Abbreviations: AA, arachidonic acid; Abhd5, abhydrolase domain containing 5; Ace, angiotensin I converting enzyme; Acsl4, Long-chain fatty-acid-CoA ligase 4; AdA, adrenic acid;Alox5ap, arachidonate 5-lipoxygenase-activating protein; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ATCC, American Type Culture Collection; CoQ, coenzyme Q; Cyp, cytochrome P450; DFO, deferoxamine; Elovl6, elongation of very long chain fatty acids protein 6; Fer-1, Ferrostatin-1; FSP1, ferroptosis suppressor protein 1; GPX4, glutathione peroxidase 4; HCC, hepatocellular carcinoma; HE, hematoxylin and eosin; Hmox1, heme oxygenase-1; Hsl, hormone-sensitive lipase; IRPs, iron regulatory proteins; KEGG, Kyoto Encyclopedia of Genes; LDs, lipid droplets; Lip-1, Liprostatin-1; Lpcat2, lysophosphatidylcholine acyltransferase 2; MCD, methionine-and choline-deficient; MCDM, methionine-and choline-deficient medium; Mcp-1, monocyte chemoattractant protein-1; NAFLD, nonalcoholic fatty liver disease; NAS score, non-alcoholic steatohepatitis score; NASH, nonalcoholic steatohepatitis; Nox2, NADPH oxidase 2; PBS, phosphate buffer solution; PE, phosphatidylethanolamine; PI, propidium iodide; Pla2g4a, phospholipase A2, group IVA; Pnpla2, patatin like phospholipase domain containing 2; PPAR, peroxisome proliferator-activator receptor; Ptgs1/2, prostaglandin-endoperoxide synthase 1/2; PUFAs, polyunsaturated fatty acids;RNA-seq, RNA-sequencing; ROS, reactive oxygen species; RTA, radical trapping agent; RT-PCR, real-time polymerase chain reaction; shRNA, short hairpin RNA; Srebp1c, sterol regulatory element-binding protein 1c; TEM, transmission electron microscopy; Tgfβ, transforming growth factor-β; Tnf-α, tumor necrosis factor-α; VLDL, very-low-density lipoprotein. Abstract Background: NASH is one of the fastest growing liver diseases that leads to severe steatosis, inflammation and ultimately liver injury. However, the pathophysiological mechanisms of NASH remain unclear and pharmacological treatment against the disease is unavailable currently. Ferroptosis is a non-apoptotic form of cell death induced by iron-dependent lipid peroxidation. Since NASH progression is accompanied by massive lipid accumulation, which generates lipotoxic species, we investigated the role of ferroptosis in NASH progression. Method: Mice were fed on MCD-diet to mimic NASH progression and gene expression in liver was analysed by RNA-seq. The occurrence of hepatic ferroptosis was measured by lipid ROS level, electron microscopy and in vivo PI staining. The beneficial effects of ferroptosis inhibitors on NASH was evaluated by liver pathology analysis. The mechanism of lipid ROS induced lipid droplets accumulation was investigated by in vitro cell culture. Results: RNA-seq analysis suggested that elevated arachidonic acid metabolism promotes ferroptosis in MCD-diet fed mouse livers, which was further demonstrated by lipid ROS accumulation, morphological change of mitochondria and increased cell death. Iron accumulation was detected in the liver and the serum of MCD-f...

No abstract

Chronic low-grade inflammation plays a central role in the pathophysiology of gestational diabetes mellitus (GDM). To investigate the ability of different inflammatory blood cell parameters in predicting the development of GDM and pregnancy outcomes, 258 women with GDM and 1,154 women without were included in this retrospective study. First-trimester neutrophil count outperformed white blood cell count and the neutrophil-tolymphocyte ratio in the predictability for GDM. Subjects were grouped based on tertiles of neutrophil count during their first-trimester pregnancy. The results showed that as the neutrophil count increased, there was a stepwise increase in GDM incidence as well as in glucose and glycosylated hemoglobin levels, HOMA for insulin resistance (HOMA-IR), macrosomia incidence, and newborn weight. Neutrophil count was positively associated with prepregnancy BMI, HOMA-IR, and newborn weight. Additionally, neutrophil count was an independent risk factor for the development of GDM, regardless of the history of GDM. Spline regression showed that there was a significant linear association between GDM incidence and the continuous neutrophil count when it was >5.0 3 10 9 /L. This work suggested that the first-trimester neutrophil count is closely associated with the development of GDM and adverse pregnancy outcomes.

