Insulin-like growth factor binding protein related protein 1 knockdown attenuates hepatic ?brosis via the regulation of MMPs/TIMPs in mice

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.

Interaction between insulin-like growth factor binding protein-related protein 1 and transforming growth factor beta 1 in primary hepatic stellate cells

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.

Insulin-like growth factor 2 mRNA-binding protein 1 promotes cell proliferation via activation of AKT and is directly targeted by microRNA-494 in pancreatic cancer

BACKGROUND Studies have shown that insulin-like growth factor 2 mRNA-binding protein 1(IGF2BP1)plays critical roles in the genesis and development of human cancers.AIM To investigate the clinical significance and role of IGF2BP1 in pancreatic cancer.METHODS Expression levels of IGF2BP1 and microRNA-494(miR-494)were mined based on Gene Expression Omnibus datasets and validated in both clinical samples and cell lines by quantitative real-time polymerase chain reaction and Western blot.The relationship between IGF2BP1 expression and clinicopathological factors of pancreatic cancer patients was analyzed.The effect and mechanism of IGF2BP1 on pancreatic cancer cell proliferation were investigated in vitro and in vivo.Analyses were performed to explore underlying mechanisms of IGF2BP1 upregulation in pancreatic cancer and assays were carried out to verify the posttranscriptional regulation of IGF2BP1 by miR-494.RESULTS We found that IGF2BP1 was upregulated and associated with a poor prognosis in pancreatic cancer patients.We showed that downregulation of IGF2BP1 inhibited pancreatic cancer cell growth in vitro and in vivo via the AKT signaling pathway.Mechanistically,we showed that the frequent upregulation of IGF2BP1 was attributed to the downregulation of miR-494 expression in pancreatic cancer.Furthermore,we discovered that reexpression of miR-494 could partially abrogate the oncogenic role of IGF2BP1.CONCLUSION Our results revealed that upregulated IGF2BP1 promotes the proliferation of pancreatic cancer cells via the AKT signaling pathway and confirmed that the activation of IGF2BP1 is partly due to the silencing of miR-494.

Insulin-like growth factor-1, IGF binding protein-3, and the risk of esophageal cancer in a nested case-control study

To assess the relationship between serum levels of insulin-like growth factor-1 (IGF1)/IGF-binding protein-3 (IGFBP3) and the risk of esophageal carcinoma.METHODSWe assessed the relationship between the serum levels of these molecules and the risk of esophageal cancer in a prospective, nested case-control study of participants from the Japan Collaborative Cohort Study. A baseline survey was conducted from 1988 to 1990. Of the 110585 enrolled participants, 35% donated blood samples. Those who had been diagnosed with esophageal cancer were considered cases for nested case-control studies. A conditional logistic model was used to estimate odds ratios for the incidence of esophageal cancer associated with serum IGF1 and IGFBP3 levels.RESULTSThirty-one cases and 86 controls were eligible for the present assessment. The molar ratio of IGF1/IGFBP3, which represents the free and active form of IGF1, was not correlated with the risk of esophageal carcinoma. A higher molar difference between IGFBP3 and IGF1, which estimates the free form of IGFBP3, was associated with a decreased risk of esophageal carcinoma (P = 0.0146), and people in the highest tertile had the lowest risk (OR = 0.107, 95%CI: 0.017-0.669). After adjustment for body mass index, tobacco use, and alcohol intake, the molar difference of IGFBP3-IGF1 was inversely correlated with the risk of esophageal carcinoma (P = 0.0150).CONCLUSIONThe free form of IGFBP3, which is estimated by this molar difference, may be inversely associated with esophageal cancer incidence.

Expression of insulin-like growth factor binding protein-2 in gastric carcinoma and its relationship with cell proliferation

AIM: To investigate the expression of insulin-like growth factor binding protein-2 (IGFBP-2) in gastric carcinoma and its clinical significance and to explore its relationship with cell proliferation. METHODS: Expressions of IGFBP-2 and Ki-67 in 118 cases of gastric carcinoma and 40 cases of normal gastric mucosa were detected by EnVision immunohistochemical technique. RESULTS: Expression of IGFBP-2 in gastric carcinoma was higher than that in normal gastric mucosa (P < 0.01). There was no difference between high- and low-grade gastric carcinoma (P > 0.05). Expression of IGFBP-2 in advanced gastric carcinoma was higher than that in early gastric carcinoma (P < 0.05). Expression of IGFBP-2 in gastric carcinoma with lymph node metastasis was higher than that without lymph node metastasis (P < 0.01). IGFBP-2 expression was a positively related to the clinical stage of gastric carcinoma (P < 0.01). There was a positive correlation between IGFBP-2 and Ki-67 (P < 0.05). CONCLUSION: IGFBP-2 may be involved in carcino- genesis and progression of gastric carcinoma by promoting cell proliferation.

