Occupational exposure to urban pollutants and plasma insulin-like growth factor 1 (IGF-1)

The aim of present study is to evaluate whether traffic policemen exposed to urban pollutants and possible psycho-social stressors could be at risk of alterations on plasma insulin-like growth factor (IGF-1) levels compared to a control group. Out of a population of 395 Municipal Police employees, the subjects with principal confounding factors (cigarette smoking habits, drinking habits, oral contraceptives being taken, use of paints, solvents and pesticides) were excluded from the study. The remaining traffic policemen were matched with those not exposed by sex, age and length of service; 49 traffic policemen (22 men and 27 women) with outdoor activity exposed to urban pollutants and 49 not exposed subjects (22 men and 27 women) with indoor activity were included in the study. The plasma levels of IGF-1 resulted significantly higher in the male and female traffic policemen compared with control subjects (respectively P<0.001; P<0.001). The authors hypothesise that occupational exposure to chemical stressors, that may interact with possible psycho-social stressors, could cause an alteration on IGF-1 levels in traffic policemen.     

Inhibition of colon cancer cell growth by dietary components: role of the insulin-like growth factor (IGF) system

Large bowel cancer is one of the leading causes of deaths from cancer in Western countries, and the incidence of colorectal cancer is increasing with the steady increase in life expectancy. Modification of diet and lifestyle provide measures of reducing the risk of developing colon cancer. Evidence suggests that the components of the insulin-like growth factor (IGF) system may be appropriate targets for cancer prevention and therapy. A positive correlation was found between dietary and lifestyle, plasma IGF-I, and colon cancer incidence rates. Diet, nutrition, and other lifestyle features affect the expression and production of IGF-1 and other members of the IGF family. The purpose of this review is to examine current evidence obtained from our recent studies and others that investigated the role of dietary components in the regulation of the IGF system and colon cancer cell growth.     

妊娠高血压疾病患者IGF-1与脂代谢相关性分析

目的:分析妊娠高血压疾病患者血清IGF-1水平及其与血脂代谢的相关性。方法:选择40例妊娠高血压疾病患者(轻度及重度子痫前期患者各20名)与20例正常孕晚期孕妇(22~35岁),检测IGF-1及血脂水平,包括血清总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-CH)及低密度脂蛋白胆固醇(LDL-CH)等,同时分析血清IGF-1水平与血脂各项指标的相关性。结果:妊娠高血压疾病患者血清IGF-1水平较正常孕妇低;而其血脂(包括TC、TG、LDL-CH)水平较正常孕妇增高;妊娠高血压疾病患者IGF-1降低的同时伴有TC、TG、LDL-CH的升高,呈负相关,而与HDL-CH无相关性。结论:妊娠高血压疾病患者存在胰岛素抵抗,IGF-1与脂类代谢有相关性。     

Effect of a tomato drink intervention on insulin-like growth factor (IGF)-1 serum levels in healthy subjects

There is concern that dietary factors can modulate the insulin-like growth factor (IGF) system. The aim of this work was to evaluate the effect of a tomato drink intervention providing small amounts of lycopene and other carotenoids on serum levels of IGF-1. Twenty healthy young subjects participated in a repeated measure double-blind, cross-over design. Subjects consumed 250 ml of a tomato drink or a placebo drink for 26 days separated by 26 days wash-out. The tomato drink intake increased plasma lycopene, phytoene, phytofluene, and beta-carotene concentrations by 0.22, 0.12, 0.13, and 0.18 micromol/L, respectively (P < 0.05). No significant effect of the tomato drink intake on IGF-1 levels was observed. However, changes in lycopene before and after each experimental period were inversely and significantly correlated with those of IGF-1 (r = -0.33, P < 0.05, N = 20). No correlation was found with the other carotenoids. A significant reduction of IGF-1 serum level (-5.7%) was observed in subjects (n = 11) with the highest plasma lycopene response but also IGF-1 levels following the tomato drink intake (P < 0.05). No effect was evident after the placebo treatment. The results suggest that further exploration of the role of tomato lycopene on IGF-1 modulation both on healthy and on subjects at risk is necessary.     

