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.
Humans ; Insulin-Like Growth Factor Binding Protein 3/metabolism* ; Culture Media, Conditioned/pharmacology* ; Cachexia/pathology* ; Gastrointestinal Neoplasms ; Somatomedins/metabolism* ; Insulins/metabolism* ; Lipids

OBJECTIVETo investigate the influencing factors and pathogenesis of osteopenia in the patients with hemophilia.

METHODSTwenty-three patients with hemophilia were admitted in the hospital affiliated to North China University of Science and technology from March to August 2015, including 13 severe cases, 10 mild and moderate cases. All the patients accepted the detection of serum I collagen cross-linking N terminal peptide (NTX I), osteoprotegerin (OPG), bone alkaline phosphatase (BALP), basic fibroblast growth factor (bFGF), insulin-like growth factor (IGF) and transforming growth factor-β1 (TGF-β1), the score scale of activity ability was recorded according to the criteria published by the U.S. Center for disease prevention and control in 2002, and 21 patients received the measurement of bone mineral density. According to the World Health Organization (WHO) definition, the clinical significance of bone mineral density (BMD) was assessed by measuring the Z level.

RESULTSZ level>-2 was recorded in 10 cases, Z≤-2 was recorded in 11 cases; the levels of body mass index (BMI) and human bone alkaline phosphatase (BALP) reflecting bone formation in 11 cases (Z≤-2) were lower than there in 10 cases (Z>-2) (P<0.05); the levels of BALP (r=0.489, P<0.05), IGF (r=0.538, P<0.05) and BMI (r=0.572, P<0.01) positively correlated significantly with BMD (P<0.05); the levels of bFGF (r=0.570, P<0.01) and OPG (r=0.505, P<0.05) positively correlated with NTX I, indicating bone destruction (P<0.05); the score of activity ability of severe patients was significantly lower than that of mild and moderate cases (P<0.05), BMD levels of these 2 groups were not statistically different (P>0.05).

CONCLUSIONThe BMD level does not correlate with the clinial grouping of hemophilia, the low body mass index may be a risk factor for bone lose; the mechanism of hemophilia patient's bone lose may be related with the decrease of osteogenic activity, the IGF can prevent bone lose in hemophilia, the bFGF and OPG can promote bone metabolism of the patients with hemophilia.

Alkaline Phosphatase ; metabolism ; Biomarkers ; Bone Density ; Bone Diseases, Metabolic ; pathology ; Bone and Bones ; pathology ; Collagen Type I ; metabolism ; Fibroblast Growth Factor 2 ; metabolism ; Hemophilia A ; pathology ; Humans ; Osteogenesis ; Osteoprotegerin ; metabolism ; Peptides ; metabolism ; Somatomedins ; metabolism ; Transforming Growth Factor beta1 ; metabolism

Animals ; Gene Expression ; Hypoxia ; metabolism ; Prefrontal Cortex ; metabolism ; Rats ; Somatomedins ; metabolism

OBJECTIVETo observe the changes in the expressions of somatomedins in the prostate epithelial cells in anoxic condition.

METHODSWe cultured prostate epithelial cell line RWPE-1 in vitro. At 4, 8, 12, 24, 48 hours after seeding of the cells, we determined the gene and protein expressions of the epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), transforming growth factor-beta (TGF-beta), insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF) in the prostate epithelial cells by RT-PCR and ELISA, respectively.

RESULTSWith the increase of time, the expressions of the EGF, bFGF, TGF-beta, IGF-1 and VEGF genes were obviously up-regulated, more significantly in the anoxic than in the normoxic prostate epithelial cells. Take FGF mRNA, its expression level was 0.14 +/- 0.01 in the anoxic and 0. 12 +/- 0.01 in the normoxic prostate epithelial cells at 8 hours (P = 0.01), but increased to 0.29 +/- 0.01 and 0.14 +/- 0.01, respectively, at 48 hours (P < 0.001). The expression of the TGF-beta protein was also more significantly increased in the anoxic than in the normoxic prostate epithelial cells, 0.32 +/- 0.01 versus 0.26 +/- 0.01 at 4 hours (P = 0.017) and 1.56 +/- 0.13 versus 0.87 +/- 0.06 at 48 hours (P < 0.001). The other 4 somatomedins showed no significant differences in their protein expressions between anoxic and normoxic conditions.

CONCLUSIONAnoxia can up-regulate the gene expressions of somatomedins and increase the secretion of TGF-beta in prostate epithelial cells.

