AIM: To investigate the functional significance of insulin-like growth factor binding protein-5 (IGFBP-5) overexpression in pancreatic cancer (PaC).METHODS: The effects of IGFBP-5 on cell growth were assessed by stabl...AIM: To investigate the functional significance of insulin-like growth factor binding protein-5 (IGFBP-5) overexpression in pancreatic cancer (PaC).METHODS: The effects of IGFBP-5 on cell growth were assessed by stable transfection of BxPC-3 and PANC-1 cell lines and measuring cell number and DNA synthesis. Alterations in the cell cycle were assessed by flow cytometry and immunoblot analyses. Changes in cell survival and signal transduction were evaluated after mitogen activated protein kinase and phosphatidylinositol 3-kinase (PI3K) inhibitor treatment.RESULTS: After serum deprivation, IGFBP-5 expression increased both cell number and DNA synthesis in BxPC-3 cells, but reduced cell number in PANC-1 cells. Consistent with this observation, cell cycle analysis of IGFBP-5-expressing cells revealed accelerated cell cycle progression in BxPC-3 and G2/M arrest of PANC-1 cells. Signal transduction analysis revealed that Akt activation was increased in BxPC-3, but reduced in PANC-1 cells that express IGFBP-5. Inhibition of PI3K with LY294002 suppressed extracellular signal-regulated kinase-1 and -2 (ERK1/2) activation in BxPC-3, but enhanced ERK1/2 activation in PANC-1 cells that express IGFBP-5. When MEK1/2 was blocked, Akt activation remained elevated in IGFBP-5 expressing PaC cells; however, inhibition of PI3K or MEK1/2 abrogated IGFBP-5-mediated cell survival.CONCLUSION: These results indicate that IGFBP-5 expression affects the cell cycle and survival signal pathways and thus it may be an important mediator of PaC cell growth.展开更多
AIM: To investigate the effect of microR NA on insulinlike growth factor binding protein-3(IGFBP-3) and hence on insulin-like growth factor-Ⅱ(IGF-Ⅱ) bioavailability in hepatocellular carcinoma(HCC).METHODS: Bioinfor...AIM: To investigate the effect of microR NA on insulinlike growth factor binding protein-3(IGFBP-3) and hence on insulin-like growth factor-Ⅱ(IGF-Ⅱ) bioavailability in hepatocellular carcinoma(HCC).METHODS: Bioinformatic analysis was performed using microrna.org, DIANA lab and Segal lab softwares. Total RNA was extracted from 23 HCC and 10 healthy liver tissues using mir Vana mi RNA Isolation Kit. microR NA-17-5p(miR-17-5p) expression was mimicked and antagonized in Hu H-7 cell lines using Hi Per Fect Transfection Reagent, then total RNA was extracted using Biozol reagent then reverse transcribed into cD NA followed by quantification of mi R-17-5p and IGFBP-3 expression using Taq Man real-time quantitative PCR. Luciferase reporter assay was performed to validate the binding of miR-17-5p to the 3'UTR of IGFBP-3. Free IGF-Ⅱ protein was measured in transfected Hu H-7 cells using IGF-Ⅱ ELISA kit. RESULTS: Bioinformatic analysis revealed IGFBP-3 as a potential target for miR-17-5p. Screening of miR-17-5p and IGFBP-3 revealed a moderate negative correlation in HCC patients, where mi R-17-5p was extensively underexpressed in HCC tissues(P = 0.0012), while IGFBP-3 showed significant upregulation in the same set of patients(P = 0.0041) compared to healthy donors. Forcing mi R-17-5p expression in Hu H-7 cell lines showed a significant downregulation of IGFBP-3 mR NA expression(P = 0.0267) and a significant increase in free IGF-Ⅱ protein(P = 0.0339) compared to mock untransfected cells using unpaired t-test. Luciferase assay validated IGFBP-3 as a direct target of mi R-17-5p; luciferase activity was inhibited by 27.5% in cells co-transfected with miR-17-5p mimics and the construct harboring the wild-type binding region 2 of IGFBP-3 compared to cells transfected with this construct alone(P = 0.0474).CONCLUSION: These data suggest that regulating IGF-Ⅱ bioavailability and hence HCC progression can be achieved through targeting IGFBP-3 via manipulating the expression of miR NAs.展开更多
BACKGROUND: We previously showed that insulin-like growth factor binding protein-related protein 1 (IGFBPrP1) is a novel mediator in liver fibrosis. Transforming growth factor beta 1 (TGF beta 1) is known as the stron...BACKGROUND: We previously showed that insulin-like growth factor binding protein-related protein 1 (IGFBPrP1) is a novel mediator in liver fibrosis. Transforming growth factor beta 1 (TGF beta 1) is known as the strongest effector of liver fibrosis. Therefore, we aimed to investigate the detailed interaction between IGFBPrP1 and TGF beta 1 in primary hepatic stellate cells (HSCs). METHODS: We overexpressed TGF beta 1 or IGFBPrP1 and inhibited TGF beta 1 expression in primary HSCs for 6, 12, 24, 48, 72, and 96 hours to investigate their interaction and observe the accompanying expressions of a-smooth muscle actin (alpha-SMA), collagen I, fibronectin, and phosphorylated-mothers against decapentaplegic homolog 2/3 (p-Smad2/3). RESULTS: We found that the adenovirus vector encoding the TGF beta 1 gene (AdTGF beta 1) induced IGFBPrP1 expression while that of alpha-SMA, collagen I, fibronectin, and TGF beta 1 increased gradually. Concomitantly, AdIGFBPrP1 upregulated TGF beta 1, alpha-SMA, collagen I, fibronectin, and p-Smad2/3 in a time-dependent manner while IGFBPrP1 expression was decreased at 96 hours. Inhibition of TGF beta 1 expression reduced the IGFBPrP1-stimulated expression of alpha-SMA, collagen I, fibronectin, and p-Smad2/3. CONCLUSIONS: These findings for the first time suggest the existence of a possible mutually regulation between IGFBPrP1 and TGF beta 1, which likely accelerates liver fibrosis progression. Furthermore, IGFBPrP1 likely participates in liver fibrosis in a TGF beta 1-depedent manner, and may act as an upstream regulatory factor of TGF beta 1 in the Smad pathway.展开更多
BACKGROUND A twin pregnancy can carry greater risks than singleton pregnancies.About 60 in 100 twin pregnancies result in spontaneous birth before 37 wk,which is associated with several complications in the premature ...BACKGROUND A twin pregnancy can carry greater risks than singleton pregnancies.About 60 in 100 twin pregnancies result in spontaneous birth before 37 wk,which is associated with several complications in the premature babies.Clinical detection of biomarkers may help to predict the possibility of premature birth so that corresponding interventions can be given to the pregnant women in a timely manner,in order to reduce the risk of preterm birth and improve the outcomes of the newborn infants.AIM To explore the clinical value of transvaginal ultrasound measurement of cervical length combined with insulin-like growth factor binding protein-1(IGFBP-1)hyperphosphorylation in cervical secretions as predictors of preterm delivery in twin pregnancies.METHODS A total of 254 pregnant women with twin pregnancies,who were admitted to Hainan General Hospital and underwent maternity examination,were selected as the study subjects from January 2015 to December 2018.All participants received transvaginal ultrasound measurement of cervical length and phosphorylated IGFBP-1(phIGFBP-1)test between 24 and 34 wk gestation.The pregnancy outcomes were analyzed.RESULTS Of the women with a positive phIGFBP-1 test result,preterm birth rate was higher in those with a cervical length≤25 mm than those with a cervical length>25 mm(all P<0.05).Similarly,in women with a negative phIGFBP-1 test result,preterm birth rate was higher in those with a cervical length≤25 mm than those with a cervical length>25 mm(all P<0.05).The sensitivity,specificity,and positive and negative predictive values of the phIGFBP-1 test combined with the cervical length test were 95.71%,91.21%,95.12%and 92.22%,respectively,for the prediction of preterm birth.CONCLUSION Cervical length combined with phIGFBP-1 tests is of value for the prediction of outcomes of preterm delivery in twin pregnancies.展开更多
Male Igfbp2-/-mice have a significant reduction in bone mass and administration of a peptide that contains the insulin-like growth factor binding protein-2(IGFBP-2) receptor-binding domain stimulates bone formation in...Male Igfbp2-/-mice have a significant reduction in bone mass and administration of a peptide that contains the insulin-like growth factor binding protein-2(IGFBP-2) receptor-binding domain stimulates bone formation in these animals. Female Igfbp2-/-mice do not have this phenotype but following ovariectomy(OVX) lose more bone than OVX wild-type mice. This suggests that in the absence of estrogen, IGFBP-2 is required to maintain bone mass. Therefore these studies were undertaken to determine if this peptide could stimulate bone acquisition in OVX rats. OVX rats were divided into seven treatment groups: sham animals, OVX animals, OVX animals receiving a control scrambled peptide, or one of three doses of the active peptide termed PEG-HBD-1(0.7, 2,and 6 mg·kg^(-1)) and an OVX group receiving parathyroid hormone(PTH)(50 μg·kg-1 per day). The peptides were administered for8 weeks. DXA revealed a significant reduction in femoral and tibial areal bone mineral density(aBMD) after OVX, whereas treatment with the high-dose peptide increased aBMD by 6.2% ± 2.4%(P < 0.01) compared to control peptide; similar to the increase noted with PTH(5.6% ± 3.0%, P < 0.01). Similar increases were noted with two lower doses of the peptide(3.8% ± 1.5%, P < 0.05 for low dose; 3.1% ± 1.6%, P = 0.07 for middle dose). Micro CT showed that the OVX control peptide animals had reductions of 41% and64% in femoral trabecular BV/TV and trabecular number, respectively. All three doses of the peptide increased bone volume/total volume(BV/TV) significantly, while the low and middle doses increased trabecular number. Cortical BV/TV and thickness at the midshaft increased significantly with each dose of peptide(18.9% ± 9.8%, P < 0.01 and 14.2% ± 7.9%, P < 0.01 for low dose; 23.7% ±10.7%, P < 0.001 and 15.8% ± 6.1%, P < 0.001 for middle dose; 19.0% ± 6.9%, P < 0.01 and 16.2% ± 9.7%, P < 0.001 for high dose)and with PTH(25.8% ± 9.2%, P < 0.001 and 19.4% ± 8.8%, P < 0.001). Histomorphometry showed that the lowest dose of peptide stimulated BV/TV, trabecular thickness, mineral apposition rate(MAR), bone formation rate/bone surface(BFR/BS), number of osteoblasts/bone perimeter(N.ob/B.pm), and decreased osteoclast surface/bone perimeter(Oc.S/B.Pm). The highest dose stimulated each of these parameters except MAR and BFR/BS. Thus, the heparin-binding domain receptor region of IGFBP-2 accounts for its anabolic activity in bone. Importantly, this peptide enhances bone mass in estrogen-deficient animals.展开更多
