High-Glucose-Induced Injury to Proximal Tubules of the Renal System Is Alleviated by Netrin-1 Suppression of Akt/mTOR.

The kidneys have a high level of Netrin-1 expression, which protects against some acute and chronic kidney disorders. However, it is yet unknown how Netrin-1 affects renal proximal tubule cells in diabetic nephropathy (DN) under pathological circumstances. Research has shown that autophagy protects the kidneys in animal models of renal disease. In this study, we looked at the probable autophagy regulation mechanism of Netrin-1 and its function in the pathogenesis of DN. We proved that in HK-2 cell, high blood sugar levels caused Netrin-1 to be downregulated, which then triggered the Akt/mTOR signaling pathway and enhanced cell death and actin cytoskeleton disruption. By adding Netrin-1 or an autophagy activator in vitro, these pathogenic alterations were reverted. Our results indicate that Netrin-1 stimulates autophagy by blocking the Akt/mTOR signaling pathway, which underlies high-glucose-induced malfunction of the renal proximal tubules. After HK-2 cells were incubated with Netrin-1 recombination protein and rapamycin under HG conditions for 24 h, the apoptosis was significantly reduced, as shown by the higher levels of Bcl-2, as well as lower levels of Bax and cleaved caspase-3 (P = 0.012, Cohen's d = 0.489, Glass's delta = 0.23, Hedges' g = 0.641). This study reveals that targeting Netrin-1-related signaling has therapeutic potential for DN and advances our knowledge of the processes operating in renal proximal tubules in DN.

Uric acid is independently associated with interleukin-1ß levels in tear fluid of hyperuricemia and gout patients.

OBJECTIVES: To explore pro-inflammatory cytokines status in the tear fluid of patients with hyperuricemia and gout and its association with uric acid level. METHODS: A total of 58 control subjects, 58 hyperuricemia patients including 40 asymptomatic hyperuricemia and 18 gout participants were recruited in this study. For tear analysis, each patient's tears were collected using capillary action microcaps after stimulation. Tear uric acid levels were measured using chemiluminescence. Tear and serum interleukin-1beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α) levels were measured using enzyme-linked immunosorbent assay. The correlation of serum and tear uric acid levels with IL-1ß and TNF-α were determined. RESULTS: Tear uric acid levels were significantly higher in hyperuricemia group (98.2 ± 51.5 vs. 42.7 ± 24.0 µmol/L, p < .001) than in controls group. IL-1ß concentrations were significantly higher in hyperuricemia eyes compared to control eyes (210.2 ± 113.9 vs. 142.6 ± 29.8 pg/mL, p < .001). Multiple linear regression analysis showed that tear uric acid levels were independently positively associated with tear IL-1ß concentrations (B = 0.192, p < .001). However, no significant correlations were found between serum or tear uric acid and TNF-α level. Moreover, there were no statistically differences of tear IL-1ß and TNF-α levels between the asymptomatic hyperuricemia and gout groups. CONCLUSIONS: Tear uric acid levels were higher in patients with hyperuricemia and gout than in controls. There was a significant positive correlation between tear uric acid value and tear IL-1ß level, implying an interaction between hyperuricemia and ocular inflammation responses.

Autoimmune polyglandular syndrome type 1 with diabetes insipidus: a case report.

BACKGROUND: Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare monogenic inherited disease caused by mutations of the autoimmune regulator gene (AIRE). The three major components of this syndrome are chronic mucocutaneous candidiasis, hypoparathyroidism and adrenocortical insufficiency. CASE PRESENTATION: We report a 20-year-old male who was clinically diagnosed with APS-1 at the age of 15. He was admitted to our department this time for suffering from polyuria and polydipsia for 6 months and was finally diagnosed with diabetes insipidus. Whole-exome sequencing (WES) revealed a novel compound heterozygous mutation of the AIRE gene -the c.239 T > G (p.Val80Gly) variant on one allele and the copy number variant (CNV) of 21q22.3(chr21:45,670,150-45,706,528)*1 on the other. CONCLUSIONS: This case suggests that diabetes insipidus is a rare component of APS-1 and expands the variety of mutations on AIRE gene.

Associations Between Peripheral Blood Microbiome and the Risk of Hypertension.

