Evaluating TIMP-2 and IGFBP-7 as a predictive tool for kidney injury in ureteropelvic junction obstruction

ABSTRACT A major challenge in the management of ureteropelvic junction obstruction (UPJO) is the selection of patients who would benefit from surgical treatment. Tissue inhibitor metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) indicate renal cell stress and are associated with cell cycle arrest. The [TIMP-2] [IGFBP7] ratio (Nephrocheck®) has been recently applied in patients in intensive care units patients to predict the development of acute kidney injury. In this study, we evaluated the performance of these biomarkers performance to distinguishing obstructive hydronephrosis (HN) from non-obstructive HN. Materials and Methods: Consecutive patients with UPJO were enrolled in this study. Urinary [TIMP-2] [IGFBP7] and clinical characteristics (hydronephrosis grade, differential renal function, and drainage half-time) were measured in the following groups: 26 children with obstructive HN at initial diagnosis (group 1A) and after six months of dismembered pyeloplasty (group 1B); 22 children with non-obstructive HN (group 2), and 26 children without any urinary tract condition, as the control group (group 3). Results: Comparing the initial samples, [TIMP-2] [IGFBP7] had higher levels in the HN groups and lower levels in the control group; however, no difference was observed between the HN groups (obstructive vs. non-obstructive). After six months of follow-up, patients who underwent dismembered pyeloplasty showed stability in the urinary concentration of [TIMP-2] [IGFBP7]. All patients with [TIMP-2] [IGFBP7] higher than 1.0 (ng/mL)2/1000 had diffuse cortical atrophy on ultrasonography. Conclusions: We showed that urinary levels of urinary [TIMP-2] [IGFBP7] are higher in children with HN than controls. Nephrocheck® is not reliable in predicting the need for surgical intervention for pediatric patients with UPJO.

Changes in Serum Concentrations of Insulin-like Growth Factor Binding Protein-3 after General Anesthesia Using Propofol or Isoflurane / 이화의대지

OBJECTIVES: The insulin-like growth factor binding proteins (IGFBP) regulate the bioavailability and bioactivity of insulin-like growth factor. We aimed to evaluate whether the IGFBP-3 level undergo major changes during perioperative periods according to the different kind of anesthetic agents. METHODS: Eighteen adults scheduled for elective total abdominal hysterectomy were enrolled. The patients were randomly assigned to have either propofol or isoflurane for maintenance of general anesthesia. A venous sample was taken for analysis of IGFBP-3 at the following time points: before induction, at the time of peritoneal closure, 1 hour after extubation at recovery room, and 2 and 5 postoperative days. The samples were analyzed by enzyme linked immunosolvent assay. RESULTS: Demographic data were similar between groups. In the both groups, the IGFBP-3 concentration decreased after anesthesia induction, reaching a nadir at the time of peritoneal closure without a significant difference between groups. In analysis between groups, the IGFBP-3 concentration in the isoflurane group on the postoperative 5th day was recovered to preoperative value and significantly higher than that in the propofol group (P < 0.05). CONCLUSION: This is the first study to show that the anesthetics used for general anesthesia affect the IGFBP-3 level during perioperative periods. The decrease of IGFBP-3 level following anesthesia induction in the isoflurane group was recovered to preoperative value, whereas that observed in the propofol group was not recovered on the postoperative 5th day. Further study is needed to establish the definitive effect of general anesthetics on IGFBP-3 and provide a comprehensive interpretation.

Recent Insights into Insulin-Like Growth Factor Binding Protein 2 Transcriptional Regulation

Insulin-like growth factor binding proteins (IGFBPs) are major regulators of insulin-like growth factor bioavailability and activity in metabolic signaling. Seven IGFBP family isoforms have been identified. Recent studies have shown that IGFBPs play a pivotal role in metabolic signaling and disease, including the pathogenesis of obesity, diabetes, and cancer. Although many studies have documented the various roles played by IGFBPs, transcriptional regulation of IGFBPs is not well understood. In this review, we focus on the regulatory mechanisms of IGFBP gene expression, and we summarize the findings of transcription factor activity in the IGFBP promoter region.

