrate that IGF-I significantly ameliorated steatosis, inflammation, and fibrosis in a NASH model, methionine-choline-deficient diet-fed db/db mice and ameliorated fibrosis in cirrhotic model, dimethylnitrosamine-treated mice. As the underlying mechanisms, IGF-I improved oxidative stress and mitochondrial function in the liver. In addition, IGF-I receptor was strongly expressed in HSCs and IGF-I induced cellular senescence in HSCs in vitro and in vivo. Furthermore, in mice lacking the key senescence regulator p53, IGF-I did not induce cellular senescence in HSCs or show any effects on fibrosis. Taken together, these results indicate that IGF-I induces senescence of HSCs, inactivates these cells and limits fibrosis in a p53-dependent manner and that IGF-I may be applied to treat NASH and cirrhosis. PMID:27721459

  14. Ovarian receptors for insulin and insulin-like growth factor I (IGF-I) and effects of IGF-I on steroid production by isolated follicular layers of the preovulatory coho salmon ovarian follicle.

    PubMed

    Maestro, M A; Planas, J V; Moriyama, S; Gutiérrez, J; Planas, J; Swanson, P

    1997-05-01

    In this study, receptors for insulin and insulin-like growth factor I (IGF-I) in isolated theca-interstitial layers and granulosa cells of the coho salmon preovulatory ovary were characterized, and the effects of IGF-I on ovarian steroidogenesis were examined. Specific receptors for insulin and IGF-I were found in granulosa and theca-interstitial layers. In both follicular layers, IGF-I receptors were greater in number and higher in affinity than insulin receptors. The effects of IGF-I on in vitro production of testosterone (T) and 17 alpha-hydroxyprogesterone (17OH-P) by theca-interstitial layers and of 17 beta-estradiol (E2) and 17 alpha, 20 beta-dihydroxy-4-pregnen-3-one (17,20 beta-P) by granulosa cell layers were evaluated during the preovulatory period. Both human and salmon recombinant IGF-I inhibited the basal and GTH II-stimulated T and 17OH-P production by theca-interstitial layers throughout the preovulatory period. In contrast, IGF-I stimulated the production of both E2 and 17,20 beta-P by granulosa cell layers prior to germinal vesicle breakdown (GVBD) but only stimulated the production of 17,20 beta-P by granulosa cell layers after GVBD. The inhibitory effects of IGF-I on steroid production by the theca-interstitial layer and the opposite stimulatory effects on steroid production by the granulosa cell layer, coupled by the presence of specific IGF-I receptors in both follicular layers, suggest that IGF-I may play a role in the regulation of steroidogenesis in the preovulatory coho salmon ovary.

  15. Linear growth, growth-hormone secretion and IGF-I generation in children with neglected hypothyroidism before and after thyroxine replacement.

    PubMed

    Soliman, Ashraf T; Omar, Magdy; El Awwa, Ahmad; Rizk, Mostafa M; El Alaily, Rania K; Bedair, Elsaid M A

    2008-10-01

    We studied growth hormone (GH) stimulation and insulin-like growth factor -I (IGF-I) generation tests in 15 children with neglected congenital hypothyroidism (CH) (age = 6.4 +/- 4.2 years) and measured their growth parameters for >1 years after starting thyroxine (T4) replacement. One year after treatment, height SDS (HtSDS) increased from -4.3 +/- 2.5 to -2.7 +/- 2.3. Peak GH response to clonidine increased from 3.2 +/- 1.2 ng ml(-1) to 7.62 +/- 1.38 ng ml(-1) after treatments. Basal and peak IGF-I response to GH increased from (34.66 +/- 17.3 ng ml(-1) and 58.4 +/- 36.99 ng ml(-1), respectively) before treatment to (130.6 +/- 97.8 ng ml(-1) and 193.75 +/- 122.5 ng ml(-1), respectively). HtSDS increments were correlated significantly with basal free T4 concentrations (r = 0.622, P < 0.01). In summary, after long period of hypothyroidism, T4 replacement produced significant, although incomplete, catch-up growth through a partial recovery of GH- IGF-I axis.

  16. Cloning, characterization and tissue specific expression of Amur tiger (Panthera tigris altaica) IGF-I.

    PubMed

    Hu, Xi-Lian; Zhu, Mu-Yuan; Zhang, Zhi-He; Hou, Rong; Shen, Fu-Jun; Li, Fu-Zhen; Zhang, An-Ju

    2006-08-01

    Insulin-like growth factor I (IGF-I) plays an important role in regulating gonad function, which is essential for normal reproduction in animals, especially in sexual receptivity and reproductive behavior. In this study, a cDNA encoding Amur tiger (Panthera tigris altaica) IGF-I was isolated from liver total RNA using RT-PCR. The IGF-I cDNA of Amur tiger (ATIGF-I) was highly homologous to that of other animals, 84.8% to rat, 93.7% to human and horse. Alignment analysis showed that the cysteine residues and many amino acid residues of putative mature ATIGF-I are highly conserved in mammalian species, confirming the high sequence homology observed in other species. DNA encoding the mature ATIGF-I peptide was ligated with pET-DsbA expression vector and highly expressed in Escherichia coli BL21 with IPTG induction. The recombinant proteins expressed existed mostly in the soluble protein fraction, and were purified with metal affinity resins. Western blotting confirmed that the recombinant proteins reacted with antibodies against IGF-I. The results obtained here should be useful for large-scale production of biological active ATIGF-I protein, as well as for further research on growth, development, and reproduction in the Amur tiger. Tissue specific expression of ATIGF-I mRNA in the Amur tiger was examined by reverse transcription-polymerase chain reaction (RT-PCR), The major ATIGF-I mRNA expression tissue was the liver, while medium signals were found in the uterus, ovary, and pituitary, and minor signals were detected in various tissues including the heart, spleen, pancreas, and kidney. The results indicate that IGF-I might play an important role in the reproductive system and in cub development in the Amur tiger.

  17. Potential triple helix-mediated inhibition of IGF-I gene expression significantly reduces tumorigenicity of glioblastoma in an animal model.

    PubMed

    Shevelev, A; Burfeind, P; Schulze, E; Rininsland, F; Johnson, T R; Trojan, J; Chernicky, C L; Hélène, C; Ilan, J; Ilan, J

    1997-01-01

    Oligonucleotide-directed triple helix formation is a powerful approach to block transcription of specific genes. Although the oligonucleotide triplex approach is efficient for inhibiting gene expression in cultured cells, suppression is transient. We developed an approach which inhibits insulin-like growth factor-I (IGF-I) expression following stable transfection of C6 rat glioblastoma cells with a plasmid from which an RNA is transcribed that codes for the third strand of a potential triple helix. We tested the ability of this expression vector to inhibit IGF-I gene expression in vitro as well as tumorigenesis in an animal. A dramatic reduction of IGF-I RNA and protein levels in cultured cells occurred following transfection of rat C6 cells with a eukaryotic expression plasmid encoding the oligopurine variant of the triple helix but not the oligopyrimidine or a control sequence. The cells transfected with the oligopurine variant displayed morphological changes, upregulation of major histocompatibility complex I, and increased expression of protease nexin I. Dramatic inhibition of tumor growth occurred in nude mice following injection of transfected C6 cells. To our knowledge, this is the first example of tumor growth inhibition in an animal model employing a triple helix approach.

  18. Interaction of Mechanical Load with Growth Hormone (GH) and Insulin-Like Growth Factor I (IGF-I) on Slow-Twitch Skeletal Muscle and Bone

    NASA Technical Reports Server (NTRS)

    Linderman, Jon K.; Gosselink, Kristin L.; Wang, Tommy J.; Mukku, Venkat R.; Grindeland, Richard E.

    1994-01-01

    Exogenous humoral growth factors, combined with increased mechanical loading, reportedly induce hypertrophy of fast-, but not slow-twitch skeletal muscles, and have little effect in attenuating atrophy of slow-twitch muscle associated with exposure to microgravity in animals with intact neuroendocrine systems. These observations suggest that anabolic adjuvants and muscle tension do not interact to stimulate growth or maintenance of slow-twitch skeletal muscle. The purpose of the present study was to determine whether a chronic increase in mechanical loading (synergistic ablation) or hindlimb unweighting (hindlimb suspension) interact with exogenous GH and IGF-I (Genentech, So San Francisco, CA) in the slow-twitch soleus muscles of female rats (approx. 250 g). Bilateral ablation of the plantaris and gastrocnemius muscles induced 38% and 40% increases in the absolute (mg/pair) and relative (mg/100 g body weight) weights of the soleus, respectively (p less than or = 0.05), in ambulatory rats. GH and IGF-I interacted with chronic loading to increase absolute soleus mass an additional 20% (p less than or = 0.05), and mixed and myofibrillar protein contents an additional 12% and 7%, respectively (NS). In contrast, hindlimb suspension (HLS) resulted in 20% and 18% decreases in the absolute and relative weights of the soleus, respectively (p less than or = 0.05); GH and IGF-I did not spare loss of soleus mass or protein content in HLS rats. HLS decreased tibial plate thickness approx. 11% (p less than or = 0.05), but not weights of the tibia or femus. GH and IGF-I increased tibial plate thickness approx. 30% (p less than or = 0.05), in ambulatory and HLS rats, and increased femur and tibial weights 12% (p less than or = 0.05) and 8% (NS), respectively, in ambulatory rats, but had no effect in HLS rats. Results of the present investigation suggest that GH and IGF-I can stimulate hypertrophy of slow-twitch skeletal muscle when chronically overloaded, but can also stimulate

  19. Insulin-like growth factors (IGFs) as autocrine/paracrine regulators of granulosa cell differentiation and growth: Studies with a neutralizing monoclonal antibody to IGF-I

    SciTech Connect

    Mondschein, J.S.; Canning, S.F.; Miller, D.Q.; Hammond, J.M. )

    1989-07-01

    Evidence that granulosa cells secrete and respond to insulin-like growth factors (IGFs) suggests, but does not prove, the importance of IGFs as intraovarian regulators. To further assess the role of these peptides in ovarian function, a neutralizing monoclonal antibody to IGF-I was employed to block the actions of IGFs in porcine follicular fluid and in granulosa cell-conditioned medium. In one series of experiments, granulosa cells from immature porcine follicles were cultured in medium containing porcine follicular fluid that had been charcoal-treated to remove steroids. As noted before, fluid from large follicles (LFF) stimulated progesterone production in a dose-dependent manner. The stimulatory effect of LFF (30% v/v) could be inhibited by greater than 50% by the anti-IGF monoclonal antibody. This inhibitory action was specific for the anti-IGF antibody and could be overcome by the addition of excess exogenous IGFs. In another series of experiments, granulosa cells were made dependent on endogenously produced IGFs by culturing them in a serum-free medium without exogenous growth factors. The effects of follicle-stimulating hormone (FSH), estradiol (E2), growth hormone (GH), and combinations thereof on progesterone production were inhibited by approximately 50% by the anti-IGF antibody. The effects of IGFs on indices of cell growth (judged by the criterion of being inhibited by the anti-IGF antibody) were less dramatic. A modest 18% increase in cell number was observed with FSH and E2 treatment in serum-free medium; this effect was virtually abolished by the antibody.

  20. Treatment with N- and C-Terminal Peptides of Parathyroid Hormone-Related Protein Partly Compensate the Skeletal Abnormalities in IGF-I Deficient Mice

    PubMed Central

    Portal-Núñez, Sergio; Murillo-Cuesta, Silvia; Lozano, Daniel; Cediel, Rafael; Esbrit, Pedro

    2014-01-01

    Insulin-like growth factor-I (IGF-I) deficiency causes growth delay, and IGF-I has been shown to partially mediate bone anabolism by parathyroid hormone (PTH). PTH-related protein (PTHrP) is abundant in bone, and has osteogenic features by poorly defined mechanisms. We here examined the capacity of PTHrP (1–36) and PTHrP (107–111) (osteostatin) to reverse the skeletal alterations associated with IGF-I deficiency. Igf1-null mice and their wild type littermates were treated with each PTHrP peptide (80 µg/Kg/every other day/2 weeks; 2 males and 4 females for each genotype) or saline vehicle (3 males and 3 females for each genotype). We found that treatment with either PTHrP peptide ameliorated trabecular structure in the femur in both genotypes. However, these peptides were ineffective in normalizing the altered cortical structure at this bone site in Igf1-null mice. An aberrant gene expression of factors associated with osteoblast differentiation and function, namely runx2, osteoprotegerin/receptor activator of NF-κB ligand ratio, Wnt3a, cyclin D1, connexin 43, catalase and Gadd45, as well as in osteocyte sclerostin, was found in the long bones of Igf1-null mice. These mice also displayed a lower amount of trabecular osteoblasts and osteoclasts in the tibial metaphysis than those in wild type mice. These alterations in Igf1-null mice were only partially corrected by each PTHrP peptide treatment. The skeletal expression of Igf2, Igf1 receptor and Irs2 was increased in Igf1-null mice, and this compensatory profile was further improved by treatment with each PTHrP peptide related to ERK1/2 and FoxM1 activation. In vitro, PTHrP (1–36) and osteostatin were effective in promoting bone marrow stromal cell mineralization in normal mice but not in IGF-I-deficient mice. Collectively, these findings indicate that PTHrP (1–36) and osteostatin can exert several osteogenic actions even in the absence of IGF-I in the mouse bone. PMID:24503961

  1. Effects of resistance training on expression of IGF-I splice variants in younger and older men.

    PubMed

    Ahtiainen, Juha P; Hulmi, Juha J; Lehti, Maarit; Kraemer, William J; Nyman, Kai; Selänne, Harri; Alen, Markku; Komulainen, Jyrki; Kovanen, Vuokko; Mero, Antti A; Philippou, Anastassios; Laakkonen, Eija K; Häkkinen, Keijo

    2016-11-01

    Insulin-like growth factor-I (IGF-I) and its splice variants Insulin-like growth factor-I isoform Ea (IGF-IEa) and mechano growth factor (MGF) may play an important role in muscular adaptations to resistance training (RT) that may be modulated by ageing. It has been suggested that IGF-I induces cellular responses via AKT8 virus oncogene cellular homolog (Akt) and Extracellular signal-regulated kinase (Erk) signalling pathways. Therefore, resistance exercise-induced changes in skeletal muscle IGF-IEa and MGF messenger ribonucleic acid (mRNA), and MGF, Erk1/2, Akt and p70S6K protein expression were investigated before and after 21 weeks of RT in younger (YM, 20-34 yrs., n = 7) and older men (OM, 51-71 yrs., n = 10). Experimental resistance exercises (RE) of 5 × 10 repetition maximum leg presses were performed pre- and post-RT. Muscle biopsies were obtained before and 48 h after REs, to study the late response to muscle loading. The muscle proteins or mRNAs of interest were not systematically influenced by the REs or RT, except for MGF mRNA expression which was increased (p < .01) following RE before RT in OM. No differences were observed between YM and OM in any variables. This study demonstrated that basal levels or RE-induced responses in skeletal muscle MGF, Erk1/2, Akt and p70S6K protein levels or IGF-IEa and MGF mRNA expression did not differ between YM and OM, nor change systematically due to RT. Thus, ageing appears not to effect expression of the present signalling molecules involved in skeletal muscle hypertrophy.

  2. Insulin-like growth factor-I (IGF-I) system during follicle development in the bovine ovary: relationship among IGF-I, type 1 IGF receptor (IGFR-1) and pregnancy-associated plasma protein-A (PAPP-A).

    PubMed

    Sudo, N; Shimizu, T; Kawashima, C; Kaneko, E; Tetsuka, M; Miyamoto, A

    2007-01-29

    Insulin-like growth factor-I (IGF-I) system that is exerted mainly through the type 1 IGF receptor (IGFR-1) and releasing of free IGF-I is regulated by the proteases of IGF-binding proteins (IGFBPs), an important factor in follicle development of bovine ovary. The aims of the present study were to examine the mRNA expressions of IGF-I, IGFR-1 and pregnancy-associated plasma protein-A (PAPP-A) in granulosa cells and theca tissues during bovine follicular development and the effects of follicle-stimulating hormone (FSH) and estradiol (E2) on the expression of these genes in cultured bovine granulosa cells. Follicles were classified into four groups such as small follicle (SF), estrogen inactive dominant follicle (EID), estrogen active dominant follicle (EAD) and preovulatory follicle (POF). The concentration of free IGF-I in follicular fluid of POF was significantly higher than those in EID, whereas the total IGF-I in follicular fluid did not change at all developmental stages. The expression of IGF-I mRNA was not detected in the granulosa cells at all at any developmental stages but the expression was detected in the theca tissues. The amount of IGFR-1 mRNA in granulosa cell showed the constant level at all developmental stages except EID. The expressions of IGFR-1 and PAPP-A in cultured bovine granulosa cells were stimulated with FSH but not with E2. The PAPP-A mRNA expression was stimulated by FSH in presence of 1 ng/ml E2. These results indicate that IGF-I in follicular fluid is mainly derived from the circulation and that FSH is an inducer for the expression of IGFR-1 and PAPP-A genes in granulosa cells. Therefore, we suggest that PAPP-A stimulated with FSH play a crucial role for IGF-I system in bovine follicular development.

  3. IGF-I/PI3K/Akt and IGF-I/MAPK/ERK pathways in vivo in skeletal muscle are regulated by nutrition and contribute to somatic growth in the fine flounder.

    PubMed

    Fuentes, Eduardo N; Björnsson, Björn Thrandur; Valdés, Juan Antonio; Einarsdottir, Ingibjörg Eir; Lorca, Belen; Alvarez, Marco; Molina, Alfredo

    2011-06-01

    The insulin-like growth factor-I (IGF-I) is a key regulator of skeletal muscle growth in vertebrates, promoting mitogenic and anabolic effects through the activation of the MAPK/ERK and the PI3K/Akt signaling pathways. Nutrition also affects skeletal muscle growth, activating intracellular pathways and inducing protein synthesis and accretion. Thus, both hormonal and nutritional signaling regulate muscle mass. In this context, plasma IGF-I levels and the activation of both pathways in response to food were evaluated in the fine flounder using fasting and refeeding trials. The present study describes for the first time in a nonmammalian species that the MAPK/ERK and PI3K/Akt are activated by exogenous circulating IGF-I, as well as showing that the MAPK/ERK pathway activation is modulated by the nutritional status. Also, these results show that there is a time-dependent regulation of IGF-I plasma levels and its signaling pathways in muscle. Together, these results suggest that the nutritionally managed IGF-I could be regulating the activation of the MAPK/ERK and the PI3K/Akt signaling pathways differentially according to the nutritional status, triggering different effects in growth parameters and therefore contributing to somatic growth in fish. This study contributes to the understanding of the nutrient regulation of IGF-I and its signaling pathways in skeletal muscle growth in nonmammalian species, therefore providing insight concerning the events controlling somatic growth in vertebrates.

  4. Pure erythropoietic colony and burst formations in serum-free culture and their enhancement by insulin-like growth factor I.

    PubMed

    Akahane, K; Tojo, A; Urabe, A; Takaku, F

    1987-08-01

    Recombinant human insulin-like growth factor I (IGF-I) increased human and murine erythropoietic colony formation in serum-free culture. In order to investigate the effects of purified factors such as IGF-I on hemopoietic progenitor cells, we have established a serum-free culture system which supports the clonal growth of CFU-E- and BFU-E-derived colonies. Exogenously supplied ingredients were bovine serum albumin (BSA), transferrin, lipid suspensions, 2-mercaptoethanol, and recombinant human erythropoietin (epo). Among these, BSA and cholesterol were found to be essential ingredients. The optimum concentration of BSA sufficient to grow BFU-E was 3%. Erythroid colony and burst formation of human and murine marrow cells was enhanced twofold (p less than 0.05) by a physiological concentration of recombinant human IGF-I. Potentiation was observed in a dose-dependent manner between 10(-9) and 10(-7) M. A few murine CFU-E colonies were formed in the absence of epo. These results suggest that IGF-I has a supportive effect on the proliferation and differentiation of erythroid precursor cells stimulated by epo and that its action is synergistic with that of epo.

  5. Aging influences steroid hormone release by mink ovaries and their response to leptin and IGF-I.

    PubMed

    Sirotkin, Alexander V; Mertin, Dušan; Süvegová, Karin; Harrath, Abdel Halim; Kotwica, Jan

    2016-01-21

    The aim of our study was to understand whether ovarian steroid hormones, and their response to the metabolic hormones leptin and IGF-I leptin, could be involved in the control of mink reproductive aging via changes in basal release of ovarian progesterone and estradiol. For this purpose, we compared the release of progesterone and estradiol by ovarian fragments isolated from young (yearlings) and old (3-5 years of age) minks cultured with and without leptin and IGF-I (0, 1, 10 or 100 ng/ml). We observed that isolated ovaries of older animals produced less progesterone but not less estradiol than the ovaries of young animals. Leptin addition stimulated estradiol release by the ovarian tissue of young animals but inhibited it in older females. Leptin did not influence progesterone output by the ovaries of either young or older animals. IGF-I inhibited estradiol output in young but not old animals, whereas progesterone release was inhibited by IGF-I irrespective of the animal age. Our observations demonstrate the involvement of both leptin and IGF-I in the control of mink ovarian steroid hormones release. Furthermore, our findings suggest that reproductive aging in minks can be due to (a) reduction in basal progesterone release and (b) alterations in the response of estradiol but not of progesterone to leptin and IGF-I.

  6. Aging influences steroid hormone release by mink ovaries and their response to leptin and IGF-I

    PubMed Central

    Sirotkin, Alexander V.; Mertin, Dušan; Süvegová, Karin; Harrath, Abdel Halim; Kotwica, Jan

    2016-01-01

    ABSTRACT The aim of our study was to understand whether ovarian steroid hormones, and their response to the metabolic hormones leptin and IGF-I leptin, could be involved in the control of mink reproductive aging via changes in basal release of ovarian progesterone and estradiol. For this purpose, we compared the release of progesterone and estradiol by ovarian fragments isolated from young (yearlings) and old (3-5 years of age) minks cultured with and without leptin and IGF-I (0, 1, 10 or 100 ng/ml). We observed that isolated ovaries of older animals produced less progesterone but not less estradiol than the ovaries of young animals. Leptin addition stimulated estradiol release by the ovarian tissue of young animals but inhibited it in older females. Leptin did not influence progesterone output by the ovaries of either young or older animals. IGF-I inhibited estradiol output in young but not old animals, whereas progesterone release was inhibited by IGF-I irrespective of the animal age. Our observations demonstrate the involvement of both leptin and IGF-I in the control of mink ovarian steroid hormones release. Furthermore, our findings suggest that reproductive aging in minks can be due to (a) reduction in basal progesterone release and (b) alterations in the response of estradiol but not of progesterone to leptin and IGF-I. PMID:26794607

  7. Effects of tomato- and soy-rich diets on the IGF-I hormonal network: a crossover study of postmenopausal women at high risk for breast cancer.

    PubMed

    McLaughlin, John M; Olivo-Marston, Susan; Vitolins, Mara Z; Bittoni, Marisa; Reeves, Katherine W; Degraffinreid, Cecilia R; Schwartz, Steven J; Clinton, Steven K; Paskett, Electra D

    2011-05-01

    To determine whether dietary modifications with tomato products and/or a soy supplement affected circulating levels of insulin-like growth factor (IGF)-1 and other markers of cell signaling in postmenopausal women at risk for developing breast cancer. Eligible and consented postmenopausal women at high risk for developing breast cancer were enrolled in a 26-week, two-arm (tomato and soy, 10 weeks each) longitudinal dietary intervention study in which each woman served as her own control. Changes in biochemical endpoints including IGF-I, IGF-binding protein (IGFBP)-3, estradiol, sex hormone-binding globulin (SHBG), C-peptide, and insulin were measured for each intervention arm. Carotenoid and isoflavone levels were measured to assess adherence. Significant increases in carotenoid and isoflavone levels during the tomato and soy study arms, respectively, suggested that women were adherent to both arms of the intervention. The tomato-rich diet had little effect on cell-signaling biomarkers previously associated with breast cancer risk. However, results of the soy intervention showed that concentrations of IGF-I and IGFBP-3 increased by 21.6 and 154.7 μmol/L, respectively (P = 0.001 for both) and SHBG decreased by 5.4 μmol/L (P < 0.001) after consumption of the soy protein supplement. Increased soy protein intake may lead to small, but significant, increases in IGF-I and IGFBP-3. Soy consumption also led to a significant decrease in SHBG, which has been hypothesized to promote, rather than prevent, cancer growth. Previous epidemiologic studies, however, have confirmed protective effect of soy on breast cancer. Additional investigation about the effect of soy on breast cancer risk and its mechanism of action is warranted.

  8. PSM, a mediator of PDGF-BB-, IGF-I-, and insulin-stimulated mitogenesis.

    PubMed

    Riedel, H; Yousaf, N; Zhao, Y; Dai, H; Deng, Y; Wang, J

    2000-01-06

    PSM/SH2-B has been described as a cellular partner of the FcepsilonRI receptor, insulin receptor (IR), insulin-like growth factor-I (IGF-I) receptor (IGF-IR), and nerve growth factor receptor (TrkA). A function has been proposed in neuronal differentiation and development but its role in other signaling pathways is still unclear. To further elucidate the physiologic role of PSM we have identified additional mitogenic receptor tyrosine kinases as putative PSM partners including platelet-derived growth factor (PDGF) receptor (PDGFR) beta, hepatocyte growth factor receptor (Met), and fibroblast growth factor receptor. We have mapped Y740 as a site of PDGFR beta that is involved in the association with PSM. We have further investigated the putative role of PSM in mitogenesis with three independent experimental strategies and found that all consistently suggested a role as a positive, stimulatory signaling adapter in normal NIH3T3 and baby hamster kidney fibroblasts. (1) PSM expression from cDNA using an ecdysone-regulated transient expression system stimulated PDGF-BB-, IGF-I-, and insulin- but not EGF-induced DNA synthesis in an ecdysone dose-responsive fashion; (2) Microinjection of the (dominant negative) PSM SH2 domain interfered with PDGF-BB- and insulin-induced DNA synthesis; and (3) A peptide mimetic of the PSM Pro-rich putative SH3 domain-binding region interfered with PDGF-BB-, IGF-I-, and insulin- but not with EGF-induced DNA synthesis in NIH3T3 fibroblasts. This experiment was based on cell-permeable fusion peptides with the Drosophila antennapedia homeodomain which effectively traverse the plasma membrane of cultured cells. These experimental strategies independently suggest that PSM functions as a positive, stimulatory, mitogenic signaling mediator in PDGF-BB, IGF-I, and insulin but not in EGF action. This function appears to involve the PSM SH2 domain as well as the Pro-rich putative SH3 domain binding region. Our findings support the model that PSM

  9. Effects of an evaporative cooling system on plasma cortisol, IGF-I, and milk production in dairy cows in a tropical environment.

    PubMed

    Titto, Cristiane Gonçalves; Negrão, João Alberto; Titto, Evaldo Antonio Lencioni; Canaes, Taissa de Souza; Titto, Rafael Martins; Pereira, Alfredo Manuel Franco

    2013-03-01

    Access to an evaporative cooling system can increase production in dairy cows because of improved thermal comfort. This study aimed to evaluate the impact of ambient temperature on thermoregulation, plasma cortisol, insulin-like growth factor 1 (IGF-I), and productive status, and to determine the efficiency of an evaporative cooling system on physiological responses under different weather patterns. A total of 28 Holstein cows were divided into two groups, one with and the other without access to a cooling system with fans and mist in the free stall. The parameters were analyzed during morning (0700 hours) and afternoon milking (1430 hours) under five different weather patterns throughout the year (fall, winter, spring, dry summer, and rainy summer). Rectal temperature (RT), body surface temperature (BS), base of tail temperature (TT), and respiratory frequency (RF) were lower in the morning (P < 0.01). The cooling system did not affect RT, and both the groups had values below 38.56 over the year (P = 0.11). Cortisol and IGF-I may have been influenced by the seasons, in opposite ways. Cortisol concentrations were higher in winter (P < 0.05) and IGF-I was higher during spring-summer (P < 0.05). The air temperature and the temperature humidity index showed positive moderate correlations to RT, BS, TT, and RF (P < 0.001). The ambient temperature was found to have a positive correlation with the physiological variables, independent of the cooling system, but cooled animals exhibited higher milk production during spring and summer (P < 0.01).

  10. Effects of an evaporative cooling system on plasma cortisol, IGF-I, and milk production in dairy cows in a tropical environment

    NASA Astrophysics Data System (ADS)

    Titto, Cristiane Gonçalves; Negrão, João Alberto; Titto, Evaldo Antonio Lencioni; Canaes, Taissa de Souza; Titto, Rafael Martins; Pereira, Alfredo Manuel Franco

    2013-03-01

    Access to an evaporative cooling system can increase production in dairy cows because of improved thermal comfort. This study aimed to evaluate the impact of ambient temperature on thermoregulation, plasma cortisol, insulin-like growth factor 1 (IGF-I), and productive status, and to determine the efficiency of an evaporative cooling system on physiological responses under different weather patterns. A total of 28 Holstein cows were divided into two groups, one with and the other without access to a cooling system with fans and mist in the free stall. The parameters were analyzed during morning (0700 hours) and afternoon milking (1430 hours) under five different weather patterns throughout the year (fall, winter, spring, dry summer, and rainy summer). Rectal temperature (RT), body surface temperature (BS), base of tail temperature (TT), and respiratory frequency (RF) were lower in the morning ( P < 0.01). The cooling system did not affect RT, and both the groups had values below 38.56 over the year ( P = 0.11). Cortisol and IGF-I may have been influenced by the seasons, in opposite ways. Cortisol concentrations were higher in winter ( P < 0.05) and IGF-I was higher during spring-summer ( P < 0.05). The air temperature and the temperature humidity index showed positive moderate correlations to RT, BS, TT, and RF ( P < 0.001). The ambient temperature was found to have a positive correlation with the physiological variables, independent of the cooling system, but cooled animals exhibited higher milk production during spring and summer ( P < 0.01).

  11. Analyzing Serum-Stimulated Prostate Cancer Cell Lines After Low-Fat, High-Fiber Diet and Exercise Intervention

    PubMed Central

    Soliman, Sherry; Aronson, William J.; Barnard, R. James

    2011-01-01

    Serum from men undergoing a low-fat, high-fiber diet and exercise intervention has previously been shown to decrease growth and increase apoptosis in serum-stimulated, androgen-dependent LNCaP cells associated with a reduction in serum IGF-I. Here we sought to determine the underlying mechanisms for these anticancer effects. Again, the intervention slowed growth and increased apoptosis in LNCaP cells; responses that were eliminated when IGF-I was added back to the post-intervention samples. The p53 protein content was increased and NFκB activation reduced in the post serum-stimulated LNCaP cells. Similar results were observed when the IGF-I receptor was blocked in the pre-intervention serum. In androgen-independent PC-3 cells, growth was reduced while none of the other factors were changed by the intervention. We conclude that diet and exercise intervention might help prevent clinical PCa as well as aid in the treatment of PCa during the early stages of development. PMID:19376839

  12. IGF-I regulates the age-dependent signaling peptide humanin.

    PubMed

    Lee, Changhan; Wan, Junxiang; Miyazaki, Brian; Fang, Yimin; Guevara-Aguirre, Jaime; Yen, Kelvin; Longo, Valter; Bartke, Andrzej; Cohen, Pinchas

    2014-10-01

    Aging is influenced by endocrine pathways including the growth hormone/insulin-like growth factor-1 (GH/IGF) axis. Mitochondrial function has also been linked to the aging process, but the relevant mitochondrial signals mediating the effects of mitochondria are poorly understood. Humanin is a novel signaling peptide that acts as a potent regulator of cellular stress responses and protects from a variety of in vitro and in vivo toxic and metabolic insults. The circulating levels of humanin decline with age in mice and humans. Here, we demonstrate a negative correlation between the activity of the GH-IGF axis and the levels of humanin, as well as a positive correlation between humanin and lifespan in mouse models with altered GH/IGF-I axis. Long-lived, GH-deficient Ames mice displayed elevated humanin levels, while short-lived GH-transgenic mice have reduced humanin levels. Furthermore, treatment with GH or IGF-I reduced circulating humanin levels in both mice and human subjects. Our results indicate that GH and IGF are potent regulators of humanin levels and that humanin levels correlate with lifespan in mice. This suggests that humanin represents a circulating mitochondrial signal that participates in modulating the aging process, adding a coordinated mitochondrial element to the endocrine regulation of aging.

  13. The Role of GH/IGF-I Axis in Muscle Homeostasis During Weightlessness

    NASA Technical Reports Server (NTRS)

    Schwartz, Robert J.

    1997-01-01

    Exposure to reduced gravity during space travel profoundly alters the loads placed on bone and muscle. Astronauts suffer significant losses of muscle and bone strength during weightlessness. Exercise as a countermeasure is only partially effective in remedying severe muscle atrophy and bone demineralization. Similar wasting of muscles and bones affects people on Earth during prolonged bed rest or immobilization due to injury. In the absence of weight bearing activity, atrophy occurs primarily in the muscles that act in low power, routine movements and in maintaining posture. Hormonal disfunction could contribute in part to the loss of muscle and bone during spaceflight. Reduced levels of human Growth Hormone (hGH) were found in astronauts during space flight, as well as reduced GH secretory activity was observed from the anterior pituitary in 7-day space flight rats. Growth hormone has been shown to be required for maintenance of muscle mass and bone mineralization, in part by mediating the biosynthesis IGF-I, a small polypeptide growth factor. IGF biosynthesis and secretion plays an important role in potentiating muscle cell differentiation and has been shown to drive the expression of myogenin, a myogenic specific basic helix-loop-helix factor. IGF-I has also been shown to have an important role in potentiating muscle regeneration, repair and adult muscle hypertrophy.

  14. IGF-I Signaling in Osterix-Expressing Cells Regulates Secondary Ossification Center Formation, Growth Plate Maturation, and Metaphyseal Formation During Postnatal Bone Development.

    PubMed

    Wang, Yongmei; Menendez, Alicia; Fong, Chak; ElAlieh, Hashem Z; Kubota, Takuo; Long, Roger; Bikle, Daniel D

    2015-12-01

    To investigate the role of IGF-I signaling in osterix (OSX)-expressing cells in the skeleton, we generated IGF-I receptor (IGF-IR) knockout mice ((OSX)IGF-IRKO) (floxed-IGF-IR mice × OSX promoter-driven GFP-labeled cre-recombinase [(OSX)GFPcre]), and monitored postnatal bone development. At day 2 after birth (P2), (OSX)GFP-cre was highly expressed in the osteoblasts in the bone surface of the metaphysis and in the prehypertrophic chondrocytes (PHCs) and inner layer of perichondral cells (IPCs). From P7, (OSX)GFP-cre was highly expressed in PHCs, IPCs, cartilage canals (CCs), and osteoblasts (OBs) in the epiphyseal secondary ossification center (SOC), but was only slightly expressed in the OBs in the metaphysis. Compared with the control mice, the IPC proliferation was decreased in the (OSX)IGF-IRKOs. In these mice, fewer IPCs invaded into the cartilage, resulting in delayed formation of the CC and SOC. Immunohistochemistry indicated a reduction of vessel number and lower expression of VEGF and ephrin B2 in the IPCs and SOC of (OSX)IGF-IRKOs. Quantitative real-time PCR revealed that the mRNA levels of the matrix degradation markers, MMP-9, 13 and 14, were decreased in the (OSX)IGF-IRKOs compared with the controls. The (OSX)IGF-IRKO also showed irregular morphology of the growth plate and less trabecular bone in the tibia and femur from P7 to 7 weeks, accompanied by decreased chondrocyte proliferation, altered chondrocyte differentiation, and decreased osteoblast differentiation. Our data indicate that during postnatal bone development, IGF-I signaling in OSX-expressing IPCs promotes IPC proliferation and cartilage matrix degradation and increases ephrin B2 production to stimulate vascular endothelial growth factor (VEGF) expression and vascularization. These processes are required for normal CC formation in the establishment of the SOC. Moreover, IGF-I signaling in the OSX-expressing PHC is required for growth plate maturation and osteoblast differentiation in

  15. Combination treatment with ethyl pyruvate and IGF-I exerts neuroprotective effects against brain injury in a rat model of neonatal hypoxic-ischemic encephalopathy

    PubMed Central

    RONG, ZHIHUI; PAN, RUI; CHANG, LIWEN; LEE, WEIHUA

    2015-01-01

    Neonatal hypoxic-ischemic (HI) brain injury causes severe brain damage in newborns. Following HI injury, rapidly accumulating oxidants injure neurons and interrupt ongoing developmental processes. The antioxidant, sodium pyruvate, has been shown to reduce neuronal injury in neonatal rats under conditions of oxygen glucose deprivation (OGD) and HI injury. In this study, we evaluated the effects of ethyl pyruvate (EP) and insulin-like growth factor-I (IGF-I) alone or in combination in a similar setting. For this purpose, we used an in vitro model involving primary neonatal rat cortical neurons subjected to OGD for 2.5 h and an in vivo model involving unilateral carotid ligation in rats on post-natal day 7 with exposure to 8% hypoxia for 2.5 h. The cultured neurons were examined by lactate dehydrogenase (LDH) and cell viability assays. For the in vivo experiments, behavioral development was evaluated by the foot fault test at 4 weeks of recovery. 2,3,5-Triphenyltetrazolium chloride monohydrate and cresyl violet staining were used to evaluate HI injury. The injured neurons were Fluoro-Jade B-labeled, new neuroprecursors were double labeled with bromodeoxyuridine (BrdU) and doublecortin, new mature neurons were BrdU-labeled and neuronal nuclei were labeled by immunofluorescence. Under conditions of OGD, the LDH levels increased and neuronal viability decreased. Treatment with 0.5 mM EP or 25 ng/ml IGF-I protected the neurons (P<0.05), exerting additive effects. Similarly, either the early administration of EP or delayed treatment with IGF-I protected the neonatal rat brains against HI injury and improved neurological performance and these effects were also additive. This effect may be the result of reduced neuronal injury, and enhanced neurogenesis and maturation. On the whole, our findings demonstrate that the combination of the early administration of EP with delayed treatment with IGF-I exerts neuroprotective effects against HI injury in neonatal rat brains. PMID

  16. IGF-I: A Key Growth Factor that Regulates Neurogenesis and Synaptogenesis from Embryonic to Adult Stages of the Brain

    PubMed Central

    Nieto-Estévez, Vanesa; Defterali, Çağla; Vicario-Abejón, Carlos

    2016-01-01

    The generation of neurons in the adult mammalian brain requires the activation of quiescent neural stem cells (NSCs). This activation and the sequential steps of neuron formation from NSCs are regulated by a number of stimuli, which include growth factors. Insulin-like growth factor-I (IGF-I) exert pleiotropic effects, regulating multiple cellular processes depending on their concentration, cell type, and the developmental stage of the animal. Although IGF-I expression is relatively high in the embryonic brain its levels drop sharply in the adult brain except in neurogenic regions, i.e., the hippocampus (HP) and the subventricular zone-olfactory bulb (SVZ-OB). By contrast, the expression of IGF-IR remains relatively high in the brain irrespective of the age of the animal. Evidence indicates that IGF-I influences NSC proliferation and differentiation into neurons and glia as well as neuronal maturation including synapse formation. Furthermore, recent studies have shown that IGF-I not only promote adult neurogenesis by regulating NSC number and differentiation but also by influencing neuronal positioning and migration as described during SVZ-OB neurogenesis. In this article we will revise and discuss the actions reported for IGF-I signaling in a variety of in vitro and in vivo models, focusing on the maintenance and proliferation of NSCs/progenitors, neurogenesis, and neuron integration in synaptic circuits. PMID:26941597

  17. Expression of IGF-I and Protein Degradation Markers During Hindlimb Unloading and Growth Hormone Administration in Rats

    NASA Astrophysics Data System (ADS)

    Leinsoo, T. A.; Turtikova, O. V.; Shenkman, B. S.

    2013-02-01

    It is known that hindlimb unloading or spaceflight produce atrophy and a number of phenotypic alterations in skeletal muscles. Many of these processes are triggered by the axis growth hormone/insulin-like growth factor I. However growth hormone (GH) and insulin-like growth factor I (IGF-I) expression relationship in rodent models of gravitational unloading is weakly investigated. We supposed the IGF-I is involved in regulation of protein turnover. In this study we examined the IGF-I expression by RT-PCR assay in the rat soleus, tibialis anterior and liver after 3 day of hindlimb suspension with growth hormone administration. Simultaneously were studied expression levels of MuRF-1 and MAFbx/atrogin as a key markers of intracellular proteolysis. We demonstrated that GH administration did not prevent IGF-I expression decreasing under the conditions of simulated weightlessness. It was concluded there are separate mechanisms of action of GH and IGF-I on protein metabolism in skeletal muscles. Gravitational unloading activate proteolysis independently of growth hormone activity.

  18. Stimulation of chick embryo cartilage sulfate and thymidine uptake: comparison of human serum, purified somatomedins, and other growth factors.

    PubMed

    Jennings, J; Buchanan, F; Freeman, D; Garland, J T

    1980-11-01

    We have compared the stimulation of sulfate and thymidine uptake into 10-day-old embryonic chick cartilage by normal human serum, partially purified somatomedins (Sm) A and B, homogeneous insulin-like growth factors (IGFs) I and II, and several other substances. With the exception of epidermal growth factor, all growth factors ((GFs) were assayed in the absence of other protein. Pelvic rudiments were preincubated in buffer for 6 h and then incubated for 24 h with the GF or serum, with labels added for the final 6 h. Human serum enhanced cartilage uptake of both thymidine and sulfate. There was a dose-dependent stimulation of thymidine uptake by Sm A or B (0.05--2 microgram/ml) and IGF I or II (0.5--20 ng/ml). Unlike serum, neither Sms nor IGFs increased SO4 uptake under these conditions. Bovine GH (10--500 ng/ml), albumin (100-1000 ng/ml), fibroblast GF (1--100 ng/ml), and epidermal GF (1--100 ng/ml) were inactive for both thymidine and sulfate. When a shorter incubation was used (7 h), Sm A enhanced SO4 uptake, and discrimination was increased by preincubation of the rudiments in buffer for 24 h. With this procedure, IGF I (0.5 ng/ml) was nearly equipotent to 5% serum. On a weight basis, IGF I was more active than either Sm A or IGF II. The data suggest that assay conditions are crucial for demonstration of Sm activity. Appropriate conditions may be different for isolated GF than for a complex medium such as serum. The results further suggest that with certain protocols, the responsiveness of chick embryo cartilage is qualitatively similar to that of hypophysectomized rat cartilage.

  19. Long-term treatment of ghrelin stimulates feeding, fat deposition, and alters the GH/IGF-I axis in the tilapia, Oreochromis mossambicus.

    PubMed

    Riley, Larry G; Fox, Bradley K; Kaiya, Hiroyuki; Hirano, Tetsuya; Grau, E Gordon

    2005-05-15

    Recently, a new peptide, ghrelin, which specifically stimulates growth hormone (GH) release from the pituitary, was identified in the rat and human stomach. Ghrelin has been shown to stimulate GH release by acting through a growth hormone secretagogue receptor. We have identified two ghrelins (ghrelin-C8 and -C10) in the stomach of tilapia, a euryhaline fish. The current study was aimed at investigating the in vivo effect of the two tilapia ghrelins on feeding, fat deposition, and on the GH/IGF-I axis. Tilapia were implanted with micro-osmotic pumps containing either ghrelin-C8, ghrelin-C10 or saline (control). Ghrelin was delivered at a continuous rate of 10 ng/h for 21 days. Food consumption increased significantly in those animals that received ghrelin-C10 but not ghrelin-C8. Treatment with ghrelin-C10 increased body weight significantly without altering body length. Hence, the condition factor was significantly higher in the ghrelin-C10 group compared with the control. Liver weight and total fat content in the liver were also elevated significantly in the fish treated with ghrelin-C10. There was no effect of either ghrelin on plasma GH levels, whereas plasma IGF-I levels were reduced significantly in the ghrelin-C10 group. These findings demonstrate that ghrelin plays a role in feeding and fat metabolism in the tilapia, and suggest that the two forms of ghrelin may be acting through different receptors.

  20. IGF-I, insulin and FGFs induce outgrowth of the limb buds of amelic mutant chick embryos.

    PubMed

    Dealy, C N; Kosher, R A

    1996-04-01

    IGF-I, insulin, FGF-2 and FGF-4 have been implicated in the reciprocal interactions between the apical ectodermal ridge (AER) and underlying mesoderm required for outgrowth and patterning of the developing limb. To study further the roles of these growth factors in limb outgrowth, we have examined their effects on the in vitro morphogenesis of limb buds of the amelic mutant chick embryos wingless (wl) and limbless (ll). Limb buds of wl and ll mutant embryos form at the proper time in development, but fail to undergo further outgrowth and subsequently degenerate. Wl and ll limb buds lack thickened AERs capable of promoting limb outgrowth, and their thin apical ectoderms fail to express the homeobox-containing gene Msx-2, which is highly expressed by normal AERs and has been implicated in regulating AER activity. Here we report that exogenous IGF-I and insulin, and, to a lesser extent, FGF-2 and FGF-4 induce the proliferation and directed outgrowth of explanted wl and ll mutant limb buds, which in vitro, like in vivo, normally fail to undergo outgrowth and degenerate. IGF-I and insulin, but not FGFs, also cause the thin apical ectoderms of wl and ll limb buds to thicken and form structures that grossly resemble normal AERs and, moreover, induce high level expression of Msx-2 in these thickened AER-like structures. Neither IGF-I, insulin nor FGFs induce expression of the homeobox-containing gene Msx-1 in the subapical mesoderm of wl or ll limb buds, although FGFs, but not IGF-I or insulin, maintain Msx-1 expression in normal (non-mutant) limb bud explants lacking an AER. The implications of these results to the relationships among the wl and ll genes, IGF-I/insulin, FGFs, Msx-2 and Msx-1 in the regulation of limb outgrowth is discussed.

  1. Development and biological function of the female gonads and genitalia in IGF-I deficiency -- Laron syndrome as a model.

    PubMed

    Laron, Zvi

    2006-01-01

    Laron syndrome (LS) or primary GH insensitivity is a unique human model to study the effects of congenital IGF-I deficiency. Within our cohort of 63 patients with LS, 15 female patients were regularly followed since birth or infancy, throughout puberty. We observed that they were short at birth, with small genitalia and gonads -- during puberty, developed delayed puberty but eventually reached between 16 and 19 1/2 years full sexual development. Reproduction is unaffected at a young adult age. It is concluded that IGF-I in concert with the sex hormones has a modulatory but not essential function on female sexual development and maturation.

  2. Effects of Moderate Aerobic Exercise Combined with Caloric Restriction on Circulating Estrogens and IGF-I in Premenopausal Women

    DTIC Science & Technology

    2003-10-01

    of a novel approach to estimating energy status by measuring metabolic hormones in plasma, insulin, IGF-I, IGFBP-1 and leptin . Recently, dried blood...been properly validated for insulin, IGF-I, IGFBP- 1 and leptin , and it is unclear whether the technique is responsive to physiological changes of...IGFBP-I, Insulin, IGFBP-I, Insulin, (Days 3, 6, 8, 10, 12, IGFBP-1, In Food Frequency Detection Kit i Diet Counseling (LP) T3 , leptin j T3, leptin T3

  3. Insulin/IGF-I and Related Signaling Pathways Regulate Aging in Nondividing Cells: from Yeast to the Mammalian Brain

    PubMed Central

    Parrella, Edoardo

    2015-01-01

    Mutations that reduce glucose or insulin/insulin-like growth factor-I (IGF-I) signaling increase longevity in organisms ranging from yeast to mammals. Over the past 10 years, several studies confirmed this conserved molecular strategy of longevity regulation, and many more have been added to the complex mosaic that links stress resistance and aging. In this review, we will analyze the similarities that have emerged over the last decade between longevity regulatory pathways in organisms ranging from yeast, nematodes, and fruit flies to mice. We will focus on the role of yeast signal transduction proteins Ras, Tor, Sch9, Sir2, their homologs in higher organisms, and their association to oxidative stress and protective systems. We will discuss how the “gmolecular strategy” responsible for life span extension in response to dietary and genetic manipulations appears to be remarkably conserved in various organisms and cells, including neuronal cells in different organisms. Taken together, these studies indicate that simple model systems will contribute to our comprehension of aging of the mammalian nervous system and will stimulate novel neurotherapeutic strategies in humans. PMID:20098959

  4. 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

  5. High-Methionine Diet Attenuates Severity of Arthritis and Modulates IGF-I Related Gene Expressions in an Adjuvant Arthritis Rats Model

    PubMed Central

    2016-01-01

    Rheumatoid arthritis, a synthesized form of adjuvant arthritis exhibited throughout many animal species, inhibits liver function and circulation of IGF-I and contributes to the degradation of skeletal muscle mass. One of the primary goals of the present study is determining whether a high-Methionine (high-Met) diet is capable of reducing the adverse effects of arthritis, namely, loss of body mass. Following adjuvant injection, forty arthritic rats were randomly assigned to either a control group with a basal diet or a high-Met group with the same basal diet + 0.5% Methionine. After 14 days all rats were terminated. The high-Met group exhibited an increase in body weight and food intake in comparison with the control group (P < 0.05). High-Met diet debilitated arthritis-induced surges in the gastrocnemius in both atrogin-1 and the MuRF1 expressions; however, it was observed to have little to no effect on atrogin-1 and MuRF1 gene expression in soleus. At the same time, high-Met diet rats experienced a rise in IGF-I, with lowering of IGFBP-3 gene expression in the gastrocnemius and the soleus. These data suggest that arthritis severity can be partly attenuated by high-Met diet. PMID:27738392

  6. Characterization data of gilthead sea bream (Sparus aurata) IGF-I receptors (IGF-IRa/Rb).

    PubMed

    Vélez, Emilio J; Azizi, Sheida; Salmerón, Cristina; Chan, Shu Jin; Nematollahi, Mohammad Ali; Amiri, Bagher Mojazi; Navarro, Isabel; Capilla, Encarnación; Gutiérrez, Joaquim

    2016-03-01

    In this data article we describe the coding sequence of two IGF-IR paralogues (IGF-IRa and IGF-IRb) obtained from gilthead sea bream embryos. The putative protein architecture (domains and other important motifs) was determined and, amino acid sequences alignment and phylogenetic analysis of both receptors together with IGF-IR orthologues from different vertebrates was performed. Additionally, a semi-quantitative conventional PCR was done to analyze the mRNA expression of both receptors in different tissues of gilthead sea bream. These data will assist in further physiological studies in this species. In this sense, the expression of both receptors during ontogeny in muscle as well as the differential effects of IGF-I and IGF-II on their regulation during in vitro myogenesis has been recently studied (doi: 10.1016/j.ygcen.2015.11.011; [1]).

  7. Growth hormone/IGF-I and/or resistive exercise maintains myonuclear number in hindlimb unweighted muscles

    NASA Technical Reports Server (NTRS)

    Allen, D. L.; Linderman, J. K.; Roy, R. R.; Grindeland, R. E.; Mukku, V.; Edgerton, V. R.

