Agrin promotes the proliferation, invasion and migration of rectal cancer cells via the WNT signaling pathway to contribute to rectal cancer progression.

Rectal cancer is the most common malignant tumor in the digestive system with rapidly metastasis and highly recurrence. Agrin (AGRN) is a proteoglycan involving in a large number of human cancers. However, how AGRN regulates the progression of rectal cancer remains largely unknown. We aimed to determine the biological role of AGRN and its mechanism in rectal cancer. AGRN expression in rectal cancer tissues was detected based on TCGA. The survival curve was plotted using the Kaplan-Meier method. qRT-PCR and western blot were utilized to examine the expression level of AGRN in cells. Cell proliferation, clonogenic ability, invasion, and migration of rectal cancer cells were analyzed by CCK-8, colony formation and transwell experiments. GSEA was employed for the analysis of the potential pathways-related with AGRN in rectal cancer. The activity of WNT pathway was determined by western blot. AGRN expression was dramatically increased in rectal cancer, and its up-regulation was associated with poorer prognosis of rectal cancer patients. AGRN expression was an independent factor for the prognosis of rectal cancer. AGRN inhibition suppressed rectal cancer cell growth, invasion, and migration, whereas AGRN overexpression facilitated these behaviors of rectal cancer cells in vitro. Mechanistically, WNT signaling pathway was enriched in high AGRN-expressing patients with rectal cancer. AGRN elevated the activity of WNT pathway through increasing Cyclin D1, C-Myc, p-GSK-3ß, and p-ß-catenin expression. Our present study indicated that AGRN might function as an oncogenic indicator in rectal cancer via activating the WNT pathway, which would help develop optimized therapeutic therapies for rectal cancer.

Meat, Dietary Heme Iron, and Risk of Type 2 Diabetes Mellitus: The Singapore Chinese Health Study.

We evaluated the relationships of red meat, poultry, fish, and shellfish intakes, as well as heme iron intake, with the risk of type 2 diabetes mellitus (T2D).The Singapore Chinese Health Study is a population-based cohort study that recruited 63,257 Chinese adults aged 45-74 years from 1993 to 1998. Usual diet was evaluated using a validated 165-item semiquantitative food frequency questionnaire at recruitment. Physician-diagnosed T2D was self-reported during 2 follow-up interviews in 1999-2004 and 2006-2010. During a mean follow-up of 10.9 years, 5,207 incident cases of T2D were reported. When comparing persons in the highest intake quartiles with those in the lowest, the multivariate-adjusted hazard ratio for T2D was 1.23 (95% confidence interval (CI): 1.14, 1.33) for red meat intake (P for trend < 0.001), 1.15 (95% CI: 1.06, 1.24) for poultry intake (P for trend = 0.004), and 1.07 (95% CI: 0.99, 1.16) for fish/shellfish intake (P for trend = 0.12). After additional adjustment for heme iron, only red meat intake remained significantly associated with T2D risk (multivariate-adjusted hazard ratio = 1.13, 95% CI: 1.01, 1.25; P for trend = 0.02). Heme iron was associated with a higher risk of T2D even after additional adjustment for red meat intake (multivariate-adjusted hazard ratio = 1.14, 95% CI: 1.02, 1.28; P for trend = 0.03). In conclusion, red meat and poultry intakes were associated with a higher risk of T2D. These associations were mediated completely for poultry and partially for red meat by heme iron intake.

Impacts of bicyclo-monoterpene enhancers on transdermal delivery of ligustrazine.

The purpose of this study is to investigate the impacts of bicyclo-monoterpene promoters (i.e., borneol and camphor) on the in vitro permeation of ligustrazine (LGT) through the hairless porcine dorsal skin. Fourier transform-infrared (FT-IR), scanning electron microscope (SEM) and transdermal delivery kinetics in vitro were performed to investigate the effect of the promoters on the biophysical changes to the stratum corneum (SC), the surface changes to porcine skin and the in vitro percutaneous fluxes of ligustrazine through procine skin. FT-IR results revealed that the peak shift and the decrease in the peak area with borneol were higher than those with camphor. SEM studies demonstrated that the morphological change to SC was related to the chosen enhancer. It was observed that the SC lipid extraction with borneol and camphor led to disruption of the SC and the scutella desquamation. Apparent density (AD) was utilized to describe the desquamation extent of the scutella. Percutaneous fluxes of ligustrazine through porcine skin were evaluated in vitro by the Franz-type diffusion cells. Use of borneol led to greater penetration of ligustrazine across porcine skin. It was shown that the permeation enhancement mechanism of bicyclo-monoterpenes to ligustrazine included extracting and disordering lipids which involved the shift changes in C-H stretching and H-bonding action between enhancers and cermaide. The penetration capability of the hydroxy groups in bicyclo-monoterpenes was better than that of the ketone groups.

Plasma ferritin, C-reactive protein, and risk of incident type 2 diabetes in Singapore Chinese men and women.