The effect of economic status on height, insulin-like growth factor (IGF)-I and IGF binding protein-3 concentrations in healthy Turkish children

OBJECTIVES: The effect of economic status (ES) on growth, insulin-like growth factor (IGF)-I and IGF-binding protein (IGFBP)-3 in healthy children is not well characterized. We aimed to study the interrelationship between height, weight, IGF-I, IGFBP-3, mid-parental height (MPH) and ES. DESIGN/SUBJECTS: Eight hundred and fourteen healthy children (428 boys, 386 girls; age 3-18 years) were classified according to income of the families as low, middle and high. Standard deviation scores (SDSs) of height, weight, MPH, IGF-I and IGFBP-3 were compared between the groups. The combined effect of these parameters and ES on height SDS was investigated with complex statistical models. RESULTS: There was a significant trend for height and weight SDSs to increase with higher income levels in boys, but not in girls. Body mass index (BMI) SDSs were similar in three groups. There was a general trend for MPH SDS to increase with income levels in both sexes. In boys, IGF-I SDS was significantly higher in high ES group than low ES. In girls, IGFBP-3 SDSs were significantly higher in high ES group than in middle ES group. For both genders, height SDS was highly correlated with weight SDS and moderately correlated with BMI SDS, MPH SDS and IGF-1 SDS. All correlations were significant and positive. Complex models showed that MPH (19%), IGF-I (13%) and ES (3%) in boys, and MPH (16%) and IGF-I (7%) in girls have significant contribution to height SDSs. CONCLUSIONS: ES per se, independent of overt malnutrition, affects height, weight, IGF-I and IGFBP-3 with some gender differences in healthy children. Influence of income on height and weight show sexual dimorphism, a slight but significant effect is observed only in boys. MPH is the most prominent variable effecting height in healthy children. Higher height and MPH SDSs observed in higher income groups suggest that secular trend in growth still exists, at least in boys, in a country of favorable economic development.     

胰岛素样生长因子-1和表皮生长因子在窒息后新生儿血中水平的研究

目的:观察胰岛素样生长因子-1(IGF-1)、表皮生长因子(EGF)在窒息后新生儿血中的变化,探讨出生窒息对新生儿胃肠激素的影响。方法:用放射免疫分析法(RIA),测定40例窒息新生儿和30例正常足月新生儿出生后1d、3d、7d血中IGF-1、EGF的水平变化。结果:窒息新生儿血中IGF-1、EGF均比正常对照组显著下降(P<0·01);窒息后新生儿恢复期IGF-1、EGF升高。结论:窒息后新生儿血中IGF-1、EGF的水平下降,表明窒息新生儿胃肠激素水平异常,可能是造成患儿消化功能紊乱的因素之一。     

Markers of fetal growth and serum levels of insulin-like growth factor (IGF) I, -II and IGF binding protein 3 in adults

Fetal growth has been linked with increased risk of cancer and cardiovascular disease later in life. The insulin-like growth factor (IGF) axis has recently been proposed as a predictor of risk of subsequent cancer and cardiovascular disease. However, only few data are available on the possible association between fetal growth and levels of IGFs later in life. We examined the association between markers of fetal growth, i.e. birth weight, birth length and Ponderal Index, from birth records and serum IGF-I, IGF-II, and IGF binding protein 3 (IGFBP-3) levels in 545 middle-aged Danish men and women. We fitted separate multivariate models including birth weight, birth length, Ponderal Index and serum IGF-I, IGF-II, and IGFBP-3, respectively. After adjustment for age, alcohol intake, smoking, diabetes mellitus, systolic and diastolic blood pressure, serum total cholesterol and current height and weight, we found negative associations between birth weight and Ponderal Index, respectively, and serum IGF-II in men, i.e. the mean regression coefficients were -49.41 (95% CI: -87.06-11.77) (microg/l)/kg and -3.49 (95% CI: -6.73-0.25) (microg/l)/(kg/m3), respectively. Furthermore, in men birth weight was negatively associated with the (IGF-I + IGF-II)/IGFBP-3 and IGF-II/IGFBP-3 ratios, which are believed to be indicators of bioavailable IGF and IGF-II, respectively. However, no other associations were found in any of the models. Between 1 and 16% of the variance in serum IGF-I, IGF-II, and IGFBP-3, respectively, could be explained by the statistical models used in the analyses. We found very little support to the hypothesis of an association between fetal growth and the IGF axis throughout life.     

