Wei Ren

Association of type 2 diabetes susceptibility genes (TCF7L2, SLC30A8, PCSK1 and PCSK2) and proinsulin conversion in a Chinese population

TCF7L2 and SLC30A8 have been found to be associated with type 2 diabetes mellitus (T2DM) as well as with impaired proinsulin processing recently, enzymes encoded by PCSK1 and PCSK2 are reported to play an important role in the process of proinsulin conversion. To investigate whether the single nucleotide polymorphisms (SNPs) of TCF7L2, SLC30A8, PCSK1 and PCSK2 were associated with T2DM as well as with proinsulin conversion in a Han Chinese population from Chongqing. A case–control study was performed in Han Chinese subjects with normal control (nxa0=xa0152) and T2DM (nxa0=xa0227), we genotyped rs7903146 and rs11196218 at TCF7L2, rs13266634 at SLC30A8, rs3811951 at PCSK1 and rs2021785 at PCSK2. Plasma levels of proinsulin were measured with an Enzyme Linked Immunosorbent Assay (ELISA). Genotype distribution and associations with T2DM and fasting levels of proinsulin and proinsulin/insulin ratios were analyzed. We confirmed the association of risk allele of rs2021785 at PCSK2 with type 2 diabetes also existed in Han Chinese population [ORxa0=xa01.4489 with 95% CI (1.0285, 2.0412), Pxa0=xa00.0335]. Rs13266634 at SLC30A8 had a tendency to be associated with fasting plasma levels of proinsulin (Pxa0=xa00.0639 in additive model). We did not find the significant association between other SNPs and T2DM or fasting levels of proinsulin or proinsulin/insulin ratios. Our results provide evidence that the association of PCSK2 and T2DM was also existed in Han Chinese population in Chongqing. We were underpowered to detect the association between other SNPs and T2DM or proinsulin conversion.

BMP9 inhibits the bone metastasis of breast cancer cells by downregulating CCN2 (connective tissue growth factor, CTGF) expression.

Bone morphogenetic proteins (BMPs), which belong to the transforming growth factor-β superfamily, regulate a wide range of cellular responses including cell proliferation, differentiation, adhesion, migration, and apoptosis. BMP9, the latest BMP to be discovered, is reportedly expressed in a variety of human carcinoma cell lines, but the role of BMP9 in breast cancer has not been fully clarified. In a previous study, BMP9 was found to inhibit the growth, migration, and invasiveness of MDA-MB-231 breast cancer cells. In the current study, the effect of BMP9 on the bone metastasis of breast cancer cells was investigated. After absent or low expression of BMP9 was detected in the MDA-MB-231 breast cancer cells and breast non-tumor adjacent tissues using Western blot and immunohistochemistry, In our previous study, BMP9 could inhibit the proliferation and invasiveness of breast cancer cells MDA-MB-231 in vitro and in vivo. This paper shows that BMP9 inhibit the bone metastasis of breast cancer cells by activating the BMP/Smad signaling pathway and downregulating connective tissue growth factor (CTGF); however, when CTGF expression was maintained, the inhibitory effect of BMP9 on the MDA-MB-231 cells was abolished. Together, these observations indicate that BMP9 is an important mediator of breast cancer bone metastasis and a potential therapeutic target for treating this deadly disease.

Serum levels of proamylin and amylin in normal subjects and patients with impaired glucose regulation and type 2 diabetes mellitus.

Amylin is the major constituent of pancreatic islet amyloid whose accumulation characterizes patients with type 2 diabetes mellitus (T2DM). Although amylin is tightly linked with T2DM, in many cases, proamylin may be the more toxic species. As the precursor of amylin, however, the pathophysiological role of proamylin remains unknown. In this study, we investigate whether serum levels of proamylin or amylin or the proamylin/amylin ratios are different among normal subjects and patients with impaired glucose regulation (IGR) and T2DM. Totally 79 subjects were divided into three groups according to the results of oral glucose tolerance test (OGTT); they were T2DM group (32 cases), IGR group (23cases), and normal glucose tolerance (NGT) group (24cases). Serum levels of amylin and proamylin were measured with an enzyme-linked immunosorbent assay (ELISA). The relationships between serum levels of proamylin, amylin, their ratios and anthropometric and metabolic parameters were also analyzed. The serum levels of proamylin were significantly higher in patients with IGR and T2DM than in control subjects. The serum levels of proamylin were significantly associated with IGR and T2DM, with the odds ratios of 1.589 (95%CI, 1.228–2.055, Pxa0<xa00.01) and 1.860 (95%CI, 1.342–2.587, Pxa0<xa00.01), respectively. Both fasting serum levels of proamylin and proamylin/amylin ratios were found to correlate negatively with HOMA-B and ΔI30/ΔG30. Serum levels of proamylin, amylin, and their ratios were positively correlated with HOMA-IR. BMI and HOMA-B were independent related factors with serum levels of proamylin. Our results suggest that proamylin may play an important role in amyloid deposit in patients with IGR and T2DM.