Insulin-like growth factor (IGF)-I and IGF binding proteins axis in diabetes mellitus

Increasing evidence suggests an important role of the insulin-like growth factor (IGF)-IGF binding protein (IGFBP) axis in the maintenance of normal glucose and lipid metabolism. Significant changes occur in the local IGF-I-IGFBPs environment in response to the diabetic milieu. A significant reduction of serum IGF-I levels was observed in patients with type 1 diabetes mellitus (T1DM). Inversely, considerably increased serum levels of IGF-I and IGFBP-3 levels were detected in individuals with glucose intolerance including T2DM. Recently, several prospective studies indicated that baseline levels of IGF-I and IGFBPs are associated with the development of diabetes. These findings suggest that disturbances in insulin and IGF-I-IGFBP axis can affect the development of glucose intolerance including diabetes.

Expression and methylation status of IGFBP-rP1 gene in laryngocarcinoma / 临床耳鼻咽喉头颈外科杂志

OBJECTIVE@#To investigate the relationship between the promoter methylation and protein expression of insulin-like growth factor binding protein-related protein 1(IGFBP-rP1) in laryngeal squamous cell carcinoma (LSCC).@*METHOD@#Methylation specific PCR (MSP) approach and immunohistochemistry methods were used to examine the methylation status and protein expression of IGFBP-rP1 in 45 samples of laryngeal carcinoma and 18 samples of tissues beside cancer.@*RESULT@#For the promoter site, methylation frequency of IGFBP-rP1 in tumor specimens (33.3%, 15/45) was significantly higher than that in corresponding normal tissues (5.6%, 1/18) (P < 0.05). The protein expression of IGFBP-rP1 in tumor tissues was significantly higher than that in corresponding normal tissues (P < 0.05) and was inversely correlated with its methylation status of promoter.@*CONCLUSION@#Epigenetic silencing of IGFBP-rP1 gene expression by promoter hypermethylation may play an important role in LSCC.

Inhibitory effect of exogenous insulin-like growth factor binding protein 7 on proliferation of human breast cancer cell line MDA-MB-453 and its mechanism / 生理学报

The present study was to investigate the effects of exogenous insulin-like growth factor binding protein 7 (IGFBP7) on the proliferation of human breast cancer cell line MDA-MB-453 and its possible mechanism. By means of MTT method in vitro, the results showed exogenous IGFBP7 inhibited the growth of MDA-MB-453 cells (IC50 of IGFBP7 = 8.49 μg/mL) in time- and concentration-dependent manner. SB203580, p38(MAPK) inhibitor, blocked the anti-proliferative effect of exogenous IGFBP7. The flow cytometry assay showed that exogenous IGFBP7 remarkably induced G0/G1 arrest in MDA-MB-453 cells. The Western blot showed that exogenous IGFBP7 promoted phosphorylation of p38(MAPK), up-regulated expression of p21(CIP1/WAF1), and inhibited phosphorylation of Rb. SB203580 restrained exogenous IGFBP7-induced regulation of p21(CIP1/WAF1) and p-Rb in MDA-MB-453 cells. In conclusion, the present study suggests that exogenous IGFBP7 could activate the p38(MAPK) signaling pathway, upregulate p21(CIP1/WAF1) expression, inhibit phosphorylation of Rb, and finally induce G0/G1 arrest in MDA-MB-453 cells.

