scholarly journals Advanced glycation end-products suppress autophagic flux in podocytes by activating mammalian target of rapamycin and inhibiting nuclear translocation of transcription factor EB

2018 ◽  
Vol 245 (2) ◽  
pp. 235-248 ◽  
Author(s):  
Xingchen Zhao ◽  
Yuanhan Chen ◽  
Xiaofan Tan ◽  
Li Zhang ◽  
Hong Zhang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Advanced Glycation End Products ◽  
Nuclear Translocation ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Autophagic Flux ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products ◽  
Transcription Factor Eb

scholarly journals A Systematic Study of Mechanism of Sargentodoxa cuneata and Patrinia scabiosifolia Against Pelvic Inflammatory Disease With Dampness-Heat Stasis Syndrome via Network Pharmacology Approach

2020 ◽  
Vol 11 ◽  
Author(s):  
Luanqian Hu ◽  
Yuqi Chen ◽  
Tingting Chen ◽  
Dan Huang ◽  
Shihua Li ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Pelvic Inflammatory Disease ◽  
Advanced Glycation End Products ◽  
Inflammatory Disease ◽  
Experimental Validation ◽  
Advanced Glycation ◽  
Nuclear Transcription Factor ◽  
Tnf Α ◽  
Glycation End Products ◽  
End Products

Objective: To investigate the mechanism of Sargentodoxa cuneata (Oliv.) Rehder & E.H.Wilson (SC) and Patrinia scabiosifolia (PS) against Pelvic Inflammatory Disease with Dampness-Heat Stasis Syndrome via network pharmacological approach and experimental validation.Methods: The active compounds with OB ≥ 30% and DL ≥ 0.18 were obtained from TCMSP database and further confirmed by literature research. The targets of the compounds and disease were acquired from multiple databases, such as GeneCards, CTD and TCMSP database. The intersection targets were identified by Venny software. Cytoscape 3.7.0 was employed to construct the protein-protein interaction (PPI) network and compound-target network. Moreover, GO enrichment and KEGG pathway analysis were analyzed by DAVID database. Finally, CCK-8, Griess assay and a cytometric bead array (CBA) immunoassay were used for experimental validation by detecting the influence of the active compounds on proliferation of macrophage, release of NO and TNF-α after LPS treatment.Results: 9 bioactive compounds were identified from SC and PS. Those compounds corresponded to 134 targets of pelvic inflammatory disease with dampness-heat stasis syndrome. The targets include vascular endothelial growth factor A (VEGFA), von willebrand factor (VWF), interleukin 6 (IL6), tumor necrosis factor (TNF) and nuclear transcription factor 1 (NFκB1). They act on the signaling pathways like advanced glycation end products-receptor of advanced glycation end products (AGE-RAGE), focal adhesion (FA), Toll-like receptor (TLR) and nuclear transcription factor κB (NF-κB). In addition, by in vitro validation, the selected active components of SC and PS such as acacetin, kaempferol, linarin, isovitexin, sinoacutine could significantly inhibit the release of NO induced by LPS, respectively. Moreover, different dose of acacetin, kaempferol, isovitexin and sinoacutine significantly inhibits the TNF-α production.Conclusion: This study provides solid evidence for the anti-inflammatory mechanism of SC and PS against pelvic inflammatory disease with dampness-heat stasis syndrome, which will provide a preliminary evidence and novelty ideas for future research on the two herbs.

scholarly journals Notch/NICD/RBP-J Signaling Axis Regulates M1 Polarization of Macrophages Mediated by Advanced Glycation End Products

2021 ◽  
Author(s):  
Hao Tan ◽  
Wenjie Xu ◽  
Xiaoqian Ding ◽  
Huayu Ye ◽  
Yun Hu ◽  
...  
Keyword(s):  
Advanced Glycation End Products ◽  
Nuclear Translocation ◽  
Bone Diseases ◽  
Advanced Glycation ◽  
Raw264.7 Macrophages ◽  
Macrophages Polarization ◽  
M1 Polarization ◽  
Glycation End Products ◽  
End Products ◽  
Signaling Axis

