Inner and outer blood‐retinal barriers (BRBs), mainly composed of retinal endothelial cells and retinal pigment epithelial (RPE) cells, respectively, maintain the integrity of the retinal tissues. In ...this study, we aimed to investigate the mechanisms of the outer BRB disruption regarding the interaction between RPE and microglia. In mice with high‐fat diet‐induced obesity and streptozotocin‐induced hyperglycemia, microglia accumulated on the RPE layer, as in those after intravitreal injection of interleukin (IL)‐6, which is elevated in ocular fluids of patients with diabetic retinopathy. Although IL‐6 did not directly affect the levels of zonula occludens (ZO)‐1 and occludin in RPE cells, IL‐6 increased VEGFA mRNA in RPE cells to recruit microglial cells. In microglial cells, IL‐6 upregulated the mRNA levels of MCP1, MIP1A, and MIP1B, to amplify the recruitment of microglial cells. In this manner, IL‐6 modulated RPE and microglial cells to attract microglial cells on RPE cells. Furthermore, IL‐6‐treated microglial cells produced and secreted tumor necrosis factor (TNF)‐α, which activated NF‐κB and decreased the levels of ZO‐1 in RPE cells. As STAT3 inhibition reversed the effects of IL‐6‐treated microglial cells on the RPE monolayer in vitro, it reduced the recruitment of microglial cells and the production of TNF‐α in RPE tissues in streptozotocin‐treated mice. Taken together, IL‐6‐treated RPE and microglial cells amplified the recruitment of microglial cells and IL‐6‐treated microglial cells produced TNF‐α to disrupt the outer BRB in diabetic retinopathy.
• In diabetic retinopathy, microglia were recruited by the interaction between retinal pigment epithelial cells and microglia.
• Recruited microglia secreted tumor necrosis factor‐α and disrupted tight junction complexes among retinal pigment epithelium.
Diabetes mellitus (DM) characterized by hyperglycemia leads to a variety of complications, including cognitive impairment or memory loss. The hippocampus is a key brain area for learning and memory ...and is one of the regions that is most sensitive to diabetes. However, the pathogenesis of diabetic neuronal lesion is not yet completely understood. We focused on the association of microglia activation and brain lesions in diabetes. In this study, we investigated whether and how signal transducer and activator of transcription 3 (STAT3) activation in microglia affects neuronal lesions in diabetic brains. Using a streptozotocin‐induced type 1 DM model, we showed enhanced hippocampal neuronal apoptosis that was associated with increased STAT3 activation. We found that hyperglycemia increased the expression of inflammatory cytokines such as interferon‐γ (IFN‐γ) and interleukin‐6, in the diabetic hippocampus. In particular, IFN‐γ induced autocrine activation of microglia, and STAT3 activation is important for this process. We also demonstrated that STAT3 activation in microglia increased tumor necrosis factor‐α (TNF‐α) expression; subsequently, TNF‐α increased neuronal apoptosis by increasing reactive oxygen species (ROS) levels in the neuronal cells. We also took advantage of mice lacking STAT3 in microglia and demonstrated that depletion of microglial STAT3 reduced neuronal apoptosis in the diabetic hippocampus. Taken together, these results suggest that STAT3 activation in microglia plays an important role in hyperglycemia‐induced neuronal apoptosis in the diabetic hippocampus and provide a potential therapeutic benefit of STAT3 inhibition in microglia for preventing diabetic neuronal lesions.
We demonstrated that signal transducer and activator of transcription 3 (STAT3) activation in microglia exacerbates neuronal apoptosis of the diabetic hippocampus and that increased tumor necrosis factor‐α (TNF‐α) through STAT3 activation causes neuronal apoptosis. We also took the advantage of mice lacking STAT3 in microglia and demonstrated that depletion of microglial STAT3 reduced neuronal apoptosis in the diabetic hippocampus. There results suggest that STAT3 activation in microglia plays an important role in hyperglycemia‐induced neuronal apoptosis in the diabetic hippocampus and provide a potential therapeutic benefit of STAT3 inhibition in microglia for preventing diabetic neuronal lesions.
Intestinal epithelium is essential for maintaining normal intestinal homeostasis; its breakdown leads to chronic inflammatory pathologies, such as inflammatory bowel diseases (IBDs). Although high ...concentrations of S100A9 protein and interleukin-6 (IL-6) are found in patients with IBD, the expression mechanism of S100A9 in colonic epithelial cells (CECs) remains elusive. We investigated the role of IL-6 in S100A9 expression in CECs using a colitis model.