Insulin Like Growth Factor Binding Protein-5 Regulates Excessive Vascular Smooth Muscle Cell Proliferation in Spontaneously Hypertensive Rats via ERK 1/2 Phosphorylation

Insulin-like growth factor binding proteins (IGFBPs) are important components of insulin growth factor (IGF) signaling pathways. One of the binding proteins, IGFBP-5, enhances the actions of IGF-1, which include the enhanced proliferation of smooth muscle cells. In the present study, we examined the expression and the biological effects of IGFBP-5 in vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY). The levels of IGFBP-5 mRNA and protein were found to be higher in the VSMC from SHR than in those from WKY. Treatment with recombinant IGFBP-5-stimulated VSMC proliferation in WKY to the levels observed in SHR. In the VSMCs of WKY, incubation with angiotensin (Ang) II or IGF-1 dose dependently increased IGFBP-5 protein levels. Transfection with IGFBP-5 siRNA reduced VSMC proliferation in SHR to the levels exhibited in WKY. In addition, recombinant IGFBP-5 significantly up-regulated ERK1/2 phosphorylation in the VSMCs of WKY as much as those of SHR. Concurrent treatment with the MEK1/2 inhibitors, PD98059 or U0126 completely inhibited recombinant IGFBP-5-induced VSMC proliferation in WKY, while concurrent treatment with the phosphatidylinositol-3 kinase inhibitor, LY294002, had no effect. Furthermore, knockdown with IGFBP-5 siRNA inhibited ERK1/2 phosphorylation in VSMC of SHR. These results suggest that IGFBP-5 plays a role in the regulation of VSMC proliferation via ERK1/2 MAPK signaling in hypertensive rats.

The insulin-like growth factor system in chronic kidney disease: Pathophysiology and therapeutic opportunities

The growth hormone-insulin-like growth factor-insulin-like growth factor binding protein (GH-IGF-IGFBP) axis plays a critical role in the maintenance of normal renal function and the pathogenesis and progression of chronic kidney disease (CKD). Serum IGF-I and IGFBPs are altered with different stages of CKD, the speed of onset, the amount of proteinuria, and the potential of remission. Recent studies demonstrate that growth failure in children with CKD is due to a relative GH insensitivity and functional IGF deficiency. The functional IGF deficiency in CKD results from either IGF resistance due to increased circulating levels of IGFBPs or IGF deficiency due to increased urinary excretion of serum IGF-IGFBP complexes. In addition, not only GH and IGFs in circulation, but locally produced IGFs, the high-affinity IGFBPs, and low-affinity insulin-like growth factor binding protein-related proteins (IGFBP-rPs) may also affect the kidney. With respect to diabetic kidney disease, there is growing evidence suggesting that GH, IGF-I, and IGFBPs are involved in the pathogenesis of diabetic nephropathy (DN). Thus, prevention of GH action by blockade either at the receptor level or along its signal transduction pathway offers the potential for effective therapeutic opportunities. Similarly, interrupting IGF-I and IGFBP actions also may offer a way to inhibit the development or progression of DN. Furthermore, it is well accepted that the systemic inflammatory response is a key player for progression of CKD, and how to prevent and treat this response is currently of great interest. Recent studies demonstrate existence of IGF-independent actions of high-affinity and low-affinity-IGFBPs, in particular, antiinflammatory action of IGFBP-3 and profibrotic action of IGFBP-rP2/CTGF. These findings reinforce the concept in support of the clinical significance of the IGF-independent action of IGFBPs in the assessment of pathophysiology of kidney disease and its therapeutic potential for CKD. Further understanding of GH-IGF-IGFBP etiopathophysiology in CKD may lead to the development of therapeutic strategies for this devastating disease. It would hold promise to use of GH, somatostatin analogs, IGFs, IGF agonists, GHR and insulin-like growth factor-I receptor (IGF-IR) antagonists, IGFBP displacer, and IGFBP antagonists as well as a combination treatment as therapeutic agents for CKD.