先天性甲状腺功能减低患儿胰岛素样生长因子及其结合蛋白的变化

【目的】观察先天性甲状腺功能减低(CH)新生儿及经替代治疗的CH患儿血清中胰岛素样生长因子．1(IGF-1)及胰岛素样生长因子结合蛋白-3(IGFBP-3)的变化。【方法】收集22例CH新生儿、21例替代治疗后的CH患儿静脉血清，采用放射免疫分析法(RIA)测定ICF-1水平，免疫放射分析法(IRMA)测定IGFBP-3水平，并与20例正常新生儿做对照。【结果】与正常新生儿组比较，CH新生儿血清IGF-1和IGFBP-3水平显著降低；替代治疗1～6月后，CH患儿血清IGF-1和IGFBP．3水平较CH新生儿明显升高。各组内IGF-1与IGFBP-3呈正相关，CH新生儿血清IGF-1和IGFBP-3水平与T4、TSH无明显相关性。【结论】CH患儿治疗前血清中IGF-1和IGFBP-3水平明显降低，替代治疗后水平升高。     

Effects of lycopene on the insulin-like growth factor (IGF) system in premenopausal breast cancer survivors and women at high familial breast cancer risk

Insulin-like growth factor-I (IGF-I) is an important growth factor associated with increased risk of premenopausal breast cancer. We conducted a randomized, placebo-controlled, double-blind, crossover trial to evaluate whether tomato-derived lycopene supplementation (30 mg/day for 2 mo) decreases serum levels of total IGF-I in premenopausal women with 1) a history of breast cancer (n=24) or 2) a high familial breast cancer risk (n=36). Also, IGF binding protein (IGFBP) increasing effects were evaluated. Lycopene supplementation did not significantly alter serum total IGF-I and other IGF system components in the 2 study populations combined. However, statistically significant discordant results were observed between the 2 study populations (i.e., P<0.05 for total IGF-I, free IGF-I, and IGFBP-3). Total IGF-I and IGFBP-3 were increased in the breast cancer survivor population [total IGF-I=7.0%, 95% confidence interval (CI)= -0.2 to 14.3%; IGFBP-3=3.3%, 95% CI=0.7-6.0%), and free IGF-I was decreased in the family history population (-7.6%, 95% CI= -14.6 to -0.6%). This randomized controlled trial shows that 2 mo of lycopene supplementation has no effect on serum total IGF-I in the overall study population. However, lycopene effects were discordant between the 2 study populations showing beneficial effects in high-risk healthy women but not in breast cancer survivors.     

Hierarchical modeling of melanocortin 1 receptor variants with skin cancer risk

The human MC1R gene is highly polymorphic among lightly pigmented populations, and several variants in the MC1R gene have been associated with increased risk of both melanoma and nonmelanoma skin cancers. The functional consequences of MC1R gene variants have been studied in vitro and in vivo in postulated causal pathways, such as G‐protein‐coupled signaling transduction, pigmentation, immune response, inflammatory response, cell proliferation, and extracellular matrix adhesion. In a case‐control study nested within the Nurses’ Health Study, we utilized hierarchical modeling approaches, incorporating quantitative information from these functional studies, to examine the association between particular MC1R alleles and the risk of skin cancers. Different prior matrices were constructed according to the phenotypic associations in controls, cell surface expression, and enzymatic kinetics. Our results showed the parameter variance estimates of each single nucleotide polymorphism (SNP) were smaller when using a hierarchical modeling approach compared to standard multivariable regression. Estimates of second‐level parameters gave information about the relative importance of MC1R effects on different pathways, and odds ratio estimates changed depending on prior models (e.g., the change ranged from ?21% to 7% for melanoma risk assessment). In addition, the estimates of prior model hyperparameters in the hierarchical modeling approach allow us to determine the relevance of individual pathways on the risk of each of the skin cancer types. In conclusion, hierarchical modeling provides a useful analytic approach in addition to the widely used conventional models in genetic association studies that can incorporate measures of allelic function.     