BMP9 regulates cross-talk between breast cancer cells and bone marrow-derived mesenchymal stem cells

PurposeBreast cancer cells frequently metastasize to distant organs, including bone. Interactions between breast cancer cells and the bone microenvironment are known to enhance tumor growth and osteolytic damage. Here we investigated whether BMP9 (a secretary protein) may change the bone microenvironment and, by doing so, regulate the cross-talk between breast cancer cells and bone marrow-derived mesenchymal stem cells.MethodsAfter establishing a co-culture system composed of MDA-MB-231breast cancer cells and HS-5 bone marrow-derived mesenchymal stem cells, and exposure of this system to BMP9 conditioned media, we assessed putative changes in migration and invasion capacities of MDA-MB-231 cells and concomitant changes in osteogenic marker expressionin HS-5 cells and metastases-related genes in MDA-MB-231 cells.ResultsWe found that BMP9 can inhibit the migration and invasion of MDA-MB-231 cells, and promote osteogenesis and proliferation of HS-5 cells, in the co-culture system. We also found that the BMP9-induced inhibition of migration and invasion of MDA-MB-231 cells may be caused by a decreased RANK ligand (RANKL) secretion by HS-5 cells, leading to a block in the AKT signaling pathway.ConclusionsFrom our data we conclude that BMP9 inhibits the migration and invasion of breast cancer cells, and promotes the osteoblastic differentiation and proliferation of bone marrow-derived mesenchymal stem cells by regulating cross-talk between these two types of cells through the RANK/RANKL signaling axis.

Increase in serum pregnancy-associated plasma protein-A is correlated with increase in cardiovascular risk factors in adult patients with growth hormone deficiency

Adult Growth Hormone Deficiency (AGHD) is correlated to many adverse effects on metabolism and increased cardiovascular risk. Pregnancy-associated plasma protein-A (PAPP-A) is a protease that promotes IGF-I availability in vascular tissues in recent study, and PAPP-A levels have been proposed as an early predictor of cardiac events. The aim of our study was to compare PAPP-A levels in AGHD patients with that of healthy adult subjects to determine if there is a relationship between serum PAPP-A and glucose and lipid metabolism. Twenty AGHD patients and 20 healthy, age-matched and weight-matched persons were chosen for the study. Their weight, height, blood pressure, body mass index (BMI), body fat percentage, waist and hip circumference, and waist–hips ratio were assessed. An oral glucose tolerance test was performed and venous blood was collected from the each patient’s cubital vein for biochemical analysis. Serum PAPP-A level in AGHD patients was significantly higher than that of the control group [(7.62xa0±xa01.62 vs. 6.54xa0±xa01.31) pxa0<xa00.05], and PAPP-A was positively correlated to age, BMI, waist circumference and so on. After adjusting for the waist circumference, waist–hip ratio, 2xa0h postprandial blood glucose, triglycerides, the serum PAPP-A in AGHD patients was positively correlated to the BMI (rxa0=xa00.728, pxa0<xa00.05) and fasting insulin (rxa0=xa00.433, pxa0<xa00.05). In a multiple step-wise regression analysis, BMI, 2xa0h postprandial glucose, fasting insulin, HOMA-IR were independently associated with serum PAPP-A in AGHD patients. The increase in serum PAPP-A levels is associated with abnormal glucose metabolism and increased risk of atherosclerosis in AGHD patients.

