A candidate targeting molecule of insulin-like growth factor-Ⅰ receptor for gastrointestinal cancers

Advances in molecular research in cancer have brought new therapeutic strategies into clinical usage.One new group of targets is tyrosine kinase receptors,which can be treated by several strategies,including small molecule tyrosine kinase inhibitors(TKIs) and monoclonal antibodies(mAbs).Aberrant activation of growth factors/receptors and their signal pathways are required for malignant transformation and progression in gastrointestinal(GI) carcinomas.The concept of targeting specif ic carcinogenic receptors has been validated by successful clinical application of many new drugs.Type I insulin-like growth factor(IGF) receptor(IGF-IR) signaling potently stimulates tumor progression and cellular differentiation,and is a promising new molecular target in human malignancies.In this review,we focus on this promising therapeutic target,IGF-IR.The IGF/IGF-IR axis is an important modifier of tumor cell proliferation,survival,growth,and treatment sensitivity in many malignant diseases,including human GI cancers.Preclinical studies demonstrated that downregulation of IGF-IR signals reversed the neoplastic phenotype and sensitized cells to anticancer treatments.These results were mainly obtained through our strategy of adenoviruses expressing dominant negative IGF-IR(IGF-IR/dn) against gastrointestinal cancers,including esophagus,stomach,colon,and pancreas.We also summarize a variety of strategies to interrupt the IGFs/IGF-IR axis and their preclinical experiences.Several mAbs and TKIs targeting IGF-IR have entered clinical trials,and early results have suggested that these agents have generally acceptable safety profiles as single agents.We summarize the advantages and disadvantages of each strategy and discuss the merits/demerits of dual targeting of IGF-IR and other growth factor receptors,including Her2 and the insulin receptor,as well as other alternatives and possible drug combinations.Thus,IGF-IR might be a candidate for a molecular therapeutic target in human GI carcinomas.

Insulin-like growth factor-I receptor in proliferation and motility of pancreatic cancer

AIM:To develop a molecular therapy for pancreatic cancer, the insulin-like growth factor-I (IGF-I) signaling pathway was analyzed.METHODS: Pancreatic cancer cell lines (MIA-Paca2, NOR-P1, PANC-1, PK-45H, PK-1, PK-59 and KP-4) were cultured in media with 10 mL/L fetal bovine serum. Western blotting analysis was performed to clarify the expression of IGF-I receptor (IGF-IR). Picropodophyllin (PPP), a specific inhibitor of IGF-IR, LY294002, a specific inhibitor of phosphatidylinositol3 kinase (PI3K), and PD98059, a specific inhibitor of mitogen-activated protein kinase, were added to the media. After 72 h, a 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt (MTS) assay was performed to analyze cell proliferation. A wound assay was performed to analyze cell motility with hematoxylin and eosin (HE) staining 48 h after addition of each inhibitor. RESULTS: All cell lines clearly expressed not only IGF-IR but also phosphorylated IGF-IR. PPP significantly suppressed proliferation of MIA-Paca2, NOR-P1, PANC-1, PK-45H, PK-1, PK-59 and KP-4 cells to 36.9% ± 2.4% (mean ± SD), 30.9% ± 5.5%, 23.8% ± 3.9%, 37.1% ± 5.3%, 10.4% ± 4.5%, 52.5% ± 4.5% and 22.6% ± 0.4%, at 2 μmol/L, respectively (P < 0.05). LY294002 significantly suppressed proliferation of MIA-Paca2, NOR-P1, PANC-1, PK-45H, PK-1, PK-59 and KP-4 cells to 44.4% ± 7.6%, 32.9% ± 8.2%, 53.9% ± 8.0%, 52.8% ± 4.0%, 32.3% ± 4.2%, 51.8% ± 4.5%, and 30.6% ± 9.4%, at 50 μmol/L, respectively (P < 0.05). PD98059 did not significantly suppress cell proliferation. PPP at 2 μmol/L suppressed motility of MIA-Paca2, NOR-P1, PANC-1, PK-45H, PK-1, PK-59 and KP-4 cells to 3.0% ± 0.2%, 0%, 0%, 2.0% ± 0.1%, 5.0% ± 0.2%, 3.0% ± 0.1%, and 5.0% ± 0.2%, respectively (P < 0.05). LY294002 at 50 μmol/L suppressed motility of MIA-Paca2, NOR-P1, PANC-1, PK-45H, PK-1, PK-59 and KP-4 to 3.0% ± 0.2%, 0%, 3.0% ± 0.2%, 0%, 0%, 0% and 3% ± 0.1%, respectively (P < 0.05). PD980509 at 20 μmol/L did not suppress motility. Cells were observed by microscopy to analyze the morphological changes induced by the inhibitors. Cells in medium treated with 2 μmol/L PPP or 50 μmol/L LY294002 had pyknotic nuclei, whereas those in medium with 20 μmol/L PD98059 did not show apoptosis.CONCLUSION: IGF-IR and PI3K are good candidates for molecular therapy of pancreatic cancer.