AIMS: Ferritin is postulated to be involved in diabetogenesis as a marker of iron stores. We prospectively examined the association between ferritin levels and type 2 diabetes (T2D) risk in a Chinese population. METHODS: Plasma ferritin concentrations were assayed among 485 diabetes cases and 485 controls nested within the Singapore Chinese Health Study. Cases and controls were matched on age, gender, date of blood collection, and dialect group. Participants were free of diagnosed diabetes, cardiovascular disease, and cancer at blood collection (1999-2004). Incident self-reported T2D cases were identified at follow-up II interview (2006-2010). Multivariable conditional logistic regression models were used to compute the odds ratio (OR) and the corresponding 95% confidence intervals (CIs). RESULTS: After adjusting for T2D risk factors, including high-sensitivity C-reactive protein (hs-CRP), adiponectin, triglycerides, HDL cholesterol and alanine aminotransferase, the OR comparing the highest versus lowest quartile of ferritin levels was 1.87 (95% CI 1.10-3.19) (P-trend=0.004). When the analysis was limited to participants with hs-CRP<1.5mg/L (below median; n=482), the OR comparing extreme quartiles of ferritin levels was 1.16 (95% CI 0.62-2.16; P-trend=0.63); while the corresponding OR was 2.51 (95% CI 1.31-4.79; P-trend<0.001) when confined to those with hs-CRP≥1.5mg/L (n=488; P-interaction=0.022). Compared to participants with both ferritin and hs-CRP levels below median, those with both levels above median had markedly increased T2D risk (P-interaction for multiplicative scale=0.037). CONCLUSIONS: The elevation of blood ferritin levels, in the presence of raised hs-CRP, was significantly associated with increased risk of T2D.

Association between the ratio of triglyceride to high-density lipoprotein cholesterol and incident type 2 diabetes in Singapore Chinese men and women.

BACKGROUND: Increased triglycerides (TG) and decreased high-density lipoprotein cholesterol (HDL-C) are risk factors for type 2 diabetes (T2D). The relationship between TG:HDL-C ratio and T2D risk is not clear, and it is not known whether the association is modified by gender, body mass index, or fasting status. This study examined the relationship between TG:HDL-C ratio and risk of incident T2D, and the predictive ability of the ratio on top of other diabetes risk factors. METHODS: Blood biomarkers were determined in 571 T2D cases and 571 controls nested within a prospective, population-based cohort study, the Singapore Chinese Health Study. Participants were free of diagnosed diabetes, cardiovascular disease, and cancer at the time of blood collection (1999-2004). Incident self-reported T2D cases were identified at follow-up interview (2006-10). Controls were matched 1: 1 for age, sex, dialect group, and date of blood collection. Multivariable logistic regression was used to compute the odds ratio (OR) and 95 % confidence interval (CI). RESULTS: The ORs (95 % CI) of T2D per 1-SD increment in TG and TG: HDL-C ratio were 1.70 (1.39-2.09) and 1.72 (1.37-2.17), respectively. The relationships were stronger among females than males (Pinteraction = 0.028 and 0.017, respectively), and stronger among lean (<23 kg/m2 ) than overweight/obese participants (Pinteraction = 0.051 and 0.046, respectively). Both TG and TG: HDL-C improved T2D prediction to a similar degree. CONCLUSIONS: Both TG and TG:HDL-C ratio are independent risk factors for incident T2D, and confer greater risk in women and lean participants. The TG: HDL-C ratio is not a better predictor of diabetes than TG alone.

Association between liver enzymes and incident type 2 diabetes in Singapore Chinese men and women.

AIMS: To assess the association between liver enzymes and the risk of type 2 diabetes (T2D) in a Chinese population. METHODS: A nested case-control study comprising 571 T2D cases and 571 matched controls was conducted within the Singapore Chinese Health Study. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) were quantified in baseline plasma collected from them, while γ-glutamyltransferase (GGT) was assayed among 255 T2D cases with baseline hemoglobin A1c <6.5% and 255 matched controls. Participants were free of diagnosed diabetes, cardiovascular disease, and cancer at blood collections (1999-2004). Incident self-reported T2D cases were identified at follow-up II interview (2006-2010). Controls were matched to cases on age, sex, dialect group, and date of blood collection. RESULTS: Higher levels of ALT and GGT were significantly associated with increased risk of T2D (p for trend <0.001 for ALT, p for trend=0.03 for GGT), and the ORs (95% CIs) comparing highest versus lowest tertiles of ALT and GGT were 2.00 (1.01 to 3.96) and 2.38 (1.21 to 4.66), respectively. A null association was observed for AST, ALP, and LDH with T2D risk. Adding GGT (<23 vs ≥23 IU/L) or ALT (<21 vs ≥21 IU/L) to a prediction model resulted in significant gain in net reclassification improvement and integrated discrimination improvement of T2D prediction (all p<0.001). CONCLUSIONS: Higher levels of GGT and ALT are associated with increased T2D risk. GGT ≥23 IU/L and ALT ≥21 IU/L may identify people at higher risk of developing T2D in this Chinese population.