Preparatory training attenuates drastic response of the insulin-like growth factor binding protein 1 at the point of maximal oxygen consumption in handball players

Background:Intensive exercise changes physiological need for glucose and several biochemical pathways responsible for its metabolism response.Among them are those which involve insulin,insulin-like growth factor(IGF-1),and IGF-binding proteins(IGFBPs).Different types and degrees of exercise,as well as an athlete's fitness,may induce a range of responses regarding concentrations and time needed for the alteration.The idea of the work was to find out whether and how insulin/IGF axis responds to additional physical activity in the already trained subjects and if so,is the adaptation potentially beneficial from the aspect of metabolic control.Methods:The effect of 4-week intensive training on campus(preparatory training) on the levels of insulin,IGF-1,and IGFBPs during maximal progressive exercise test(MPET) on a treadmill was compared to the results obtained during MPET conducted after a regular training season of a female elite handball team(n = 17,age:17 ± 1 years,height:171 ± 8 cm,weight:65 ± 8 kg,body mass index:22 ± 1 kg/m^2 at the beginning of the study;there were no significant changes at the end).Serum samples were obtained from players immediately before the test(basal),at the end of the test after reaching the point of maximal oxygen consumption(VO_(2max)),and after recovery.Results:The concentration of insulin decreased at VO_(2max),but remained higher in players after preparatory training(12.2 ± 2.5 m U/L vs.8.9 ± 4.4 m U/L,p = 0.049).The level of IGFBP-1 decreased in players at VO_(2max) in either case of training,but it remained much higher in tests performed after the preparatory regime than before(p = 0.029).Concentrations of IGF-1,IGFBP-2,-3,and-4 did not change significantly.Conclusion:The inverse relation between insulin and IGFBP-1 was lost during MPET,as these 2 molecules changed in the same direction.The results obtained suggest less severe stress-induced depression of insulin and IGFBP-1 after preparatory training.But another metabolic mechanism cannot be excluded,and that is potentially impaired insulin sensitivity resulting in higher level of IGFBP-1.

Insulin-like growth factor-binding protein-3 inhibits IGF-1-induced proliferation of human hepatocellular carcinoma cells

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.

Circulating insulin-like growth factor-binding protein 3 as prognostic biomarker in liver cirrhosis

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.

Effects of transfected adenovirus-mediated transcription factor X-box binding protein 1 on hippocampal-derived neural stem cell proliferation and apoptosis under hypoxia

BACKGROUND： Neural stem cell （NSC） survival is closely associated with cell apoptosis in ischemic-hypoxic regions following transplantation. Numerous studies have revealed that X-box binding protein 1 （XBP1） is a transcription factor during endoplasmic reticulum unfolded protein response and is essential for cell survival, differentiation, and anti-apoptotic effects. OBJECTIVE： To determine the effects of the XBP1 gene on NSC proliferation and apoptosis under hypoxic conditions following XBP1 gene transfection into rat embryonic hippocampal NSCs using recombinant adenovirus vector. DESIGN, TIME AND SETTING： In vitro experiments were performed at the Laboratory of Cell Biology of Jilin University and Laboratory of Proteomics, Department of Neurology, Jilin University China from September 2008 to November 2009. MATERIALS： Recombinant adenovirus package XBP1 gene and Ad-XBPl-enhanced green fluorescent protein plasmid （Guangzhou Easywin BioMed Technology, China）, rabbit anti-XBP1 and its target gene estrogen receptor degradation-enhancing a-mannosidase-like protein （EDEM） glucose-regulated protein 78 （GRP78）, anti-apoptotic molecule Bcl-2 and proapoptotic molecule Bax polyclonal antibody （Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA）, and COCI2 （Sigma, St. Louis, MO, USA） were used in the present study. METHODS： Hippocampi from embryonic, Sprague Dawley rats on gestational day 16 were harvested for NSC isolation and cloning, followed by immunofluorescence for Nestin and sub-culturing. The recombinant adenovirus Ad-XBPl-enhanced green fluorescent protein plasmid was transfected into rat embryonic hippocampal NSCs, and then CoCl2 was applied to induce hypoxia. MAIN OUTCOME MEASURES： Cell quantification and 3-（4, 5-dimethylthiazol-2-yl）-2, 5-diphenyltetrazolium bromide colorimetric assay were utilized to detect proliferation in XBPl-transfected NSCs for 7 consecutive days. Western blot assay was utilized to quantify XBP1 GRP78, EDEM, Bcl-2, and Bax expression. Flow cytometry was used to measure apoptosis. RESULTS： NSC proliferation was significantly enhanced following XBP1 gene transfection （P 〈 0.05）. Under hypoxic conditions, GRP78, EDEM, and Bcl-2 levels increased, but Bax levels decreased. In addition, NSC apoptosis decreased following transfection （P 〈 0.05）. CONCLUSION： The XBP1 gene was successfully transfected into rat embryonic hippocampal NSCs using a recombinant adenovirus vector. NSC proliferation following transfection, as well as anti-apoptotic effects under hypoxia, was significantly increased.

