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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...

Neutrophils infiltration in liver is one of the typical histological characteristics of nonalcoholic steatohepatitis (NASH) in both animal models and human subjects. This study was aimed to investigate the role of neutrophils in the process of NASH and its underling mechanisms. C57BL/6J mice were fed with either standard chow (SC) or methionine/choline-deficient (MCD) diet for 1, 2, 4, 8 weeks, respectively. C57BL/6J APOE(-/-) mice were fed with SC or high-fat high-cholesterol (HFHC) diet. Anti-Ly6G antibody was employed to deplete neutrophils and sivelestat was used to inhibit neutrophil elastase (NE). MCD-diet-receiving mice with neutrophil depletion had much lower serum ALT activity, liver inflammation, and mRNA levels of proinflammatory genes in the early stage of NASH (1 and 2 weeks) when compared to non-neutrophil-depleted mice. NE inhibitor sivelestat could recapitulate the effects of neutrophil depletion in APOE(-/-) mice fed with HFHC diet. As the disease progressed (4 and 8 weeks), neutrophil depletion did not lower serum ALT levels and liver lesions due to activation of Kupffer cells. Finally, we found neutrophils also affected anti-inflammation cytokine interleukin-1 receptor antagonist mRNA expression. Neutrophils play a crucial role in the early stage of NASH via NE.

An imbalance between neutrophil elastase (NE) and its inhibitor α1-antitrypsin (A1 AT) is known to contribute to the development of obesity-related inflammation. This study aimed to investigate the role of the NE-A1 AT system in the histological progression of non-alcoholic fatty liver disease (NAFLD), and to evaluate the ability of it to predict nonalcoholic steatohepatitis (NASH). A total of 252 adults (NAFLD group, n = 202; healthy group, n = 50) were recruited. Clinical biochemical characteristics, NE and A1 AT concentrations were measured in all subjects. Among the NAFLD group, 86 patients had previously undergone liver biopsy and information on histological characteristics was consequently available. The area under the receiver operating characteristic curve (AUC) was used to determine the predictive accuracy of the NE-A1 AT system for NASH. NAFLD patients had an elevated serum NE concentration and a reduced A1 AT level with consequent NE/A1 AT imbalance. NE increased in the early stage of steatosis, preceding the decline in A1 AT, dating from the onset of NASH (NAS 3-4), and subsequently NE/A1 AT increased in the presence of NASH. Nonetheless, this increase began to resolve as the disease state progressed to advanced fibrosis. A1 AT had a sensitivity (SEN) of 83.8% and a specificity (SP) of 83.3% with the optimal cut-off of -1459.43, NE/A1 AT had a SEN of 88.8% and a SP of 83.3% with cut-off of 0.363 to predict NASH. An increased NE: A1 AT ratio is closely associated with liver Inflammation in patients with NASH and could serve as a novel marker to predict NASH in humans.

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Aim: This study aimed to evaluate the relationship between serum uric acid (SUA) level and non-alcoholic fatty liver disease (NAFLD) in non-obese adults.Methods: A cross-sectional study was carried out among 4098 adults, including 1936 non-obese and 2162 obese individuals. An additional 93 non-obese adults with biopsy-proven NAFLD were also included.Results: The overall prevalence of NAFLD was 39.51% in the study group, and 14.88% in non-obese adults. The NAFLD patients had significantly higher SUA levels than controls in both men and women. The non-obese group had a higher NAFLD risk with increased SUA levels than the obese group, with odd ratios (95% confidence interval) of 2.559 (1.870-3.503) and 1.692 (1.371-2.087), respectively. In 93 non-obese adults with biopsyproven NAFLD, SUA levels were significantly higher in those with non-alcoholic steatohepatitis. The prevalence of non-alcoholic steatohepatitis and lobule inflammation tended to increase to 57.58% and 66.67% as the SUA level increased to the fourth quartile. Subjects with hyperuricemia had significantly higher NAFLD activity scores and more serious lobule inflammation than the normal group.Conclusion: Non-obese adults have higher NAFLD risk with increased SUA levels than obese individuals, and the inflammation progression of NAFLD is associated with increased SUA level in non-obese subjects.

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.

Cancer stem cells are a subset of cells that are responsible for cancer initiation and relapse. They are generally resistant to the current anticancer agents. Successful anticancer therapy must consist of approaches that can target not only the differentiated cancer cells, but also cancer stem cells. Emerging evidence suggested that the dietary agent curcumin exerted its anti-cancer activities via targeting cancer stem cells of various origins such as those of colorectal cancer, pancreatic cancer, breast cancer, brain cancer, and head and neck cancer. In order to enhance the therapeutic potential of curcumin, this agent has been modified or used in combination with other agents in the experimental therapy for many cancers. In this mini-review, we discussed the effect of curcumin and its derivatives in eliminating cancer stem cells and the possible underlying mechanisms.