The risk factors of mild decline in estimated glomerular filtration rate in a community-based population

OBJECTIVESnThe study aimed to analyze the relationship between metabolic variables and estimated glomerular filtration rate (eGFR) and explore the potential risk factors for a mildly reduced eGFR in a community-based population.nnnDESIGN AND METHODSnCross-sectional study in 643 adults without a history of kidney disease whose eGFR levels were greater than 60 mL/min/1.73 m(2) according to the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI). Anthropometric measurements, blood pressure, fasting lipid profile and levels of fasting and post-load glucose, insulin, serum creatinine and uric acid (UA) were tested. The eGFR was calculated, and the correlations between eGFR and each variable were analyzed.nnnRESULTSnThe subjects were divided into two groups by using 90 mL/min/1.73 m(2) as the cut-off value of the eGFR. In the lower eGFR group, the age, systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), waist circumference (WC), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), fasting plasma glucose (FPG), 2 h post-load plasma glucose (2 h-PG) levels and UA were significantly increased, and the incidences of hypertension, diabetes, obesity, hypertriglyceridemia and hypercholesterolemia were also higher (P<0.05). A multiple linear stepwise regression analysis showed that the WC, SBP, FPG and UA were independently correlated with the eGFR after adjusting for the other covariables.nnnCONCLUSIONSnThe WC, SBP, FPG and UA were closely related to the eGFR in the subjects whose eGFR levels were greater than 60 mL/min/1.73 m(2). The increased WC, SBP, FPG and UA may be the main risk factors for a mildly reduced eGFR.

The relationship between high-sensitivity C-reactive protein and ApoB, ApoB/ApoA1 ratio in general population of China

Inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) is considered as a major predictor of cardiovascular events. Apolipoprotein B (ApoB) directly reflects the number of plasma atherogenic lipoproteins, and may play a major role in vascular inflammation. We aimed to assess whether an association between ApoB and hsCRP exists and, furthermore, to examine whether ApoB is more predictive of the inflammatory status than other cardiovascular risk factors. This was a cross-sectional study, with 511 apparently healthy adult subjects enrolled. Waist circumference (WC), body mass index (BMI), and blood pressure (BP) were measured. Plasma glucose levels, hsCRP, lipid profile, and insulin were collected after 10–14xa0h fasting. From the lowest to the highest quartile of hsCRP, the values for BMI, WC, BP, HOMA-IR, insulin, glucose level, triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), ApoB and the ApoB/apolipoprotein A1 (ApoA1) ratio were increased as the hsCRP level increased (Pxa0<xa00.01), and high-density lipoprotein cholesterol (HDL-C) and ApoA1 levels declined as hsCRP level increased (Pxa0<xa00.0001). Pearson’s correlation analysis demonstrated that hsCRP correlated with all variables (Pxa0<xa00.01), except for total cholesterol (TC) (Pxa0=xa00.154) and LDL-C (Pxa0=xa00.087). According to forward stepwise regression analysis with hsCRP as the dependent variable, WC was the only variable entered the regression model. ApoB level correlated with hsCRP level but was not the major determinant of hsCRP. WC was stronger than other cardiovascular risk factors in the associations with hsCRP. Abdominal obesity rather than atherogenic dyslipidemia was the primary cause of chronic inflammatory status.

The lipid accumulation product is highly related to serum alanine aminotransferase level in male adults

Studies confirm that the lipid accumulation product (LAP), which is based on the waist circumference and fasting serum triglycerides, is highly related to cardiovascular and metabolic diseases. Nonalcoholic fatty liver disease is a hepatic manifestation of metabolic syndrome and closely correlated with the alanine aminotransferase (ALT) elevation. Abdominal obesity and dyslipidemia are the important risk factors for nonalcoholic fatty liver disease. Our aim was to examine the correlation between the LAP and ALT in apparently healthy adults. We conducted a cross-sectional study of 587 adults. The blood pressure, anthropometric measurements, fasting and postload glucose, insulin, fasting lipid profile, and liver enzymes were measured. The LAP was calculated. For each gender, the subjects were divided into 3 groups according to the ALT level. The correlation between the LAP and ALT was analyzed. The LAP increased progressively across the ALT tertiles. A Pearson correlation analysis demonstrated that the LAP positively associated with the ALT in men and women (both P < .05) but independently related to the ALT only in men. Furthermore, after adjusting for the other confounding factors, the subjects in the upper quartile of LAP was 3.61 times more likely to show ALT elevation compared with those in the lower quartiles in men. In addition, in men, the LAP was considered as the best marker to predict increased ALT. Our findings suggested that the LAP was independently correlated with the ALT but only in men. The LAP was the main risk marker and might be superior to other variables in recognizing increased ALT.