The effect of long-term somatostatin analogue treatment on free and total insulin-like growth factor (IGF) -I, -II and IGF binding protein -1, -2 and -3 serum levels in euthyroid patients with active thyroid eye disease

The aim of this study was to investigate the effect of long-term somatostatin analogue (SM-a) treatment on serum levels of free (F) and total (T) insulin-like growth factor (IGF)-I, -II and IGF binding protein (IGFBP) - 1, -2 and -3 in euthyroid patients with active thyroid ophthalmopathy. For this purpose, we measured the above-mentioned parameters in 21 patients (11M, 10F), aged 50.8+/-11.8 years (range 35-70) and 19 healthy individuals matched for age, gender and body mass index (BMI). A total of 4 SM-a (sandostatin LAR((R))-30) injections, each monthly, were administered in each patient and measurements were performed prior to treatment and 20-30 days after the last injection, while in control individuals the same determinations were performed only once. All patients had active thyroid eye disease (TED), with clinical activity scores (CAS) >/= 4 (5.3+/-1.1) and positive orbital octreoscan in both eyes. Serum F and T IGF-I and IGF-II were determined using non-competitive, time-resolved monoclonal immunofluorometric assays. IGFBP-1 and IGFBP-2 were determined by an in-house radioimmunoassay, while IGFBP-3 by commercially available IRMA. Our results showed that F and T IGF-I, -II and IGFBP-1, -2 and -3 levels in patients before and after administration of SM-a were comparable and the levels did not differ significantly from those of controls. Furthermore, no statistically significant differences emerged in the ratio between molar weights of TIGF-I/IGFBP-3 and TIGF-II/IGFBP-3, as well as in the ratio of F/TIGF-I and F/TIGF-II in patients before and after SM-a therapy. Fourteen patients (66%) experienced a decline in CAS of at least >1 point in each eye after SM-a administration, whereas in the remaining the CAS did not change. Finally, no relationship was found between the levels of the above-mentioned parameters (post therapy) and CAS, octreoscan scores and thyroid hormones levels. In conclusion, we showed that although SM-a administration in euthyroid patients with active TED had a beneficial effect in a significant percentage of patients, this effect was not associated with a decline in the circulating IGF-I, -II and IGFBP-1, -2 and -3 levels, at least under the conditions of the present study. It can be postulated that if the mechanism of action of SM-a is through reduction of IGF-I levels, this effect is possibly exerted in the retrobulbar tissues by local paracrine/autocrine action.     

Reproducibility of assays for steroid hormones, prolactin and insulin-like growth factor-1 in umbilical cord blood

We assessed the reproducibility of measurements of plasma hormone and binding protein levels in umbilical cord blood collected from 30 male and female babies. They were delivered as singleton births from full-term pregnancies (gestational age >or= 37 weeks) in a cord blood donation programme. We assayed three plasma replicates from each cord blood sample at two points in time. Plasma oestradiol, unconjugated oestriol, testosterone, progesterone, prolactin, sex-hormone binding globulin (SHBG), insulin-like growth factor-1 (IGF-1), and IGF binding protein-3 (IGFBP-3) levels were measured in duplicates in the same batch (batch 1). In addition, another set of assays was conducted for each cord blood 1 year apart in a different batch (batch 2). Means and standard deviations for each hormone and binding protein were similar in replicates assayed in batch 1 and 2. Pearson's correlation coefficients were 0.9 or higher in duplicates assayed in batch 1. The correlation coefficients were between 0.77 and 0.96 for between-batch assays. Intra-class correlation coefficients (ICC) were higher than 0.9 for assay of SHBG [95% CI 0.92, 1.0] and progesterone [95% CI 0.87, 0.97] and between 0.8 and 0.9 for assay of oestradiol, unconjugated oestriol, prolactin, IGF-1, and IGFBP-3. The lowest ICC value was found for testosterone (ICC = 0.74; [95% CI 0.56, 1.0]). These data indicate a high reproducibility of cord blood hormone measurements; minimal differences were observed between the calibrated and the original regression coefficients for the association of hormones/binding proteins with percent of CD34+ cells in mononuclear cells.     