    1997-01-01

    In the present study of rats, we examined the role, during 2 wk of hindlimb suspension, of growth hormone/insulin-like growth factor I (GH/IGF-I) administration and/or brief bouts of resistance exercise in ameliorating the loss of myonuclei in fibers of the soleus muscle that express type I myosin heavy chain. Hindlimb suspension resulted in a significant decrease in mean soleus wet weight that was attenuated either by exercise alone or by exercise plus GH/IGF-I treatment but was not attenuated by hormonal treatment alone. Both mean myonuclear number and mean fiber cross-sectional area (CSA) of fibers expressing type I myosin heavy chain decreased after 2 wk of suspension compared with control (134 vs. 162 myonuclei/mm and 917 vs. 2,076 micron2, respectively). Neither GH/IGF-I treatment nor exercise alone affected myonuclear number or fiber CSA, but the combination of exercise and growth-factor treatment attenuated the decrease in both variables. A significant correlation was found between mean myonuclear number and mean CSA across all groups. Thus GH/IGF-I administration and brief bouts of muscle loading had an interactive effect in attenuating the loss of myonuclei induced by chronic unloading.

  8. Co-induction of hepatic IGF-I and progranulin mRNA by growth hormone in tilapia, Oreochromis mossambiccus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Like IGF-I, progranulin (pgrn) is a growth factor involved in tumorigenesis and wound healing. We report here the identification and characterization of pgrn cDNA in tilapia and the regulation of its expression by growth hormone(GH). The tilapia pgrn cDNA was cloned by RT-PCR ampliWcation, using g...

  9. Body Composition and Circulating High-Molecular-Weight Adiponectin and IGF-I in Infants Born Small for Gestational Age

    PubMed Central

    de Zegher, Francis; Sebastiani, Giorgia; Diaz, Marta; Sánchez-Infantes, David; Lopez-Bermejo, Abel; Ibáñez, Lourdes

    2012-01-01

    Prenatal growth restraint, if followed by postnatal overweight, confers risk for adult disease including diabetes. The mechanisms whereby neonatal nutrition may modulate such risk are poorly understood. We studied the effects of nutrition (breast-feeding [BRF] vs. formula-feeding [FOF]) on weight partitioning and endocrine state (as judged by high-molecular-weight [HMW] adiponectin and IGF-I) of infants born small for gestational age (SGA). Body composition (by absorptiometry), HMW adiponectin, and IGF-I were assessed at birth and 4 months in BRF infants born appropriate for gestational age (AGA; n = 72) and SGA infants receiving BRF (n = 46) or FOF (n = 56), the latter being randomized to receive a standard (FOF1) or protein-rich formula (FOF2). Compared with AGA-BRF infants, the catchup growth of SGA infants was confined to lean mass, independently of nutrition. Compared with AGA-BRF infants, SGA-BRF infants had normal HMW adiponectin and IGF-I levels at 4 months, whereas SGA-FOF infants had elevated levels of HMW adiponectin (particularly SGA-FOF1) and IGF-I (particularly SGA-FOF2). In conclusion, neonatal nutrition seems to influence endocrinology more readily than body composition of SGA infants. Follow-up will disclose whether the endocrine abnormalities in SGA-FOF infants can serve as early markers of an unfavorable metabolic course and whether they may contribute to design early interventions that prevent subsequent disease, including diabetes. PMID:22648385

  10. IGF-I and insulin in the acquisition of limb-forming ability by the embryonic lateral plate.

    PubMed

    Dealy, C N; Kosher, R A

    1996-07-10

    Acquisition of limb-forming ability by discrete regions of the lateral plate of the chick embryo is dependent on a medial-lateral inductive signaling cascade moving sequentially from the area of Hensen's node to the somitic mesoderm, the intermediate mesoderm, and then to the prospective limb-forming regions of the lateral plate. IGF-I and insulin are expressed by medial tissues as they are influencing the prospective limb-forming regions of the lateral plate. Here we report that IGF-I and insulin, but not FGF-2 or FGF-4, induce the formation of limb bud-like structures in vitro from prospective limb regions before they have acquired the ability to form limbs independent of medial tissues, and also induce the formation of limb bud-like structures from the prospective flank. The limb bud-like structures induced by IGF-I and insulin possess a thickened cap of ectoderm along their distal tips that resembles the apical ectodermal ridge (AER) and this thickened distal apical ectoderm expresses the AER-characteristic homeobox-containing gene Msx-2. Like in normal limb buds, a population of highly proliferating cells which express the homeobox-containing gene Msx-1 are localized in the mesoderm directly subjacent to the thickened AER-like structures induced by IGF-I and insulin. However, the limb bud-like structures induced by IGF-I and insulin do not express sonic hedgehog, which encodes a secreted signaling molecule that has been implicated in regulating the anteroposterior patterning of the developing limb bud. IGF-I- and insulin-treated prospective limb explants give rise to rudimentary limbs containing identifiable skeletal elements when grafted into the coelom or to somites of host embryos. Overall, these results suggest that IGF-I and insulin may be endogenous signals produced by medial tissues that are involved in conferring limb-forming ability to the lateral plate and may promote the initial outgrowth of limb buds and possibly induce the AER. However, other

  11. IGF-I and IGFBP-2 Stimulate AMPK Activation and Autophagy, Which Are Required for Osteoblast Differentiation

    PubMed Central

    Xi, Gang; Rosen, Clifford J.

    2016-01-01

    IGF-I/insulin-like growth factor binding protein 2 (IGFBP-2) coordinately stimulate osteoblast differentiation but the mechanisms by which they function have not been determined. AMP-activated protein kinase (AMPK) is induced during differentiation and AMPK knockout mice have reduced bone mass. IGF-I modulates AMPK in other cell types; therefore, these studies determined whether IGF-I/IGFBP-2 stimulate AMPK activation and the mechanism by which AMPK modulates differentiation. Calvarial osteoblasts and MC-3T3 cells expressed activated AMPK early in differentiation and AMPK inhibitors attenuated differentiation. However, expression of constitutively activated AMPK inhibited differentiation. To resolve this discrepancy we analyzed the time course of AMPK induction. AMPK activation was required early in differentiation (day 3–6) but down-regulation of AMPK after day 9 was also necessary. IGF-I/IGFBP-2 induced AMPK through their respective receptors and blocking-receptor activation blocked AMPK induction. To determine the mechanism by which AMPK functioned we analyzed components of the autophagosome. Activated AMPK stimulated ULK-1 S555 phosphorylation as well as beclin-1 and microtubule-associated protein 1A/1B light-chain phosphatidylethanolamine conjugate (LC3II) induction. Inhibition of AMPK attenuated these changes and direct inhibition of autophagy inhibited differentiation. Conversely, expression of activated AMPK was associated with persistence of these changes beyond day 9 and inhibited differentiation. Blocking AMPK activation after day 9 down-regulated these autophagosome components and rescued differentiation. This allowed induction of mechanistic target of rapamycin and AKT, which suppressed autophagy. The results show that early induction of AMPK in response to IGF-I/IGFBP-2 followed by suppression is required for osteoblast differentiation. AMPK functions through stimulation of autophagy. The findings suggest that these early catabolic changes are

  12. Insulin, IGF-I, and muscle MAPK pathway responses after sustained exercise and their contribution to growth and lipid metabolism regulation in gilthead sea bream.

    PubMed

    Sánchez-Gurmaches, J; Cruz-Garcia, L; Ibarz, A; Fernández-Borrás, J; Blasco, J; Gutiérrez, J; Navarro, I

    2013-10-01

    Herein, we studied whether sustained exercise positively affects growth of gilthead sea bream by alterations in a) plasma concentrations of insulin and IGF-I, b) signaling pathways in muscle, or c) regulation of lipid metabolism. Specifically, we evaluated the effects of moderated swimming (1.5 body lengths per second; BL/s) on the circulating concentrations of insulin and IGF-I, morphometric parameters, and expression of genes related to lipid metabolism in gilthead sea bream (80-90 g BW). Exercise increased the specific growth rate (P < 0.05) and reduced the hepatosomatic index (P = 0.006). Plasma IGF-I concentrations increased in exercised fish (P = 0.037), suggesting a role for this endocrine factor in the control of muscular growth and metabolic homeostasis during swimming. The observed decrease in plasma insulin concentrations (P = 0.016) could favor the mobilization of tissue reserves in exercised fish. In this sense, the increase in liver fatty acid content (P = 0.041) and the changes in expression of peroxisome proliferator-activated receptors PPARα (P = 0.017) and PPARγ (P = 0.033) indicated a hepatic lipid mobilization. Concentration of glycogen in both white and red muscles was decreased (P = 0.021 and P = 0.017, respectively) in exercised (n = 12) relative to control (n = 12) gilthead sea bream, whereas concentrations of glucose (P = 0.016) and lactate (P = 0.0007) were decreased only in red muscle, indicating the use of these substrates. No changes in the glucose transporter and in lipoprotein lipase mRNA expression were found in any of the tissues studied. Exercised sea bream had decreased content of PPARβ mRNA in white and red muscle relative to control sea bream expression (P = 0.001 and P = 0.049, respectively). Mitogen-activated protein kinase phosphorylation was significantly down-regulated in both white and red muscles of exercised sea bream (P = 0.0374 and P = 0.0371, respectively). Tumor necrosis factor-α expression of white muscle was

  13. Ghrelin receptor agonist GHRP-2 prevents arthritis-induced increase in E3 ubiquitin-ligating enzymes MuRF1 and MAFbx gene expression in skeletal muscle.

    PubMed

    Granado, Miriam; Priego, Teresa; Martín, Ana I; Villanúa, Maria Angeles; López-Calderón, Asunción

    2005-12-01

    Chronic arthritis is a catabolic state associated with an inhibition of the IGF system and a decrease in body weight. Cachexia and muscular wasting is secondary to protein degradation by the ubiquitin-proteasome pathway. The aim of this work was to analyze the effect of adjuvant-induced arthritis on the muscle-specific ubiquitin ligases muscle ring finger 1 (MuRF1) and muscle atrophy F-box (MAFbx) as well as on IGF-I and IGF-binding protein-5 (IGFBP-5) gene expression in the skeletal muscle. We also studied whether the synthetic ghrelin receptor agonist, growth hormone releasing peptide-2 (GHRP-2), was able to prevent arthritis-induced changes in the skeletal muscle. Arthritis induced an increase in MuRF1, MAFbx (P < 0.01), and tumor necrosis factor (TNF)-alpha mRNA (P < 0.05) in the skeletal muscle. Arthritis decreased the serum IGF-I and its gene expression in the liver (P < 0.01), whereas it increased IGF-I and IGFBP-5 gene expression in the skeletal muscle (P < 0.01). Administration of GHRP-2 for 8 days prevented the arthritis-induced increase in muscular MuRF1, MAFbx, and TNF-alpha gene expression. GHRP-2 treatment increased the serum concentrations of IGF-I and the IGF-I mRNA in the liver and in the cardiac muscle and decreased muscular IGFBP-5 mRNA both in control and in arthritic rats (P < 0.05). GHRP-2 treatment increased muscular IGF-I mRNA in control rats (P < 0.01), but it did not modify the muscular IGF-I gene expression in arthritic rats. These data indicate that arthritis induces an increase in the activity of the ubiquitin-proteasome proteolytic pathway that is prevented by GHRP-2 administration. The parallel changes in muscular IGFBP-5 and TNF-alpha gene expression with the ubiquitin ligases suggest that they can participate in skeletal muscle alterations during chronic arthritis.

  14. Mecasermin rinfabate: insulin-like growth factor-I/insulin-like growth factor binding protein-3, mecaserimin rinfibate, rhIGF-I/rhIGFBP-3.

    PubMed

    2005-01-01

    Insmed is developing mecasermin rinfabate, a recombinant complex of insulin-like growth factor-I (rhIGF-I) and binding protein-3 (rhIGFBP-3) [insulin-like growth factor-I/insulin-like growth factor binding protein-3, rhIGF-I/rhIGFBP-3, SomatoKine], for a number of metabolic and endocrine indications. In the human body, IGF-I circulates in the blood bound to a binding protein-3 (IGFBP-3), which regulates the delivery of IGF-I to target tissues, and particular proteases clip them apart in response to stresses and release IGF-I as needed. IGF-I, a naturally occurring hormone, is necessary for normal growth and metabolism. For the treatment of IGF-I deficiency, it is desirable to administer IGF-I bound to IGFBP-3 to maintain the normal equilibrium of these proteins in the blood. Mecasermin rinfabate (rhIGF-I/rhIGFBP-3) mimics the effects of the natural protein complex in the bloodstream and would augment the natural supply of these linked compounds. The most advanced indication in development of mecasermin rinfabate is the treatment of severe growth disorders due to growth hormone insensitivity syndrome (GHIS), also called Laron syndrome. GHIS is a genetic condition in which patients do not produce adequate quantities of IGF because of a failure to respond to the growth hormone signal. This results in a slower growth rate and short stature. Mecasermin rinfabate also has potential as replacement therapy for IGF-I, which may become depleted in indications such as major surgery, organ damage/failure, traumatic injury, cachexia and severe burn trauma. It also has potential for the treatment of osteoporosis. Mecasermin rinfabate was developed by Celtrix using its proprietary recombinant protein production technology. Subsequently, Celtrix was acquired by Insmed Pharmaceuticals on 1 June 2000. Insmed and Avecia of the UK have signed an agreement for manufacturing mecasermin rinfabate and its components, rhIGF-1 and rhIGFBP-3. CGMP clinical production of mecasermin rinfabate

  15. Stimulatory actions of IGF-I are mediated by IGF-IR cross-talk with GPER and DDR1 in mesothelioma and lung cancer cells

    PubMed Central

    Cirillo, Francesca; Santolla, Maria Francesca; Francesco, Ernestina Marianna De; Perri, Maria Grazia; Rigiracciolo, Damiano; Dolce, Vincenza; Belfiore, Antonino; Maggiolini, Marcello; Lappano, Rosamaria; Vivacqua, Adele

    2016-01-01

    Insulin-like growth factor-I (IGF-I)/IGF-I receptor (IGF-IR) system has been largely involved in the pathogenesis and development of various tumors. We have previously demonstrated that IGF-IR cooperates with the G-protein estrogen receptor (GPER) and the collagen receptor discoidin domain 1 (DDR1) that are implicated in cancer progression. Here, we provide novel evidence regarding the molecular mechanisms through which IGF-I/IGF-IR signaling triggers a functional cross-talk with GPER and DDR1 in both mesothelioma and lung cancer cells. In particular, we show that IGF-I activates the transduction network mediated by IGF-IR leading to the up-regulation of GPER and its main target genes CTGF and EGR1 as well as the induction of DDR1 target genes like MATN-2, FBN-1, NOTCH 1 and HES-1. Of note, certain DDR1-mediated effects upon IGF-I stimulation required both IGF-IR and GPER as determined knocking-down the expression of these receptors. The aforementioned findings were nicely recapitulated in important biological outcomes like IGF-I promoted chemotaxis and migration of both mesothelioma and lung cancer cells. Overall, our data suggest that IGF-I/IGF-IR system triggers stimulatory actions through both GPER and DDR1 in aggressive tumors as mesothelioma and lung tumors. Hence, this novel signaling pathway may represent a further target in setting innovative anticancer strategies. PMID:27384677

  16. IGF-I and relation to growth in infancy and early childhood in very-low-birth-weight infants and term born infants

    PubMed Central

    de Jong, Miranda; Cranendonk, Anneke; Twisk, Jos W. R.; van Weissenbruch, Mirjam M.

    2017-01-01

    Background In very-low-birth-weight infants IGF-I plays an important role in postnatal growth restriction and is probably also involved in growth restriction in childhood. We compared IGF-I and its relation to growth in early childhood in very-low-birth-weight infants and term appropriate for gestational age born infants. Methods We included 41 very-low-birth-weight and 64 term infants. Anthropometry was performed at all visits to the outpatient clinic. IGF-I and insulin were measured in blood samples taken at 6 months and 2 years corrected age (very-low-birth-weight children) and at 3 months, 1 and 2 years (term children). Results Over the first 2 years of life growth parameters are lower in very-low-birth-weight children compared to term children, but the difference in length decreases significantly. During the first 2 years of life IGF-I is higher in very-low-birth-weight children compared to term children. In both groups there is a significant relationship between IGF-I and (change in) length and weight over the first 2 years of life and between insulin and change in total body fat. Conclusions Considering the relation of IGF-I to growth and the decrease in difference in length, higher IGF-I levels in very-low-birth-weight infants in early childhood probably have an important role in catch-up growth in length. PMID:28182752

  17. Stimulatory actions of IGF-I are mediated by IGF-IR cross-talk with GPER and DDR1 in mesothelioma and lung cancer cells.

    PubMed

    Avino, Silvia; De Marco, Paola; Cirillo, Francesca; Santolla, Maria Francesca; De Francesco, Ernestina Marianna; Perri, Maria Grazia; Rigiracciolo, Damiano; Dolce, Vincenza; Belfiore, Antonino; Maggiolini, Marcello; Lappano, Rosamaria; Vivacqua, Adele

    2016-08-16

    Insulin-like growth factor-I (IGF-I)/IGF-I receptor (IGF-IR) system has been largely involved in the pathogenesis and development of various tumors. We have previously demonstrated that IGF-IR cooperates with the G-protein estrogen receptor (GPER) and the collagen receptor discoidin domain 1 (DDR1) that are implicated in cancer progression. Here, we provide novel evidence regarding the molecular mechanisms through which IGF-I/IGF-IR signaling triggers a functional cross-talk with GPER and DDR1 in both mesothelioma and lung cancer cells. In particular, we show that IGF-I activates the transduction network mediated by IGF-IR leading to the up-regulation of GPER and its main target genes CTGF and EGR1 as well as the induction of DDR1 target genes like MATN-2, FBN-1, NOTCH 1 and HES-1. Of note, certain DDR1-mediated effects upon IGF-I stimulation required both IGF-IR and GPER as determined knocking-down the expression of these receptors. The aforementioned findings were nicely recapitulated in important biological outcomes like IGF-I promoted chemotaxis and migration of both mesothelioma and lung cancer cells. Overall, our data suggest that IGF-I/IGF-IR system triggers stimulatory actions through both GPER and DDR1 in aggressive tumors as mesothelioma and lung tumors. Hence, this novel signaling pathway may represent a further target in setting innovative anticancer strategies.

  18. Increased serum cortisol binding in chronic active hepatitis

    SciTech Connect

    Orbach, O.; Schussler, G.C.

    1989-01-01

    A high serum cortisol concentration, apparently due to increased cortisol-binding globulin (CBG), was found in a patient (index case) with chronic active hepatitis (CAH). We therefore performed further studies to determine whether increased cortisol binding is generally associated with CAH. Serum samples were obtained from 15 hospitalized patients with long-term liver function test elevations but no evidence of cirrhosis, 15 normal subjects without a history of hepatitis, four healthy pregnant women, and 10 alcoholic patients with stigmata of cirrhosis. Serum cortisol binding was measured by an adaptation of a previously described charcoal uptake method. Thyroxine-binding globulin (TBG) and sex hormone-binding globulin were determined by radioimmunoassays. Charcoal uptake of 125I cortisol from sera of normal subjects and additional patients with CAH revealed that increased serum cortisol binding by a saturable site, presumably CBG, was associated with CAH. Cortisol binding was significantly correlated with immunoassayable TBG, suggesting that in CAH, similar mechanisms may be responsible for increasing the serum concentrations of CBG and TBG.

  19. Comparison between novel steroid-like and conventional nonsteroidal antioestrogens in inhibiting oestradiol- and IGF-I-induced proliferation of human breast cancer-derived cells.

    PubMed Central

    de Cupis, A.; Noonan, D.; Pirani, P.; Ferrera, A.; Clerico, L.; Favoni, R. E.

    1995-01-01

    1. This study has two specific aims: (a) to compare the antioestrogenic activity of two steroidal analogues of 17 beta-oestradiol, the 7 alpha-alkylamide, ICI 164,384 and the 7 alpha-alkylsulphinylamide, ICI 182,780, with that of the triphenylethylene-derived compound 4OH-tamoxifen on a pool of human breast cancer cell lines (HBCCL) with a range of hormonal responsiveness and acquired anti-oestrogen resistance and (b) to investigate the ability of such antioestrogens to modulate the potent breast carcinoma growth-stimulatory activity of the 'IGF-I system'. 2. For the chemosensitivity investigations we used a long-term colorimetric and the short-term thymidine incorporation assay; we analysed IGF-I in conditioned media by a radioimmunoassay, IGF-I mRNA in the cells by RT-PCR and molecular species of IGF-I-binding proteins, secreted in conditioned media, by Western ligand blot. IGF-I receptors were assayed on cell monolayers by binding studies and by Scatchard analysis, we calculated KD, Bmax and sites/cell. 3. Our results indicate that ICI 182,780 and ICI 164,384 are 1.5-5.5 fold more potent than 4OH-tamoxifen in inhibiting the basal proliferation of oestrogen-receptor positive (ER+) breast cancer cell lines. Moreover we demonstrate the capacity of ICI 182,780 and ICI 164,384 to reduce, in a time-dependent fashion, oestrogen- and/or IGF-I-stimulated growth of ER+cell lines, possibly by negatively interfering with an IGF-I-like material secretion and IGF-I-receptor number. 4. Our data provide the first evidence that, on ER+human breast carcinoma cell lines, steroidal antioestrogens inhibit cell growth and modulate the IGF-I mitogenic system. The mechanism of this latter effect has yet to be identified. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:8581274

  20. Des (1-3) IGF-I-stimulated growth of human stromal BPH cells is inhibited by a vitamin D3 analogue.

    PubMed

    Crescioli, C; Villari, D; Forti, G; Ferruzzi, P; Petrone, L; Vannelli, G B; Adorini, L; Salerno, R; Serio, M; Maggi, M

    2002-12-30

    Prostate growth and differentiation is under the control of androgens not only during fetal life and childhood but also in adulthood, and it has been proposed that increased prostatic concentration of androgens, or increased androgen responsiveness, causes benign prostatic hyperplasia (BPH). However, different androgen ablation strategies such as treatment with GnRH agonists and finasteride resulted in a modest decrease of the hyperplastic prostate volume. In the last few years it became evident that both androgen-dependent and androgen-independent growth factors promote prostate enlargement by inducing cell proliferation or reducing apoptosis. Therefore, new therapeutic strategies, aimed at reducing intraprostatic growth factor signaling, are under investigation. In this study, we report further evidence that a non hypercalcemic-analogue of vitamin D(3), analogue (V) decreases growth factor-induced human BPH cell proliferation and survival. We found that Des (1-3) insulin-like growth factor [Des (1-3) IGF-I], an IGF-I analogue, which does not bind to IGF-binding proteins, is a potent mitogen for BPH stromal cells via a dual mechanism: stimulation of cell growth and inhibition of apoptosis. Similar results were previously reported for another growth factor for BPH cells, keratinocyte growth factor (KGF). Accordingly, we speculate that both KGF and IGF might be involved in the pathogenesis of BPH. We also found analogue (V) not only inhibits the mitogenic activity of growth factors on BPH cells, but even decreased the basal expression of bcl-2, and induced apoptosis. Therefore, vitamin D(3) analogues might be considered for the medical treatment of BPH.

  1. Effects of recombinant bovine somatotropin implants on serum concentrations of somatotropin, insulin-like growth factor-I and blood urea nitrogen in steers.

    PubMed

    Roeder, R A; Garber, M J; Dalke, B S; Kasser, T R; Veenhuizen, J; Schelling, G T

    1994-09-01

    Four cross-bred beef steers averaging 346 kg were used in a 4 x 4 Latin square design to determine the effect of prolonged-release recombinant bovine somatotropin (rbGH) implants on serum concentrations of somatotropin (GH), insulin-like growth factor-I (IGF-I) and blood urea nitrogen (BUN). Recombinant bGH implants of 0, 40, 80 or 160 mg were administered subcutaneously in the tailhead during the 4 trial periods. Each steer received each treatment starting at 06:00 on day 0 with 21 days between treatments. Jugular vein blood samples were collected on days 0, 1, 2 and 3 (4 day time course for GH, IGF-I and BUN) and every 15 min (GH profile) for 6 h on day 3. Serum baseline GH values were higher (P < 0.10) for the 80 and 160 mg treatments than for the control, and peak amplitude was decreased (P < 0.05) by the 40 and 160 mg treatments. There was a trend (P < 0.11) for fewer GH peaks during the 160 mg treatment. Somatotropin concentrations decreased from day 1 to day 3 (P < 0.05) in a linear manner. Serum IGF-I concentrations increased (P < 0.05) in a linear dose-dependent manner from the 0 mg to the 160 mg treatment. BUN concentrations were not significantly altered by rbGH treatment. Results from this experiment indicate that rbGH implants significantly increase serum IGF-I and GH baseline concentrations while suppressing GH peak amplitude in finishing steers.

  2. Use of multifactorial analysis to develop aqueous two-phase systems for isolation of non-native IGF-I.

    PubMed

    Hart, R A; Ogez, J R; Builder, S E

    1995-04-01

    A high yield procedure was developed to solubilize and extract IGF-I from recombinant E. coli by adding chaotrope and disulfide reductant to alkaline fermentation broth. To enhance centrifugation performance and recovery yield, a salt/polymer aqueous two-phase extraction procedure was developed whereby soluble non-native IGF-I and biomass solids are enriched in separate liquid phases. To develop this extraction system a multifactorial experimental approach was used to simultaneously map the phase diagram and identify conditions to suitably partition IGF-I and cell remnants. The presence of urea in these systems tended to disrupt two-phase formation and solids sedimentation. This, in turn, constrained the concentrations of phase forming solutes which could be effectively used. Systems containing low levels of salt (less than about 4% w/w) and polymer (less than about 10% w/w) did not form two phases. Systems containing high levels of salt (greater than about 7% w/w) and polymer (greater than about 18% w/w) formed two phases with floating solids. Intermediate levels of salt (between about 4% and 7% w/w) and polymer (between about 10% and 18% w/w) formed two phases in which solids were enriched in the heavy phase. Systems in this latter desired category were produced with a variety of different salts and polymers and all enriched non-native IGF-I in the light phase. Highest recovery yield (about 90%) was obtained with systems composed of 5% sodium sulfate and 14% PEG-8000.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. Impairment of IGF-I Expression and Anabolic Signaling Following Ischemia/Reperfusion in Skeletal Muscle of Old Mice

    DTIC Science & Technology

    2011-04-01

    has a role in the impaired recovery of skeletal muscle with age. Keywords Tourniquet; sarcopenia ; muscle regeneration; mTOR; FoxO Correspondence...Prescribed by ANSI Std Z39-18 INTRODUCTION Sarcopenia is the progressive decline in skeletal muscle mass and function with advanced aging (See Adamo...atrophied aged muscles (Chakravarthy et al., 2000). Despite these effects of IGF-I on sarcopenia , it was only recently shown that the post-injury expression

  4. Increases in Serum Growth Hormone Concentrations Associated with GHB Administration.

    PubMed

    Brailsford, Alan D; Bartlett, Christiaan; Kicman, Andrew T; Cowan, David A

    2017-01-01

    The administration of gamma-hydroxybutyrate (GHB) has been reported to augment the increase in growth hormone (GH) secretion associated with the onset of sleep. The ability of GHB to stimulate GH production in the absence of sleep in both male and female volunteers was investigated as part of a GHB administration study. Twelve healthy volunteers (six men and six women) were given a small oral dose (25 mg/kg) of GHB (as Xyrem(®)) at 10:00 h. Basal blood samples (as serum) were taken 10 min prior to GHB administration, with additional samples taken at 10, 15, 20, 25, 30, 45, 60, 90, 120, 150, 180, 240, 360 and 480 min post-administration. The serum concentrations of GHB were measured by GC-MS and GH by immunometric assay. Following GHB administration, volunteers exhibited effects consistent with mild sedation, i.e., relaxed with normal responses to verbal stimuli. Despite none being asleep, an increase in serum GH concentration occurred in 11 out of the 12 volunteers (5 women and 6 men). In these volunteers, peak GH concentrations occurred 45-60 min post-administration compared with a mean serum tmax for GHB of 23 min (SD = 5.4 min). The absolute increase in GH was similar for men and women, averaging 3.4 and 3.7 ng/mL, respectively. The mean intra-individual increase in GH was much greater in males (29 times) compared with females (2 times), as males had (as expected) smaller basal GH concentrations (mean = 0.26 ng/mL) compared with females (mean = 5.4 ng/mL). After maximizing, the GH concentration decreased rapidly (in agreement with GHB concentrations), returning to basal concentrations at ~90-120 min post-administration. GHB administration at a small therapeutic dose results in increases in serum GH concentrations in healthy male and female volunteers in the absence of sleep onset.

  5. Serum Calcium Increase Correlates With Worsening of Lipid Profile

    PubMed Central

    Gallo, Luigia; Faniello, Maria C.; Canino, Giovanni; Tripolino, Cesare; Gnasso, Agostino; Cuda, Giovanni; Costanzo, Francesco S.; Irace, Concetta

    2016-01-01

    Abstract Despite the well-documented role of calcium in cell metabolism, its role in the development of cardiovascular disease is still under heavy debate. Several studies suggest that calcium supplementation might be associated with an increased risk of coronary heart disease, whereas others underline a significant effect on lowering high blood pressure and hyperlipidemia. The purpose of this study was to investigate, in a large nonselected cohort from South Italy, if serum calcium levels correlate with lipid values and can therefore be linked to higher individual cardiovascular risk. Eight-thousand-six-hundred-ten outpatients addressed to the Laboratory of Clinical Biochemistry, University of Magna Græcia, Catanzaro, Italy from January 2012 to December 2013 for routine blood tests, were enrolled in the study. Total HDL-, LDL- and non-HDL colesterol, triglycerides, and calcium were determined with standard methods. We observed a significant association between total cholesterol, LDL-cholesterol, HDL-cholesterol, non-HDL cholesterol, triglycerides, and serum calcium in men and postmenopause women. Interestingly, in premenopause women, we only found a direct correlation between serum calcium, total cholesterol, and HDL-cholesterol. Calcium significantly increased while increasing total cholesterol and triglycerides in men and postmenopause women. Our results confirm that progressive increase of serum calcium level correlates with worsening of lipid profile in our study population. Therefore, we suggest that a greater caution should be used in calcium supplement prescription particularly in men and women undergoing menopause, in which an increase of serum lipids is already known to be associated with a higher cardiovascular risk. PMID:26937904

  6. Arginine increases insulin-like growth factor-I production and collagen synthesis in osteoblast-like cells.

    PubMed

    Chevalley, T; Rizzoli, R; Manen, D; Caverzasio, J; Bonjour, J P

    1998-08-01

    Protein-energy malnutrition, which is common in elderly patients with osteoporotic hip fractures, is associated with reduced plasma levels of insulin-like growth factor-I (IGF-I). IGF-I is an important regulator of bone metabolism, particularly of osteoblastic bone formation both in vivo and in vitro. Pharmacological doses of arginine (Arg) increase growth hormone (GH) and IGF-I serum levels. Whether amino acids, particularly Arg, can directly modulate the production of IGF-I by osteoblasts is not known. We investigated the effects of increasing concentrations of Arg on IGF-I expression and production, alpha1(I) collagen expression and collagen synthesis, and cell proliferation and cell differentiation, as assessed by alkaline phosphatase (ALP) activity and osteocalcin (OC) release, in confluent mouse osteoblast-like MC3T3-E1 cells. The addition of Arg (7.5-7500 micromol/L, equivalent to 0.1- to 100-fold human plasma concentration) for 48 h increased IGF-I production (adjusted for cell number) in a concentration-dependent manner with a maximum of 2.3 +/- 0.3-fold at 7500 micromol/L Arg [x +/- standard error of the mean (SEM), n = 3 experiments, p < 0.01]. Arg (7.5-7500 micromol/L) increased the percentage of de novo collagen synthesis in a concentration-dependent manner (2.1 +/- 0.4-fold with 7500 micromol/L Arg, p < 0.001) and ALP activity with a maximal stimulation of 144% +/- 13% plateauing at 750 micromol/l Arg (p = 0.002). The steady state level of IGF-I messenger ribonucleic acid (mRNA) and alpha1(I) collagen mRNA (both normalized to cyclophilin mRNA) of cells incubated with Arg at high (100-fold) or low (0.1-fold) human plasma concentrations, was 1.4 +/- 0.2, 1.2 +/- 0.2, and 1.1 +/- 0.2 after 24 h for the 7.5, 1.8, and 0.9 kb IGF-I mRNA transcripts, respectively (n = 3 experiments) and 1.5 +/- 0.2 and 3.1 +/- 0.7 after 24 and 48 h, respectively, for the combined analysis of the 5.6 and 4.7 kb alpha1(I) collagen mRNA transcripts (n = 3 experiments). A

  7. Insulin-Like Growth Factor (IGF)-I Modulates Endothelial Blood-Brain Barrier Function in Ischemic Middle-Aged Female Rats

    PubMed Central

    Bake, Shameena; Okoreeh, Andre K.; Alaniz, Robert C.

    2016-01-01

    In comparison with young females, middle-aged female rats sustain greater cerebral infarction and worse functional recovery after stroke. These poorer stroke outcomes in middle-aged females are associated with an age-related reduction in IGF-I levels. Poststroke IGF-I treatment decreases infarct volume in older females and lowers the expression of cytokines in the ischemic hemisphere. IGF-I also reduces transfer of Evans blue dye to the brain, suggesting that this peptide may also promote blood-brain barrier function. To test the hypothesis that IGF-I may act at the blood-brain barrier in ischemic stroke, 2 approaches were used. In the first approach, middle-aged female rats were subjected to middle cerebral artery occlusion and treated with IGF-I after reperfusion. Mononuclear cells from the ischemic hemisphere were stained for CD4 or triple-labeled for CD4/CD25/FoxP3 and subjected to flow analyses. Both cohorts of cells were significantly reduced in IGF-I–treated animals compared with those in vehicle controls. Reduced trafficking of immune cells to the ischemic site suggests that blood-brain barrier integrity is better maintained in IGF-I–treated animals. The second approach directly tested the effect of IGF-I on barrier function of aging endothelial cells. Accordingly, brain microvascular endothelial cells from middle-aged female rats were cultured ex vivo and subjected to ischemic conditions (oxygen-glucose deprivation). IGF-I treatment significantly reduced the transfer of fluorescently labeled BSA across the endothelial monolayer as well as cellular internalization of fluorescein isothiocyanate–BSA compared with those in vehicle-treated cultures, Collectively, these data support the hypothesis that IGF-I improves blood-brain barrier function in middle-aged females. PMID:26556536

  8. Novel Transgenic Mouse Model for Testing the Effect of Circulating IGF-I on Mammary Stem/Progenitor Cell Number and Tumorigenesis

    DTIC Science & Technology

    2007-08-01

    AD_________________ Award Number: W81XWH-06-1-0628 TITLE: Novel Transgenic Mouse Model for Testing ...TITLE AND SUBTITLE 5a. CONTRACT NUMBER Novel Transgenic Mouse Model for Testing the Effect of Circulating IGF-I on Mammary Stem/Progenitor Cell...tumorigenesis. We found no difference in time to tumor formation in ErbB2 vs. TTR-IGF-I/ErbB2 transgenic mice . Our conclusion is either that ErbB2

  9. Interplay of IGF-I and 17beta-estradiol at age-specific levels in human sebocytes and fibroblasts in vitro.

    PubMed

    Makrantonaki, Evgenia; Vogel, Kim; Fimmel, Sabine; Oeff, Marina; Seltmann, Holger; Zouboulis, Christos C

    2008-10-01

    In order to obtain greater insights into the molecular mechanisms accompanying hormonal aging the effects of growth hormone (GH), insulin-like growth factor-I (IGF-I), 17beta-estradiol, progesterone and dehydroepiandrosterone were tested as single agents in concentrations corresponding to 20- and 60-year-old females on human SZ95 sebocytes and fibroblasts. Cell proliferation and viability were measured by 4-methylumbelliferyl heptanoate and lactate dehydrogenase microassays, respectively, whereas lipid accumulation was documented via nile red microassay and fluorescence microscopy. mRNA and protein expression were evaluated via real-time RT-PCR and Western blotting or ELISA, accordingly. Our results depict the importance of IGF-I for lipid synthesis in SZ95 sebocyte and demonstrate the lack of 17beta-estradiol, dehydroepiandrosterone and progesterone activity on lipid synthesis and SZ95 sebocyte proliferation suggesting that the action of these hormones in vivo may be implemented through indirect pathways. Fibroblast showed to be more susceptible to 17beta-estradiol treatment, while IGF-I could significantly stimulate fibroblast proliferation in a dose-dependent manner. Furthermore, an interplay between the 17beta-estradiol and IGF-I signaling pathway was documented in both cell types. In conclusion, IGF-I is a key regulator of human skin aging and declining IGF-I levels with age may play a significant role in the reduction of skin surface lipids and thickness.

  10. Detection of surface bound complement at increasing serum anticoagulant concentrations.

    PubMed

    Arvidsson, S; Askendal, A; Lindahl, T L; Tengvall, P

    2008-04-01

    Surface mediated immune complement activation can be detected by a variety of antibody utilizing methods such as ELISA, fluorescence- or radiolabelling techniques, QCM, and ellipsometry. In the present work we investigated how the common anticoagulants heparin, dalteparin, fondaparinux and sodium citrate affected the binding of anti-complement factor 3c (anti-C3c) on a model complement activator surface, immobilised IgG, after incubation in human blood serum. The results show, as expected, that different anticoagulants affect the antibody binding differently. Increasing amounts of heparin, dalteparin and sodium citrate in normal serum resulted in a decreasing anti-C3c binding. The antibody deposition was not sensitive for the fondaparinux concentration. Surprisingly high concentrations of anti-coagulantia were needed to completely eradicate the antibody binding. Experiments in EGTA-serum showed that anticoagulants interfered directly with both the classical and alternative pathways. Control C3a-des arg ELISA measurements show that the lowered antibody surface binding was not a result of complement depletion in serum. Kallikrein generation by hydrophilic glass surfaces was not affected by high anticoagulant concentrations.

  11. Soy protein supplementation increases serum insulin-like growth factor-I in young and old men but does not affect markers of bone metabolism.

    PubMed

    Khalil, Dania A; Lucas, Edralin A; Juma, Shanil; Smith, Brenda J; Payton, Mark E; Arjmandi, Bahram H

    2002-09-01

    Recent studies suggest that soy protein (SP) protects bone in women; however, its effects on bone metabolism in men have not been investigated. Healthy men (59.2 +/- 17.6 y) were assigned to consume 40 g of either SP or milk-based protein (MP) daily for 3 mo in a double-blind, randomized, controlled, parallel design. Serum insulin-like growth factor-I (IGF-I), which is associated with higher rates of bone formation, was greater (P < 0.01) in men supplemented with SP than in those consuming MP. Serum alkaline phosphatase and bone-specific alkaline phosphatase activities, markers of bone formation, and urinary deoxypyridinoline excretion, a specific marker of bone resorption, were not different between the SP and MP groups. Furthermore, because substantial reductions in bone density occur in men at approximately 65 y of age, data were analyzed separately for men >/=65 y and those <65 y of age. The response to protein supplementation was consistent in the two age groups. The effects of SP on serum IGF-I levels suggest that SP may positively influence bone in men. Longer-duration studies examining the effects of SP or its isoflavones on bone turnover and bone mineral density and content in men are warranted.

  12. The novel finding of four distinct prepro-IGF-I E domains in a perciform fish, Sciaenops ocellatus, during ontogeny.

    PubMed

    Faulk, Cynthia K; Pérez-Domínguez, Rafael; Webb, Kenneth A; Holt, G Joan

    2010-10-01

    In fishes, insulin-like growth factor-I (IGF-I) stimulates growth and differentiation but also plays a role in a number of other processes including osmoregulation, metabolism, immune response and reproduction. This study presents the cDNA encoding multiple prepro-IGF-I transcripts obtained from red drum, Sciaenopsocellatus, and examines differential expression in select adult tissues and during ontogeny. Four distinct transcripts were sequenced which were identical in the coding region for the signal (132 bp) and mature (204 bp) peptides but differed in the coding region of the E peptide by the exclusion of 117 (Ea-1), 81 (Ea-2) or 36 (Ea-3) bp compared to the 222 bp present in Ea-4. Analysis of the pertinent portion of the genomic sequence of this gene suggests that the transcripts are a result of alternative splicing. This is the first report of the expression of all four known prepro-IGF-I transcripts in a teleost other than a salmonid. The deduced amino acid sequences exhibited 70-95% identity with teleosts and somewhat lower identity to other vertebrates (60-75%). Three of the 4 transcripts (Ea-2, Ea-3, Ea-4) were expressed in the liver, ovary, spleen, gall bladder, brain, red muscle, pancreas and spinal cord of adults. Only the Ea-4 transcript was expressed in adult stomach tissue while no signal was detected in pituitary, retina, intestine, adipose or white muscle. In contrast, all 4 transcripts were expressed throughout ontogeny. The apparent expression of the Ea-1 transcript only during the larval stage may indicate a developmental role for this E peptide in red drum.

  13. Conditionally immortalized human pancreatic stellate cell lines demonstrate enhanced proliferation and migration in response to IGF-I

    SciTech Connect

    Rosendahl, Ann H.; Gundewar, Chinmay; Said Hilmersson, Katarzyna; Ni, Lan; Saleem, Moin A.; Andersson, Roland

    2015-01-15

    Pancreatic stellate cells (PSCs) play a key role in the dense desmoplastic stroma associated with pancreatic ductal adenocarcinoma. Studies on human PSCs have been minimal due to difficulty in maintaining primary PSC in culture. We have generated the first conditionally immortalized human non-tumor (NPSC) and tumor-derived (TPSC) pancreatic stellate cells via transformation with the temperature-sensitive SV40 large T antigen and human telomerase (hTERT). These cells proliferate at 33°C. After transfer to 37°C, the SV40LT is switched off and the cells regain their primary PSC phenotype and growth characteristics. NPSC contained cytoplasmic vitamin A-storing lipid droplets, while both NPSC and TPSC expressed the characteristic markers αSMA, vimentin, desmin and GFAP. Proteome array analysis revealed that of the 55 evaluated proteins, 27 (49%) were upregulated ≥3-fold in TPSC compared to NPSC, including uPA, pentraxin-3, endoglin and endothelin-1. Two insulin-like growth factor binding proteins (IGFBPs) were inversely expressed. Although discordant IGFBP-2 and IGFBP-3 levels, IGF-I was found to stimulate proliferation of both NPSC and TPSC. Both basal and IGF-I stimulated motility was significantly enhanced in TPSC compared to NPSC. In conclusion, these cells provide a unique resource that will facilitate further study of the active stroma compartment associated with pancreatic cancer. - Highlights: • Generation of human conditionally immortalized human pancreatic stellate cell lines. • Temperature-sensitive SV40LT allows switch to primary PSC phenotype characteristics. • Proteome profiling revealed distinct expression patterns between TPSC and NPSC. • Enhanced IGF-I-stimulated proliferation and motility by TPSC compared to NPSC.

  14. Effect of improved nutrition during calfhood on serum metabolic hormones, gonadotropins, and testosterone concentrations, and on testicular development in bulls.

    PubMed

    Brito, Leonardo F C; Barth, Albert D; Rawlings, Norm C; Wilde, Randal E; Crews, Denny H; Mir, Priya S; Kastelic, John P

    2007-11-01

    The objective of the present study was to evaluate the effects of improved nutrition during calfhood on serum metabolic hormones, gonadotropins and testosterone concentrations, and on sexual development in bulls. Bulls received high (n=17) or control nutrition (n=16) diets from 10 to 30 week of age and the same control nutrition diet from 31 to 74 week of age. Improved nutrition during calfhood resulted in a more sustained period of elevated LH secretion (pulse frequency and total secretion in 10h) during the early gonadotropin rise. GnRH-stimulated LH secretion was not affected by diet, indicating that pituitary responsiveness was not altered; therefore, improved nutrition had direct effects on GnRH secretion by the hypothalamus. Insulin and insulin-like growth factor-I (IGF-I) concentrations were greater during calfhood in bulls receiving high nutrition, indicating that these metabolic hormones might be involved in regulating GnRH and LH secretion. Improved nutrition also resulted in increased testosterone secretion that was associated with greater circulating IGF-I concentrations, suggesting a role for this metabolic hormone in regulating Leydig cell number and function. Furthermore, improved nutrition during calfhood resulted in greater testicular weight and sperm production in mature bulls, indicating that increased LH secretion during calfhood, and increased IGF-I and testosterone concentrations during calfhood and peripubertal period were associated with greater testicular cell proliferation and enhanced function.

  15. Reducing blood glucose levels in TIDM mice with an orally administered extract of sericin from hIGF-I-transgenic silkworm cocoons.

    PubMed

    Song, Zuowei; Zhang, Mengyao; Xue, Renyu; Cao, Guangli; Gong, Chengliang

    2014-05-01

    In previous studies, we reported that the blood glucose levels of mice with type I diabetes mellitus (TIDM) was reduced with orally administered silk gland powder from silkworms transgenic for human insulin-like growth factor-I (hIGF-I). However, potential safety hazards could not be eliminated because the transgenic silk gland powder contained heterologous DNA, including the green fluorescent protein (gfp) and neomycin resistance (neo) genes. These shortcomings might be overcome if the recombinant hIGF-I were secreted into the sericin layer of the cocoon. In this study, silkworm eggs were transfected with a novel piggyBac transposon vector, pigA3GFP-serHS-hIGF-I-neo, containing the neo, gfp, and hIGF-I genes controlled by the sericin-1 (ser-1) promoter with the signal peptide DNA sequence of the fibrin heavy chain (Fib-H) and a helper plasmid containing the piggyBac transposase sequence under the control of the Bombyx mori actin 3 (A3) promoter, using sperm-mediated gene transfer to generate the transformed silkworms. The hIGF-I content estimated by enzyme-linked immunosorbent assay was approximately 162.7 ng/g. To estimate the biological activity of the expressed hIGF-I, streptozotocin-induced TIDM mice were orally administered sericin from the transgenic silkworm. The blood glucose levels of the mice were significantly reduced, suggesting that the extract from the transgenic hIGF-I silkworm cocoons can be used as an orally administered drug.

  16. Serum Neopterin Is Not Increased in Obese Juveniles

    PubMed Central

    Mangge, Harald; Freytag, Florian; Almer, Gunter; Weghuber, Daniel; Bauer-Denk, Carmen; Fuchs, Dietmar

    2011-01-01

    Objective. Cardiovascular disease is associated with inflammation and immune activation, concentrations of immune activation markers like neopterin predict outcome in adults. Methods. Serum neopterin concentrations and early metabolic and pre-atherosclerotic symptoms were analyzed in 295 obese juveniles and 101 normal weight controls of similar age. Additionally, the influence of a 12 months weight reduction program on neopterin levels was investigated in 31 obese juveniles. Results. Intima-media thickness of common carotid arteries (IMT) and the concentrations of C-reactive protein (CRP) were increased in the obese juveniles (P < .001). Also triglycerides, oxidized LDL, fasted insulin levels, HOMA-index, leptin, liver transaminases and uric acid were increased compared to the controls. However, serum neopterin was decreased in the obese versus non-obese juveniles (P < .03). The intervention consisting of regular sports, nutritional devices, and a psychologic attendance led after 12 months to an increase of neopterin concentration (P < .05; paired test). Conclusions. Neopterin concentrations in juvenile obesity behaved considerably different from what was demonstrated in adults, levels did not correlate with metabolic and pre-atherosclerotic symptoms found in early phases although early vascular burden and chronic low grade inflammation was indicated by increased IMT and CRP. Neopterin concentrations increased after a 12 months intervention program. PMID:21274279

  17. Serum neopterin is not increased in obese juveniles.

    PubMed

    Mangge, Harald; Freytag, Florian; Almer, Gunter; Weghuber, Daniel; Bauer-Denk, Carmen; Fuchs, Dietmar

    2011-01-01

    Objective. Cardiovascular disease is associated with inflammation and immune activation, concentrations of immune activation markers like neopterin predict outcome in adults. Methods. Serum neopterin concentrations and early metabolic and pre-atherosclerotic symptoms were analyzed in 295 obese juveniles and 101 normal weight controls of similar age. Additionally, the influence of a 12 months weight reduction program on neopterin levels was investigated in 31 obese juveniles. Results. Intima-media thickness of common carotid arteries (IMT) and the concentrations of C-reactive protein (CRP) were increased in the obese juveniles (P < .001). Also triglycerides, oxidized LDL, fasted insulin levels, HOMA-index, leptin, liver transaminases and uric acid were increased compared to the controls. However, serum neopterin was decreased in the obese versus non-obese juveniles (P < .03). The intervention consisting of regular sports, nutritional devices, and a psychologic attendance led after 12 months to an increase of neopterin concentration (P < .05; paired test). Conclusions. Neopterin concentrations in juvenile obesity behaved considerably different from what was demonstrated in adults, levels did not correlate with metabolic and pre-atherosclerotic symptoms found in early phases although early vascular burden and chronic low grade inflammation was indicated by increased IMT and CRP. Neopterin concentrations increased after a 12 months intervention program.

  18. A comprehensive analysis of common IGF1, IGFBP1 and IGFBP3 genetic variation with prospective IGF-I and IGFBP-3 blood levels and prostate cancer risk among Caucasians†

    PubMed Central

    Schumacher, Fredrick R.; Cheng, Iona; Freedman, Matthew L.; Mucci, Lorelei; Allen, Naomi E.; Pollak, Michael N.; Hayes, Richard B.; Stram, Daniel O.; Canzian, Federico; Henderson, Brian E.; Hunter, David J.; Virtamo, Jarmo; Manjer, Jonas; Gaziano, J. Michael; Kolonel, Laurence N.; Tjønneland, Anne; Albanes, Demetrius; Calle, Eugenia E.; Giovannucci, Edward; Crawford, E. David; Haiman, Christopher A.; Kraft, Peter; Willett, Walter C.; Thun, Michael J.; Le Marchand, Loïc; Kaaks, Rudolf; Feigelson, Heather Spencer; Bueno-de-Mesquita, H. Bas; Palli, Domenico; Riboli, Elio; Lund, Eiliv; Amiano, Pilar; Andriole, Gerald; Dunning, Alison M.; Trichopoulos, Dimitrios; Stampfer, Meir J.; Key, Timothy J.; Ma, Jing

    2010-01-01

    The insulin-like growth factor (IGF) pathway has been implicated in prostate development and carcinogenesis. We conducted a comprehensive analysis, utilizing a resequencing and tagging single-nucleotide polymorphism (SNP) approach, between common genetic variation in the IGF1, IGF binding protein (BP) 1, and IGFBP3 genes with IGF-I and IGFBP-3 blood levels, and prostate cancer (PCa) risk, among Caucasians in the NCI Breast and Prostate Cancer Cohort Consortium. We genotyped 14 IGF1 SNPs and 16 IGFBP1/IGFBP3 SNPs to capture common [minor allele frequency (MAF) ≥ 5%] variation among Caucasians. For each SNP, we assessed the geometric mean difference in IGF blood levels (N = 5684) across genotypes and the association with PCa risk (6012 PCa cases/6641 controls). We present two-sided statistical tests and correct for multiple comparisons. A non-synonymous IGFBP3 SNP in exon 1, rs2854746 (Gly32Ala), was associated with IGFBP-3 blood levels (Padj = 8.8 × 10−43) after adjusting for the previously established IGFBP3 promoter polymorphism A-202C (rs2854744); IGFBP-3 blood levels were 6.3% higher for each minor allele. For IGF1 SNP rs4764695, the risk estimates among heterozygotes was 1.01 (99% CI: 0.90–1.14) and 1.20 (99% CI: 1.06–1.37) for variant homozygotes with overall PCa risk. The corrected allelic P-value was 8.7 × 10−3. IGF-I levels were significantly associated with PCa risk (Ptrend = 0.02) with a 21% increase of PCa risk when compared with the highest quartile to the lowest quartile. We have identified SNPs significantly associated with IGFBP-3 blood levels, but none of these alter PCa risk; however, a novel IGF1 SNP, not associated with IGF-I blood levels, shows preliminary evidence for association with PCa risk among Caucasians. PMID:20484221

  19. 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.

