Association between aberrant dynein cytoplasmic 1 light intermediate chain 1 expression levels, mucins and chemosensitivity in colorectal cancer.

Dynein transport along the cytoskeletal microtubules towards the minus end is essential for cell division, cell migration and other basic cellular functions. Dynein cytoplasmic 1 light intermediate chain 1 (DYNC1LI1) has been previously associated with pancreatic ductal adenocarcinoma, hepatocellular carcinoma and prostate cancer. Cytoskeletal structures are involved in the regulation of the mucosal barrier integrity. Thus, improving our understanding of the molecular mechanisms that regulate the mucosal barrier is critical for cancer management and treatment. The present study aimed to investigate DYNC1LI1 expression in colorectal cancer (CRC) tissues. The American Joint Committee on Cancer Stage II CRC cell line LS 174T was used to determine the association between the cellular expression levels of DYNC1LI1 and different types of mucin (MUC) by reverse transcription­quantitative PCR. The role of DYNC1LI1 in cell chemosensitivity and proliferation was also evaluated in the presence of the DNA analog 5­fluorouracil (5­FU) or the platinum­based drug, oxaliplatin by the MTT assay. LS 174T cells with decreased expression levels of DYNC1LI1 were discovered to be more sensitive to 5­FU compared with LS 174T cells with endogenous DYNC1LI1 expression levels. Moreover, LS 174T cells transfected with short hairpin RNA targeting DYNC1LI1 were associated with low MUC1 and high MUC2, MUC4 and MUC5AC expression levels. Notably, the CRC cells with low MUC1 expression levels and high expression levels of the other MUCs (MUC2, MU4 and MUC5AC) were shown to benefit from 5­FU treatment. In conclusion, the findings of the present study have suggested that DYNC1LI1 expression may be significantly associated with MUC expression levels and may be used to predict the chemotherapeutic efficiency. However, additional functional studies and clinical reports are required for an improved understanding of the significance of these molecular interactions in tumorigenesis.

Red Blood Cell Aggregation-Associated Dietary Pattern Predicts Hyperlipidemia and Metabolic Syndrome.

Red blood cell (RBC) aggregation and iron status are interrelated and strongly influenced by dietary factors, and their alterations pose a great risk of dyslipidemia and metabolic syndrome (MetS). Currently, RBC aggregation-related dietary patterns remain unclear. This study investigated the dietary patterns that were associated with RBC aggregation and their predictive effects on hyperlipidemia and MetS. Anthropometric and blood biochemical data and food frequency questionnaires were collected from 212 adults. Dietary patterns were derived using reduced rank regression from 32 food groups. Adjusted linear regression showed that hepcidin, soluble CD163, and serum transferrin saturation (%TS) independently predicted RBC aggregation (all p < 0.01). Age-, sex-, and log-transformed body mass index (BMI)-adjusted prevalence rate ratio (PRR) showed a significant positive correlation between RBC aggregation and hyperlipidemia (p-trend < 0.05). RBC aggregation and iron-related dietary pattern scores (high consumption of noodles and deep-fried foods and low intake of steamed, boiled, and raw food, dairy products, orange, red, and purple vegetables, white and light-green vegetables, seafood, and rice) were also significantly associated with hyperlipidemia (p-trend < 0.05) and MetS (p-trend = 0.01) after adjusting for age, sex, and log-transformed BMI. Our results may help dieticians develop dietary strategies for preventing dyslipidemia and MetS.

Effects of ferric citrate supplementation on advanced glycation end products in a rat model of streptozotocin/nicotinamide-induced diabetes.