Abstract Advanced glycation end products (AGEs) aggregation and macrophages polarization both play essential roles in degenerative bone diseases caused by aging or diabetes, such as senile or diabetic osteoporosis. Here, we aimed to understand the involvement and potential mechanism of AGEs in macrophages polarization and osteoclastogenesis. We found that RAW264.7 macrophages treated with AGEs highly expressed M1-associated genes and surface antigen markers CD86, and released a large amount of NO to the extracellular environment. Through the detection of osteoclast-related markers and TRAP staining, we revealed that the osteoclastogenesis of M1 macrophages could be markedly enhanced by AGEs. To explore the potential mechanisms of AGEs-mediated M1 polarization, we first demonstrated that AGEs effectively activated the transduction of Notch signaling pathway, including nuclear translocation of NICD1. Subsequently, it was observed that the M1 polarization effects induced by AGEs were significantly mitigated, when γ-secretase inhibitor DAPT and siRNA targeting silencing RBP-J were applied to block the signal transduction of Notch. In conclusion, our findings revealed a series of phenomena that AGEs induce macrophage M1 polarization and enhance its osteoclastogenesis ability, and Notch/NICD/RBP-J signaling axis is involved in the regulation of this polarization process.

Mangiferin suppressed advanced glycation end products (AGEs) through NF-κB deactivation and displayed anti-inflammatory effects in streptozotocin and high fat diet-diabetic cardiomyopathy rats

2016 ◽  
Vol 94 (3) ◽  
pp. 332-340 ◽  
Author(s):  
Jun Hou ◽  
Dezhi Zheng ◽  
Gabriel Fung ◽  
Haoyu Deng ◽  
Lin Chen ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Diabetic Cardiomyopathy ◽  
Advanced Glycation End Products ◽  
High Fat Diet ◽  
Nuclear Translocation ◽  
High Fat ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products ◽  
Mrna And Protein Expression

Given the importance of the aggregation of advanced glycation end products (AGEs) and cardiac inflammation in the onset and progression of diabetic cardiomyopathy (DCM), our objective in this study was to demonstrate the cardioprotective effect of mangiferin, an antidiabetic and anti-inflammatory agent, on diabetic rat model. The DCM model was established by a high-fat diet and a low dose of streptozotocin. DCM rats were treated orally with mangiferin (20 mg/kg) for 16 weeks. Serum and left ventricular myocardium were collected for determination of inflammatory cytokines. AGEs mRNA and protein expression of nuclear factor kappa B (NF-κB) and receptor for AGEs (RAGE) in myocardium were assayed by real-time PCR and Western blot. ROS levels were measured by dihydroethidium fluorescence staining. NF-κB binding activity was assayed by TransAM NF-κB p65 ELISA kit. Chronic treatment with mangiferin decreased the levels of myocardial enzymes (CK-MB, LDH) and inflammatory mediators (TNF-α, IL-1β). Meanwhile, NF-κB is inhibited by the reduction of nuclear translocation of p65 subunit, and mangiferin reduced AGE production and decreased the mRNA and protein expression of RAGE in DCM rats. Our data indicated that mangiferin could significantly ameliorate DCM by preventing the release of inflammatory cytokines, and inhibiting ROS accumulation, AGE/RAGE production, and NF-κB nuclear translocation, suggesting that mangiferin treatment might be beneficial in DCM.

Impaired transcription factor interplay in addition to advanced glycation end products suppress podocalyxin expression in high glucose-treated human podocytes

2009 ◽  
Vol 297 (3) ◽  
pp. F594-F603 ◽  
Author(s):  
Garyfalia I. Drossopoulou ◽  
Nikolaos E. Tsotakos ◽  
Effie C. Tsilibary
Keyword(s):  
Transcription Factor ◽  
Advanced Glycation End Products ◽  
Wilms Tumor ◽  
Mrna Levels ◽  
Advanced Glycation ◽  
Protein Levels ◽  
Glucose Levels ◽  
Glycation End Products ◽  
End Products