No abstract

The potassium voltage-gated channel, KQT-like subfamily member 1 (KCNQ1) is a member of 11 mammalian Kv channel families that plays a key role for the repolarization of the cardiac action potential as well as water and salt transport. Genome-wide association studies have identified KCNQ1 as a type 2 diabetes (T2D) susceptibility gene in populations of Asian descent. After that, a number of studies reported that the rs2237892, rs2237895, rs2237897, rs2283228, and rs231362 polymorphism in KCNQ1 has been implicated in T2D risk. However, studies on the association between these polymorphism and T2D remain conflicting. To derive a more precise estimation of the relationship, a meta-analysis of 114,140 patients and 167,322 controls from 30 published case-control studies was performed. Overall, significantly elevated T2D risk was associated with rs2237892, rs2237895, rs2237897, rs2283228, and rs231362 risk allele when all studies were pooled into the meta-analysis. In the subgroup analysis by ethnicity, sample size, and Hardy-Weinberg equilibrium status of controls, significantly increased risks were found for these polymorphisms. In conclusion, this meta-analysis suggests that rs2237892, rs2237895, rs2237897, rs2283228, and rs231362 polymorphisms in KCNQ1 are associated with elevated T2D risk.

Background: This study aims to investigate the potential association of peripheral inflammatory blood cell parameters with the incidence and progression of chronic kidney disease (CKD) in patients with diabetes. Methods: The cross-sectional study included 1192 subjects with diabetes derived from one center. The cohort study included 2060 subjects with diabetes derived from another two centers followed up for 4 years. Logistic regression and Cox proportional hazards models were used to evaluate the association of peripheral inflammatory blood cell with CKD. Results: In the cross-sectional study, neutrophil count performed best as an independent risk factor for CKD (odds ratio 2.556 [95% confidence interval 1.111, 5.879]) even after 1:1 case-control matching for age, gender, history of high blood pressure and duration of diabetes. Spline regression revealed a significant linear association of CKD incidence with continuous neutrophil count in excess of 3.6 Â 10 9 /L. In the cohort study, subjects were grouped based on tertile of neutrophil count and neutrophil-to-lymphocyte ratio. Cox regression analysis results showed that only neutrophil count was independently # Co-first author

Invasive nonfunctioning pituitary adenomas (NFPAs) grow rapidly and the mechanisms are unclear. Among many complex mechanisms, the role of immunity in the development of NFPAs has not been fully explored. Here, we analyzed the clinical features 146 NFPA patients who underwent trans-sphenoidal surgery or craniotomy and examined the effects of immune tolerance in invasiveness of NFPA patients using fluorescence-activated cell sorting and immunohistochemical methods. We found patients with invasive NFPAs had more visual deficits and defective fields, higher tumor size, and lower white blood cell count compared with patients with noninvasive NFPAs. Additionally, compared with patients with noninvasive NFPAs, patients with invasive NFPAs had conspicuously lower CD3−CD56+ natural killer (NK) cells and significantly higher levels of CD3+CD8+CD28-T cells (CD8+ Tregs) and interleukin-10 (IL-10) in peripheral blood. Moreover, patients with invasive NFPAs had lower infiltrated CD56+ cells, less infiltrated CD28+ cells, and significantly greater IL-10 expression. These results demonstrated that low CD56+ cells infiltration and CD28+ cells infiltration, as well as high IL-10 expression in pituitary tumor tissues, were related with increased invasiveness of NFPAs. Levels of CD3−CD56+ NK cells, CD8+ Tregs and IL-10 in the peripheral blood could be feasible diagnostic markers for invasive NFPAs.

No abstract