IL-6 and S100A9 expression, signal transducer and activator of transcription 3 (STAT3) phosphorylation, and infiltration of immune cells were analyzed in mice with dextran sulfate sodium (DSS)-induced colitis. The effects of soluble gp130-Fc protein (sgp130Fc) and S100A9 small interfering (si) RNA (si-S100A9) on DSS-induced colitis were evaluated. The molecular mechanism of S100A9 expression was investigated in an IL-6-treated Caco-2 cell line using chromatin immunoprecipitation assays.
IL-6 concentrations increased significantly in the colon tissues of DSS-treated mice. sgp130Fc or si-S100A9 administration to DSS-treated mice reduced granulocyte infiltration in CECs and induced the down-regulation of S100A9 and colitis disease activity. Treatment with STAT3 inhibitors upon IL-6 stimulation in the Caco-2 cell line demonstrated that IL-6 mediated S100A9 expression through STAT3 activation. Moreover, we found that phospho-STAT3 binds directly to the S100A9 promoter. S100A9 may recruit immune cells into inflamed colon tissues.
Elevated S100A9 expression in CECs mediated by an IL-6/STAT3 signaling cascade may play an important role in the development of colitis.
AIM:To investigate the prognostic usefulness of several existing scoring systems in predicting the severity of acute pancreatitis(AP).METHODS:We retrospectively analyzed the prospectively collected ...clinical database from consecutive patients with AP in our institution between January 2011 and December 2012.Ranson,Acute Physiology and Chronic Health Evaluation(APACHE)-Ⅱ,and bedside index for severity in acute pancreatitis(BISAP)scores,and computed tomography severity index(CTSI)of all patients were calculated.Serum C-reactive protein(CRP)levels were measured at admission(CRPi)and after 24h(CRP24).Severe AP was defined as persistent organ failure for more than 48 h.The predictive accuracy of each scoring system was measured by the area under the receiver-operating curve(AUC).RESULTS:Of 161 patients,21(13%)were classified as severe AP,and 3(1.9%)died.Statistically significant cutoff values for prediction of severe AP were Ranson≥3,BISAP≥2,APACHE-Ⅱ≥8,CTSI≥3,and CRP24≥21.4.AUCs for Ranson,BISAP,APACHE-Ⅱ,CTSI,and CRP24 in predicting severe AP were 0.69(95%CI:0.62-0.76),0.74(95%CI:0.66-0.80),0.78(95%CI:0.70-0.84),0.69(95%CI:0.61-0.76),and0.68(95%CI:0.57-0.78),respectively.APACHE-Ⅱdemonstrated the highest accuracy for prediction of severe AP,however,no statistically significant pairwise differences were observed between APACHE-Ⅱand the other scoring systems,including CRP24.CONCLUSION:Various scoring systems showed similar predictive accuracy for severity of AP.Unique models are needed in order to achieve further improvement of prognostic accuracy.
As silicon-based electronics approach the limit of improvements to performance and capacity through dimensional scaling, attention in the semiconductor field has turned to graphene, a single layer of ...carbon atoms arranged in a honeycomb lattice. Its high mobility of charge carriers (electrons and holes) could lead to its use in the next generation of high-performance devices. Graphene is unlikely to replace silicon completely, however, because of the poor on/off current ratio resulting from its zero bandgap. But it could be used to improve silicon-based devices, in particular in high-speed electronics and optical modulators.
Abstract
Tumor acidosis, a common phenomenon in solid cancers such as breast cancer, is caused by the abnormal metabolism of cancer cells. The low pH affects cells surrounding the cancer, and tumor ...acidosis has been shown to inhibit the activity of immune cells. Despite many previous studies, the immune surveillance mechanisms are not fully understood. We found that the expression of PD-L1 was significantly increased under conditions of extracellular acidosis in MDA-MB-231 cells. We also confirmed that the increased expression of PD-L1 mediated by extracellular acidosis was decreased when the pH was raised to the normal range. Gene set enrichment analysis (GSEA) of public breast cancer patient databases showed that PD-L1 expression was also highly correlated with IL-6/JAK/STAT3 signaling. Surprisingly, the expression of both phospho-tyrosine STAT3 and PD-L1 was significantly increased under conditions of extracellular acidosis, and inhibition of STAT3 did not increase the expression of PD-L1 even under acidic conditions in MDA-MB-231 cells. Based on these results, we suggest that the expression of PD-L1 is increased by tumor acidosis via activation of STAT3 in MDA-MB-231 cells.