BACKGROUND: Recent studies have found that insulin-like growth factors (IGFs) and insulin-like growth factor binding protein-3 (IGFBP-3) have stronger neurotrophic and neuroprotective effects. But whether their l...BACKGROUND: Recent studies have found that insulin-like growth factors (IGFs) and insulin-like growth factor binding protein-3 (IGFBP-3) have stronger neurotrophic and neuroprotective effects. But whether their levels in cerebrospinal fluid could be used as an auxiliary indicator in differentially diagnosing tuberculous meningitis and viral encephalitis is not yet clear. OBJECTIVE: To explore the changes of insulin-like growth factor-Ⅱ (IGF-Ⅱ ) and IGFBP-3 in cerebrospinal fluid (CSF) of children with tuberculous meningitis and the significance of the changes. DESIGN: A non-randomized concurrent controlled study. SETTING: Department of Pediatric Internal Medicine, the First Affiliated Hospital of Xinxiang Medical College. PARTICIPANTS: Thirty children with tuberculous meningitis (14 males and 16 females) were selected from the Department of Pediatric Internal Medicine, the First Affiliated Hospital of Xinxiang Medical College from January 2005 to December 2006. Tuberculous meningitis was diagnosed according to their clinical manifestations, the history of close contact with tuberculosis, typical cerebrospinal fluid changes of tuberculous meningitis, positive tuberculosis antibody and effective antituberculosis treatment. There were 30 children (13 males and 17 females) with viral encephalitis, and viral encephalitis was diagnosed according to epidemiological history, clinical manifestations, conventional and biochemical changes of cerebrospinal fluid, and negative bacteriology judgment. Meanwhile, 30 children (13 males and 17 females) without infectious and central nervous system disease were selected as the control group. Informed consent was obtained from the parents of all the enrolled children. METHODS: ①The lumbar puncture operation was implemented immediately to obtain cerebrospinal fluid (3 mL). The contents of IGF-Ⅱ and IGFBP-3 were detected with immunoradiometric assay. The concentrations of glucose and protein in cerebrospinal fluid were determined with a dry-chemical method. The number of white blood cells was counted by Fushi Method. ②The Pearson correlation analysis was used to analyze the correlation of the contents of IGF-Ⅱ and IGFBP-3 in cerebrospinal fluid with the leucocyte counting and the concentrations of glucose and protein in cerebrospinal fluid. MAIN OUTCOME MEASURES: The contents of IGF- Ⅱ and IGFBP-3 in cerebrospinal fluid, and their correlation with the leucocyte counting and the concentrations of glucose and protein in cerebrospinal fluid. RESULTS: ①Contents of IGF-Ⅱ and IGFBP-3 in cerebrospinal fluid: The contents of IGF-Ⅱ and IGFBP-3 in cerebrospinal fluid in the tuberculous meningitis group were significantly higher than those in the encephalitis virus group and control group (P 〈 0.05). There was no significant difference in the contents of IGF- Ⅱ and IGFBP-3 in cerebrospinal fluid between the viral encephalitis group and control group (P 〉 0.05). ②Correlation: The IGF- Ⅱ and IGFBP-3 contents in cerebrospinal fluid were positively correlated with the protein concentration in cerebrospinal fluid (r =0.821, 0.855, P 〈 0.01), but negatively with the glucose (r =0.742, - 0.605, P 〈 0.01). CONCLUSION- ①IGFs and IGVBPs are involved in the pathophysiological process of tuberculous meningitis, as well as the glucose and protein metabolism in cerebrospinal fluid. ②The IGF-Ⅱ and IGFBP-3 contents in cerebrospinal fluid can be used as the auxiliary indicators to differentially diagnose tuberculous meningitis and viral enceohalitis.展开更多
OBJECTIVE Basic fibroblast growth factor(b FGF)and platelet-derived growth factor(PDGF)produced by hepatocellular carcinoma(HCC)cells are responsible for the cell growth.Accumulating evidence shows that insulin-like g...OBJECTIVE Basic fibroblast growth factor(b FGF)and platelet-derived growth factor(PDGF)produced by hepatocellular carcinoma(HCC)cells are responsible for the cell growth.Accumulating evidence shows that insulin-like growth factor-binding protein-3(IGFBP-3)suppresses HCC cell proliferation in both IGF-dependent and independent manners.The present study is to investigate whether treatment with exogenous IGFBP-3 inhibits bF GF and PDGF production and the cell proliferation of HCC cells.METHODS Cell Counting Kit 8 assay were designed to detect HCC cell proliferation,transcription factor early growth response-1(EGR1)involving in IGFBP-3 regulation of b FGF and PDGF were detected by RT-PCR and Western blot assays.Western blot assay was adopted to detect the IGFBP-3 regulating insulin-like growth factor 1 receptor(IGF-1R)signaling pathway.RESULTS The present study demonstrates that IGFBP-3 suppressed IGF-1-induced b FGF and PDGF expression while it does not affect their expression in the absence of IGF-1.To delineate the underlying mechanism,Western-blot and RT-PCR assays confirmed that the transcription factor early growth response protein 1(EGR1)is involved in IGFBP-3 regulation of b FGF and PDGF.IGFBP-3 inhibition of type 1 insulin-like growth factor receptor(IGF1R),ERK and AKT activation is IGF-1-dependent.Furthermore,transient transfection with constitutively activated AKT or MEK partially blocks the IGFBP-3 inhibition of EGR1,b FGF and PDGF expression.CONCLUSION In conclusion,these findings suggest that IGFBP-3suppresses transcription of EGR1 and its target genes b FGF and PDGF through inhibiting IGF-1-dependent ERK and AKT activation.It demonstrates the importance of IGFBP-3 in the regulation of HCC cell proliferation,suggesting that IGFBP-3 could be a target for the treatment of HCC.展开更多
AIM:To investigate serum insulin-like growth factorbinding protein 5(IGFBP-5)levels and intestinal IGFBP-5expression in patients with Crohn’s disease(CD).METHODS:We analyzed the serum concentrations and intestinal ex...AIM:To investigate serum insulin-like growth factorbinding protein 5(IGFBP-5)levels and intestinal IGFBP-5expression in patients with Crohn’s disease(CD).METHODS:We analyzed the serum concentrations and intestinal expression of IGFBP-5 in 42 patients with CD,of whom 26 had endoscopically or radiologically proven stricture formation.Nine of the 42 patients had active disease,with a Crohn’s disease activity index>150.Serum IGFBP-5 levels were analyzed in 20 healthy controls matched by sex and age to the CD patients.Serum IGFBP-5 was measured using an enzyme-linked immunosorbent assay.Intestinal tissue was obtained from patients through endoscopic biopsies.IGFBP-5expression was detected using immunohistochemistry and was scored semiquantitatively.RESULTS:The median serum IGFBP-5 concentrations of CD patients were significantly lower compared with healthy controls[median 7.2(IQR:5.5-11.3)ng/mL vs 11.3(8.0-44.6)ng/mL,P<0.001].There was no significant difference between median serum IGFBP-5levels in CD patients with or without stricture formation[6.9(5.5-11.3)ng/mL vs 7.8(5.3-10.1)ng/mL,P=0.815].The serum IGFBP-5 levels were not significantly different between patients with active disease and inactive disease[7.2(6.5-7.6)ng/mL vs 7.2(5.5-11.3)ng/mL,P=0.890].However,a significant correlation was observed between serum IGFBP-5 levels and platelet count(PLT)(r=0.319,P=0.0395).No significant correlation was found between tissue IGFBP-5 immunohistochemical staining intensity scores and serum IGFBP-5 levels.No significant difference was found when comparing the serum IGFBP-5 levels among the patients with different tissue IGFBP-5 staining scores(absent/very weak,weak,moderate or strong).There was a significant correlation between tissue IGFBP-5staining scores and white blood cell count(r=0.391,P=0.01)and PLT(r=0.356,P=0.021).CONCLUSION:Our results indicate that serum IGFBP-5 concentrations were lower in CD patients compared to healthy controls regardless of disease activity or the presence of stricture formation.展开更多