Cell Hypoxia ; Cell Line ; Epithelial Cells ; metabolism ; Gene Expression Regulation ; Humans ; Male ; Prostate ; cytology ; Somatomedins ; metabolism ; Transforming Growth Factor beta ; metabolism ; Up-Regulation

The present study was to investigate the effects of exogenous insulin-like growth factor binding protein 7 (IGFBP7) on the proliferation of human breast cancer cell line MDA-MB-453 and its possible mechanism. By means of MTT method in vitro, the results showed exogenous IGFBP7 inhibited the growth of MDA-MB-453 cells (IC50 of IGFBP7 = 8.49 μg/mL) in time- and concentration-dependent manner. SB203580, p38(MAPK) inhibitor, blocked the anti-proliferative effect of exogenous IGFBP7. The flow cytometry assay showed that exogenous IGFBP7 remarkably induced G0/G1 arrest in MDA-MB-453 cells. The Western blot showed that exogenous IGFBP7 promoted phosphorylation of p38(MAPK), up-regulated expression of p21(CIP1/WAF1), and inhibited phosphorylation of Rb. SB203580 restrained exogenous IGFBP7-induced regulation of p21(CIP1/WAF1) and p-Rb in MDA-MB-453 cells. In conclusion, the present study suggests that exogenous IGFBP7 could activate the p38(MAPK) signaling pathway, upregulate p21(CIP1/WAF1) expression, inhibit phosphorylation of Rb, and finally induce G0/G1 arrest in MDA-MB-453 cells.
Breast Neoplasms ; pathology ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Cyclin-Dependent Kinase Inhibitor p21 ; metabolism ; Female ; Humans ; Imidazoles ; pharmacology ; Insulin-Like Growth Factor Binding Proteins ; pharmacology ; Phosphorylation ; Pyridines ; pharmacology ; Signal Transduction ; Somatomedins ; p38 Mitogen-Activated Protein Kinases ; antagonists & inhibitors ; metabolism

Insulin-like growth factor-binding proteins(IGFBPs) are critical regulators of the mitogenic activity of insulin-like growth factors (IGFs). IGFBP5, one of these IGFBPs, has special structural features, including a nuclear transport domain, heparin-binding motif, and IGF/extracellular matrix/acid-labile subunit-binding sites. Furthermore, IGFBP5 has several functional effects on carcinogenesis and even normal cell processes, such as cell growth, death, motility, and tissue remodeling. These biological effects are sometimes related with IGF (IGF-dependent effects) and sometimes not (IGF-independent effects). The functional role of IGFBP5 is most likely determined in a cell-type and tissue-type specific manner but also depends on cell context, especially in terms of the diversity of interacting proteins and the potential for nuclear localization. Clinical findings show that IGFBP5 has the potential to be a useful clinical biomarker for predicting response to therapy and clinical outcome of cancer patients. In this review, we summarize the functional diversity and clinical importance of IGFBP5 in different types of cancers.
Animals ; Apoptosis ; Cell Differentiation ; Cell Movement ; Humans ; Insulin-Like Growth Factor Binding Protein 5 ; genetics ; metabolism ; physiology ; Neoplasm Metastasis ; Neoplasms ; metabolism ; pathology ; Protein Binding ; RNA, Messenger ; metabolism ; Signal Transduction ; Somatomedins ; metabolism

Obesity is defined as BMI (calculated as weight in kg divided by height in m2) more than 30, and overweight is defined as BMI of 25-29.9. Obesity has been considered as a risk factor for pancreatic diseases, including pancreatitis and pancreatic cancer. Severe acute pancreatitis is significantly more frequent in obese patients. Furthermore, obese patients develop systemic and local complications of acute pancreatitis more frequently. The underlying mechanisms are increased inflammation and necrosis from increased amount of intra- and peri-pancreatic fat. In addition, obesity is a poor prognostic factor in acute pancreatitis, and overweight before disease onset appears to be a risk factor for chronic pancreatitis. Overweight and/or obesity are associated with greater risk of pancreatic cancer and younger age of onset. Physical activity appears to decrease the risk of pancreatic cancer, especially among those who are overweight. Long-standing diabetes increases the risk of pancreatic cancer. The pathogenic mechanism is that obesity and physical inactivity increase insulin resistance. In a state of hypersinulinemia, increased circulating level of insulin-like growth factor-1 induces cellular proliferation of pancreatic cancer. Obesity is associated with negative prognostic factor and increased mortality in pancreatic cancer. However, there are controversies regarding the effects of obesity on long-term post-operative results in the patient with pancreatic cancer.
Body Mass Index ; Humans ; Hypertriglyceridemia/complications ; Obesity/*complications ; Overweight ; Oxidative Stress ; Pancreatic Diseases/*etiology ; Pancreatic Neoplasms/etiology ; Somatomedins/metabolism/physiology