Effect of IGFBP7 gene down-regulation on leukemia cells / 中华血液学杂志

<p><b>OBJECTIVE</b>To explore the effect of down-regulation of insulin-like growth factor binding protein 7 (IGFBP7) on the proliferation and invasiveness of leukemia cell line U937 cells.</p><p><b>METHODS</b>Three pairs of double-strand siRNA targeting IGFBP7 gene were transfected into SMMC7721 cells to select the most efficient one for U937 cells. qRT-PCR and Western blot were used to detect the expression of IGFBP7 in U937 cells after transiently transfected with siRNA of IGFBP7. Cell proliferation, adhesion, trans-endothelial migration and invasion were performed in transfected cells and control groups.</p><p><b>RESULTS</b>After transfected with siRNA of IGFBP7 in U937 cells, the ability of cell proliferation was significantly decreased at 24 h (0.580 ± 0.159) compared to that of parental cells and scramble negative control (1.049 ± 0.274, 0.946 ± 0.195, respectively) (P < 0.01). Adhesion of U937 cells transfected with IGFBP7 gene specific siRNA to ECV304 cells was significantly lower than that of the control groups (0.247 ± 0.031 vs 0.406 ± 0.023 and 0.395 ± 0.011) (P < 0.01). Transendothelial membrane of U937 cells into the bottom of the 24-well plate for experimental group were less than those in the control groups \[(0.387 ± 0.021)×10(5) vs (1.017 ± 0.031)×10(5) and (0.908 ± 0.027)×10(5)\]. Cells adherent to the matrigel for experimental group were less than those in the control groups \[(0.197 ± 0.098)×10(5) vs (0.493 ± 0.067)×10(5) and (0.469 ± 0.083)×10(5)\]. The difference was significant (P < 0.01).</p><p><b>CONCLUSION</b>IGFBP7 gene plays a contributing role in leukemogenesis involving in leukemic cells' proliferation and interaction with endothelial cells through adhesion, invasion and migration.</p>

Enrichment analysis of Fanconi anemia gene expression profiles in cancer related genesets / 中华血液学杂志

<p><b>OBJECTIVE</b>To investigate the underlying tumor susceptibility mechanisms and reasons for the high risk of cancer in Fanconi anemia (FA).</p><p><b>METHODS</b>Gene Set Enrichment Analysis (GSEA) was performed to compare gene expression profiles between 21 FA patients' bone marrow (BM) mononuclear cell (BMNC) and 11 normal controls in cancer related gene sets from NCBI GEO database, then core enriched genes were identified by further investigation. Through enrichment analyzing biological processes of gene ontology sets and structural genomic gene sets between FA expression profiles and control, more details related with its tumor susceptibility had been revealed.</p><p><b>RESULTS</b>Compared with normal control, gene expression in FA group had significant been enriched in resistance to Bcl-2 inhibitor gene set, fibroblast growth factors signalling pathways, insulin and insulin-like growth factors (IGF) signalling pathways induced cancer genesis gene sets. The high level of D4S234E, SST, FGFs, IGFs, FGFRs and IGFBP expression provided an initiate environment for tumorgenesis and drug resistance. There were significant differences in biogenesis extracellular molecules and cytomembrane structure organizations between FA and control. Genes with promoter regions around transcription start sites containing either motif RRCAGGTGNCV or CCTNTMAGA were enriched and those former genes match annotation for tumorgenic transcription factor 3 (TCF3).</p><p><b>CONCLUSIONS</b>The high tumor susceptibility of FA patients may be closely related with the dramatic changes in cancer related growth factors and hormones environment. This study provides new insights into tumor susceptibility mechanism in FA patients.</p>

Construction of venus vector carrying IGFBP7 gene and its expression in K562 cells / 中国实验血液学杂志

The aim of this study was to construct venus vector carrying the gene encoding insulin-like growth factor binding protein 7 (IGFBP7), which provides an effective platform for exploring the function of this gene in leukemia. After digestion by restriction endonuclease, the IGFBP7 gene was recombined with the transfer plasmid. The venus particles were packaged using 293T cells to transfect K562 cells, and identification was performed by means of flow cytometry, RT-PCR and Western blot. The results showed that the sequence of cloned IGFBP7 gene was the same as that in GenBank. The size of product restricted by BamHI was same as the predicted one. GFP expression was observed in 293T and K562 cells with the fluorescent microscopy and flow cytometry. The expression level of mRNA and protein of IGFBP7 was confirmed by RT-PCR and Western blotting in K562 cells. It is concluded that venus vector carrying IGFBP7 gene has been successfully constructed and provides basis for exploring function of IGFBP7 in K562 cells.