Background: Previous research suggested that insulin-like growth factor binding protein related protein 1(IGFBPrP1), as a novel mediator, contributes to hepatic fibrogenesis. Matrix metalloproteinases(MMP) and tissue ...Background: Previous research suggested that insulin-like growth factor binding protein related protein 1(IGFBPrP1), as a novel mediator, contributes to hepatic fibrogenesis. Matrix metalloproteinases(MMP) and tissue inhibitors of metalloproteinases(TIMP) play an essential role in hepatic fibrogenesis by regulating homeostasis and remodeling of the extracellular matrix(ECM). However, the interaction between IGFBPrP1 and MMP/TIMP is not clear. The present study was to knockdown IGFBPrP1 to investigate the correlation between IGFBPrP1 and MMP/TIMP in hepatic fibrosis. Methods: Hepatic fibrosis was induced by thioacetamide(TAA) in mice. Knockdown of IGFBPrP1 expression by ultrasound-targeted microbubble destruction-mediated CMB-shRNA-IGFBPrP1 delivery, or inhibition of the Hedgehog(Hh) pathway by cyclopamine treatment, was performed in TAA-induced liver fibrosis mice. Hepatic fibrosis was determined by hematoxylin and eosin and Sirius red staining. Hepatic expression of IGFBPrP1, α-smooth muscle actin( α-SMA), transforming growth factor β 1(TGF β1), collagen I, MMPs/TIMPs, Sonic Hedgehog(Shh), and glioblastoma family transcription factors(Gli1) were investigated by immunohistochemical staining and Western blotting analysis. Results: We found that hepatic expression of IGFBPrP1, TGF β1, α-SMA, and collagen I were increased longitudinally in mice with TAA-induced hepatic fibrosis, concomitant with MMP2/TIMP2 and MMP9/TIMP1 imbalance and Hh pathway activation. Knockdown of IGFBPrP1 expression, or inhibition of the Hh pathway, reduced the hepatic expression of IGFBPrP1, TGF β1, α-SMA, and collagen I and re-established MMP2/TIMP2 and MMP9/TIMP1 balance. Conclusions: Our findings suggest that IGFBPrP1 knockdown attenuates liver fibrosis by re-establishing MMP2/TIMP2 and MMP9/TIMP1 balance, concomitant with the inhibition of hepatic stellate cell activation, down-regulation of TGF β1 expression, and degradation of the ECM. Furthermore, the Hh pathway mediates IGFBPrP1 knockdown-induced attenuation of hepatic fibrosis through the regulation of MMPs/TIMPs balance.展开更多
AIM: To investigate the prognostic significance of insulin-like growth factor-binding protein 3(IGFBP-3) in patients with cirrhosis.METHODS: Prospective study that included two cohorts: outpatients with stable cirrhos...AIM: To investigate the prognostic significance of insulin-like growth factor-binding protein 3(IGFBP-3) in patients with cirrhosis.METHODS: Prospective study that included two cohorts: outpatients with stable cirrhosis(n = 138) and patients hospitalized for acute decompensation(n = 189). Development of complications, mortality or liver transplantation was assessed by periodical phone calls and during outpatient visits. The cohort of stable cirrhosis also underwent clinical and laboratory evaluation yearly(2013 and 2014) in predefined study visits. In patients with stable cirrhosis, IGFBP-3 levels were measured at baseline(2012) and at second re-evaluation(2014). In hospitalized subjects, IGFBP-3 levels were measured in serum samples collected in the first and in the third day after admission and stored at-80 ℃. IGFBP-3 levels were measured by immunochemiluminescence.RESULTS: IGFBP-3 levels were lower in hospitalized patients as compared to outpatients(0.94 mcg/mL vs 1.69 mcg/m L, P < 0.001) and increased after liver transplantation(3.81 mcg/m L vs 1.33 mcg/mL, P = 0.008). During the follow-up of the stable cohort, 17 patients died and 11 received liver transplantation. Bivariate analysis showed that death or transplant was associated with lower IGFBP-3 levels(1.44 mcg/mL vs 1.74 mcg/m L, P = 0.027). The Kaplan-Meier transplant-free survival probability was 88.6% in patients with IGFBP-3 ≥ 1.67 mcg/mL and 72.1% for those with IGFBP3 < 1.67 mcg/mL(P = 0.015). In the hospitalized cohort, 30-d mortality was 24.3% and was independently associated with creatinine, INR, SpO_2/FiO_2 ratio and IGFBP-3 levels in the logistic regression. The 90-d transplant-free survival probability was 80.4% in patients with IGFBP-3 ≥ 0.86 mcg/mL and 56.1% for those with IGFBP3 < 0.86 mcg/mL(P < 0.001). CONCLUSION: Lower IGFBP-3 levels were associated with worse outcomes in patients with cirrhosis, and might represent a promising prognostic tool that can be incorporated in clinical practice.展开更多
BACKGROUND Atrial fibrillation(AF)is one of the most common persistent arrhythmias among adult cardiovascular diseases.It is important to identify potential risk factors for AF.Members of the insulin-like growth facto...BACKGROUND Atrial fibrillation(AF)is one of the most common persistent arrhythmias among adult cardiovascular diseases.It is important to identify potential risk factors for AF.Members of the insulin-like growth factor(IGF)family exert a variety of effects on various cell types in the context of the pathogenesis of cardiovascular diseases,and previous population-based studies indicate associations between IGF family members and AF.However,the causal effects of IGF family members in AF have not been evaluated.assess genetic relationships between IGF family members and AF.METHODS MR was performed based on genome-wide association study(GWAS)datasets,and concentration levels of 14 IGF family members were retrieved.An initial MR analysis was conducted to identify single nucleotide polymorphisms potentially associated with IGF serum concentrations.A GWAS meta-analysis including 60620 AF cases and 970216 control participants of European ancestry was then conducted to identify AF causal effects.Two-sample MR packages were used to perform MR analysis in R.MR-Egger,weighted median(WM),and inverse va-riance weighted(IVW)methods were used.RESULTS Core Tip:Due to the high prevalence of atrial fibrillation(AF),and adverse outcomes related to it,it is important to identify risk factors associated with development of the condition.Insulin-like growth factor(IGF)family members exert a variety of effects on various cell types in the context of the pathogenesis of cardiovascular diseases,and previous population-based studies indicate associations between IGF family members and AF.However,the causal effects of IGF family members in AF have not been evaluated.The results of the current study provide novel insights on the pathogenesis of AF,and implic-ations of serum IGF family member concentrations when assessing the risk of AF.The study generated evidence on the potential roles of developmental pathological effects in the pathogenesis of AF.Further observational and experimental studies are critically needed.展开更多
Aim: To study effects of recombinant human growth hormone (rhGH) on growth hormone-insulin-like growth factor axis (GH-IGFs) of human gastric cancer cell in vivo in order to reveal part mechanism of growth effects of ...Aim: To study effects of recombinant human growth hormone (rhGH) on growth hormone-insulin-like growth factor axis (GH-IGFs) of human gastric cancer cell in vivo in order to reveal part mechanism of growth effects of rhGH on gastric cancer. Methods: Nude mice were randomly divided into control group, cisplatin (DDP) group, rhGH group and DDP + rhGH group after human gastric cancer xenograft model of node mice was successfully founded and drugs were used for 6 days. We investigated volume of tumor, inhibitory rate of tumor and cell cycle by slide gauge and flow cytometry. In addition, We also respectively investigated insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) of blood serum of nude mice, IGF-ImRNA, insulin-like growth factor-I receptor (IGF-IR) mRNA and IGFBP-3 mRNA of xenograft of nude mice by enzyme linked immunosorbent assay (ELISA) and semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) on the first day of completing use of drugs later. Results: Tumor grew obviously slowly and tumor inhibitory rate obviously rose in DDP group and DDP + rhGH group compared with control group and rhGH group (p p p < 0.05). Expressions of IGF-I mRNA and IGF-IR mRNA were not obviously different in all groups. But expression of IGFBP-3 mRNA obviously increased in rhGH group, DDP group and DDP + rhGH group compared with control group;meanwhile, expression of IGFBP-3 mRNA also obviously increased in DDP + rhGH group compared with control group, DDP group and rhGH group. Conclusion: Our results indicated rhGH in short-time use did not improve proliferation of human gastric cancer cells and its mechanism was possible that rhGH in short-time use raised simultaneously IGF-I and IGFBP-3 of blood serum and increased IGFBP-3 mRNA, but degraded ratio of IGF-I and IGFBP-3 of blood serum in human gastric cancer cells.展开更多
Purpose: To investigate the effects of Tribulus terrestris(TT) extracts on muscle mass, muscle damage, and anaerobic performances of trained male boxers and its mechanisms: roles of plasma androgen, insulin growth fac...Purpose: To investigate the effects of Tribulus terrestris(TT) extracts on muscle mass, muscle damage, and anaerobic performances of trained male boxers and its mechanisms: roles of plasma androgen, insulin growth factor 1(IGF-1), and IGF-1 binding protein-3(IGFBP-3).Methods: Fifteen male boxers were divided into exercise group(E, n = 7) and exercise plus TT group(E + TT, n = 8). The 2 groups both undertook3-week high-intensity and 3-week high-volume trainings separated by a 4-week rest. TT extracts(1250 mg/day) were orally administered by boxers in E + TT group. TT extract compositions were detected by UHPLC–Q-TOF/MS. Before and at the end of the 2 trainings, muscle mass, anaerobic performance, and blood indicators were explored.Results: Compared with E group, decreases of plasma CK(1591.5 ± 909.6 U/L vs. 2719.9 ± 832.5 U/L) and IGFBP-3(3075.5 ± 1072.5 ng/m L vs. 3950.8 ± 479.3 ng/m L) as well as increases of mean power(MP, 459.4 ± 122.3 W vs. 434.6 ± 69.5 W) and MP/body weight(MP/BW, 7.5 ± 0.9 W/kg vs. 7.1 ± 1.1 W/kg) were detected in E + TT group after a high-intensity training. For high-volume training, reduction of IGFBP-3(2946.4 ± 974.1 ng/m L vs. 3632.7 ± 470.1 ng/m L) and increases of MP(508.7 ± 103.2 W vs. 477.8 ± 49.9 W) and MP/BW(8.2 ± 0.3 W/kg vs.7.5 ± 0.9 W/kg) were detected in E + TT group, compared with E group. Muscle mass, blood levels of testosterone, dihydrotestosterone(DHT),and IGF-1 were not signifiantly changed between the 2 groups.Conclusion: Taking 1250 mg capsules containing TT extracts did not change muscle mass and plasma levels of testosterone, DHT, and IGF-1 but significantly alleviated muscle damage and promoted anaerobic performance of trained male boxers, which may be related to the decrease of plasma IGFBP-3 rather than androgen in plasma.展开更多
