bims-stacyt 2018-12-23 papers

Front Neurol. 2018 ;9 998

Endothelial Atg7 Deficiency Ameliorates Acute Cerebral Injury Induced by Ischemia/Reperfusion.

Hui-Jie Wang, Jia-Yi Wei, Dong-Xin Liu, Shi-Fang Zhuang, Yuan Li, Hui Liu, Meng Ban, Wen-Gang Fang, Liu Cao, Wei-Dong Zhao, Yu-Hua Chen.

Ischemic strokes often result in cerebral injury due to ischemia/reperfusion (I/R). Although the local inflammatory responses are known to play a primary role in the brain I/R injury, the underlying mechanism remains unclear. In the current study, we investigated the effect of brain endothelial Atg7 (autophagy related 7) depletion in the acute brain injury induced by ischemia and reperfusion. Endothelial knockout of Atg7 in mice (Atg7 eKO) was found to significantly attenuate both the infarct volume and the neurological defects induced by I/R when compared to the controls. In fact, brain inflammatory responses induced by I/R were alleviated by the Atg7 eKO. Furthermore, an increased expression of pro-inflammatory cytokines, including IL-1β, IL-6, IL-8, and TNF-α, was observed in brain endothelial cells in response to oxygen/glucose depletion/reoxygenation, which was decreased by the shRNA-mediated Atg7 knockdown. Interestingly, Atg7 knockdown reduced IKKβ phosphorylation, leading to NF-κB deactivation and downregulation of the pro-inflammatory cytokines mRNA levels. Further, Atg7 transcriptional regulation function is independent of its role in autophagy. Taken together, our results demonstrated that brain endothelial Atg7 contributes to brain damage during I/R by modulating the expression of pro-inflammatory cytokines. Depletion of Atg7 in brain endothelium has a neuroprotective effect against the ischemia/reperfusion-induced acute cerebral injury during stroke.

Keywords: Atg7; brain microvascular endothelial cells; ischemia/reperfusion injury; pro-inflammatory cytokines; transient focal cerebral ischemia

DOI: https://doi.org/10.3389/fneur.2018.00998

Arch Med Res. 2018 Dec 13. pii: S0188-4409(18)30413-2. [Epub ahead of print]

Ischemic Preconditioning Preserves Liver Energy Charge and Function on Hepatic Ischemia/Reperfusion Injury in Rats.

Sergio Rodríguez-Reynoso, Caridad Leal-Cortés, Eliseo Portilla-de Buen, Selene Paulina López-De la Torre.

BACKGROUND: Cell energy during ischemia/reperfusion depends on mechanisms including adenosine diphosphate degradation, oxygen species and cytokine liberation, neutrophil infiltration, and endothelial dysfunction. Preconditioning-a brief ischemic episode that confers a state of protection against subsequent ischemia-reperfusion injury-involves NO and adenosine production, reduction in oxygen species liberation, and preservation of microcirculation. During hypoxia, constitutive NO production assures adequate oxygen delivery and reduced energy loss. The aim was to determine the role of ischemic preconditioning in the stimulation of constitutive endothelial nitric oxide (NO) production and its effect on energy charge, radical oxygen species generation, cytokine liberation, and neutrophil infiltration during reperfusion.
MATERIALS AND METHODS: Rats were assigned to one of four groups depending on the preconditioning protocol: hepatic ischemia/reperfusion, or hepatic ischemia/reperfusion and ischemic preconditioning, for 5, 10, or 20 min. A portosystemic shunt was established between the portal and left jugular veins during ischemia.
RESULTS: Preconditioning produced rises in plasma nitrites, but no rise in inducible nitric oxide synthase gene expression. A 5 or 10 min preconditioning period allowed for higher energy charge, bile production, and glutathione levels, with less lipoperoxide, alanine aminotransferase, tumor necrosis factor-α, and interleukin-1 production and neutrophil infiltration, compared with 20 min or control. Survival was 80% in the G10 group, 70 in G5, 10 in GC, and 0% in the G20 group.
CONCLUSIONS: Ten-min liver preconditioning improves survival and prevents energy loss during hepatic ischemia/reperfusion by stimulating constitutive NO production, maintaining glutathione concentrations and reducing oxygen species and proinflammatory cytokine generation as well as neutrophil infiltration.

Keywords: Arterial ketone body ratio; Energy charge; Inflammatory response; Interleukin 1; Ischemia/reperfusion; Lipid peroxidation; Liver; Nitric oxide; Tumor necrosis factor

DOI: https://doi.org/10.1016/j.arcmed.2018.11.004

J Hepatol. 2018 Dec 17. pii: S0168-8278(18)32622-9. [Epub ahead of print]

Metformin modulates innate immune-mediated inflammation and early progression of NAFLD-associated hepatocellular carcinoma in zebrafish.