Discovery of the serum biomarker proteins in severe preeclampsia by proteomic analysis

Preeclapsia (PE) is a severe disorder that occurs during pregnancy, leading to maternal and fetal morbidity and mortality. PE affects about 3-8% of all pregnancies. In this study, we conducted liquid chromatographymass spectrometry/mass spectrometry (LC-MS/MS) to analyze serum samples depleted of the six most abundant proteins from normal and PE-affected pregnancies to profile serum proteins. A total of 237 proteins were confidently identified with < 1% false discovery rate from the two groups of duplicate analysis. The expression levels of those identified proteins were compared semiquantitatively by spectral counting. To further validate the candidate proteins with a quantitative mass spectrometric method, selective reaction monitoring (SRM) and enzyme linked immune assay (ELISA) of serum samples collected from pregnant women with severe PE (n = 8) or normal pregnant women (n = 5) was conducted. alpha2-HS-glycoprotein (AHSG), retinol binding protein 4 (RBP4) and alpha-1-microglobulin/bikunin (AMBP) and Insulin like growth factor binding protein, acid labile subunit (IGFBP-ALS) were confirmed to be differentially expressed in PE using SRM (P < 0.05). Among these proteins, AHSG was verified by ELISA and showed a statistically significant increase in PE samples when compared to controls.

Screening of Tag SNPs and prediction of their potential function in genetic studies of complex diseases / 浙江大学学报·医学版

We applied public databases of single nucleotide polymorphism (SNP) to screen complex disease-related SNPs and assessed the potential functions of selected SNPs through SNP function prediction software, including FastSNP, SNP Function Prediction, F-SNP. We selected Tag SNP in HapMap database and compared all results with above software. With above strategies we screened IGFBP7 gene and obtained total 47 SNPs, including 11 TFBS SNPs, 31 intronic enhancer SNPs, 4 intronic enhancer and TFBS SNPs and 1 splicing sites SNPs.

Serum levels of insulin-like growth factor-1 and growth factor binding protein-3 in children with acute lymphocytic leukemia / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To study serum levels and clinical significance of insulin-like growth factor-1 (IGF-1) and growth factor binding protein 3 (IGFBP-3) in children with acute lymphocytic leukemia (ALL).</p><p><b>METHODS</b>Serum samples were obtained from 36 children with ALL before treatment and 6 months after complete remission. Thirty children with surgical diseases severed as the control group. Serum IGF-1 levels were measured using radioimmunoassay (RIA). Serum IGFBP-3 levels were measured using immunoradioassays (IRMA).</p><p><b>RESULTS</b>Serum levels of IGF-1 and IGFBP-3 in the ALL group were 19±4 ng/mL and 1216±132 ng/mL, respectively before treatment, which were lower than those in the control group (32±3 ng/mL and 2104±191 ng/mL respectively) (P<0.01). Serum levels of IGF-1 and IGFBP-3 in the ALL group increased to 30±3 ng/mL and 1941±164 ng/mL respectively 6 months after complete remission, which were significantly higher than those before treatment (P<0.01) and were similar to the levels of the control group.</p><p><b>CONCLUSIONS</b>Serum levels of IGF-1 and IGFBP-3 are reduced in children with ALL, but increase significantly after complete remission, suggesting that IGF-1 and IGFBP-3 might serve as useful markers for the diagnosis and evaluation of therapeutic effects of childhood ALL.</p>

Clinical diagnosis and WISP3 gene mutation analysis for progressive pseudorheumatoid dysplasia / 中华儿科杂志

