ONO-2506 alleviates lipopolysaccharide-induced hippocampal neuroinflammation and apoptosis

2019 ◽  
Author(s):  
Jian-yu Liu ◽  
Wei Fang ◽  
Shi-xia Cai ◽  
Ming-ying Dai ◽  
Bo Yao
Keyword(s):  
S100 Protein ◽  
Brain Cell ◽  
Potential Treatment ◽  
Advanced Glycation ◽  
High Concentration ◽  
Tnf Α ◽  
Glycation End Products ◽  
End Products ◽  
Neurotoxic Effects ◽  
Rage Expression

Abstract Background Sepsis associated encephalopathy has high mortality rate, but there is no targeted therapy to reduce brain damage in septic patients. In our previous study, we found that S100β concentration was higher in patients with SAE. At high concentration, S100β exerts neurotoxic effects through receptor for advanced glycation end products (RAGE). RAGE-activated signalling could induce the inflammatory response. And neuroinflammation is an important mechanism of SAE. So inhibiting S100β expression may be a potential treatment of SAE. ONO-2506 can inhibit the production and release of S100 protein from astrocytes. In this study, we administered ONO-2506 to mice in order to evaluate its effectiveness on neuroinflammation and apoptosis in hippocampus induced by lipopolysaccharides. Results We found administration with lipopolysaccharides increased the levels of S100β, RAGE, IL-β, TNF-α and the TUNEL positive brain cells in hippocampus tissue. The ONO-2506 30mg/kg and 90mg/kg could reduce the levels of neuroinflammation (IL-β and TNF-α), and alleviate the apoptosis in hippocampus. Conclusions ONO-2506 could reduce the neuroinflammation and alleviate brain cell apoptosis in hippocampus of LPS mice models. Moreover, the RAGE expression was inhibited after ONO-2506 treatment.

scholarly journals Sitagliptin attenuates arterial calcification by downregulating oxidative stress-induced receptor for advanced glycation end products in LDLR knockout mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Chih-Pei Lin ◽  
Po-Hsun Huang ◽  
Chi-Yu Chen ◽  
Meng-Yu Wu ◽  
Jia-Shiong Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Advanced Glycation End Products ◽  
Calcium Deposition ◽  
Arterial Calcification ◽  
Advanced Glycation ◽  
Tnf Α ◽  
Glycation End Products ◽  
End Products ◽  
Rage Expression

AbstractDiabetes is a complex disease characterized by hyperglycemia, dyslipidemia, and insulin resistance. Plasma advanced glycation end products (AGEs) activated the receptor for advanced glycation end products (RAGE) and the activation of RAGE is implicated to be the pathogenesis of type 2 diabetic mellitus (T2DM) patient vascular complications. Sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, is a new oral hypoglycemic agent for the treatment of T2DM. However, the beneficial effects on vascular calcification remain unclear. In this study, we used a high-fat diet (HFD)-fed low-density lipoprotein receptor deficiency (LDLR−/−) mice model to investigate the potential effects of sitagliptin on HFD-induced arterial calcification. Mice were randomly divided into 3 groups: (1) normal diet group, (2) HFD group and (3) HFD + sitagliptin group. After 24 weeks treatment, we collected the blood for chemistry parameters and DPP4 activity measurement, and harvested the aorta to evaluate calcification using immunohistochemistry and calcium content. To determine the effects of sitagliptin, tumor necrosis factor (TNF)-α combined with S100A12 was used to induce oxidative stress, activation of nicotinamide adenine dinucleotide phosphate (NADPH), up-regulation of bone markers and RAGE expression, and cell calcium deposition on human aortic smooth muscle cells (HASMCs). We found that sitagliptin effectively blunted the HFD-induced artery calcification and significantly lowered the levels of fasting serum glucose, triglyceride (TG), nitrotyrosine and TNF-α, decreased the calcium deposits, and reduced arterial calcification. In an in-vitro study, both S100A12 and TNF-α stimulated RAGE expression and cellular calcium deposits in HASMCs. The potency of S100A12 on HASMCs was amplified by the presence of TNF-α. Sitagliptin and Apocynin (APO), an NADPH oxidase inhibitor, inhibited the TNF-α + S100A12-induced NADPH oxidase and nuclear factor (NF)-κB activation, cellular oxidative stress, RAGE expression, osteo transcription factors expression and calcium deposition. In addition, treatment with sitagliptin, knockdown of RAGE or TNF-α receptor blunted the TNF-α + S100A12-induced RAGE expression. Our findings suggest that sitagliptin may suppress the initiation and progression of arterial calcification by inhibiting the activation of NADPH oxidase and NF-κB, followed by decreasing the expression of RAGE.

scholarly journals Dipeptidyl Peptidase-4 Inhibitor Sitagliptin Attenuates Arterial Calcification By Downregulating Oxidative Stress-Induced Receptor for Advanced Glycation End Products in Low-Density Lipoprotein Receptor Knockout Mice

2021 ◽  
Author(s):  
Chih Pei Lin ◽  
Po-Hsun Huang ◽  
Chi-Yu Chen ◽  
Jia-Shiong Chen ◽  
Jaw-Wen Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Advanced Glycation End Products ◽  
Calcium Deposition ◽  
Advanced Glycation ◽  
Dipeptidyl Peptidase 4 ◽  
Tnf Α ◽  
Glycation End Products ◽  
End Products ◽  
Rage Expression