Inhibitor of β-catenin and TCF (ICAT) promotes cervical cancer growth and metastasis by disrupting E-cadherin/β-catenin complex

The inhibitor of β-catenin and TCF (ICAT) blocks the binding of TCF to β-catenin and has been demonstrated as a suppressor of the Wnt/β-catenin signaling pathway. It has been reported to exert a different function around a wide variety of cancers. However, its function and underlying mechanisms in human cervical cancer remains unknown. In the present study, the expression of ICAT in 41 human cervical cancer tissues and 30 normal cervical tissues was evaluated by immunohistochemical analysis. ICAT was found highly expressed in cancer tissues. ICAT overexpression significantly promoted SiHa cell proliferation in vitro by causing G1 arrest, and enhanced cell migration and invasion whereas, ICAT knockdown induced opposite effects in Caski cells which have higher expression of ICAT. Downregulation or overexpression of ICAT resulted in an altered expression of the epithelial-mesenchymal transition (EMT). Furthermore, immunoprecipitation assays revealed that ICAT pormoted cervical cancer EMT by competing in E-cadhenin binding to β-caterin. Overexpression of ICAT in SiHa cells promoted tumor growth and EMT was also demonstrated by the xenograft mouse experiment. These results demonstrate that ICAT contributed to the progression of cervical cancer and may play a role in the regulation of EMT by distrupting the E-cadherin/β-catenin complex. It may be a novel potential therapeutic target for therapy in human cervical cancer.

The Great Chinese Famine Exposure in Early Life and the Risk of Nonalcoholic Fatty Liver Disease in Adult Women

INTRODUCTION AND AIMnPrevious studies found famine exposure was associated with a higher risk of metabolic syndrome (MetS). In the study, we investigated the relationship between Chinese famine exposure and the risk of nonalcoholic fatty liver disease (NAFLD) in adult women.nnnMATERIALS AND METHODSnData were obtained from subjects via routine physical examinations in the Public Health Center of our hospital between 2011 and 2014. Women were categorized into the following three groups: control, pre-natally exposed, and postnatally exposed. Hepatic steatosis was diagnosed according to the guidelines established for the diagnosis and treatment of NAFLD.nnnRESULTSnThe prevalence rates of NAFLD among non-exposed, prenatally, and postnatally exposed women were 17.3, 23.0, and 22.9%, respectively. Pre-exposed and postnatally exposed women had higher risks of NAFLD, exhibiting ORs (95% CI) of 1.33 (1.04-1.70) and 1.26 (1.03-1.55), respectively. Prenatally, but not postnatally, exposed women had significantly higher risks of having abnormal alanine aminotransferase (ALT), with ORs of 1.30 (1.05-1.61).nnnCONCLUSIONSnThe results indicate a significant association between famine exposure in early life and the risk of NAFLD in adult women. Prenatally exposed women displayed higher risks of NAFLD and mild, moderate and severe steatosis.INTRODUCTION AND AIMnPrevious studies found famine exposure was associated with a higher risk of metabolic syndrome (MetS). In the study, we investigated the relationship between Chinese famine exposure and the risk of nonalcoholic fatty liver disease (NAFLD) in adult women.nnnMATERIALS AND METHODSnData were obtained from subjects via routine physical examinations in the Public Health Center of our hospital between 2011 and 2014. Women were categorized into the following three groups: control, prenatally exposed, and postnatally exposed. Hepatic steatosis was diagnosed according to the guidelines established for the diagnosis and treatment of NAFLD.nnnRESULTSnThe prevalence rates of NAFLD among non-exposed, prenatally, and postnatally exposed women were 17.3, 23.0, and 22.9%, respectively. Pre-exposed and postnatally exposed women had higher risks of NAFLD, exhibiting ORs (95% CI) of 1.33 (1.04-1.70) and 1.26 (1.03-1.55), respectively. Prenatally, but not postnatally, exposed women had significantly higher risks of having abnormal alanine aminotransferase (ALT), with ORs of 1.30 (1.05-1.61).nnnCONCLUSIONSnThe results indicate a significant association between famine exposure in early life and the risk of NAFLD in adult women. Prenatally exposed women displayed higher risks of NAFLD and mild, moderate and severe steatosis.