<p><b>OBJECTIVE</b>Progressive pseudorheumatoid dysplasia (PPD) (MIM#208230) is a rare autosomal recessive disease of cartilage homeostasis characterized by axial and peripheral skeletal dysplasia. Analysis of WISP3 (Wnt1-inducible signaling pathway protein 3, MIM#603400) gene mutation can confirm the clinical and radiographic diagnosis for PPD. This study aimed to recognize PPD based on clinical manifestations and imaging characteristics of bones, and to investigate the mutations of WISP3 gene in three patients with PPD.</p><p><b>METHOD</b>Three male patients (9 - 16 years old) from three unrelated Chinese families, who presented with joint pain, swelling, deformities and motion limitation, were referred to this study. PPD was diagnosed on the basis of the clinical manifestations, imaging characteristics of bones and laboratory evaluation. All five exons and their exon/intron boundaries of the WISP3 gene were amplified by polymerase chain reaction (PCR) from the peripheral blood DNA of three PPD family members, and mutation analysis was performed by bidirectional DNA sequencing.</p><p><b>RESULT</b>(1) Three patients were diagnosed as PPD by characteristic evidences: all patients presented with non-inflammatory multiple joints swelling and stiffness including joints in hand and feet as they age. Radiographs showed platyspondyly, ovoid or wedged anterior end-plate of vertebral bodies, coxa vara, widened epiphyses or metaphyses including capital femoral, metacarpophalangeal, interphalangeal joints and metatarsals. Normal laboratory values were found for the erythrocyte sedimentation rate and C-reactive protein, rheumatoid factors, antinuclear antibodies etc. (2) The three different mutations of WISP3 gene were identified in three patients with PPD, including two small insert mutations (c.624_625insA, c.866_867insA), one was deletion mutation (c.729_735delGAGAAAA). The types of mutation of two alleles in three patients were c.624_625insA/c.729_735delGAGAAAA, c.624_625insA/c.866_867insA and c.866_867 insA/c.866_867insA, respectively. These mutations were found in exon 4 and exon 5 of WISP3 gene, accounting for 50%(3/6) respectively. All three different mutations were novel variations, and none of 3 novel variations was found in the 50 controls.</p><p><b>CONCLUSION</b>The characteristic evidences of PPD were non-inflammatory multiple enlarged joints (including hand and feet), limited movement, normal laboratory values such as rheumatoid factors. It is essential for making diagnosis to carefully examine the entire skeleton including spine. The characteristics of bone imaging are platyspondyly, widened epiphyses or metaphyses including large and small joints and narrow joint spaces. Three different novel variations of WISP3 gene were identified in three PPD patients, they are c.624_625insA, c.866_867insA and c.729_735delGAGAAAA. Each of novel mutations is insert or deletion mutation.</p>

Effects of insulin-like growth factor binding protein-related protein 1 in mice with hepatic fibrosis induced by thioacetamide / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Insulin-like growth factor binding protein-related protein 1 (IGFBPrP1) can activate hepatic stellate cells and increase extracellular matrix (ECM) in vitro. However, the effects of IGFBPrP1 in mice with hepatic fibrosis, and the mechanisms of these effects, are currently unknown. We aim to address these issues in this study.</p><p><b>METHODS</b>Intraperitoneal injection of thioacetamide (TAA) is a classic method for establishing a mouse model of hepatic fibrosis. Using this model, we administered anti-IGFBPrP1 antibody, again via intraperitoneal injection. The morphological changes of liver fibrosis were observed with both HE and Masson stainning. The immunohistochemical assays and Western blotting were used to measure changes in IGFBPrP1, α-smooth muscle actin (α-SMA) and ECM in liver tissues, and the expression of transforming growth factor-β1 (TGF-β1) and Smad3. Data were statistically analyzed using one-way analysis of variance (ANOVA), the SNK-q test for inter-group differences.</p><p><b>RESULTS</b>The Masson staining analysis showed that compared with normal control group, content of collagen fiber in TAA5w group was significantly increased (P < 0.01), and it was significantly decreased in TAA5w/aIGFBPrP1 group compared with in TAA5w group (P < 0.01). The expression of hepatic IGFBPrP1, α-SMA, TGF-β1, Smad3, collagen I and fibronectin (FN) was significantly up-regulated in the TAA5w group (P < 0.01). Anti-IGFBPrP1 treatment reversed these changes (P < 0.01).</p><p><b>CONCLUSIONS</b>IGFBPrP1 plays an important role in the development of hepatic fibrosis. Anti-IGFBPrP1 prevents fibrosis in mice by suppressing the activation of hepatic stellate cells, inhibiting the synthesis of major components of the ECM (namely, collagen I and FN). The mechanism for this suppression of fibrosis is associated with the TGF-β1/Smad3 signaling pathways.</p>