SCOPE: Diabetes is associated with the increased risks of anemia and activation of advanced glycation end products (AGEs) and the receptor for AGEs (RAGE). However, the effects of pharmacological doses of iron supplementation on AGE metabolism are less clear. The aim was to investigate the effect of ferric citrate supplementation on AGE metabolism. METHODS AND RESULTS: Diabetes was induced in overnight starved rats by intraperitoneal injections of 40 mg/kg streptozotocin and 120 mg/kg nicotinamide. Diabetic rats were fed a standard diet or pharmacological doses of ferric citrate (0.5, 1, 2, and 3 g of ferric iron/kg diet) for 10 weeks. Ferric citrate supplementation showed a dose-related effect on the hepatic steatosis score, malondialdehyde, cathepsin D, and glyoxalase I. A Western blot analysis revealed that >1 g of ferric iron suppressed hepatic AGE receptor 1 and high-mobility group-box 1 expressions but increased heme oxygenase-1 and RAGE expressions. Further analysis showed that high doses of ferric iron triggered sterol regulatory element-binding protein 1c, p38-mitogen-activated protein kinase, and nuclear factor-κB protein expressions. CONCLUSION: Overall, the present results suggest a dose-related effect of ferric citrate supplementation on AGE metabolism, and this effect was more evident at high iron doses (>1 g of ferric iron/kg diet).

Hb and dyslipidaemia as predicting markers of serum alanine aminotransferase elevation in Chinese adolescents.

OBJECTIVE: Fe is an essential element for erythropoiesis and Hb synthesis. High Hb levels affect the blood's viscosity and are associated with cardiovascular dysfunction. The aim of the present study was to examine relationships of Hb and cardiometabolic abnormalities with the risk of alanine aminotransferase (ALT) elevation in adolescents. DESIGN: A population-based, cross-sectional study. SETTING: National Nutrition and Health Survey in Taiwan (2010-2011, adolescents). SUBJECTS: Healthy adolescents aged 13-18 years. RESULTS: In total, 1941 adolescents (963 boys and 978 girls) were entered in the study. The mean age was 15·3 (sd 0·1) years (boys, 15·3 (sd 0·1) years; girls, 15·2 (sd 0·1) years). ALT tertile cut-off points for boys were 11 and 16 U/l, and for girls were 9 and 12 U/l. Girls without dyslipidaemia and presenting in the highest quartile (Q1) of Hb (>13·6 g/dl) were 1·89 and 3·76 times more likely to have raised serum ALT (9 and >12 U/l, respectively) than the reference (lowest quartile of Hb (Q1), 12 U/l) than the reference (Q1 of Hb, 15·4 g/dl), who were 7·40 times more likely to have elevated serum ALT of >16 U/l than the reference (Q1 of Hb, <14·1 g/dl). CONCLUSIONS: Our findings suggest that an increased Hb level is a predictor of elevated serum ALT in adolescent girls with dyslipidaemia. Our study also highlights the importance of further research to establish cut-off points for Hb and its utility in diagnosing and preventing the onset of dyslipidaemia in adolescents.

Serum Ferritin Is Inversely Correlated with Testosterone in Boys and Young Male Adolescents: A Cross-Sectional Study in Taiwan.

OBJECTIVE: The transition from childhood to teenaged years is associated with increased testosterone and a decreased iron status. It is not clear whether higher testosterone levels cause the decreased iron status, and to what extent, obesity-related inflammation influences the iron-testosterone relationship. The aim of the present study was to examine relationships of testosterone, iron status, and anti-/proinflammatory cytokines in relation to nutritional status in boys and young adolescent Taiwanese males. METHODS: In total, 137 boys aged 7~13 yr were included. Parameters for obesity, the iron status, testosterone, and inflammatory markers were evaluated. RESULTS: Overweight and obese (ow/obese) boys had higher mean serum testosterone, interleukin (IL)-1ß, and nitric oxide (NO) levels compared to their normal-weight counterparts (all p<0.05). Mean serum ferritin was slightly higher in ow/obese boys compared to normal-weight boys, but this did not reach statistical significance. A multiple linear regression showed that serum ferritin (ß = -0.7470, p = 0.003) was inversely correlated with testosterone, while serum IL-10 (ß = 0.3475, p = 0.009) was positively associated with testosterone after adjusting for covariates. When normal-weight boys were separately assessed from ow/obesity boys, the association between testosterone and serum ferritin became stronger (ß = -0.9628, p<0.0001), but the association between testosterone and IL-10 became non-significant (ß = 0.1140, p = 0.4065) after adjusting for covariates. In ow/obese boys, only IL-10 was weakly associated with serum testosterone (ß = 0.6444, p = 0.051) after adjusting for age. CONCLUSIONS: Testosterone and serum ferritin are intrinsically interrelated but this relationship is weaker in ow/obese boys after adjusting for age.