Mendelian randomization provides evidence for a causal effect of serum insulin-like growth factor family concentration on risk of atrial fibrillation

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.

Phosphatase and tensin homology deleted in chromosome 10,hypoxia-inducible factor-1 alpha gene expression in colorectal adenoma and adenocarcinoma and their relation to vascular endothelial growth factor protein expression

To examine phosphatase and tensin homology deleted in chromosome 10 (PTEN),hypoxia-inducible factor-1 alpha (HIF-1 alpha) gene expressions and their relation to vascular endothelial growth factor(VEGF) protein expression in the patients with human colorectal adenomas and adenocarcinomas.Methods The expression of PTEN,HIF-1 alpha gene was detected by using in situ hybridization,and the VEGF expression levels by immunohistochemistry in colorectal adenomas and primary colorectal adenocarcinoma.Results Strong expression of HIF-1 alpha was detectable in the majority of colorectal dadenocarcinoma,particularly surrounding areas of necrosis in adenocarcinoma.PTEN,HIF-1 alpha mRNA and VEGF protein were positive in 51.6%,67.7% and 59.7% respectively in 62 cases of adenocarcinomas,and 77.8%,44.4% and 33.3% respectively in 18 cases of adenomas.The positive rate of VEGF was higher in the patients with colorectal adenocarcinomas than that in those with adenomas,whereas that of PTEN mRNA was contrary.HIF-1 mRNA expression was correlated significantly with lymph node metastasis,liver metastasis,Duke’s stage and recurrence.During colorectal tumor progression,the expression of HIF-1 alpha mRNA was positively correlated with the VEGF protein expression (χ2= 4.751 ,P<0.05),but negatively with the PTEN mRNA expression(χ2=21.84,P<0.01).Conclusion The absence or low expression of PTEN and the increased levels of HIF-1α and VEGF may paly an important role in carcinogenesis and progression of colorectal carcinoma.These results suggest that VEGF upregulated by HIF-1 alpha gene may be involved in angiogenesis of colorectal adenocarcinoma.4 refs,1 tab.

Tribulus terrestris extracts alleviate muscle damage and promote anaerobic performance of trained male boxers and its mechanisms： Roles of androgen, IGF-1, and IGF binding protein-3

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.

Effects of insulin-like growth factor binding protein-related protein 1 in mice with hepatic fibrosis induced by thioacetamide

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.

Insulin-like growth factor binding proteins 7 prevents dental pulp-derived mesenchymal stem cell senescence via metabolic downregulation of p21

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.

Insulin-like growth factor binding protein 1 and human embryonic development during 6-10 gestational weeks