Utilization of germinated brown rice (GBR) in sugar-snap cookies and effect of heat-moisture treatment of the GBR were investigated. Brown rice was germinated at 30 °C for 48 h and then a ...heat-moisture treatment was conducted for the moistened GBR (17 g/100 g moisture content) at 100 °C for 4 h. Sugar-snap cookies were prepared with white rice, brown rice, GBR and the treated GBR flours, as substitutes for wheat flour (30–100 g/100 g). All cookies containing rice flours, regardless of germination and heat-moisture treatment, required significantly less force to compress than did the wheat flour cookie, and this softening effect was increased as the level of rice flour substitution increased. The cookies made with the GBR flour displayed inferior physical characteristics compared to those with wheat flour, but the cookies containing the treated GBR flour showed improved physical properties with lower moisture content and higher spread factor than those containing untreated GBR flour. The cookies containing the treated GBR flours showed relatively a low degree of firming during the ambient storage. The overall results showed that the cookies with acceptable quality and improved nutrition could be prepared by partial or complete replacement of wheat flour with the heat-moisture treated GBR flour.
•Germinated brown rice (GBR) and treated GBR were incorporated into sugar-snap cookies.•The substitution of rice flour in cookies caused increased moisture retention.•The cookies containing the treated GBR flours showed improved physical properties.•The cookies containing the treated GBR flours appeared acceptable for storage.
While wound healing is completed, the epithelium functions to normalize the interstitial context by eliminating fibroblasts excited during matrix reconstruction. If not, tissues undergo pathologic ...fibrosis. Pulmonary fibrosis is a fatal and hardly curable disorder. We here tried to identify epithelium-derived cytokines capable of ameliorating pulmonary fibrosis. Human lung fibroblasts were inactivated in epithelial cell-conditioned media. Cystatin C (CST3) and growth differentiation factor 15 (GDF15) were found to be enriched in the conditioned media and to inhibit the growth and activation of lung fibroblasts by inactivating the TGF-Smad pathway. In mouse and human lungs with interstitial fibrosis, CST3 and GDF15 expressions were markedly reduced, and the restoration of these cytokines alleviated the fibrotic changes in mouse lungs. These results suggest that CST3 and GDF15 are bona fide regulators to prevent excessive proliferation and activation of fibroblasts in injured lungs. These cytokines could be potential therapeutics for ameliorating interstitial lung fibrosis.
Self-regulated "smart" insulin administration system that mimic pancreatic endocrine function would be highly desirable for diabetes management. Here, a glucose-responsive continuous insulin delivery ...system is developed, where novel polyhedral oligosilsesquioxane (POSS) modified with 3-aminophenylboronic acid (APBA) were used to encapsulate insulin (insulin entrapment efficiency: 73.2%) to prepare a fast response, high stability, good distribution, and excellent biocompatible system. Due to the strong hydrophobicity of POSS, the POSS moiety is located at the core in aqueous solution and combines with the boronic group of APBA and the diol generated in PEG-insulin to form a nanomicelle structure, that is, nanoparticles naturally. Micelles self-assembled from these molecules possess glucose-responsiveness at varying glucose concentrations. The interaction of the PBA and diol containing insulin via boronate ester bond and its interchange with glucose was investigated by FT-IR,
H NMR and XPS. Furthermore, the successful glucose-triggered release of insulin from the POSS-APBA micelles was investigated at neutral pH. A linear graph was plotted with the measured released insulin vs glucose concentrations, with a linear correlation coefficient (R2) value close to 1. Circular dichroism (CD) spectroscopy analysis was performed to measure insulin activity by comparing secondary structures of insulin, PEG-Insulin, and POSS-APBA@insulin. When confirming intracellular apoptosis signaling, cleaved caspase 3 and caspase 9 were not increased by 640 μg/ml POSS-APBA and POSS-APBA@insulin in HeLa, HDF and HUVE cells. Application in the biomedical field for controlled delivery of insulin appear to be promising.
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