Podocalyxin represents a Wilms’ tumor suppressor protein (WT1)-regulated differentiation marker for glomerular epithelium. We provide evidence concerning mechanisms involved in the regulation of podocalyxin expression following long-term exposure to increased (25 mM) glucose levels. Prolonged culture of conditionally immortalized human podocytes in 25 mM glucose induced suppression of podocalyxin expression both at the protein and mRNA levels, whereas WT1 protein levels remained unaltered. WT1 interacted with another transcription factor, CRE-binding protein (CBP). This association was decreased by 40% in the presence of 25 mM glucose. Chromatin immunoprecipitation assays on chromatin from podocytes cultured in 25 mM glucose revealed reduced WT1 binding to podocalyxin promoter sequences, probably resulting from impaired WT1-CBP interactions. We explored the possible role of glucose-induced adducts (advanced glycation end products; AGEs) in impairing interactions between WT1 and CBP, with the use of aminoguanindine, an inhibitor of AGE formation. Podocytes were cultured in the simultaneous presence of 20 mM aminoguanidine and 25 mM glucose, and podocalyxin protein levels were examined. Aminoguanidine effectively prevented downregulation of podocalyxin protein levels but could not restore podocalyxin levels once expression was suppressed. Thus increased glucose apparently impaired the ability of WT1 to initiate transcription in part by decreased association of WT1 with CBP. Administration of aminoguanidine concomitant with increasing glucose levels in our in vitro model system protected from glucose-induced “silencing” of the podocalyxin gene, suggesting that AGEs play an important role in suppressing its expression in diabetic conditions.

scholarly journals Advanced Glycation End-Products and Hyperglycemia Increase Angiopoietin-2 Production by Impairing Angiopoietin-1-Tie-2 System

2019 ◽  
Vol 2019 ◽  
pp. 1-7
Author(s):  
Alessandra Puddu ◽  
Roberta Sanguineti ◽  
Davide Maggi ◽  
Massimo Nicolò ◽  
Carlo E. Traverso ◽  
...  
Keyword(s):  
Advanced Glycation End Products ◽  
Intracellular Signaling ◽  
Nuclear Translocation ◽  
Microvascular Complications ◽  
Vascular Complications ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products ◽  
Angiopoietin 2 ◽  
Angiopoietin 1

The angiopoietin-Tie-2 system plays a crucial role in the maintenance of endothelial integrity. Hyperglycemia and advanced glycation end-products (AGEs) are involved in endothelial cell dysfunction responsible of the pathogenesis of microvascular complications of diabetes. Here, we investigated whether glycated serum (GS) or hyperglycemia (HG) affect the angiopoietin-Tie-2 system in the microvascular endothelial cells HMEC-1. We found that culture for 5 days in the presence of AGEs and HG (alone or in combination) decreased cell proliferation, increased reactive oxygen species (ROS) production, and reduced ratio between the oxidized and the reduced form of glutathione. Since angiopoietin-1 (Ang-1) signaling regulates angiopoietin-2 (Ang-2) expression through inactivation of the forkhead transcription factor FoxO1, we investigated intracellular signaling of Ang-1 and expression of Ang-2. HG and AGEs reduced phosphorylation of Akt and abrogated phosphorylation of FoxO1 induced by Ang-1 without affecting neither Tie-2 expression nor its activation. Furthermore, AGEs and/or HG induced nuclear translocation of FoxO1 and increased Ang-2 production. In conclusion, we demonstrated that both hyperglycemia and AGEs affect the angiopoietin-Tie-2 system by impairing Ang-1/Tie-2 signaling and by increasing Ang-2 expression. These results suggest that therapeutic strategies useful in preventing or delaying the onset of diabetic vascular complications should be aimed to preserve Ang-1 signaling.

Advanced glycation end products induce apoptosis in fibroblasts through activation of ROS, MAP kinases, and the FOXO1 transcription factor

2007 ◽  
Vol 292 (2) ◽  
pp. C850-C856 ◽  
Author(s):  
Mani Alikhani ◽  
Christine M. MacLellan ◽  
Markos Raptis ◽  
Siddarth Vora ◽  
Philip C. Trackman ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Advanced Glycation End Products ◽  
Map Kinases ◽  
Caspase 3 ◽  
Fold Increase ◽  
Advanced Glycation ◽  
Kinase Activation ◽  
Glycation End Products ◽  
End Products ◽  
Induced Apoptosis