Effect of tanshinone II on hepatic fibrosis in mice / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To explore the mechanism of action of tanshinone II A for liver protection in hepatic fibrotic mice by observing its effects on signaling pathway of insulin-like growth factor binding protein 7 (IGFBP7) and TGFbeta1/Smad3.</p><p><b>METHODS</b>Hepatic fibrosis model was induced by intraperitoneal injection of thioacetamide (TAA). Thirty-six male Kunming mice were divided into five groups: the normal control group (N), the 4-week model group (A), the 4-week tanshinone II A prevented group (B), the 6-week model group (C) and the 3-week tanshinone II A treated group (D). Changes of serum levels of alanine aminotransferase (ALT) and lactate dehydrogenase (LDH), histopathology of liver (HE staining), area density of collagen in liver (Masson staining), expressions of alpha-smooth muscle actin (alpha-SMA), collagen I , fibronectin (FN), transforming growth factor-beta1 (TGF-beta1), Smad3 and IGFBP7 in liver (by immunohiStochemistry), liver content of FN, Smad3 and IGFBP7 (by Western blot), and the hepatocyte apoptosis (by TUNEL) were observed.</p><p><b>RESULTS</b>The serum levels of ALT and LDH, the expressions of alpha-SMA, collagen I , TGF-beta1 in liver, expressions and contents of FN, Smad3 and IGFBP7 in liver were significantly lower; the liver damage and the hepatic apoptosis index were lesser in Group B than in Group A, also in Group D than in Group C, respectively, all showing statistical significance (P < 0.05).</p><p><b>CONCLUSION</b>Tanshinone II A could improve liver function, inhibit the activation of hepatic stellate cells, reduce the production of extracellular matrix, and protect the hepatocytes, and its of mechanisms of actions might be related with blocking TGF-beta1/Smad3 signaling pathway and down-regulating the expression of IGFBP7 in liver.</p>

Fibroblasts-colorectal cancer cells interaction induces the expression of IGFBP7 / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To investigate the impact of intracellular interaction between fibroblasts and colorectal cancer cells on the expression of insulin growth factor binding protein7 (IGFBP7).</p><p><b>METHODS</b>Colorectal cancer cells SW480 were cultured with or without fibroblasts HELF cells in RPMI 1640 medium for 0 h, 48 h, 7 2 h and 96 h, respectively. By RT-PCR and immunohistochemical staining methods,the expression of IGFBP7 was detected in mono-and co-cultured cells.</p><p><b>RESULT</b>When SW480 cells were co-cultured with HELF cells, IGFBP7 expression in SW480 cells was significantly upregulated. Furthermore, IGFBP7 was induced in HELF cells both at mRNA and protein levels, which did not express when cells were mono-cultured.</p><p><b>CONCLUSION</b>Fibroblasts-colorectal cancer cells interaction induces the expression of IGFBP7, which indicates tumor-stroma interactions may play an important role in colorectal cancer development.</p>