IGF-1对体外培养囊胚细胞抗凋亡的作用

目的:探讨胰岛素样生长因子-1(IGF-1)对体外培养囊胚细胞抗凋亡的作用。方法:获取妊娠3.5天小鼠囊胚,分别移入3个培养皿中,为A、B、C 3组,A组(基础培养液)、B组(基础培养液+30 mmol/L的葡萄糖溶液)、C组(基础培养液+30 mmol/L的葡萄糖溶液+100 ng/ml的人重组IGF-1)。连续培养72 h后,采用免疫组化S-P法检测各组囊胚细胞中Bax和Bcl-2的表达,利用计算机图像分析技术测量各组囊胚细胞中Bax和Bcl-2蛋白表达的平均光密度和平均阳性面积。结果:B组囊胚细胞中Bax的表达明显高于A组和C组(P<0.05),而B组囊胚细胞中Bcl-2的表达却低于A组和C组(P<0.05)。结论:IGF-1对高糖诱导的小鼠着床前早期胚胎凋亡起了抑制作用。     

Levels of plasma insulin-like growth factor I (IGF I), IGF II,IGF binding proteins,type 1 IGF receptor and growth hormone binding protein in community-dwelling elderly subjects with no malnutrition and no inflammation

Plasma samples from community-dwelling subjects aged 65 to 92 presenting no malnutrition and no inflammation (as assessed by albumin, transthyretin, CRP, and orosomucoid levels and BMI) were compared to those of healthy controls aged 20 to 65 to determine the effect of aging on the IGF system. Concentrations of IGF I, IGF II and IGFBP3 significantly decreased, and those of GHBP slightly increased with age from 20 to 92 years (n=327 r=-0.64 p<0.0001; n=45 r=-0.44 p<0.003; n=91 r=-0.23 p<0.03 and n=61 r=0.26; p<0.05 respectively). Western immunoblotting showed that the proteolysis of IGFBP3 was not significantly different in elderly and younger subjects. The affinity of the IGF type 1 receptor for IGF I was moderately lower (Ki=0.56 0.2 vs 0.33 0.1, nM respectively; p<0.005) and the number of binding sites was moderately higher (10.4 1.5 vs 8.1 1.9 binding sites/cell, respectively; p<0.03) in the elderly than in the younger adults. Our results suggest that the age-related decline in plasma levels of IGF I, IGF II and IGFBP3 occurs independently from malnutrition and inflammation processes. GHBP plasma levels, which reflect the number of GH receptors at the level of the liver, do not decline in our malnutrition-free elderly population, and thus are not involved in the decline of IGF I plasma levels with age. In the elderly, affinity and number of type 1 IGF receptor were close to those of younger subjects; the decline in IGF I plasma levels may account for the small rise in the number of type 1 IGF receptors binding sites per cell.     

胰岛素样生长因子受体(IGF-1R)重组单链可变片段的纯化优化

目的:将DoE应用于IGF-IR重组scFv的纯化优化,建立最优纯化条件,得到纯度高、收率高的最终产物。方法:本研究采用DoE方法对大肠杆菌中表达的1型胰岛素样生长因子受体(IGF-1R)进行重组单链可变片段(scFv)的优化纯化。结果:最终得到纯度为98%的scFv。最后通过20倍放大实验对优化条件进行了验证。结论:我们提出,这里描述的DoE方法也适用于生产其他重组抗体结构。     

Serum insulin-like growth factor (IGF)-I concentrations are reduced by short-term dietary restriction and restored by refeeding in domestic cats (Felis catus).