Advanced glycation end products (AGEs) are elevated in aged and diabetic individuals and are associated with pathological changes associated with both. Previously we demonstrated that the AGE Nε-(carboxymethyl)lysine (CML)-collagen induced fibroblast apoptosis through the cytoplasmic and mitochondrial pathways and the global induction of proapoptotic genes. In the present study we investigated upstream mechanisms of CML-collagen-induced apoptosis. CML-collagen induced activation of the proapoptotic transcription factor FOXO1 compared with unmodified collagen. When FOXO1 was silenced, CML-collagen-stimulated apoptosis was reduced by ∼75% compared with fibroblasts incubated with nonsilencing small interfering RNA, demonstrating the functional significance of FOXO1 activation ( P < 0.05). CML-collagen but not control collagen also induced a 3.3-fold increase in p38 and a 5.6-fold increase in JNK(1/2) activity ( P < 0.05). With the use of specific inhibitors, activation of p38 and JNK was shown to play an important role in CML-collagen-induced activation of FOXO1 and caspase-3. Moreover, inhibition of p38 and JNK reduced CML-collagen-stimulated apoptosis by 48 and 57%, respectively, and by 89% when used together ( P < 0.05). In contrast, inhibition of the phosphatidylinositol 3-kinase/Akt pathway enhanced FOXO1 activation. p38 and JNK stimulation by CML-collagen was almost entirely blocked when formation of ROS was inhibited and was partially reduced by NO and ceramide inhibitors. These inhibitors also reduced apoptosis to a similar extent. Together these data support a model in which AGE-induced apoptosis involves the formation of ROS, NO, and ceramide and leads to p38 and JNK MAP kinase activation, which in turn induces FOXO1 and caspase-3.

scholarly journals In Vitro Evaluation of the Toxicological Profile and Oxidative Stress of Relevant Diet-Related Advanced Glycation End Products and Related 1,2-Dicarbonyls

2021 ◽  
Vol 2021 ◽  
pp. 1-20
Author(s):  
Vanesa Cepas ◽  
Friederike Manig ◽  
Juan C. Mayo ◽  
Michael Hellwig ◽  
Debora Collotta ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Amino Acids ◽  
Cell Death ◽  
Advanced Glycation End Products ◽  
Intracellular Signaling ◽  
Nuclear Translocation ◽  
Advanced Glycation ◽  
Dicarbonyl Compounds ◽  
Glycation End Products ◽  
End Products

During food processing and storage, and in tissues and fluids under physiological conditions, the Maillard reaction occurs. During this reaction, reactive 1,2-dicarbonyl compounds arise as intermediates that undergo further reactions to form advanced glycation end products (AGEs). Diet is the primary source of exogenous AGEs. Endogenously formed AGEs have been proposed as a risk factor in the pathogenesis of diet-related diseases such as diabetes, insulin resistance, cardiovascular diseases, or chronic disease. AGEs may differently contribute to the diet-related exacerbation of oxidative stress, inflammation, and protein modifications. Here, to understand the contribution of each compound, we tested individually, for the first time, the effect of five 1,2-dicarbonyl compounds 3-deoxyglucosone (3-DG), 3-deoxygalactosone (3-DGal), 3,4-dideoxyglucosone-3-ene (3,4-DGE), glyoxal (GO), and methylglyoxal (MGO) and four different glycated amino acids N-ε-(carboxyethyl)lysine (CEL), N- ε -(carboxymethyl)lysine (CML), methylglyoxal-derived hydroimidazolone-1 (MG-H1), and pyrraline (Pyrr) in a cell line of human keratinocytes (HaCaT). We found that most of the glycated amino acids, i.e., CEL, CML, and MG-H1, did not show any cytotoxicity. At the same time, 1,2-dicarbonyl compounds 3-DGal, 3,4-DGE, GO, and MGO increased the production of reactive oxygen species and induced cell death. MGO induced cell death by apoptosis, whereas 3-DGal and 3,4-DGE induced nuclear translocation of the proinflammatory NF-κB transcription pathway, and the activation of the pyroptosis-related NLRP3 inflammasome cascade. Overall, these results demonstrate the higher toxic impact of 1,2-dicarbonyl compounds on mucosal epithelial cells when compared to glycated amino acids and the selective activation of intracellular signaling pathways involved in the crosstalk mechanisms linking oxidative stress to excessive inflammation.

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