Obesity worldwide is constantly increasing. Obesity acts as an independent significant risk factor for malignant tumors of various organs including colorectal cancer. Visceral adipose tissue is physiologically more important than subcutaneous adipose tissue. The relative risk of colorectal cancer of obese patients is about 1.5 times higher than the normal-weight individuals, and obesity is also associated with premalignant colorectal adenoma. The colorectal cancer incidence of obese patients has gender-specific and site-specific characteristics that it is higher in men than women and in the colon than rectum. Obesity acts as a risk factor of colorectal carcinogenesis by several mechanisms. Isulin, insulin-like growth factor, leptin, adiponectin, microbiome, and cytokines of chronic inflammation etc. have been understood as its potential mechanisms. In addition, obesity in patients with colorectal cancer negatively affects the disease progression and response of chemotherapy. Although the evidence is not clear yet, there are some reports that weight loss as well as life-modification such as dietary change and physical activity can reduce the risk of colorectal cancer. It is very important knowledge in the point that obesity is a potentially modifiable risk factor that can alter the incidence and outcome of the colorectal cancer.
Adipokines/metabolism/physiology ; Body Mass Index ; Colorectal Neoplasms/*etiology/prevention & control ; Energy Intake ; Exercise ; Humans ; Insulin Resistance ; Meta-Analysis as Topic ; Obesity/*complications ; Somatomedins/metabolism/physiology ; Weight Loss

Despite a higher incidence and less favorable outcome of malignant tumors in obese patients, much less recognized is the link between obesity and cancer. The mechanism of the association of obesity with carcinogenesis remains incompletely understood. Postulated mechanisms include insulin resistance, insulin-like growth factor signaling, chronic inflammation, immunomodulation, hyperglycemia-induced oxidative stress, and changes of intestinal microbiome. Insulin resistance leads to direct mitogenic and antiapoptotic signaling by insulin and the insulin-like growth factor axis. Obesity can be considered to be a state of chronic low-grade inflammation. In obesity, numerous proinflammatory cytokines are released from adipose tissue which may involve in carcinogenesis. Hyperglycemia in susceptible cells results in the overproduction of superoxide and this process is the key to initiating all damaging pathways related to diabetes. This hyperglycemia-induced oxidative stress could be one possible link among obesity, diabetes, and cancer development. The role of obesity-related changes in the intestinal microbiome in gastrointestinal carcinogenesis deserves further attention.
Adipokines/metabolism/physiology ; Gastrointestinal Neoplasms/*etiology/microbiology ; Humans ; Inflammation/etiology ; Insulin/metabolism/physiology ; Leptin/metabolism/physiology ; Obesity/*complications/immunology/metabolism ; Oxidative Stress ; Somatomedins/metabolism/physiology

OBJECTIVECytokines such as VEGF and IGF play an important role in maintaining the function of blood vascular endothelium. And Akt1 is an important molecule in the intra-cellular signaling transduction. This study aims to investigate the molecular mechanism of Shugan Yiyang (SGYY) capsule in the treatment of arteriogenic erectile dysfunction (AED) by detecting the expressions and phosphorylation of VEGF, IGF and Akt1 in AED rats.

METHODSWe established AED models in 60 three-month-old adult male SD rats by bilateral ligation of the internal iliac artery, and assigned them to a sham operation group, a model control group, a sildenafil group, a low-dose SGYY group (0.5 g/[kg x d]) and a high-dose SGYY group (1 g/[kg x d]). After 30 days of gavage, we assayed the plasma concentrations of VEGF and IGF in the carotid artery of the rats by ELISA, detected the expressions of VEGF and IGF mRNA by real-time PCR and determined the expression and phosphorylation of Aktl protein in the corpus cavernosum penis by Western blot.

RESULTSIn the model control group, the expressions of VEGF and IGF mRNA were 0.41 +/- 0.06 and 0.42 +/- 0.06, the plasma concentrations of VEGF and IGF were (28.59 +/- 24.97) pg/ml and (15.82 +/- 4.37) ng/ml, and the expression of p-Aktl/Akt1 was 0.93 +/- 0.14. While in the high-dose SGYY group, the expressions of VEGF and IGF mRNA were 0.77 +/- 0.04 and 0.78 +/- 0.05, the plasma concentrations of VEGF and IGF were (95.83 +/- 37.34) pg/ml and (20.45 +/- 3.83) ng/ml, and the expression of p-Aktl/Aktl was 1.43 +/- 0.50. All the parameters above were significantly higher in the high-dose SGYY than in the model control group (P < 0.05), and so were they in the low-dose SGYY group except the plasma concentration of IGF (P < 0.05).

CONCLUSIONSGYY can significantly upregulate the expressions of VEGF, IGF and Akt1 in the corpus cavernosum penis of AED rats, and improve the function of blood vascular endothelium, which is probably an important mechanism of SGYY capsule acting on AED.

Animals ; Disease Models, Animal ; Drugs, Chinese Herbal ; therapeutic use ; Erectile Dysfunction ; drug therapy ; etiology ; metabolism ; Insulin-Like Growth Factor I ; metabolism ; Male ; Phytotherapy ; Proto-Oncogene Proteins c-akt ; metabolism ; Rats ; Rats, Sprague-Dawley ; Somatomedins ; metabolism ; Vascular Endothelial Growth Factor A ; metabolism