DIAGNOSTIC VALUE OF SERUM INSULIN- LIKE GROWTH FACTOR BINDING PROTEIN- 3 IN CHILDREN WITH OR WITHOUT GROWTH HORMONE DEFICIENCY

OBJECTIVE: To study the value of serum insulin-like growth factor binding protein-3 (IGFBP-3) levels in differential diagnosis of growth hormone deficiency (GHD). METHODS: To measure serum IGFBP-3 levels by RIA in normal children and adolescents, GHD children and short-stature children without GHD. RESULTS: Serum level of IGFBP-3 in 129 children with untreated GHD and with no pubertal development was 1.6 +/- 0.9 mg/L, which was less than that in normal group of the same age, but overlapped with the normal children in Tanner stage I. After six-month treatment with recombinant human growth hormone (rhGH), serum level of IGFBP-3 in 59 GHD significantly increased from 1.3 +/- 0.7 mg/L to 2.7 +/- 0.9 mg/L, accompanied by an increase of body heights, growth velocities and serum level of IGF-1. Serum level of IGFBP-3 in 55 short-stature children without GHD was 3.3 +/- 2.2 mg/L, which was not significantly different from that in normal group. CONCLUSION: Serum IGFBP-3 level can reflect the status of GH secretion in children with GHD and is a useful marker for differential diagnosis of GHD.

Insulin-like Growth Factor-Ⅰ Gene Cloning and Protein Expression in Bovine Trabecular Meshwork Tissue and Cells

Whether cultured bovine trabecular meshwork cells and trabecular tissue ex vivo express insulin like growth factor I (IGF Ⅰ) messenger RNA (mRNA) and protein was investigated. Total RNA of cultured bovine trabecular meshwork cells as well as trabecular meshwork tissue freshly excised from bovine eyes was extracted, and reverse transcriptase polymerase chain reaction (RT PCR) was used to detect IGF Ⅰ mRNA. RT PCR product was verified by sequencing. Immunohistochemical stain was used to detect IGF Ⅰ protein. The results showed that a single PCR amplified product was obtained, and the sequence was homologous to the known sequence.. IGF Ⅰ immunostain was positive in the cytoplasm of trabecular meshwork cells. It was concluded that trabecular meshwork cells produce IGF Ⅰ and contribute to the presence of IGF Ⅰ in trabecular meshwork microenvironment as well as aqueous humor. Trabecular meshwork cells were affected by IGF Ⅰ not only through paracrine, but also autocrine action. Whether abnormal down regulations in IGF Ⅰ production may contribute to the pathogenesis of primary open angle glaucoma and the possibility of promoting the autocrine action of IGF Ⅰ by trabecular meshwork cells to treat the diesease is worth further investigation.

