Plasma Clusterin and the CLU Gene rs11136000 Variant Are Associated with Mild Cognitive Impairment in Type 2 Diabetic Patients

Objective: Type 2 diabetes mellitus (T2DM) is related to an elevated risk of mild cognitive impairment (MCI). Plasma clusterin is reported associated with the early pathology of Alzheimer's disease (AD) and longitudinal brain atrophy in subjects with MCI. The rs11136000 single nucleotide polymorphism within the clusterin (CLU) gene is also associated with the risk of AD. We aimed to investigate the associations among plasma clusterin, rs11136000 genotype and T2DM-associated MCI. Methods: A total of 231 T2DM patients, including 126 MCI and 105 cognitively healthy controls were enrolled in this study. Demographic parameters were collected and neuropsychological tests were conducted. Plasma clusterin and CLU rs11136000 genotype were examined.Results: Plasma clusterin was significantly higher in MCI patients than in control group (p=0.007). In subjects with MCI, plasma clusterin level was negatively correlated with Montreal cognitive assessment and auditory verbal learning test_delayed recall scores (p=0.027 and p=0.020, respectively). After adjustment for age, educational attainment, and gender, carriers of rs11136000 TT genotype demonstrated reduced risk for MCI compared with the CC genotype carriers (OR=0.158, χ2=4.113, p=0.043). Multivariable regression model showed that educational attainment, duration of diabetes, HDL-c, and plasma clusterin levels are associated with MCI in T2DM patients.Conclusions: Plasma clusterin was associated with MCI and may reflect a protective response in T2DM patients. TT genotype exhibited a reduced risk of MCI compared to CC genotype. Further investigations should be conducted to determine the role of clusterin in cognitive decline

Link Prediction based on Deep Latent Feature Model by Fusion of Network Hierarchy Information

Link prediction aims at predicting latent edges according to the existing network structure information and it has become one of the hot topics in complex networks. Latent feature model that has been used in link prediction directly projects the original network into the latent space. However, traditional latent feature model cannot fully characterize the deep structure information of complex networks. As a result, the prediction ability of the traditional method in sparse networks is limited. Aiming at the above problems, we propose a novel link prediction model based on deep latent feature model by Deep Non-negative Matrix Factorization (DNMF). DNMF method can obtain more comprehensive network structure information through multi-layer factorization. Experiments on ten typical real networks show that the proposed method has performances superior to the state-of-the-art link prediction methods

The Energy Crisis in CPT II Variant Fibroblasts

Carnitine palmitoyltransferase II (CPT II) deficiency is one of the most common causes of fatty acid oxidation metabolism disorders. However, the molecular mechanism between CPT2 gene polymorphisms and metabolic stress has not been fully clarified. We previously reported that a number of patients show a thermal instable phenotype of compound hetero/homozygous variants of CPT II. To understand the mechanism of the metabolic disorder resulting from CPT II deficiency, the present study investigated CPT II variants in patient fibroblasts, [c.1102 G>A (p.V368I)] (heterozygous), [c.1102 G>A (p.V368I)] (homozygous), and [c.1055 T>G (p.F352C)] (heterozygous) + [c.1102 G>A (p.V368I)] (homozygous) compared with fibroblasts from healthy controls. CPT II variants exerted an effect of dominant negative on the homotetrameric proteins that showed thermal instability, reduced residual enzyme activities and a short half-life. Moreover, CPT II variant fibroblasts showed a significant decrease in fatty acid β-oxidation and adenosine triphosphate generation, combined with a reduced mitochondrial membrane potential, resulting in cellular apoptosis. Collectively, our data indicate that the CPT II deficiency induces an energy crisis of the fatty acid metabolic pathway. These findings may contribute to the elucidation of the genetic factors involved in metabolic disorder encephalopathy caused by the CPT II deficiency

Increased Ratio of Global O-GlcNAcylation to Tau Phosphorylation at Thr212 Site Is Associated With Better Memory Function in Patients With Type 2 Diabetes