  20. Diversities in hepatic HIF-1, IGF-I/IGFBP-1, LDH/ICD, and their mRNA expressions induced by CoCl(2) in Qinghai-Tibetan plateau mammals and sea level mice.

    PubMed

    Chen, Xue-Qun; Wang, Shi-Jun; Du, Ji-Zeng; Chen, Xiao-Cheng

    2007-01-01

    Ochotona curzoniae and Microtus oeconomus are the native mammals living on the Qinghai-Tibetan-Plateau of China. The molecular mechanisms of their acclimatization to the Plateau-hypoxia remain unclear. Expressions of hepatic hypoxia-inducible factor (HIF)-1alpha, insulin-like growth factor-I (IGF-I)/IGF binding protein (BP)-1(IGFBP-1; including genes), and key metabolic enzymatic genes [lactate dehydrogenase (LDH)-A/isocitrate dehydrogenase (ICD)] are compared in Qinghai-Tibetan-Plateau mammals and sea-level mice after injection of CoCl(2) (20, 40, or 60 mg/kg) and normobaric hypoxia (16.0% O(2), 10.8% O(2), and 8.0% O(2)) for 6 h, tested by histochemistry, Western blot analysis, ELISA, and RT-PCR. Major results are CoCl(2) markedly increased 1) HIF-1alpha only in mice, 2) hepatic and circulatory IGF-I in M. oeconomus, 3) hepatic IGFBP-1 in mice and O. curzoniae, and 4) LDH-A but reduced ICD mRNA in mice (CoCl(2) 20 mg/kg) but were unchanged in the Tibetan mammals. Normobaric hypoxia markedly 1) increased HIF-1alpha and LDH-A mRNA in mice and M. oeconomus (8.0% O(2)) not in O. curzoniae, and 2) reduced ICD mRNA in mice and M. oeconomus (8.0% O(2)) not in O. curzoniae. Results suggest that 1) HIF-1alpha responsiveness to hypoxia is distinct in lowland mice and plateau mammals, reflecting a diverse tolerance of the three species to hypoxia; 2) CoCl(2) induces diversities in HIF-1, IGF-I/IGFBP-1 protein or genes in mice, M. oeconomus, and O. curzoniae. In contrast, HIF-1 mediates IGFBP-1 transcription only in mice and in M. oeconomus (subjected to severe hypoxia); 3) differences in IGF-I/IGFBP-1 expressions induced by CoCl(2) reflect significant diversities in hormone regulation and cell protection from damage; and 4) activation of anaerobic glycolysis and reduction of Krebs cycle represents strategies of lowland-animals vs. the stable metabolic homeostasis of plateau-acclimatized mammals.

  1. Separating myoblast differentiation from muscle cell fusion using IGF-I and the p38 MAP kinase inhibitor SB202190

    PubMed Central

    Gardner, Samantha; Gross, Sean M.; David, Larry L.; Klimek, John E.

    2015-01-01

    The p38 MAP kinases play critical roles in skeletal muscle biology, but the specific processes regulated by these kinases remain poorly defined. Here we find that activity of p38α/β is important not only in early phases of myoblast differentiation, but also in later stages of myocyte fusion and myofibrillogenesis. By treatment of C2 myoblasts with the promyogenic growth factor insulin-like growth factor (IGF)-I, the early block in differentiation imposed by the p38 chemical inhibitor SB202190 could be overcome. Yet, under these conditions, IGF-I could not prevent the later impairment of muscle cell fusion, as marked by the nearly complete absence of multinucleated myofibers. Removal of SB202190 from the medium of differentiating myoblasts reversed the fusion block, as multinucleated myofibers were detected several hours later and reached ∼90% of the culture within 30 h. Analysis by quantitative mass spectroscopy of proteins that changed in abundance following removal of the inhibitor revealed a cohort of upregulated muscle-enriched molecules that may be important for both myofibrillogenesis and fusion. We have thus developed a model system that allows separation of myoblast differentiation from muscle cell fusion and should be useful in identifying specific steps regulated by p38 MAP kinase-mediated signaling in myogenesis. PMID:26246429

  2. Separating myoblast differentiation from muscle cell fusion using IGF-I and the p38 MAP kinase inhibitor SB202190.

    PubMed

    Gardner, Samantha; Gross, Sean M; David, Larry L; Klimek, John E; Rotwein, Peter

    2015-10-01

    The p38 MAP kinases play critical roles in skeletal muscle biology, but the specific processes regulated by these kinases remain poorly defined. Here we find that activity of p38α/β is important not only in early phases of myoblast differentiation, but also in later stages of myocyte fusion and myofibrillogenesis. By treatment of C2 myoblasts with the promyogenic growth factor insulin-like growth factor (IGF)-I, the early block in differentiation imposed by the p38 chemical inhibitor SB202190 could be overcome. Yet, under these conditions, IGF-I could not prevent the later impairment of muscle cell fusion, as marked by the nearly complete absence of multinucleated myofibers. Removal of SB202190 from the medium of differentiating myoblasts reversed the fusion block, as multinucleated myofibers were detected several hours later and reached ∼90% of the culture within 30 h. Analysis by quantitative mass spectroscopy of proteins that changed in abundance following removal of the inhibitor revealed a cohort of upregulated muscle-enriched molecules that may be important for both myofibrillogenesis and fusion. We have thus developed a model system that allows separation of myoblast differentiation from muscle cell fusion and should be useful in identifying specific steps regulated by p38 MAP kinase-mediated signaling in myogenesis.

  3. IGF-I and retinoic acid regulate the distribution pattern of IGFBPs synthesized by the canine mammary tumor cell line CMT-U335.

    PubMed

    Oosterlaken-Dijksterhuis, M A; Kwant, M M; Slob, A; Hellmén, E; Mol, J A

    1999-03-01

    Stromal-epithelial interactions modulate growth and development in normal and neoplastic mammary gland. The release of IGF binding proteins (IGFBPs) by the stromal compartment of the mammary gland may play a modulating role in the IGF-mediated proliferation of mammary epithelium. Therefore, the IGFBP-expression pattern of the canine mammary tumor cell line U335 (CMT-U335), which has a mesenchymal phenotype, was determined. In addition, the effects of IGFs and all trans retinoic acid (RA) on DNA synthesis, and IGFBP secretion and distribution were examined. The IGFBPs secreted by CMT-U335 were characterized as IGFBP-2, -4, -5, and -6. Moreover, CMT-U335 appeared to be a suitable mammary mesenchymal cell line for study of the regulatory factors of IGFBP expression and the mechanism(s) involved. IGFs and RA enhanced IGFBP concentrations in cell-conditioned medium with IGF-I and RA having an additive effect. The IGF-I-stimulated DNA synthesis, however, was inhibited by RA. The difference between IGF-I and RA was an enhanced IGFBP-5 binding to the extracellular matrix (ECM) by RA, whereas IGF-I reduced binding to the ECM. Because high doses of insulin had no significant effects on IGFBP concentrations in the medium, it is concluded that IGF-I-induced changes in IGFBP concentrations are not mediated by type-IIGF receptors and may be the consequence of IGFBP redistribution.

  4. Growth hormone suppresses the expression of IGFBP-5, and promotes the IGF-I-induced phosphorylation of Akt in bovine mammary epithelial cells.

    PubMed

    Sakamoto, Kazuhito; Yano, Tomoki; Kobayashi, Takuya; Hagino, Akihiko; Aso, Hisashi; Obara, Yoshiaki

    2007-05-01

    Growth hormone (GH) plays a specific role to inhibit apoptosis in the bovine mammary gland through the insulin-like growth factor (IGF)-I system, however, the mechanism of GH action is poorly understood. In this study, we show that GH dramatically inhibits the expression of IGFBP-5, and GH along with IGF-I enhanced the phosphorylation of Akt through the reduction of IGF binding protein (IGFBP)-5. To determine how GH affects Akt through IGF-I in bovine mammary epithelial cells (BMECs), we examined the phosphorylation of Akt in GH treated BMECs and found that IGF-I induced phosphorylation of Akt was significantly enhanced by the treatment with GH. We demonstrated that GH reduces mRNA and protein expression of IGFBP-5 in BMECs, but it does not affect the expression of IGFBP-3. To determine that the enhanced effect of the Akt phosphorylation by the treatment of GH is due to the inhibition of the expression of IGFBP-5, we examined the effect of IGFBP-3 and -5 on the phosphorylation of Akt through IGF-I in the GH-treated BMECs. The phosphorylation of Akt was inhibited in a dose-dependent manner when IGFBP-5 was added at varying concentrations and was also inhibited in the presence of IGFBP-3. The results of this study suggest that GH plays an important role on mammary gland involution in bovine mammary epithelial cells.

  5. Increases in serum estrogen levels during major illness are caused by increased peripheral aromatization.

    PubMed

    Spratt, Daniel I; Morton, Jeremy R; Kramer, Robert S; Mayo, Sara W; Longcope, Christopher; Vary, Calvin P H

    2006-09-01

    Although serum testosterone levels decrease acutely in critically ill patients, estrogen levels rise. We hypothesized that increased rates of aromatization of androgens to estrogens underlie the increase in serum estrogen levels. Eleven men and three women (age 42-69 yr) were prospectively studied before and again after elective coronary artery bypass graft surgery (CABG). Each patient received priming doses of [(14)C]androgen and [(3)H]estrogen that were immediately followed by peripheral infusions for 210 min. Eight men and three women received androstenedione (A(4))/estrone (E(1)) and three men received testosterone (T)/estradiol (E(2)). Adipose tissue biopsies were obtained in another six men before and after CABG to evaluate levels of P450 aromatase mRNA. Serum T levels decreased postoperatively in all 17 men (P < 0.001), whereas E(1) levels rose (P = 0.004), with a trend toward a rise in E(2) (P = 0.23). Peripheral aromatization rates of androgens to estrogens rose markedly in all 14 patients (P < 0.0001). Estrogen clearance rates rose (P < 0.002). Mean serum A(4) levels increased slightly postoperatively (P = 0.04), although no increase in A(4) production rates (PRs) was observed. T PRs decreased in two of three men, whereas clearance rates increased in all three. Adipose tissue P450 aromatase mRNA content increased postoperatively (P < 0.001). We conclude that the primary cause of increased estrogen levels in acute illness is increased aromatase P450 gene expression, resulting in enhanced aromatization of androgens to estrogens, a previously undescribed endocrine response to acute illness. Both increased T clearance and decreased T production contribute to decreased serum T levels. Animal studies suggest that these opposing changes in circulating estrogen and androgen levels may be important to reduce morbidity and mortality in critical illness.

  6. Compound Pollen Protein Nutrient Increases Serum Albumin in Cirrhotic Rats

    PubMed Central

    Shi, Hong Bo; Kong, Ming; Chen, Gong; Zhao, Jun; Shi, Hong Lin; Chen, Yu; Rowan, Frank G

    2010-01-01

    Background Malnutrition, especially protein-calorie malnutrition, is common in patients with liver cirrhosis. When in the status of malnutrition, the complications increase, liver function deteriorates, and the prognosis of patients with liver cirrhosis worsens. Hence, nutritional support and treatment is essential in patients with liver cirrhosis. Previous studies suggested that compound nutrition based on pollen can improve liver function, and can be a basic nutrient for patients with liver cirrhosis. However, the nutritional support based on pollen for malnutrition of cirrhotic patients needs to be further evaluated. In this study, we investigated the nutritional support of Noveliver, a new compound pollen protein nutrient, in the cirrhotic rats induced by carbon tetrachloride (CCl4). Methods The cirrhotic rats induced by CCl4 were treated with Noveliver in different doses, and treated with a regular compound pollen nutrient, untreated cirrhotic rats and normal rats were used as controls. Serum albumin were measured before and after the nutritional treatment in each group. At the same time, liver function, cytokines and pathological changes were also determined. Results In the second week of nutritional treatment, the levels of serum albumin in normal control group, low dose noveliver group, high dose noveliver group, compound protein pollen group and spontaneous recovery group were 35.67 ± 1.42, 33.07 ± 1.27, 32.27 ± 1.50, 30.53 ± 0.25, 24.53 ± 3.56 (g/L), respectively, the differences among the groups were significant (F = 14.007, P = 0.000); The levels of serum albumin in low dose Noveliver group, high dose Noveliver group and the compound protein pollen group were higher than that in the spontaneous recovery group (P = 0.000, 0.001, 0.003, respectively). In the second week of nutritional treatment, the serum levels of HGF in normal control group, low dose Noveliver group, high dose Noveliver group, compound protein pollen group and spontaneous recovery

  7. Estradiol regulates the insulin-like growth factor-I (IGF-I) signalling pathway: A crucial role of phosphatidylinositol 3-kinase (PI 3-kinase) in estrogens requirement for growth of MCF-7 human breast carcinoma cells

    SciTech Connect

    Bernard, Laurence; Legay, Christine; Adriaenssens, Eric; Mougel, Alexandra; Ricort, Jean-Marc . E-mail: ricort@lbpa.ens-cachan.fr

    2006-12-01

    Estrogens can stimulate the proliferation of estrogen-responsive breast cancer cells by increasing their proliferative response to insulin-like growth factors. With a view to investigating the molecular mechanisms implicated, we studied the effect of estradiol on the expression of proteins implicated in the insulin-like growth factor signalling pathway. Estradiol dose- and time-dependently increased the expression of insulin receptor substrate-1 and the p85/p110 subunits of phosphatidylinositol 3-kinase but did not change those of ERK2 and Akt/PKB. ICI 182,780 did not inhibit estradiol-induced IRS-1 and p85 expression. Moreover, two distinct estradiol-BSA conjugate compounds were as effective as estradiol in inducing IRS-1 and p85/p110 expression indicating the possible implication of an estradiol membrane receptor. Comparative analysis of steroids-depleted and steroids-treated cells showed that IGF-I only stimulates cell growth in the latter condition. Nevertheless, expression of a constitutively active form of PI 3-kinase in steroid-depleted cells triggers proliferation. These results demonstrate that estradiol positively regulates essential proteins of the IGF signalling pathway and put in evidence that phosphatidylinositol 3-kinase plays a central role in the synergistic pro-proliferative action of estradiol and IGF-I.

  8. 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

  9. IGF-I mediated inhibition of leptin receptor expression in porcine hepatocytes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A study was conducted to elucidate hormonal control of leptin receptor gene expression in primary cultures of porcine hepatocytes. Hepatocytes were isolated from pigs (52 kg) and seeded into collagen-coated T-25 flasks. Monolayer cultures were established in medium containing fetal bovine serum fo...

  10. Insulin-like growth factor I (IGF-I) in Chinese alligator, Alligator sinensis: Molecular characterization, tissue distribution and mRNA expression changes during the active and hibernating periods.

    PubMed

    Zhu, Xue; Zhang, Shengzhou; Zhao, Shuai; Zhang, Rui; Zhou, Yongkang; Wu, Xiaobing

    2017-02-01

    The Chinese alligator Alligator sinensis is an endangered species endemic to China, up to date, little is known about the regulation of its growth and development. Insulin-like growth factor I (IGF-I) plays a vital role in regulating vertebrate growth and development. In this study, the full-length cDNA of IGF-I in Chinese alligator (caIGF-I) was obtained for the first time, it contains 890-bp nucleotides encoding a 153-amino acid precursor, the mature caIGF-I consists of 70 amino acids by cleaving the signal peptide and C-terminal extension (E domain). The caIGF-I contains all the features of IGF-I peptide with B, C, A, and D domains and the six conservative cysteine residues involved in the stable tertiary structure. Multiple alignment analysis showed that the amino acid sequence of caIGF-I shares high identity with American alligator Alligator mississippiensis (100%) and birds (95-97%). Phylogenetic tree analysis of the IGF-I amino acid sequences indicated that alligators cluster into the bird branch. Real-time quantitative PCR technique showed that caIGF-I is widely expressed in all the examined tissues with the highest expression level in liver, higher in pancreas and oviduct while lower in heart, spleen, lung, kidney, stomach, intestines, ovary and muscles. During hibernation, the caIGF-I expression level decreased significantly in liver, pancreas, oviduct and kidney, while did not significantly change in heart, spleen, lung, stomach, small intestine, ovary and muscles. The mRNA expression changes during the two periods implicate that caIGF-I might play an important role in the regulation of feeding and growth in the Chinese alligator.

  11. Estimates of inbreeding depression for serum insulin-like growth factor I concentrations, body weights, and body weight gains in Angus beef cattle divergently selected for serum insulin-like growth factor I concentration.

    PubMed

    Davis, M E; Simmen, R C M

    2010-02-01

    Data for the current study were obtained from a divergent selection experiment in which the selection criterion was the average serum IGF-I concentration of 3 postweaning blood samples collected from purebred Angus calves. Multiple trait derivative-free REML procedures were used to obtain estimates of inbreeding depression for IGF-I concentration and for BW and BW gains measured from birth to the conclusion of a 140-d postweaning performance test. Included in the analysis were 3,243 animals in the A(-1) matrix, 2,182 of which had valid records for IGF-I concentration. Over the course of the entire selection experiment, inbreeding of the calf averaged 3.3% (SD = 3.1%) and inbreeding of the dam averaged 1.8% (SD = 2.7%). Mean inbreeding levels at the end of the study were 6.82 +/- 0.38% and 4.20 +/- 0.36% for calves and dams, respectively. Annual rates of increase in inbreeding of calves and dams were 0.36 +/- 0.01 (P < 0.0001) and 0.25 +/- 0.01%/yr (P < 0.0001), respectively. Insulin-like growth factor I concentration at d 28 (IGF28), 42 (IGF42), and 56 (IGF56) of the 140-d postweaning test and mean IGF-I concentration decreased by 0.62 +/- 0.88, 1.86 +/- 0.96, 1.92 +/- 0.89, and 1.48 +/- 0.76 ng/mL per 1% increase in inbreeding of calf. Only the regression coefficient for IGF56 differed significantly from zero, although the regression coefficients for IGF42 and mean IGF-I approached significance (P < 0.10). Increases in inbreeding levels of the dams also tended to result in reduced IGF-I concentrations, although the regression coefficients were not significantly different from zero. Inbreeding of calf had highly significant negative effects on all BW and BW gain traits examined, except for birth weight, with regression coefficients ranging from -0.74 +/- 0.20 kg/% increase in calf inbreeding for postweaning BW gain to -1.68 +/- 0.33 kg/% increase in calf inbreeding for off-test BW. Inbreeding of dam had a significant negative effect on birth weight of progeny and

  12. Serum insulin-like growth factor-I, iron, C-reactive protein, and serum amyloid A for prediction of outcome in dogs with pyometra.

    PubMed

    Jitpean, Supranee; Holst, Bodil Ström; Höglund, Odd V; Pettersson, Ann; Olsson, Ulf; Strage, Emma; Södersten, Fredrik; Hagman, Ragnvi

    2014-07-01

    Pyometra, accumulation of pus in the uterus, is a bacterial infection that frequently initiates systemic inflammation. The disease may have lethal consequences when the systemic effects are severe or complications occur. Markers for identifying high-risk patients and predicting outcome are therefore in high demand. The objective of this study was to measure serum concentrations of insulin-like growth factor-I (IGF-I), iron, C-reactive protein (CRP), and serum amyloid A (SAA) in bitches with pyometra and to explore the possible value of these variables for detection of increased morbidity. In total, 31 bitches were diagnosed with pyometra and destined for surgical treatment (ovariohysterectomy) and 17 healthy bitches were included in the study. Concentrations of IGF-I and iron were lower in the pyometra group (mean concentration 221.2 ± 22.5 ng/mL and 16.9 ± 1.6 μmol/L, respectively) compared with the healthy control group (mean concentration 366.7 ± 46.2 ng/mL and 38.1 ± 2.7 μmol/L, respectively). In contrast, concentrations of CRP and SAA were significantly higher in bitches with pyometra (mean concentrations 212.9 ± 17.3 mg/L and 119.9 ± 8.5 mg/L, respectively) compared with the control group (<5 mg/L and <10 mg/L, respectively). None of the explored variables were associated with morbidity as measured by duration of postoperative hospitalization. In conclusion, IGF-I and iron concentrations were decreased in pyometra, whereas SAA and CRP concentrations were increased in the disease. Although unspecific, measurement of these variables may be valuable as adjunctive markers for prognosis in cases of pyometra.

  13. The essential role of IGF-I: lessons from the long-term study and treatment of children and adults with Laron syndrome.

    PubMed

    Laron, Z

    1999-12-01

    Fifty patients with primary GH resistance (Laron syndrome) due to molecular defects of the GH receptor or post-receptor pathways were followed from infancy through adulthood. This condition leading to long-term insulin-like growth factor-I (IGF-I) deprivation caused marked growth retardation (-4 to 8 height SD), acromicia, organomicria, retarded development of the skeletal and muscular systems, a small cranium, slow motor development, and impairment of intellectual development in some of the patients. In addition, there was progressive obesity, insulin resistance, a tendency for hypoglycemia, followed later in life by hypercholesterolemia and by glucose intolerance and even diabetes. IGF-I treatment of children with Laron syndrome, by our and other groups (150-240 microg/day sc), stimulated growth (8 cm in the first year and 4-5 cm in the following years) and normalized the biochemical abnormalities. Overdosage led to adverse effects such as hypoglycemia, edema, swelling of soft tissues, and hyperandrogenism. It is concluded that primary IGF-I deprivation induces severe auxological, biochemical, and hormonal changes, the only treatment being biosynthetic IGF-I administration.

  14. Body composition and circulating high-molecular-weight adiponectin and IGF-I in infants born small for gestational age: breast- versus formula-feeding.

    PubMed

    de Zegher, Francis; Sebastiani, Giorgia; Diaz, Marta; Sánchez-Infantes, David; Lopez-Bermejo, Abel; Ibáñez, Lourdes

    2012-08-01

    Prenatal growth restraint, if followed by postnatal overweight, confers risk for adult disease including diabetes. The mechanisms whereby neonatal nutrition may modulate such risk are poorly understood. We studied the effects of nutrition (breast-feeding [BRF] vs. formula-feeding [FOF]) on weight partitioning and endocrine state (as judged by high-molecular-weight [HMW] adiponectin and IGF-I) of infants born small for gestational age (SGA). Body composition (by absorptiometry), HMW adiponectin, and IGF-I were assessed at birth and 4 months in BRF infants born appropriate for gestational age (AGA; n = 72) and SGA infants receiving BRF (n = 46) or FOF (n = 56), the latter being randomized to receive a standard (FOF1) or protein-rich formula (FOF2). Compared with AGA-BRF infants, the catchup growth of SGA infants was confined to lean mass, independently of nutrition. Compared with AGA-BRF infants, SGA-BRF infants had normal HMW adiponectin and IGF-I levels at 4 months, whereas SGA-FOF infants had elevated levels of HMW adiponectin (particularly SGA-FOF1) and IGF-I (particularly SGA-FOF2). In conclusion, neonatal nutrition seems to influence endocrinology more readily than body composition of SGA infants. Follow-up will disclose whether the endocrine abnormalities in SGA-FOF infants can serve as early markers of an unfavorable metabolic course and whether they may contribute to design early interventions that prevent subsequent disease, including diabetes.

  15. Level of maternal winter supplement and feed restriction during postweaning development influence circulating concentrations of IGF-I in heifers during the peripartum and rebreeding period

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Objective of this research was to evaluate effects of 2 levels of supplemental feed provided to cows during late gestation and 2 levels of feed provided to their daughters during postweaning development on circulating concentrations of IGF-I in the daughters before calving, after calving and before ...

  16. Dietary Hizikia fusiformis glycoprotein-induced IGF-I and IGFBP-3 associated to somatic growth, polyunsaturated fatty acid metabolism, and immunity in juvenile olive flounder Paralichthys olivaceus.

    PubMed

    Choi, Youn Hee; Kim, Kang-Woong; Han, Hyon-Sob; Nam, Taek Jeong; Lee, Bong-Joo

    2014-01-01

    This study was aimed to examine the effect of dietary glycoprotein extracted from the sea mustard Hizikia fusiformis (Phaeophyceae: Sargassaceae) as a dietary supplement on growth performance in association with somatotropin level, proximate compositions, and immunity in juvenile olive flounder Paralichthys olivaceus. Water-ethanol extracted glycoprotein from H. fusiformis was supplemented to three fishmeal-based diets at the concentration of 0, 5, and 10gkg(-1) diet (designated as H0, H5, and H10, respectively). After a 12week-long feeding trial, growth performance and biochemical responses were analyzed including proximate composition, and whole body amino acids and fatty acids. We also measured plasma insulin like growth factor (IGF), IGF-binding protein (IGFBP) and interleukin (IL). The fish fed H5 showed the greatest weight gain among the dietary treatments. In parallel with the growth, the fish fed the diets containing H. fusiformis glycoprotein showed an increased plasma IGF-I activity and increased expression of 43-kDa IGFBP-3 compared to that in the control, whereas an opposite trend was observed for 34-kDa IGFBP-1. Although no differences were found in the level of whole body linoleic acid (C18:2n-6) and linolenic acid (C18:3n-3) among treatments, increases in arachidonic acid (ARA, C20:4n-6), eicosapentaenoic acid (EPA, C20:5n-3) and docosahexaenoic acid (DHA, C22:6n-3) were observed in fish fed H5 compared to control. IL-2 and -6 levels increased significantly in fish fed H10 compared to those in the control indicating increased immunity. These results suggest that supplementation of H. fusiformis glycoprotein in fish diet may be beneficial for fish growth and immunity in juvenile olive flounder.

  17. Central injection of CDP-choline suppresses serum ghrelin levels while increasing serum leptin levels in rats.

    PubMed

    Kiyici, Sinem; Basaran, Nesrin Filiz; Cavun, Sinan; Savci, Vahide

    2015-10-05

    In this study we aimed to test central administration of CDP-choline on serum ghrelin, leptin, glucose and corticosterone levels in rats. Intracerebroventricular (i.c.v.) 0.5, 1.0 and 2.0 µmol CDP-choline and saline were administered to male Wistar-Albino rats. For the measurement of serum leptin and ghrelin levels, blood samples were obtained baseline and at 5, 15, 30, 60 and 120 min following i.c.v. CDP-choline injection. Equimolar doses of i.c.v. choline (1.0 µmol) and cytidine (1.0 µmol) were administered and measurements were repeated throughout the second round of the experiment. Atropine (10 µg) and mecamylamine (50 µg) were injected intracerebroventricularly prior to CDP-choline and measurements repeated in the third round of the experiment. After 1 µmol CDP-choline injection, serum ghrelin levels were suppressed significantly at 60 min (P=0.025), whereas serum leptin levels were increased at 60 and 120 min (P=0.012 and P=0.017 respectively). CDP-choline injections also induced a dose- and time-dependent increase in serum glucose and corticosterone levels. The effect of choline on serum leptin and ghrelin levels was similar with CDP-choline while no effect was seen with cytidine. Suppression of serum ghrelin levels was eliminated through mecamylamine pretreatment while a rise in leptin was prevented by both atropine and mecamylamine pretreatments. In conclusion; centrally injected CDP-choline suppressed serum ghrelin levels while increasing serum leptin levels. The observed effects following receptor antagonist treatment suggest that nicotinic receptors play a role in suppression of serum ghrelin levels,whereas nicotinic and muscarinic receptors both play a part in the increase of serum leptin levels.

  18. GH, IGF-I and GH receptors mRNA expression in response to growth impairment following a food deprivation period in individually housed cichlid fish Cichlasoma dimerus.

    PubMed

    Delgadin, Tomás Horacio; Pérez Sirkin, Daniela Irina; Di Yorio, María Paula; Arranz, Silvia Eda; Vissio, Paula Gabriela

    2015-02-01

    Cichlasoma dimerus is a social cichlid fish capable of growing at high rates under laboratory conditions, but knowledge on somatic growth regulation is still unclear. Growth hormone (GH)/insulin-like growth factor I (IGF-I) axis is the key regulator of somatic growth in vertebrates. Two types of growth hormone receptors have been described in teleost fish, named GH receptor type 1 (GHR1) and type 2 (GHR2). In addition, isoforms of these receptors lacking part of the intracellular region have been described. The aim of this study was to evaluate the somatic growth, liver histology and changes in the GH/IGF-I axis after 4 weeks of food deprivation in C. dimerus. Four-week fasted fish showed reductions in specific growth rates in body weight (p < 0.001) and standard length (p < 0.001). Additionally, the hepatosomatic index (p < 0.001) and hepatocyte area (p < 0.001) decreased in fasted fish, while no changes in glucose levels were detected in plasma. The starvation protocol failed to induce changes in GH mRNA levels in the pituitary and IGF-I mRNA levels in liver. In contrast, IGF-I mRNA levels in muscle decreased in fasted fish (p = 0.002). On the other hand, GHR2 (detected with primer sets designed over the extracellular and intracellular region) was upregulated by starvation both in liver and muscle (p < 0.05), while GHR1 remained unchanged. These results show that a fasting period reduced somatic growth both in length and body weight concomitantly with alterations on liver and muscle GHR2 and muscle IGF-I mRNA expression.

  19. Expression profile of IGF-I-calcineurin-NFATc3-dependent pathway genes in skeletal muscle during early development between duck breeds differing in growth rates.

    PubMed

    Shu, Jingting; Li, Huifang; Shan, Yanju; Xu, Wenjuan; Chen, Wenfeng; Song, Chi; Song, Weitao

    2015-06-01

    The insulin-like growth factor I (IGF-I)-calcineurin (CaN)-NFATc signaling pathways have been implicated in the regulation of myocyte hypertrophy and fiber-type specificity. In the present study, the expression of the CnAα, NFATc3, and IGF-I genes was quantified by RT-PCR for the first time in the breast muscle (BM) and leg muscle (LM) on days 13, 17, 21, 25, and 27 of embryonic development, as well as at 7 days posthatching (PH), in Gaoyou and Jinding ducks, which differ in their muscle growth rates. Consistent expression patterns of CnAα, NFATc3, and IGF-I were found in the same anatomical location at different development stages in both duck breeds, showing significant differences in an age-specific fashion. However, the three genes were differentially expressed in the two different anatomical locations (BM and LM). CnAα, NFATc3, and IGF-I messenger RNA (mRNA) could be detected as early as embryonic day 13 (ED13), and the highest level appeared at this stage in both BM and LM. Significant positive relationships were observed in the expression of the studied genes in the BM and LM of both duck breeds. Also, the expression of these three genes showed a positive relationship with the percentage of type IIb fibers and a negative relationship with the percentage of type I fibers and type IIa fibers. Our data indicate differential expression and coordinated developmental regulation of the selected genes involved in the IGF-I-calcineurin-NFATc3 pathway in duck skeletal muscle during embryonic and early PH growth and development; these data also indicate that this signaling pathway might play a role in the regulation of myofiber type transition.

  20. The coordinate cellular response to insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-2 (IGFBP-2) is regulated through vimentin binding to receptor tyrosine phosphatase β (RPTPβ).

    PubMed

    Shen, Xinchun; Xi, Gang; Wai, Christine; Clemmons, David R

    2015-05-01

    Insulin-like growth factor-binding protein-2 (IGFBP-2) functions coordinately with IGF-I to stimulate cellular proliferation and differentiation. IGFBP-2 binds to receptor tyrosine phosphatase β (RPTPβ), and this binding in conjunction with IGF-I receptor stimulation induces RPTPβ polymerization leading to phosphatase and tensin homolog inactivation, AKT stimulation, and enhanced cell proliferation. To determine the mechanism by which RPTPβ polymerization is regulated, we analyzed the protein(s) that associated with RPTPβ in response to IGF-I and IGFBP-2 in vascular smooth muscle cells. Proteomic experiments revealed that IGF-I stimulated the intermediate filament protein vimentin to bind to RPTPβ, and knockdown of vimentin resulted in failure of IGFBP-2 and IGF-I to stimulate RPTPβ polymerization. Knockdown of IGFBP-2 or inhibition of IGF-IR tyrosine kinase disrupted vimentin/RPTPβ association. Vimentin binding to RPTPβ was mediated through vimentin serine phosphorylation. The serine threonine kinase PKCζ was recruited to vimentin in response to IGF-I and inhibition of PKCζ activation blocked these signaling events. A cell-permeable peptide that contained the vimentin phosphorylation site disrupted vimentin/RPTPβ association, and IGF-I stimulated RPTPβ polymerization and AKT activation. Integrin-linked kinase recruited PKCζ to SHPS-1-associated vimentin in response to IGF-I and inhibition of integrin-linked kinase/PKCζ association reduced vimentin serine phosphorylation. PKCζ stimulation of vimentin phosphorylation required high glucose and vimentin/RPTPβ-association occurred only during hyperglycemia. Disruption of vimetin/RPTPβ in diabetic mice inhibited RPTPβ polymerization, vimentin serine phosphorylation, and AKT activation in response to IGF-I, whereas nondiabetic mice showed no difference. The induction of vimentin phosphorylation is important for IGFBP-2-mediated enhancement of IGF-I-stimulated proliferation during hyperglycemia, and it

  1. The effect of polymorphism in gene of insulin-like growth factor-I on the serum periparturient concentration in Holstein dairy cows

    PubMed Central

    Mirzaei, A; Sharifiyazdi, H; Ahmadi, MR; Ararooti, T; Ghasrodashti, A Rowshan; Kadivar, A

    2012-01-01

    Objective To investigate the relationship between polymorphism within the 5′-untranslated region (5′-UTR) of IGF-I gene and its periparturient concentration in Iranian Holstein dairy cows. Methods Blood samples (5 mL, n = 37) were collected by caudal venipuncture from each animal into sample tubes containing the EDTA and DNA was extracted from blood. In order to measure IGF-I concentration the collection of blood samples (n = 111) was also done at 14 d before calving (prepartum), 25 and 45 d postpartum. Results We found evidence for a significant effect of C to T mutation in position 512 of IGF-I gene on its serum concentration in dairy cows in Iran. Cows with CC genotype had significantly higher concentration (Mean±SD) of IGF-I at 14 d prepartum (91.8±18.1) µg/L compared to those with TT genotype (73.3±14.4) µg/L (P=0.04). A significant trend (quadratic) was found for IGF-I concentration, as higher in CC cows compared to ones with TT genotype, during the 14 d before calving to 45 d postpartum (P=0.01). Conclusions We concluded that C/T transition in the promoter region of IGF-I gene can influence the serum concentration of IGF-I in periparturient dairy cows. PMID:23569844

  2. Retardation of fetal dendritic development induced by gestational hyperglycemia is associated with brain insulin/IGF-I signals.

    PubMed

    Jing, Yu-Hong; Song, Yan-Feng; Yao, Ya-Ming; Yin, Jie; Wang, De-Gui; Gao, Li-Ping

    2014-10-01

    Hyperglycemia is an essential risk factor for mothers and fetuses in gestational diabetes. Clinical observation has indicated that the offspring of mothers with diabetes shows impaired somatosensory function and IQ. However, only a few studies have explored the effects of hyperglycemia on fetal brain development. Neurodevelopment is susceptible to environmental conditions. Thus, this study aims to investigate the effects of maternal hyperglycemia on fetal brain development and to evaluate insulin and insulin-like growth factor-I (IGF-I) signals in fetal brain under hyperglycemia or controlled hyperglycemia. At day 1 of pregnancy, gestational rats were intraperitoneally injected with streptozocin (60 mg/kg). Some of the hyperglycemic gestational rats were injected with insulin (20 IU, two times a day) to control hyperglycemia; the others were injected with saline of equal volume. The gestational rats were sacrificed at days 14, 16, and 18 of embryo development. The dendritic spines of subplate cortex neurons in the fetal brain were detected by Golgi-Cox staining. The mRNA levels of insulin receptors (IRs) and IGF-IR in the fetal brain were measured using qRT-PCR. The protein levels of synaptophysin, IR, and IGF-IR in the fetal brain were detected by western blot. No significant difference in fetal brain formation was observed between the maternal hyperglycemic group and insulin-treated group. By contrast, obvious retardation of dendritic development in the fetus was observed in the maternal hyperglycemic group. Similarly, synaptophysin expression was lower in the fetus of the maternal hyperglycemic group than in that of the insulin-treated group. The mRNA and protein expression levels of IRs in the fetal brain were higher in the hyperglycemic group than in the insulin-treated group. By contrast, the levels of IGF-IR in the brain were lower in the fetus of the maternal hyperglycemic group than in that of the insulin-treated group. These results suggested that

  3. Pyoderma gangrenosum with increased levels of serum cytokines.

    PubMed

    Kozono, Kana; Nakahara, Takeshi; Kikuchi, Satoko; Itoh, Eriko; Kido-Nakahara, Makiko; Furue, Masutaka

    2015-12-01

    A 66-year-old woman presented after an episode of accidental trauma with a painful ulcer on her scalp which rapidly enlarged in size, accompanied by central necrosis and undermining ulceration. The patient's past history was negative for underlying systemic disease, although she had had a similar post-traumatic intractable leg ulcer 3 years prior, which was unresponsive to surgical management but successfully treated with systemic steroids. A biopsied specimen from the scalp showed marked neutrophilic infiltrates in the dermis, compatible with a diagnosis of pyoderma gangrenosum (PG). The large ulcerative lesion responded very well to oral steroid therapy, showing rapid epithelialization. Serum levels of granulocyte colony-stimulating factor and interleukin-6 were significantly elevated prior to treatment, with decrease to normal levels after treatment. Serum tumor necrosis factor (TNF)-α and granulocyte macrophage colony-stimulating factor levels were within normal limits. The significance and pathogenic role of cytokine burst in PG is reviewed and discussed.

  4. Increased Serum Sodium and Serum Osmolarity Are Independent Risk Factors for Developing Chronic Kidney Disease; 5 Year Cohort Study

    PubMed Central

    Kuwabara, Masanari; Hisatome, Ichiro; Roncal-Jimenez, Carlos A.; Niwa, Koichiro; Andres-Hernando, Ana; Jensen, Thomas; Bjornstad, Petter; Milagres, Tamara; Cicerchi, Christina; Song, Zhilin; Garcia, Gabriela; Sánchez-Lozada, Laura G.; Ohno, Minoru; Lanaspa, Miguel A.; Johnson, Richard J.

    2017-01-01

    Background Epidemics of chronic kidney disease (CKD) not due to diabetes mellitus (DM) or hypertension have been observed among individuals working in hot environments in several areas of the world. Experimental models have documented that recurrent heat stress and water restriction can lead to CKD, and the mechanism may be mediated by hyperosmolarity that activates pathways (vasopressin, aldose reductase-fructokinase) that induce renal injury. Here we tested the hypothesis that elevated serum sodium, which reflects serum osmolality, may be an independent risk factor for the development of CKD. Methods This study was a large-scale, single-center, retrospective 5-year cohort study at Center for Preventive Medicine, St. Luke’s International Hospital, Tokyo, Japan, between 2004 and 2009. We analyzed 13,201 subjects who underwent annual medical examination of which 12,041 subjects (age 35 to 85) without DM and/or CKD were enrolled. This analysis evaluated age, sex, body mass index, abdominal circumference, hypertension, dyslipidemia, hyperuricemia, fasting glucose, BUN, serum sodium, potassium, chloride and calculated serum osmolarity. Results Elevated serum sodium was an independent risk factor for development of CKD (OR: 1.03, 95% CI, 1.00–1.07) after adjusted regression analysis with an 18 percent increased risk for every 5 mmol/L change in serum sodium. Calculated serum osmolarity was also an independent risk factor for CKD (OR: 1.04; 95% CI, 1.03–1.05) as was BUN (OR: 1.08; 95% CI, 1.06–1.10) (independent of serum creatinine). Conclusions Elevated serum sodium and calculated serum osmolarity are independent risk factors for developing CKD. This finding supports the role of limiting salt intake and preventing dehydration to reduce risk of CKD. PMID:28081152

  5. The proto-oncogene product c-Crk associates with insulin receptor substrate-1 and 4PS. Modulation by insulin growth factor-I (IGF) and enhanced IGF-I signaling.

    PubMed

    Beitner-Johnson, D; Blakesley, V A; Shen-Orr, Z; Jimenez, M; Stannard, B; Wang, L M; Pierce, J; LeRoith, D

    1996-04-19

    The Crk proto-oncogene product is an SH2 and SH3 domain-containing adaptor protein which we have previously shown to become rapidly tyrosine phosphorylated in response to stimulation with insulin-like growth factor I (IGF-I) in NIH-3T3 cells. In order to further characterize the role of Crk in the IGF-I signaling pathway, NIH-3T3 and 293 cells were stably transfected with an expression vector containing the Crk cDNA. The various resultant 3T3-Crk clones expressed Crk at approximately 2-15-fold higher levels than parental 3T3 cells. In 3T3-Crk cells, Crk immunoreactivity was detected in insulin receptor substrate-1 (IRS-1) immunoprecipitates. Stimulation with IGF-I resulted in a dissociation of Crk protein from IRS-1. In contrast, the association of the related adaptor protein Grb2 with IRS-1 was enhanced by IGF-I stimulation. Similar results were obtained in stably transfected 293-Crk cells, which express both IRS-1 and the IRS-1-related signaling protein 4PS. In these cells, IRS-1 and 4PS both associated with Crk, and this association was also decreased by IGF-I treatment, whereas the association of Grb2 with IRS-1 and 4PS was enhanced by IGF-I. Overexpression of Crk also enhanced IGF-I-induced mitogenesis of NIH-3T3 cells, as measured by [3H]thymidine incorporation. The levels of IGF-I-induced mitogenesis were proportional to the level of Crk expression. These results suggest that Crk is a positive effector of IGF-I signaling, and may mediate its effects via interaction with IRS-1 and/or 4PS.

  6. Prostate Cancer Risk in Relation to IGF-I and Its Genetic Determinants: A Case Control Study Within the Cancer Prostate Sweden Project (CAPS)

    DTIC Science & Technology

    2005-05-01

    is provided by growth hormone (GH). Thus, elevated IGF-I in blood most likely reflects an elevated pituitary GH secretion, and most likely indicates...candidate genes to be examined are those involved in the pituitary release or biological action of growth hormone - the primary physiological stimulus for...transcription factor (or POU-domain class 1 transcription factor 1 (POUIFI); growth hormone (GHI) and its receptor (GHR), growth hormone releasing hormone

  7. Overexpression of IGF-I receptor in HeLa cells enhances in vivo radioresponse

    SciTech Connect

    Kaneko, Haruna; Yu, Dong; Miura, Masahiko

    2007-11-30

    Insulin-like growth factor I receptor (IGF-IR) is a transmembrane receptor tyrosine kinase whose activation strongly promotes cell growth and survival. We previously reported that IGF-IR activity confers intrinsic radioresistance in mouse embryo fibroblasts in vitro. However, it is still unclear whether tumor cells overexpressing IGF-IR exhibit radioresistance in vivo. For this purpose, we established HeLa cells that overexpress IGF-IR (HeLa-R), subcutaneously transplanted these cells into nude mice, and examined radioresponse in the resulting solid tumors. HeLa-R cells exhibited typical in vitro phenotypes generally observed in IGF-IR-overexpressing cells, as well as significant intrinsic radioresistance in vitro compared with parent cells. As expected, the transplanted HeLa-R tumors grew at a remarkably higher rate than parent tumors. Histological analysis revealed that HeLa-R tumors expressed more VEGF and had a higher density of tumor vessels. Unexpectedly, a marked growth delay was observed in HeLa-R tumors following 10 Gy of X-irradiation. Immunostaining of HeLa-R tumors for the hypoxia marker pimonidazole revealed a significantly lower level of hypoxic cells. Moreover, clamp hypoxia significantly increased radioresistance in HeLa-R tumors. Tumor microenvironments in vivo generated by the IGF-IR expression thus could be a major factor in determining the tumor radioresponse in vivo.

  8. Sequential release kinetics of two (gentamicin and BMP-2) or three (gentamicin, IGF-I and BMP-2) substances from a one-component polymeric coating on implants.

    PubMed

    Strobel, Catrin; Bormann, Nicole; Kadow-Romacker, Anke; Schmidmaier, Gerhard; Wildemann, Britt

    2011-11-30

    The local application of antibiotics in combination with timely controlled growth factor delivery might be beneficial for the prevention of infections and to stimulate bone healing. Therefore, in this study a variable sequential drug delivery system with three distinctly different release profiles was developed: i) a burst release of gentamicin, ii) a burst release of IGF-I followed by a sustained release, and iii) a slow sustained release of BMP-2 out of an implant coating. Only one polymer [poly(D,L-lactide)], incorporating gentamicin, IGF-I or BMP-2, was used for two- or three-layer coatings of K-wires. To control the release kinetics, the polymer concentrations in the solvent were varied. The activity of early released gentamicin from a two-layer coating was confirmed microbiologically and BMP-2 stimulated the metabolic activity and alkaline phosphatase activity of C2C12 cells after 2 weeks. From the three-layer coated wires, IGF-I continuously stimulated the cell proliferation, whereas BMP-2 enhanced ALP between 1 and 3 weeks. The sequential release of growth factors revealed an additive effect on the metabolic activity and ALP of primary osteoblast-like cells compared to the single coated controls. The controlled delivery of different factors from one implant might prevent infections and subsequently stimulate the different phases of bone healing.

  9. Serum carcinoembryonic antigen specifically increases among various serum markers of adenocarcinoma in hypohidrosis or conditions related to hypohidrosis.

    PubMed

    Honma, Masaru; Nozaki, Hiroyoshi; Nagahata, Hiroko; Fujii, Mizue; Shibuya, Takashi; Kanno, Kyoko; Minami-Hori, Masako; Ishida-Yamamoto, Akemi

    2017-03-11

    Anhidrosis/hypohidrosis are conditions presenting various level of sweating dysfunction. Among them, acquired idiopathic generalized anhidrosis (AIGA) presents inadequate decrease or loss of sweating without apparent neurological and dermatological symptoms except cholinergic urticaria. Recently, serum level of carcinoembryonic antigen (CEA), one of the most well-known tumor markers, has been proposed as a clinical marker reflecting activity of AIGA. This study was performed to verify the specificity and independence of serum CEA level from the other serum tumor markers especially related to adenocarcinoma. The expression of various tumor markers in the serum collected from three healthy control subjects, four AIGA cases, and a cholinergic urticaria (CU) case with elevation of serum CEA level and history of hyperthermia was analyzed using a membrane-based antibody array. In all AIGA and CU cases, the intensity of CEA was significantly increased (7.60-15.9 times compared with that of control), relatively well-reflecting the serum CEA level, and the mean intensity of CEA was 11.8 times higher than the control subjects (P = 0.0011). On the other hand, the ratio of carbohydrate antigen (CA)125 and CA19-9 was 1.93 and 0.23 times compared with the mean intensity of the control subjects, respectively, and there was no statistical significance. Immunohistochemistry on 10 AIGA cases showed increased expression of CEA but not CA19-9 and CA125 in the eccrine sweat glands. In conclusion, the elevation of serum CEA level was independent from the other tumor markers in hypohidrotic condition represented by AIGA.

  10. Increased sialidase activity in serum of cancer patients: Identification of sialidase and inhibitor activities in human serum.

    PubMed

    Hata, Keiko; Tochigi, Tatsuo; Sato, Ikuro; Kawamura, Sadafumi; Shiozaki, Kazuhiro; Wada, Tadashi; Takahashi, Kohta; Moriya, Setsuko; Yamaguchi, Kazunori; Hosono, Masahiro; Miyagi, Taeko

    2015-04-01

    Aberrant sialylation in glycoproteins and glycolipids is a characteristic feature of malignancy. Human sialidases, which catalyze the removal of sialic acid residues from glycoconjugates, have been implicated in cancer progression. They have been detected in a wide variety of human cells and tissues, but few studies have focused on their existence in human serum. Among the four types identified to date, we previously demonstrated that plasma membrane-associated ganglioside sialidase (NEU3) is markedly upregulated in various human cancers, including examples in the colon and prostate. Here, using a sensitive assay method, we found a significant increase of sialidase activity in the serum of patients with prostate cancer compared with that in healthy subjects having low activity, if any. Activity was apparent with gangliosides as substrates, but only to a very limited extent with 4-methylumbelliferyl sialic acid, a good synthetic substrate for sialidases other than human NEU3. The serum sialidase was also almost entirely immunoprecipitated with anti-NEU3 antibody, but not with antibodies for other sialidases. Interestingly, sera additionally contained inhibitory activity against the sialidase and also against recombinant human NEU3. The sialidase and inhibitor activities could be separated by exosome isolation and by hydrophobic column chromatography. The serum sialidase was assessed by a sandwich ELISA method using two anti-NEU3 antibodies. The results provide strong evidence that the serum sialidase is, in fact, NEU3, and this subtype may, therefore, be a potential utility for novel diagnosis of human cancers.

  11. [The effect of tobacco smoking on serum concentration of selected angiogenic factors and somatomedin C in pregnant women and umbilical cord blood].

    PubMed

    Chełchowska, Magdalena; Gajewska, Joanna; Ambroszkiewicz, Jadwiga; Lewandowski, Leszek; Maciejewski, Tomasz M; Ołtarzewski, Mariusz; Laskowska-Klita, Teresa

    2013-01-01

    blood of mothers and umbilical cord blood (group of smokers: mothers r = 0.43, p < 0.05, cord blood r = 0.50, p < 0.01; group of tobacco abstinent: mothers r = 0.51, p < 0.01, cord blood r = 0.41, p < 0.05). The birth weight of the smoking mothers' infants was lower by about 400 g (p < 0.01) and their birth body length by 1.5 cm (p < 0.05) and negatively correlated with number of cigarettes smoked per day (r = -0.55; p < 0.005). Our results indicate, that tobacco smoking during pregnancy increased serum PIGF levels in the final stages of gestation and has no effect on the concentration of VEGF, which may lead to an increase of trophoblast proliferation and uteroplacental dysfunction. Lower than in tobacco abstinent levels of IGF-I in serum of smoking mothers and in umbilical cord blood and their close relationship with birth weight, may suggests a direct effect of this factor on birth anthropometric parameters.

  12. Dietary Mannoheptulose Increases Fasting Serum Glucagon Like Peptide-1 and Post-Prandial Serum Ghrelin Concentrations in Adult Beagle Dogs.

    PubMed

    McKnight, Leslie L; Eyre, Ryan; Gooding, Margaret A; Davenport, Gary M; Shoveller, Anna Kate

    2015-06-16

    There is a growing interest in the use of nutraceuticals for weight management in companion animals. The purpose of this study was to determine the effects of mannoheptulose (MH), a sugar in avocados that inhibits glycolysis, on energy metabolism in adult Beagle dogs. The study was a double-blind, randomized controlled trial where dogs were allocated to a control (CON, n = 10, 10.1 ± 0.4 kg) or MH containing diet (168 mg/kg, n = 10, 10.3 ± 0.4 kg). Blood was collected after an overnight fast and 1 h post-feeding (week 12) to determine serum satiety related hormones and biochemistry. Resting and post-prandial energy expenditure and respiratory quotient were determined by indirect calorimetry (weeks 4 and 8). Physical activity was measured using an accelerometer (weeks 3, 7, 11). Body composition was assessed using dual X-ray absorptiometry (week 12). MH significantly (p < 0.05) increased fasting serum glucagon-like peptide-1 and post-prandial serum ghrelin. MH tended (p < 0.1) to increase fasting serum gastric inhibitory peptide and decrease physical activity. Together, these findings suggest that dietary MH has the ability to promote satiation and lowers daily energy expenditure.