Interleukin 10 and clustering of metabolic syndrome components in pediatrics.

BACKGROUND: Interleukin 10 (IL-10) has multifaceted anti-inflammatory properties that are known to regulate insulin sensitivity and atherosclerotic development. However, studies in children are limited and have yielded conflicting results. The aim of this study was to evaluate whether changes in this circulating anti-inflammatory cytokine is a marker for metabolic syndrome. MATERIALS AND METHODS: This cross-sectional study involved children and young adolescents from eight elementary schools and two junior high schools located in Taipei and New Taipei City. A total of 553 children ages 8, 11 and 13 years old were included in the analysis. Parameters for obesity, anti- and pro-inflammatory cytokines, and metabolic risk profiles were evaluated. RESULTS: Overweight/obese children had lower serum IL-10 concentrations compared with normal weight children in the same age group (all P < 0·001). IL-10 quartiles were negatively associated with body mass index (BMI) and percentage (%) body fat (all P < 0·05). Multivariate regression analysis showed significant inverse relationship between IL-10 concentrations and % body fat (ß = -0·009, P < 0·0001), and total cholesterol (ß = -0·726, P = 0·003), and a small positive correlation between IL-10 and systolic blood pressure (ß = 0·980, P = 0·027). In normal weight children, IL-10 concentrations were independently associated with fasting plasma insulin (ß = 0·2912, P = 0·001) and waist circumference (ß = 0·0069, P = 0·022). By contrast, % body fat (ß = -0·016, P = 0·0009) was independently associated with IL-10 concentrations in overweight and obese children. Association between IL-10 and fasting plasma insulin concentrations was weaker in overweight/obese children compared with normal weight (ß = 0·283, P = 0·011 vs. ß = 0·2912, P = 0·001). CONCLUSION: Our data indicate that changes in circulating IL-10 concentrations are marker of metabolic risk in children.

Association between interleukin 1ß and interleukin 10 concentrations: a cross-sectional study in young adolescents in Taiwan.

BACKGROUND: In adults, low circulating interleukin 10 (IL10) has been associated with obesity and type 2 diabetes. However, studies investigating IL10 in overweight and obese children have yielded conflicting results. The aim of this study was to investigate factors associated with serum IL10 concentration in young Chinese adolescents. METHODS: Young adolescents (n=325) ages 13.33±1.10 years were recruited into the cross-sectional study from 2010 to 2011. Parameters of obesity, individual components of MetS, iron status and serum IL10 were evaluated. RESULTS: Compared with their normal weight counterparts, overweight adolescents had lower serum IL10 but higher TNFα, nitric oxide (NO) and IL1ß concentrations (all p<0.05). Obese adolescents had increased IL1ß but decreased hepcidin concentration compared with normal weight (p<0.01 and p<0.05; respectively). A strong inverse relationship (p<0.0001) was found between IL10 and pro-inflammatory cytokines (TNFα and IL1ß). Multivariate linear regression analysis showed serum IL1ß was significantly correlated with IL10 (ß=-0.156, p<0.0001). When overweight and obese adolescents were assessed separately from normal weight, only IL1ß was inversely associated with serum IL10 (ß=-0.231, p=0.0009). The association between IL10 and IL1ß was weaker in adolescents with normal weight (ß=-0.157, p=0.0002), after adjusting for gender, TNFα, IFNγ and NO. CONCLUSIONS: Our study confirmed that low IL10 concentration is associated with overweight and obesity in young adolescents. We also demonstrated for the first time that pro-inflammatory cytokine IL1ß is independently associated with IL10. A decline in IL10 concentration in overweight and obese adolescents may further contribute to the IL1ß-mediated inflammatory environment associated with obesity.

Human umbilical cord mesenchymal stem cells suppress breast cancer tumourigenesis through direct cell-cell contact and internalization.