Modified insulin-like growth factor 1 containing collagen-binding domain for nerve regeneration

Insulin-like growth factor 1 （IGF-I） is a potential nutrient for nerve repair. However, it is impractical as a therapy because of its limited half- life, rapid clearance, and limited target specificity. To achieve targeted and long-lasting treatment, we investigated the addition of a binding structure by fusing a collagen-binding domain to IGF- 1. After confirming its affinity for collagen, the biological activity of this construct was examined by measuring cell proliferation after transfection into PC12 and Schwann cells using a 3-（4,5-dimethyl-2-thiazolyl）-2,5-di- phenyl-2-H-tetrazolium bromide assay. Immunofluorescence staining was conducted to detect neurofilament and microtubule-associated protein 2 expression, while real time-polymerase chain reaction was utilized to determine IGF-1 receptor and nerve growth/actor mRNA expression. Our results demonstrate a significant increase in collagen-binding activity of the recombinant protein compared with IGF-1. Moreover, the recombinant protein promoted proliferation of PC12 and Schwann cells, and increased the expression of neurofilament and microtubule-associated protein 2. Importantly, the recombinant protein also stimulated sustained expression of IGF-1 receptor and nerve growth factor mRNA for days. These results show that the recombinant protein achieved the goal of targeting and long-lasting treatment, and thus could become a clinically used factor for promoting nerve regeneration with a prolonged therapeutic effect.

^(131)I治疗对分化型甲状腺癌患者术后血清iPTH、IGF-1水平的影响

目的探讨^(131)I治疗对分化型甲状腺癌患者术后血清全段甲状旁腺激素(iPTH)、胰岛素样生长因子1(IGF-1)水平的影响。方法回顾性分析河南科技大学第一附属医院2020年1月至2022年9月收治的73例分化型甲状腺癌患者,均接受甲状腺全切除并于术后2个月采用^(131)I治疗,随访1个月根据治疗情况将患者分为有效组(51例)和无效组(22例)。比较两组患者治疗前及治疗7 d iPTH和IGF-1水平,以及有效组治疗后各时间点血清iPTH、IGF-1水平。结果两组患者治疗后7 d血清iPTH、IGF-1水平均低于治疗前,且有效组低于无效组(P<0.05);有效组治疗后不同时间点血清iPTH、IGF-1水平差异有统计学意义(P<0.05)。结论分化型甲状腺癌患者^(131)I治疗后血清iPTH、IGF-1水平变化可用于判断甲状旁腺功能恢复情况,血清iPTH还可预示术后低钙血症的发生。

On implications of somatostatin in diabetic retinopathy

Somatostatin,a naturally produced neuroprotective peptide,depresses excitatory neurotransmission and exerts anti-proliferative and anti-inflammatory effects on the retina.In this review,we summarize the progress of somatostatin treatment of diabetic retinopathy through analysis of relevant studies published from February 2019 to February 2023 extracted from the PubMed and Google Scholar databases.Insufficient neuroprotection,which occurs as a consequence of declined expression or dysregulation of retinal somatostatin in the very early stages of diabetic retinopathy,triggers retinal neurovascular unit impairment and microvascular damage.Somatostatin replacement is a promising treatment for retinal neurodegeneration in diabetic retinopathy.Numerous pre-clinical and clinical trials of somatostatin analog treatment for early diabetic retinopathy have been initiated.In one such trial(EUROCONDOR),topical administration of somatostatin was found to exert neuroprotective effects in patients with pre-existing retinal neurodysfunction,but had no impact on the onset of diabetic retinopathy.Overall,we concluded that somatostatin restoration may be especially beneficial for the growing population of patients with early-stage retinopathy.In order to achieve early prevention of diabetic retinopathy initiation,and thereby salvage visual function before the appearance of moderate non-proliferative diabetic retinopathy,several issues need to be addressed.These include the needs to:a)update and standardize the retinal screening scheme to incorporate the detection of early neurodegeneration,b)identify patient subgroups who would benefit from somatostatin analog supplementation,c)elucidate the interactions of somatostatin,particularly exogenously-delivered somatostatin analogs,with other retinal peptides in the context of hyperglycemia,and d)design safe,feasible,low cost,and effective administration routes.