Background 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 wit...Background 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. Methods 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, a-smooth muscle actin (a-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. Results 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/alGFBPrP1 group compared with in TAA5w group (P 〈0.01). The expression of hepatic IGFBPrP1, a-SMA, TGF-β1, Smad3, collagen 1 and fibronectin (FN) was significantly up-regulated in the TAA5w group (P 〈0.01). Anti-IGFBPrP1 treatment reversed these changes (P 〈0.01). Conclusions 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.展开更多
Aim:Prostate cancer(PCa)is the second most prevalent male cancer worldwide and designated the sixth most frequent male cancer in Arab countries.Although prostate specific antigen(PSA)has become the best and most valua...Aim:Prostate cancer(PCa)is the second most prevalent male cancer worldwide and designated the sixth most frequent male cancer in Arab countries.Although prostate specific antigen(PSA)has become the best and most valuable biomarker for screening of PCa,elevated levels of PSA can reflect the presence of malignant cells but can overlap with benign prostatic diseases.There is a necessity to develop and improve current tools for early detection and diagnosis of PCa.This study was done to evaluate the validation of serum insulin-like growth factor-1(IGF-1),IGF binding protein-3(IGFBP-3),chromogranin A(CgA)and combination with PSA in treatment of benign prostatic hyperplasia(BPH)and PCa patients.Methods:The study included 72 patients with PCa,70 BPH patients and 56 healthy male subjects of matched age.Full history and clinical data were recorded for all subjects.Results:Serum PSA attained sensitivity of 84%at 82%specificity with an accuracy of 83%,although IGF-1,IGFBP-3 and CgA did not recognize PCa patients.Conclusion:Combinations of IGF-1 and IGFBP-3 biomarkers with PSA were effectively differentiated between PCa and control groups as well as improving the overall value of sensitivity,specificity and diagnostic accuracy of PCa to 85%and 86%for IGF-1/PSA and IGFP-3/PSA respectively.展开更多
Cellular senescence affects the efficacy of mesenchymal stem cells(MSCs)-mediated tissue regeneration.Insulin-like growth factor binding proteins-7(IGFBP7),as a member of the IGF family,is associated with osteogenic d...Cellular senescence affects the efficacy of mesenchymal stem cells(MSCs)-mediated tissue regeneration.Insulin-like growth factor binding proteins-7(IGFBP7),as a member of the IGF family,is associated with osteogenic differentiation and the senescence of MSCs,but its exact function and mechanism remain unclear.We found IGFBP7 promoted the osteogenic differentiation and prevented the senescence of dental pulp-derived MSCs(DPSCs),as observed in the gain-of-function and lossof-function analyses,the senescence-associated marker p21 showed the most pronounced expression changes.We demonstrated that IGFBP7 activated the biological activity of SIRT1 deacetylase via metabolism,resulting in a deacetylation of H3K36ac and a decrease of the binding affinity of H3K36ac to p21 promoter,thereby reducing the transcription of p21,which ultimately prevents DPSCs senescence and promotes tissue regeneration.The activation of the mitochondrial electron transport chain(ETC)by Coenzyme Q10 could rescue the promotion of DPSC senescence induced by the knockdown of IGFBP7,whereas the inhibition of ETC by rotenone attenuated the prevention of DPSC senescence induced by IGFBP7 overexpression.In conclusion,our present results reveal a novel function of IGFBP7 in preventing DPSC senescence via the metabolism-induced deacetylation of H3K36ac and reduction of p21 transcription,suggesting that IGFBP7 is a potential target for promoting tissue regeneration in an aging environment.展开更多
Background:Progressive lipid loss of adipose tissue is a major feature of cancer-associated cachexia.In addition to systemic immune/inflammatory effects in response to tumor progression,tumor-secreted cachectic ligand...Background:Progressive lipid loss of adipose tissue is a major feature of cancer-associated cachexia.In addition to systemic immune/inflammatory effects in response to tumor progression,tumor-secreted cachectic ligands also play essential roles in tumor-induced lipid loss.However,the mechanisms of tumor-adipose tissue interaction in lipid homeostasis are not fully understood.Methods:The yki-gut tumors were induced in fruit flies.Lipid metabolic assays were performed to investigate the lipolysis level of different types of insulin-like growth factor binding protein-3(IGFBP-3)treated cells.Immunoblotting was used to display phenotypes of tumor cells and adipocytes.Quantitative polymerase chain reaction(qPCR)analysis was carried out to examine the gene expression levels such as Acc1,Acly,and Fasn et al.Results:In this study,it was revealed that tumor-derived IGFBP-3 was an important ligand directly causing lipid loss in matured adipocytes.IGFBP-3,which is highly expressed in cachectic tumor cells,antagonized insulin/IGF-like signaling(IIS)and impaired the balance between lipolysis and lipogenesis in 3T3-L1 adipocytes.Conditioned medium from cachectic tumor cells,such as Capan-1 and C26 cells,contained excessive IGFBP-3 that potently induced lipolysis in adipocytes.Notably,neutralization of IGFBP-3 by neutralizing antibody in the conditioned medium of cachectic tumor cells significantly alleviated the lipolytic effect and restored lipid storage in adipocytes.Furthermore,cachectic tumor cells were resistant to IGFBP-3 inhibition of IIS,ensuring their escape from IGFBP-3-associated growth suppression.Finally,cachectic tumor-derived ImpL2,the IGFBP-3 homolog,also impaired lipid homeostasis of host cells in an established cancer-cachexia model in Drosophila.Most importantly,IGFBP-3 was highly expressed in cancer tissues in pancreatic and colorectal cancer patients,especially higher in the sera of cachectic cancer patients than non-cachexia cancer patients.Conclusion:Our study demonstrates that tumor-derived IGFBP-3 plays a critical role in cachexia-associated lipid loss and could be a biomarker for diagnosis of cachexia in cancer patients.展开更多
Objective To investigate the effects of insulin-like growth factor binding protein 7(IGFBP7)on the proliferation,cell cycle of gastric cancer cell and the expression of cynlin D1,cyclin-dependent kinase(CDK)4,and to o...Objective To investigate the effects of insulin-like growth factor binding protein 7(IGFBP7)on the proliferation,cell cycle of gastric cancer cell and the expression of cynlin D1,cyclin-dependent kinase(CDK)4,and to observe the effects of IGFBP7 on the growth of gastric tumor xenografts in nude mice.Methods The MKN-28cell line was interfered by small interfere ribonucleic acid(siRNA)(interfered group),and blank control group,展开更多
基金Supported by A grant from the Arkansas Master Tobacco Settlement and Arkansas Biosciences Institute
文摘AIM: To investigate the functional significance of insulin-like growth factor binding protein-5 (IGFBP-5) overexpression in pancreatic cancer (PaC).METHODS: The effects of IGFBP-5 on cell growth were assessed by stable transfection of BxPC-3 and PANC-1 cell lines and measuring cell number and DNA synthesis. Alterations in the cell cycle were assessed by flow cytometry and immunoblot analyses. Changes in cell survival and signal transduction were evaluated after mitogen activated protein kinase and phosphatidylinositol 3-kinase (PI3K) inhibitor treatment.RESULTS: After serum deprivation, IGFBP-5 expression increased both cell number and DNA synthesis in BxPC-3 cells, but reduced cell number in PANC-1 cells. Consistent with this observation, cell cycle analysis of IGFBP-5-expressing cells revealed accelerated cell cycle progression in BxPC-3 and G2/M arrest of PANC-1 cells. Signal transduction analysis revealed that Akt activation was increased in BxPC-3, but reduced in PANC-1 cells that express IGFBP-5. Inhibition of PI3K with LY294002 suppressed extracellular signal-regulated kinase-1 and -2 (ERK1/2) activation in BxPC-3, but enhanced ERK1/2 activation in PANC-1 cells that express IGFBP-5. When MEK1/2 was blocked, Akt activation remained elevated in IGFBP-5 expressing PaC cells; however, inhibition of PI3K or MEK1/2 abrogated IGFBP-5-mediated cell survival.CONCLUSION: These results indicate that IGFBP-5 expression affects the cell cycle and survival signal pathways and thus it may be an important mediator of PaC cell growth.