  13. Supplementation with vitamin D does not increase serum testosterone levels in healthy males.

    PubMed

    Jorde, R; Grimnes, G; Hutchinson, M S; Kjærgaard, M; Kamycheva, E; Svartberg, J

    2013-09-01

    Cross-sectional studies indicate a positive relation between serum 25-hydroxyvitamin D [25(OH)D] and testosterone. It is not known if this relation is causal, which in theory could be in both directions. A cross-sectional population based study was designed with pooled data from 3 vitamin D randomized clinical trials (RCTs) performed in Tromsø with weight reduction, insulin sensitivity, and depression scores as endpoints, and one testosterone RCT in subjects with low serum testosterone (<11.0 nmol/l) and with body composition as endpoint. Serum 25(OH)D and androgens were measured in 893 males in the cross-sectional part, at baseline and after 6-12 months of supplementation with vitamin D 20 000 IU-40 000 IU per week vs. placebo in the vitamin D RCTs (n=282), and at baseline and after one year treatment with testosterone undecanoate 1 000 mg or placebo injections (at baseline and after 6, 16, 28, and 40 weeks) in the testosterone RCT (n=37). In the cross-sectional study, serum 25(OH)D was found to be a significant and positive predictor of serum testosterone. In the vitamin D RCTs, no significant effect on serum total or free testosterone levels was seen, and in the testosterone RCT no significant effect on serum 25(OH)D was seen. This was unchanged in sub-analyses in subjects with low serum 25(OH)D (or testosterone) levels. In conclusion, in subjects without significant vitamin D deficiency, there is no increase in serum testosterone after high dose vitamin D supplementation. Similarly, in subjects with moderately low serum testosterone levels, substitution with testosterone does not increase serum 25(OH)D.

  14. Muscle force during an acute exacerbation in hospitalised patients with COPD and its relationship with CXCL8 and IGF-I

    PubMed Central

    Spruit, M; Gosselink, R; Troosters, T; Kasran, A; Gayan-Ramirez, G; Bogaerts, P; Bouillon, R; Decramer, M

    2003-01-01

    Background: Chronic obstructive pulmonary disease (COPD) is often associated with peripheral muscle weakness, which is caused by several factors. Acute exacerbations may contribute, but their impact on muscle force remains unclear. Correlations between peripheral muscle force and inflammatory and anabolic markers have never been studied in COPD. The effect of an acute exacerbation on quadriceps peak torque (QPT) was therefore studied in hospitalised patients, and the aforementioned correlations were examined in hospitalised and in stable patients. Methods: Lung function, respiratory and peripheral muscle force, and inflammatory and anabolic markers were assessed in hospitalised patients on days 3 and 8 of the hospital admission and 90 days later. The results on day 3 (n=34) were compared with those in clinically stable outpatients (n=13) and sedentary healthy elderly subjects (n=10). Results: Hospitalised patients had lowest mean (SD) QPT (66 (22)% predicted) and highest median (IQR) levels of systemic interleukin-8 (CXCL8, 6.1 (4.5 to 8.3) pg/ml). Insulin-like growth factor I (IGF-I) tended to be higher in healthy elderly subjects (p=0.09). QPT declined between days 3 and 8 in hospital (mean -5% predicted (95% CI -22 to 8)) and partially recovered 90 days after admission to hospital (mean 6% predicted (95% CI -1 to 23)). QPT was negatively correlated with CXCL8 and positively correlated with IGF-I and lung transfer factor in hospitalised and in stable patients. Conclusions: Peripheral muscle weakness is enhanced during an acute exacerbation of COPD. CXCL8 and IGF-I may be involved in the development of peripheral muscle weakness in hospitalised and in stable patients with COPD. PMID:12947130

  15. Nutrient intake in the bovine during early and mid-gestation causes sex-specific changes in progeny plasma IGF-I, liveweight, height and carcass traits.

    PubMed

    Micke, G C; Sullivan, T M; Gatford, K L; Owens, J A; Perry, V E A

    2010-09-01

    Fetal and postnatal growth are mediated by insulin-like growth factors (IGFs) and their binding proteins (IGFBPs). Maternal nutrient intake during gestation can program the postnatal IGF-axis. This may have significant economic implications for beef cattle production. We investigated the effect of high (H=240%) and low (L=70%) levels of recommended daily crude protein (CP) intake for heifers during the first and second trimesters of gestation in a two-by-two factorial design on progeny (n=68) plasma IGF-I, IGF-II, total IGFBP (tIGFBP), postnatal growth and carcass traits. Calves were heavier at birth following high CP diets during the second trimester (P=0.03) and this persisted to 29d. Plasma IGF-I concentrations of males were greater for HL compared to LL (P<0.01) and HH (P>0.04) from 29 to 657d, and for LH compared to LL from 29 until 379d (P=0.02). Exposure to low CP diets during the first trimester resulted in heavier males from 191d onwards (P=0.04) but a tendency for lighter females from 552d onwards (P=0.07) that had lighter carcass weights (P=0.04). Longissimus dorsi cross-sectional area of all carcasses was greater following exposure to low CP diets during the second trimester (P=0.04). Heifer nutrient intake during the first and second trimesters causes persistent and sex-specific programming of progeny plasma IGF-I, postnatal liveweight and carcass weight. Refining heifer nutritional programs during early gestation may optimize production objectives in progeny.

  16. Energy balance, leptin, NEFA and IGF-I plasma concentrations and resumption of post partum ovarian activity in swedish red and white breed cows

    PubMed Central

    Konigsson, Kristian; Savoini, Giovanni; Govoni, Nadia; Invernizzi, Guido; Prandi, Alberto; Kindahl, Hans; Veronesi, Maria Cristina

    2008-01-01

    In the purpose to provide further information in respect of the relationship between metabolism and post partum (PP) ovarian activity resumption in dairy cows, the aim of the present study was to characterize the energy balance (EB) and leptin, NEFA and IGF-I plasma levels in Swedish Red and White (SRW) cows with and without ovarian activity re-initiation within 7 weeks PP. The study was conducted on 12 primiparous SRW cows fed the same diet as total mixed ration for ad libitum intake. The EB was calculated weekly from parturition until seven weeks PP. Blood samples were collected weekly from one week before until 7 weeks after calving for leptin, NEFA and IGF-I analysis. For progesterone (P4) analysis, blood samples were collected two times per week from parturition until the end of the study. P4 profile was used in addition to the clinical examination to detect cows with and without ovarian activity resumption. The clinical and ultrasonographic examination, coupled with P4 profile analysis showed the resumption of ovarian activity within 7 weeks after calving in 8 (group A) and no ovarian resumption in 4 cows (group B). No significant differences were detected in the whole period of observation in the amount of milk production between the two groups, while the mean milk protein content was significantly lower in group B at the third week PP. The calculated EB was negative in both groups in the first three weeks after calving, but more marked in group B. NEFA and Leptin plasma levels did not show significant differences between the two groups. In conclusion, the results of the present study showed that, when low milk producing primiparous cows are concerned, no significant differences in BW loss, milk yield, EB and leptin and NEFA plasma levels between the cows with and without resumption of ovarian activity within 7 weeks post partum were seen. However, significantly higher IGF-I levels in the first two weeks after calving were found in cows with post partum

  17. [Two cases of Lambert-Eaton syndrome with an increase of serum cholinesterase activity].

    PubMed

    Ciechanowski, K; Cebula, D

    1997-02-01

    Paraneoplastic Lambert-Eaton myasthenia syndrome is presented in two cases with small cell lung cancer. An increase of serum cholinesterase activity was explained by induced release of biologically active proteins by neoplastic tissue.

  18. Increase in Dickkopf-1 Serum Level in Recent Spondyloarthritis. Data from the DESIR Cohort

    PubMed Central

    Nocturne, Gaetane; Pavy, Stephan; Boudaoud, Saida; Seror, Raphaèle; Goupille, Philippe; Chanson, Philippe; van der Heijde, Désirée; van Gaalen, Floris; Berenbaum, Francis; Mariette, Xavier; Briot, Karine; Feydy, Antoine; Claudepierre, Pascal; Dieudé, Philippe; Nithitham, Joanne; Taylor, Kimberly E.; Criswell, Lindsey A.; Dougados, Maxime; Roux, Christian; Miceli-Richard, Corinne

    2015-01-01

    Objectives To investigate DKK-1 and SOST serum levels among patients with recent inflammatory back pain (IBP) fulfilling ASAS criteria for SpA and associated factors. Methods The DESIR cohort is a prospective, multicenter French cohort of 708 patients with early IBP (duration >3 months and <3 years) suggestive of AxSpA. DKK-1 and SOST serum levels were assessed at baseline and were compared between the subgroup of patients fulfilling ASAS criteria for SpA (n = 486; 68.6%) and 80 healthy controls. Results Mean SOST serum levels were lower in ASAS+ patients than healthy controls (49.21 ± 25.9 vs. 87.8 ± 26 pmol/L; p<0.0001). In multivariate analysis, age (p = 5.4 10−9), CRP level (p<0.0001) and serum DKK-1 level (p = 0.001) were associated with SOST level. Mean DKK-1 serum levels were higher in axial SpA patients than controls (30.03 ± 15.5 vs. 11.6 ± 4.2 pmol/L; p<0.0001). In multivariate analysis, DKK-1 serum levels were associated with male gender (p = 0.03), CRP level (p = 0.006), SOST serum level (p = 0.002) and presence of sacroiliitis on radiography (p = 0.05). Genetic association testing of 10 SNPs encompassing the DKK-1 locus failed to demonstrate a significant contribution of genetics to control of DKK-1 serum levels. Conclusions DKK-1 serum levels were increased and SOST levels were decreased among a large cohort of patients with early axial SpA compared to healthy controls. DKK-1 serum levels were mostly associated with biological inflammation and SOST serum levels. PMID:26313358

  19. Serum Resistin Levels May Contribute to an Increased Risk of Acute Cerebral Infarction.

    PubMed

    Dong, Xiao-Liu; Xu, Shi-Jun; Zhang, Li; Zhang, Xiu-Qing; Liu, Ting; Gao, Qiu-Yan; Qian, Qing-Qiang; Sun, Bao-Liang; Yang, Ming-Feng

    2017-04-01

    The objective of this study was to investigate the association between serum resistin levels and acute cerebral infarction (ACI). PubMed, SpringerLink, Wiley, EBSCO, Ovid, Web of Science, Wanfang, China National Knowledge Infrastructure, and VIP databases (last updated search in October 2014) were exhaustively searched, and data from the eligible studies were extracted and analyzed to assess the association between serum resistin levels and ACI. STATA software (version 12.0, Stata Corporation, College Station, TX, USA) was utilized for data analysis. Ten studies including 1829 ACI patients and 1557 healthy controls were eligible for inclusion in the meta-analysis. Our major result revealed that ACI patients exhibited higher serum resistin levels compared with healthy controls. Asubgroup analysis based on ethnicity showed a significant association between serum resistin levels and ACI in Asians, but surprisingly not in Caucasians. The results of our meta-analysis suggest that serum resistin levels are associated with an increased risk of ACI.

  20. Insulin-Like Growth Factor-I Increases Laminin, Integrin Subunits and Metalloprotease ADAM12 in Mouse Myoblasts.

    PubMed

    Grzelkowska-Kowalczyk, Katarzyna; Grabiec, Kamil; Tokarska, Justyna; Gajewska, Małgorzata; Błaszczyk, Maciej; Milewska, Marta

    2015-01-01

    The extracellular matrix (ECM) is considered a part of the myogenesis signaling mechanism. we hypothesized that insulin-like growth factor-I (IGF-I) modifies ECM during differentiation of mouse C2C12 cells. The myogenic effect of IGF-I (30 nmol/l) was manifested by increased myogenin and myosin heavy chain (MyHC) levels as well as fusion index (2.6 times over control) on the 3rd day of differentiation. IGF-I markedly augmented laminin, but not fibronectin. Cellular contents of integrin α3, α5 and β1 during 3-day differentiation increased in the presence of IGF-I. Treatment with IGF-I increased the expression of the long form of metalloprotease ADAM12 (100 kDa) in myocytes. In conclusion: i) IGF-I caused an increase of laminin, integrin α3 and β1 in C2C12 myogenic cells that can be secondary to stimulation of myogenesis; ii) IGF-I augmented integrin α5 and ADAM12 levels, suggesting a role of this growth factor in determination of the pool of reserve cells during myogenesis.

  1. Vegan proteins may reduce risk of cancer, obesity, and cardiovascular disease by promoting increased glucagon activity.

    PubMed

    McCarty, M F

    1999-12-01

    Amino acids modulate the secretion of both insulin and glucagon; the composition of dietary protein therefore has the potential to influence the balance of glucagon and insulin activity. Soy protein, as well as many other vegan proteins, are higher in non-essential amino acids than most animal-derived food proteins, and as a result should preferentially favor glucagon production. Acting on hepatocytes, glucagon promotes (and insulin inhibits) cAMP-dependent mechanisms that down-regulate lipogenic enzymes and cholesterol synthesis, while up-regulating hepatic LDL receptors and production of the IGF-I antagonist IGFBP-1. The insulin-sensitizing properties of many vegan diets--high in fiber, low in saturated fat--should amplify these effects by down-regulating insulin secretion. Additionally, the relatively low essential amino acid content of some vegan diets may decrease hepatic IGF-I synthesis. Thus, diets featuring vegan proteins can be expected to lower elevated serum lipid levels, promote weight loss, and decrease circulating IGF-I activity. The latter effect should impede cancer induction (as is seen in animal studies with soy protein), lessen neutrophil-mediated inflammatory damage, and slow growth and maturation in children. In fact, vegans tend to have low serum lipids, lean physiques, shorter stature, later puberty, and decreased risk for certain prominent 'Western' cancers; a vegan diet has documented clinical efficacy in rheumatoid arthritis. Low-fat vegan diets may be especially protective in regard to cancers linked to insulin resistance--namely, breast and colon cancer--as well as prostate cancer; conversely, the high IGF-I activity associated with heavy ingestion of animal products may be largely responsible for the epidemic of 'Western' cancers in wealthy societies. Increased phytochemical intake is also likely to contribute to the reduction of cancer risk in vegans. Regression of coronary stenoses has been documented during low-fat vegan diets

  2. Effects of chromium methionine supplementation on growth performance, serum metabolites, endocrine parameters, antioxidant status, and immune traits in growing pigs.

    PubMed

    Tian, Yao-Yao; Zhang, Li-Ying; Dong, Bing; Cao, Jun; Xue, Jian-Xiang; Gong, Li-Min

    2014-12-01

    The effects of dietary chromium methionine (CrMet) on growth performance, serum metabolites, endocrine parameters, antioxidant status, and immune traits in growing pigs were investigated. A total of 180 crossbred pigs (30.18 ± 0.28 kg initial body mass) were randomly divided into five groups, each group with six pens, six pigs per pen. Pigs were fed on the same basal diet supplemented with 0 (control), 100, 200, 400, and 800 μg/kg Cr from CrMet for 35 days. The results showed that supplemental CrMet did not affect growth performance. Cr at 200-800 μg/kg significantly decreased serum glucose levels (P < 0.05), while other serum metabolites were unaffected by Cr supplementation. Serum growth hormone (GH) levels were significantly decreased by Cr addition (P < 0.05). Furthermore, serum insulin-like growth factor I (IGF-I) levels were linearly decreased with increased Cr dose, and a significant reduction was observed in pigs fed 800 μg/kg Cr diets (P < 0.05). Serum immunoglobulin A, G, and M concentrations were increased linearly with increased Cr dosage, and pigs fed 400 μg/kg Cr had greater serum immunoglobulin M contents (P < 0.05). Cr at 400 μg/kg significantly increased serum superoxide dismutase and total antioxidant capacity activities (T-AOC) (P < 0.05). However, Cr at 800 μg/kg increased serum catalase activities, while decreasing serum T-AOC contents (P < 0.05). Additionally, there was a significant increase in serum malondialdehyde levels for pigs fed 800 μg/kg Cr diets (P < 0.05). These results indicated that dietary supplementation CrMet decreased serum glucose, GH, and IGF-I levels. Besides, supplemental 400 μg/kg Cr as CrMet improved serum antioxidant status and immune responses, but additional 800 μg/kg Cr resulted in lipid peroxidation in growing pigs.

  3. An increase in lipoprotein oxidation and endogenous lipid peroxides in serum of obese women.

    PubMed

    Mutlu-Türkoğlu, U; Oztezcan, S; Telci, A; Orhan, Y; Aykaç-Toker, G; Sivas, A; Uysal, M

    2003-02-01

    Endogenous malondialdehyde and diene conjugate levels, the susceptibility of apolipoprotein B-containing lipoproteins to copper-induced lipid peroxidation, and antibody titer against oxidized low-density lipoproteins were increased, but serum antioxidant activity was unchanged in obese women. Serum cholesterol, low-density lipoproteincholesterol, and trigliceride levels were also elevated, but high-density lipoprotein-cholesterol levels remained unchanged in obese women. In vitro, oxidation of apolipoprotein B-containing lipoproteins and levels of antibody against oxidized low-density lipoprotein correlated with body mass index, serum total cholesterol, and low-density lipoproteincholesterol levels in obese women. These results indicate that obesity is associated with increases in endogenous lipid peroxides, oxidation of low-density lipoproteins, and lipids in serum.

  4. Increased serum IgE in acute type A, B and delta hepatitis.

    PubMed

    Gutiérrez, D; Guardia, P; Delgado, J; Gutiérrez, J; Monteseirin, F J; de la Calle, A; Lobatón, P; Senra, A; Conde, J

    1997-01-01

    Serum IgE levels have been documented in patients of acute type B hepatitis. There are very few studies on serum IgE in acute type A hepatitis and, to our knowledge, there are no data on serum IgE in acute delta hepatitis patients. The purpose of this study was to measure total IgE levels in 38 patients with acute A, B and delta hepatitis and in 181 controls in order to determine the possible existence of changes in this parameter in the course of these infections. Our results showed a relevant increase in IgE levels in the three groups (hepatitis A, B and delta) with respect to the control group. Moreover, the hepatitis B group showed increased total serum IgE levels with respect to the hepatitis delta group.

  5. Congenital hypothyroidism in a kitten resulting in decreased IGF-I concentration and abnormal liver function tests.

    PubMed

    Quante, Saskia; Fracassi, Federico; Gorgas, Daniela; Kircher, Patrick R; Boretti, Felicitas S; Ohlerth, Stefanie; Reusch, Claudia E

    2010-06-01

    A 7-month-old male kitten was presented with chronic constipation and retarded growth. Clinical examination revealed disproportional dwarfism with mild skeletal abnormalities and a palpable thyroid gland. The presumptive diagnosis of congenital hypothyroidism was confirmed by low serum total thyroxine (tT(4)) concentration prior to and after the administration of thyroid stimulation hormone (TSH), increased endogenous TSH concentration and abnormal thyroid scintigraphic scan. The kitten had abnormal liver function tests and decreased insulin-like growth factor 1 (IGF-1) concentration, both of which returned to normal in correspondence with an improvement of the clinical signs after 6 weeks of thyroxine therapy. Congenital hypothyroidism is a rare disease that may present with considerable variation in clinical manifestation. In cases in which clinical signs are ambiguous, disorders such as portosystemic shunt and hyposomatotropism have to be taken into account as differential diagnosis. As hypothyroidism may be associated with abnormal liver function tests and low IGF-1 concentrations, test results have to be interpreted carefully.

  6. Possible Increase in Serum FABP4 Level Despite Adiposity Reduction by Canagliflozin, an SGLT2 Inhibitor

    PubMed Central

    Furuhashi, Masato; Matsumoto, Megumi; Hiramitsu, Shinya; Omori, Akina; Tanaka, Marenao; Moniwa, Norihito; Yoshida, Hideaki; Ishii, Junnichi; Miura, Tetsuji

    2016-01-01

    Background Fatty acid-binding protein 4 (FABP4/A-FABP/aP2) is secreted from adipocytes in association with catecholamine-induced lipolysis, and elevated serum FABP4 level is associated with obesity, insulin resistance and atherosclerosis. Secreted FABP4 as a novel adipokine leads to insulin resistance via increased hepatic glucose production (HGP). Sodium-glucose cotransporter 2 (SGLT2) inhibitors decrease blood glucose level via increased urinary glucose excretion, though HGP is enhanced. Here we investigated whether canagliflozin, an SGLT2 inhibitor, modulates serum FABP4 level. Methods Canagliflozin (100 mg/day) was administered to type 2 diabetic patients (n = 39) for 12 weeks. Serum FABP4 level was measured before and after treatment. Results At baseline, serum FABP4 level was correlated with adiposity, renal dysfunction and noradrenaline level. Treatment with canagliflozin significantly decreased adiposity and levels of fasting glucose and HbA1c but increased average serum FABP4 level by 10.3% (18.0 ± 1.0 vs. 19.8 ± 1.2 ng/ml, P = 0.008), though elevation of FABP4 level after treatment was observed in 26 (66.7%) out of 39 patients. Change in FABP4 level was positively correlated with change in levels of fasting glucose (r = 0.329, P = 0.044), HbA1c (r = 0.329, P = 0.044) and noradrenaline (r = 0.329, P = 0.041) but was not significantly correlated with change in adiposity or other variables. Conclusions Canagliflozin paradoxically increases serum FABP4 level in some diabetic patients despite amelioration of glucose metabolism and adiposity reduction, possibly via induction of catecholamine-induced lipolysis in adipocytes. Increased FABP4 level by canagliflozin may undermine the improvement of glucose metabolism and might be a possible mechanism of increased HGP by inhibition of SGLT2. Trial Registration UMIN-CTR Clinical Trial UMIN000018151 PMID:27124282

  7. CMKLR1 activation ex vivo does not increase proportionally to serum total chemerin in obese humans

    PubMed Central

    Toulany, Jay; Parlee, Sebastian D; Sinal, Christopher J; Slayter, Kathryn; McNeil, Shelly

    2016-01-01

    Prochemerin is the inactive precursor of the adipokine chemerin. Proteolytic processing is obligatory for the conversion of prochemerin into active chemerin and subsequent regulation of cellular processes via the chemokine-like receptor 1 (CMKLR1). Elevated plasma or serum chemerin concentrations and differential processing of prochemerin have been reported in obese humans. The impact of these changes on CMKLR1 signalling in humans is unknown. The objective of this pilot study was to develop a cellular bioassay to measure CMKLR1 activation by chemerin present in human serum and to characterise how obesity modifies serum activation of CMKLR1 under fasted and fed conditions. Blood samples were collected from control (N = 4, BMI 20–25) and obese (N = 4, BMI >30) female subjects after an overnight fast (n = 2) and at regular intervals (n = 7) following consumption of breakfast over a period of 6 h. A cellular CMKLR1-luminescent reporter assay and a pan-chemerin ELISA were used to determine CMKLR1 activation and total chemerin concentrations, respectively. Serum total chemerin concentration (averaged across all samples) was higher in obese vs control subjects (17.9 ± 1.8 vs 10.9 ± 0.5 nM, P < 0.05), but serum activation of CMKLR1 was similar in both groups. The CMKLR1 activation/total chemerin ratio was lower in obese vs control subjects (0.33 ± 0.04 vs 0.58 ± 0.05, P < 0.05). After breakfast, serum total chemerin or CMKLR1 activation did not differ from baseline values. In conclusion, the unexpected observation that obese serum activation of CMKLR1 did not match increased total chemerin concentrations suggests impaired processing to and/or enhanced degradation of active chemerin in serum of obese humans. PMID:27881447

  8. Increased (/sup 125/I)trypsin-binding in serum from cystic fibrosis patients

    SciTech Connect

    Cox, K.L.; Frates, R.C. Jr.; Sheikholislam, B.M.; Iwahashi-Hosoda, C.K.

    1982-01-01

    The capacities of normal and cystic fibrosis (CF) sera to bind to exogenous human (/sup 125/I)trypsin were compared. Sera from eight older CF patients bound significantly more exogenous human (/sup 125/I)trypsin than did sera from eight normal subjects (p less than 0.001). Disregarding the increased trypsin-binding (TB) of CF sera, serum immunoreactive trypsinogen (SIRT) levels were not detectable in these eight older CF patients. However, when SIRT levels were corrected for TB, four CF patients had normal SIRT concentrations and four had low but detectable SIRT levels. As compared to five normal newborns' sera, serum from a newborn with CF had normal TB and the SIRT levels were very high. In conclusion, increased TB in CF serum lowers results of SIRT assays. Therefore, unless SIRT levels are corrected for TB, results obtained from currently available SIRT kits may be invalid.

  9. Increased serum level of homocysteine correlates with retinal nerve fiber layer thinning in diabetic retinopathy

    PubMed Central

    Srivastav, Khushboo; Mahdi, Abbas A.; Shukla, Rajendra K.; Meyer, Carsten H.; Akduman, Levent; Khanna, Vinay K.

    2016-01-01

    Purpose To study the correlation between serum levels of vitamin B12, folic acid, and homocysteine and the severity of diabetic retinopathy and the correlation with retinal nerve fiber layer (RNFL) thinning on spectral domain optical coherence tomography (SD-OCT). Methods In a tertiary care center–based prospective cross-sectional study, 60 consecutive cases and 20 healthy controls in the age group of 40–65 years were included. The eyes of the cases were divided into three groups according to Early Treatment Diabetic Retinopathy Study (ETDRS) classification: diabetes mellitus without retinopathy (n = 20), non-proliferative diabetic retinopathy with macular edema (n = 20), and proliferative diabetic retinopathy with macular edema (n = 20). The serum levels of vitamin B12 and folic acid were measured using a standard protocol. The serum homocysteine assay was performed using an enzyme-linked immunosorbent assay (ELISA) kit. Average RNFL thickness was measured using SD-OCT. Statistical analysis was used to assess the correlations between the study variables. Results Increased severity of diabetic retinopathy was found to correlate with an increase in the serum levels of homocysteine (F = 53.79; p<0.001). The mean serum levels of vitamin B12 and folic acid were found to be within the normal reference range. A positive correlation was found between retinal nerve fiber layer thinning and serum levels of homocysteine (p<0.001). Conclusions This study, for the first time, demonstrated a correlation between increased homocysteine with a decrease in RNFL thickness and increased severity of diabetic retinopathy. PMID:27994434

  10. Increased matrix metalloproteinase-3 serum levels in rheumatic diseases: relationship with synovitis and steroid treatment

    PubMed Central

    Ribbens, C; Martin, y; Franchimont, N; Kaiser, M; Jaspar, J; Damas, P; Houssiau, F; Malaise, M

    2002-01-01

    Objective: To determine matrix metalloproteinase-3 (MMP-3) serum levels in patients with rheumatic diseases and to study the relation between MMP-3 and C reactive protein (CRP) levels. Methods: MMP-3 serum levels were determined by enzyme linked immunosorbent assay (ELISA) in (a) patients with active inflammatory rheumatic diseases: rheumatoid arthritis (RA), psoriatic arthritis, polymyalgia rheumatica, acute crystal arthritis, and ankylosing spondylitis; (b) patients with active inflammatory systemic diseases: cutaneo-articular or renal systemic lupus erythematosus (SLE), systemic sclerosis, and vasculitides; (c) patients with non-inflammatory rheumatic diseases: osteoarthritis and fibromyalgia; (d) critically ill patients without rheumatic diseases, representing an acute inflammatory control group; (e) healthy controls. Results: MMP-3 serum levels were significantly increased in patients with active RA, psoriatic arthritis, and polymyalgia rheumatica, whether treated or not by corticosteroids, and in female patients with acute crystal arthritis. MMP-3 serum levels were normal in steroid-free patients with active cutaneo-articular or renal SLE, systemic sclerosis, and vasculitides but were significantly increased in steroid treated patients. MMP-3 levels were normal in fibromyalgia, osteoarthritis, ankylosing spondylitis, and acute inflammatory controls. MMP-3 was significantly correlated with CRP in RA (r=0.5, p=0.0004) but not in any of the other disease groups. Conclusions: MMP-3 serum levels are increased in inflammatory rheumatic diseases characterised by joint synovitis, such as RA, polymyalgia rheumatica, psoriatic arthritis, and acute crystal arthritis—that is, whether the diseases are acute or chronic, erosive or not. They are normal in SLE, systemic sclerosis, and vasculitides as well as in non-rheumatic inflammatory controls, but are significantly increased by steroids. These data strongly suggest that serum MMP-3 reflects synovial inflammation. PMID

  11. Serum factor induces selective increase in Na-channel expression in cultured skeletal muscle

    SciTech Connect

    Brodie, C.; Sampson, S.R. )

    1991-07-01

    The authors have examined effects of horse serum (HS) and various fractions (1 million-1M, 300K, 100K, and 30K nominal molecular weight limit) obtained by ultrafiltration on expression of TTX-sensitive Na-channels and on activities of the Na-K pump and glucose transport systems in cultured myotubes obtained from 1-2-day-old neonatal rat pups. Five-day-old cells were transferred to serum-free medium with no hormone or growth factor supplements (DMEM) for 24 hr and then treated with the various serum fractions for 48 hr. Measurements were made of specific (3H)-saxitoxin (STX) binding, action potential properties, 86Rb-uptake and 2-deoxyglucose (2-DG) uptake. HS significantly increased all parameters compared to DMEM (increases in STX-binding, 69%; Rb-uptake, 65%; 2-DG uptake, 93%). Results of treatment with the separate fractions showed that the 300K fraction caused a significantly greater increase in STX-binding than either HS or the other fractions. In contrast, the increases in Rb and 2-DG uptakes induced by the different fractions were not different from that obtained with HS. They conclude that serum contains a factor that selectively increases expression of TTX-sensitive Na-channels in skeletal muscle.

  12. [The effects of the GH, IGF-I and IGF-IBP3 gene on growth and development traits of Nanyang cattle in different growth period].

    PubMed

    Gao, Xue; Xu, Xiu-Rong; Ren, Hong-Yan; Zhang, Ying-Han; Xu, Shang-Zhong

    2006-08-01

    This study was conducted to identify polymorphisms of the Nangyang cattle's growth hormone (GH) and insulin-like growth factor-I (IGF-I) and insulin-like growth factor-I binding protein 3(IGF-IBP3) gene by the single nucleotide Polymorphisms and Polymerase chain reaction-based restriction fragment length polymorphism and to study association of polymorphisms identified in these genes with growth traits of the birth, 6 months, 12 months, 18 months, 24 months and 36 months. Results from the analysis showed a significant association of the BB genotype in the promoter of GH gene (GH-P5) with higher body length and body height during from 6 month to 18 month. From 24 month to 36 month, the IGF-IBP3 locus has a dominance modulation and control effect on backbody in Nanyang Cattle, and the BB genotype with higher Rump width than AA.

  13. The associations of diet with serum insulin-like growth factor I and its main binding proteins in 292 women meat-eaters, vegetarians, and vegans.

    PubMed

    Allen, Naomi E; Appleby, Paul N; Davey, Gwyneth K; Kaaks, Rudolf; Rinaldi, Sabina; Key, Timothy J

    2002-11-01

    The lower rates of some cancers in Asian countries than in Western countries may be partly because of diet, although the mechanisms are unknown. The aim of this cross-sectional study was to determine whether a plant-based (vegan) diet is associated with a lower circulating level of insulin-like growth factor I (IGF-I) compared with a meat-eating or lacto-ovo-vegetarian diet among 292 British women, ages 20-70 years. The mean serum IGF-I concentration was 13% lower in 92 vegan women compared with 99 meat-eaters and 101 vegetarians (P = 0.0006). The mean concentrations of both serum IGF-binding protein (IGFBP)-1 and IGFBP-2 were 20-40% higher in vegan women compared with meat-eaters and vegetarians (P = 0.005 and P = 0.0008 for IGFBP-1 and IGFBP-2, respectively). There were no significant differences in IGFBP-3, C-peptide, or sex hormone-binding globulin concentrations between the diet groups. Intake of protein rich in essential amino acids was positively associated with serum IGF-I (Pearson partial correlation coefficient; r = 0.27; P < 0.0001) and explained most of the differences in IGF-I concentration between the diet groups. These data suggest that a plant-based diet is associated with lower circulating levels of total IGF-I and higher levels of IGFBP-1 and IGFBP-2.

  14. Oral lixivaptan effectively increases serum sodium concentrations in outpatients with euvolemic hyponatremia.

    PubMed

    Abraham, William T; Decaux, Guy; Josiassen, Richard C; Yagil, Yoram; Kopyt, Nelson; Thacker, Hemant P; Mannelli, Massimo; Bichet, Daniel G; Orlandi, Cesare

    2012-12-01

    Hyponatremia is the most common electrolyte disorder in clinical practice. Its incidence increases with age and it is associated with increased morbidity and mortality. Recently, the vaptans, antagonists of the arginine vasopressin pathway, have shown promise for safe treatment of hyponatremia. Here we evaluated the efficacy, safety, and tolerability of oral lixivaptan, a selective vasopressin V2-receptor antagonist, for treatment of nonhospitalized individuals with euvolemic hyponatremia (sodium less than 135 mmol/l) in a multicenter, randomized, double-blind, placebo-controlled, phase III study. About half of the 206 patients were elderly in a chronic care setting. Of these patients, 52 were given a placebo and 154 were given 25-100 mg per day lixivaptan, titrated based on the daily serum sodium measurements. Compared with placebo (0.8 mmol/l), the serum sodium concentration significantly increased by 3.2 mmol/l from baseline to day 7 (primary efficacy endpoint) with lixivaptan treatment. A significantly greater proportion of patients that received lixivaptan achieved normal serum sodium (39.4%) by day 7 relative to placebo (12.2%). Overall, lixivaptan was considered safe and well-tolerated. Thus, oral lixivaptan can be safely initiated in the outpatient setting and effectively increases serum sodium concentrations in outpatients with euvolemic hyponatremia.

  15. Increased cancer cell proliferation in prostate cancer patients with high levels of serum folate

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Introduction: A recent clinical trial revealed that folic acid supplementation is associated with an increased incidence of prostate cancer (1). The present study evaluates serum and prostate tissue folate levels in men with prostate cancer, compared to histologically normal prostate glands from can...

  16. Increased serum IgD concentrations in patients with Hodgkin's disease.

    PubMed

    Corte, G; Ferrarini, M; Tonda, P; Bargellesi, A

    1977-05-01

    Serum IgD concentrations have been determined in twenty-one patients with Hodgkin's disease, in eight patients with non-Hodgkin's lymphomas and in twenty-eight normal (control) individuals by both a solidphase radio-immuno-assay and radial-immunodiffusion. Fourteen of the Hodgkin's patients displayed three to forty-five-fold increased serum IgD levels as compared to control individuals, while in the remaining seven patients IgD concentrations were practically normal. Patients with non-Hodgkin's lymphomas had decreased IgD concentrations.

  17. Effects of martial arts exercise on body composition, serum biomarkers and quality of life in overweight/obese premenopausal women: a pilot study

    PubMed Central

    Chyu, Ming-Chien; Zhang, Yan; Brismée, Jean-Michel; Dagda, Raul Y.; Chaung, Eugene; Von Bergen, Vera; Doctolero, Susan; Shen, Chwan-Li

    2013-01-01

    Various exercise interventions have been shown to benefit weight control and general health in different populations. However, very few studies have been conducted on martial arts exercise (MAE). The objective of this pilot study is to evaluate the efficacy of 12 weeks of MAE intervention on body composition, serum biomarkers and quality of life (QOL) in overweight/obese premenopausal women. We found that subjects in the MAE group did not lose body weight, while they significantly decreased fat-free mass and muscle mass as compared to those in the control group, who demonstrated an increase in these parameters. The MAE group demonstrated an increase in serum IGF-I concentration, but no change in others. MAE may be a feasible and effective approach to improve body composition and QOL in overweight/obese premenopausal women. Our study underscores the need for further studies using larger samples to establish possible benefits of MAE in various populations. PMID:24665215

  18. Conivaptan increases serum sodium in hyponatremic patients with end-stage liver disease.

    PubMed

    O'Leary, Jacqueline G; Davis, Gary L

    2009-10-01

    Hyponatremia is associated with increased mortality in patients with end-stage liver disease and a greater risk of perioperative mortality with liver transplantation. We performed a retrospective review of our experience with conivaptan as a means of acutely increasing serum sodium in end-stage liver disease patients. The primary group consisted of 15 patients with end-stage liver disease who remained hyponatremic despite discontinuation of diuretics and a 1-L fluid restriction. Twenty milligrams of conivaptan was intravenously administered over 30 minutes, and this was followed by an infusion of 20 mg over 24 hours for 1 to 4 days. A second group of 9 hyponatremic end-stage liver disease patients was treated with 1-L fluid restriction and conivaptan while remaining on diuretics. In the group without diuretics, the mean serum sodium was 124 mmol/L 1 day before and on the day of conivaptan initiation, but the serum sodium rose to a mean of 127.7 mmol/L by day 1 and further increased to 128.6 mmol/L by the second day of the infusion. Despite the continuation of diuretics, the second group of 9 patients also had an increase in serum sodium from the day of conivaptan initiation (125.7 mmol/L) to 2 days after the treatment (130.6 mmol/L). Eleven patients underwent successful liver transplantation, 2 remained on the list for transplantation, and 11 were not candidates for transplantation and either died (7) or were discharged home and lost to follow-up (4). In conclusion, a short course of conivaptan increases serum sodium in patients with end-stage liver disease and may reduce the risk of proceeding to liver transplantation. Further study in a prospective clinical trial is needed to confirm safety and efficacy.

  19. Bisphosphonate treatment of postmenopausal osteoporosis is associated with a dose dependent increase in serum sclerostin.

    PubMed

    Gatti, Davide; Viapiana, Ombretta; Adami, Silvano; Idolazzi, Luca; Fracassi, Elena; Rossini, Maurizio

    2012-03-01

    The benefits coming from long-term treatment of postmenopausal osteoporosis with bisphophonates are limited by a coupled decrease in bone formation. The objective of this study is to determine whether this decrease in bone formation is associated with changes in serum levels of the WNT signaling antagonist sclerostin or Dickkopf-1 (DKK1). This is an ancillary observation from patients participating in a 12 months, phase 2, randomized clinical trial. We analyzed 107 patients given either monthly intramuscular neridronate (12.5, 25 or 50 mg) or placebo. Serum C-terminal telopeptide of type I collagen (sCTX, a bone-resorption marker) decreased by 61%, 75% and 73% in the 12.5, 25 and 50 mg dose groups, respectively. Mean changes in bone alkaline phosphatase (bAP) at 12 months were -47%, -60.0% and -52.6% in the groups receiving 12.5, 25 or 50 mg neridronate, respectively. Serum DKK1 remained unchanged at all time points in the 3 groups. Serum sclerostin increased versus placebo group gradually and significantly only in patients treated with 25 or 50 mg neridronate monthly, reaching 138-148% of baseline values (P<0.001). Changes in serum sclerostin at 12 months were negatively correlated with changes in bAP (P<0.001) even when data were adjusted for sCTX changes and only treated patients were included. In conclusions, decreased bone formation after several months of bisphosphonate therapy is associated with increased serum levels of sclerostin. This might suggest that Wnt signaling may play a role in the coupling between resorption and formation.

  20. Increased Cytokine and Nitric Oxide Levels in Serum of Dogs Experimentally Infected with Rangelia vitalii

    PubMed Central

    Da Silva, Aleksandro S.; Paim, Carlos Breno V.; França, Raqueli T.; Costa, Márcio M.; Duarte, Marta M. M. F.; Sangoi, Manuela B.; Moresco, Rafael N.; Monteiro, Silvia G.; Lopes, Sonia Terezinha A.

    2013-01-01

    This study aimed to measure the levels of interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), interleukin 1 (IL-1), interleukin 6 (IL-6), and nitrite/nitrate (NOx) in serum of dogs experimentally infected with Rangelia vitalii. Twelve female mongrel dogs were divided into 2 groups; group A (uninfected controls) composed by healthy dogs (n=5) and group B consisting of dogs inoculated with R. vitalii (n=7). Animals were monitored by blood smear examinations, which showed intraerythrocytic forms of the parasite on day 5 post-infection (PI). Blood samples were collected through the jugular vein on days 0, 10, and 20 PI to determine the serum levels of IFN-γ, TNF-α, IL-1, IL-6, and NOx. Cytokines were assessed by ELISA quantitative sandwich technique, and NOx was measured by the modified Griess method. Cytokine levels (IFN-γ, TNF-α, IL-1, and IL-6) were increased (P<0.01) in serum of infected animals. Serum levels of NOx were also increased on days 10 PI (P<0.01) and 20 PI (P<0.05) in infected animals. Therefore, the infection with R. vitalii causes an increase in proinflammatory cytokines and nitric oxide content. These alterations may be associated with host immune protection against the parasite. PMID:23467990

  1. Aerobic exercise improves hippocampal function and increases BDNF in the serum of young adult males.

    PubMed

    Griffin, Éadaoin W; Mullally, Sinéad; Foley, Carole; Warmington, Stuart A; O'Mara, Shane M; Kelly, Aine M

    2011-10-24

    Physical activity has been reported to improve cognitive function in humans and rodents, possibly via a brain-derived neurotrophic factor (BDNF)-regulated mechanism. In this study of human subjects, we have assessed the effects of acute and chronic exercise on performance of a face-name matching task, which recruits the hippocampus and associated structures of the medial temporal lobe, and the Stroop word-colour task, which does not, and have assessed circulating concentrations of BDNF and IGF-1 in parallel. The results show that a short period of high-intensity cycling results in enhancements in performance of the face-name matching, but not the Stroop, task. These changes in cognitive function were paralleled by increased concentration of BDNF, but not IGF-1, in the serum of exercising subjects. 3 weeks of cycling training had no effect on cardiovascular fitness, as assessed by VO2 scores, cognitive function, or serum BDNF concentration. Increases in fitness, cognitive function and serum BDNF response to acute exercise were observed following 5 weeks of aerobic training. These data indicate that both acute and chronic exercise improve medial temporal lobe function concomitant with increased concentrations of BDNF in the serum, suggesting a possible functional role for this neurotrophic factor in exercise-induced cognitive enhancement in humans.

  2. Enhancement of maternal lactation performance during prolonged lactation in the mouse by mouse GH and long-R3-IGF-I is linked to changes in mammary signaling and gene expression

    Technology Transfer Automated Retrieval System (TEKTRAN)

    GH, prolactin (PRL), and IGF-I stimulate lactation-related metabolic processes in mammary epithelial cells. However, the ability of these factors to stimulate milk production in animals varies depending on species and experimental variables. Previous work in our laboratory demonstrated that transgen...

  3. Iron overload alters glucose homeostasis, causes liver steatosis, and increases serum triacylglycerols in rats.

    PubMed

    Silva, Maísa; Silva, Marcelo E; de Paula, Heberth; Carneiro, Cláudia Martins; Pedrosa, Maria Lucia

    2008-06-01

    The objective of this study was to investigate the effect of iron overload with a hyperlipidemic diet on the histologic feature of hepatic tissue, the lipid and glycemic serum profiles, and the markers of oxidative damage and stress in a rat model. Twenty-four male Fischer rats, purchased from Experimental Nutrition Laboratory, Federal University of Ouro Preto, were assigned to 4 equal groups, 2 were fed a standard cholesterol-free diet (group C or control and CI or control with iron) containing 8.0% soybean oil and 2 were fed a hyperlipidemic diet (group H or hyperlipidemic and HI or hyperlipidemic with iron) containing 1.0% cholesterol and 25.0% soybean oil. A total of 50 mg of iron was administered to rats in groups CI and HI in 5 equal doses (1 every 3 weeks for a 16-week period) by intraperitoneal injections of 0.1 mL of iron dextran solution (100 g Fe(2+)/L; Sigma, St Louis, Mo). The other rats in groups C and H were treated in a similar manner but with sterile saline (0.1 mL). Irrespective of the diet, iron excess enhanced serum triacylglycerols (P < .05) and reduced serum glucose and glycated hemoglobin levels (P < .05) but did not affect serum cholesterol concentration. Histologic analysis showed steatosis in groups H and to a lesser extent in HI. No significant differences (P > .05) were observed in paraoxonase activities or in serum levels of free or total sulfhydryl radicals, malondialdehyde, or total antioxidants. The findings suggest that iron excess in the rat probably modifies lipid metabolism and, as a consequence, alters glucose homeostasis and increases the level of serum triacylglycerols but not of cholesterol.

  4. Radiotherapy for Rectal Cancer Is Associated With Reduced Serum Testosterone and Increased FSH and LH

    SciTech Connect

    Bruheim, Kjersti Svartberg, Johan; Carlsen, Erik; Dueland, Svein; Haug, Egil; Skovlund, Eva; Tveit, Kjell Magne; Guren, Marianne G.

    2008-03-01

    Purpose: It is known that scattered radiation to the testes during pelvic radiotherapy can affect fertility, but there is little knowledge on its effects on male sex hormones. The aim of this study was to determine whether radiotherapy for rectal cancer affects testosterone production. Methods and Materials: All male patients who had received adjuvant radiotherapy for rectal cancer from 1993 to 2003 were identified from the Norwegian Rectal Cancer Registry. Patients treated with surgery alone were randomly selected from the same registry as control subjects. Serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and sex hormone binding globulin (SHBG) were analyzed, and free testosterone was calculated (N = 290). Information about the radiotherapy treatment was collected from the patient hospital charts. Results: Serum FSH was 3 times higher in the radiotherapy group than in the control group (median, 18.8 vs. 6.3 IU/L, p <0.001), and serum LH was 1.7 times higher (median, 7.5 vs. 4.5 IU/l, p <0.001). In the radiotherapy group, 27% of patients had testosterone levels below the reference range (8-35 nmol/L), compared with 10% of the nonirradiated patients (p <0.001). Irradiated patients had lower serum testosterone (mean, 11.1 vs. 13.4 nmol/L, p <0.001) and lower calculated free testosterone (mean, 214 vs. 235 pmol/L, p <0.05) than control subjects. Total testosterone, calculated free testosterone, and gonadotropins were related to the distance from the bony pelvic structures to the caudal field edge. Conclusions: Increased serum levels of gonadotropins and subnormal serum levels of testosterone indicate that curative radiotherapy for rectal cancer can result in permanent testicular dysfunction.

  5. Differential roles of MAPK-Erk1/2 and MAPK-p38 in insulin or insulin-like growth factor-I (IGF-I) signaling pathways for progesterone production in human ovarian cells.

    PubMed

    Seto-Young, D; Avtanski, D; Varadinova, M; Park, A; Suwandhi, P; Leiser, A; Parikh, G; Poretsky, L

    2011-06-01

    Insulin and insulin like-growth factor-I (IGF-I) participate in the regulation of ovarian steroidogenesis. In insulin resistant states ovaries remain sensitive to insulin because insulin can activate alternative signaling pathways, such as phosphatidylinositol-3-kinase (PI-3 kinase) and mitogen-activated protein-kinase (MAPK) pathways, as well as insulin receptors and type 1 IGF receptors. We investigated the roles of MAPK-Erk1/2 and MAPK-p38 in insulin and IGF-I signaling pathways for progesterone production in human ovarian cells. Human ovarian cells were cultured in tissue culture medium in the presence of varying concentrations of insulin or IGF-I, with or without PD98059, a specific MAPK-Erk1/2 inhibitor, with or without SB203580, a specific MAPK-p38 inhibitor or with or without a specific PI-3-kinase inhibitor LY294002. Progesterone concentrations were measured using radioimmunoassay. PD98059 alone stimulated progesterone production in a dose-dependent manner by up to 65% (p<0.001). Similarly, LY294002 alone stimulated progesterone production by 13-18% (p<0.005). However, when used together, PD98059 and LY294002 inhibited progesterone production by 17-20% (p<0.001). SB203580 alone inhibited progesterone production by 20-30% (p<0.001). Insulin or IGF-I alone stimulated progesterone production by 40-60% (p<0.001). In insulin studies, PD98059 had no significant effect on progesterone synthesis while SB203580 abolished insulin-induced progesterone production. Either PD98059 or SB203580 abolished IGF-I-induced progesterone production. Both MAPK-Erk1/2 and MAPK-p38 participate in IGF-I-induced signaling pathways for progesterone production, while insulin-induced progesterone production requires MAPK-p38, but not MAPK-Erk1/2. These studies provide further evidence for divergence of insulin and IGF-I signaling pathways for human ovarian cell steroidogenesis.

  6. Low T3 syndrome in canine babesiosis associated with increased serum IL-6 concentration and azotaemia.

    PubMed

    Zygner, Wojciech; Gójska-Zygner, Olga; Bąska, Piotr; Długosz, Ewa

    2015-06-30

    Low triiodothyronine (T3) syndrome, also named euthyroid sick syndrome or non-thyroidal illness syndrome, has been recognized in canine babesiosis caused by Babesia rossi, where it manifested by lowering of the serum thyrotropin (TSH), total thyroxin (TT4) and free thyroxin (FT4) concentrations. This syndrome has also been observed in critical diseases in humans and animals, and the severity of the disease is considered an important factor in lowering of thyroid hormone concentrations. Interleukin-6 (IL-6) plays a role in the development of low T3 syndrome by causing a decrease in deiodinases 1 and 2 activity and increased activity of deiodinase 3, enzymes involved in the conversion of thyroxin (T4) to T3. The purpose of this study was to compare the concentrations of serum thyroid hormones and TSH between healthy dogs and dogs with babesiosis, and to determine correlations between serum IL-6 concentration and serum total T3 (TT3), TT4, FT4, and TSH concentrations, and the level of azotaemia in dogs with babesiosis. The concentrations of IL-6, TT3, TT4, FT4, TSH, urea and creatinine were determined in 13 dogs with canine babesiosis caused by Babesia canis and in 10 healthy dogs. The results of this study showed decreases in TT3, TT4, FT4, and TSH and increases in IL-6, urea and creatinine concentrations in affected dogs in comparison to healthy dogs. The concentration of IL-6 was negatively correlated with TT3 and TSH concentrations and the TT3 concentration was negatively correlated with serum urea and creatinine concentrations. This study showed low T3 syndrome in canine babesiosis, which was confirmed by the determination of the T3 concentration, and demonstrates that in canine babesiosis the T3 concentration is associated with IL-6 concentration.

  7. Increased serum hepcidin levels in subjects with the metabolic syndrome: a population study.

    PubMed

    Martinelli, Nicola; Traglia, Michela; Campostrini, Natascia; Biino, Ginevra; Corbella, Michela; Sala, Cinzia; Busti, Fabiana; Masciullo, Corrado; Manna, Daniele; Previtali, Sara; Castagna, Annalisa; Pistis, Giorgio; Olivieri, Oliviero; Toniolo, Daniela; Camaschella, Clara; Girelli, Domenico

    2012-01-01

    The recent discovery of hepcidin, the key iron regulatory hormone, has changed our view of iron metabolism, which in turn is long known to be linked with insulin resistant states, including type 2 diabetes mellitus and the Metabolic Syndrome (MetS). Serum ferritin levels are often elevated in MetS (Dysmetabolic hyperferritinemia--DHF), and are sometimes associated with a true mild-to-moderate hepatic iron overload (dysmetabolic iron overload syndrome--DIOS). However, the pathophysiological link between iron and MetS remains unclear. This study was aimed to investigate, for the first time, the relationship between MetS and hepcidin at population level. We measured serum hepcidin levels by Mass Spectrometry in 1,391 subjects from the Val Borbera population, and evaluated their relationship with classical MetS features. Hepcidin levels increased significantly and linearly with increasing number of MetS features, paralleling the trend of serum ferritin. In multivariate models adjusted for relevant variables including age, C-Reactive Protein, and the HFE C282Y mutation, ferritin was the only significant independent predictor of hepcidin in males, while in females MetS was also independently associated with hepcidin. Overall, these data indicate that the fundamental iron regulatory feedback is preserved in MetS, i.e. that hepcidin tends to progressively increase in response to the increase of iron stores. Due to recently discovered pleiotropic effects of hepcidin, this may worsen insulin resistance and contribute to the cardiovascular complications of MetS.