Growth hormone stimulates remnant small bowel epithelial cell proliferation

INTRODUCTIONCurrently the major treatment choices for shortbowel syndrome are parenteral nutrition and smallbowel transplantation.Both therapies involvegreat fiscal challenge and recurring complications.Recent years have witnessed the promisingexperimental results of pharmacologicalrehabilitation of remnant small bowel.

Effect of growth hormone on small intestinal homeostasis relation to cellular mediators IGF-I and IGFBP-3

AIM:To evaluate the effects of growth hormone(GH) on the histology of small intestines which might be related to the role of insulin like growth factor(IGF)-I, IGF-binding protein 3(IGFBP-3)and its receptors. METHODS:Twelve week-old adult male Wistar albino rats were divided into two groups.The study group(n =10),received recombinant human growth hormone (rGH)at a dose of 2 mg/kg per day subcutaneously for 14 d and the control group(n=10)received physiologic serum.Paraffin sections of jejunum were stained with periodic acid shift(PAS)and hematoxylin and eosin(HE) for light microscopy.They were also examined for IGF-I, IGFBP-3 and IGF-receptor immunoreactivities.Staining intensity was graded semi-quantitatively using the HS- CORE. RESULTS:Goblet cells and the cells in crypt epitheliawere significantly increased in the study group compared to that of the control group.We have demonstrated an increase of IGF-I and IGFBP-3 immunoreactivities in surface epithelium of the small intestine by GH application.IGF-I receptor immunoreactivities of crypt,villous columnar cells,enteroendocrine cells and muscularis mucosae were also more strongly positive in the study group compared to those of in the control group. CONCLUSION:These findings confirm the important trophic and protective role of GH in the homeostasis of the small intestine.The trophic effect is mediated by an increase in IGF-I synthesis in the small intestine, but the protective effect is not related to IGF-I.

Effect of glucocorticoid treatment on insulin like growth factor-Ⅰ and its binding proteins in children with nephrotic syndrome

Objective To identify the changes in serum insulin like growth factor Ⅰ (IGF Ⅰ) and IGF binding proteins (IGFBPs) in children with nephrotic syndrome (NS) and the effect of glucocorticoid on serum IGF Ⅰ and IGFBPs Methods We measured serum IGF Ⅰ and IGFBPs levels by radioimmune assay and immune radiomagnetic assay in 36 children with NS, consisting of an active stage group (ANS, n=12), a remission stage group (RE, n=12), an active stage group with glucocorticoid treatment (GNS, n=12), and a normal control group (NC, n=10) Results 1) Compared to NC, serum levels of IGF Ⅰ and IGFBP 3 were decreased ( P <0 01); serum levels of IGFBP 1 and IGFBP 2 were increased ( P <0 01) in the ANS group 2) Serum levels of IGF Ⅰ and IGFBP 3 were higher and IGFBP 1 and IGFBP 2 were lower in the RE Group than in theANS Group ( P <0 01) 3) Compared to the ANS group, serum levels of IGF Ⅰ and IGFBP 3 were increased ( P <0 01) and serum levels of IGFBP 1 and IGFBP 2 were decreased ( P <0 01) in the GNS group 4) A correlation was found between serum levels of IGFBP 3 and albumin in the active stage group ( r =0 76, P <0 01) There was also a correlation between serum levels of IGF Ⅰ and IGFBP 3 and an inverse correlation between the serum level of IGF Ⅰ and serum levels of IGFBP 1 and IGFBP 2 in the ANS group No other correlations were observed Conclusions The serum levels of IGF Ⅰ and IGFBPs are altered in children in the active stage of NS, but return to normal in the remission stage GC treatment may influence serum IGF Ⅰ and IGFBPs in children with NS Changes in IGF Ⅰ and IGFBPs levels may play a role in the growth retardation of NS children

Research on construction and identification of lentiviral vector of expressing miRNA targeting IGF1R gene regulated by survivin promoter and its inhibition to liver cancer cell growth