文摘AIM: To investigate the effect of microR NA on insulinlike growth factor binding protein-3(IGFBP-3) and hence on insulin-like growth factor-Ⅱ(IGF-Ⅱ) bioavailability in hepatocellular carcinoma(HCC).METHODS: Bioinformatic analysis was performed using microrna.org, DIANA lab and Segal lab softwares. Total RNA was extracted from 23 HCC and 10 healthy liver tissues using mir Vana mi RNA Isolation Kit. microR NA-17-5p(miR-17-5p) expression was mimicked and antagonized in Hu H-7 cell lines using Hi Per Fect Transfection Reagent, then total RNA was extracted using Biozol reagent then reverse transcribed into cD NA followed by quantification of mi R-17-5p and IGFBP-3 expression using Taq Man real-time quantitative PCR. Luciferase reporter assay was performed to validate the binding of miR-17-5p to the 3'UTR of IGFBP-3. Free IGF-Ⅱ protein was measured in transfected Hu H-7 cells using IGF-Ⅱ ELISA kit. RESULTS: Bioinformatic analysis revealed IGFBP-3 as a potential target for miR-17-5p. Screening of miR-17-5p and IGFBP-3 revealed a moderate negative correlation in HCC patients, where mi R-17-5p was extensively underexpressed in HCC tissues(P = 0.0012), while IGFBP-3 showed significant upregulation in the same set of patients(P = 0.0041) compared to healthy donors. Forcing mi R-17-5p expression in Hu H-7 cell lines showed a significant downregulation of IGFBP-3 mR NA expression(P = 0.0267) and a significant increase in free IGF-Ⅱ protein(P = 0.0339) compared to mock untransfected cells using unpaired t-test. Luciferase assay validated IGFBP-3 as a direct target of mi R-17-5p; luciferase activity was inhibited by 27.5% in cells co-transfected with miR-17-5p mimics and the construct harboring the wild-type binding region 2 of IGFBP-3 compared to cells transfected with this construct alone(P = 0.0474).CONCLUSION: These data suggest that regulating IGF-Ⅱ bioavailability and hence HCC progression can be achieved through targeting IGFBP-3 via manipulating the expression of miR NAs.
基金supported by a grant from the Shanxi Province Foundation for Returness(2012-4)
文摘BACKGROUND: We previously showed that insulin-like growth factor binding protein-related protein 1 (IGFBPrP1) is a novel mediator in liver fibrosis. Transforming growth factor beta 1 (TGF beta 1) is known as the strongest effector of liver fibrosis. Therefore, we aimed to investigate the detailed interaction between IGFBPrP1 and TGF beta 1 in primary hepatic stellate cells (HSCs). METHODS: We overexpressed TGF beta 1 or IGFBPrP1 and inhibited TGF beta 1 expression in primary HSCs for 6, 12, 24, 48, 72, and 96 hours to investigate their interaction and observe the accompanying expressions of a-smooth muscle actin (alpha-SMA), collagen I, fibronectin, and phosphorylated-mothers against decapentaplegic homolog 2/3 (p-Smad2/3). RESULTS: We found that the adenovirus vector encoding the TGF beta 1 gene (AdTGF beta 1) induced IGFBPrP1 expression while that of alpha-SMA, collagen I, fibronectin, and TGF beta 1 increased gradually. Concomitantly, AdIGFBPrP1 upregulated TGF beta 1, alpha-SMA, collagen I, fibronectin, and p-Smad2/3 in a time-dependent manner while IGFBPrP1 expression was decreased at 96 hours. Inhibition of TGF beta 1 expression reduced the IGFBPrP1-stimulated expression of alpha-SMA, collagen I, fibronectin, and p-Smad2/3. CONCLUSIONS: These findings for the first time suggest the existence of a possible mutually regulation between IGFBPrP1 and TGF beta 1, which likely accelerates liver fibrosis progression. Furthermore, IGFBPrP1 likely participates in liver fibrosis in a TGF beta 1-depedent manner, and may act as an upstream regulatory factor of TGF beta 1 in the Smad pathway.
文摘BACKGROUND A twin pregnancy can carry greater risks than singleton pregnancies.About 60 in 100 twin pregnancies result in spontaneous birth before 37 wk,which is associated with several complications in the premature babies.Clinical detection of biomarkers may help to predict the possibility of premature birth so that corresponding interventions can be given to the pregnant women in a timely manner,in order to reduce the risk of preterm birth and improve the outcomes of the newborn infants.AIM To explore the clinical value of transvaginal ultrasound measurement of cervical length combined with insulin-like growth factor binding protein-1(IGFBP-1)hyperphosphorylation in cervical secretions as predictors of preterm delivery in twin pregnancies.METHODS A total of 254 pregnant women with twin pregnancies,who were admitted to Hainan General Hospital and underwent maternity examination,were selected as the study subjects from January 2015 to December 2018.All participants received transvaginal ultrasound measurement of cervical length and phosphorylated IGFBP-1(phIGFBP-1)test between 24 and 34 wk gestation.The pregnancy outcomes were analyzed.RESULTS Of the women with a positive phIGFBP-1 test result,preterm birth rate was higher in those with a cervical length≤25 mm than those with a cervical length>25 mm(all P<0.05).Similarly,in women with a negative phIGFBP-1 test result,preterm birth rate was higher in those with a cervical length≤25 mm than those with a cervical length>25 mm(all P<0.05).The sensitivity,specificity,and positive and negative predictive values of the phIGFBP-1 test combined with the cervical length test were 95.71%,91.21%,95.12%and 92.22%,respectively,for the prediction of preterm birth.CONCLUSION Cervical length combined with phIGFBP-1 tests is of value for the prediction of outcomes of preterm delivery in twin pregnancies.