Sofia de Oliveira, Ruth A Houseright, Alyssa L Graves, Netta Golenberg, Benjamin G Korte, Veronika Miskolci, Anna Huttenlocher.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) is an increasing clinical problem associated with progression to hepatocellular carcinoma (HCC). The effect of high fat diet on the early immune response in HCC is poorly understood. In addition, the role of metformin in treating NAFLD and HCC remains controversial. Here we visualized the early immune responses to the liver and the effect of metformin on progression of HCC using optically transparent zebrafish.
METHODS: We used live imaging to visualize liver inflammation and disease progression in a NAFLD/NASH-HCC zebrafish model. We combined a high fat diet (HFD) with a transgenic zebrafish HCC model induced by hepatocyte-specific activated beta-catenin and assessed liver size, angiogenesis, micronuclei formation and inflammation in the liver. In addition, we probed the effects of metformin on immune cell composition and early HCC progression.
RESULTS: We found that HFD induced an increase in liver size, enhanced angiogenesis, micronuclei formation and neutrophil infiltration in the liver. Although macrophage number was not affected by diet, high fat diet induced changes in macrophage morphology and polarization with an increase in liver associated TNFα positive-macrophages. Treatment with metformin altered macrophage polarization, reduced liver size and micronuclei formation in NAFLD/NASH-associated HCC larvae. Moreover, high fat diet reduced T cell density in the liver and this effect was rescued by treatment with metformin.
CONCLUSIONS: These findings suggest that diet alters macrophage polarization and exacerbates the liver inflammatory microenvironment and cancer progression in a zebrafish model of NAFLD/NASH-associated HCC. Metformin specifically affects the progression induced by diet and modulates the immune response by affecting macrophage polarization and T cell infiltration, suggesting possible effects of metformin on tumor surveillance.
LAY SUMMARY: This paper reports a new zebrafish model to study the effects of diet on liver cancer. We found that high-fat diet promotes nonresolving inflammation in the liver and enhances cancer progression. In addition, we found that metformin, a drug used to treat diabetes, inhibits high fat diet-induced cancer progression in this model, by reducing diet-induced nonresolving inflammation and potentially restoring tumor surveillance.

Keywords: High-fat diet; Metformin; NAFLD-associated HCC; NAFLD/NASH; Zebrafish model

DOI: https://doi.org/10.1016/j.jhep.2018.11.034

Mol Med Rep. 2018 Dec 12.

Curcumin inhibits high glucose‑induced inflammatory injury in human retinal pigment epithelial cells through the ROS‑PI3K/AKT/mTOR signaling pathway.

Zhenlong Ran, Yueling Zhang, Xiaoying Wen, Jingxue Ma.

Diabetic retinopathy (DR) is a retinal disease caused by metabolic disorders of glucose tolerance that can lead to irreversible blindness if not adequately treated. Retinal pigment epithelial cell (RPEC) dysfunction contributes to the pathogenesis of DR. In the present study the anti‑inflammatory effect of curcumin (CUR) was investigated in RPECs damaged by high glucose levels. RPEC treated with 30 mmol/l glucose was regarded as high glucose group, and cells treated with 24.4 mmol/l mannitol was set as equivalent osmolarity group. Cell Counting Kit‑8 assay was used to measure RPEC viability, the expression of phosphorylated (p)‑AKT and p‑mammalian target of rapamycin (mTOR) were assessed by western blot, and secretion of tumor necrosis factor (TNF)‑α, interleukin (IL)‑6 and IL‑1β in the culture medium was measured by ELISA. Intracellular reactive oxygen species (ROS) levels were measured by laser scanning confocal microscope. The present data indicated that, compared with mannitol treatment, high glucose treatment reduced RPEC viability, increased TNF‑α, IL‑6 and IL‑1β secretion, increased ROS formation and promoted phosphorylation of AKT and mTOR. The antioxidant N‑acetylcysteine, the phosphoinositide 3‑kinase (PI3K)/AKT inhibitor LY294002 and the mTOR inhibitor rapamycin ameliorated the effects of high glucose. In addition, pretreatment with 10 µmol/l CUR reduced secretion levels of TNF‑α, IL‑6 and IL‑1β, ROS formation and phosphorylation of AKT and mTOR. In conclusion, CUR inhibited high glucose‑induced inflammatory injury in RPECs by interfering with the ROS/PI3K/AKT/mTOR signaling pathway. The present study may reveal the molecular mechanism of CUR inhibition effects to high glucose‑induced inflammatory injury in RPEC.

DOI: https://doi.org/10.3892/mmr.2018.9749