Objective： The aim of the study was to investigate the interference and anti-tumor effects of lentiviral vector of miRNA targeting IGF1R gene regulated by survivin promoter. Methods： The fragment of the survivin promoter was acquired by PCR amplification and inserted into pPRIME to recombinant plasmid sur-pPRIME. The complementary DNA containing both sense and antisense Oligo DNA of the targeting sequence was designed, synthesized and cloned into the sur-pPRIME vector, named sur-pPRIME-IGF1R-miR30-shRNA. Viruses were propagated on 293T cells. Viruses were purified by CsCI gradient according to standard techniques, and functional PFU titers were determined by plaque assay on 293 cells. The effect of sur-pPRIME-IGF1R-miR30-shRNA on IGF1R expression of Hep3B cells was detected by RT-PCR and Western blot. The antitumor potential of sur-pPRIME-IGF1R-miR30-shRNA to Hep3B cells was evaluated by CCK-8 assay. Results： sur-pPRIME-IGF1R-miR30-shRNA was constructed successfully. Functional PFU titers of sur-pPRIME-IGF1R-miR30-shRNA were 4.58×10^9 PFU/rnL. Sur-pPRIME-IGF1R-miR30-shRNA was more effective to inhibit IGF1R expression in mRNA or protein levels and the proliferation of Hep3B cells. Conclusion： sur-pPRIME-IGF1R-miR30-shRNA expressing IGF1R-siRNA can inhibit IGF1R expression and may be used for further investigation of gene therapy of liver cancer.

癫痫发作患者病情严重程度与氧化应激指标、BDNF、IGF-1水平的关系

【目的】探讨癫痫发作患者病情程度与氧化应激指标、脑源性神经营养因子(BDNF)和胰岛素样生长因子(IGF-1)水平的关系。【方法】本院收治的198例癫痫发作患者,根据发作严重程度,分为轻度组71例、中度组74例、重度组53例,另选取本院同期体检健康者68例为对照组。比较四组一般资料和血清氧化应激指标[丙二醛(MDA)、过氧化氢酶(CAT)、超氧化物歧化酶(SOD)、总抗氧化力(T-AOC)]及血清BDNF和IGF-1水平;分析不同病情程度癫痫发作患者各指标水平与病情程度的相关性,并分析血清MDA、CAT、SOD、T-AOC与BDNF、IGF-1水平的相关性。【结果】不同病情程度癫痫发作患者血清CAT、SOD、T-AOC水平显著低于对照组,MDA水平显著高于对照组,且随着病情严重程度增加,CAT、SOD、T-AOC水平呈递减趋势,MDA水平呈递增趋势(均P<0.05)。不同分级癫痫发作患者血清BDNF水平显著低于对照组,IGF-1水平显著高于对照组,且随着病情严重程度增加,BDNF呈递减趋势,IGF-1呈递增趋势(均P<0.05)。Pearson相关分析显示,患者血清CAT、SOD、T-AOC、BDNF水平与病情严重程度均呈负相关(P<0.05),MDA、IGF-1水平则与病情严重程度呈正相关(P<0.05)。BDNF与MDA水平呈负相关(P<0.05),与CAT、SOD、T-AOC水平呈正相关(P<0.05),IGF-1与MDA水平正相关(P<0.05),与CAT、SOD、T-AOC水平负相关(P<0.05)。【结论】癫痫发作患者氧化应激水平及BDNF、IGF-1水平在不同病情程度中存在明显差异,癫痫发作患者病情程度与氧化应激指标、BDNF、IGF-1水平及氧化应激指标水平与BDNF、IGF-1水平存在明显相关性。