Background Insulin-like growth factor binding protein-1 (IGFBP-1), which is a carrier of Insulin-like growth factors (IGFs) regulates the fetal development by working as an active factor controlling the combination of IGFs with their receptors. This study was designed to investigate the relationship between IGFBP-1 and human embryonic development during weeks 6-10 of gestation. Methods A total of 44 pregnant women with singleton pregnancy were divided into two groups: one with abnormal embryo development (n=32) and the other with normal embryo development (n=12). Enzyme-linked immunosorbent assay (ELISA) was employed to detect IGFBP-1 levels in maternal serum and decidual tissue. The expression of IGFBP-1 mRNA in deciduas was examined by reverse transcription polymerase chain reaction (RT-PCR) technique. Results The level of IGFBP-1 protein in maternal serum was significantly higher in the abnormal group [(125.36±47.93) μg/ml] than in the normal group [(70.72±21.21) μg/ml]. Both of IGFBP-1 and IGFBP-1 mRNA in deciduas were higher in abnormal group [(1.60±1.39) μg/ml and 1.66±1.64, respectively] than in the normal group [(0.35±0.23) μg/ml and 0.40±0.20, respectively]. The level of IGFBP-1 in maternal serum was positively correlated with IGFBP-1 mRNA (r=0.90, P<0.05) and IGFBP-1 protein (r=0.92, P<0.05) in decidual tissue. Conclusions During weeks 6-10 of gestation, abnormal embryonic development is correlated with elevated IGFBP-1. The level of IGFBP-1 in maternal serum is related to the concentrations of IGFBP-1 mRNA and IGFBP-1 in decidual tissue. The IGFBP-1 level in maternal serum may be used as a predictive marker to evaluate embryonic development.

血清LTBP2、TM4SF1在大肠癌患者预后评估中的研究

目的探讨血清转化生长因子结合蛋白2(LTBP2)、四次跨膜蛋白1(TM4SF1)在大肠癌患者预后评估中的意义。方法将南阳市中心医院2016年7月至2019年7月手术治疗的大肠癌患者108例作为试验组,同期108例健康体检者作为对照组。采用酶联免疫吸附试验(ELISA)检测两组血清LTBP2、TM4SF1水平;比较不同血清LTBP2和TM4SF1表达水平的大肠癌患者临床资料的差异;采用免疫组化染色法分析大肠癌组织中LTBP2、TM4SF1的表达;Pearson相关分析明确血清LTBP2和TM4SF1表达的相关性;受试者工作特征(ROC)曲线分析血清LTBP2和TM4SF1联合评估大肠癌患者预后的价值。结果试验组血清LTBP2和TM4SF1水平均高于对照组(P<0.05),二者表达水平呈正相关(r=0.305,P<0.05),大肠癌组织LTBP2和TM4SF1表达阳性率高于癌旁组织(P<0.05)。肿瘤直径>5cm、肿瘤低分化、有淋巴结转移、TNM分期Ⅲ~Ⅳ期、有脉管瘤栓的大肠癌患者血清LTBP2和TM4SF1表达水平高于患者肿瘤直径≤5 cm、肿瘤中高分化、无淋巴结转移、TNM分期Ⅰ~Ⅱ期、无脉管瘤栓的大肠癌患者(P<0.05)。血清LTBP2、TM4SF1联合预测大肠癌患者预后不良的AUC为0.886。结论大肠癌患者血清LTBP2和TM4SF1水平升高,二者联合对大肠癌患者预后不良具有较好的预测价值。

脑脊液IGF-1、β_(2)-MG、HBP与儿童化脓性脑膜炎发生发展的相关性

目的探究脑脊液中胰岛素样生长因子-1(IGF-1)、β_(2)微球蛋白(β_(2)-MG)、肝素结合蛋白(HBP)水平与儿童化脓性脑膜炎疾病发生发展的相关性。方法选取2021年2月至2023年2月郑州大学第一附属医院儿科收治的86例化脓性脑膜炎患儿为研究组,另选取86例非中枢神经系统感染患儿为对照组,比较两组脑脊液IGF-1、β_(2)-MG、HBP水平,探究其与研究组患儿病情严重程度及预后的相关性。结果研究组脑脊液中IGF-1、β_(2)-MG、HBP水平均高于对照组(P<0.05),且对化脓性脑膜炎具有较高的诊断价值,其曲线下面积分别为0.925、0.930、0.850;重度组脑脊液IGF-1、β_(2)-MG、HBP水平高于轻度组(P<0.05);预后不良组脑脊液IGF-1、β_(2)-MG、HBP水平高于预后良好组(P<0.05),且对化脓性脑膜炎预后不良具有较高的预测价值,其曲线下面积分别为0.879、0.854、0.822。结论监测化脓性脑膜炎患儿脑脊液中IGF-1、β_(2)-MG、HBP的水平对于早期诊断、判断病情严重程度以及预测疾病预后具有重要价值。