Nutritional modulation of insulin-like growth factors (IGF) and their binding proteins (IGFBP) is well established. The effect of nutritional restriction on the serum IGF/IGFBP system of adult cats was investigated to evaluate serum IGF-I as a biochemical marker of nutritional status. Assays for measuring feline serum IGF and IGFBP were validated and normal ranges established in a study population of 46 healthy nonobese adult cats. Serum concentrations of IGF-I and IGF-II correlated significantly with body weight (r = 0.75, P < 0. 0001 and r = 0.34, P < 0.03, respectively). Serum IGFBP profiles were similar to other species, including humans, dogs and guinea pigs. IGFBP-3 was the predominant binding protein reflecting IGF-I concentrations and body size. Serum IGFBP-2 concentrations were high relative to the normal human serum pool (NHS) control. Food withdrawal for 18 h followed by refeeding did not alter circulating IGF or IGFBP concentrations, including IGFBP-1, in nine cats. Short-term dietary restriction of nine adult cats to supply initially 56% (56%M) and then 42.5% (42.5%M) of calculated maintenance energy requirements for 14 d resulted in a significant weight loss (P < 0.01). However, serum IGF-I concentrations fell significantly (-51%, P < 0.01) only with 42.5%M restriction. Serum IGF-II, IGFBP, insulin and albumin concentrations were not altered during the study. We conclude that nutrition does modulate the adult feline IGF/IGFBP system, but to a lesser extent than in other species. Further evaluation is required before serum IGF-I can be used for the assessment of nutritional status in adult cats.     

胰岛素样生长因子受体-1在子宫内膜癌组织中的表达及意义

目的研究胰岛素样生长因子(insulin like growth factor,IGF)在子宫内膜癌组织中的表达情况,并探讨IGF系统与子宫内膜癌发生之间的关系。方法选择子宫内膜癌患者30例和因良性疾病切除子宫的患者20例作为对照,选用Western Blot方法检测子宫内膜癌组织中胰岛素样生长因子受体-1(insulinlike growth factor receptor-1,IGF-1R)的水平。结果发现子宫内膜癌组织中IGF-1R的表达明显高于正常子宫内膜组织,且与分期密切相关。结论 IGF-1R在子宫内膜癌的发生发展中起着重要作用,其受体阻断剂的应用可能是一个有前景的治疗方法 。     

缺氧诱导因子-1在宫颈癌发生中的作用研究

缺氧诱导因子-1是一种重要的缺氧应答调控因子,能与缺氧反应基因上特定位点结合,启动靶基因的转录,使机体对缺氧产生一系列适应性反应。其在维持氧稳定、细胞能量代谢、肿瘤血管生成及转移、细胞增殖与凋亡等诸多方面起着重要作用。该文就缺氧诱导因子-1的生物学特性和在宫颈癌中的研究现状作以概述。     

Lycopene inhibition of IGF-induced cancer cell growth depends on the level of cyclin D1

Summary Background Insulin-like growth factors (IGFs) play an important role in normal and cancerous cell proliferation. Moreover, in recent studies IGF-I has been implicated as a major cancer risk factor. The tomato carotenoid lycopene and all-trans retinoic acid (atRA) have been shown to inhibit growth factor-induced proliferation of different types of cancer cells. This action is associated with inhibition of cell cycle progression in G₀/G₁ phase. Cyclin D1 acts as a growth factor sensor in G₁ phase and is overexpressed in many breast cancer tumors. We have previously demonstrated that slowdown of serum-stimulated cell cycle progression from G₁ to S phase by lycopene correlates with reduction in cyclin D1 levels, suggesting that the expression of this protein is a main target for lycopene’s action. Aim of the study To determine whether the reported reduction in cyclin D1 level is the key mechanism for lycopene and atRA inhibitory action on IGF-I-induced cell cycle progression. Results Human breast (MCF-7) and endometrial (ECC-1) cancer cells were synchronized in G₀/G₁ phase by serum deprivation followed by stimulation with IGF-I. Cell treatment with lycopene and atRA inhibited IGF-I-stimulated cell cycle progression from G₁ to S phase and decreased retinoblastoma protein (pRb) phosphorylation. These events were associated with a reduction in cyclin D1 and p21^CIP1/WAF1 level, but not that of p27^KIP1. To test the hypothesis that the decrease in cyclin D1 has a major role in the inhibitory effects of lycopene and atRA, we examined the ability of these two agents to suppress cell cycle progression in MCF-7.7D1.13 cells which are capable of expressing cyclin D1 under the control of the Zn-inducible metallothionein promoter. Our results showed that ectopic expression of cyclin D1 can overcome cell cycle inhibition caused by lycopene and atRA. Conclusions Our findings suggest that attenuation of cyclin Dl levels by lycopene and atRA is an important mechanism for the reduction of the mitogenic action of IGF-I.