基金supported by grant from Alize PharmaⅢand the Harrington Scholar Program of Harrington Research Foundation
文摘Male Igfbp2-/-mice have a significant reduction in bone mass and administration of a peptide that contains the insulin-like growth factor binding protein-2(IGFBP-2) receptor-binding domain stimulates bone formation in these animals. Female Igfbp2-/-mice do not have this phenotype but following ovariectomy(OVX) lose more bone than OVX wild-type mice. This suggests that in the absence of estrogen, IGFBP-2 is required to maintain bone mass. Therefore these studies were undertaken to determine if this peptide could stimulate bone acquisition in OVX rats. OVX rats were divided into seven treatment groups: sham animals, OVX animals, OVX animals receiving a control scrambled peptide, or one of three doses of the active peptide termed PEG-HBD-1(0.7, 2,and 6 mg·kg^(-1)) and an OVX group receiving parathyroid hormone(PTH)(50 μg·kg-1 per day). The peptides were administered for8 weeks. DXA revealed a significant reduction in femoral and tibial areal bone mineral density(aBMD) after OVX, whereas treatment with the high-dose peptide increased aBMD by 6.2% ± 2.4%(P < 0.01) compared to control peptide; similar to the increase noted with PTH(5.6% ± 3.0%, P < 0.01). Similar increases were noted with two lower doses of the peptide(3.8% ± 1.5%, P < 0.05 for low dose; 3.1% ± 1.6%, P = 0.07 for middle dose). Micro CT showed that the OVX control peptide animals had reductions of 41% and64% in femoral trabecular BV/TV and trabecular number, respectively. All three doses of the peptide increased bone volume/total volume(BV/TV) significantly, while the low and middle doses increased trabecular number. Cortical BV/TV and thickness at the midshaft increased significantly with each dose of peptide(18.9% ± 9.8%, P < 0.01 and 14.2% ± 7.9%, P < 0.01 for low dose; 23.7% ±10.7%, P < 0.001 and 15.8% ± 6.1%, P < 0.001 for middle dose; 19.0% ± 6.9%, P < 0.01 and 16.2% ± 9.7%, P < 0.001 for high dose)and with PTH(25.8% ± 9.2%, P < 0.001 and 19.4% ± 8.8%, P < 0.001). Histomorphometry showed that the lowest dose of peptide stimulated BV/TV, trabecular thickness, mineral apposition rate(MAR), bone formation rate/bone surface(BFR/BS), number of osteoblasts/bone perimeter(N.ob/B.pm), and decreased osteoclast surface/bone perimeter(Oc.S/B.Pm). The highest dose stimulated each of these parameters except MAR and BFR/BS. Thus, the heparin-binding domain receptor region of IGFBP-2 accounts for its anabolic activity in bone. Importantly, this peptide enhances bone mass in estrogen-deficient animals.
基金a grant from the New Century Talents Supporting Scheme in Universities of Henan Province
文摘BACKGROUND: Recent studies have found that insulin-like growth factors (IGFs) and insulin-like growth factor binding protein-3 (IGFBP-3) have stronger neurotrophic and neuroprotective effects. But whether their levels in cerebrospinal fluid could be used as an auxiliary indicator in differentially diagnosing tuberculous meningitis and viral encephalitis is not yet clear. OBJECTIVE: To explore the changes of insulin-like growth factor-Ⅱ (IGF-Ⅱ ) and IGFBP-3 in cerebrospinal fluid (CSF) of children with tuberculous meningitis and the significance of the changes. DESIGN: A non-randomized concurrent controlled study. SETTING: Department of Pediatric Internal Medicine, the First Affiliated Hospital of Xinxiang Medical College. PARTICIPANTS: Thirty children with tuberculous meningitis (14 males and 16 females) were selected from the Department of Pediatric Internal Medicine, the First Affiliated Hospital of Xinxiang Medical College from January 2005 to December 2006. Tuberculous meningitis was diagnosed according to their clinical manifestations, the history of close contact with tuberculosis, typical cerebrospinal fluid changes of tuberculous meningitis, positive tuberculosis antibody and effective antituberculosis treatment. There were 30 children (13 males and 17 females) with viral encephalitis, and viral encephalitis was diagnosed according to epidemiological history, clinical manifestations, conventional and biochemical changes of cerebrospinal fluid, and negative bacteriology judgment. Meanwhile, 30 children (13 males and 17 females) without infectious and central nervous system disease were selected as the control group. Informed consent was obtained from the parents of all the enrolled children. METHODS: ①The lumbar puncture operation was implemented immediately to obtain cerebrospinal fluid (3 mL). The contents of IGF-Ⅱ and IGFBP-3 were detected with immunoradiometric assay. The concentrations of glucose and protein in cerebrospinal fluid were determined with a dry-chemical method. The number of white blood cells was counted by Fushi Method. ②The Pearson correlation analysis was used to analyze the correlation of the contents of IGF-Ⅱ and IGFBP-3 in cerebrospinal fluid with the leucocyte counting and the concentrations of glucose and protein in cerebrospinal fluid. MAIN OUTCOME MEASURES: The contents of IGF- Ⅱ and IGFBP-3 in cerebrospinal fluid, and their correlation with the leucocyte counting and the concentrations of glucose and protein in cerebrospinal fluid. RESULTS: ①Contents of IGF-Ⅱ and IGFBP-3 in cerebrospinal fluid: The contents of IGF-Ⅱ and IGFBP-3 in cerebrospinal fluid in the tuberculous meningitis group were significantly higher than those in the encephalitis virus group and control group (P 〈 0.05). There was no significant difference in the contents of IGF- Ⅱ and IGFBP-3 in cerebrospinal fluid between the viral encephalitis group and control group (P 〉 0.05). ②Correlation: The IGF- Ⅱ and IGFBP-3 contents in cerebrospinal fluid were positively correlated with the protein concentration in cerebrospinal fluid (r =0.821, 0.855, P 〈 0.01), but negatively with the glucose (r =0.742, - 0.605, P 〈 0.01). CONCLUSION- ①IGFs and IGVBPs are involved in the pathophysiological process of tuberculous meningitis, as well as the glucose and protein metabolism in cerebrospinal fluid. ②The IGF-Ⅱ and IGFBP-3 contents in cerebrospinal fluid can be used as the auxiliary indicators to differentially diagnose tuberculous meningitis and viral enceohalitis.
基金supported by National Natural Science Foundation of China(81502123 and81330081)Natural Science Foundation of Anhui Province(1308085QH130)Anhui Province Nature Science Foundation in University(KJ2014A119)
文摘OBJECTIVE Basic fibroblast growth factor(b FGF)and platelet-derived growth factor(PDGF)produced by hepatocellular carcinoma(HCC)cells are responsible for the cell growth.Accumulating evidence shows that insulin-like growth factor-binding protein-3(IGFBP-3)suppresses HCC cell proliferation in both IGF-dependent and independent manners.The present study is to investigate whether treatment with exogenous IGFBP-3 inhibits bF GF and PDGF production and the cell proliferation of HCC cells.METHODS Cell Counting Kit 8 assay were designed to detect HCC cell proliferation,transcription factor early growth response-1(EGR1)involving in IGFBP-3 regulation of b FGF and PDGF were detected by RT-PCR and Western blot assays.Western blot assay was adopted to detect the IGFBP-3 regulating insulin-like growth factor 1 receptor(IGF-1R)signaling pathway.RESULTS The present study demonstrates that IGFBP-3 suppressed IGF-1-induced b FGF and PDGF expression while it does not affect their expression in the absence of IGF-1.To delineate the underlying mechanism,Western-blot and RT-PCR assays confirmed that the transcription factor early growth response protein 1(EGR1)is involved in IGFBP-3 regulation of b FGF and PDGF.IGFBP-3 inhibition of type 1 insulin-like growth factor receptor(IGF1R),ERK and AKT activation is IGF-1-dependent.Furthermore,transient transfection with constitutively activated AKT or MEK partially blocks the IGFBP-3 inhibition of EGR1,b FGF and PDGF expression.CONCLUSION In conclusion,these findings suggest that IGFBP-3suppresses transcription of EGR1 and its target genes b FGF and PDGF through inhibiting IGF-1-dependent ERK and AKT activation.It demonstrates the importance of IGFBP-3 in the regulation of HCC cell proliferation,suggesting that IGFBP-3 could be a target for the treatment of HCC.
文摘AIM:To investigate serum insulin-like growth factorbinding protein 5(IGFBP-5)levels and intestinal IGFBP-5expression in patients with Crohn’s disease(CD).METHODS:We analyzed the serum concentrations and intestinal expression of IGFBP-5 in 42 patients with CD,of whom 26 had endoscopically or radiologically proven stricture formation.Nine of the 42 patients had active disease,with a Crohn’s disease activity index>150.Serum IGFBP-5 levels were analyzed in 20 healthy controls matched by sex and age to the CD patients.Serum IGFBP-5 was measured using an enzyme-linked immunosorbent assay.Intestinal tissue was obtained from patients through endoscopic biopsies.IGFBP-5expression was detected using immunohistochemistry and was scored semiquantitatively.RESULTS:The median serum IGFBP-5 concentrations of CD patients were significantly lower compared with healthy controls[median 7.2(IQR:5.5-11.3)ng/mL vs 11.3(8.0-44.6)ng/mL,P<0.001].There was no significant difference between median serum IGFBP-5levels in CD patients with or without stricture formation[6.9(5.5-11.3)ng/mL vs 7.8(5.3-10.1)ng/mL,P=0.815].The serum IGFBP-5 levels were not significantly different between patients with active disease and inactive disease[7.2(6.5-7.6)ng/mL vs 7.2(5.5-11.3)ng/mL,P=0.890].However,a significant correlation was observed between serum IGFBP-5 levels and platelet count(PLT)(r=0.319,P=0.0395).No significant correlation was found between tissue IGFBP-5 immunohistochemical staining intensity scores and serum IGFBP-5 levels.No significant difference was found when comparing the serum IGFBP-5 levels among the patients with different tissue IGFBP-5 staining scores(absent/very weak,weak,moderate or strong).There was a significant correlation between tissue IGFBP-5staining scores and white blood cell count(r=0.391,P=0.01)and PLT(r=0.356,P=0.021).CONCLUSION:Our results indicate that serum IGFBP-5 concentrations were lower in CD patients compared to healthy controls regardless of disease activity or the presence of stricture formation.