BACKGROUND: Although previous studies have reported the gut microbiome is closely related to hypertension development, whether the change in blood microbiome is associated with the risk of hypertension remains unclear. METHODS: One hundred and fifty incident hypertension cases and 150 age (± 2 years) and gender (1:1) matched nonhypertension controls included in this nested case-control study were recruited from a prospective cohort study of "135." The composition of the blood microbiome was characterized using bacterial 16S ribosomal RNA gene sequencing. The relative abundance of detected bacteria was converted to a negative logarithm of 10 for the statistical analysis. RESULTS: Totally, 10,689,961 high-quality sequences were acquired. The Chao1 index of the blood microbiome in nonhypertension controls was significantly higher than in hypertensive group (2,302.08 ± 752.78 vs. 1,598.21 ± 500.88, P < 0.001). Compared with the nonhypertension controls, the relative abundance of Proteobacteria phylum was significantly increased (P < 0.001), whereas the relative abundance of phyla Firmicutes and Bacteroidetes were significantly reduced in the hypertensive cases (P < 0.001 and P = 0.039, respectively). At genus level, the risk of hypertension was directly associated with the relative abundance of Acinetobacter (odds ratio [OR]: 1.43, 95% confidence interval [CI]: 1.01-2.03), Sphingomonas (OR: 1.84, 95% CI: 1.32-2.56), and Staphylococcus (OR: 0.51, 95% CI: 0.36-0.73), respectively. In addition, the relative abundance of Pseudomonas was minor positively correlated with the total cholesterol level. However, the relative Staphylococcus level was minor positively correlated with high-density lipoprotein cholesterol level. CONCLUSIONS: The composition of the blood microbiome is significantly associated with the development of hypertension.

JAB1 promotes palmitate-induced insulin resistance via ERK pathway in hepatocytes.

Insulin resistance (IR) is the primary pathological mechanism underlying Type 2 diabetes mellitus (T2DM). Many researches have reported the relationship between chronic inflammation and IR, while the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway is rapidly activated in inflammatory conditions. However, the functional role of ERK1/2 in IR remains to be identified. We here reported that C-Jun activation domain-binding protein-1 (JAB1) was upregulated in IR. In addition, we showed that depletion of JAB1 led to recovery of insulin sensitivity. Given the fact that JAB1 played as an activator of ERK1/2, we assumed JAB1 was involved in IR through ERK pathway. So we assessed the effects of JAB1 knockdown in palmitate acid (PA) treated HepG2 cells. Importantly, JAB1 siRNA blocked the effect of PA-induced activation of ERK1/2. Furthermore, silencing of JAB1 could reduce the release of inflammatory factors, facilitate hepatic glucose uptake and improve lipid metabolism. All these data implicated that JAB1 knockdown might alleviate PA-induced IR through ERK pathway in hepatocytes.

Interaction Between AGTR1 and PPARγ Gene Polymorphisms on the Risk of Nonalcoholic Fatty Liver Disease.

AIMS: Nonalcoholic fatty liver disease (NAFLD) is an important public health issue worldwide. Several recent studies have reported that peroxisome proliferator-activated receptor-γ (PPARγ) and angiotensin II type 1 receptor (AGTR1) variants are associated with NAFLD occurrence, but the results have been inconsistent. The aim of this study was to analyze the interactions between PPARγ and AGTR1 polymorphisms and their associations with NAFLD in Chinese adults. METHODS: Seven single nucleotide polymorphisms (SNPs) of the PPARγ gene and 5 SNPs of the AGTR1 gene were selected and genotyped in 1591 unrelated Chinese adults. The SNPAssoc package of R was used to examine the relationships between the selected SNPs and NAFLD. RESULTS: After adjusting the covariance, the results from the overdominant model showed that participants carrying the T/C genotype of rs2638360 in AGTR1 have a decreased risk of NAFLD compared with those with T/T-C/C genotypes (odds ratio: 0.70, 95% confidence interval: 0.49-1.00). However, our results showed that none of the selected PPARγ variants were significantly associated with the risk of NAFLD after applying a false discovery rate correction. Among the 12 selected SNPs from PPARγ and AGTR1, model-based multifactor dimensionality reduction (MB-MDR) analyses for gene-gene interactions revealed that all the models were significantly associated with the increased risk of NAFLD (p < 0.05) except the 2-, 10-, 11-, and 12-locus models. Further, among the 10 SNPs negatively associated with NAFLD, the four-locus model (rs13431696 and rs3856806 in PPARγ, and rs5182, rs1492100 in ATGR1) and the five-locus model (rs9817428, rs1175543, rs13433696, and rs2920502 in PPARγ, and rs1492100 in ATGR1) were closely related with NAFLD susceptibility (p = 0.019 and p = 0.048, respectively). CONCLUSION: Our present study suggests that interactions among multiple AGTR1 and PPARγ polymorphisms are associated with the risk of NAFLD in the Chinese population.