IGF-1、IGFBP-3在非小细胞肺癌患者血清中的表达及其临床意义

目的探讨胰岛素样生长因子-1(IGF-1)、胰岛素样生长因子结合蛋白-3(IGFBP-3)在非小细胞肺癌(NSCLC)患者血清中的表达及其临床意义。方法选择84例NSCLC患者作为肺癌组,84例肺部良性疾病患者作为对照组。采集所有患者入院第2 d时空腹静脉血4 ml,应用全自动化学发光免疫分析仪检测血清IGF-1、IGFBP-3含量。对比两组受检者血清IGF-1、IGFBP-3差异,分析血清IGF-1、IGFBP-3表达与NSCLC患者临床病理特征的关系。结果肺癌组血清IGF-1水平高于对照组,IGFBP-3水平低于对照组,有统计学差异(P<0.05);不同年龄、性别、肿瘤部位、肿瘤最大直径、病理类型、分化程度NSCLC患者血清IGF-1、IGFBP-3水平比较,无统计学差异(P<0.05);局部侵犯T_(1)~T_(2)、Ⅰ~Ⅱ期NSCLC患者血清IGF-1水平低于T_(3)~T_(4)、Ⅲ期者,IGFBP-3水平高于T_(3)~T_(4)、Ⅲ期者,有淋巴结转移者血清IGF-1水平高于T_(3)~T_(4)者,IGFBP-3水平低于T_(3)~T_(4)者,有统计学差异(P<0.05)。Pearson分析显示,血清IGF-1水平与NSCLC患者局部侵犯程度、TNM分期、淋巴结转移呈正相关(P<0.05),血清IGFBP-3-水平与NSCLC患者局部侵犯程度、TNM分期、淋巴结转移呈负相关(P<0.05)。结论NSCLC患者血清IGF-1、IGFBP-3水平表达异常,其水平高低与患者局部侵犯程度、TNM分期、淋巴结转移有关。

鉴定LTBP1作为胃癌预后的生物标志物及其与肿瘤免疫微环境的相关性

目的探索潜在转化生长因子β结合蛋白1(latent transforming growth factor beta binding protein 1,LTBP1)在胃癌发生发展及免疫微环境中的生物学功能。方法在TCGA数据库中分析LTBP1在泛癌中的表达,然后通过胃癌组织和癌旁组织进行验证。通过回归比例分析法分析LTBP1表达与临床病理变量之间的相关性。Cox回归分析和Kaplan-Meier图用于评估LTBP1在胃癌中的预后价值。通过TIMER分析LTBP1的表达水平与胃癌中免疫细胞浸润之间的相关性。免疫组织化学染色检测LTBP1蛋白在胃癌组织及癌旁组织中的表达水平。结果与正常胃组织相比,胃癌组织中LTBP1表达显著上调。其表达与病理TNM分期显著相关。LTBP1高表达的胃癌患者的总体生存率(overall survival,OS)缩短。免疫组化结果显示,与癌旁组织相比,LTBP1在胃癌组织中显著高表达。TIMER检测发现LTBP1的表达与3种免疫细胞浸润呈正相关。结论LTBP1可能是胃癌预后的一个潜在生物标志物,并影响癌症的肿瘤免疫微环境。

安图A2000全自动化学发光分析仪检测IGFBP3的性能验证及与IGF-1相关性研究

目的:对安图A2000全自动化学发光仪检测血清胰岛素样生长因子结合蛋白3(IGFBP3)的性能进行评价,并探讨其在矮小症、性早熟及垂体性病变中与IGF-1的相关性。方法:对安图A2000系统检测IGFBP3的精密度(CV)、线性范围、可报告范围、参考区间进行验证。选取2023年1月-2023年9月在本院诊断或治疗的矮小症21例、性早熟10例、垂体性病变19例,回顾性分析其胰岛素生长因子-Ⅰ(IGF-1)和IGHBP3水平,并进行Spearman相关性分析。结果:IGFBP3高低水平质控品批内CV为2.019%、2.931%,批间CV为3.818%、4.137%;测定结果在0.3~16.0μg/mL范围内呈线性,线性回归方程为Y=0.9995X~0.0213,R2=0.9974;临床可报告范围为0.3~32.0μg/mL;18~70岁和>70岁健康体检者检测结果均在厂家提供的参考区间内;IGFBP3和IGF-1在矮小症、性早熟和垂体性病变患者中具有较好的相关性(r=0.81,P<0.0001)。结论:安图A2000检测血清IGFBP3的性能能够满足实验室质量要求,且与IGF-1具有较好的相关性。