The purpose of this study was to investigate how human umbilical cord mesenchymal stem cells (HUMSCs) affect breast cancer tumourigenesis. To observe the influence of HUMSCs on tumourigenesis in vitro, we performed a co-culture of MDA MB-231 breast cancer cells with HUMSCs, and a result of HUMSCs on tumourigenesis in vivo was achieved by injection of HUMSCs into nonobese diabetic/severe combined immunodeficient mice following tumour establishment with MDA-MB231. During the co-culture, apoptosis of MDA-MB231 was noted, which was driven either by binding with HUMSC through direct cell-cell contact or by formation of a novel cell-in-cell phenomenon after internalization of HUMSC. Also, treatment with HUMSC injection was efficacious in both in situ and metastatic breast cancers in the animal models. Since HUMSCs were proved to efficaciously suppress breast cancer tumourigenesis both in vitro and in vivo, it is our expectation that treatment with HUMSCs can be a viable therapy for breast cancer in the near future. In addition, we share a new point of view on the role of HUMSCs in foetal development during pregnancy.

A novel human stem cell coculture system that maintains the survival and function of culture islet-like cell clusters.

Islet-like cell clusters (ICCs) have been suggested to be a source of insulin-producing tissue for xenotransplantation in type 1 diabetes. We designed an approach to maintain the cultured rat pancreatic ICC survival and function, when cocultured with human umbilical cord mesenchymal stem cells (HUMSCs). HUMSCs in coculture have the ability to maintain ICC survival and function, for which number and insulin secretion of ICCs are increasing and lasting for 3 months, while ICCs gradually crash, which results in cell death after a period of 12 days of culture without HUMSCs. Cytokine protein array showed it has more than a twofold increase in levels of several cytokines (interleukin-6, tissue inhibitor of metalloproteinases-1, tissue inhibitor of metalloproteinases-2, monocyte chemoattractant protein-1, growth related oncogene, hepatocyte growth factor, insulin-like growth factor binding proteins 4, and interleukin-8) on coculture medium, implying an important role of these cytokines in this coculture system. These findings suggest that coculture with HUMSCs may have a significant potential to protect ICCs from damage during culture, and may be employed in a novel culture approach to maintain islet cell survival and function before transplantation.

Islet-like clusters derived from mesenchymal stem cells in Wharton's Jelly of the human umbilical cord for transplantation to control type 1 diabetes.

BACKGROUND: There is a widespread interest in developing renewable sources of islet-replacement tissue for type I diabetes mellitus. Human mesenchymal cells isolated from the Wharton's jelly of the umbilical cord (HUMSCs), which can be easily obtained and processed compared with embryonic and bone marrow stem cells, possess stem cell properties. HUMSCs may be a valuable source for the generation of islets. METHODOLOGY AND PRINCIPAL FINDINGS: HUMSCs were induced to transform into islet-like cell clusters in vitro through stepwise culturing in neuron-conditioned medium. To assess the functional stability of the islet-like cell clusters in vivo, these cell clusters were transplanted into the liver of streptozotocin-induced diabetic rats via laparotomy. Glucose tolerance was measured on week 12 after transplantation accompanied with immunohistochemistry and electron microscopy analysis. These islet-like cell clusters were shown to contain human C-peptide and release human insulin in response to physiological glucose levels. Real-time RT-PCR detected the expressions of insulin and other pancreatic beta-cell-related genes (Pdx1, Hlxb9, Nkx2.2, Nkx6.1, and Glut-2) in these islet-like cell clusters. The hyperglycemia and glucose intolerance in streptozotocin-induced diabetic rats was significantly alleviated after xenotransplantation of islet-like cell clusters, without the use of immunosuppressants. In addition to the existence of islet-like cell clusters in the liver, some special fused liver cells were also found, which characterized by human insulin and nuclei-positive staining and possessing secretory granules. CONCLUSIONS AND SIGNIFICANCE: In this study, we successfully differentiate HUMSCs into mature islet-like cell clusters, and these islet-like cell clusters possess insulin-producing ability in vitro and in vivo. HUMSCs in Wharton's Jelly of the umbilical cord seem to be the preferential source of stem cells to convert into insulin-producing cells, because of the large potential donor pool, its rapid availability, no risk of discomfort for the donor, and low risk of rejection.