The purpose of this study was to explore the difference and association between intestinal microbiota and plasma metabolomics between type 2 diabetes mellitus (T2DM) and normal group and to identify potential microbiota biomarkers that contribute the most to the difference in metabolites. Methods: Six male ZDF model (fa/fa) rats were fed by a Purina #5008 Lab Diet (crude protein 23.5%, crude fat 6.5%) for 3 weeks and their age-matched 6 ZDF control (fa/+) rats were fed by normal rodent diet. Their stool and blood samples were collected at 12 weeks. To analyze the microbial populations in these samples, we used a 16S rRNA gene sequencing approach. Liquid chromatography-mass spectrometry (LC-MS) followed by multivariate statistical analysis was applied to the plasma metabolites profiling. Correlation analysis of them was calculated by Pearson statistical method. Results: Twelve potential biomarkers of intestinal microbial flora and 357 differential metabolites were found in ZDF fa/fa rats, among which there are three flora that contributed the most to the perturbation of metabolites, including genus Phocea, Pseudoflavonifractor and species Lactobacillus intestinalis. Conclusion: Our study demonstrates the alterations of the abundance and diversity of the intestinal microbiota and the perturbation of metabolites in ZDF rats (fa/fa). We found three potential biomarkers of intestinal microbiota that may lead to perturbation in plasma metabolites. This may prompt new pathogenesis of obesity-related T2DM, but we also need to study further about the causal relationship between intestinal microbe and T2DM, so as to find the target of T2DM treatment or preventive measures.

Upregulation of the pro-inflammatory cytokine tumor necrosis factor α (TNF-α) is involved in the development and progression of numerous neurological disorders. Recent reports have challenged the concept that TNF-α exhibits only deleterious effects of pro-inflammatory destruction, and have raised the awareness that it may play a beneficial role in neuronal growth and function in particular conditions, which prompts us to further investigate the role of this cytokine. Insulin-like growth factor-1 (IGF-1) is a cytokine possessing powerful neuroprotective effects in promoting neuronal survival, neuronal differentiation, neurite elongation, and neurite regeneration. The association of IGF-1 with TNF-α and the biological effects, produced by interaction of IGF-1 and TNF-α, on neuronal outgrowth status of primary sensory neurons are still to be clarified. In the present study, using an in vitro model of primary cultured rat dorsal root ganglion (DRG) neurons, we demonstrated that TNF-α challenge at different concentrations elicited diverse biological effects. Higher concentration of TNF-α (10 ng/mL) dampened neurite outgrowth, induced activating transcription factor 3 (ATF3) expression, reduced growth-associated protein 43 (GAP-43) expression, and promoted GAP-43 and ATF3 coexpression, which could be reversed by IGF-1 treatment; while lower concentration of TNF-α (1 ng/mL) promoted neurite sprouting, decreased ATF3 expression, increased GAP-43 expression, and inhibited GAP-43 and ATF3 coexpression, which could be potentiated by IGF-1 supplement. Moreover, IGF-1 administration restored the activation of Akt and p70 S6 kinase (S6K) suppressed by higher concentration of TNF-α (10 ng/mL) challenge. In contrast, lower concentration of TNF-α (1 ng/mL) had no significant effect on Akt or S6K activation, and IGF-1 administration activated these two kinases. The effects of IGF-1 were abrogated by phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. These data imply that IGF-1 counteracts the toxic effect of higher concentration of TNF-α, while potentiates the growth-promoting effect of lower concentration of TNF-α, with the node for TNF-α and IGF-1 interaction being the PI3K/Akt/S6K signaling pathway. This study is helpful for interpretation of the association of IGF-1 with TNF-α and the neurobiological effects elicited by interaction of IGF-1 and TNF-α in neurological disorders.

Manganese (Mn) is an essential element in the human body, and it has a significant impact on cardiovascular risk factors such as diabetes, blood pressure, and cholesterol levels. However, no research has been conducted on the association between Mn and cardiovascular disease (CVD), to the best of our knowledge. This study thus examined the association between dietary Mn intake and CVD mortality in the general Japanese population. Methods:The CVD mortality among 58,782 participants from the Japan Collaborative Cohort Study (JACC) aged 40-79 years was determined during a median follow-up period of 16.5 years. The Mn intake was estimated using a food frequency questionnaire at the baseline (1989-1990), and multivariate-adjusted hazard ratios (HRs) for mortality were computed according to quintiles of energy-adjusted Mn intake.Results: During the follow-up period, a total of 3408 CVD deaths were recorded. Participants in the highest quintile of Mn intake had a lower risk of mortality from total stroke (HR:95% CI, 0.76: 0.64-0.90), ischemic stroke (HR: 0.77, 0.61-0.97), ischemic heart disease (HR: 0.76, 0.58-0.98), and total CVD (HR: 0.86, 0.76-0.96) compared with those in the lowest quintile. The reduced risk of mortality from intraparenchymal hemorrhage with high Mn intake was observed among women (HR: 0.60, 0.37-0.96) but not men (HR: 0.93, 0.59-1.47). The observed associations were more robust in postmenopausal than in premenopausal women. Conclusions:Our study is the first to show the prospective association between dietary Mn intake and reduced risk of mortality from CVD in the Japanese population.green tea 2) . However, the average dietary Mn intake varies across populations. Thus, the estimated average nutritional Mn intake in the United States is 2.25 mg/ day for men and 1.74 mg/day for women 3) , 2.6 mg/ day for Belgian men 4) , 2.37 mg/day for Spanish men 5) , and 4.0 mg/day for Korean men and 3.5 mg/day for Korean women 6) . In Japan, the daily intake was estimated at 5.1 and 4.9 mg/day for men and women, respectively 7) . A recent cohort study has suggested that the Japanese diet has a positive effect on preventing