Objective: Aberrant O-GlcNAc modification has been implicated in type 2 diabetes mellitus (T2DM) and the pathogenesis of neurodegenerative diseases via competition with tau phosphorylation. We aimed to investigate the association between global O-GlcNAcylation, tau phosphorylation levels and mild cognitive impairment (MCI) in the whole blood of patients with T2DM.Methods: Sociodemographic, clinical characteristics and cognitive performances of the enrolled T2DM subjects were extensively assessed. Global O-GlcNAcylation and tau phosphorylation levels in the whole blood were also determined using Western blot.Results: Forty-eight T2DM subjects, including 24 with MCI and 24 with normal cognition, were enrolled in this study. Compared with cognitively normal controls, T2DM with MCI subjects displayed decreased global O-GlcNAcylation level, but increased tau phosphorylation levels (all p < 0.05). To reflect the combined effect, the ratios of global O-GlcNAcylation to tau phosphorylation levels, including specific sites, such as Ser396, Ser404, Thr212, and Thr231, were all significantly decreased in MCI subjects (all p < 0.05). Further multivariable logistic regression analysis revealed that high glycated hemoglobin A1c was an independent risk factor, whereas increased O-GlcNAc/p-T212 was an independent protective factor for MCI in patients with T2DM (odds ratio [OR] = 2.452, 95% confidence interval [CI] 1.061–5.668, p = 0.036; OR = 0.028, 95%CI 0.002–0.388, p = 0.008, respectively). With regard to each cognitive domain, O-GlcNAc/p-T212 was positively correlated with the score of Auditory Verbal Learning Test-delayed recall (r = 0.377, p = 0.010).Conclusion: Our study suggests that increased ratio of global O-GlcNAcylation to tau phosphorylation at Thr212 site in the whole blood is associated with decreased risk of MCI, especially with better memory function in T2DM subjects.Clinical Trial Registration:www.ClinicalTrials.gov, identifier ChiCTR-OCC-15006060

Relationship between lactone ratios of 9-nitrocamptothecin and their lactone/carboxylate equilibria in vitro and in vivo

The aim of this study was to evaluate the effect of lactone ratios on the lactone/carboxylate equilibria of 9-nitrocamptothecin (9-NC) in vitro and in vivo. The interconversion of lactone and carboxylate forms of 9-NC was studied. Then the lactone ratio vs time profiles of these 9-NC solutions were further investigated in pH 7.4 PBS, rat plasma and blood. 9-NC solutions with different lactone ratios (lactone ratios=100 %, 75 %, 50 %, 25 % and 0 %, respectively) were obtained by modifying the pH of solution and it was found that the effects on lactone/carboxylate equilibrium were in the order: blood cells > plasma albumin > pH. After i.v. administration, between the groups of 100 % and 75 % lactone ratios, the AUC0-t values of lactone 9-NC were almost equal. Therefore, there might be no difference between the anticancer activities of 9-NC solution in the range of 75~100 % lactone ratios.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Ethnicity-Specific Association Between Ghrelin Leu72Met Polymorphism and Type 2 Diabetes Mellitus Susceptibility: An Updated Meta-Analysis