[Immobilization impact of different fixatives on heavy metals contaminated soil].

Four kinds of amendments including humus, ammonium sulfate, lime, superphosphate and their complex combination were added to rapid immobilize the heavy metals in contaminated soils. The best material was chosen according to the heavy metals' immobilization efficiency and the Capacity Values of the fixative in stabilizing soil heavy metals. The redistributions of heavy metals were determined by the European Communities Bureau of Referent(BCR) fraction distribution experiment before and after treatment. The results were as follows: (1) In the single material treatment, lime worked best with the dosage of 2% compared to the control group. In the compound amendment treatments, 2% humus combined with 2% lime worked best, and the immobilization efficiency of Pb, Cu, Cd, Zn reached 98.49%, 99.40%, 95.86%, 99.21%, respectively. (2) The order of Capacity Values was lime > humus + lime > ammonium sulfate + lime > superphosphate > ammonium sulfate + superphosphate > humus + superphosphate > humus > superphosphate. (3) BCR sequential extraction procedure results indicated that 2% humus combined with 2% lime treatment were very effective in immobilizing heavy metals, better than 2% lime treatment alone. Besides, Cd was activated firstly by 2% humus treatment then it could be easily changed into the organic fraction and residual fraction after the subsequent addition of 2% lime.

[The prospective study of association between C-reactive protein and hypertension in community population].

OBJECTIVE: The aim was to explore the association between high-sensitivity C-reactive protein level at baseline and hypertension in follow-up periods in a Chinese cohort. METHODS: We analyzed data from a cohort established in "Prevention of metabolic syndrome and multi-metabolic disorders in Jiangsu province" in April 2000. A follow-up investigation was carried out for those whose follow up time met 5 years in June 2006. A total of 2035 persons completed investigation and hs-CRP was tested. Subjects with normal baseline blood pressure were classified into four groups(514, 498, 515 and 508 subjects in each group) according to quartiles of hs-CRP level (<1.3, 1.3-1.9, 2.0-3.2 and ≥ 3.3 mg/L). The relationship between the risk of hypertension and baseline level of hs-CRP were analyzed using Cox proportional hazards regression model. RESULTS: The median of follow up time was 6.39 years among the 2035 subjects (926 males and 1109 females). Hypertension incidence was 2378/100 000 person-years, 2942/100 000 person-years, 3693/100 000 person-years and 4390/100 000 person-years in hs-CRP < 1.3, 1.3-1.9, 2.0-3.2 and ≥ 3.3 mg/L groups respectively. Compared to the group of hs-CRP < 1.3 mg/L, the relative risk (RR) (95%CI) of hypertension in groups of hs-CRP 1.3-1.9, 2.0-3.2 and ≥ 3.3 mg/L was 1.22 (0.87-1.72), 1.43 (1.03-2.00), 1.70 (1.21-2.41) respectively, adjusted for sex, age, baseline blood pressure, BMI, smoking, alcohol drinking, physical activity and family history of myocardial infarction and diabetes.When stratified by quartiles of baseline blood pressure, the incidence of hypertension in each group increased with level of hs-CRP.In the group whose baseline SBP < 110 mm Hg (1 mm Hg = 0.133 kPa) , compared to the group of hs-CRP < 1.3 mg/L, RR (95%CI) were 2.24 (1.32-4.03), 2.57 (1.57-4.57) and 3.57 (2.54-5.90) in hs-CRP 1.3-1.9, 2.0-3.2 and ≥ 3.3 mg/L groups respectively.In the group whose baseline DBP < 65 mm Hg, RR (95%CI) were 1.78 (1.03-3.24), 2.74 (1.63-4.93) and 4.13 (2.35-7.27) respectively. CONCLUSION: Inflammation was an important process in the development of hypertension.