  8. Increased Serum Hepcidin Levels in Subjects with the Metabolic Syndrome: A Population Study

    PubMed Central

    Martinelli, Nicola; Traglia, Michela; Campostrini, Natascia; Biino, Ginevra; Corbella, Michela; Sala, Cinzia; Busti, Fabiana; Masciullo, Corrado; Manna, Daniele; Previtali, Sara; Castagna, Annalisa; Pistis, Giorgio; Olivieri, Oliviero; Toniolo, Daniela; Camaschella, Clara; Girelli, Domenico

    2012-01-01

    The recent discovery of hepcidin, the key iron regulatory hormone, has changed our view of iron metabolism, which in turn is long known to be linked with insulin resistant states, including type 2 diabetes mellitus and the Metabolic Syndrome (MetS). Serum ferritin levels are often elevated in MetS (Dysmetabolic hyperferritinemia - DHF), and are sometimes associated with a true mild-to-moderate hepatic iron overload (dysmetabolic iron overload syndrome - DIOS). However, the pathophysiological link between iron and MetS remains unclear. This study was aimed to investigate, for the first time, the relationship between MetS and hepcidin at population level. We measured serum hepcidin levels by Mass Spectrometry in 1,391 subjects from the Val Borbera population, and evaluated their relationship with classical MetS features. Hepcidin levels increased significantly and linearly with increasing number of MetS features, paralleling the trend of serum ferritin. In multivariate models adjusted for relevant variables including age, C-Reactive Protein, and the HFE C282Y mutation, ferritin was the only significant independent predictor of hepcidin in males, while in females MetS was also independently associated with hepcidin. Overall, these data indicate that the fundamental iron regulatory feedback is preserved in MetS, i.e. that hepcidin tends to progressively increase in response to the increase of iron stores. Due to recently discovered pleiotropic effects of hepcidin, this may worsen insulin resistance and contribute to the cardiovascular complications of MetS. PMID:23144745

  9. IL-33 circulating serum levels are increased in patients with non-segmental generalized vitiligo.

    PubMed

    Vaccaro, Mario; Cicero, Francesca; Mannucci, Carmen; Calapai, Gioacchino; Spatari, Giovanna; Barbuzza, Olga; Cannavò, Serafinella P; Gangemi, Sebastiano

    2016-09-01

    IL-33 is a recently identified cytokine, encoded by the IL-33 gene, which is a member of the IL-1 family that drives the production of T-helper-2 (Th-2)-associated cytokines. Serum levels of IL-33 have been reported to be up-regulated in various T-helper (Th)-1/Th-17-mediated diseases, such as psoriasis, rheumatoid arthritis, and inflammatory bowel. To investigate whether cytokine imbalance plays a role in the pathogenesis of vitiligo, we performed a case-control association study by enzyme-linked immunosorbent assay of IL-33 in our patients. IL-33 serum levels were measured by a quantitative enzyme immunoassay technique in patients with non-segmental generalized vitiligo and compared with those of healthy controls. IL-33 serum levels in patients with vitiligo were significantly increased than those in healthy controls. There was a positive correlation of IL-33 serum levels with extension of vitiligo and disease activity. This study suggests a possible systemic role of IL-33 in the pathogenesis of vitiligo. Inhibiting IL-33 activity might be a novel therapeutic strategy in the treatment of autoimmune inflammatory disease, like vitiligo.

  10. Dietary quercetin supplementation increases serum antioxidant capacity and alters hepatic gene expression profile in rats.

    PubMed

    Zhao, Liting; Wu, Jianquan; Yang, Jijun; Wei, Jingyu; Gao, Weina; Guo, Changjiang

    2011-06-01

    The aim of this study was to determine the effect of quercetin on hepatic gene expression profile in rats. Twenty male Wistar rats were divided into the control group and the quercetin-treated group, in which a diet containing 0.5% quercetin was provided. After two weeks of feeding, serum and liver samples were collected. Biomarkers of oxidative stress, including serum ferric reducing antioxidant power (FRAP) values and levels of ascorbic acid, vitamin E (VE), glutathione (GSH) and malondialdehyde (MDA) were measured. The hepatic gene expression profile was examined using a microarray technique. The results showed that serum FRAP value, levels of ascorbic acid and VE were increased significantly, whereas serum levels of GSH and MDA were not changed significantly after quercetin supplementation. The microarray analysis revealed that some hepatic genes involved in phase 2 reaction, metabolism of cholesterol and homocysteine, and energy production were expressed differentially in response to quercetin administration. These findings provide a molecular basis for the elucidation of the actions played by quercetin in vivo.

  11. Increased serum levels of lipogenic enzymes in patients with severe liver steatosis

    PubMed Central

    2012-01-01

    Background Lipid metabolism is altered in subjects with liver steatosis. FAS is a key enzyme in de novo lipogenesis and both FAS gene expression and enzymatic activity are primarily regulated by metabolic signals in the liver. Lipoprotein lipase (LPL), the rate-limiting enzyme for the hydrolysis of core triglycerides, plays a pivotal role in lipid metabolism. This study aims to investigate if circulating levels of FAS and LPL could be clinically associated with liver steatosis. Methods In this work, we present data obtained from a subsample of 94 subjects with liver steatosis enrolled by NUTRIEPA study, a nutritional trial in subjects with liver steatosis. Serum levels of FAS protein and LPL activity were evaluated by ELISA test and by a fluorescent method, respectively. The diagnosis and the degree of liver steatosis were based on laboratory and ecographic measurements. Statistical methods included Kruskal-Wallis analysis of variance and Wilcoxon signed-rank test, where appropriate. The χ2 test has been performed to analyse categorical variables. Results The subjects with severe steatosis had significantly higher serum levels of FAS protein and LPL activity compared to subjects with mild and moderate liver steatosis. Moreover, a positive trend in serum levels of FAS expression from lower to higher degree of steatosis was also detected. Conclusions We describe a relationship between human liver steatosis and elevated levels of circulating lipogenic enzymes. Increased serum levels of FAS expression and LPL activity could be considered a marker of severe liver steatosis. PMID:23110339

  12. Basic fibroblast growth factor priming increases the responsiveness of immortalized hypothalamic luteinizing hormone releasing hormone neurones to neurotrophic factors.

    PubMed

    Gallo, F; Morale, M C; Tirolo, C; Testa, N; Farinella, Z; Avola, R; Beaudet, A; Marchetti, B

    2000-10-01

    The participation of growth factors (GFs) in the regulation of luteinizing hormone releasing hormone (LHRH) neuronal function has recently been proposed, but little is known about the role played by GFs during early LHRH neurone differentiation. In the present study, we have used combined biochemical and morphological approaches to study the ability of a number of GFs normally expressed during brain development, including basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I) to induce survival, differentiation, proliferation, and phenotypic expression of immortalized (GT1-1) LHRH neurones in vitro, at early (3-days in vitro, 3-DIV) and late (8-DIV) stages of neuronal differentiation. Comparison of GF-treated vs untreated neurones grown in serum-deprived (SD) medium demonstrated bFGF to be the most potent, and insulin the least active in promoting neuronal differentiation. Thus, at both 3-DIV and 8-DIV, but especially at 8-DIV, bFGF induced the greatest increase in the total length and number of LHRH processes/cell and in growth cone surface area. bFGF was also the most active at 3-DIV, and IGF-I at 8-DIV, in counteracting SD-induced cell death, whereas EGF was the most potent in increasing [3H]thymidine incorporation. All GFs studied decreased the spontaneous release of LHRH from GT1-1 cells when applied at 3-DIV or 8-DIV, except for insulin which was inactive at both time-points and bFGF which was inactive at 8-DIV. Pre-treatment of GT1-1 cells with a suboptimal ('priming') dose of bFGF for 12 h followed by application of the different GFs induced a sharp potentiation of the neurotrophic and proliferative effects of the latter and particularly of those of IGF-I. Moreover, bFGF priming counteracted EGF-induced decrease in LHRH release and significantly stimulated LHRH secretion following IGF-I or insulin application, suggesting that bFGF may sensitize LHRH neurones to differentiating effects of

  13. Association of Low Serum Concentration of Bilirubin with Increased Risk of Coronary Artery Disease

    DTIC Science & Technology

    1994-01-01

    concentrations were decreased in individuals baseline tracing obtained before the subjects reached with CAD, whereas some of the liver-function enzyme age...Angiographic Data lis, IN). After July 1987, dextran sulfate, Mr 50 000 Summary statistics for the two groups are given in (Ciba Corning, Oberlin, OH), was...low serum bilirubin con- activity or increases in iron stores (9). centrations have been associated with good health, and It remains to be seen

  14. Low Serum DHEAS Predicts Increased Fracture Risk in Older Men: The MrOS Sweden Study.

    PubMed

    Ohlsson, Claes; Nethander, Maria; Kindmark, Andreas; Ljunggren, Östen; Lorentzon, Mattias; Rosengren, Björn E; Karlsson, Magnus K; Mellström, Dan; Vandenput, Liesbeth

    2017-03-09

    The adrenal-derived hormones dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) are the most abundant circulating hormones and their levels decline substantially with age. DHEAS is considered an inactive precursor, which is converted into androgens and estrogens via local metabolism in peripheral target tissues. The predictive value of serum DHEAS for fracture risk is unknown. The aim of this study was, therefore, to assess the associations between baseline DHEAS levels and incident fractures in a large cohort of older men. Serum DHEAS levels were analyzed with mass spectrometry in the population-based Osteoporotic Fractures in Men study in Sweden (n = 2568, aged 69 to 81 years). Incident X-ray validated fractures (all, n = 594; non-vertebral major osteoporotic, n = 255; hip, n = 175; clinical vertebral, n = 206) were ascertained during a median follow-up of 10.6 years. DHEAS levels were inversely associated with the risk of any fracture (hazard ratio [HR] per SD decrease = 1.14, 95% confidence interval [CI] 1.05-1.24), non-vertebral major osteoporotic fractures (HR = 1.31, 95% CI 1.16-1.48), and hip fractures (HR = 1.18, 95% CI 1.02-1.37) but not clinical vertebral fractures (HR = 1.09, 95% CI 0.95-1.26) in Cox regression models adjusted for age, body mass index (BMI) and prevalent fractures. Further adjustment for traditional risk factors for fracture, bone mineral density (BMD), and/or physical performance variables as well as serum sex steroid levels only slightly attenuated the associations between serum DHEAS and fracture risk. Similarly, the point estimates were only marginally reduced after adjustment for FRAX estimates with BMD. The inverse association between serum DHEAS and all fractures or major osteoporotic fractures was nonlinear, with a substantial increase in fracture risk (all fractures 22%, major osteoporotic fractures 33%) for those participants with serum DHEAS levels below the median (0.60 μg/mL). In

  15. Effects of dietary corn gluten meal on growth performance and protein metabolism in relation to IGF-I and TOR gene expression of juvenile cobia ( Rachycentron canadum)

    NASA Astrophysics Data System (ADS)

    Luo, Yiwen; Ai, Qinghui; Mai, Kangsen; Zhang, Wenbing; Xu, Wei; Zhang, Yanjiao; Liufu, Zhiguo

    2013-09-01

    A growth experiment was conducted on cobia ( Rachycentron canadum, initial weight 108.2 g ± 3.0 g) to investigate the effects of dietary corn gluten meal (CGM) levels on the fish growth, whole body composition and protein metabolism in relation to specific gene expression. Five isonitrogenous (crude protein 45%) and isoenergetic (gross energy 20 kJ g-1) practical diets were formulated by replacing 0% (the control), 17.5%, 35.0%, 52.5%, and 70.0% of fish meal (FM) protein with CGM protein. No significant differences were observed in the survival, feed intake (FI), specific growth rate (SGR), feed efficiency (FE) and protein productive value (PPV) among fish fed diets with 0%, 17.5%, 35.0%, and 52.5% of CGM protein. However, these indices were significantly lower in fish fed the diet with 70.0% of CGM protein than those in fish fed the control diet ( P < 0.05). The whole-body crude protein and lipid contents were significantly lower while the whole-body moisture content was significantly higher in fish fed the diet with 70.0% of CGM protein compared with the control group ( P < 0.05). When 70.0% of FM protein was replaced by CGM, plasma total protein and cholesterol contents were significantly lower than those in the control group ( P < 0.05). Fish fed the diet with 70.0% of CGM protein had significantly lower hepatic insulin-like growth factor I (IGF-I) expression levels than those in the control group ( P < 0.05). However, no significant differences were observed in hepatic target of rapamycin (TOR), dorsal muscle IGF-I and TOR expression levels among dietary treatments. Results of the present study indicated that 52.5% of FM protein could be replaced by CGM in the diets without significant influences on the growth, feed utilization and protein metabolism of juvenile cobia. The present results might be useful for developing cost effective and sustainable cobia dietary formulations.

  16. Substantial Increases Occur in Serum Activins and Follistatin during Lung Transplantation

    PubMed Central

    de Kretser, David M.; Bensley, Jonathan G.; Phillips, David J.; Levvey, Bronwyn J.; Snell, Greg I.; Lin, Enjarn; Hedger, Mark P.; O’Hehir, Robyn E.

    2016-01-01

    Background Lung transplantation exposes the donated lung to a period of anoxia. Re-establishing the circulation after ischemia stimulates inflammation causing organ damage. Since our published data established that activin A is a key pro-inflammatory cytokine, we assessed the roles of activin A and B, and their binding protein, follistatin, in patients undergoing lung transplantation. Methods Sera from 46 patients participating in a published study of remote ischemia conditioning in lung transplantation were used. Serum activin A and B, follistatin and 11 other cytokines were measured in samples taken immediately after anaesthesia induction, after remote ischemia conditioning or sham treatment undertaken just prior to allograft reperfusion and during the subsequent 24 hours. Results Substantial increases in serum activin A, B and follistatin occurred after the baseline sample, taken before anaesthesia induction and peaked immediately after the remote ischemia conditioning/sham treatment. The levels remained elevated 15 minutes after lung transplantation declining thereafter reaching baseline 2 hours post-transplant. Activin B and follistatin concentrations were lower in patients receiving remote ischemia conditioning compared to sham treated patients but the magnitude of the decrease did not correlate with early transplant outcomes. Conclusions We propose that the increases in the serum activin A, B and follistatin result from a combination of factors; the acute phase response, the reperfusion response and the use of heparin-based anti-coagulants. PMID:26820896

  17. Lansoprazole increases serum IgG and IgM in H. pylori-infected patients.

    PubMed

    Matsukawa, Y; Kurosaka, H; Kato, K; Hayashi, I; Minekawa, K; Arakawa, Y; Sawada, S

    2007-01-01

    Proton-pump inhibitors have been reported to influence the human immune system, we therefore evaluated the effect of lansoprazole, a proton-pump inhibitor, on humoral immunity. Patients with gastric ulcer received lansoprazole 30 mg/day for 8 weeks, and serum immunoglobulins were evaluated before and upon completion of the treatment. There were 79 patients with gastric ulcer; 51 were H. pylori-infected and 28 were H. pylori-uninfected. Eighteen patients positive for H. pylori were receiving at least one non-steroidal anti-inflammatory drug, and 12 patients negative for H. pylori received one non-steroidal anti-inflammatory drug. H. pylori-infected patients showed significant increases in serum immunoglobulins G and M 8 weeks after the start of lansoprazole treatment (P<0.001 for IgG and P<0.01 for IgM), but uninfected patients did not. Even when H. pylori-infected patients receiving a non-steroidal anti-inflammatory drug or low-dose aspirin were analyzed separately, these increases were seen (P<0.001 for IgG and P<0.005 for IgM). Lansoprazole elevated serum levels of immunoglobulins G and M in gastric ulcer patients with H. pylori infection, particularly in those receiving non-steroidal anti-inflammatory drugs. Deducing from these observations, lansoprazole might alter the Th1 shift in the immune response induced by H. pylori infection.

  18. Ulcerative Colitis and Crohn's Disease Are Associated with Decreased Serum Selenium Concentrations and Increased Cardiovascular Risk.

    PubMed

    Castro Aguilar-Tablada, Teresa; Navarro-Alarcón, Miguel; Quesada Granados, Javier; Samaniego Sánchez, Cristina; Rufián-Henares, José Ángel; Nogueras-Lopez, Flor

    2016-12-01

    The incidence of inflammatory bowel disease (IBD) and associated oxidative stress is increasing. The antioxidant mineral selenium (Se) was measured in serum samples from 106 IBD patients (53 with ulcerative colitis (UC) and 53 with Crohn's disease (CD)) and from 30 healthy controls. Serum Se concentrations were significantly lower in UC and CD patients than in healthy controls (p < 0.001) and significantly lower in CD patients than in UC patients (p = 0.006). Se concentrations in patients were significantly influenced by sex, body mass index (BMI), the inflammatory biomarker α-1-antitrypsin, surgery, medical treatment, the severity, extent, and form of the disease and the length of time since onset (p < 0.05). Se concentrations in IBD patients were positively and linearly correlated with nutritional (protein, albumin, prealbumin, cholinesterase and total cholesterol) and iron status-related (hemoglobin, Fe and hematocrit) parameters (p < 0.05). A greater impairment of serum Se and cardiovascular status was observed in CD than in UC patients. An adequate nutritional Se status is important in IBD patients to minimize the cardiovascular risk associated with increased inflammation biomarkers, especially in undernourished CD patients, and is also related to an improved nutritional and body iron status.

  19. Association between increased serum thyrotropin concentration and the oldest old: what do we know?

    PubMed Central

    Duarte, Glaucia Cruzes; Cendoroglo, Maysa Seabra; Araújo, Lara Miguel Quirino; Almada, Clineu de Mello

    2015-01-01

    To assess studies that evaluate the relation between serum thyrotropin concentration, very old subjects, and their events. We searched the PubMed, SciELO, and LILACS databases for articles published between 2004 and 2012. Our search was restricted to studies involving humans aged 65 years or older, and written in English, Spanish, or Portuguese. Studies that evaluated the association between elevated serum thyrotropin concentration among elderly subjects with subclinical hypothyroidism were chosen since at least in part they included a subpopulation of individuals aged 80 years and above. Thirteen studies were selected. No significant increase in risk of cardiovascular events, coronary heart disease, or total mortality was observed. Elevated thyrotropin concentration was associated with longevity. More randomized controlled trials are required to better define the potential benefits of elevated thyrotropin concentration in this oldest old population, hormone replacement, and longevity. PMID:25807244

  20. Serum neurotrophin-3 is increased during manic and depressive episodes in bipolar disorder.

    PubMed

    Walz, Julio C; Andreazza, Ana C; Frey, Benício N; Cacilhas, Alice A; Ceresér, Keila M M; Cunha, Angelo B M; Weyne, Fernanda; Stertz, Laura; Santin, Aida; Gonçalves, Carlos A; Kapczinski, Flávio

    2007-03-19

    Accumulating evidence suggest that neural changes and cognitive impairment may accompany the course of bipolar disorder. Such detrimental effects of cumulative mood episodes may be related to changes in neurotrophins that take place during mood episodes but not during euthymic phases. The present study investigated serum neurotrophin-3 (NT-3) levels in patients with bipolar disorder during manic, depressed, and euthymic states, using an enzyme-linked immunosorbent assay (sandwich-ELISA). Serum NT-3 levels were increased in manic (p<0.001) and depressed (p<0.001) BD patients, as compared with euthymic patients and normal controls. These findings suggest that the NT-3 signaling system may play a role in the pathophysiology of BD.

  1. Increased serum IgD concentrations in children with Henoch-Schönlein purpura.

    PubMed

    Saulsbury, F T

    1998-05-01

    Serum IgD concentrations were measured in 39 children with Henoch Schonlein purpura (HSP) and 40 control children by means of radial immunodiffusion. Serum IgG, IgA and IgM concentrations in the HSP patients were measured by nephelometry. The geometric mean IgD concentration in children with HSP (16.7 microg/ml) was significantly higher than in control children (9.1 microg/ml; P=0.03). Serial testing in 10 HSP patients revealed no significant change in IgD concentrations over periods ranging from 1 to 12 months. There was no relationship between IgD and IgA concentrations in the HSP patients. Nineteen of the 39 HSP patients (49%) had nephritis. The mean IgD concentration in patients with nephritis (10.7 microg/ml) did not differ from control values, but was significantly lower than the mean IgD level in the remaining 20 patients who did not have nephritis (25.4 microg/ml; P=0.02). These results indicate that serum IgD levels are increased in children with HSP who did not have nephritis. IgD concentrations in patients with nephritis were similar to levels in control children.

  2. Metabolic control may influence the increased superoxide generation in diabetic serum.

    PubMed

    Ceriello, A; Giugliano, D; Quatraro, A; Dello Russo, P; Lefèbvre, P J

    1991-07-01

    Superoxide anion (O2-) generation in serum from 10 Type 1 diabetic patients and 10 normal subjects was measured ex vivo. The amount of O2- production was significantly increased in diabetic serum 0.41 +/- 0.04 (+/- SD) vs 0.14 +/- 0.04 mumol l-1 min-1, p less than 0.001) and correlated with fasting plasma glucose and glycosylated protein levels in both diabetic (r = 0.72, p less than 0.01, and r = 0.62, p less than 0.05) and normal r = 0.75, p less than 0.01 and r = 0.64, p less than 0.05) subjects. Improved metabolic control in the diabetic patients was associated with a reduction of serum O2- production (0.28 +/- 0.06 mumol l-1 min-1, p less than 0.01), but the correlation between O2- levels and fasting plasma glucose and glycosylated protein concentrations was retained (r = 0.86 and r = 0.72, respectively, both p less than 0.01).

  3. In postmenopausal osteoporosis the bone increasing effect of monofluorophosphate is not dependent on serum fluoride.

    PubMed

    Rigalli, A; Pera, L; Morosano, M; Masoni, A; Bocanera, R; Tozzini, R; Puche, R C

    1999-01-01

    According to previous pharmacokinetic studies the bioavailability of fluorine (F) from sodium monofluorophosphate (MFP) doubles that of sodium fluoride (NaF). This paper reports a study designed to verify whether the vertebral bone mass increasing effect of NaF (30 mg F/day) was comparable to that of MFP (15 mg F/day), given for 18 months to osteoporotic postmenopausal women. The BMD of lumbar vertebrae of both groups showed significant increases (MFP: 60 +/- 15 mg/cm2, NaF: and 71 +/- 12 mg/cm2) over basal levels (P < 0.001). The difference between treatments was not significant (P = 0.532). The serum levels of ionic F (the mitogenic species on osteoblasts) were not related to the above mentioned effects. In NaF-treated patients, the fasting levels of total serum F increased significantly (6.7 +/- 0.9 microM vs. Basal: 2.0 +/- 0.8 microM; P < 0.001). This phenomenon was accounted for by ionic fluoride that increased over 20-fold (6.5 +/- 1.9 microM vs. Basal: 0.3 +/- 0.04 microM). In MFP-treated patients the fasting serum levels of total (7.0 +/- 0.7 microM vs. Basal: 2.2 +/- 0.9 M) and diffusible F (0.5 +/- 0.02 microM vs. Basal 0.2 +/- 0.02 microM) increased significantly (P < 0.001). The increase in the non diffusible F fraction is accounted for by protein-bound F, probably by the complexes formed between MFP and alpha 2-macroglobulin and C3. Serum diffusible F was formed by two fractions: ionic F and F bound to low molecular weight macromolecule/s (2,200 +/- 600 Da), in approximately equal amounts. The general information afforded by the present observations support the hypothesis that ionic F is released progressively during the metabolism of MFP bound to alpha 2-macroglobulin and C3. These phenomena explain why comparable effects to those obtained with 30 mg F/d of NaF could by obtained with one half the dose of MFP.

  4. Low water conductivity increases the effects of copper on the serum parameters in fish (Oreochromis niloticus).

    PubMed

    Canli, Esin G; Canli, Mustafa

    2015-03-01

    The conductivity is largely determined by ion levels in water, predominant ion being Ca(2+) in the freshwaters. For this reason, the effects of copper were evaluated as a matter of conductivity of exposure media in the present study. Thus, freshwater fish Oreochromis niloticus were exposed to copper in differing conductivities (77, 163 and 330 μS/cm), using acute (0.3 μM, 3 d) and chronic (0.03 μM, 30 d) exposure protocols. Following the exposure serum parameters of fish were measured. Data showed that there was no significant alteration (P>0.05) in serum parameters of control fish. However, activities of ALP, ALT and AST decreased significantly at the lower conductivities in chronic copper exposure, but not in acute ones. Protein levels did not differ significantly in any of the exposure conditions. However, Cu exposure at the lowest conductivity sharply increased the levels of glucose in the acute exposure, while there was no significant difference in the chronic exposure. Cholesterol levels decreased only at the lower conductivities in chronic exposure, but increased in acute exposure. Similarly, triglyceride levels increased in acute exposures and decreased in chronic exposures at the lowest conductivity. There was no change in Na(+) levels, while there was an increase in K(+) levels and a decrease in Ca(2+) level at the lowest conductivity of acute exposures. However, Cl(-) levels generally decreased at the higher conductivities of chronic exposures. There was a strong negative relationship between significant altered serum parameters and water conductivity. In conclusion, this study showed that copper exposure of fish at lower conductivities caused more toxicities, indicating the protective effect of calcium ions against copper toxicity. Data suggest that conductivity of water may be used in the evaluation of metal data from different waters with different chemical characteristics.

  5. Increased total serum random cortisol levels predict mortality in critically ill trauma patients.

    PubMed

    Pandya, Urmil; Polite, Nathan; Wood, Teresa; Lieber, Michael

    2014-11-01

    Dysfunction in the hypothalamopituitary adrenal axis is thought to exist; however, there continues to be controversy about what level of serum cortisol corresponds to adrenal insufficiency. Few studies have focused on the significance of serum random cortisol in the critically ill trauma patient. Trauma patients with total serum random cortisol levels drawn in the intensive care unit within the first seven days of hospitalization were retrospectively reviewed. The primary outcome measured was in-hospital mortality. Two hundred forty-two patients were analyzed. Nonsurvivors had significantly higher mean cortisol levels than survivors (28.7 ± 15.80 μg/dL vs 22.9 ± 12.35 μg/dL, P = 0.01). Patients with cortisol 30 μg/dL or greater were more likely to die with odds ratio of 2.7 (95% confidence interval [CI], 1.5 to 5). The odds ratio increased to 4.0 and 3.8 (95% CI, 1.4 to 11.4 and 1.3 to 10.9) when cortisol was drawn on hospital Day 2 and Days 3 through 7, respectively. Among nonsurvivors, patients with an injury severity score less than 25 had significantly higher cortisol levels than patients with an Injury Severity Score 25 or higher (35.3 ± 19.21 μg/dL vs 25.7 ± 13.21 μg/dL, P = 0.009). Patients with massive transfusion, traumatic brain injury, spinal cord injury, or solid organ injury did not have significantly different cortisol levels. The covariate-adjusted area under the receiver operating characteristic curve indicated that cortisol level has a 77 per cent accuracy in differentiating survivors from nonsurvivors. Higher cortisol levels were predictive of mortality in critically ill trauma patients. Whether serum cortisol level is a marker that can be modified remains an area of interest for future study.

  6. Low-fat diet with omega-3 fatty acids increases plasma insulin-like growth factor concentration in healthy postmenopausal women.

    PubMed

    Young, Lindsay R; Kurzer, Mindy S; Thomas, William; Redmon, J Bruce; Raatz, Susan K

    2013-07-01

    The insulin-like growth factor pathway plays a central role in the normal and abnormal growth of tissues; however, nutritional determinants of insulin-like growth factor I (IGF-I) and its binding proteins in healthy individuals are not well defined. Three test diets-high-fat diet (40% energy as fat), low-fat diet (LF; 20% energy as fat), and a diet with low fat and high omega-3 fatty acid (LFn3; 23% energy as fat)--were tested in a randomized crossover designed controlled feeding trial in healthy postmenopausal women. Plasma IGF-I, IGF binding protein-3 (IGFBP-3), insulin, glucose, and ratio of IGF-I/IGFBP-3 concentrations were measured in response to diets. Insulin sensitivity was calculated using the homeostatic model assessment of insulin resistance We hypothesized that IGF-I, insulin, and glucose concentrations would decrease and IGFBP-3 concentration would increase in response to the low-fat diets. Eight weeks of the LFn3 diet increased circulating IGF-I (P < .001) and IGFBP-3 (P = .01) and the LF diet increased IGFBP-3 (P = .04), resulting in trends toward an increased IGF-I/IGFBP-3 ratio with the LFn3 diet and a decreased IGF-I/IGFBP-3 ratio with the LF diet (P = .13 for both comparisons). No statistically significant differences were detected between treatments at baseline or 8 weeks for IGF-1, IGFBP-3, or the ratio of IGF-1/IGFBP-3. Insulin, glucose, and the homeostatic model assessment of insulin resistance were not altered by the interventions. Low-fat diet with high n-3 fatty acids may increase circulating IGF-I concentrations without adversely affecting insulin sensitivity in healthy individuals.

  7. Accumulation of cholesterol and increased demand for zinc in serum-deprived RPE cells

    PubMed Central

    Mishra, Sanghamitra; Peterson, Katherine; Yin, Lili; Berger, Alan; Fan, Jianguo

    2016-01-01

    Purpose Having observed that confluent ARPE-19 cells (derived from human RPE) survive well in high-glucose serum-free medium (SFM) without further feeding for several days, we investigated the expression profile of RPE cells under the same conditions. Methods Expression profiles were examined with microarray and quantitative PCR (qPCR) analyses, followed by western blot analysis of key regulated proteins. The effects of low-density lipoprotein (LDL) and zinc supplementation were examined with qPCR. Immunofluorescence was used to localize the LDL receptor and to examine LDL uptake. Cellular cholesterol levels were measured with filipin binding. Expression patterns in primary fetal RPE cells were compared using qPCR. Results Microarray analyses of gene expression in ARPE-19, confirmed with qPCR, showed upregulation of lipid and cholesterol biosynthesis pathways in SFM. At the protein level, the cholesterol synthesis control factor SRBEF2 was activated, and other key lipid synthesis proteins increased. Supplementation of SFM with LDL reversed the upregulation of lipid and cholesterol synthesis genes, but not of cholesterol transport genes. The LDL receptor relocated to the plasma membrane, and LDL uptake was activated by day 5–7 in SFM, suggesting increased demand for cholesterol. Confluent ARPE-19 cells in SFM accumulated intracellular cholesterol, compared with cells supplemented with serum, over 7 days. Over the same time course in SFM, the expression of metallothioneins decreased while the major zinc transporter was upregulated, consistent with a parallel increase in demand for zinc. Supplementation with zinc reversed expression changes for metallothionein genes, but not for other zinc-related genes. Similar patterns of regulation were also seen in primary fetal human RPE cells in SFM. Conclusions ARPE-19 cells respond to serum deprivation and starvation with upregulation of the lipid and cholesterol pathways, accumulation of intracellular cholesterol, and

  8. Participation of decreased serum cholesteryl ester transfer activity, independent of increased serum lipoprotein(a), in angina pectoris in normolipemic elderly subjects.

    PubMed

    Miyashita, Y; Morimoto, S; Fukuo, K; Imanaka, S; Koh, E; Tamatani, M; Ogihara, T

    1992-01-01

    The cholesteryl ester transfer activity (CETA) is a measurement of the transfer of cholesteryl ester from HDL to VLDL, LDL or peripheral cells. Its role in the development of early coronary heart disease is not clear. In the present study, serum levels of CETA, lipoprotein(a) [Lp(a)] and other lipid-related factors were compared in 10 normal young subjects, 28 healthy elderly subjects and 14 normolipemic elderly patients with angina pectoris. Compared to the young normals and healthy elderly subjects, the elderly patients with angina pectoris showed significantly decreased mean serum CETA levels, and significantly increased mean serum levels of Lp(a) and apoprotein B. These results may indicate that decreased serum values of CETA participate in the development of angina pectoris in normolipemic elderly patients.

  9. Anabolic treatment with GH, IGF-I, or anabolic steroids in patients with HIV-associated wasting.

    PubMed

    Mulligan, Kathleen; Schambelan, Morris

    2002-09-01

    Wasting, and particularly loss of metabolically active lean tissue, contributes to increased mortality, accelerated disease progression, and impairment of strength and functional status in patients with HIV infection. A variety of protein anabolic agents, including growth hormone, insulin-like growth factor-I, testosterone, nandrolone decanoate, oxandrolone, and oxymetholone, have been studied in patients with HIV-associated wasting. Overall, these studies have demonstrated that treatment with protein anabolic agents can increase lean body mass (LBM) and in some cases provide functional benefits and improvements in quality of life. Further research is needed to determine whether such treatment prolongs survival or reduces the overall health care burden of HIV infection. The advances in identification of successful treatments for HIV-associated wasting can provide a model for using these therapies in other catabolic states, including end-stage renal disease, cancer, chronic obstructive pulmonary disease, and cardiac cachexia.

  10. Effects of Moderate Aerobic Exercise Combined With Calorie Restriction on Circulating Estrogens and IGF-I in Premenopausal Women

    DTIC Science & Technology

    2004-10-01

    menstrual cycles has produced significant increases in aerobic capacity (28-33%), weight loss ranging from 1.0 to 9 kg, and loss Of body fat ranging...decrease in body fat percent (-3.1%), and no changes in body weight . \\. Despite the highly significant changes in body composition and body weight ...breast cancer. BODY Study Design: The study utilizes a prospective, randomized design that tests the effects of a moderate exercise program (4X/wk; 4

  11. Effect of Increasing Maximal Aerobic Exercise on Serum Muscles Enzymes in Professional Field Hockey Players

    PubMed Central

    Hazar, Muhsin; Otağ, Aynur; Otağ, İlhan; Sezen, Mehmet; Sever, Ozan

    2015-01-01

    Background and Objectives: Exercise results in oxidative enzyme increase and micro-injuries in skeletal muscles. The aim of this study was to investigate the effect of maximal aerobic exercise on serum muscle enzymes in professional field hockey players. This study aims to determine the effect of increasing maximal aerobic exercise on creatine kinase (CK), creatine kinase-MB (CK-MB), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) serum levels. Material and Methods: 31 young professional field hockey players (13 female and 18 male players) volunteered for this study. All participants underwent the shuttle run test. Blood samples were taken from each participant before the shuttle run test. Post test blood samples were taken immediately after exercise and one hour after respectively. Pre and post test CK, CK-MB, AST and ALT values were measured by means of auto analyzer using original kits. Results: The acute post test measure of the CK level increased in male (p=0.002) and female (p=0.00) sportsmen. CK-MB values obtained one hour after the exercise was lower than those before the exercise in males (p=0.02). In females (p=0.017) and males (p=0.05) AST activity significantly increased immediately after exercise and decreased to resting activity 1 h recovery. ALT significantly increased immediately after exercise in female (p=0.03) and male (p=0.00) athletes and after 1 h recovery ALT activities decreased below resting values. Conclusion: The timing and severity of exercise used in our study increased CK values, decreased CK-MB values and AST, ALT values increased in female and male field hockey players. PMID:25948428

  12. Structure of the IGF-binding domain of the insulin-like growth factor-binding protein-5 (IGFBP-5): implications for IGF and IGF-I receptor interactions.

    PubMed Central

    Kalus, W; Zweckstetter, M; Renner, C; Sanchez, Y; Georgescu, J; Grol, M; Demuth, D; Schumacher, R; Dony, C; Lang, K; Holak, T A

    1998-01-01

    Binding proteins for insulin-like growth factors (IGFs) IGF-I and IGF-II, known as IGFBPs, control the distribution, function and activity of IGFs in various cell tissues and body fluids. Insulin-like growth factor-binding protein-5 (IGFBP-5) is known to modulate the stimulatory effects of IGFs and is the major IGF-binding protein in bone tissue. We have expressed two N-terminal fragments of IGFBP-5 in Escherichia coli; the first encodes the N-terminal domain of the protein (residues 1-104) and the second, mini-IGFBP-5, comprises residues Ala40 to Ile92. We show that the entire IGFBP-5 protein contains only one high-affinity binding site for IGFs, located in mini-IGFBP-5. The solution structure of mini-IGFBP-5, determined by nuclear magnetic resonance spectroscopy, discloses a rigid, globular structure that consists of a centrally located three-stranded anti-parallel beta-sheet. Its scaffold is stabilized further by two inside packed disulfide bridges. The binding to IGFs, which is in the nanomolar range, involves conserved Leu and Val residues localized in a hydrophobic patch on the surface of the IGFBP-5 protein. Remarkably, the IGF-I receptor binding assays of IGFBP-5 showed that IGFBP-5 inhibits the binding of IGFs to the IGF-I receptor, resulting in reduction of receptor stimulation and autophosphorylation. Compared with the full-length IGFBP-5, the smaller N-terminal fragments were less efficient inhibitors of the IGF-I receptor binding of IGFs. PMID:9822601

  13. Increased Serum Level of MicroRNA-663 Is Correlated with Poor Prognosis of Patients with Nasopharyngeal Carcinoma

    PubMed Central

    Liang, Shaoqiang; Deng, Yanming; Chen, Lusi; Zhang, Yang; Zheng, Zhenhe; Luo, Weijun; Lv, Zhiqian; Li, Shaoen; Xun, Tao

    2016-01-01

    MicroRNAs (miRs) play crucial roles in the carcinogenesis and malignant progression of human cancers including nasopharyngeal carcinoma (NPC). In this study, we aimed to investigate the association of serum miR-663 levels with the clinical factors and prognosis of NPC patients. Real-time PCR was performed to examine the amount of miR-663 in serum in NPC patients and healthy controls. Our data showed that the amount of miR-663 in serum was significantly higher in NPC patients than in healthy controls. Moreover, the serum levels of miR-663 were significantly correlated with the grade, lymph node metastasis, and clinical stage of NPC. Furthermore, higher serum miR-663 levels were closely associated with worse 5-year overall survival (OS) and relapse-free survival (RFS) of patients with NPC, and the serum level of miR-663 was found to be an independent predicator for the prognosis of NPC. In addition, after receiving chemoradiotherapy, the serum levels of miR-663 were significantly reduced in NPC patients. In summary, miR-663 was upregulated in the serum of NPC patients, which was downregulated after chemoradiotherapy, and its increased levels were closely associated with malignant progression and poor prognosis in NPC patients. Therefore, the amount of miR-663 in serum may become a potential predicator for the clinical outcome of NPC patients. PMID:27667893

  14. In contrast to matrix metalloproteinases, serum adiponectin concentrations increase after radioiodine treatment of thyrotoxicosis

    PubMed Central

    2012-01-01

    Background Matrix metalloproteinases (MMPs), together with their tissue inhibitors (TIMPs), remodel extracellular matrix under physiological and pathological conditions and are implicated in pathogenesis of cardiovascular diseases, cancer and in chronic inflammation. We have endeavoured to assess whether concentrations of MMPs, TIMPs, and anti-inflammatory adiponectin are altered by pharmacological treatment of acute thyrotoxicosis or by radioiodine therapy (RIT). Material and methods We measured serum concentrations of MMP-2, MMP-9, TIMP-1, TIMP-2, and adiponectin, TSH, free T4 (FT4) and free T3 (FT3) in 15 patients (4 males), age (years) 51.8±15.3 (mean±SD) with hyperthyroidism treated with thiamazole (Group 1) and in 20 subjects (2 males), treated for thyrotoxicosis with radioiodine, age 52.3±12.4 (Group 2), where blood samples were taken before RIT, visit 1 (V1), seven days post RIT, visit 2 (V2), and two to three months post RIT, visit 3 (V3). Results In Group 1 there was no significant change in concentrations of MMP-2, MMP-9, TIMP-1, TIMP-2 or adiponectin, despite a fall in FT4 and FT3 (8.74±4.79 pg/ml vs 3.54±2.40 pg/ml, for FT3, and 4.48 ±2.21 ng/ml vs 1.02±1.07 ng/ml, for FT4, p<0.001). In Group 2 RIT did not cause any acute change in serum MMP-2, MMP-9, TIMP-1 and TIMP-2 or adiponectin (V1 vs V2). However, there was a significant increase in serum adiponectin [from 15201±8860 ng/ml (V1) to 19373±8657 ng/ml (at V3), p<0.05], and TIMP-2 at V3 [from 129±45 ng/ml (V1) to 149±38 ng/ml (V3), p<0.01]. There was no significant change MMP-2, MMP-9 and TIMP-1 between V1 and V3. There was a decrease in FT4 and FT3 from 24.4±15.4 pmol/l (V1) to 14.7±10.6 pmol/l (V3), and from 10.0±5.65 (V1) to 6.1±4.8 pmol/l (V2), p<0.01, for FT4 and FT3, respectively. Conclusions Radioiodine therapy of thyrotoxicosis does not alter serum MMP-2, MMP-9 or TIMP-1 concentrations either acutely or after about three months of observation. An increase in serum adiponectin

  15. Resilience to traumatic events related to urban violence and increased IL10 serum levels.

    PubMed

    Teche, Stefania P; Rovaris, Diego L; Aguiar, Bianca W; Hauck, Simone; Vitola, Eduardo S; Bau, Claiton H D; Freitas, Lucia H; Grevet, Eugenio H

    2017-04-01

    The exposition to traumatic events related to urban violence is epidemic in Brazil, with rate of 80% in the general population, and is becoming a major cause of post-traumatic stress disorder (PTSD). The objective of the study was to compare serum levels of pro-inflammatory interleukin-6 (IL-6) and anti-inflammatory interleukin-10 (IL-10) in PTSD and resilient individuals. We hypothesized that resilient individuals present an attenuated pro-inflammatory and enhanced anti-inflammatory state. We conducted a case-control study comparing 30 resilient individuals and 30 PTSD patients exposed to traumatic events related to urban violence. The groups were evaluated using Self-Report Questionnaire (SRQ-20), Mini-International Neuropsychiatric Interview (MINI) and the Davidson Trauma Scale. For all individuals, blood samples were collected to determine IL-6, IL-10 and cortisol serum levels. All samples were frozen at -80°C until the assay and were analyzed with the same immunoassay kit and in duplicates. The resilient group presented higher IL-10 levels than PTSD patients [mean (CI95%); 1.03 (0.52-2.08) pg/mL vs. 0.29 (0.20-0.43) pg/mL; P=0.002]. There were no differences in terms of IL-6 or cortisol levels. The results provided evidence for increased levels of IL-10 in resilient individuals when compared to PTSD patients, probably conferring them a better anti-inflammatory response after exposition.

  16. Neurotensin is increased in serum of young children with autistic disorder.

    PubMed

    Angelidou, Asimenia; Francis, Konstantinos; Vasiadi, Magdalini; Alysandratos, Konstantinos-Dionysios; Zhang, Bodi; Theoharides, Athanasios; Lykouras, Lefteris; Sideri, Kyriaki; Kalogeromitros, Dimitrios; Theoharides, Theoharis C

    2010-08-23

    Autism spectrum disorders (ASD) are a group of pervasive neurodevelopmental disorders diagnosed in early childhood. They are associated with a set of "core symptoms" that include disabilities in social interaction skills, verbal and non-verbal communication, as well as repetitive and stereotypic behaviors. There is no definite pathogenetic mechanism or diagnostic tests. Many children with ASD also have "allergic-like" symptoms, but test negative implying mast cell activation by non-allergic triggers. We measured by Milliplex arrays serum levels of 3 neuropeptides that could stimulate mast cells in children with autistic disorder (n = 19; 16 males and 3 females; mean age 3.0 ± 0.4 years) and healthy, unrelated controls (n = 16; 13 males and 3 females; mean age 3 ± 1.2 years). Only neurotensin (NT) was significantly increased from 60.5 ± 6.0 pg/ml in controls to 105.6 ± 12.4 pg/ml in autistic disorder (p = 0.004). There was no statistically significant difference in the serum levels of β-endorphin or substance P (SP). NT could stimulate immune cells, especially mast cells, and/or have direct effects on brain inflammation and ASD.

  17. Liver congestion in heart failure contributes to inappropriately increased serum hepcidin despite anemia.

    PubMed

    Ohno, Yukako; Hanawa, Haruo; Jiao, Shuang; Hayashi, Yuka; Yoshida, Kaori; Suzuki, Tomoyasu; Kashimura, Takeshi; Obata, Hiroaki; Tanaka, Komei; Watanabe, Tohru; Minamino, Tohru

    2015-01-01

    Hepcidin is a key regulator of mammalian iron metabolism and mainly produced by the liver. Hepcidin excess causes iron deficiency and anemia by inhibiting iron absorption from the intestine and iron release from macrophage stores. Anemia is frequently complicated with heart failure. In heart failure patients, the most frequent histologic appearance of liver is congestion. However, it remains unclear whether liver congestion associated with heart failure influences hepcidin production, thereby contributing to anemia and functional iron deficiency. In this study, we investigated this relationship in clinical and basic studies. In clinical studies of consecutive heart failure patients (n = 320), anemia was a common comorbidity (41%). In heart failure patients without active infection and ongoing cancer (n = 30), log-serum hepcidin concentration of patients with liver congestion was higher than those without liver congestion (p = 0.0316). Moreover, in heart failure patients with liver congestion (n = 19), the anemia was associated with the higher serum hepcidin concentrations, which is a type of anemia characterized by induction of hepcidin. Subsequently, we produced a rat model of heart failure with liver congestion by injecting monocrotaline that causes pulmonary hypertension. The monocrotaline-treated rats displayed liver congestion with increase of hepcidin expression at 4 weeks after monocrotaline injection, followed by anemia and functional iron deficiency observed at 5 weeks. We conclude that liver congestion induces hepcidin production, which may result in anemia and functional iron deficiency in some patients with heart failure.

  18. Muscle enzyme and fiber type-specific sarcomere protein increases in serum after inertial concentric-eccentric exercise.

    PubMed

    Carmona, G; Guerrero, M; Cussó, R; Padullés, J M; Moras, G; Lloret, M; Bedini, J L; Cadefau, J A

    2015-12-01

    Muscle damage induced by inertial exercise performed on a flywheel device was assessed through the serum evolution of muscle enzymes, interleukin 6, and fiber type-specific sarcomere proteins such as fast myosin (FM) and slow myosin (SM). We hypothesized that a model of muscle damage could be constructed by measuring the evolution of serum concentration of muscle proteins following inertial exercise, according to their molecular weight and the fiber compartment in which they are located. Moreover, by measuring FM and SM, the type of fibers that are affected could be assessed. Serum profiles were registered before and 24, 48, and 144 h after exercise in 10 healthy and recreationally active young men. Creatine kinase (CK) and CK-myocardial band isoenzyme increased in serum early (24 h) and returned to baseline values after 48 h. FM increased in serum late (48 h) and remained elevated 144 h post-exercise. The increase in serum muscle enzymes suggests increased membrane permeability of both fast and slow fibers, and the increase in FM reveals sarcomere disruption as well as increased membrane permeability of fast fibers. Consequently, FM could be adopted as a fiber type-specific biomarker of muscle damage.

  19. Parenteral nutrition in short bowel syndrome patients, regardless of its duration, increases serum proinflammatory cytokines.

    PubMed

    Bizari, Letícia; da Silva Santos, Andressa Feijó; Foss, Norma Tiraboschi; Marchini, Júlio Sérgio; Suen, Vivian Marques Miguel

    2016-07-01

    Short bowel syndrome is a severe malabsorption disorder, and prolonged parenteral nutrition is essential for survival in some cases. Among the undesirable effects of long-term parenteral nutrition is an increase in proinflammatory cytokines. The aim of the present study was to measure the serum levels of interleukin-6, interleukin-10, tumor necrosis factor alpha, and transforming growth factor beta, in patients with short bowel syndrome on cyclic parenteral nutrition and patients who had previously received but no longer require parenteral nutrition. The study was cross-sectional and observational. Three groups were studied as follows: Parenteral nutrition group, 9 patients with short bowel syndrome that receive cyclic parenteral nutrition; Oral nutrition group, 10 patients with the same syndrome who had been weaned off parenteral nutrition for at least 1 year prior to the study; Control group, 13 healthy adults, matched for age and sex to parenteral and oral groups. The following data were collected: age, tobacco use, drug therapies, dietary intake, body weight, height, blood collection. All interleukins were significantly higher in the parenteral group compared with the control group as follows: interleukin-6: 22 ± 19 vs 1.5 ± 1.4 pg/mL, P= .0002; transforming growth factor β: 854 ± 204 vs 607 ± 280 pg/mL, P= .04; interleukin-10: 8 ± 37 vs 0.6 ± 4, P= .03; tumor necrosis factor α: 20 ± 8 vs 8 ± 4 pg/mL, P< .0001. We concluded that parenteral nutrition in short bowel syndrome patients, regardless of its duration, increases serum proinflammatory cytokines.

  20. Increased serum free tryptophan in patients with diarrhea-predominant irritable bowel syndrome.

    PubMed

    Christmas, David M; Badawy, Abdulla A-B; Hince, Dana; Davies, Simon J C; Probert, Christopher; Creed, Tom; Smithson, John; Afzal, Muhammad; Nutt, David J; Potokar, John P

    2010-10-01

    Irregularities of serotonin function in irritable bowel syndrome (IBS) may be due to changes in the metabolism of the serotonin precursor l-tryptophan. Dietary alteration of tryptophan intake may impact upon the mood and bowel symptoms of IBS. We hypothesized that diarrhea-predominant irritable bowel syndrome (d-IBS) patients would exhibit an increase in plasma tryptophan due to alterations in tryptophan metabolism. We also hypothesized that a diet low in tryptophan would reverse this change and reduce symptoms. Thirteen patients with d-IBS had fasting serum free and total tryptophan, large neutral amino acids, and 6 kynurenine metabolites measured before and after 2 weeks of a strict dairy-free diet. Baseline tryptophan parameters were compared with an age- and sex-matched control group. Changes in the specific tryptophan parameters before and after dairy-free diet were correlated with symptoms of IBS and mood. Compared with the control group, d-IBS patients at baseline exhibited significantly higher free serum tryptophan (10.5 ± 4.35 vs 4.75 ± 2.43 μmol/L [means ± standard deviation], P = .006) and significantly lower tryptophan dioxygenase and total tryptophan oxidation as measured by the kynurenine to free tryptophan and total kynurenines to free tryptophan ratios (23.37 ± 10.12 vs 55.33 ± 16.02, P < .001 and 49.34 ± 17.84 vs 258.46 ± 98.67, P < .001, respectively). Dairy-free diet did not modulate metabolites of the kynurenine pathway or symptoms. Tryptophan metabolism along the kynurenine pathway is inhibited in d-IBS, and a dairy-free diet does not alter this. Our findings are consistent with possible enhanced serotonin activity in d-IBS.

  1. Insulin-like growth factor-I decreases serum lipoprotein (a) during long-term treatment of patients with Laron syndrome.