基金supported by grants from National Natural Science Foundation of China(81670559)Key Research and Development Project of Shanxi Province(201603D421023)+2 种基金Youth Fund of Shanxi Medical University(02201514)Graduate Student Education Innovation Project of Shanxi(2016BY077)Youth Fund of Ap-plied Basic Research Program of Shanxi(201701D221175)
文摘Background: Previous research suggested that insulin-like growth factor binding protein related protein 1(IGFBPrP1), as a novel mediator, contributes to hepatic fibrogenesis. Matrix metalloproteinases(MMP) and tissue inhibitors of metalloproteinases(TIMP) play an essential role in hepatic fibrogenesis by regulating homeostasis and remodeling of the extracellular matrix(ECM). However, the interaction between IGFBPrP1 and MMP/TIMP is not clear. The present study was to knockdown IGFBPrP1 to investigate the correlation between IGFBPrP1 and MMP/TIMP in hepatic fibrosis. Methods: Hepatic fibrosis was induced by thioacetamide(TAA) in mice. Knockdown of IGFBPrP1 expression by ultrasound-targeted microbubble destruction-mediated CMB-shRNA-IGFBPrP1 delivery, or inhibition of the Hedgehog(Hh) pathway by cyclopamine treatment, was performed in TAA-induced liver fibrosis mice. Hepatic fibrosis was determined by hematoxylin and eosin and Sirius red staining. Hepatic expression of IGFBPrP1, α-smooth muscle actin( α-SMA), transforming growth factor β 1(TGF β1), collagen I, MMPs/TIMPs, Sonic Hedgehog(Shh), and glioblastoma family transcription factors(Gli1) were investigated by immunohistochemical staining and Western blotting analysis. Results: We found that hepatic expression of IGFBPrP1, TGF β1, α-SMA, and collagen I were increased longitudinally in mice with TAA-induced hepatic fibrosis, concomitant with MMP2/TIMP2 and MMP9/TIMP1 imbalance and Hh pathway activation. Knockdown of IGFBPrP1 expression, or inhibition of the Hh pathway, reduced the hepatic expression of IGFBPrP1, TGF β1, α-SMA, and collagen I and re-established MMP2/TIMP2 and MMP9/TIMP1 balance. Conclusions: Our findings suggest that IGFBPrP1 knockdown attenuates liver fibrosis by re-establishing MMP2/TIMP2 and MMP9/TIMP1 balance, concomitant with the inhibition of hepatic stellate cell activation, down-regulation of TGF β1 expression, and degradation of the ECM. Furthermore, the Hh pathway mediates IGFBPrP1 knockdown-induced attenuation of hepatic fibrosis through the regulation of MMPs/TIMPs balance.
文摘AIM: To investigate the prognostic significance of insulin-like growth factor-binding protein 3(IGFBP-3) in patients with cirrhosis.METHODS: Prospective study that included two cohorts: outpatients with stable cirrhosis(n = 138) and patients hospitalized for acute decompensation(n = 189). Development of complications, mortality or liver transplantation was assessed by periodical phone calls and during outpatient visits. The cohort of stable cirrhosis also underwent clinical and laboratory evaluation yearly(2013 and 2014) in predefined study visits. In patients with stable cirrhosis, IGFBP-3 levels were measured at baseline(2012) and at second re-evaluation(2014). In hospitalized subjects, IGFBP-3 levels were measured in serum samples collected in the first and in the third day after admission and stored at-80 ℃. IGFBP-3 levels were measured by immunochemiluminescence.RESULTS: IGFBP-3 levels were lower in hospitalized patients as compared to outpatients(0.94 mcg/mL vs 1.69 mcg/m L, P < 0.001) and increased after liver transplantation(3.81 mcg/m L vs 1.33 mcg/mL, P = 0.008). During the follow-up of the stable cohort, 17 patients died and 11 received liver transplantation. Bivariate analysis showed that death or transplant was associated with lower IGFBP-3 levels(1.44 mcg/mL vs 1.74 mcg/m L, P = 0.027). The Kaplan-Meier transplant-free survival probability was 88.6% in patients with IGFBP-3 ≥ 1.67 mcg/mL and 72.1% for those with IGFBP3 < 1.67 mcg/mL(P = 0.015). In the hospitalized cohort, 30-d mortality was 24.3% and was independently associated with creatinine, INR, SpO_2/FiO_2 ratio and IGFBP-3 levels in the logistic regression. The 90-d transplant-free survival probability was 80.4% in patients with IGFBP-3 ≥ 0.86 mcg/mL and 56.1% for those with IGFBP3 < 0.86 mcg/mL(P < 0.001). CONCLUSION: Lower IGFBP-3 levels were associated with worse outcomes in patients with cirrhosis, and might represent a promising prognostic tool that can be incorporated in clinical practice.
文摘BACKGROUND Atrial fibrillation(AF)is one of the most common persistent arrhythmias among adult cardiovascular diseases.It is important to identify potential risk factors for AF.Members of the insulin-like growth factor(IGF)family exert a variety of effects on various cell types in the context of the pathogenesis of cardiovascular diseases,and previous population-based studies indicate associations between IGF family members and AF.However,the causal effects of IGF family members in AF have not been evaluated.assess genetic relationships between IGF family members and AF.METHODS MR was performed based on genome-wide association study(GWAS)datasets,and concentration levels of 14 IGF family members were retrieved.An initial MR analysis was conducted to identify single nucleotide polymorphisms potentially associated with IGF serum concentrations.A GWAS meta-analysis including 60620 AF cases and 970216 control participants of European ancestry was then conducted to identify AF causal effects.Two-sample MR packages were used to perform MR analysis in R.MR-Egger,weighted median(WM),and inverse va-riance weighted(IVW)methods were used.RESULTS Core Tip:Due to the high prevalence of atrial fibrillation(AF),and adverse outcomes related to it,it is important to identify risk factors associated with development of the condition.Insulin-like growth factor(IGF)family members exert a variety of effects on various cell types in the context of the pathogenesis of cardiovascular diseases,and previous population-based studies indicate associations between IGF family members and AF.However,the causal effects of IGF family members in AF have not been evaluated.The results of the current study provide novel insights on the pathogenesis of AF,and implic-ations of serum IGF family member concentrations when assessing the risk of AF.The study generated evidence on the potential roles of developmental pathological effects in the pathogenesis of AF.Further observational and experimental studies are critically needed.
文摘Aim: To study effects of recombinant human growth hormone (rhGH) on growth hormone-insulin-like growth factor axis (GH-IGFs) of human gastric cancer cell in vivo in order to reveal part mechanism of growth effects of rhGH on gastric cancer. Methods: Nude mice were randomly divided into control group, cisplatin (DDP) group, rhGH group and DDP + rhGH group after human gastric cancer xenograft model of node mice was successfully founded and drugs were used for 6 days. We investigated volume of tumor, inhibitory rate of tumor and cell cycle by slide gauge and flow cytometry. In addition, We also respectively investigated insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) of blood serum of nude mice, IGF-ImRNA, insulin-like growth factor-I receptor (IGF-IR) mRNA and IGFBP-3 mRNA of xenograft of nude mice by enzyme linked immunosorbent assay (ELISA) and semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) on the first day of completing use of drugs later. Results: Tumor grew obviously slowly and tumor inhibitory rate obviously rose in DDP group and DDP + rhGH group compared with control group and rhGH group (p p p < 0.05). Expressions of IGF-I mRNA and IGF-IR mRNA were not obviously different in all groups. But expression of IGFBP-3 mRNA obviously increased in rhGH group, DDP group and DDP + rhGH group compared with control group;meanwhile, expression of IGFBP-3 mRNA also obviously increased in DDP + rhGH group compared with control group, DDP group and rhGH group. Conclusion: Our results indicated rhGH in short-time use did not improve proliferation of human gastric cancer cells and its mechanism was possible that rhGH in short-time use raised simultaneously IGF-I and IGFBP-3 of blood serum and increased IGFBP-3 mRNA, but degraded ratio of IGF-I and IGFBP-3 of blood serum in human gastric cancer cells.