Background: The Leu72Met polymorphism of ghrelin gene has been associated with genetic predisposition to type 2 diabetes mellitus (T2DM), while conclusions remain conflicting. Hence, we performed this updated meta-analysis to clarify the association between Leu72Met polymorphism and T2DM susceptibility.Methods: Six electronic databases were consulted for articles published before 1 January, 2018. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated under five genetic models to assess this association. We used I2-test and Q statistics to measure heterogeneity across the included studies. Subgroup analyses and publication bias were also performed.Results: Thirteen case-control studies involving 4720 T2DM patients and 4206 controls were included in this meta-analysis. The overall results using fixed-effects models showed that Leu72Met polymorphism was significantly associated with an increased risk of T2DM under homozygous model (OR = 1.307, 95%CI 1.001–1.705, p = 0.049). Further subgroup analyses stratified by ethnicity revealed that the risk for T2DM was only increased in Asians (homozygous model: OR = 1.335, 95%CI 1.014–1.758, p = 0.040), while decreased in Caucasians (dominant model: OR = 0.788, 95%CI 0.635–0.978, p = 0.030; heterozygous model: OR = 0.779, 95%CI 0.626–0.969, p = 0.025; allelic model: OR = 0.811, 95%CI 0.661–0.995, p = 0.045). Funnel plots were basically symmetrical, and all p-values of Egger's test under five genetic models were >0.050, which indicated no evidence of publication bias.Conclusions: Our results demonstrate that the Leu72Met polymorphism of ghrelin gene may be protective against T2DM in Caucasians, while predisposing to T2DM in Asians

Screening and Stability Evaluation of Angiotensin Converting Enzyme Inhibitory Peptides from Bangia fusco-purpurea

In this study, peptide fractions (F1-F4) with different molecular masses were obtained from Bangia fusco-purpurea through enzymatic hydrolysis and ultrafiltration. F2, with molecular masses of 800–2 000 Da, exhibited the highest in vitro angiotensin-converting enzyme (ACE) inhibitory activity as determined by high performance liquid chromatography (HPLC). The amino acid sequence of F2 was identified through liquid chromatography-tandem mass spectrometry (LC-MS/MS) and de novo sequencing using PEAKS Studio software. Six ACE inhibitory peptides that stably bind to ACE were selected through molecular docking. The predicted peptides were synthesized by solid-phase synthesis and their in vitro ACE inhibitory activity was verified. Among them, L1 (LVLLFLFGE) showed the highest ACE inhibitory activity with a half maximal inhibitory concentration (IC50) value of 14.22 μg/mL. Molecular docking results indicated that the inhibition of ACE by L1 was mainly attributed to its ability to form hydrogen bond interactions with the active site of ACE. Finally, the effects of temperature, pH, metal ions, light exposure, and simulated gastrointestinal digestion on the stability of L1 were investigated. The results revealed that L1 was highly stable to heat and ionic strength. However, its activity gradually decreased at pH > 2, and was affected by ultraviolet treatment. The ACE inhibitory activity of L1 decreased after simulated gastric and intestinal digestion, but was still significant

Exploring the Fecal Microbial Composition and Metagenomic Functional Capacities Associated With Feed Efficiency in Commercial DLY Pigs

Gut microbiota has indispensable roles in nutrient digestion and energy harvesting, especially in processing the indigestible components of dietary polysaccharides. Searching for the microbial taxa and functional capacity of the gut microbiome associated with feed efficiency (FE) can provide important knowledge to increase profitability and sustainability of the swine industry. In the current study, we performed a comparative analysis of the fecal microbiota in 50 commercial Duroc × (Landrace × Yorkshire) (DLY) pigs with polarizing FE using 16S rRNA gene sequencing and shotgun metagenomic sequencing. There was a different microbial community structure in the fecal microbiota of pigs with different FE. Random forest analysis identified 24 operational taxonomic units (OTUs) as potential biomarkers to improve swine FE. Multiple comparison analysis detected 8 OTUs with a significant difference or tendency toward a difference between high- and low-FE pigs (P < 0.01, q < 0.1). The high-FE pigs had a greater abundance of OTUs that were from the Lachnospiraceae and Prevotellaceae families and the Escherichia-Shigella and Streptococcus genera than low-FE pigs. A sub-species Streptococcus gallolyticus subsp. gallolyticus could be an important candidate for improving FE. The functional capacity analysis found 18 KEGG pathways and CAZy EC activities that were different between high- and low-FE pigs. The fecal microbiota in high FE pigs have greater functional capacity to degrade dietary cellulose, polysaccharides, and protein and may have a greater abundance of microbes that can promote intestinal health. These results provided insights for improving porcine FE through modulating the gut microbiome