    PubMed

    Laron, Z; Wang, X L; Klinger, B; Silbergeld, A; Wilcken, D E

    1996-10-01

    An increased circulating level of lipoprotein(a) [Lp(a)] is a well-recognized risk factor for coronary artery disease. While much remains to be understood about its regulation and physiological functions, we explored the effect of recombinant insulin-like growth factor-I (IGF-I) administration on circulating Lp(a) levels in 10 Laron syndrome (LS) patients (five children and five adults) with inherited IGF-I deficiency. There was no relationship between pretreatment or posttreatment Lp(a) levels and age and sex of the patients. With IGF-I treatment for 6 to 12 months, there was a significant reduction in Lp(a) (65.7% +/- 15.5%, P < .0001) from the pretreatment level of 76 +/- 45 mg/L to the posttreatment level of 29 +/- 26 mg/L. This decrease was dosage-dependent on the IGF-I administered (r = .685, F = 0.708, P = .029) and correlated more strongly with the dosage ratio of the end to the beginning of treatment (r = .78, F = 12.23, P = .008). The higher the IGF-I dose and the higher the dose ratio, the greater the Lp(a) decrease and the lower the Lp(a) at the end of treatment. In conclusion, we observed a dose-dependent relationship between IGF-I administration and Lp(a) reduction in patients with LS. Further studies are needed to elucidate the mechanism of the effect, but our findings suggest a possible metabolic link between these two and shed more light on the regulation of apolipoprotein(a) [apo(a)] expression. It could also open an avenue for additional therapeutic usage of IGF-I.

  2. Increased serum resistin levels in patients with type 2 diabetes are not linked with markers of insulin resistance and adiposity.

    PubMed

    Hasegawa, G; Ohta, M; Ichida, Y; Obayashi, H; Shigeta, M; Yamasaki, M; Fukui, M; Yoshikawa, T; Nakamura, N

    2005-06-01

    The role of resistin in human biology remains uncertain. We measured serum resistin levels in Japanese patients with (n=111) and without (n=98) type 2 diabetes mellitus and investigated the significance of this hormone in the pathophysiology of diabetes. The levels of serum adiponectin and leptin were also measured. Resistin levels were increased significantly in patients with type 2 diabetes compared with non-diabetic subjects (24.7+/-2.6 vs. 15.0+/-1.2 ng/ml, p=0.0013). However, there was no correlation in either patient group between serum resistin levels and markers of insulin resistance, obesity or hyperlipidaemia. These results were in direct contrast to the data of leptin or adiponectin, both of which were closely related to these clinical markers of diabetes. Multivariate regression analysis on the combined data of the two groups demonstrated that the presence of diabetes and HDL cholesterol levels were significant predictors of serum resistin levels (diabetes: beta=0.159, p=0.035; HDL: beta=-0.172, p=0.039). No correlation was observed between C-reactive protein and resistin adjusted for BMI. Taken together, these findings demonstrate that serum resistin levels are increased in patients with type 2 diabetes, but this increase is not linked to markers of insulin resistance or adiposity. Further studies are necessary to elucidate the significance of serum resistin concentration in human pathophysiology.

  3. High Levels of Serum Prolactin Protect Against Diabetic Retinopathy by Increasing Ocular Vasoinhibins

    PubMed Central

    Arnold, Edith; Rivera, José C.; Thebault, Stéphanie; Moreno-Páramo, Daniel; Quiroz-Mercado, Hugo; Quintanar-Stéphano, Andrés; Binart, Nadine; Martínez de la Escalera, Gonzalo; Clapp, Carmen

    2010-01-01

    OBJECTIVE Increased retinal vasopermeability (RVP) occurs early in diabetes and is crucial for the development of sight-threatening proliferative diabetic retinopathy (DR). The hormone prolactin (PRL) is proteolytically processed to vasoinhibins, a family of peptides that inhibit the excessive RVP related to DR. Here, we investigate the circulating levels of PRL in association with DR in men and test whether increased circulating PRL, by serving as a source of ocular vasoinhibins, can reduce the pathological RVP in diabetes. RESEARCH DESIGN AND METHODS Serum PRL was evaluated in 40 nondiabetic and 181 diabetic men at various stages of DR. Retinal vasoinhibins were measured in rats rendered hyperprolactinemic by placing two anterior pituitary grafts under the kidney capsule and in PRL receptor–null mice. RVP was determined in hyperprolactinemic rats subjected to the intraocular injection of vascular endothelial growth factor (VEGF) or made diabetic with streptozotocin. RESULTS The circulating levels of PRL increased in diabetes and were higher in diabetic patients without retinopathy than in those with proliferative DR. In rodents, hyperprolactinemia led to vasoinhibin accumulation within the retina; genetic deletion of the PRL receptor prevented this effect, indicating receptor-mediated incorporation of systemic PRL into the eye. Hyperprolactinemia reduced both VEGF-induced and diabetes-induced increase of RVP. This reduction was blocked by bromocriptine, an inhibitor of pituitary PRL secretion, which lowers the levels of circulating PRL and retinal vasoinhibins. CONCLUSIONS Circulating PRL influences the progression of DR after its intraocular conversion to vasoinhibins. Inducing hyperprolactinemia may represent a novel therapy against DR. PMID:20823101

  4. NZ-GMP Approved Serum Improve hDPSC Osteogenic Commitment and Increase Angiogenic Factor Expression

    PubMed Central

    Spina, Anna; Montella, Roberta; Liccardo, Davide; De Rosa, Alfredo; Laino, Luigi; Mitsiadis, Thimios A.; La Noce, Marcella

    2016-01-01

    Human dental pulp stem cells (hDPSCs), selected from the stromal-vascular fraction of dental pulp, are ecto-mesenchymal stem cells deriving from neural crests, successfully used in human bone tissue engineering. For their use in human therapy GMP procedures are required. For instance, the use of fetal bovine serum (FBS) is strongly discouraged in clinical practice due to its high risk of prions and other infections for human health. Alternatively, clinical grade sera have been suggested, including the New Zealand FBS (NZ-FBS). Therefore, the aim of this study was to evaluate the behavior of hDPSCs expanded in culture medium containing NZ-FBS. Since it was widely demonstrated hDPSCs display relevant capabilities to differentiate into osteogenic and angiogenic lineages, we performed a comparative study to assess if these features are also retained by cultivating the cells with a safer serum never tested on this cell line. hDPSCs were grown using NZ-FBS and conventional (C-FBS) for 7, 14, and 21 days, in both 2D and 3D cultures. Growth curves, expression of bone-related markers, calcification and angiogenesis were evaluated. NZ-FBS induced significant cell growth with respect to C-FBS and promoted an earlier increase expression of osteogenic markers, in particular of those involved in the formation of mineralized matrix (BSP and OPN) within 14 days. In addition, hDPSCs cultured in presence of NZ-FBS were found to produce higher mRNA levels of the angiogenic factors, such as VEGF and PDGFA. Taken together, our results highlight that hDPSCs proliferate, enhance their osteogenic commitment and increase angiogenic factors in NZ-FBS containing medium. These features have also been found when hDPSC were seeded on the clinical-grade collagen I scaffold (Bio-Gide®), leading to the conclusion that for human therapy some procedures and above all the use of GMP-approved materials have no negative impact. PMID:27594842

  5. Conjugation of a dipicolyl chelate to polypeptide conjugates increases binding affinities for human serum albumin and survival times in human serum.

    PubMed

    Balliu, Aleksandra; Baltzer, Lars

    2017-03-16

    The affinity for human serum albumin (HSA) of a series of 2-5 kDa peptides covalently linked to 3,5-bis[[bis(2-pyridylmethyl)amino]methyl]benzoic acid, a dipicolyl chelator with μM affinity for Zn2+, was found by surface plasmon resonance to increase in the presence of 1μM ZnCl2 at physiological pH. The dependence on polypeptide hydrophobicity was found to be minor, suggesting that the conjugates bound to the metal binding site and not to the fatty acid binding site. The affinity of the conjugates increased strongly with the positive charge of the polypeptides suggesting proximity to the negatively charged protein surface surrounding the metal binding site. The survival times of the peptides in human serum were extended as a consequence of stronger binding to HSA suggesting that Zn2+ ion chelating agents may provide a general route to increased survival times of peptides in serum in therapeutic and diagnostic applications without significantly increasing their molecular weights.

  6. Older men with low serum IGF-1 have an increased risk of incident fractures: the MrOS Sweden study.

    PubMed

    Ohlsson, Claes; Mellström, Dan; Carlzon, Daniel; Orwoll, Eric; Ljunggren, Osten; Karlsson, Magnus K; Vandenput, Liesbeth

    2011-04-01

    Osteoporosis-related fractures constitute a major health concern not only in women but also in men. Insulin-like growth factor 1 (IGF-1) is a key determinant of bone mass, but the association between serum IGF-1 and incident fractures in men remains unclear. To determine the predictive value of serum IGF-1 for fracture risk in men, older men (n = 2902, mean age of 75 years) participating in the prospective, population-based Osteoporotic Fractures in Men (MrOS) Sweden study were followed for a mean of 3.3 years. Serum IGF-1 was measured at baseline by radioimmunoassay. Fractures occurring after the baseline visit were validated. In age-adjusted hazards regression analyses, serum IGF-1 associated inversely with risk of all fractures [hazard ratio (HR) per SD decrease = 1.23, 95% confidence interval (CI) 1.07-1.41], hip fractures (HR per SD decrease = 1.45, 95% CI 1.07-1.97), and clinical vertebral fractures (HR per SD decrease = 1.40, 95% CI 1.10-1-78). The predictive role of serum IGF-1 for fracture risk was unaffected by adjustment for height, weight, prevalent fractures, falls, and major prevalent diseases. Further adjustment for bone mineral density (BMD) resulted in an attenuated but still significant association between serum IGF-1 and fracture risk. Serum IGF-1 below but not above the median was inversely related to fracture incidence. The population-attributable risk proportion was 7.5% for all fractures and 22.9% for hip fractures. Taken together, older men with low serum IGF-1 have an increased fracture risk, especially for the two most important fracture types, hip and vertebral fractures. The association between serum IGF-1 and fracture risk is partly mediated via BMD.

  7. Changes in serum growth factors in stroke rehabilitation patients and their relation to hemiparesis improvement.

    PubMed

    Okazaki, Hideto; Beppu, Hidehiko; Mizutani, Kenmei; Okamoto, Sayaka; Sonoda, Shigeru

    2014-07-01

    Predicting recovery from hemiparesis after stroke is important for rehabilitation. A few recent studies reported that the levels of some growth factors shortly after stroke were positively correlated with the clinical outcomes during the chronic phase. The aim of this study was to examine the relationships between the serum levels of growth factors (vascular endothelial growth factor [VEGF], insulin-like growth factor-I [IGF-I], and hepatocyte growth factor [HGF]) and improvement in hemiparesis in stroke patients who received rehabilitation in a postacute rehabilitation hospital. Subjects were 32 stroke patients (cerebral infarction: 21 and intracerebral hemorrhage [ICH]: 11). We measured serum levels of VEGF, IGF-I, and HGF and 5 items of the Stroke Impairment Assessment Set (SIAS) for hemiparesis on admission and at discharge. Age-matched healthy subjects (n=15) served as controls. Serum levels of VEGF and HGF in cerebral infarct patients on admission were higher than those in control subjects, and the serum levels of IGF-I in stroke patients were lower than those in controls. The level of HGF in ICH patients on admission was negatively correlated with gains in SIAS, and higher outliers in HGF concentration were correlated with lower gains in SIAS. Focusing on the extremely high levels of these factors may be a predictor of the low recovery from hemiparesis after stroke.

  8. Increased Serum Activity of Matrix Metalloproteinase-9 in Patients with Acute Variceal Bleeding

    PubMed Central

    Kwon, Oh Sang; Jung, Hyuk Sang; Bae, Kyung Sook; Jung, Young Kul; Kim, Yeon Suk; Choi, Duck Joo; Kim, Yun Soo

    2012-01-01

    Background/Aims Matrix metalloproteinases (MMP)-2 and -9 can degrade essential components of vascular integrity. The aim of this study was to investigate the association between those MMPs and variceal bleeding (VB). Methods Fifteen controls, 12 patients with acute ulcer bleeding (UB) group, 37 patients with varix (V group), and 35 patients with acute VB group were enrolled. Serum was obtained to measure MMP-2 and -9 activity by zymogram protease assays. Results The activity levels of these compounds were compared with the controls' median value. The median MMP-9 activity was 1.0 in controls, 1.05 in the UB group, 0.43 in the V group, and 0.96 in the VB group. The level of MMP-9 activity was higher in the VB group than in the V group (p<0.001). In the VB group, there was a signifi cant decrease in MMP-9 activity over time after bleeding (p<0.001). The median MMP-2 activity level was 1.0 in controls, 1.01 in the UB group, 1.50 in the V group, and 1.55 in the VB group. The level of MMP-2 activity was similar in the VB and V groups. Conclusions The level of MMP-9 activity increased in association with VB. The role of MMP-9 in the pathogenesis of VB should be verified. PMID:22570756

  9. Mild increases in serum hepcidin and interleukin-6 concentrations impair iron incorporation in haemoglobin during an experimental human malaria infection.

    PubMed

    de Mast, Quirijn; van Dongen-Lases, Edmee C; Swinkels, Dorine W; Nieman, An-Emmie; Roestenberg, Meta; Druilhe, Pierre; Arens, Theo A; Luty, Adrian J; Hermsen, Cornelis C; Sauerwein, Robert W; van der Ven, Andre J

    2009-06-01

    The correct selection of individuals who will benefit from iron supplements in malaria-endemic regions requires improved insight in the effects of malaria on host iron homeostasis and innovative biomarkers. We assessed sequential changes in serum hepcidin and in traditional biochemical iron status indicators during an experimental Plasmodium falciparum malaria infection with five adult volunteers. The haemoglobin content of reticulocytes (Ret-H(e)) and of mature red blood cells (RBC-H(e)) represented iron incorporation into haemoglobin. Low-density parasitaemia and its treatment induced a mild increase in interleukin (IL)-6 and serum hepcidin concentrations. Despite this only mild increase, a marked hypoferraemia with a strong increase in serum ferritin concentrations developed, which was associated with a sharp fall in Ret-H(e), while RBC-H(e) remained unchanged. The ratio of soluble transferrin receptor (sTfR) to log ferritin concentrations decreased to an average nadir of 63% of the baseline value. We concluded that even mild increases in serum hepcidin and IL-6 concentrations result in a disturbed host iron homeostasis. Serum hepcidin, Ret-H(e) and Delta-H(e) (Ret-H(e) minus RBC-H(e)) are promising biomarkers to select those individuals who will benefit from iron supplements in malaria endemic regions, while the sTfR/log ferritin ratio should be used with caution to assess iron status during malaria.

  10. Fever and increased serum IL-1 activity as a systemic manifestation of acute phototoxicity in New Zealand White rabbits.

    PubMed

    Ansel, J C; Luger, T A; Green, I

    1987-07-01

    Ultraviolet (UV) radiation is a significant environmental hazard for humans and animals. Although the clinical effect of an acute UV exposure such as cutaneous inflammation, malaise, somnolence, chills, and fever have been appreciated for many years, the underlying mechanisms mediating these effects are poorly understood. Since chills and fever are the most dramatic systemic sequelae after a prolonged exposure to UV, we specifically examined the effect of whole-body UV irradiation on core body temperature and serum endogenous pyrogen activity of New Zealand White rabbits, correlating this with serum interleukin 1 (IL-1) activity and alterations of serum divalent cation levels. We found that an acute dose of UV irradiation (Westinghouse FS-40 lamps, 0.2 mJ/cm2/s X 8 h) resulted in a significant increase in the core body temperature 2 h post UV (0.8 degree C), peaking 5 h post UV (1.8 degree C), and returning to normal 24 h post UV. Likewise, the sera from the UV-irradiated rabbits had significant endogenous pyrogen activity when transferred into naive recipient animals, causing an increase in core body temperature within 45 min (0.65 +/- 0.12 degree C), decreasing over the next 2 h, and returning to normal 6 h post injection. No endotoxin contamination was detected in any serum samples. This post-UV febrile response was accompanied by a prolonged increase in serum IL-1 activity (5-10 X) and a significant alteration in serum divalent cation levels, with the rabbits becoming euthermic even as the serum IL-1 levels remained elevated. These findings provide new information concerning the pathogenesis and kinetics of these systemic effects after an acute dose of UV irradiation.

  11. Increased Serum Pepsinogen II Level as a Marker of Pangastritis and Corpus-Predominant Gastritis in Gastric Cancer Prevention.

    PubMed

    Massarrat, Sadegh; Haj-Sheykholeslami, Arghavan

    2016-02-01

    Serum pepsinogen I and II are considered as indicators of changes in gastric morphology. Important publications from the last decades are reviewed with regard to the serum level of these biomarkers for the diagnosis of normal gastric mucosa, diffuse gastritis and its change to atrophic gastritis and intestinal metaplasia as well as gastric cancer. Due to the low sensitivity of serum biomarkers for diagnosis of gastric cancer, especially at its early stage and the poor prognosis of the tumor at the time of diagnosis, its prevention by eradication of H. pylori remains the mandatory strategy. On the other hand, the severity of regression and non-reversibility of precancerous lesions and intestinal metaplasia in gastric mucosa through eradication of H. pylori make it necessary to diagnose diffuse gastritis at its early stage. Increased serum pepsinogen II compared to normal serum pepsinogen I seems to indicate the presence of diffuse gastritis without precancerous lesions suitable for eradication of H. pylori infection, when it is serologically positive. A diagram illustrates the strategy of this therapeutic measure depending on the age of people and the level of serum biomarkers in areas with high gastric cancer prevalence.

  12. Increased serum C-reactive protein level in Japanese patients of psoriasis with cardio- and cerebrovascular disease.

    PubMed

    Takahashi, Hidetoshi; Iinuma, Shin; Honma, Masaru; Iizuka, Hajime

    2014-11-01

    Psoriasis is a chronic inflammatory skin disease, which may be associated with metabolic syndrome accompanied by cardio- and cerebrovascular diseases. We investigated the relation between serum C-reactive protein (CRP) and cardio- and cerebrovascular diseases in Japanese psoriasis vulgaris patients. Ninety-seven psoriasis vulgaris patients and 79 healthy controls were assessed for serum CRP levels by immunoturbidimetry. The data were analyzed in terms of Psoriasis Area and Severity Index (PASI) scores, and comorbidity of cardio- and cerebrovascular disease and metabolic syndrome. Serum CRP levels in psoriasis vulgaris patients were significantly higher than those of healthy controls. There was no significant difference between male and female CRP levels in either psoriasis or healthy controls. No correlation was detected between PASI scores and serum CRP levels, either. Psoriasis with cardio- and cerebrovascular disease showed significantly higher CRP levels compared with those without the diseases. Furthermore, psoriasis with metabolic syndrome showed significantly higher serum CRP levels than those without the metabolic syndrome. In conclusion, serum CRP level is increased in psoriasis, and may be a useful marker for the prediction of the future risk of cardio- and cerebrovascular disease.

  13. Glycosylation of serum ribonuclease 1 indicates a major endothelial origin and reveals an increase in core fucosylation in pancreatic cancer.

    PubMed

    Barrabés, Sílvia; Pagès-Pons, Lluís; Radcliffe, Catherine M; Tabarés, Glòria; Fort, Esther; Royle, Louise; Harvey, David J; Moenner, Michel; Dwek, Raymond A; Rudd, Pauline M; De Llorens, Rafael; Peracaula, Rosa

    2007-04-01

    Human pancreatic ribonuclease 1 (RNase 1) is a glycoprotein expressed mainly by the pancreas and also found in endothelial cells. The diagnosis of pancreatic cancer (PaC) remains difficult and therefore the search for sensitive and specific markers is required. Previous studies showed that RNase 1 from human healthy pancreas contained only neutral glycans, whereas RNase 1 from PaC cell lines contained sialylated structures. To determine whether these glycan tumor cell-associated changes were also characteristic of serum RNase 1 and could be used as a marker of PaC, we have analyzed the glycosylation of serum RNase 1. The origin of serum RNase 1 was also investigated. Serum RNase 1 from two PaC patients and two controls was purified and the glycans analyzed by high-performance liquid chromatography (HPLC)-based sequencing and mass spectrometry. Although normal and tumor serum RNase 1 contained the same glycan structures, there was an increase of 40% in core fucosylation in the main sialylated biantennary glycans in the PaC serum RNase 1. This change in proportion would be indicative of a subset of tumor-associated glycoforms of RNase 1, which may provide a biomarker for PaC. Two-dimensional electrophoresis of the RNase 1 from several endothelial cell lines, EA.hy926, human umbilical vein endothelial cells (HUVEC), human mammary microvessel endothelial cells (HuMMEC), and human lung microvessel endothelial cells (HuLEC), showed basically the same pattern and was also very similar to that of serum RNase 1. RNase 1 from EA.hy926 was then purified and presented a glycosylation profile very similar to that from serum RNase 1, suggesting that endothelial cells are the main source of this enzyme.

  14. Hyperphosphatemia, hypocalcemia and increased serum potassium concentration as distinctive features of early hypomagnesemia in magnesium-deprived mice.

    PubMed

    Ortega, Bernardo; MacWilliams, Jacob R; Dey, Jason M; Courtright, Valerie B

    2015-12-01

    Magnesium-deficient patients show dysfunctional calcium (Ca(2+)) metabolism due to defective parathyroid hormone (PTH) secretion. In mice and rats, long-term magnesium (Mg(2+)) deprivation causes hyperphosphaturia and increases fibroblast growth factor 23 (FGF23) secretion, despite normal serum phosphate (Pi) and Ca(2+). Electrolyte disturbances during early hypomagnesemia may explain the response of mice to long-term Mg(2+) deprivation, but our knowledge of electrolyte homeostasis during this stage is limited. This study compares the effect of both short- and long-term Mg(2+) restriction on the electrolyte balance in mice. Mice were fed control or Mg(2+)-deficient diets for one to three days, one week, or three weeks. Prior to killing the mice, urine was collected over 24 h using metabolic cages. Within 24 h of Mg(2+) deprivation, hypomagnesemia, hypocalcemia and hyperphosphatemia developed, and after three days of Mg(2+) deprivation, serum potassium (K(+)) was increased. These changes were accompanied by a reduction in urinary volume, hyperphosphaturia, hypocalciuria and decreased Mg(2+), sodium (Na(+)) and K(+) excretion. Surprisingly, after one week of Mg(2+) deprivation, serum K(+), Pi and Ca(2+) had normalized, showing that mineral homeostasis is most affected during early hypomagnesemia. Serum Pi and K(+) are known to stimulate secretion of FGF23 and aldosterone, which are usually elevated during Mg(2+) deficiency. Thus, the hyperphosphatemia and increased serum K(+) concentration observed during short-term Mg(2+) deprivation may help our understanding of adaptation to chronic Mg(2+) deficiency.

  15. Increased Interleukin-17 and decreased BAFF serum levels in drug-free acute schizophrenia.

    PubMed

    El Kissi, Yousri; Samoud, Samar; Mtiraoui, Ahlem; Letaief, Leila; Hannachi, Neila; Ayachi, Mouna; Ali, Bechir Ben Hadj; Boukadida, Jalel

    2015-01-30

    Hypotheses regarding an immune-cytokine basis of schizophrenia have been postulated with controversial findings and a lack of data related to many cytokines. The aim of this study was to assess serum levels of Interferon-γ (IFN-γ), Interleukin-4 (IL-4), Transforming Growth Factor-β (TGF-β), Interleukin-17 (IL-17) and B-cell Activating Factor (BAFF) in schizophrenic patients and to determine correlations between cytokine levels and clinical parameters. Serum cytokine levels were measured with ELISA techniques in 60 neuroleptic-free patients on acute phase of the disease (BPRS≥40) and 28 healthy controls matched for age and sex. Current symptoms were assessed with Brief Psychiatric Rating Scale (BPRS), Positive and Negative Syndrome Scale (PANSS), Scale for the Assessment of Positive Symptoms (SAPS) and Scale for the Assessment of Negative Symptoms (SANS). No significant difference was found between patients and controls regarding IFN-γ serum levels. IL-4 was not detected in both groups. Patients exhibited significantly higher IL-17 and lower BAFF serum levels. IL-17 and BAFF levels were negatively correlated in schizophrenic patients. SANS global score was negatively correlated with IL-17 and positively correlated with IFN-γ serum levels. These results argue against the involvement of Th1 or Th2 population cells in schizophrenia. IL-17 and BAFF could be valuable markers for schizophrenia.

  16. Increased Serum Antibody Titer against HPV-16 Antigen in Patients with Behçet's Disease

    PubMed Central

    2017-01-01

    Quadrivalent human papillomavirus (HPV) vaccine has been reported to be significantly associated with Behçet's disease (BD). However, no reports have described HPV infection as a possible cause for the development of BD. The objective of this study was to evaluate whether anti-HPV immunoglobulin G (IgG) antibody titer is increased in BD. Serum samples from 93 Korean BD patients, who fulfilled the diagnostic criteria of the International Study Group for BD, were used in an enzyme-linked immunosorbent assay (ELISA). The clinical activity of BD was evaluated at the time of blood sampling. HPV-16 L1 virus-like particle (VLP) antigen was used in this study for the ELISA. Patients with BD had significantly higher antibody titers against HPV-16 (optical density [OD], 0.210–3.675; mean 0.992) than that of healthy controls (OD, 0.248–0.762; mean 0.517; P < 0.001). Using a receiver operating characteristic (ROC) analysis, a cut-off value of 0.578 OD for the anti-HPV antibody titer was determined that differentiated BD patients from healthy controls. When we compared the clinical features of BD between the 2 groups, articular involvement of BD was more likely in patients with an anti-HPV-16 antibody titer < 0.578 OD (P = 0.035). In addition, patients with an anti-HPV-16 antibody titer < 0.578 were significantly younger than those with a titer ≥ 0.578 OD. HPV itself may be a possible extrinsic triggering infectious agent causing the development of BD. PMID:28244285

  17. Policosanol Attenuates Statin-Induced Increases in Serum Proprotein Convertase Subtilisin/Kexin Type 9 When Combined with Atorvastatin

    PubMed Central

    Guo, Yuan-Lin; Xu, Rui-Xia; Zhu, Cheng-Gang; Wu, Na-Qiong; Cui, Zhi-Ping; Li, Jian-Jun

    2014-01-01

    Objective. Statin treatment alone has been demonstrated to significantly increase plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) levels. The effect of policosanol combined with statin on PCSK9 is unknown. Methods. Protocol I: 26 patients with atherosclerosis were randomly assigned to receive either atorvastatin 20 mg/d or policosanol 20 mg/d + atorvastatin 20 mg/d for 8 weeks. Protocol II: 15 healthy volunteers were randomly assigned to either policosanol 20 mg/d or a control group for 12 weeks. Serum levels of PCSK9 were determined at day 0 and the end of each protocol. Results. Protocol I: atorvastatin 20 mg/d significantly increased serum PCSK9 level by 39.4% (256 ± 84 ng/mL versus 357 ± 101 ng/mL, P = 0.002). However, policosanol 20 mg/d + atorvastatin 20 mg/d increased serum PCSK9 level by only 17.4% without statistical significance (264 ± 60 ng/mL versus 310 ± 86 ng/mL, P = 0.184). Protocol II: there was a trend toward decreasing serum PCSK9 levels in the policosanol group (289 ± 71 ng/mL versus 235 ± 46 ng/mL, P = 0.069). Conclusion. Policosanol combined with statin attenuated the statin-induced increase in serum PCSK9 levels. This finding indicates that policosanol might have a modest effect of lowering serum PCSK9 levels. PMID:25478000

  18. Increased Levels of miRNA-146a in Serum and Histologic Samples of Patients with Uveal Melanoma.

    PubMed

    Russo, Andrea; Caltabiano, Rosario; Longo, Antonio; Avitabile, Teresio; Franco, Livio M; Bonfiglio, Vincenza; Puzzo, Lidia; Reibaldi, Michele

    2016-01-01

    Purpose: To analyze MiRs expression in serum of UM patients, respect to healthy donors, and to compare this data with MiRs expressed in formalin-fixed, paraffin-embedded UM samples. Methods: Expression profile of 754 miRNAs was performed in serum of patients with uveal melanoma who underwent primary enucleation. The level of miRNAs increased in serum was individually analyzed on FFPE UM samples and compared to choroidal melanocytes from unaffected eyes. Results: Fourteen patients with uveal melanoma were included in the study. We found 8 serum miRNAs differentially expressed compared to normal controls: 2 upregulated miRNAs (miRNA-146a, miR-523); 6 downregulated miRNAs (miR-19a, miR-30d, miR-127, miR-451, miR-518f, miR-1274B). When data on upregulated miRNAs were singularly validated only a significant overexpression of miRNA-146a was found. A statistically significant upregulation of miRNA-146a was also found on FFPE UM samples, compared to choroidal melanocytes from unaffected eyes. Conclusions: miRNA-146a is increased in serum of patients with UM and in FFPE tumor samples. Further studies will show if it could be considered a potential marker of UM in the blood.

  19. Increased Levels of miRNA-146a in Serum and Histologic Samples of Patients with Uveal Melanoma

    PubMed Central

    Russo, Andrea; Caltabiano, Rosario; Longo, Antonio; Avitabile, Teresio; Franco, Livio M.; Bonfiglio, Vincenza; Puzzo, Lidia; Reibaldi, Michele

    2016-01-01

    Purpose: To analyze MiRs expression in serum of UM patients, respect to healthy donors, and to compare this data with MiRs expressed in formalin-fixed, paraffin-embedded UM samples. Methods: Expression profile of 754 miRNAs was performed in serum of patients with uveal melanoma who underwent primary enucleation. The level of miRNAs increased in serum was individually analyzed on FFPE UM samples and compared to choroidal melanocytes from unaffected eyes. Results: Fourteen patients with uveal melanoma were included in the study. We found 8 serum miRNAs differentially expressed compared to normal controls: 2 upregulated miRNAs (miRNA-146a, miR-523); 6 downregulated miRNAs (miR-19a, miR-30d, miR-127, miR-451, miR-518f, miR-1274B). When data on upregulated miRNAs were singularly validated only a significant overexpression of miRNA-146a was found. A statistically significant upregulation of miRNA-146a was also found on FFPE UM samples, compared to choroidal melanocytes from unaffected eyes. Conclusions: miRNA-146a is increased in serum of patients with UM and in FFPE tumor samples. Further studies will show if it could be considered a potential marker of UM in the blood. PMID:27895580

  20. Infection of growing swine with porcine reproductive and respiratory syndrome virus and Mycoplasma hyopneumoniae--effects on growth, serum metabolites, and insulin-like growth factor-I.

    PubMed

    Roberts, N Elizabeth; Almond, Glen W

    2003-01-01

    This study evaluated the influence of concomitant infections with porcine reproductive and respiratory syndrome virus (PRRSV) and Mycoplasma hyopneumoniae on growth performance, serum metabolite concentrations, and serum insulin-like growth factor-I (IGF-I) in growing pigs. Twenty-two barrows (10 weeks of age) were treated with either an intranasal administration of PRRSV and an intratracheal infusion of M. hyopneumoniae (treatment; n = 8) or a sham inoculation with medium (sham; n = 8), or were not treated (control; n = 6). The sham pigs were matched by body weight and pair-wise fed with treatment pigs. Pigs were weighed on the day of inoculation (day 0) and at 4 weeks postinoculation (day 28). Blood samples were collected prior to inoculation and at weekly intervals for 4 weeks. Pigs in the treatment group exhibited clinical signs consistent with PRRSV infection and M. hyopneumoniae pneumonia. Diagnostic procedures confirmed that treatment pigs were inoculated with PRRSV and M. hyopneumoniae and that sham and control pigs remained free of both pathogens. Average daily gain and feed conversion did not differ among the 3 groups. The IGF-I levels differed (P < 0.05) between control and treatment pigs, even after feed intake returned to similar levels among groups. At day 7, IGF-I concentrations were greater in sham pigs compared with treatment pigs, despite similar feed intake. Sham inoculation and decreased feed intake in sham pigs did not alter serum IGF-I concentrations. Evidently, IGF-I status of pigs affected with disease is influenced by nutritional and nonnutritional factors during the disease process.

  1. Increased serum levels of interleukin 6 are associated with severe intraventricular haemorrhage in extremely premature infants

    PubMed Central

    Heep, A; Behrendt, D; Nitsch, P; Fimmers, R; Bartmann, P; Dembinski, J

    2003-01-01

    Background: Intraventricular haemorrhage (IVH) and periventricular leucomalacia (PVL) in premature infants presumably have many causes. It has been proposed that inflammatory processes in the fetomaternal unit play an important role in the pathogenesis of these lesions. Objective: To study the correlation of postpartum serum interleukin 6 (IL6) concentration as a marker of inflammation and neonatal cerebral morbidity in preterm infants < 28 weeks of gestational age. Methods: A total of 88 infants were grouped according to maximum serum IL6 levels within 12 hours post partum: group A (n = 50), ⩽ 100 pg/ml; group B (n = 38), > 100 pg/ml. Ultrasound studies and clinical assessment were performed routinely. Results: IVH was noted significantly more often in group B (24/38; 63%) than in group A (19/50; 38%) (p = 0.02). In a multiple logistic regression model, raised serum IL6 independently predicted development of severe IVH (odds ratio 8.4; 95% confidence interval 2.85 to 24.9; p = 0.0001). Conclusions: Raised serum IL6 may serve as a marker for severe IVH in infants < 28 weeks of gestational age. Although cerebral morbidity in premature infants is determined by different variables, the identification of systemic inflammation can help to define the need for anti-inflammatory strategies to prevent cerebral morbidity. PMID:14602698

  2. Serum fetuin B level increased in subjects of nonalcoholic fatty liver disease: a case-control study.

    PubMed

    Zhu, Jinzhou; Wan, Xingyong; Wang, Yuming; Zhu, Kefu; Li, Chunxiao; Yu, Chaohui; Li, Youming

    2017-04-01

    Fetuin is an endogenous inhibitor of the insulin receptor tyrosine kinase. Recent studies supported the possible role of fetuin B in metabolic diseases. This study is to evaluate the role of serum fetuin B in nonalcoholic fatty liver disease (NAFLD). A hospital-based case-control study of 184 subjects was conducted. Serum level of fetuin B was measured by enzyme-linked immunosorbent assay. The serum level of fetuin B in the control (91.0 ± 36.9 μg/ml) was lower than it in NAFLD (108.7 ± 38.5 μg/ml, P < 0.001). The percentage of NAFLD increased (42.9%, 58.7% and 60.2%; P < 0.001; linear-by-linear association: P < 0.001), as fetuin B concentration elevated in its tertiles, after adjustment of body mass index (BMI). Furthermore, compared with the 1st tertile, the 3rd tertile of fetuin B indicated an association with the presence of NAFLD (adjusted odds ratio = 2.087, 95% confidence interval [1.016 - 3.937], P = 0.023), after controlling age, sex, BMI, diabetes, hypertension and hypertriglyceridemia. Lastly, fetuin B correlated with diastolic blood pressure, serum alanine transaminase and triglycerides, among the controls. It suggested a potential association between serum fetuin B and the presence of NAFLD.

  3. Meningococcal surface fibril (Msf) binds to activated vitronectin and inhibits the terminal complement pathway to increase serum resistance.

    PubMed

    Griffiths, Natalie J; Hill, Darryl J; Borodina, Elena; Sessions, Richard B; Devos, Nathalie I; Feron, Christiane M; Poolman, Jan T; Virji, Mumtaz

    2011-12-01

    Complement evasion is an important survival strategy of Neisseria meningitidis (Nm) during colonization and infection. Previously, we have shown that Nm Opc binds to serum vitronectin to inhibit complement-mediated killing. In this study, we demonstrate meningococcal interactions with vitronectin via a novel adhesin, Msf (meningococcal surface fibril, previously NhhA or Hsf). As with Opc, Msf binds preferentially to activated vitronectin (aVn), engaging at its N-terminal region but the C-terminal heparin binding domain may also participate. However, unlike Opc, the latter binding is not heparin-mediated. By binding to aVn, Msf or Opc can impart serum resistance, which is further increased in coexpressers, a phenomenon dependent on serum aVn concentrations. The survival fitness of aVn-binding derivatives was evident from mixed population studies, in which msf/opc mutants were preferentially depleted. In addition, using vitronectin peptides to block Msf-aVn interactions, aVn-induced inhibition of lytic C5b-9 formation and of serum killing could be reversed. As Msf-encoding gene is ubiquitous in the meningococcal strains examined and is expressed in vivo, serum resistance via Msf may be of significance to meningococcal pathogenesis. The data imply that vitronectin binding may be an important strategy for the in vivo survival of Nm for which the bacterium has evolved redundant mechanisms.

  4. Feeding a Modified Fish Diet to Bottlenose Dolphins Leads to an Increase in Serum Adiponectin and Sphingolipids

    PubMed Central

    Sobolesky, Philip M.; Harrell, Tyler S.; Parry, Celeste; Venn-Watson, Stephanie; Janech, Michael G.

    2016-01-01

    Feeding a modified fish diet has been suggested to improve insulin sensitivity in bottlenose dolphins; however, insulin sensitivity was not directly measured. Since demonstrating an improvement in insulin sensitivity is technically difficult in dolphins, we postulated that directional changes in the hormone axis: fibroblast growth factor 21 (FGF21)/Adiponectin/Ceramide (Cer), could provide further support to this hypothesis. We measured 2-h post-prandial serum FGF21, total adiponectin, percent unmodified adiponectin, ceramide, and sphingosine levels from dolphins fed a diet rich in heptadecanoic acid (C17:0) over 24 weeks. Serum FGF21 was quantified by ELISA with an observed range of 129–1599 pg/ml, but did not significantly change over the 24-week study period. Total adiponectin levels (mean ± SD) significantly increased from 776 ± 400 pmol/ml at week 0 to 1196 ± 467 pmol/ml at week 24. The percent unmodified adiponectin levels (mean ± SD) decreased from 23.8 ± 6.0% at week 0 to 15.2 ± 5.2% at week 24. Interestingly, although FGF21 levels did not change, there was a good correlation between FGF21 and total adiponectin (ρ = 0.788, P < 0.001). We quantified the abundances of serum ceramides and sphingosines (SPH) because adiponectin has a defined role in sphingolipid metabolism through adiponectin receptor-mediated activation of ceramidases. The most abundant ceramide in dolphin sera was Cer 24:1 comprising 49% of the ceramides measured. Significant reductions were observed in the unsaturated Cer 18:1, Cer 20:1, and Cer 24:1, whereas significant increases were observed in saturated Cer 22:0, Cer 24:0, and Cer 26:0. However, total serum ceramides did not change. Significant elevations were detected for total sphingosine, dihydrosphingosine, sphingosine-1-phosphate, and dihydrosphingosine-1-phosphate. Proteomic analysis of the serum proteins revealed few changes in serum proteins over the study period. In conclusion

  5. Studies on the increase in serum concentrations of urea cycle amino acids among subjects exposed to cadmium

    SciTech Connect

    Nishino, H.; Shiroishi, K. ); Kagamimori, S.; Naruse, Y. ); Watanabe, M. )

    1988-05-01

    Itai-itai disease (I disease) is a combination of renal tubular damage and osteomalacia accompanied by osteoporosis among subjects exposed to cadmium (Cd). When the renal tubular damage progresses, the excretion of amino acids, especially, threonine, hydroxyproline, proline, citrulline, ornithine, arginine, etc. increase in urine. It was reported that the increase in urinary excretion of citrulline, arginine and ornithine may be associated with an inhibition of urea synthesis in the urea cycle. The authors have found that serum citrulline, arginine and ornithine also increased in I disease patients. In order to investigate the mechanism of the increase in these serum amino acids, comparative studies were performed using both healthy subjects and patients with renal disease as control groups.

  6. Another smoking hazard: raised serum IgE concentration and increased risk of occupational allergy.

    PubMed Central

    Zetterström, O; Osterman, K; Machado, L; Johansson, S G

    1981-01-01

    Individual smoking histories of a general population sample and of two groups of workers exposed to occupational allergens were related to serum IgE concentrations and results of radioallergosorbent and prick tests in the workers. The geometric mean IgE concentration was higher in smokers than in non-smokers. The distribution of serum IgE values in the two groups showed an apparent difference, with a bimodal appearance in the smokers. Evidence of sensitisation against occupational allergens was more common in workers who smoked. The adjuvant effect of smoking on IgE antibody production might be due to damage to airways mucosa and supports the mucosal theory of atopy. PMID:6797514

  7. Weekly iron supplementation does not block increases in serum zinc due to weekly zinc supplementation in Bangladeshi infants.

    PubMed

    Baqui, Abdullah H; Walker, Christa L Fischer; Zaman, K; El Arifeen, Shams; Chowdhury, Hafizur Rahman; Wahed, Mohammed A; Black, Robert E; Caulfield, Laura E

    2005-09-01

    Because infants and young children in many developing countries are deficient in both iron and zinc, and zinc can affect iron metabolism, evaluation of optimum strategies to simultaneously supplement iron and zinc is an important public health priority. This study evaluated the efficacy of weekly supplementation of iron or zinc or both on iron, zinc, and copper status in Bangladeshi infants. In a double-blind, randomized, controlled community trial, 6-mo-old infants were assigned to receive weekly supplements of 1 mg riboflavin (control, n = 82) or 1 mg riboflavin + 20 mg iron (n = 83), 20 mg zinc (n = 83), or both (n = 85) for 6 mo. Hemoglobin, serum ferritin, transferrin receptor, zinc, and copper concentrations were measured at baseline and at the end of intervention. Serum Zn increased in both groups receiving zinc; the increase was greatest among children with low baseline serum zinc concentration. Iron status indicators did not differ among the groups before or after 6 mo of supplementation. Supplementation with either zinc or iron decreased serum copper after 6 mo. Joint supplementation did not alter the individual effects of iron or zinc supplementation in these Bangladeshi children. However, the dosing regimen may not have been adequate to achieve the desired biochemical effects.

  8. Increased vascular permeability, angiogenesis and wound healing induced by the serum of natural latex of the rubber tree Hevea brasiliensis.

    PubMed

    Mendonça, Ricardo José; Maurício, Vanessa Beatriz; Teixeira, Larissa de Bortolli; Lachat, João José; Coutinho-Netto, Joaquim

    2010-05-01

    Increases in vascular permeability and angiogenesis are crucial events to wound repair, tumoral growth and revascularization of tissues submitted to ischemia. An increased vascular permeability allows a variety of cytokines and growth factors to reach the damaged tissue. Nevertheless, the angiogenesis supply tissues with a wide variety of nutrients and is also important to metabolites clearance. It has been suggested that the natural latex from Hevea brasiliensis showed wound healing properties and angiogenic activity. Thus, the purpose of this work was to characterize its angiogenic activity and its effects on vascular permeability and wound healing. The serum fraction of the latex was separated from the rubber with reduction of the pH. The activity of the dialyzed serum fraction on the vascular permeability injected in subcutaneous tissue was assayed according Mile's method. The angiogenic activity was determined using a chick embryo chorioallantoic membrane assay and its effects on the wound-healing process was determined by the rabbit ear dermal ulcer model. The serum fraction showed evident angiogenic effect and it was effective in enhancing vascular permeability. In dermal ulcers, this material significantly accelerated wound healing. Moreover, the serum fraction boiled and treated with proteases lost these activities. These results are in accordance with the enhancement of wound healing observed in clinical trials carried out with a biomembrane prepared with the same natural latex.

  9. Relative hypoadiponectinemia, insulin resistance, and increased visceral fat in euthyroid prepubertal girls with low-normal serum free thyroxine.

    PubMed

    Prats-Puig, Anna; Sitjar, Carme; Ribot, Rosa; Calvo, Mar; Clausell-Pomés, Núria; Soler-Roca, Maria; Soriano-Rodríguez, Pilar; Osiniri, Inés; Ros-Miquel, Montserrat; Bassols, Judit; de Zegher, Francis; Ibáñez, Lourdes; López-Bermejo, Abel

    2012-07-01

    A lower activity of the thyroid axis within the clinical reference range is related to a dysmetabolic phenotype in adult populations. We posited that such an association is already present as early as in prepubertal childhood. Serum thyroid stimulating hormone (TSH) and free T4, body fat (bioelectric impedance), insulin resistance (homeostasis model assessment of insulin resistance (HOMA(IR))), total and high molecular weight (HMW)-adiponectin and serum lipids were assessed in 234 euthyroid prepubertal children (113 boys and 121 girls) attending primary care clinics. Visceral fat (abdominal ultrasound) was measured in a subset of these subjects (n = 147; 74 boys and 73 girls). Explants of visceral adipose tissue from an additional six prepubertal children (three boys and three girls) were used to study the regulation of total and HMW-adiponectin by thyroid hormone. Serum free T4 was in girls independently associated with HMW-adiponectin, HOMA(IR) and visceral fat, so that circulating HMW-adiponectin decreased by 30% (β = 0.305 P < 0.005, R(2) = 0.13) and HOMA(IR) and visceral fat increased, respectively, by 90% (β = -0.255 P < 0.01, R(2) = 0.05) and 30% (β = -0.369, P < 0.005, R(2) = 0.12) from the highest to the lowest tertile of serum free T4. Nonsignificant differences in these parameters were found in boys. Treatment of visceral fat explants with thyroid hormone increased total and HMW-adiponectin by 70% and 53%, respectively, above control values (P < 0.01). In conclusion, a dysmetabolic phenotype, consisting of relative hypoadiponectinemia, insulin resistance and increased visceral fat, is associated with low-normal serum free thyroxine in euthyroid prepubertal girls. These associations may be partly explained by a positive regulation of HMW-adiponectin secretion by thyroid hormone.

  10. Increased Serum Hyaluronic Acid and Heparan Sulfate in Dengue Fever: Association with Plasma Leakage and Disease Severity

    PubMed Central

    Tang, Tommy Hing-Cheung; Alonso, Sylvie; Ng, Lisa Fong-Poh; Thein, Tun-Linn; Pang, Vincent Jun-Xiong; Leo, Yee-Sin; Lye, David Chien-Boon; Yeo, Tsin-Wen

    2017-01-01

    Plasma leakage is a major pathogenic mechanism of severe dengue, but the etiology remains unclear. The association between endothelial glycocalyx integrity and vascular permeability in older adults with dengue has not been evaluated. A prospective cohort study of adults with undifferentiated fever screened for dengue by RT-PCR or NS1 antigen testing was performed. Patients were assessed daily while symptomatic and at convalescence. Serum hyaluronic acid (HA), heparan sulfate (HS) and selected cytokines (TNF-α, IL-6, IL-10) were measured on enrollment and convalescence. Patients were diagnosed as dengue fever (DF, n = 30), dengue hemorrhagic fever (DHF, n = 20) and non-dengue (ND) febrile illness (n = 11). Acute HA and HS levels were significantly higher in all dengue patients compared to ND (p = 0.0033 and p = 0.0441 respectively), but not different between DF and DHF (p = 0.3426 and p = 0.9180 respectively). Enrolment HA inversely correlated with serum albumin, protein and platelets in all dengue and DHF (p < 0.05). HA and HS in all dengue patients decreased significantly at convalescence. Serum IL-10 was significantly associated with HA in all dengue patients (p = 0.002). Serum HA and HS levels were increased in adult dengue and HA was associated with markers of disease severity. Endothelial glycocalyx damage may have a role in vascular leakage in dengue. PMID:28393899

  11. Increased serum sTRAIL levels were correlated with survival in bevacizumab-treated metastatic colon cancer

    PubMed Central

    2012-01-01

    Background Colorectal cancer is the third most common cancer and the third leading cause of cancer-related death. Bevacizumab is a humanized monoclonal antibody developed against vascular endothelial growth factor (VEGF) for the treatment of metastatic cancer. The parameters of RECIST (Response Evaluation Criteria for Solid Tumors) are not adequate to detect important treatment effects and response. Our goal was to evaluate the possibility of using sTRAIL (serum-soluble TNF-related apoptosis-inducing ligand) and VEGF as markers of treatment efficacy and prognosis in patients with metastatic colon cancer. Methods sTRAIL and VEGF levels were measured by ELISA in the sera of 16 bevacizumab-treated metastatic colon cancer patients and 10 presumably healthy age-matched controls. The measurements were taken before and after treatment for comparison purposes. Results Elevated levels of sTRAIL were found in seven out of 16 patients after bevacizumab treatment. Although these patients had a median survival time of 20.6 months, the remaining bevacizumab-treated patients who did not show an increase in sTRAIL had a median survival time of 9.4 months. As expected, serum VEGF levels were decreased in all patients who received bevacizumab therapy and showed no correlation between serum VEGF levels and patient survival (data not shown). Conclusions Serum sTRAIL levels might be a useful predictor of prognosis in metastatic colon cancer, in the early evaluation stages following bevacizumab treatment. PMID:22313795

  12. Nutritional Supplementation Inhibits the Increase in Serum Malondialdehyde in Patients with Wet Age-Related Macular Degeneration

    PubMed Central

    Fukukita, Hiroshi; Tsunekawa, Taichi; Kataoka, Keiko; Hwang, Shiang-Jyi; Nagasaka, Yosuke; Ito, Yasuki; Terasaki, Hiroko

    2017-01-01

    Purpose. To compare serum levels of malondialdehyde (MDA) in patients with wet age-related macular degeneration (wAMD), patients with dry AMD (dAMD), and patients without AMD and to evaluate the efficacy of nutritional supplementation for treating elevated serum MDA in patients with wAMD. Methods. MDA levels were measured in sera from 20 patients with wAMD, 20 with dAMD, and 24 without AMD. Patients with wAMD were randomized to receive or not receive nutritional supplementation (10 patients in each group), and MDA levels were measured after 3 months of treatment. Results. MDA levels in patients with wAMD were significantly greater compared with patients without AMD. In eyes with wAMD, there was a significant correlation between MDA levels and choroidal neovascularization lesion area. Serum MDA levels decreased in most patients that received supplementation and significantly increased in those who did not. Conclusion. Baseline serum MDA levels were elevated in patients with wAMD, and MDA levels were directly correlated with choroidal neovascularization lesion area. In addition, nutritional supplementation appeared to exert a protective effect against oxidative stress in patients with wAMD. PMID:28243361

  13. Nutritional Supplementation Inhibits the Increase in Serum Malondialdehyde in Patients with Wet Age-Related Macular Degeneration.

    PubMed

    Matsuura, Toshiyuki; Takayama, Kei; Kaneko, Hiroki; Ye, Fuxiang; Fukukita, Hiroshi; Tsunekawa, Taichi; Kataoka, Keiko; Hwang, Shiang-Jyi; Nagasaka, Yosuke; Ito, Yasuki; Terasaki, Hiroko

    2017-01-01

    Purpose. To compare serum levels of malondialdehyde (MDA) in patients with wet age-related macular degeneration (wAMD), patients with dry AMD (dAMD), and patients without AMD and to evaluate the efficacy of nutritional supplementation for treating elevated serum MDA in patients with wAMD. Methods. MDA levels were measured in sera from 20 patients with wAMD, 20 with dAMD, and 24 without AMD. Patients with wAMD were randomized to receive or not receive nutritional supplementation (10 patients in each group), and MDA levels were measured after 3 months of treatment. Results. MDA levels in patients with wAMD were significantly greater compared with patients without AMD. In eyes with wAMD, there was a significant correlation between MDA levels and choroidal neovascularization lesion area. Serum MDA levels decreased in most patients that received supplementation and significantly increased in those who did not. Conclusion. Baseline serum MDA levels were elevated in patients with wAMD, and MDA levels were directly correlated with choroidal neovascularization lesion area. In addition, nutritional supplementation appeared to exert a protective effect against oxidative stress in patients with wAMD.