基金supported by grants from the National Natural Science Foundation of China (No. 31271274)the Graduate Education Innovation Projects (No. yjscx2014035)
文摘Purpose: To investigate the effects of Tribulus terrestris(TT) extracts on muscle mass, muscle damage, and anaerobic performances of trained male boxers and its mechanisms: roles of plasma androgen, insulin growth factor 1(IGF-1), and IGF-1 binding protein-3(IGFBP-3).Methods: Fifteen male boxers were divided into exercise group(E, n = 7) and exercise plus TT group(E + TT, n = 8). The 2 groups both undertook3-week high-intensity and 3-week high-volume trainings separated by a 4-week rest. TT extracts(1250 mg/day) were orally administered by boxers in E + TT group. TT extract compositions were detected by UHPLC–Q-TOF/MS. Before and at the end of the 2 trainings, muscle mass, anaerobic performance, and blood indicators were explored.Results: Compared with E group, decreases of plasma CK(1591.5 ± 909.6 U/L vs. 2719.9 ± 832.5 U/L) and IGFBP-3(3075.5 ± 1072.5 ng/m L vs. 3950.8 ± 479.3 ng/m L) as well as increases of mean power(MP, 459.4 ± 122.3 W vs. 434.6 ± 69.5 W) and MP/body weight(MP/BW, 7.5 ± 0.9 W/kg vs. 7.1 ± 1.1 W/kg) were detected in E + TT group after a high-intensity training. For high-volume training, reduction of IGFBP-3(2946.4 ± 974.1 ng/m L vs. 3632.7 ± 470.1 ng/m L) and increases of MP(508.7 ± 103.2 W vs. 477.8 ± 49.9 W) and MP/BW(8.2 ± 0.3 W/kg vs.7.5 ± 0.9 W/kg) were detected in E + TT group, compared with E group. Muscle mass, blood levels of testosterone, dihydrotestosterone(DHT),and IGF-1 were not signifiantly changed between the 2 groups.Conclusion: Taking 1250 mg capsules containing TT extracts did not change muscle mass and plasma levels of testosterone, DHT, and IGF-1 but significantly alleviated muscle damage and promoted anaerobic performance of trained male boxers, which may be related to the decrease of plasma IGFBP-3 rather than androgen in plasma.
基金This study was supported by grants from the National Natural Science Foundation of China (No. 30871146), and the New Century Excellent Talent of the Ministry of Education of China (No. NCET-06-0264).
文摘Background 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. Methods 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, a-smooth muscle actin (a-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. Results 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/alGFBPrP1 group compared with in TAA5w group (P 〈0.01). The expression of hepatic IGFBPrP1, a-SMA, TGF-β1, Smad3, collagen 1 and fibronectin (FN) was significantly up-regulated in the TAA5w group (P 〈0.01). Anti-IGFBPrP1 treatment reversed these changes (P 〈0.01). Conclusions 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.
文摘Aim:Prostate cancer(PCa)is the second most prevalent male cancer worldwide and designated the sixth most frequent male cancer in Arab countries.Although prostate specific antigen(PSA)has become the best and most valuable biomarker for screening of PCa,elevated levels of PSA can reflect the presence of malignant cells but can overlap with benign prostatic diseases.There is a necessity to develop and improve current tools for early detection and diagnosis of PCa.This study was done to evaluate the validation of serum insulin-like growth factor-1(IGF-1),IGF binding protein-3(IGFBP-3),chromogranin A(CgA)and combination with PSA in treatment of benign prostatic hyperplasia(BPH)and PCa patients.Methods:The study included 72 patients with PCa,70 BPH patients and 56 healthy male subjects of matched age.Full history and clinical data were recorded for all subjects.Results:Serum PSA attained sensitivity of 84%at 82%specificity with an accuracy of 83%,although IGF-1,IGFBP-3 and CgA did not recognize PCa patients.Conclusion:Combinations of IGF-1 and IGFBP-3 biomarkers with PSA were effectively differentiated between PCa and control groups as well as improving the overall value of sensitivity,specificity and diagnostic accuracy of PCa to 85%and 86%for IGF-1/PSA and IGFP-3/PSA respectively.
基金the National Natural Science Foundation of China(82030031,81991504,92149301,82001067)the Chinese Research Unit of Tooth Development and Regeneration,Academy of Medical Sciences(2019-12M-5-031)+7 种基金the Beijing Municipal Science and Technology Commission(Z181100001718208)the Beijing Municipal Education Commission(119207020201)Beijing Advanced Innovation Center for Big Data-based Precision Medicine(PXM2021_014226_000026)the Beijing Municipal Government(Beijing Scholar program PXM2020_014226_000005,PXM2021_014226_000020)Innovation Research Team Project of Beijing Stomatological Hospital,Capital Medical University(CXTD202201)Beijing Municipal Administration of Hospitals’Youth Program(QML20191504)Scientific Research Common Program of Beijing Municipal Commission of Education(KM202110025009)Beijing Talents Fund(2018000021469G285)。
文摘Cellular senescence affects the efficacy of mesenchymal stem cells(MSCs)-mediated tissue regeneration.Insulin-like growth factor binding proteins-7(IGFBP7),as a member of the IGF family,is associated with osteogenic differentiation and the senescence of MSCs,but its exact function and mechanism remain unclear.We found IGFBP7 promoted the osteogenic differentiation and prevented the senescence of dental pulp-derived MSCs(DPSCs),as observed in the gain-of-function and lossof-function analyses,the senescence-associated marker p21 showed the most pronounced expression changes.We demonstrated that IGFBP7 activated the biological activity of SIRT1 deacetylase via metabolism,resulting in a deacetylation of H3K36ac and a decrease of the binding affinity of H3K36ac to p21 promoter,thereby reducing the transcription of p21,which ultimately prevents DPSCs senescence and promotes tissue regeneration.The activation of the mitochondrial electron transport chain(ETC)by Coenzyme Q10 could rescue the promotion of DPSC senescence induced by the knockdown of IGFBP7,whereas the inhibition of ETC by rotenone attenuated the prevention of DPSC senescence induced by IGFBP7 overexpression.In conclusion,our present results reveal a novel function of IGFBP7 in preventing DPSC senescence via the metabolism-induced deacetylation of H3K36ac and reduction of p21 transcription,suggesting that IGFBP7 is a potential target for promoting tissue regeneration in an aging environment.
基金National Natural Science Foundation of China(No.82073876)Beijing Natural Science Foundation(No.7202012)
文摘Background:Progressive lipid loss of adipose tissue is a major feature of cancer-associated cachexia.In addition to systemic immune/inflammatory effects in response to tumor progression,tumor-secreted cachectic ligands also play essential roles in tumor-induced lipid loss.However,the mechanisms of tumor-adipose tissue interaction in lipid homeostasis are not fully understood.Methods:The yki-gut tumors were induced in fruit flies.Lipid metabolic assays were performed to investigate the lipolysis level of different types of insulin-like growth factor binding protein-3(IGFBP-3)treated cells.Immunoblotting was used to display phenotypes of tumor cells and adipocytes.Quantitative polymerase chain reaction(qPCR)analysis was carried out to examine the gene expression levels such as Acc1,Acly,and Fasn et al.Results:In this study,it was revealed that tumor-derived IGFBP-3 was an important ligand directly causing lipid loss in matured adipocytes.IGFBP-3,which is highly expressed in cachectic tumor cells,antagonized insulin/IGF-like signaling(IIS)and impaired the balance between lipolysis and lipogenesis in 3T3-L1 adipocytes.Conditioned medium from cachectic tumor cells,such as Capan-1 and C26 cells,contained excessive IGFBP-3 that potently induced lipolysis in adipocytes.Notably,neutralization of IGFBP-3 by neutralizing antibody in the conditioned medium of cachectic tumor cells significantly alleviated the lipolytic effect and restored lipid storage in adipocytes.Furthermore,cachectic tumor cells were resistant to IGFBP-3 inhibition of IIS,ensuring their escape from IGFBP-3-associated growth suppression.Finally,cachectic tumor-derived ImpL2,the IGFBP-3 homolog,also impaired lipid homeostasis of host cells in an established cancer-cachexia model in Drosophila.Most importantly,IGFBP-3 was highly expressed in cancer tissues in pancreatic and colorectal cancer patients,especially higher in the sera of cachectic cancer patients than non-cachexia cancer patients.Conclusion:Our study demonstrates that tumor-derived IGFBP-3 plays a critical role in cachexia-associated lipid loss and could be a biomarker for diagnosis of cachexia in cancer patients.
文摘Objective To investigate the effects of insulin-like growth factor binding protein 7(IGFBP7)on the proliferation,cell cycle of gastric cancer cell and the expression of cynlin D1,cyclin-dependent kinase(CDK)4,and to observe the effects of IGFBP7 on the growth of gastric tumor xenografts in nude mice.Methods The MKN-28cell line was interfered by small interfere ribonucleic acid(siRNA)(interfered group),and blank control group,