Fisiologia do eixo GH-sistema IGF / Physiology of the GH-IGF axis

O crescimento, principal característica da infância e da adolescência, apresenta padrão semelhante na maioria dos indivíduos. A herança genética e os componentes do eixo GH-IGF são os fatores que diretamente influenciam esse processo. O GH, produzido na hipófise, exerce sua ação sobre o crescimento mediante regulação do sistema IGF. Os IGFs (IGF-1 e IGF-2) são fatores de crescimento produzidos na maioria dos órgãos e tecidos do organismo, possuindo ações autócrinas, parácrinas e endócrinas sobre o metabolismo intermediário, proliferação, crescimento e diferenciação celular. Associam-se com elevado grau de especificidade e de afinidade à família de seis proteínas carreadoras, denominadas IGFBPs (IGFBP-1 a -6), as quais modulam suas bioati-vidades. A maioria das ações conhecidas dos IGFs é exercida mediante sua ligação com o receptor tipo 1 (IGF-1R). Neste artigo será revisada a composição e a regulação do eixo GH-sistema IGF, assim como a participação de cada um dos seus diferentes componentes no processo de regulação do crescimento humano.

Growth, the main characteristic of childhood and adolescence, has a similar pattern in the majority of the individuals. Genetic background and GH-IGF axis are the factors that directly influence this process. Pituitary GH acts on growth mainly through the regulation of IGF system. The IGFs (IGF-1 and IGF-2) are growth factors produced in the majority of the organs and body tissues. They have autocrine, paracrine and endocrine actions on metabolism and cell proliferation, growth and differentiation. The IGFs bind with high specificity and affinity to a family of 6 binding proteins, called IGFBPs (1 to 6) that modulate their bioactivity. Most of the known IGF actions are mediated via IGF type 1 receptor (IGF1R). In this article we are going to review the composition and regulation of the GH-IGF axis and the role of each component in the regulation of the growth process.

Avaliação dos métodos diagnósticos para deficiência de GH (DGH) na infância: IGFs, IGFBPs, testes de liberação, ritmo de GH e exames de imagem: [revisão] / Evaluating diagnosis methods on childhood GH (DGH) deficiency: IGFs, IGFBPs, releasing tests, GH rhythm and image exams: [review]

O emprego das diversas metodologias diagnósticas da deficiência de hormônio de crescimento (DGH) em crianças é controverso. Neste artigo serão analisadas estas alternativas revisando a literatura e apresentando dados prospectivos obtidos pelos autores, sugerindo que a DGH seja diagnosticada empregando-se testes de triagem seguidos de testes de confirmação. Assim, recomenda-se que crianças com baixa estatura sejam avaliadas clínica e laboratorialmente para exclusão de doenças crônicas e genéticas. Naquelas com estatura < 3º percentil ou velocidade de crescimento (VC) < percentil 25, dosar IGF-1 como triagem. Se IGF-1 < -1 desvio-padrão (DP), a DGH deve ser confirmada pela ausência de resposta do hormônio de crescimento (GH) a dois testes de estímulo (pico < 5 mcg/L). Em paciente com fatores de risco, IGF-1 < -1 DP e um teste não-responsivo também é diagnóstico de DGH. As crianças com IGF-1 > -1 DP, devem ter a VC acompanhada e, se alterada, pode-se indicar reavaliação do eixo GH/IGF-1 excluindo ou confirmando a DGH.

The diagnostic approach to growth hormone deficiency (GHD) in children with short stature (SS) is controversial. Here we review the available methodology and present prospective data obtained in a cohort of patients with SS suggesting the use of screening test followed by the confirmation test. Thus, the children with SS should be submitted to clinical and laboratorial evaluation to exclude of chronic and genetic diseases. In addition patients with height < 3 percentil or growth velocity < percentil 25, IGF-1 levels should be measured. If the IGF1 levels < -1 standard deviation (SD) compared to the age, GHD should be confirmed by two GH-stimulations tests (peak < 5 mcg/L). In risk factor patients, IGF-1 < -1 SD and one non-responsible GH-test, the GHD was confirmed. Children with IGF-1 > -1 SD, the growth velocity should have observed and GH/IGF-1 axis re-evaluated if the growth pattern is not satisfactory.