  14. Serum enzyme status of Chios ewes fed increasing amounts of copper from copper sulfate.

    PubMed

    Bampidis, V A; Christodoulou, V; Chatzipanagiotou, A; Sossidou, E; Salangoudis, A

    2010-06-01

    This study aimed to evaluate effects of orally administered copper (Cu) to Chios sheep breed on serum levels of aspartate aminotransferase (AST), l-alanine aminotransferase (ALT), lactate deydrogenase (LDH) and alkaline phosphatase (ALP), in order to establish a practical and effective method in diagnosing the prehemolytic stage of chronic Cu poisoning. Eighteen ewes were allocated to three treatments of six ewes and fed a diet that contained 16.4 mg/day of Cu. Ewes in treatment Cu-0 received no additional Cu (control), while those in treatments Cu-60 and Cu-95 received 60 and 95 mg additional Cu/day, respectively, as an oral solution of copper sulfate. Therefore the ewes in treatment Cu-0, Cu-60 and Cu-95 consumed 16.4, 76.4 and 111.4 mg Cu/day, respectively. Serum enzyme levels were similar among treatments and all ewes remained clinically healthy until the end of the experiment. Results suggest that Chios ewes exhibit tolerance to Cu supplementation for up to 6 weeks.

  15. Blackcurrant seed press residue increases tocopherol concentrations in serum and stool whilst biomarkers in stool and urine indicate increased oxidative stress in human subjects.

    PubMed

    Helbig, Dorit; Wagner, Andreas; Glei, Michael; Basu, Samar; Schubert, Rainer; Jahreis, Gerhard

    2009-08-01

    Berry seeds are a tocopherol-rich by-product of fruit processing without specific commercial value. In a human intervention study, the physiological impact of blackcurrant seed press residue (PR) was tested. Thirty-six women (aged 24 +/- 3 years; twenty non-smokers, sixteen smokers) consumed 250 g bread/d containing 8% PR for a period of 4 weeks (period 3). Comparatively, a control bread without PR (250 g/d) was tested (period 2) and baseline data were obtained (period 1). Blood, stool and 24 h urine were collected during a 5 d standardised diet within each period. Tocopherol and Fe intakes were calculated from food intake. In serum, tocopherol concentration and Fe parameters were determined. In urine, oxidative stress markers 8-oxo-2'-deoxyguanosine, 8-iso-PGF2alpha and inflammatory response marker 15-keto-dihydro-PGF2alpha were analysed. Stool tocopherol concentration, genotoxicity of faecal water (comet assay) and antioxidant capacity of stool (aromatic hydroxylation of salicylic acid) were determined. Fe and total tocopherol intake, total tocopherol concentrations in serum and stool, and genotoxicity of faecal water increased with PR bread consumption (P < 0.05). The antioxidant capacity of stool decreased between baseline and intervention, expressed by increased formation of 2,3- and 2,5-dihydroxybenzoic acid in vitro (P < 0.05). In smokers, 8-oxo-2'-deoxyguanosine increased with PR consumption (P < 0.05). Prostane concentrations were unaffected by PR bread consumption. In summary, the intake of bread containing blackcurrant PR for 4 weeks increased serum and stool total tocopherol concentrations. However, various biomarkers indicated increased oxidative stress, suggesting that consumption of ground berry seed may not be of advantage.

  16. Increased serum levels of lipocalin-1 and -2 in patients with stable chronic obstructive pulmonary disease.

    PubMed

    Wang, Xiao-ru; Li, Yong-pu; Gao, Shui; Xia, Wei; Gao, Kun; Kong, Qing-hua; Qi, Hui; Wu, Ling; Zhang, Jing; Qu, Jie-ming; Bai, Chun-xue

    2014-01-01

    Despite a number of studies on biomarkers in chronic obstructive pulmonary disease (COPD), only a few disease-related markers have been identified, yet we still have no satisfactory markers specific to innate immune system and neutrophil activation, which is essential in airway inflammation in COPD. Recent biological studies indicated that lipocalins (LCNs) might be involved in airway inflammation and innate immunity; however, results from available studies on the association of LCNs with COPD are not consistent. We carried out a multicenter prospective observational cohort study to investigate the differences in serum levels of LCN1 and LCN2 between subjects with COPD (n=58) and healthy controls (n=29). Several validated inflammatory markers, including C-reactive protein, tumor necrosis factor-α, interleukin-6, and interleukin-8, were measured. The correlation of LCN1 and LCN2 with clinical features such as smoking habits, lung function, symptoms, and disease category was also analyzed. When comparing with healthy controls, serum levels of LCN1 (66.35±20.26 ng/mL versus 41.16±24.19 ng/mL, P<0.001) and LCN2 (11.29±3.92 ng/mL versus 6.09±5.13 ng/mL, P<0.001) were both elevated in subjects with COPD after adjusting for age, sex, smoking habits, and inflammatory biomarkers. Smoking history and tobacco exposure, as quantified by pack-year, had no impact on systemic expressions of LCN1 and LCN2 in our study. Blood levels of LCN1 and LCN2, respectively, were negatively correlated to COPD Assessment Test and Modified Medical British Research Council score (P<0.001). Disease category by Global Initiative for Chronic Obstructive Lung Disease grade 1-4 or group A-D was not associated with levels of LCNs. Patient-reported exacerbations and body mass index were also tested, but no relationship with LCNs was found. In summary, serum concentrations of LCN1 and LCN2 were both elevated in patients with COPD, with their levels correlating to COPD Assessment Test and Modified

  17. Serum DHEA-S increases in dogs naturally infected with Ehrlichia canis.

    PubMed

    Rondelli, M C H; Munhoz, T D; Catandi, P B; Freschi, C R; Palacios Junior, R J G; Machado, R Z; Tinucci-Costa, M

    2015-06-01

    Adrenocortical disturbances are expected in canine ehrlichiosis due to the immunological challenges caused by infection and consequent inflammation. Thus, this study aimed to evaluate the occurrence of adrenocortical hormonal alterations in dogs naturally infected with Ehrlichia canis (n = 21) as positively confirmed by the presence of anti-E. canis antibodies (Dot-ELISA) and nested PCR (nPCR). Serum dehydroepiandrosterone sulfate (DHEA-S) concentrations were assessed via ELISA before and one hour after ACTH stimulation. Another 10 healthy dogs were subjected to the same stimulation protocol and used as controls. The results revealed that baseline and post-ACTH DHEA-S concentrations were significantly greater in sick dogs, regardless of gender, and this finding illustrates the stress induced by naturally acquired ehrlichiosis in dogs.

  18. Ulcerative Colitis and Crohn’s Disease Are Associated with Decreased Serum Selenium Concentrations and Increased Cardiovascular Risk

    PubMed Central

    Castro Aguilar-Tablada, Teresa; Navarro-Alarcón, Miguel; Quesada Granados, Javier; Samaniego Sánchez, Cristina; Rufián-Henares, José Ángel; Nogueras-Lopez, Flor

    2016-01-01

    The incidence of inflammatory bowel disease (IBD) and associated oxidative stress is increasing. The antioxidant mineral selenium (Se) was measured in serum samples from 106 IBD patients (53 with ulcerative colitis (UC) and 53 with Crohn’s disease (CD)) and from 30 healthy controls. Serum Se concentrations were significantly lower in UC and CD patients than in healthy controls (p < 0.001) and significantly lower in CD patients than in UC patients (p = 0.006). Se concentrations in patients were significantly influenced by sex, body mass index (BMI), the inflammatory biomarker α-1-antitrypsin, surgery, medical treatment, the severity, extent, and form of the disease and the length of time since onset (p < 0.05). Se concentrations in IBD patients were positively and linearly correlated with nutritional (protein, albumin, prealbumin, cholinesterase and total cholesterol) and iron status-related (hemoglobin, Fe and hematocrit) parameters (p < 0.05). A greater impairment of serum Se and cardiovascular status was observed in CD than in UC patients. An adequate nutritional Se status is important in IBD patients to minimize the cardiovascular risk associated with increased inflammation biomarkers, especially in undernourished CD patients, and is also related to an improved nutritional and body iron status. PMID:27916926

  19. Serum hormone profiles, pregnancy rates, and offspring performance of Rambouillet ewes treated with recombinant bovine somatotropin before breeding.

    PubMed

    Camacho, L E; Benavidez, J M; Hallford, D M

    2012-08-01

    An experiment was conducted to examine effects of bovine ST (bST) on serum hormone concentrations, pregnancy rates, and offspring performance. Before initiation of a fall breeding period, 75 Rambouillet ewes (68.8 ± 1.5 kg) received an intravaginal insert containing 0.3 g of progesterone (P4) to synchronize onset of estrus. After 12 d, inserts were removed (d 0), and ewes (stratified by BW and age) received either 0 (control, n = 37) or 250 (n = 38) mg of recombinant bST (Posilac, Monsanto, St. Louis, MO, subcutaneously). Ewes were joined with fertile rams 24 h after insert removal. Blood samples were collected from 12 ewes in each treatment group daily from d 0 to 20 after insert removal. Serum IGF-I concentrations were 315 and 437 (± 58) ng/mL in control and bST-treated ewes 2 d after receiving bST (P = 0.02) and remained increased (P < 0.03) in bST-treated ewes throughout the 13-d period (P < 0.05). Serum prolactin (P > 0.10) and estradiol (P = 0.65) were similar between treatments. Serum triiodothyronine (T3) and thyroxine (T4) concentrations were similar (P > 0.20) between treatments from d 0 through 8. Controls had greater (P < 0.04) serum T3 and T4 concentrations than treated ewes did until d 18. Serum P4 was similar (P > 0.10) in control and bST-treated ewes from d 0 through 3 but was increased (P < 0.05) from d 4 to 8 in control ewes. Serum P4 was again similar (P > 0.10) between treatments from d 9 to 20. Serum insulin concentrations were 0.44 and 1.74 (± 0.19) ng/mL in control and bST-treated ewes, respectively, 1 d after receiving bST (P < 0.001) and remained increased (P < 0.03) in bST-treated ewes through d 9 (P < 0.03). Serum glucose was increased (P = 0.003) from d 0 to 10 in bST-treated ewes compared with controls. Thirty-three of 37 (89%) control ewes were pregnant, whereas 27 of 38 (71%) bST-treated ewes were pregnant (P = 0.05). As a percentage of ewes lambing, 61% and 39% of control ewes produced single and twin lambs, respectively, compared

  20. DAAs Rapidly Reduce Inflammation but Increase Serum VEGF Level: A Rationale for Tumor Risk during Anti-HCV Treatment

    PubMed Central

    Villani, Rosanna; Facciorusso, Antonio; Bellanti, Francesco; Tamborra, Rosanna; Piscazzi, Annamaria; Landriscina, Matteo; Vendemiale, Gianluigi; Serviddio, Gaetano

    2016-01-01

    Background Novel direct-acting antivirals (DAAs) have completely changed the panorama of hepatitis C due to their high efficacy and optimal safety profile. Unfortunately, an unexpectedly high rate of early recurrence of hepatocellular carcinoma has been reported within weeks of starting treatment, but the mechanism is not known. Methods We monitored the serum level of vascular endothelial growth factor (VEGF) and changes in the pattern of circulating interleukins in 103 chronic hepatitis C patients during antiviral treatment with DAA-regimens. VEGF, epidermal growth factor (EGF), and several interleukins were assessed at baseline, during treatment, and after treatment. The biological effect of DAA-treated patient serum on human umbilical vein endothelial cell (HUVEC) proliferation was also confirmed. Results After 4 weeks of therapy, VEGF increased approximately 4-fold compared to baseline, remained elevated up to the end of treatment, and returned to the pre-treatment level after the end of therapy. In contrast, interleukin-10 and tumor necrosis factor-alpha significantly decreased during therapy, which was coincident with HCV clearance. The levels of both remained low after treatment. The addition of serum from patients collected during therapy induced HUVEC proliferation; however, this disappeared after the end of therapy. Conclusions DAA administration induces an early increase in serum VEGF and a change in the inflammatory pattern, coinciding with HCV clearance. This may alter the balance between inflammatory and anti-inflammatory processes and modify the antitumor surveillance of the host. Fortunately, such modifications return reverse to normal after the end of treatment. PMID:27997563

  1. Increased serum concentrations of circulating glycocalyx components in HELLP syndrome compared to healthy pregnancy: an observational study.

    PubMed

    Hofmann-Kiefer, Klaus F; Knabl, J; Martinoff, N; Schiessl, B; Conzen, P; Rehm, M; Becker, B F; Chappell, D

    2013-03-01

    Severe inflammation has been shown to induce a shedding of the endothelial glycocalyx (EGX). Inflammatory cytokines, such as tumor necrosis factor α (TNF-α), impede the thickness of the EGX. While a controlled inflammatory reaction occurs already in normal pregnancy, women with hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome had an exaggerated inflammatory response. This study investigates the shedding of the glycocalyx during normal pregnancy and in women with HELLP syndrome. Glycocalyx components (syndecan 1, heparan sulfate, and hyaluronic acid) were measured in serum of healthy women throughout pregnancy (4 time points, n = 26), in women with HELLP syndrome (n = 17) before delivery and in nonpregnant volunteers (n = 10). Serum concentrations of TNF-α and soluble TNF-α receptors (sTNF-Rs) were assessed once in all 3 groups. Syndecan 1 serum concentrations constantly rose throughout normal pregnancy. Immediately before delivery, a 159-fold increase was measured compared to nonpregnant controls (P < .01). Even higher amounts were observed in patients with HELLP prior to delivery (median 12 252 ng/mL) compared to healthy women matched by gestational age (median 5943 ng/mL; P < .01). Relevantly, increased serum levels of heparan sulfate, hyaluronic acid, and sTNF-Rs were only detected in patients with HELLP (P < .01). These findings suggest that considerable amounts of syndecan 1 are released into maternal blood during uncomplicated pregnancy. The HELLP syndrome is associated with an even more pronounced shedding of glycocalyx components. The maternal vasculature as well as the placenta has to be discussed as a possible origin of circulating glycocalyx components.

  2. Increased risk of non-Hodgkin lymphoma and serum organochlorine concentrations among neighbors of a municipal solid waste incinerator.

    PubMed

    Viel, Jean-François; Floret, Nathalie; Deconinck, Eric; Focant, Jean-François; De Pauw, Edwin; Cahn, Jean-Yves

    2011-02-01

    Organochlorine chemicals may contribute to an increased risk of non-Hodgkin lymphoma (NHL) within non-occupationally exposed populations. Among these chemicals, dioxins and furans were mainly released by municipal solid waste incinerators (MSWIs) until a recent past in France, a source of exposure that is of public concern. We investigated organochlorines and the risk of NHL among neighbors of a French MSWI with high levels of dioxin emissions (Besançon, France), using serum concentrations to assess exposure. The study area consisted of three electoral wards, containing or surrounding the MSWI. Pesticides, dioxins, furans, and polychlorinated biphenyls (PCBs) were measured in the serum of 34 newly diagnosed NHL cases (2003-2005) and 34 controls. Risks of NHL associated with each lipid-corrected serum concentration were estimated using exact logistic regression. The pesticides β-hexachlorocyclohexane (odds ratio [OR]=1.05, 95% confidence interval [CI]=1.00-1.12, per 10 ng/g lipid) and p,p' dichloro-diphenyl-trichloroethane (DDT) (OR=1.20, 95% CI=1.01-1.45, per 10 ng/g lipid) were associated with NHL risk. Evidence indicated an increased NHL risk associated with cumulative WHO(1998)-toxic equivalency factor (TEQ) concentrations (dioxins, OR=1.12, 95% CI=1.03-1.26; furans, OR=1.16, 95% CI=1.03-1.35; dioxin-like PCBs, OR=1.04, 95% CI=1.00-1.07; and total TEQ, OR=1.04, 95% CI=1.01-1.05), as well as with non dioxin-like PCBs (OR=1.02, 95% CI=1.01-1.05, per 10 ng/g lipid). Most congener-specific associations were statistically significant. This study provides strong and consistent support for an association between serum cumulative WHO(1998)-TEQ concentrations, at levels experienced by people residing in the vicinity of a polluting MSWI, and risk of NHL.

  3. Increased serum levels of C21 steroids in female patients with multiple sclerosis.

    PubMed

    Kanceva, R; Stárka, L; Kancheva, L; Hill, M; Veliková, M; Havrdová, E

    2015-01-01

    Multiple sclerosis (MS) is one of the most common neurological diseases. This neurodegenerative autoimmune disease manifests as inflammatory and demyelinating impairment of the central nervous system (CNS). Although some studies demonstrated associations between altered steroidogenesis and pathophysiology of MS as well as the importance of steroids in the pathophysiology of MS, the knowledge concerning the steroid metabolome in female patients is limited. Hence, 51 steroids and steroid polar conjugates were measured in the serum of 12 women with MS, untreated with steroids and 6 age-corresponding female controls with the use of gas chromatography - mass spectrometry (GC-MS). The data were processed using age adjusted ANCOVA, receiver operating characteristics (ROC) analysis and orthogonal projections to latent structures (OPLS). Our data show higher levels of circulating C21 steroids including steroid modulators of ionotropic type A gamma-aminobutyric acid (GABA A) receptors and glutamate receptors. Furthermore, the levels of GABAergic androsterone and 5-androsten-3beta,7alpha,17beta-triol were also higher in the female MS patients. In conclusion, the data demonstrate higher levels of circulating C21 steroids and their polar conjugates and some bioactive C19 steroids in women with MS, which may influence neuronal activity and affect the balance between neuroprotection and excitotoxicity.

  4. Increased Resistin Serum Concentrations in Patients with Type 1 Diabetes Mellitus

    PubMed Central

    Geyikli, İclal; Keskin, Mehmet; Kör, Yılmaz; Akan, Müslüm

    2013-01-01

    Objective: Adiponectin, leptin, and resistin are adipokines which play a significant role in the regulation of lipid and carbohydrate metabolism in patients with type 2 diabetes, while little is known about their role in type 1 diabetes mellitus (T1DM). The aim of this study was to measure serum adiponectin, leptin, and resistin levels and to investigate their relationships with some parameters in patients with T1DM and healthy controls. Methods: Fifty children and adolescents with T1DM (21 boys and 29 girls) and 33 healthy control subjects (18 boys and 15 girls) participated in the study. All subjects were patients followed in the Pediatric Endocrinology and Metabolism Unit of Gaziantep University Faculty of Medicine. None of the subjects had hypertension, obesity, hyperlipidemia, anemia, or infection. Adiponectin, leptin, and resistin levels were analyzed with ELISA. Results: There were no statistically significant differences related with age, sex, pubertal status, or body mass index distribution between the diabetic and control groups. Resistin levels were significantly higher in the diabetic group compared to controls (5.26±3.15 ng/mL vs. 3.50±1.26 ng/mL; p<0.01). Conclusion: Of the three investigated adipokines, only resistin was associated with T1DM. Resistin may play a role in the process of inflammation and also in the pathophysiology of T1DM. Conflict of interest:None declared. PMID:24072088

  5. Enterostatin deficiency increases serum cholesterol but does not influence growth and food intake in mice.

    PubMed

    Miller, Rita; D'Agostino, Dymphna; Erlanson-Albertsson, Charlotte; Lowe, Mark E

    2009-10-01

    A pentapeptide released from procolipase, enterostatin, selectively attenuates dietary fat intake when administered peripherally or centrally. Enterostatin may act through the afferent vagus nerve and in the hypothalamus and amygdala, primarily in the central nucleus of the amygdala. To investigate the physiological role of endogenous enterostatin, we created an enterostatin-deficient, colipase-sufficient (Ent(-/-)) mouse. Ent(-/-) mice are viable, normally active, and fertile. They exhibit normal growth on low-fat and high-fat diets. Furthermore, Ent(-/-) mice develop diet-induced obesity, as do Ent(+/+) mice, and have normal responses to a two-macronutrient choice diet and to a switch from a high-fat to a low-fat diet. Levels of total serum (P = 0.004) and non-HDL (P

  6. Increase in Sialylation and Branching in the Mouse Serum N-glycome Correlates with Inflammation and Ovarian Tumour Progression

    PubMed Central

    Saldova, Radka; Piccard, Helene; Pérez-Garay, Marta; Harvey, David J.; Struwe, Weston B.; Galligan, Marie C.; Berghmans, Nele; Madden, Stephen F.; Peracaula, Rosa; Opdenakker, Ghislain; Rudd, Pauline M.

    2013-01-01

    Ovarian cancer is the most lethal gynaecological cancer and is often diagnosed in late stage, often as the result of the unavailability of sufficiently sensitive biomarkers for early detection, tumour progression and tumour-associated inflammation. Glycosylation is the most common posttranslational modification of proteins; it is altered in cancer and therefore is a potential source of biomarkers. We investigated the quantitative and qualitative effects of anti-inflammatory (acetylsalicylic acid) and pro-inflammatory (thioglycolate and chlorite-oxidized oxyamylose) drugs on glycosylation in mouse cancer serum. A significant increase in sialylation and branching of glycans in mice treated with an inflammation-inducing compound was observed. Moreover, the increases in sialylation correlated with increased tumour sizes. Increases in sialylation and branching were consistent with increased expression of sialyltransferases and the branching enzyme MGAT5. Because the sialyltransferases are highly conserved among species, the described changes in the ovarian cancer mouse model are relevant to humans and serum N-glycome analysis for monitoring disease treatment and progression might be a useful biomarker. PMID:24023608

  7. Periodontitis increases rheumatic factor serum levels and citrullinated proteins in gingival tissues and alter cytokine balance in arthritic rats

    PubMed Central

    Corrêa, Mônica G.; Sacchetti, Silvana B.; Ribeiro, Fernanda Vieira; Pimentel, Suzana Peres; Casarin, Renato Corrêa Viana; Cirano, Fabiano Ribeiro; Casati, Marcio Z.

    2017-01-01

    This study investigated some immunological features by experimental periodontitis (EP) and rheumatoid arthritis (RA) disease interact in destructive processes in arthritic rats. Rats were assigned to the following groups: EP +RA; RA; EP; and Negative Control. RA was induced by immunizations with type-II collagen and a local immunization with Complete Freund’s adjuvant in the paw. Periodontitis was induced by ligating the right first molars. The serum level of rheumatoid factor (RF) and anti-citrullinated protein antibody (ACCPA) were measured before the induction of EP (T1) and at 28 days after (T2) by ELISA assay. ACCPA levels were also measured in the gingival tissue at T2. The specimens were processed for morphometric analysis of bone loss, and the gingival tissue surrounding the first molar was collected for the quantification of interleukin IL-1β, IL-4, IL-6, IL-17 and TNF-α using a Luminex/MAGpix assay. Paw edema was analyzed using a plethysmometer. Periodontitis increased the RF and ACCPA levels in the serum and in the gingival tissue, respectively. Besides, the level of paw swelling was increased by EP and remained in progress until the end of the experiment, when EP was associated with RA. Greater values of IL-17 were observed only when RA was present, in spite of PE. It can be concluded that periodontitis increases rheumatic factor serum levels and citrullinated proteins level in gingival tissues and alter cytokine balance in arthritic rats; at the same time, arthritis increases periodontal destruction, confirming the bidirectional interaction between diseases. PMID:28358812

  8. Four cases of type 1 diabetes mellitus showing sharp serum transaminase increases and hepatomegaly due to glycogenic hepatopathy.

    PubMed

    Ikarashi, Yuichi; Kogiso, Tomomi; Hashimoto, Etsuko; Yamamoto, Kuniko; Kodama, Kazuhisa; Taniai, Makiko; Torii, Nobuyuki; Takaike, Hiroko; Uchigata, Yasuko; Tokushige, Katsutoshi

    2017-03-01

    Poorly controlled diabetes mellitus (DM) patients sometimes show serum transaminase elevations due to steatohepatitis. However, we experienced four cases with type 1 DM with sharp elevations in serum transaminases that could not be explained by steatohepatitis alone and showed bright liver. They were diagnosed with glycogenic hepatopathy (GH) clinicopathologically. The four patients had a median age of 22.5 years (range, 19-29 years) and 12.5 (4-15)-year histories of type 1 DM and showed marked increases in serum transaminases (aspartate aminotransferase, 698 U/L [469-2763 U/L]; alanine transaminase, 255 U/L [216-956 U/L]). Diabetes mellitus control was poor and hemoglobin A1c was 12.7% (11-16.5%). Three cases had a past history of diabetic ketoacidosis. Hepatomegaly and hyperdense liver were seen on computed tomography scans. Magnetic resonance imaging showed low intensity in T2-weighted images. The pathological findings revealed pale and swollen hepatocytes and glycogenated nuclei. The architecture of the liver was preserved, and steatosis and fibrosis were mild. The cytoplasm of hepatocytes stained densely positive with periodic acid-Schiff, and the positive staining disappeared after diastase digestion, suggesting glycogen deposition. No other cause of hepatitis was evident, and the diagnosis was GH. Elevated transaminases improved within 1 month with good glycemic control. Transaminase elevations were observed several times in three cases with poor glycemic control. Glycogenic hepatopathy is rare, but extremely high serum elevations of transaminases are important to identify clinically. Despite showing a good clinical course in general, GH sometimes recurs and requires strict glycemic control. Clinicians should be aware of and recognize GH when dealing with uncontrolled DM patients.

  9. Hypomorphic, homozygous mutations in Phosphoglucomutase 3 impair immunity and increase serum IgE levels

    PubMed Central

    Sassi, Atfa; Lazaroski, Sandra; Wu, Gang; Haslam, Stuart M.; Fliegauf, Manfred; Mellouli, Fethi; Patiroglu, Turkan; Unal, Ekrem; Ozdemir, Mehmet Akif; Jouhadi, Zineb; Khadir, Khadija; Ben-Khemis, Leila; Ben-Ali, Meriem; Ben-Mustapha, Imen; Borchani, Lamia; Pfeifer, Dietmar; Jakob, Thilo; Khemiri, Monia; Asplund, A. Charlotta; Gustafsson, Manuela O.; Lundin, Karin E.; Falk-Sörqvist, Elin; Moens, Lotte N.; Gungor, Hatice Eke; Engelhardt, Karin R.; Dziadzio, Magdalena; Stauss, Hans; Fleckenstein, Bernhard; Meier, Rebecca; Prayitno, Khairunnadiya; Maul-Pavicic, Andrea; Schaffer, Sandra; Rakhmanov, Mirzokhid; Henneke, Philipp; Kraus, Helene; Eibel, Hermann; Kölsch, Uwe; Nadifi, Sellama; Nilsson, Mats; Bejaoui, Mohamed; Schäffer, Alejandro A.; Edvard Smith, C. I.; Dell, Anne; Barbouche, Mohamed-Ridha; Grimbacher, Bodo

    2016-01-01

    Background Recurrent bacterial and fungal infections, eczema and elevated serum IgE levels characterize patients with the hyper-IgE syndrome (HIES). Known genetic causes for HIES are mutations in STAT3 and DOCK8, involved in signal transduction pathways. However, glycosylation defects have not been described in HIES. One crucial enzyme in the glycosylation pathway is Phosphoglucomutase 3 (PGM3), which catalyzes a key step in the synthesis of UDP-GlcNAc which is required for the biosynthesis of N-glycans. Objective To elucidate the genetic cause in HIES patients who do not carry mutations in STAT3 or DOCK8. Methods After establishing a linkage interval by SNP-chip genotyping and homozygosity mapping in two HIES families from Tunisia, mutational analysis was performed with selector-based, high-throughput sequencing. Protein expression was analyzed by Western blotting and glycosylation was profiled by mass spectrometry. Results Mutational analysis of candidate genes in a 11.9 Mb linkage region on chromosome 6 shared by two multiplex families identified two homozygous mutations in PGM3 which segregated with the disease status and followed a recessive inheritance trait. The mutations predict amino acid changes in Phosphoglucomutase-3; PGM3 (p.Glu340del and p.Leu83Ser). A third homozygous mutation (p.Asp502Tyr) and the p.Leu83Ser variant were identified in two other affected families, respectively. These hypomorphic mutations have impact on the biosynthetic reactions involving UDP-GlcNAc. Glycomic analysis revealed an aberrant glycosylation pattern in leukocytes demonstrated by a reduced level of tri-/tetra-antennary N-glycans. T cell proliferation and differentiation was impaired in patients. Most patients showed developmental delay and many had psychomotor retardation. Conclusion Impairment of PGM3 function leads to a novel primary (inborn) error of development and immunity, as biallelic hypomorphic mutations are associated with impaired glycosylation and a hyper

  10. Increased serum IgA concentration and plasmablast frequency in patients with age-related macular degeneration.

    PubMed

    Yu, Honghua; Yuan, Ling; Yang, Yahan; Ma, Suihong; Peng, Lianghong; Wang, Yong; Zhang, Chu; Li, Tao

    2016-05-01

    Age-related macular degeneration (AMD) is the leading cause of blindness among senior citizens of developed countries, with currently unknown etiology. Despite the close associations between AMD development and inhibitory complement factor H mutations, the first step of complement activation, which is the antibody response in AMD patients, has not been studied. Here, we obtained blood and tear samples from AMD patients and Non-AMD controls. We found that compared to Non-AMD controls, AMD subjects had increased IgA titers in serum and tear, and had elevated levels of circulating antibody-secreting plasmablasts. The increase in antibody titer was limited to the IgA isotype, since no significant differences were observed in IgM and IgG isotypes between AMD patients and Non-AMD controls. Interestingly, this increased antibody response in AMD patients was correlated with disease severity, as late AMD patients had increased IgA titers in serum and tear, as well as elevated plasmablast frequency after staphylococcal enterotoxin B stimulation, compared to early AMD patients. Together, our results implicated a role of overreactive IgA responses in AMD pathogenesis.

  11. Increased expression of the IgE Fc receptors on rat macrophages induced by elevated serum IgE levels.

    PubMed Central

    Boltz-Nitulescu, G; Plummer, J M; Spiegelberg, H L

    1984-01-01

    Macrophages (M phi) from rats with elevated serum IgE levels induced by (i) Nippostrongylus brasiliensis (Nb) infection, (ii) IgE-secreting plasmacytoma IR 162, or (iii) i.p. injection of purified rat IgE, and M phi from normal animals cultured in the presence of 10 micrograms/ml IgE were analysed for Fc IgE receptors (Fc epsilon R) expression. To detect Fc epsilon R-bearing cells, a rosette assay employing fixed ox erythrocytes coated with rat IgE was used. With undersensitized indicator cells a significantly (P less than 0.002) greater number of M phi from animals having elevated serum IgE levels or of M phi cultured in the presence of IgE formed IgE rosettes than M phi from normal donors. The IgE rosettes were IgE class-specific, since they were inhibited by rat IgE in a dose-dependent manner, but not by any other rat Ig class, heat-denatured rat IgE or human IgE. The modulating effect of Fc epsilon R expression on M phi was IgE specific, because neither rat IgG nor heated rat IgE induced increased IgE rosette formation. Furthermore, elevated serum IgE levels did not increase the expression of Fc receptors for IgG subclasses. Studies of 125I-IgE binding showed that alveolar macrophages (AM phi) from Nb-infected rats bind IgE with similar affinity (Ka 1.1 X 10(7) M-1) as AM phi from normal animals, but they have increased numbers of IgE binding sites. Collectively, the results demonstrate that in vivo and in vitro elevated serum IgE concentrations induce increased IgE rosette formation as a result of a marked increase in the number of Fc epsilon R per macrophage. PMID:6236146

  12. Increased Serum Uric Acid Levels Blunt the Antihypertensive Efficacy of Lifestyle Modifications in Children at Cardiovascular Risk.

    PubMed

    Viazzi, Francesca; Rebora, Paola; Giussani, Marco; Orlando, Antonina; Stella, Andrea; Antolini, Laura; Valsecchi, Maria Grazia; Pontremoli, Roberto; Genovesi, Simonetta

    2016-05-01

    Primary hypertension is a growing concern in children because of the obesity epidemic largely attributable to western lifestyles. Serum uric acid is known to be influenced by dietary habits, correlates with obesity, and could represent a risk factor for hypertension. Preliminary studies in children highlighted uric acid as a potentially modifiable risk factor for the prevention and treatment of hypertension. The effect of lifestyle changes (increase of physical activity and dietary modifications) on blood pressure values, weight status, and serum uric acid levels in a cohort of 248 children referred for cardiovascular risk assessment were evaluated over a mean 1.5-year follow-up. At baseline, 48% of children were obese and 50% showed blood pressure values >90th percentile. At follow-up, a significant improvement in weight class (24% obese;P<0.0001) and blood pressure category (22% >90th percentile;P<0.0001) was found. Systolic blood pressure z-score (P<0.0001), uric acid value (P=0.0056), and puberty at baseline (P=0.0048) were independently associated with higher systolic blood pressure z-score at follow-up, whereas a negative association was observed with body mass index z-score decrease during follow-up (P=0.0033). The risk of hypertension at follow-up was associated with body mass index (P=0.0025) and systolic blood pressure (P<0.0001) z-score at baseline and inversely related to delta body mass index (P=0.0002), whereas the risk of showing hypertension ≥99th percentile was more than doubled for each baseline 1 mg/dL increase of serum uric acid (P=0.0130). Uric acid is a powerful determinant of blood pressure over time, independent of lifestyle modifications.

  13. Morphine and cocaine increase serum- and glucocorticoid-inducible kinase 1 activity in the ventral tegmental area.

    PubMed

    Heller, Elizabeth A; Kaska, Sophia; Fallon, Barbara; Ferguson, Deveroux; Kennedy, Pamela J; Neve, Rachael L; Nestler, Eric J; Mazei-Robison, Michelle S

    2015-01-01

    Drugs of abuse modulate the function and activity of the mesolimbic dopamine circuit. To identify novel mediators of drug-induced neuroadaptations in the ventral tegmental area (VTA), we performed RNA sequencing analysis on VTA samples from mice administered repeated saline, morphine, or cocaine injections. One gene that was similarly up-regulated by both drugs was serum- and glucocorticoid-inducible kinase 1 (SGK1). SGK1 activity, as measured by phosphorylation of its substrate N-myc downstream regulated gene (NDRG), was also increased robustly by chronic drug treatment. Increased NDRG phosphorylation was evident 1 but not 24 h after the last drug injection. SGK1 phosphorylation itself was similarly modulated. To determine the role of increased SGK1 activity on drug-related behaviors, we over-expressed constitutively active (CA) SGK1 in the VTA. SGK1-CA expression reduced locomotor sensitization elicited by repeated cocaine, but surprisingly had the opposite effect and promoted locomotor sensitization to morphine, without affecting the initial locomotor responses to either drug. SGK1-CA expression did not significantly affect morphine or cocaine conditioned place preference, although there was a trend toward increased conditioned place preference with both drugs. Further characterizing the role of this kinase in drug-induced changes in VTA may lead to improved understanding of neuroadaptations critical to drug dependence and addiction. We find that repeated, but not acute, morphine or cocaine administration induces an increase in serum- and glucocorticoid-inducible kinase (SGK1) gene expression and activity in the ventral tegmental area (VTA). This increase in SGK1 activity may play a role in drug-dependent behaviors and suggests a novel signaling cascade for potential intervention in drug dependence and addiction.

  14. Serum cytokines are increased and circulating micronutrients are not altered in subjects with early compared to advanced knee osteoarthritis.

    PubMed

    Barker, Tyler; Rogers, Victoria E; Henriksen, Vanessa T; Aguirre, Dale; Trawick, Roy H; Rasmussen, G Lynn; Momberger, Nathan G

    2014-08-01

    Knee osteoarthritis (OA) is a leading cause of physical disability. At the early stage of knee OA, the increase in synovial fluid cytokine concentrations could contribute to the pathogenesis of OA by degrading articular cartilage. It is unknown, however, if inflammatory cytokines increase systemically at the early or advanced stage of knee OA. The systemic increase of inflammatory cytokines could be detrimental to the endogenous status of micronutrients that protect against excessive inflammation and cytokine-mediated events. The purpose of this study was to test the hypothesis that an increase in serum cytokines associate with a decrease in circulating micronutrients in subjects with early compared to advanced knee OA. Advanced knee OA subjects (n=14) displayed radiographic, pain, and muscular weakness symptoms of knee OA. Early knee OA subjects (n=14) were matched (age, gender, and body mass index) to the advanced OA group and displayed one or two of the aforementioned symptoms of knee OA. Inflammatory cytokines, vitamins C (ascorbic acid), D (25-hydroxyvitamin D), and E (α- and γ-tocopherols), and β-carotene were measured in fasting blood samples. In the early OA group, serum tumor necrosis factor (TNF)-α, interleukin (IL)-5, IL-6, IL-12, and IL-13 concentrations were significantly (all p<0.05) increased. Circulating ascorbic acid, 25-hydroxyvitamin D, α- and γ-tocopherol's, and β-carotene concentrations were not significantly different between groups. Based on these preliminary results, we conclude that the systemic increase of inflammatory cytokines is not associated with a decrease in circulating micronutrients in subjects with early compared to advanced knee OA.

  15. Apolipoprotein E-knockout mice show increased titers of serum anti-nuclear and anti-dsDNA antibodies

    SciTech Connect

    Wang, Yuehai; Huang, Ziyang; Lu, Huixia; Lin, Huili; Wang, Zhenhua; Chen, Xiaoqing; Ouyang, Qiufang; Tang, Mengxiong; Hao, Panpan; Ni, Jingqin; Xu, Dongming; Zhang, Mingxiang; Zhang, Qunye; Lin, Ling; and others

    2012-07-13

    Highlights: Black-Right-Pointing-Pointer Titers of ANA and anti-dsDNA antibodies were higher in ApoE{sup -/-} than C57B6/L mice. Black-Right-Pointing-Pointer Spleen was greater and splenocyte apoptosis lower in ApoE{sup -/-} than B6 mice. Black-Right-Pointing-Pointer Level of TLR4 was lower in spleen tissue of ApoE{sup -/-} than B6 mice. Black-Right-Pointing-Pointer The TLR4 pathway may participate in maintaining the balance of splenocyte apoptosis. Black-Right-Pointing-Pointer The TLR4 pathway may participate in antibody production in spleen tissue. -- Abstract: Apolipoprotein E-knockout (ApoE{sup -/-}) mice, atherosclerosis-prone mice, show an autoimmune response, but the pathogenesis is not fully understood. We investigated the pathogenesis in female and male ApoE{sup -/-} mice. The spleens of all ApoE{sup -/-} and C57BL/6 (B6) mice were weighed. The serum IgG level and titers of anti-nuclear antibody (ANA) and anti-double-stranded DNA (anti-dsDNA) antibody were assayed by ELISA. Apoptosis of spleen tissue was evaluated by TUNEL. TLR4 level in spleen tissue was tested by immunohistochemistry and Western blot analysis. Levels of MyD88, p38, phosphorylated p38 (pp38), interferon regulatory factor 3 (IRF3) and Bcl-2-associated X protein (Bax) in spleen tissue were detected by Western blot analysis. We also survey the changes of serum autoantibodies, spleen weight, splenocyte apoptosis and the expressions of TLR4, MyD88, pp38, IRF3 and Bax in spleen tissue in male ApoE{sup -/-} mice after 4 weeks of lipopolysaccharide (LPS), Toll-like receptor 4 ligand, administration. ApoE{sup -/-} mice showed splenomegaly and significantly increased serum level of IgG and titers of ANA and anti-dsDNA antibody as compared with B6 mice. Splenocyte apoptosis and the expression of TLR4, MyD88, pp38, IRF3 and Bax in spleen tissue were significantly lower in ApoE{sup -/-} than B6 mice. The expression of TLR4, MyD88, IRF3, pp38, and Bax differed by sex in ApoE{sup -/-} spleen tissue. The

  16. Uremic Serum and Solutes Increase Post–Vascular Interventional Thrombotic Risk Through Altered Stability of Smooth Muscle Cell Tissue Factor

    PubMed Central

    Chitalia, Vipul C.; Shivanna, Sowmya; Martorell, Jordi; Balcells, Mercedes; Bosch, Irene; Kolandaivelu, Kumaran; Edelman, Elazer R.

    2013-01-01

    Background Stent thrombosis (ST), a postinterventional complication with a mortality rate of 50%, has an incidence that rises precipitously in patients at risk. Chronic renal failure and end-stage renal disease have emerged as particularly strong ST risk factors, yet the mechanism remains elusive. Tissue factor (TF) is a crucial mediator of injury-related thrombosis and has been implicated for ST. We posit that uremia modulates TF in the local vessel wall to induce postinterventional thrombosis in patients with end-stage renal disease. Methods and Results As a model of the de-endothelialized, postinterventional state, we exposed primary human vascular smooth muscle cells (vSMCs) pretreated with uremic serum (obtained from ESRD patients on hemodialysis) to coronary-like blood flow. vSMC TF expression, activity, stability, and posttranslational modification were examined after vSMCs were treated with uremic serum or solutes. We found significantly greater clot formation after uremic serum exposure, which was substantially reduced with the prior treatment with anti-TF neutralizing antibody. Uremic sera induced 2- to 3-fold higher TF expression and activity in vSMCs independent of diabetes mellitus. Relevant concentrations of isolated uremic solutes such as indole-3-acetic acid (3.5 μg/mL), indoxyl sulfate (25 μg/mL), and uric acid (80 μg/mL) recapitulated these effects in cell culture and the flow loop model. We show further that TF undergoes ubiquitination at baseline and that uremic serum, indole-3-acetic acid, and indoxyl sulfate significantly prolong TF half-life by inhibiting its ubiquitination. Conclusions The uremic milieu is profoundly thrombogenic and upregulates vSMC TF levels by increasing TF stability and decreasing its ubiquitination. Together, these data demonstrate for the first time that the posttranslational regulation of TF in uremia may have a causative role in the increased ST risk observed in uremic patients. These data suggest that

  17. Little effects of Insulin-like Growth Factor-I on testicular atrophy induced by hypoxia

    PubMed Central

    Diez-Caballero, Fernando; Castilla-Cortázar, Inma; Garcia-Fernandez, Maria; Puche, Juan Enrique; Diaz-Sanchez, Matias; Casares, Amelia Diaz; Aliaga-Montilla, M Aurelia; Rodriguez-Borrajo, Coronación; Gonzalez-Barón, Salvador

    2006-01-01

    Background Insulin-like Growth Factor-I (IGF-I) supplementation restores testicular atrophy associated with advanced liver cirrhosis that is a condition of IGF-I deficiency. The aim of this work was to evaluate the effect of IGF-I in rats with ischemia-induced testicular atrophy (AT) without liver disease and consequently with normal serum level of IGF-I. Methods Testicular atrophy was induced by epinephrine (1, 2 mg/Kg intra-scrotal injection five times per week) during 11 weeks. Then, rats with testicular atrophy (AT) were divided into two groups (n = 10 each): untreated rats (AT) receiving saline sc, and AT+IGF, which were treated with IGF-I (2 μg.100 g b.w.-1.day-1, sc.) for 28d. Healthy controls (CO, n = 10) were studied in parallel. Animals were sacrificed on day 29th. Hypophyso-gonadal axis, IGF-I and IGFBPs levels, testicular morphometry and histopathology, immuno-histochemical studies and antioxidant enzyme activity phospholipid hydroperoxide glutathione peroxidase (PHGPx) were assessed. Results Compared to controls, AT rats displayed a reduction in testicular size and weight, with histological testicular atrophy, decreased cellular proliferation and transferrin expression, and all of these alterations were slightly improved by IGF-I at low doses. IGF-I therapy increased signifincantly steroidogenesis and PHGPx activity (p < 0.05). Interestingly, plasma IGF-I did not augment in rats with testicular atrophy treated with IGF-I, while IGFBP3 levels, that reduces IGF-I availability, was increased in this group (p < 0.05). Conclusion In testicular atrophy by hypoxia, condition without IGF-I deficiency, IGF-treatment induces only partial effects. These findings suggest that IGF-I therapy appears as an appropriate treatment in hypogonadism only when this is associated to conditions of IGF-I deficiency (such as Laron Syndrom or liver cirrhosis). PMID:16504030

  18. Prednisone lowers serum uric acid levels in patients with decompensated heart failure by increasing renal uric acid clearance.

    PubMed

    Liu, Chao; Zhen, Yuzhi; Zhao, Qingzhen; Zhai, Jian-Long; Liu, Kunshen; Zhang, Jian-Xin

    2016-07-01

    Clinical studies have shown that large doses of prednisone could lower serum uric acid (SUA) in patients with decompensated heart failure (HF); however, the optimal dose of prednisone and underlying mechanisms are unknown. Thirty-eight patients with decompensated HF were randomized to receive standard HF care alone (n = 10) or with low-dose (15 mg/day, n = 8), medium-dose (30 mg/day, n = 10), or high-dose prednisone (60 mg/day, n = 10), for 10 days. At the end of the study, only high-dose prednisone significantly reduced SUA, whereas low- and medium-dose prednisone and standard HF care had no effect on SUA. The reduction in SUA in high-dose prednisone groups was associated with a significant increase in renal uric acid clearance. In conclusion, prednisone can reduce SUA levels by increasing renal uric acid clearance in patients with decompensated HF.

  19. Increased Serum and Musculotendinous Fibrogenic Proteins following Persistent Low-Grade Inflammation in a Rat Model of Long-Term Upper Extremity Overuse

    PubMed Central

    Gao, Helen G. L.; Fisher, Paul W.; Lambi, Alex G.; Wade, Christine K.; Barr-Gillespie, Ann E.; Popoff, Steven N.; Barbe, Mary F.

    2013-01-01

    We examined the relationship between grip strength declines and muscle-tendon responses induced by long-term performance of a high-repetition, low-force (HRLF) reaching task in rats. We hypothesized that grip strength declines would correlate with inflammation, fibrosis and degradation in flexor digitorum muscles and tendons. Grip strength declined after training, and further in weeks 18 and 24, in reach limbs of HRLF rats. Flexor digitorum tissues of reach limbs showed low-grade increases in inflammatory cytokines: IL-1β after training and in week 18, IL-1α in week 18, TNF-α and IL-6 after training and in week 24, and IL-10 in week 24, with greater increases in tendons than muscles. Similar cytokine increases were detected in serum with HRLF: IL-1α and IL-10 in week 18, and TNF-α and IL-6 in week 24. Grip strength correlated inversely with IL-6 in muscles, tendons and serum, and TNF-α in muscles and serum. Four fibrogenic proteins, TGFB1, CTGF, PDGFab and PDGFbb, and hydroxyproline, a marker of collagen synthesis, increased in serum in HRLF weeks 18 or 24, concomitant with epitendon thickening, increased muscle and tendon TGFB1 and CTGF. A collagenolytic gelatinase, MMP2, increased by week 18 in serum, tendons and muscles of HRLF rats. Grip strength correlated inversely with TGFB1 in muscles, tendons and serum; with CTGF-immunoreactive fibroblasts in tendons; and with MMP2 in tendons and serum. Thus, motor declines correlated with low-grade systemic and musculotendinous inflammation throughout task performance, and increased fibrogenic and degradative proteins with prolonged task performance. Serum TNF-α, IL-6, TGFB1, CTGF and MMP2 may serve as serum biomarkers of work-related musculoskeletal disorders, although further studies in humans are needed. PMID:24015193

  20. A Blend of Chlorophytum Borivilianum and Velvet Bean Increases Serum Growth Hormone in Exercise-Trained Men

    PubMed Central

    Alleman, Rick J.; Canale, Robert E.; McCarthy, Cameron G.; Bloomer, Richard J.

    2011-01-01

    Background: Several isolated ingredients have been proposed to increase growth hormone (GH) release, including Chlorophytum borivilianum and Velvet bean. A combination of these two ingredients has been packaged within an investigational dietary supplement. It was the purpose of the present investigation to determine the impact of acute ingestion of this supplement on circulating GH in healthy, exercise-trained men. Methods: Fifteen men ingested the dietary supplement on two different days, separated by one week. Blood was collected from subjects before ingestion of the supplement and at 20, 40, 60, 80, 100, and 120 minutes post ingestion. GH was analyzed in serum samples using an ELISA method. Values for GH for each subject, at each collection time, were averaged over both test days and used in the main analysis. Results: Serum GH increased over time, with higher values at 60 minutes (1.56 ± 0.65 ng · mL−1; P = 0.04; +767%), 80 minutes (1.76 ± 0.69 ng · mL−1; P = 0.02; +878%), and 100 minutes (1.48 ± 0.62 ng · mL−1; P = 0.05; +722%) compared to pre ingestion (0.18 ± 0.04 ng · mL−1). A great deal of subject variability existed in the area under the curve (AUC) for GH, with pooled values ranging from 0.49 to 61.2 ng · mL−1 · 2 hr−1 Conclusion: Acute ingestion of an investigational dietary supplement containing the active ingredients Chlorophytum borivilianum and Velvet bean results in an increase in circulating GH in exercise-trained men. Additional placebo controlled investigations are needed to extend these findings. Moreover, studies are needed to determine if chronic use of such supplementation leads to favorable changes in health-related parameters associated with increased circulating GH. PMID:23946662

  1. Depression of serum calcium by increased plasma free fatty acids in the rat: a mechanism for hypocalcemia in acute pancreatitis.

    PubMed

    Warshaw, A L; Lee, K H; Napier, T W; Fournier, P O; Duchainey, D; Axelrod, L

    1985-10-01

    Some patients with hypertriglyceridemia and acute pancreatitis have marked hypocalcemia and high levels of plasma free fatty acids (FFAs). This study tests the hypothesis that increased plasma FFAs can significantly reduce the calcium level in vivo, a phenomenon which is different from local formation of calcium soaps due to lipolysis of adipose tissue lipids. Free fatty acid elevation was induced in rats by the administration of heparin and by the infusion of triglycerides. The results show that, compared with controls, induction of elevated FFA (from 1.57 +/- 0.08 mEq/L to 5.64 +/- 0.35, mean +/- SEM) causes the concentration of calcium to fall rapidly (from 9.04 +/- 0.06 mg/dl to 8.42 +/- 0.10, p less than 0.001). There is a significant (p less than 0.001) positive correlation between spontaneous baseline concentration of FFA and the responsiveness of calcium concentration to FFA challenge. At near-normal levels of FFA there is a significant (p less than 0.001) correlation between the magnitude of increased FFA concentration and decreased calcium concentration. Additional studies in vivo and in vitro show that elevated plasma triglycerides per se did not interfere with measurement of calcium concentration; however, FFA-albumin complexes bind calcium and lower its measured value. These findings suggest that (a) changes in the concentration of FFA occurring spontaneously may affect measured serum calcium concentration; (b) the observed depression of serum calcium concentration may be due in part to intravascular sequestration of calcium by FFA, but increased flux of circulating calcium-FFA complexes into extravascular and intracellular sites may also be important; (c) the markedly increased FFA concentration in some patients with acute pancreatitis may contribute significantly to hypocalcemia and calcium flux in these patients. As parathyroid hormone secretion, function, or integrity may be impaired in pancreatitis, the depressant effect of FFA could be even

  2. Increase in rT3 serum levels observed during extended Alaskan field operations of Naval personnel.

    PubMed

    McCormack, P D; Reed, H L; Thomas, J R; Malik, M J

    1996-01-01

    Members of a US Navy Special Warfare platoon had blood samples drawn by venipuncture and other baseline measurements carried out prior to departure for a three-month period of field operations in Alaska. Assays of serum reverse triiodothyronine (rT3), free thyroxine (fT3), free T4 (fT4), and thyroid stimulating hormone (TSH) were subsequently done at the Naval Medical Research Institute (NMRI), Bethesda, Maryland. In the field and at baseline, hematocrits and urine specific gravities were also measured to track hydration status, and body weights and fat were recorded to track nutritional status. After plasma volume change and weight change corrections, an approximate 30% increase in serum rT3 level and 20% decrease in free T3 level over 76 days of cold exposure were recorded. The necessity for an rT3 kinetic study is indicated. The mean residence time for rT3 in the circulation is about 8 hours with respect to about 36 hours for free T3, so rT3 kinetic studies would be advantageous with respect to long term cold exposure of military personnel.