IGF-Ⅰ、Anti-HBs及IL-4对乙型肝炎的诊断价值

目的探讨胰岛素样生长因子Ⅰ(IGF-Ⅰ)、乙型肝炎病毒表面抗原抗体(Anti-HBs)以及微环境因子白细胞介素-4(IL-4)对乙型肝炎的诊断价值,以期为临床治疗提供参考。方法本研究选择大连市第五人民医院2019年2月—2022年2月收治的71例乙型肝炎患者作为研究组研究对象,另选同期于该院进行体检的50例健康个体为对照组研究对象。比较2组研究对象IGF-Ⅰ、Anti-HBs及IL-4水平;采用绘制ROC曲线的方式分别计算IGF-Ⅰ、Anti-HBs及IL-4水平对乙型肝炎的诊断效能;通过Pearson相关分析探究乙型肝炎患者IGF-Ⅰ、Anti-HBs及IL-4水平的相关性。结果研究组患者IGF-Ⅰ及IL-4水平均高于对照组,而Anti-HBs水平低于对照组,差异有统计学意义(P<0.05)。分别绘制IGF-Ⅰ、AntiHBs及IL-4水平诊断乙型肝炎的ROC曲线,结果显示IGF-Ⅰ、Anti-HBs及IL-4水平诊断乙型肝炎的AUC分别为0.9133(P<0.001)、0.9500(P<0.001)、0.7067(P=0.006)。Pearson相关分析结果显示,乙型肝炎患者IGF-Ⅰ、AntiHBs及IL-4呈明显相关性,其中IGF-Ⅰ与Anti-HBs呈负相关关系(r=-0.5363,P<0.001),与IL-4呈正相关关系(r=0.2826,P<0.001),Anti-HBs与IL-4呈负相关关系(r=-0.2408,P<0.001)。结论IGF-Ⅰ、Anti-HBs以及IL-4水平在乙型肝炎患者中呈现异常表达状态,且相互之间存在明显的相关性,可以考虑将它们应用于乙型肝炎的鉴别诊断中。

甲状腺功能亢进对2型糖尿病患者血清IGF-1及骨代谢指标的影响

【目的】探讨甲状腺功能亢进(简称甲亢)对2型糖尿病(T2DM)患者血清胰岛素样生长因子-1(IGF-1)及骨代谢指标的影响。【方法】选取铜川矿务局中心医院2017年2月至2022年2月收治的77例T2DM合并甲亢患者(观察组),另选取同期铜川矿务局中心医院收治的70例单纯T2DM患者(对照组)。比较两组血糖[空腹血糖(FPG)、糖化血红蛋白(HbA1c)]、甲状腺功能指标[游离三碘甲状腺原氨酸(FT_(3))、游离甲状腺素(FT_(4))、促甲状腺激素(TSH)]指标、胰岛素样生长因子[胰岛素样生长因子-1(IGF-1)、胰岛素样生长因子-2(IGF-2)]水平、骨代谢指标[骨特异性碱性磷酸酶(BAP)、N-端中段骨钙素(N-MID-OT)、总1型胶原氨基端延长肽(T-P1NP)、β-胶原特殊序列(β-CTX)]、1,25二羟维生素D 3[1,25(OH)_(2)D_(3)]、不同部位[第2~4腰椎(L_(2~4))、Ward's三角、股骨颈、大转子区]骨密度。【结果】观察组FPG、FT_(3)、FT_(4)、BAP、N-MID-OT、T-P1NP、β-CTX水平显著高于对照组(P<0.05),TSH、IGF-1、IGF-2、1,25(OH)_(2)D_(3)水平显著低于对照组(P<0.05);两组HbA1c水平比较,差异无统计学意义(P>0.05)。观察组L_(2~4)、Ward's三角、股骨颈、大转子区骨密度显著低于对照组(P<0.05)。【结论】T2DM合并甲亢患者血糖及甲状腺激素水平异常升高,血清IGF-1降低,骨代谢异常,骨密度减少,临床需监测患者骨代谢情况,从而预防骨质疏松的发生。

非小细胞肺癌患者血清IGF-1、IL-1α水平与新辅助化疗临床疗效的关系

【目的】探讨非小细胞肺癌(NSCLC)患者血清胰岛素样生长因子-1(IGF-1)、白细胞介素-1α(IL-1α)水平与新辅助化疗(NCT)疗效的关系。【方法】两院收治的87例NSCLC患者,接受NCT治疗2个周期后观察疗效。应用多因素Logistic回归分析评价血清IGF-1、IL-1α是否为影响NCT疗效的独立危险因素,绘制受试者工作特征(ROC)曲线评价血清IGF-1、IL-1α预测患者NCT疗效的效能。【结果】87例患者治疗后完全缓解7例,部分缓解39例,归入有效组;疾病稳定37例,疾病进展4例,归入无效组。有效组靶向治疗患者占比高于无效组(P<0.05),IGF-1、IL-1α水平均低于无效组(P<0.05)。多因素回归分析显示,IGF-1、IL-1α是影响NCT患者疗效的独立危险因素(P<0.05),靶向治疗是影响NCT疗效的独立保护因素(P<0.05)。ROC曲线分析显示,IGF-1、IL-1α对患者NCT疗效均有一定预测效能,曲线下面积(AUC)分别为0.756、0.734;两项联合预测疗效的AUC为0.917。【结论】NSCLC患者血清IGF-1、IL-1α水平是NCT疗效的独立影响因素,对NCT疗效具有重要的预测价值,且两者联合预测效能更高。

Influence of growth hormone-insulin-like growth factor Ⅰ axis on normal pregnancy

Objective To investigate the role of growth hormone-insulin-like growth factor Ⅰ (IGF-Ⅰ) axis in normal pregnancy.Methods Totally, 116 normal pregnant women were recruited from January 1997 to June 1998, with 20 normal nonpregnant women as controls. Maternal growth hormone (GH) and IGF-Ⅰ concentrations were assayed by RIA and enzyme-linked immunosorbent assay, respectively.Results Maternal serum levels of GH increased throughout gestation, reached a peak at 25 weeks of pregnancy and remained fairly high (χ2=40.458, P<0.0001). There was a significant difference between samples at 5-9 week gestational age and the controls (3.45?μg/L vs 1.61?μg/L, P<0.05). The maternal serum levels of IGF-Ⅰ increased rapidly throughout gestation from 29-week gestation and reached a peak of 188.86?μg/L at term delivery (χ2=50.224, P<0.0001).Conclusions Maternal GH levels increased progressively throughout gestation, which correlated with fetal growth. Maternal GH may regulate nutrition supply among mother, placenta and the fetus and play an important role in transporting nutritional substrates by the placenta. The maternal IGF-Ⅰ in the third trimester may promote fetal growth and placental functions.

Retinoic acid regulated insulin-like growth factor gene expression in cord blood lymphocytes

Objective To explore the immune promotion mechanism of retinoic acid (RA).Methods Reverse Transcription-Polymerase chain reaction (RT-PCR) was used to detect the gene expression of insulin like growth factor Ⅰ (IGF-Ⅰ) and IGF receptors (IGF-IR and IGF-IIR) in vitro, and their regulation by RA in human cord blood lymphocyte (CBL). Results Significant upregulation of IGF-I, IGF-IR and IGF-IIR mRNA was found at 6-24 hours in CBL incubated with physiologic concentrations of RA as compared to those without RA. Conclusion The enhancement of IGF expression may be an important pathway for vitamin A to promote immune cellular functions.

The change of insulin-like growth factor-1 in diabetic patients with neuropathy

Objective To evaluate the possible relationship between insulin like growth factor 1 (IGF 1) and diabetic neuropathy (DNP). Methods Sixty nine patients with Type 2 non insulin dependent diabetes (54 with peripheral neuropathy and 15 without neuropathy) were observed. Normal controls were 34 non diabetic persons. Diabetic peripheral neuropathy diagnosis was carried out taking into account results of NS, ND, NC and AF. After an overnight fast, blood was taken for IGF 1, glucose, hemoglobin Alc, C peptide, and insulin. Plasma IGF 1 was measured by radioimmunoassay (RIA) method. Results The neuropathic group had significantly lower levels for IGF 1 (86.43 ng/ml ±45.18 ng/ml) compared to normal controls (119.68 ng/ml ±89.42 ng/ml) (P<0.05), and to diabetic patients without neuropathy (113.75 ng/ml ±66.58 ng/ml) (P< 0.05). No significant difference was found between diabetic non neuropathic group and normal control subjects (P>0.05). In diabetic subjects there was a positive correlation (γ=0.27, P<0.05) between IGF 1 and beat to variation in heart rate. There were negative correlation bwteen IGF 1 and postprandial blood glucose (γ=-0.3, P< 0.05), and aspartic acid translocase (γ=-0.27, P<0.05). Conclusion In diabetic patients with peripheral neuropathy there are abnormalities of IGF 1 that may contribute to the pathogeneses of diabetic neuropathy.