  3. Association of Increased Serum Leptin with Ameliorated Anemia and Malnutrition in Stage 5 Chronic Kidney Disease Patients after Parathyroidectomy.

    PubMed

    Jiang, Yao; Zhang, Jingjing; Yuan, Yanggang; Zha, Xiaoming; Xing, Changying; Shen, Chong; Shen, Zhixiang; Qin, Chao; Zeng, Ming; Yang, Guang; Mao, Huijuan; Zhang, Bo; Yu, Xiangbao; Sun, Bin; Ouyang, Chun; Xu, Xueqiang; Ge, Yifei; Wang, Jing; Zhang, Lina; Cheng, Chen; Yin, Caixia; Zhang, Jing; Chen, Huimin; Ma, Haoyang; Wang, Ningning

    2016-06-16

    Leptin is an adipokine that regulates various metabolism, but its association with secondary hyperparathyroidism (SHPT), a clinical manifestation of chronic kidney disease-mineral and bone disorder (CKD-MBD), remains obscure. Parathyroidectomy (PTX) is recommended for severe SHPT patients. Here, the associations between circulating leptin and clinical characteristics in CKD patients were investigated. Effects of PTX on leptin production were analyzed in vivo and in vitro. Controls and CKD patients had approximate serum leptin levels in that a larger proportion of CKD patients with body mass index (BMI) <23 kg/m(2). Serum leptin was related to anemia, albumin, and bone metabolism disorders in CKD patients. Lower intact parathyroid hormone (PTH) was related with higher leptin in PTX patients group. Severe SHPT inhibited uremia-enhanced leptin production in 3T3-L1 adipocytes, which was attenuated after PTX. High levels of PTH were found to reduce Akt phosphorylation and leptin production in vitro but high levels of calcium and phosphorus were not. Successful PTX was found to improve anemia and malnutrition in severe SHPT patients, and this was correlated with increased circulating leptin levels via up-regulated Akt signaling in adipocytes. These findings indicated the therapeutic potential of leptin and related target pathway for improving survival and quality of life in CKD.

  4. Fluorescent Probe Encapsulated in Avidin Protein to Eliminate Nonspecific Fluorescence and Increase Detection Sensitivity in Blood Serum.

    PubMed

    Wu, Ting-Wei; Lee, Fang-Hong; Gao, Ruo-Cing; Chew, Chee Ying; Tan, Kui-Thong

    2016-08-16

    Quantitative detection of trace amounts of a biomarker in protein rich human blood plasma using fluorescent probes is a great challenge as the real signal is usually obscured by nonspecific fluorescence. This problem occurs because most of the fluorescent dyes bind very tightly with blood proteins to produce a large fluorescence increase, resulting in overestimation of the biomarker concentrations and false positive diagnosis. In this paper, we report that biotinylated fluorescent probes encapsulated in avidin protein can generate very specific fluorescence in blood serum by blocking out nonspecific dye-protein interactions. We applied our novel probe design to detect two different types of biomolecules, hydrogen sulfide and nitroreductase. Our Avidin conjugated probes achieved quantitative analyte detection in blood serum; whereas concentrations were overestimated up to 320-fold when bare fluorescent probes were employed. As compared to conventional approaches where fluorescent probes are encapsulated into polymers and nanoparticles, our simple approach successfully overcomes many key issues such as dye leakage, long preparation steps, inconsistent dye-host ratios, difficulty in constructing in situ in a complex medium, and limited application to detect only small metabolites.

  5. Plasma insulin-like growth factor binding protein-3 proteolysis is increased in primary breast cancer

    PubMed Central

    Helle, S I; Geisler, S; Aas, T; Paulsen, T; Holly, J M P; Lønning, P E

    2001-01-01

    Fasting blood samples were obtained before definitive surgery or biopsy in 128 patients referred to the department of surgery with suspected or manifest breast cancer. Insulin-like growth factor (IGF)-I, IGF-II and free IGF-I were measured by radioimmunoassay/immunoradiometric assay, while IGFBP-3 proteolysis was evaluated by Western immunoblot. 12 patients had ductal carcinoma in situ benign conditions, while staging revealed metastatic disease in 15 of 16 patients with invasive cancers. IGFBP-3 proteolysis above the normal range was recorded in 19 patients with invasive cancers, but in none of the patients suffering from DCIS/benign conditions. Increased IGFBP-3 proteolysis was most frequently recorded in patients harbouring large tumours and metastatic disease (Stage I: 0/19, 0%; Stage II: 3/45, 7%, Stage III: 9/37, 24%, and Stage IV: 7/15, 47%). IGFBP-3 proteolysis was significantly higher in Stage III (P =0.01) and IV (P< 0.001) patients compared to the other stage groups (P = 0.001). IGF-I and IGF-II correlated negatively to IGFBP-3 proteolysis and age. Plasma levels of IGF-I and -II were significantly lower in patients with elevated IGFBP-3 proteolysis compared to those within the normal range. Our findings reveal alterations in the IGF-system among a substantial number of patients with large primary breast cancers. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11437405

  6. Serum Eotaxin-1 is Increased in Extremely Low Birth Infants with Bronchopulmonary Dysplasia or Death

    PubMed Central

    Kandasamy, Jegen; Roane, Claire; Szalai, Alexander; Ambalavanan, Namasivayam

    2015-01-01

    Background Early systemic inflammation in extremely low birth weight (ELBW) infants is associated with an increased risk of bronchopulmonary dysplasia (BPD). Our objective was to identify circulating biomarkers and develop prediction models for BPD/death soon after birth. Methods Blood samples from postnatal day 1 were analyzed for CRP by ELISA and for 39 cytokines/chemokines by a multiplex assay in 152 ELBW infants. The primary outcome was physiologic BPD or death by 36w. CRP, cytokines, and clinical variables available at ≤24 h were used for forward stepwise regression and Classification and Regression Tree (CART) analysis to identify predictors of BPD/death. Results Overall, 24% developed BPD and 35% died or developed BPD. Regression analysis identified birth weight and eotaxin (CCL11) as the two most significant variables. CART identified FiO2 at 24h (11% BPD/death if FiO2 ≤28%, 49% if >28%) and eotaxin in infants with FiO2>28% (29% BPD/death if eotaxin was ≤84 pg/ml; 65% if >84) as variables most associated with outcome. Conclusion Eotaxin measured on the day of birth is useful for identifying ELBW infants at risk of BPD/death. Further investigation is required to determine if eotaxin is involved in lung injury and pathogenesis of BPD. PMID:26270578

  7. Serum betatrophin levels are increased and associated with insulin resistance in patients with polycystic ovary syndrome.

    PubMed

    Qu, Qinglan; Zhao, Dongmei; Zhang, Fengrong; Bao, Hongchu; Yang, Qiuhua

    2017-02-01

    Objective Betatrophin is a newly identified circulating protein that is significantly associated with type 2 diabetes mellitus (T2DM), adiposity, and metabolic syndrome. The aim of this study was to investigate whether betatrophin levels and polycystic ovary syndrome (PCOS) were associated. Methods Circulating betatrophin levels were measured in 162 patients with PCOS and 156 matched control females using specific enzyme-linked immunosorbent assay kits. Correlations between betatrophin levels and PCOS incidence as well as multiple key endocrine PCOS parameters were analyzed using multiple statistical methods. Results Betatrophin levels were significantly increased in patients with PCOS (685.3 ± 27.7 vs. 772.6 ± 42.5 pg/ml). When sub-grouping all investigated subjects according to the presence of insulin resistance, women with PCOS and insulin resistance exhibited markedly higher betatrophin concentrations. Furthermore, betatrophin levels were significantly correlated with fasting insulin levels and homeostatic model assessment of insulin resistance only in females with PCOS ( r = 0.531 and r = 0.628, respectively). Conclusion We provide the first report that betatrophin is strongly associated with PCOS. This study suggests that betatrophin may potentially serve as an independent predictor for the development of PCOS in at-risk women, especially those with insulin resistance.

  8. Resveratrol Increases Serum BDNF Concentrations and Reduces Vascular Smooth Muscle Cells Contractility via a NOS-3-Independent Mechanism.

    PubMed

    Wiciński, Michał; Malinowski, Bartosz; Węclewicz, Mateusz M; Grześk, Elżbieta; Grześk, Grzegorz

    2017-01-01

    Resveratrol is a polyphenol that presents both antineuroinflammatory properties and the ability to interact with NOS-3, what contributes to vasorelaxation. Brain-derived neurotrophic factor (BNDF), a molecule associated with neuroprotection in many neurodegenerative disorders, is considered as an important element of maintaining stable cerebral blood flow. Vascular smooth muscle cells (VSMCs) are considered to be an important element in the pathogenesis of neurodegeneration and a potential preventative target by agents which reduce the contractility of the vessels. Our main objectives were to define the relationship between serum and long-term oral resveratrol administration in the rat model, as well as to assess the effect of resveratrol on phenylephrine- (PHE-) induced contraction of vascular smooth muscle cells (VSMCs). Moreover, we attempt to define the dependence of contraction mechanisms on endothelial NO synthase. Experiments were performed on Wistar rats (n = 17) pretreated with resveratrol (4 weeks; 10 mg/kg p.o.) or placebo. Serum BDNF levels were quantified after 2 and 4 weeks of treatment with ELISA. Contraction force was measured on isolated and perfused tail arteries as the increase of perfusion pressure with a constant flow. Values of serum BNDF in week 0 were 1.18 ± 0.12 ng/mL (treated) and 1.17 ± 0.13 ng/mL (control) (p = ns). After 2 weeks of treatment, BDNF in the treatment group was higher than in controls, 1.52 ± 0.23 ng/mL and 1.24 ± 0.13 ng/mL, respectively. (p = 0.02) Following 4 weeks of treatment, BDNF values were higher in the resveratrol group compared to control 1.64 ± 0.31 ng/mL and 1.32 ± 0.26 ng/mL, respectively (p = 0.031). EC50 values obtained for PHE in resveratrol pretreated arteries were significantly higher than controls (5.33 ± 1.7 × 10(-7 )M/L versus 4.53 ± 1.2 × 10(-8 )M/L, p < 0.05). These results show a significant increase in BDNF concentration in the resveratrol pretreated group. The

  9. Resveratrol Increases Serum BDNF Concentrations and Reduces Vascular Smooth Muscle Cells Contractility via a NOS-3-Independent Mechanism

    PubMed Central

    Malinowski, Bartosz; Grześk, Elżbieta; Grześk, Grzegorz

    2017-01-01

    Resveratrol is a polyphenol that presents both antineuroinflammatory properties and the ability to interact with NOS-3, what contributes to vasorelaxation. Brain-derived neurotrophic factor (BNDF), a molecule associated with neuroprotection in many neurodegenerative disorders, is considered as an important element of maintaining stable cerebral blood flow. Vascular smooth muscle cells (VSMCs) are considered to be an important element in the pathogenesis of neurodegeneration and a potential preventative target by agents which reduce the contractility of the vessels. Our main objectives were to define the relationship between serum and long-term oral resveratrol administration in the rat model, as well as to assess the effect of resveratrol on phenylephrine- (PHE-) induced contraction of vascular smooth muscle cells (VSMCs). Moreover, we attempt to define the dependence of contraction mechanisms on endothelial NO synthase. Experiments were performed on Wistar rats (n = 17) pretreated with resveratrol (4 weeks; 10 mg/kg p.o.) or placebo. Serum BDNF levels were quantified after 2 and 4 weeks of treatment with ELISA. Contraction force was measured on isolated and perfused tail arteries as the increase of perfusion pressure with a constant flow. Values of serum BNDF in week 0 were 1.18 ± 0.12 ng/mL (treated) and 1.17 ± 0.13 ng/mL (control) (p = ns). After 2 weeks of treatment, BDNF in the treatment group was higher than in controls, 1.52 ± 0.23 ng/mL and 1.24 ± 0.13 ng/mL, respectively. (p = 0.02) Following 4 weeks of treatment, BDNF values were higher in the resveratrol group compared to control 1.64 ± 0.31 ng/mL and 1.32 ± 0.26 ng/mL, respectively (p = 0.031). EC50 values obtained for PHE in resveratrol pretreated arteries were significantly higher than controls (5.33 ± 1.7 × 10−7 M/L versus 4.53 ± 1.2 × 10−8 M/L, p < 0.05). These results show a significant increase in BDNF concentration in the resveratrol pretreated group. The

  10. Genetic associations of residual feed intake with serum insulin-like growth factor-I and leptin concentrations, meat quality, and carcass cross sectional fat area ratios in Duroc pigs.

    PubMed

    Hoque, M A; Katoh, K; Suzuki, K

    2009-10-01

    Genetic relationships of measures of residual feed intake and daily feed intake with serum IGF-I concentrations at 8 wk of age and at 105 kg of BW, serum leptin concentration at 105 kg of BW, meat quality, and different fat accumulation traits on 834 Duroc pigs in 7 generations were estimated. Two measures of residual feed intake were estimated from the differences between actual and predicted feed intake: phenotypic residual feed intake (RFI(phe)) and nutritional residual feed intake (RFI(nut)). Meat quality traits included drip loss, cooking loss, pork color score, pork lightness (L*), and pH, whereas fat accumulation traits were subcutaneous fat, intermuscular fat, and total fat percent at 5-6th thoracic vertebra; subcutaneous fat, intermuscular fat, abdominal fat, and total fat percent at one-half body length and at last thoracic vertebra, and seam fat score. The IGF-I concentrations at 8 wk of age and 105 kg of BW had weak genetic correlations with measures of residual feed intake and daily feed intake (absolute values ranging from 0.14 to 0.24). The genetic correlations between measures of residual feed intake and serum leptin concentration were strong and positive (r(g) with RFI(phe) and RFI(nut) were 0.74 and 0.80, respectively). Residual feed intake was moderately but negatively correlated with cooking loss (r(g) with RFI(phe) and RFI(nut) were -0.42 and -0.49, respectively), whereas daily feed intake was moderately and positively correlated with drip loss and pH (0.33 and 0.36, respectively). Daily feed intake was also moderately correlated with subcutaneous fat accumulations at the 5-6th thoracic vertebra (0.31) and one-half body length (0.31) regions and was strongly correlated with accumulations at the last thoracic vertebra region (0.57). The genetic correlations between daily feed intake and intermuscular fat accumulations at all of the carcass sites were strong (0.60, 0.76, and 0.56 for intermuscular fat at 5-6th thoracic vertebra, one-half body

  11. Acute ingestion of catechin-rich green tea improves postprandial glucose status and increases serum thioredoxin concentrations in postmenopausal women.

    PubMed

    Takahashi, Masaki; Miyashita, Masashi; Suzuki, Katsuhiko; Bae, Seong-Ryu; Kim, Hyeon-Ki; Wakisaka, Takuya; Matsui, Yuji; Takeshita, Masao; Yasunaga, Koichi

    2014-11-14

    Elevated postprandial hyperglycaemia and oxidative stress increase the risks of type 2 diabetes and CVD. Green tea catechin possesses antidiabetic properties and antioxidant capacity. In the present study, we examined the acute and continuous effects of ingestion of catechin-rich green tea on postprandial hyperglycaemia and oxidative stress in healthy postmenopausal women. Participants were randomly assigned into the placebo (P, n 11) or green tea (GT, n 11) group. The GT group consumed a catechin-rich green tea (catechins 615 mg/350 ml) beverage per d for 4 weeks. The P group consumed a placebo (catechins 92 mg/350 ml) beverage per d for 4 weeks. At baseline and after 4 weeks, participants of each group consumed their designated beverages with breakfast and consumed lunch 3 h after breakfast. Venous blood samples were collected in the fasted state (0 h) and at 2, 4 and 6 h after breakfast. Postprandial glucose concentrations were 3 % lower in the GT group than in the P group (three-factor ANOVA, group × time interaction, P< 0·05). Serum concentrations of the derivatives of reactive oxygen metabolites increased after meals (P< 0·05), but no effect of catechin-rich green tea intake was observed. Conversely, serum postprandial thioredoxin concentrations were 5 % higher in the GT group than in the P group (three-factor ANOVA, group × time interaction, P< 0·05). These findings indicate that an acute ingestion of catechin-rich green tea has beneficial effects on postprandial glucose and redox homeostasis in postmenopausal women.

  12. Rapid Increase in Serum Low-Density Lipoprotein Cholesterol Concentration during Hepatitis C Interferon-Free Treatment

    PubMed Central

    Abiru, Seigo; Komori, Atsumasa; Nagaoka, Shinya; Saeki, Akira; Uchida, Shinjiro; Bekki, Shigemune; Kugiyama, Yuki; Nagata, Kazuyoshi; Nakamura, Minoru; Migita, Kiyoshi; Nakao, Kazuhiko

    2016-01-01

    Background & Aim We performed lipid analyses at the early period of therapy in patients with chronic hepatitis C who underwent interferon (IFN)-free direct-acting antiviral (DAA) treatment, and we attempted to identify the factors that contributed to a rapid increase in the patients’ serum low-density lipoprotein cholesterol (LDL-C) concentration. Methods We retrospectively analyzed the cases of 100 consecutive patients with HCV infection treated at the National Hospital Organization Nagasaki Medical Center: 24 patients underwent daclatasvir (DCV) and asunaprevir (ASV) combination therapy (DCV/ASV) for 24 weeks, and the other 76 patients underwent ledipasvir and sofosbuvir combination therapy (LDV/SOF) for 12 weeks. ΔLDL-C was defined as the changed in LDL-C level at 28 days from the start of therapy. To determine whether ΔLDL-C was associated with several kinds of factors including viral kinetics, we performed a stepwise multiple linear regression analysis. Results The LDL-C levels in patients treated with LDV/SOF were markedly and significantly elevated (87.45 to 122.5 mg/dl; p<10−10) compared to those in the DCV/ASV-treated patients (80.15 to 87.8 mg/dl; p = 0.0056). The median levels of ΔLDL-C in the LDV/SOF and DCV/ASV groups were 33.2 and 13.1, respectively. LDV/SOF combination therapy as an IFN-free regimen (p<0.001) and ΔHCV core antigen (0–1 day drop) (p<0.044) were identified as independent factors that were closely related to the ΔLDL-C. Conclusions A rapid increase in the serum LDL-C concentration during the IFN-free treatment of hepatitis C was associated with the type of HCV therapy and a decline of HCV core protein. PMID:27680885

  13. Growth hormone (GH) increases cognition and expression of ionotropic glutamate receptors (AMPA and NMDA) in transgenic zebrafish (Danio rerio).

    PubMed

    Studzinski, Ana Lupe Motta; Barros, Daniela Martí; Marins, Luis Fernando

    2015-11-01

    The growth hormone/insulin-like factor I (GH/IGF-I) somatotropic axis is responsible for somatic growth in vertebrates, and has important functions in the nervous system. Among these, learning and memory functions related to the neural expression of ionotropic glutamate receptors, mainly types AMPA (α-amino-3hydroxy-5methylisoxazole-4propionic) and NMDA (N-methyl-d-aspartate) can be highlighted. Studies on these mechanisms have been almost exclusively conducted on mammal models, with little information available on fish. Consequently, this study aimed at evaluating the effects of the somatotropic axis on learning and memory of a GH-transgenic zebrafish (Danio rerio) model (F0104 strain). Long-term memory (LTM) was tested in an inhibitory avoidance apparatus, and brain expression of igf-I and genes that code for the main subunits of the AMPA and NMDA receptors were evaluated. Results showed a significant increase in LTM for transgenic fish. Transgenic animals also showed a generalized pattern of increase in the expression of AMPA and NMDA genes, as well as a three-fold induction in igf-I expression in the brain. When analyzed together, these results indicate that GH, mediated by IGF-I, has important effects on the brain, with improvement in LTM as a result of increased glutamate receptors. The transgenic strain F0104 was shown to be an interesting model for elucidating the intricate mechanisms related to the effect of the somatotropic axis on learning and memory in vertebrates.

  14. Increased serum IL-2R levels in coeliac disease are related to CD4 but not CD8 antigens.

    PubMed

    Blanco, A; Garrote, J A; Arranz, E; Alonso, M; Clavo, C

    1992-11-01

    Forty-three coeliac children, ranging from 1 year and 3 months to 14 years and 9 months, were studied. Twenty-eight patients were in an active phase of the disease, and 15 were in remission. The criteria of coeliac disease (CD) activity were established according to the results of IgA anti-endomysial antibodies (IgA-AEm). Interleukin 2 receptor (IL-2R) and CD4 and CD8 antigens were measured in serum samples by an ELISA technique using two noncompetitive monoclonal antibodies. Antigliadin antibodies of IgG (IgG-AGA) and IgA (IgA-AGA) classes were also measured. The AEm-positive coeliac patient group showed values of 1,860 +/- 948 U/ml for IL-2R, 430 +/- 228 U/ml for CD8, and 36.8 +/- 25.1 U/ml for CD4. AEm-negative patients showed values of 980 +/- 436 U/ml, 350 +/- 243 U/ml, and 24.1 +/- 20 U/ml, respectively. IL-2R levels were the only ones significantly elevated (p < 0.005) in the active coeliac group. On the other hand, IgG-AGA and IgA-AGA were both clearly increased (p < 0.001). IL-2R levels in active coeliac patients correlated with CD4 levels (p < 0.05), but not with CD8, IgG-AGA, and IgA-AGA levels. We also found a surprising negative correlation between AEm antibodies of IgA2 class with both IL-2R (r = 0.471; p < 0.05) and CD8 (r = 0.616; p < 0.05). The results show that in CD there is a lymphocyte activation affecting mainly CD4+ cells and not correlated with serum AGA levels, suggesting an independence of both immunological phenomena and probably with different locations of origin.

  15. Serum HER2 levels are increased in cats with mammary carcinomas and predict tissue HER2 status

    PubMed Central

    Soares, Maria; Ribeiro, Rita; Najmudin, Shabir; Gameiro, Andreia; Rodrigues, Rita; Cardoso, Fátima; Ferreira, Fernando

    2016-01-01

    HER2 is overexpressed in about 30% of feline mammary carcinomas (FMC) and in 15-30% of breast cancers. Women with HER2-positive breast tumors are associated with shorter survival. This study aimed to optimize the detection and quantification of serum HER2 (sHER2) in cats and to evaluate its potential in diagnosing cats with mammary carcinomas (MC) overexpressing HER2. A prospective study was conducted in 60 queens showing MC and 20 healthy animals. Pre-operative serum samples were collected for sHER2 quantification using two immunoassays: ELISA and Dot blot assay. sHER2 levels were compared with tissue HER2 status assessed by immunohistochemistry. Queens with FMC showed significantly higher mean levels of sHER2 by both ELISA and Dot blot assay. A significant difference in the sHER2 levels was also found between cats with HER2-positive MC and those with low-expressing HER2 MC. A significant correlation between sHER2 levels and tumor HER2 status was also found, particularly when ELISA was used (r = 0.58, p < 0.0001). The value of 10 ng/ml was proposed as the optimal cutoff for both immunoassays by ROC analysis. Like in humans, sHER2 levels are increased in cats with MC HER2-positive, strongly suggesting that evaluation of sHER2 levels can be very useful in feline oncology. The results show that ELISA and Dot blot assay can replace the immunohistochemistry technique, due to their efficacy and lower costs for diagnostic purposes and for monitoring the response to anti-HER2 therapies in cats. PMID:26909614

  16. Increased serum interleukin-22 levels in patients with PRL-secreting and non-functioning pituitary macroadenomas.

    PubMed

    Cannavo, S; Ferrau, F; Cotta, O R; Saitta, S; Barresi, V; Cristani, M T; Saija, A; Ruggeri, R M; Trimarchi, F; Gangemi, S

    2014-02-01

    Cytokines' involvement in tumorigenesis has been hypothesized. Interleukin-22 (IL-22) is implicated in proliferative and anti-apoptotic pathways via its receptor IL-22R. Its role in pituitary adenomas has never been investigated. Twenty-seven patients with pituitary macroadenomas (PA, 21 males, mean age 53.8 ± 14.4 years) and 30 healthy controls (19 males, mean age 50.4 ± 8.4 years) were enrolled. Out of 27 PA patients, 17 had a non-functioning tumour (NFPA) and 10 a PRL-secreting adenoma (PRL-oma). Serum IL-22 levels were measured in both patients and controls. Immunohistochemical (IHC) tumoral IL-22R expression was evaluated in 10 patients with NFPA and 4 with PRL-oma. IL-22 levels were significantly higher in PA patients than in controls [32.47 (11.29-70.12) vs. 5.58 (0.19-21.46) pg/mL, p < 0.0001] but did not correlate with tumor maximum diameter and were not associated to pituitary function impairment. PRL-oma patients had significantly higher IL-22 levels than NFPA patients [37.18 (14.82-70.12) vs. 21.29 (11.29-56) pg/mL, p = 0.039]. IHC revealed a strong IL-22R staining in 100 % of PRL-omas and 60 % of NFPAs. We provide the first evidence of increased serum IL-22 levels in patients with pituitary macroadenoma, especially in PRL-omas, regardless of tumor size and/or degree of pituitary function impairment. We also demonstrated the expression of IL22R in all PRL-omas and in 60 % of NFPAs.

  17. Increased pentosidine, an advanced glycation end product, in serum and synovial fluid from patients with knee osteoarthritis and its relation with cartilage oligomeric matrix protein

    PubMed Central

    Senolt, L; Braun, M; Olejarova, M; Forejtova, S; Gatterova, J; Pavelka, K

    2005-01-01

    Background: Pentosidine, an advanced glycation end product, increasingly accumulates in articular cartilage with age, and contributes to the pathogenesis of osteoarthritis (OA). Increased pentosidine concentrations are associated with inflammatory disorders—for example, rheumatoid arthritis. Objective: To compare pentosidine serum concentrations in patients with knee OA and in healthy volunteers and to determine a relationship between pentosidine and cartilage oligomeric matrix protein (COMP)—a marker of articular cartilage destruction. Methods: Paired serum and synovial fluid samples were obtained by arthrocentesis from 38 patients with knee OA and from 38 healthy volunteers. Pentosidine concentration was measured by reverse phase high performance liquid chromatography with fluorescent detection and COMP was determined by sandwich ELISA. Results: Significantly increased serum pentosidine (p<0.01) and COMP (p<0.05) levels were detected in the patients with OA compared with the control group. Serum pentosidine correlated significantly with synovial fluid pentosidine (p<0.001). Pentosidine in synovial fluid (p<0.05) and in serum (p<0.05) correlated significantly with synovial fluid COMP. Pentosidine and COMP concentrations did not correlate significantly with the radiological stage of the disease. Conclusion: Increased pentosidine serum concentration in patients with OA and its correlation with the cartilage destruction marker COMP in synovial fluid suggests that pentosidine may be important in OA pathology and is a new potential OA marker. PMID:15897309

  18. 13C Natural Abundance in Serum Retinol Acts as a Biomarker for Increases in Dietary Provitamin A

    PubMed Central

    Howe, Julie A; Valentine, Ashley R; Hull, Angela K; Tanumihardjo, Sherry A

    2009-01-01

    The natural isotopic composition of 13C and 12C in tissues is largely determined by the diet. Sources of provitamin A carotenoids (e.g., vegetables) typically have a lower 13C to 12C ratio (13C:12C) than preformed vitamin A sources (i.e., dairy and meat) from corn-fed animals, which are prevalent in the US. The 13C:12C of serum retinol (13C:12C-retinol) was evaluated as a biomarker for vegetable intake in a 3-mo dietary intervention designed to promote weight-loss by increased vegetable consumption or reduced calorie and fat intake. Subjects were 21–50 y of age with a BMI between 30–40 kg/m2 and were enrolled from one geographic area in the US. The high vegetable group (n = 20) was encouraged to increase daily vegetable and fruit consumption to 0.95 liter vegetables and 0.24–0.35 liter fruits. The caloric reduction group (n = 17) was encouraged to lower caloric intake by 500 kcal and consume ≤25% kcal from fat daily. Provided meals supplied 75–100% vegetable and fruit goals and 50–67% kcal and fat g per day. Carotenoid supplementation was discontinued by subjects during the study. Serum retinol and provitamin A carotenoid concentrations; intake of preformed vitamin A, provitamin A, and fat; and body weight, fat mass, and lean mass were analyzed for correlations to 13C:12C-retinol. 13C:12C-Retinol decreased in the vegetable group after intervention (P = 0.050) and the correlation with provitamin A intake was approaching significance (P = 0.079). 13C:12C-Retinol did not change in the caloric reduction group (P = 0.43). 13C:12C-Retinol changes with the vitamin A source in the diet and can be used as a biomarker for increases in dietary provitamin A vegetable intake. PMID:19116317

  19. SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria.

    PubMed

    Chino, Yukihiro; Samukawa, Yoshishige; Sakai, Soichi; Nakai, Yasuhiro; Yamaguchi, Jun-ichi; Nakanishi, Takeo; Tamai, Ikumi

    2014-10-01

    Sodium glucose cotransporter 2 (SGLT2) inhibitors have been reported to lower the serum uric acid (SUA) level. To elucidate the mechanism responsible for this reduction, SUA and the urinary excretion rate of uric acid (UE(UA)) were analysed after the oral administration of luseogliflozin, a SGLT2 inhibitor, to healthy subjects. After dosing, SUA decreased, and a negative correlation was observed between the SUA level and the UE(UA), suggesting that SUA decreased as a result of the increase in the UE(UA). The increase in UE(UA) was correlated with an increase in urinary D-glucose excretion, but not with the plasma luseogliflozin concentration. Additionally, in vitro transport experiments showed that luseogliflozin had no direct effect on the transporters involved in renal UA reabsorption. To explain that the increase in UE(UA) is likely due to glycosuria, the study focused on the facilitative glucose transporter 9 isoform 2 (GLUT9ΔN, SLC2A9b), which is expressed at the apical membrane of the kidney tubular cells and transports both UA and D-glucose. It was observed that the efflux of [(14) C]UA in Xenopus oocytes expressing the GLUT9 isoform 2 was trans-stimulated by 10 mm D-glucose, a high concentration of glucose that existed under SGLT2 inhibition. On the other hand, the uptake of [(14) C]UA by oocytes was cis-inhibited by 100 mm D-glucose, a concentration assumed to exist in collecting ducts. In conclusion, it was demonstrated that the UE(UA) could potentially be increased by luseogliflozin-induced glycosuria, with alterations of UA transport activity because of urinary glucose.

  20. Analysis of the effects of increasing doses of ionizing radiation to the exteriorized rat ovary on follicular development, atresia, and serum gonadotropin levels

    SciTech Connect

    Jarrell, J.; YoungLai, E.V.; Barr, R.; O'Connell, G.; Belbeck, L.; McMahon, A.

    1986-02-01

    There is increasing interest in the effects of environmental and therapeutic agents on the reproductive system, in particular, the ovary. To study the effects of controlled doses of ionizing radiation to the ovary, Sprague-Dawley rats had their ovaries exteriorized and subjected to increasing doses of radiation. There was a significant increase in ovarian follicular atresia, a significant increase in serum follicle-stimulating hormone levels, but no change in serum luteinizing hormone levels. This experimental protocol may facilitate the testing putative radioprotectants.

  1. Serum insulin-like growth factors I and II, insulin-like growth factor binding protein-3 and risk of breast cancer in the Japan Collaborative Cohort study.

    PubMed

    Sakauchi, Fumio; Nojima, Masanori; Mori, Mitsuru; Wakai, Kenji; Suzuki, Sadao; Tamakoshi, Akiko; Ito, Yoshinori; Watanabe, Yoshiyuki; Inaba, Yutaka; Tajima, Kazuo; Nakachi, Kei

    2009-12-01

    The Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC Study) was planned in the late 1980s as a large-scale cohort study of persons in various areas of Japan. In the present study, we conducted a nested case-control study and examined associations of breast cancer risk with serum levels of insulin-like growth factors I and II (IGF-I, IGF-II), as well as insulin-like growth factor binding protein-3 (IGFBP-3), among women who participated in the JACC Study and donated blood at the baseline. Sixty-three women who died or suffered from breast cancer were examined. Two or three controls were selected to match each case for age at recruitment and the study area. Controls were alive and not diagnosed as having breast cancer at the diagnosis date of the cases. Associations between the serum IGF-I, IGF-II, IGFBP-3 and breast cancer risk were evaluated using a conditional logistic regression model. In premenopausal Japanese women, IGF-I showed a marginal negative dose-dependent association with the breast cancer risk (trend P= 0.08), but any link disappeared on taking into account IGFBP-3 (trend P= 0.47), which was likely to be inversely associated with the risk. In postmenopausal women, IGFBP-3 showed a marginal dose-dependent association with the risk (trend P= 0.06). Further studies are needed to confirm these findings.

  2. Rapid increase in fibroblast growth factor 21 in protein malnutrition and its impact on growth and lipid metabolism.

    PubMed

    Ozaki, Yori; Saito, Kenji; Nakazawa, Kyoko; Konishi, Morichika; Itoh, Nobuyuki; Hakuno, Fumihiko; Takahashi, Shin-Ichiro; Kato, Hisanori; Takenaka, Asako

    2015-11-14

    Protein malnutrition promotes hepatic steatosis, decreases insulin-like growth factor (IGF)-I production and retards growth. To identify new molecules involved in such changes, we conducted DNA microarray analysis on liver samples from rats fed an isoenergetic low-protein diet for 8 h. We identified the fibroblast growth factor 21 gene (Fgf21) as one of the most strongly up-regulated genes under conditions of acute protein malnutrition (P<0·05, false-discovery rate<0·001). In addition, amino acid deprivation increased Fgf21 mRNA levels in rat liver-derived RL-34 cells (P<0·01). These results suggested that amino acid limitation directly increases Fgf21 expression. FGF21 is a polypeptide hormone that regulates glucose and lipid metabolism. FGF21 also promotes a growth hormone-resistance state and suppresses IGF-I in transgenic mice. Therefore, to determine further whether Fgf21 up-regulation causes hepatic steatosis and growth retardation after IGF-I decrease in protein malnutrition, we fed an isoenergetic low-protein diet to Fgf21-knockout (KO) mice. Fgf21-KO did not rescue growth retardation and reduced plasma IGF-I concentration in these mice. Fgf21-KO mice showed greater epididymal white adipose tissue weight and increased hepatic TAG and cholesterol levels under protein malnutrition conditions (P<0·05). Overall, the results showed that protein deprivation directly increased Fgf21 expression. However, growth retardation and decreased IGF-I were not mediated by increased FGF21 expression in protein malnutrition. Furthermore, FGF21 up-regulation rather appears to have a protective effect against obesity and hepatic steatosis in protein-malnourished animals.

  3. Tumor-dependent increase of serum amino acid levels in breast cancer patients has diagnostic potential and correlates with molecular tumor subtypes

    PubMed Central

    2013-01-01

    Background Malignancies induce changes in the levels of serum amino acids (AA), which may offer diagnostic potential. Furthermore, changes in AA levels are associated with immune cell function. In this study, serum AA levels were studied in breast cancer patients versus patients with benign breast lesions. Methods In a prospective study, serum levels of 15 AA were measured by high performance liquid chromatography before and after surgery in 41 breast cancer patients (BrCA) and nine patients with benign breast lesions (healthy donors, HD). Results were analyzed in relation to clinical tumor data and tested against immunological flow cytometry data. Principal component analysis was performed and the accuracy of AA levels as a potential diagnostic tool was tested. Results Pre- but not postoperative serum AA levels were increased in BrCA in eight out of 15 AA compared with HD. Serum AA levels were highest in the most aggressive (basal-like) as compared with the least aggressive tumor subtype (luminal A). A principal component (PC1) of all measured AA correlated with a mainly pro-inflammatory immune profile, while a second one (PC2, selectively considering AA preoperatively differing between HD and BrCA) could predict health state with an area under the curve of 0.870. Conclusions Breast cancer shows a tumor-dependent impact on serum AA levels, which varies with intrinsic tumor subtypes and is associated with a pro-inflammatory state. Serum AA levels need further evaluation as a potential diagnostic tool. PMID:24237611

  4. Increased Serum Levels of IL-17A and IL-23 Are Associated with Decreased Vitamin D3 and Increased Pain in Osteoarthritis

    PubMed Central

    Askari, Alireza; Naghizadeh, Mohammad Mehdi; Shahi, Abbas; Afsarian, Mohammad Hosein; Paknahad, Abbas; Kennedy, Derek

    2016-01-01

    Introduction Osteoarthritis (OA) is the most common type of arthritis and proinflammatory cytokines have been considered as the main etiologic factor in the pathogenesis of the disease. Serum levels of cytokines, that are associated with innate immunity and TH1 cells, have been analyzed in OA patients, however, there is limited research that profiles cytokines associated with Th17 cells and their relation to vitamin D3 and pain. Material and methods The sera from 131 patients with OA and 262 healthy controls were evaluated for serum levels of IL-17A, IL-21, IL-23 and vitamin D3 using ELISA. Results Serum levels of IL-17A, and IL-23 were statistically higher in OA patients than in healthy controls, while IL-21 and vitamin D3 were significantly lower in OA patients when compared to controls. A significant positive correlation was found between the serum levels of IL-17A and IL-23 using WOMAC pain scores and vitamin D3 serum levels. Discussion The results suggest that IL-17A plays a significant role in OA pathogenesis and the induction of pain. Decreased serum levels of vitamin D3 may reflect a positive role played by the factor in the regulation of immune responses in OA patients. PMID:27820818

  5. Short-term strength training and the expression of myostatin and IGF-I isoforms in rat muscle and tendon: differential effects of specific contraction types.

    PubMed

    Heinemeier, K M; Olesen, J L; Schjerling, P; Haddad, F; Langberg, H; Baldwin, K M; Kjaer, M

    2007-02-01

    In skeletal muscle, an increased expression of insulin like growth factor-I isoforms IGF-IEa and mechano-growth factor (MGF) combined with downregulation of myostatin is thought to be essential for training-induced hypertrophy. However, the specific effects of different contraction types on regulation of these factors in muscle are still unclear, and in tendon the functions of myostatin, IGF-IEa, and MGF in relation to training are unknown. Female Sprague-Dawley rats were subjected to 4 days of concentric, eccentric, or isometric training (n = 7-9 per group) of the medial gastrocnemius, by stimulation of the sciatic nerve during general anesthesia. mRNA levels for myostatin, IGF-IEa, and MGF in muscle and Achilles' tendon were measured by real-time RT-PCR. Muscle myostatin mRNA decreased in response to all types of training (2- to 8-fold) (P < 0.05), but the effect of eccentric training was greater than concentric and isometric training (P < 0.05). In tendon, myostatin mRNA was detected, but no changes were seen after exercise. IGF-IEa and MGF increased in muscle (up to 15-fold) and tendon (up to 4-fold) in response to training (P < 0.01). In tendon no difference was seen between training types, but in muscle the effect of eccentric training was greater than concentric training for both IGF-IEa and MGF (P < 0.05), and for IGF-IEa isometric training had greater effect than concentric (P < 0.05). The results indicate a possible role for IGF-IEa and MGF in adaptation of tendon to training, and the combined changes in myostatin and IGF-IEa/MGF expression could explain the important effect of eccentric actions for muscle hypertrophy.

  6. From Genotype to Phenotype: Nonsense Variants in SLC13A1 Are Associated with Decreased Serum Sulfate and Increased Serum Aminotransferases

    PubMed Central

    Tise, Christina G.; Perry, James A.; Anforth, Leslie E.; Pavlovich, Mary A.; Backman, Joshua D.; Ryan, Kathleen A.; Lewis, Joshua P.; O’Connell, Jeffrey R.; Yerges-Armstrong, Laura M.; Shuldiner, Alan R.

    2016-01-01

    Using genomic applications to glean insights into human biology, we systematically searched for nonsense single nucleotide variants (SNVs) that are rare in the general population but enriched in the Old Order Amish (Amish) due to founder effect. We identified two nonlinked, nonsense SNVs (R12X and W48X) in SLC13A1 (allele frequencies 0.29% and 0.74% in the Amish; enriched 1.2-fold and 3.7-fold, compared to the outbred Caucasian population, respectively). SLC13A1 encodes the apical sodium-sulfate cotransporter (NaS1) responsible for sulfate (re)absorption in the kidneys and intestine. SLC13A1 R12X and W48X were independently associated with a 27.6% (P = 2.7 × 10−8) and 27.3% (P = 6.9 × 10−14) decrease in serum sulfate, respectively (P = 8.8 × 10-20 for carriers of either SLC13A1 nonsense SNV). We further performed the first exome- and genome-wide association study (ExWAS/GWAS) of serum sulfate and identified a missense variant (L348P) in SLC26A1, which encodes the basolateral sulfate-anion transporter (Sat1), that was associated with decreased serum sulfate (P = 4.4 × 10−12). Consistent with sulfate’s role in xenobiotic detoxification and protection against acetaminophen-induced hepatotoxicity, SLC13A1 nonsense SNV carriers had higher aminotransferase levels compared to noncarriers. Furthermore, SLC26A1 L348P was associated with lower whole-body bone mineral density (BMD) and higher serum calcium, consistent with the osteochondrodysplasia exhibited by dogs and sheep with naturally occurring, homozygous, loss-of-function mutations in Slc13a1. This study demonstrates the power and translational potential of systematic identification and characterization of rare, loss-of-function variants and warrants additional studies to better understand the importance of sulfate in human physiology, disease, and drug toxicity. PMID:27412988

  7. Role of insulin-like growth factor-I in the regulation of skeletal muscle adaptation to increased loading

    NASA Technical Reports Server (NTRS)

    Adams, G. R.

    1998-01-01

    Adaptations in muscle mass stimulated by changes in muscle loading state entail alternations in the synthesis and degradation of myofiber proteins and the modulation of myonuclear number such that the ratio between the number of myonuclei and the size of the myofibers remains relatively constant. As depicted schematically in Figure 2.6, the literature regarding the role of IGF-in mediating muscle adaptation to alterations in loading state suggests the following conclusions: During periods of increased loading, myofibers upregulate the expression and secretion of IGF-I. Acting as an autocrine and/or paracrine growth factor, IGF-I stimulates myofiber anabolic processes. Acting as a paracrine growth factor, IGF-I also stimulates adjacent satellite cells to enter the cell cycle and proliferate. Continued myofiber production of IGF-I stimulates some satellite cells to differentiate and then fuse with myofibers, thus providing additional myonuclei in order to maintain or reestablish the myonucleus to myofiber size ratios of the enlarged myofibers.

  8. Elevated Serum Levels of NSE and S-100β Correlate with Increased Risk of Acute Cerebral Infarction in Asian Populations

    PubMed Central

    Li, Ke; Jia, JianJun; Wang, ZhenFu; Zhang, ShanChun

    2015-01-01

    Background We investigated the clinical value of serum levels of neuron-specific enolase (NSE) and human soluble protein-100β (S-100β) in acute cerebral infarction (ACI) patients. Material/Methods A literature search of electronic databases identified relevant case-control studies that examined the correlations between NSE and S-100β serum levels, and ACI. The retrieved studies were screened based on our strict inclusion and exclusion criteria, and high-quality studies were subsequently selected for meta-analysis. STATA software (Version 12.0, Stata Corporation, College Station, TX, USA) was utilized for statistical analysis. Results A total of 13 case-control studies, containing 911 ACI patients and 686 healthy controls, were enrolled in this meta-analysis. The results of the meta-analysis showed that serum levels of NSE and S-100β in ACI patients were significantly higher than the control group. Subgroup analysis based on ethnicity revealed that the serum levels of NSE and S-100β in ACI patients were significantly higher than the control group in Asian population. In Caucasian population, the serum levels of NSE in case group was significantly higher than the control group, but no significant differences in serum levels of S-100β were observed between ACI patients and the control group. Conclusions Based on our results, we conclude that serum levels of NSE and S-100β strongly correlate with ACI in Asian population, and may be important clinical markers for diagnosis and treatment of ACI. PMID:26124190

  9. Deep sea minerals prolong life span of streptozotocin-induced diabetic rats by compensatory augmentation of the IGF-I-survival signaling and inhibition of apoptosis.

    PubMed

    Liao, Hung-En; Shibu, Marthandam Asokan; Kuo, Wei-Wen; Pai, Pei-Ying; Ho, Tsung-Jung; Kuo, Chia-Hua; Lin, Jing-Ying; Wen, Su-Ying; Viswanadha, Vijaya Padma; Huang, Chih-Yang

    2016-07-01

    Consumption of deep sea minerals (DSM), such as magnesium, calcium, and potassium, is known to reduce hypercholesterolemia-induced myocardial hypertrophy and cardiac-apoptosis and provide protection against cardiovascular diseases. Heart diseases develop as a lethal complication among diabetic patients usually due to hyperglycemia-induced cardiac-apoptosis that causes severe cardiac-damages, heart failure, and reduced life expectancy. In this study, we investigated the potential of DSM and its related cardio-protection to increase the life expectancy in diabetic rats. In this study, a heart failure rat model was developed by using streptozotocin (65 mg kg(-1) ) IP injection. Different doses of DSM-1× (37 mg kg(-1) day(-1) ), 2× (74 mg kg(-1) day(-1) ) and 3× (111 mg kg(-1) day(-1) ), were administered to the rats through gavages for 4 weeks. The positive effects of DSM on the survival rate of diabetes rats were determined with respect to the corresponding effects of MgSO4 . Further, to understand the mechanism by which DSM enhances the survival of diabetic rats, their potential to regulate cardiac-apoptosis and control cardiac-dysfunction were examined. Echocardiogram, tissue staining, TUNEL assay, and Western blotting assay were used to investigate modulations in the myocardial contractile function and related signaling protein expression. The results showed that DSM regulate apoptosis and complement the cardiomyocyte proliferation by enhancing survival mechanisms. Moreover DSM significantly reduced the mortality rate and enhanced the survival rate of diabetic rats. Experimental results show that DSM administration can be an effective strategy to improve the life expectancy of diabetic subjects by improving cardiac-cell proliferation and by controlling cardiac-apoptosis and associated cardiac-dysfunction. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 769-781, 2016.

  10. Increased body condition score through increased lean muscle, but not fat deposition, is associated with reduced reproductive response to oestrus induction in beef cows.

    PubMed

    Guzmán, A; Gonzalez-Padilla, E; Garcés-Yepez, P; Rosete-Fernández, J V; Calderón-Robles, R C; Whittier, W D; Keisler, D H; Gutierrez, C G

    2016-10-01

    Energy reserve, estimated as body condition score (BCS), is the major determinant of the re-initiation of ovarian activity in postpartum cows. Leptin, IGF-I and insulin are positively related to BCS and are putative mediators between BCS and reproductive function. However, when BCS and body composition dissociates, concentrations of these metabolic hormones are altered. We hypothesized that increasing lean muscle tissue, but not fat tissue, would diminish the reproductive response to oestrus induction treatments. Thirty lactating beef cows with BCS of 3.10±1.21 and 75.94±12 days postpartum were divided in two groups. Control cows (n=15) were supplemented with 10.20 kg of concentrate daily for 60 days. Treated cows (n=15) were supplemented equally, and received a β-adrenergic receptor agonist (β-AA; 0.15 mg/kg BW) to achieve accretion of lean tissue mass and not fat tissue mass. Twelve days after ending concentrate supplementation/β-AA treatment, cows received a progestin implant to induce oestrus. Cows displaying oestrus were inseminated during the following 60 days, and maintained with a fertile bull for a further 21 days. Cows in both groups gained weight during the supplementation period (Daily weight gain: Control=0.75 kg v. β-AA=0.89 kg). Cows treated with β-AA had a larger increase in BCS (i.e. change in BCS: control=1 point (score 4.13) v. β-AA=2 points (score 5.06; P0.05) did not differ between groups. However, the number of cows displaying oestrus (control 13/15 v. β-AA 8/15; P<0.05) and the percentage cycling (control 6/8 v. β-AA 3/10; P=0.07) after progestin treatment and the pregnancy percentage at the end of the breeding period (control 13/15 v. β-AA 8/15; P<0.05) were lower in β-AA than control cows. In summary, the increase BCS through muscle tissue accretion, but not through fat tissue accretion, resulted in a lower response to oestrus induction, lower percentage of cycling animals and lower pregnancy percentage after progestin treatment

  11. Low Serum Potassium Levels Increase the Infectious-Caused Mortality in Peritoneal Dialysis Patients: A Propensity-Matched Score Study

    PubMed Central

    Ribeiro, Silvia Carreira; Figueiredo, Ana Elizabeth; Barretti, Pasqual; Pecoits-Filho, Roberto; de Moraes, Thyago Proenca

    2015-01-01

    Background and Objectives Hypokalemia has been consistently associated with high mortality rate in peritoneal dialysis. However, studies investigating if hypokalemia is acting as a surrogate marker of comorbidities or has a direct effect in the risk for mortality have not been studied. Thus, the aim of this study was to analyze the effect of hypokalemia on overall and cause-specific mortality. Design, Setting, Participants and Measurements This is an analysis of BRAZPD II, a nationwide prospective cohort study. All patients on PD for longer than 90 days with measured serum potassium levels were used to verify the association of hypokalemia with overall and cause-specific mortality using a propensity match score to reduce selection bias. In addition, competing risks were also taken into account for the analysis of cause-specific mortality. Results There was a U-shaped relationship between time-averaged serum potassium and all-cause mortality of PD patients. Cardiovascular disease was the main cause of death in the normokalemic group with 133 events (41.8%) followed by PD-non related infections, n=105 (33.0%). Hypokalemia was associated with a 49% increased risk for CV mortality after adjustments for covariates and the presence of competing risks (SHR 1.49; CI95% 1.01-2.21). In contrast, in the group of patients with K <3.5mEq/L, PD-non related infections were the main cause of death with 43 events (44.3%) followed by cardiovascular disease (n=36; 37.1%). For PD-non related infections the SHR was 2.19 (CI95% 1.52-3.14) while for peritonitis was SHR 1.09 (CI95% 0.47-2.49). Conclusions Hypokalemia had a significant impact on overall, cardiovascular and infectious mortality even after adjustments for competing risks. The causative nature of this association suggested by our study raises the need for intervention studies looking at the effect of potassium supplementation on clinical outcomes of PD patients. PMID:26091005

  12. Trichomonas vaginalis NTPDase and ecto-5'-nucleotidase hydrolyze guanine nucleotides and increase extracellular guanosine levels under serum restriction.

    PubMed

    Menezes, Camila Braz; Durgante, Juliano; de Oliveira, Rafael Rodrigues; Dos Santos, Victor Hugo Jacks Mendes; Rodrigues, Luiz Frederico; Garcia, Solange Cristina; Dos Santos, Odelta; Tasca, Tiana

    2016-05-01

    Trichomonas vaginalis is the aethiologic agent of trichomoniasis, the most common non-viral sexually transmitted disease in the world. The purinergic signaling pathway is mediated by extracellular nucleotides and nucleosides that are involved in many biological effects as neurotransmission, immunomodulation and inflammation. Extracellular nucleotides can be hydrolyzed by a family of en