Effects of insulin, insulin-like growth factor-I and -II on proliferation and intracellular signaling in endometrial carcinoma cells with different expression levels of insulin receptor isoform A

Background Hyperinsulinemia, insulin-like growth factor （IGF）-I and -Ⅱ （IGF-Ⅱ） are associated with increased risk of endometrial carcinoma. Insulin receptor isoform A （IR-A） is more frequently expressed in endombtrial carcinoma than in normal endometrial tissues. To better understand their roles in endometrial carcinoma, we investigated the effects of insulin, IGF-I, and IGF-II in endometrial carcinomas cells with different IR-A expression levels. Methods To explore the role of IR-A in mediating the activity of IGF-I, IGF-II, and insulin, we investigate the cellular proliferation of endometrial carcinoma cell lines RL95-2 and RL95-2-1R-A by MTS assays. Then we examined the protein kinase Akt phosphorylation and extracellular signal-regulated kinase （ERK） 1/2 phosphorylation in both cell lines by Western blotting. The effect of IGF-II and AG1024 on cell cycle progression and apoptosis was assessed by fiowcytometry. To examine whether the effects of IGFs were mediated by IR-A, we blocked IGF-I receptor （IGF-IR） in both cell lines using AG1024, an IGF-IR-specific inhibitor. Results IGF-I and IGF-II significantly enhanced proliferation of both cell lines （P 〈0.05）. By contrast, insulin significantly increased proliferation of RL95-2-1R-A cells only （P 〈0.05）. IGF-I and IGF-II significantly increased pAkt levels in RL95-2 cells and pERK1/2 levels in RL95-2-1R-A cells （all, P 〈0.05）. Insulin increased pERK1/2 levels in RL95-2-1R-A cells only （P 〈0.05）. LY294002 and PD98059 inhibited the specific signaling activities and cellular proliferation. After AG1024 pretreatment, neither IGF-I nor IGF-II affected pAkt levels in RL95-2 cells. IGF-II, but not IGF-I, increased pERK1/2 levels in RL95-2-1R-A cells. After AG1024 pretreatment, the proliferation rate and DNA content corresponding to the S phase increased and apoptosis decreased significantly in IGF-II-treated RL95-2-1R-A cells only （P 〈0.05）. Conclusions The proliferation effect of insulin is mediated by IR-A. When IR-A dominates in a cell line, IGF-II activated cell proliferation mainly through the ERKI/2 pathway. On the other hand, IGF-II activated cell proliferation mainly through the Akt pathway. IR-A can at least partly mediate the proliferative and anti-apoptotic effects of IGF-II through the ERKI/2 pathway.

PI-3K/Akt/GSK-3p signaling cascades stimulated by insulin like growth factor-Ⅰcontribute to multiple myeloma cells proliferation and survival

Multiple myeloma is characterized by the accumulation of malignant plasma cells in thebone marrow. Significant progress in molecular mechanisms of signaling pathways underlying the survival and/or proliferation of these cells has been achieved. Interleukin 6 （IL-6） is an important cytokine leading to multiple myeloma （MM） cells growth and survival. However, some MM cells isolated from MM patients are poorly responsive to IL-6 stimulation or IL-6 independent. This phenomenon raises the possibility that other growth factors may also be involved in the development of MM. Insulin like growth factor-I （IGF-I） plays an important role in the proliferation of a variety of cell types, in the development and growth of multiple tumors and in the prevention of apoptosis. IGF-I has recently been reported to play such a role in stimulating the MM cells growth, it even induces MM cells proliferation in IL-6 dependent cells, yet the detailed signaling components triggered by IGF-I have not been completely clarified. Thus, the present study are to address the signaling cascades triggered by IGF-I in MM cells.