Abstract Background: Plasma advanced glycation end products (AGEs) activates the receptor for advanced glycation end products (RAGE) and the activation of RAGE is implicated to be the pathogenesis of type 2 diabetic mellitus patient vascular complications. Attenuating the activation of RAGE may exert a protective effect against the development of cardiovascular disease. Dipeptidyl peptidase-4 (DPP4) inhibitors are a new class of oral hypoglycemic agents for the treatment of type 2 diabetes mellitus. Whether sitagliptin, a DPP-4 inhibitor, has a beneficial effect on vascular calcification remains undetermined. Methods: In the present study, we fed low-density lipoprotein receptor knockout (LDLR-/-) mice a high fat diet to induce diabetic mellitus and studied the effect of orally administered sitagliptin on the high fat diet fed LDLR-/- mice aorta medial calcification, RAGE expression, oxidative stress, aorta calcium content. Tumor necrosis factor (TNF)-α combined with S100A12 was used to induce HASMC oxidative stress, activation of NADPH, up-regulation of the bone markers and RAGE expression, and cell calcium deposition. Effect of sitagliptin, siRNA for RAGE and apocynin on blunting TNF-α and S100A12 induced HASMC oxidative stress, calcification and NADPH activation were also investigated. Results: Sitagliptin attenuated the HFD-induced LDLR-/- mice hyperlipidemia, hyperglycemia, increase in serum TNF-α, aorta calcium deposition and the expression of RAGE in the medial layer of the aorta. TNF-α combined with S100A12 stimulated HASMC RAGE expression, calcium deposition, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) activation, and up-regulation of bone marker (bone morphogenetic protein-2, Msh homeobox 2, and runt‑related transcription factor 2) expression. Sitagliptin and apocynin (APO), an NADPH oxidase inhibitor, suppressed the TNF-α+S100A12 treatment effects on the activation of NADPH oxidase and Nuclear factor (NF)-κB and the resultant oxidative stress, up-regulation of RAGE and bone markers expression and calcium deposition. Our findings suggest that sitagliptin imparts its protective effect by suppressing NADPH oxidase and NF-κB activation to blunt the up-regulation of RAGE expression.Conclusion: Our findings suggest that sitagliptin may suppress the initiation and progression of artery calcification by inhibiting the activation of NADPH oxidase and NF-κB and the resultant up-regulation of expression of RAGE.

scholarly journals Overexpression of the receptor for advanced glycation end-products in the auditory cortex of rats with noise-induced hearing loss

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Chang Ho Lee ◽  
Kyung Woon Kim ◽  
Da-hye Lee ◽  
So Min Lee ◽  
So Young Kim
Keyword(s):  
Hearing Loss ◽  
Auditory Cortex ◽  
Noise Exposure ◽  
Advanced Glycation ◽  
Expression Levels ◽  
Tnf Α ◽  
Glycation End Products ◽  
End Products ◽  
Metalloproteinase 9 ◽  
Rage Expression

Abstract Background The receptor for advanced glycation end-products (RAGE) is involved in neuroinflammation. This study investigated the changes in RAGE expression following noise-induced hearing loss. Methods Three-week-old female Sprague–Dawley rats were exposed to 115 dB SPL white noise for 4 h daily for 3 d (noise group, n = 16). In parallel, age and sex-matched control rats were raised under standard conditions without noise exposure (control group, n = 16). After 2 h (noise immediate, n = 8) and 4 wk (noise 4-week, n = 8) of noise exposure, the auditory cortex was harvested and cytoplasmic and nuclear fractions were isolated. The gene expression levels of tumor necrosis factor alpha (TNF-α), interleukin 6 (IL6), interleukin 1 beta (IL1β), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and RAGE were evaluated using real-time reverse transcription polymerase chain reaction. The protein expression levels of nuclear RAGE and cytosolic RAGE were evaluated using western blotting. Additionally, matrix metalloproteinase 9 (MMP9) was pharmacologically inhibited in the noise immediate group, and then nuclear and cytosolic RAGE expression levels were evaluated. Results The noise immediate and noise 4-week groups exhibited increased auditory thresholds at 4, 8, 16, and 32 kHz frequencies. The genes encoding the pro-inflammatory cytokines TNF-α, IL6, IL1β, and NF- κB were increased 3.74, 1.63, 6.42, and 6.23-fold in the noise immediate group, respectively (P = 0.047, 0.043, 0.044, and 0.041). RAGE mRNA expression was elevated 1.42-fold in the noise 4-week group (P = 0.032). Cytosolic RAGE expression was increased 1.76 and 6.99-fold in the noise immediate and noise 4-week groups, respectively (P = 0.04 and 0.03). Nuclear RAGE expression was comparable between the noise and control groups. matrix metalloproteinase 9 (MMP9) inhibition reduced cytosolic RAGE expression in the noise immediate group (P = 0.004). Conclusions Noise exposure increased the expression of cytosolic RAGE in the auditory cortex and upregulated pro-inflammatory genes, but this response could be alleviated by MMP9 inhibition.

scholarly journals Evidence for Activation of Toll-Like Receptor and Receptor for Advanced Glycation End Products in Preterm Birth

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Taketoshi Noguchi ◽  
Toshiyuki Sado ◽  
Katsuhiko Naruse ◽  
Hiroshi Shigetomi ◽  
Akira Onogi ◽  
...  
Keyword(s):  
Preterm Birth ◽  
Advanced Glycation End Products ◽  
Expression Profiles ◽  
Receptor Activation ◽  
Advanced Glycation ◽  
Specific Expression ◽  
Downstream Signaling ◽  
Glycation End Products ◽  
End Products ◽  
Rage Expression

Objective. Individuals with inflammation have a myriad of pregnancy aberrations including increasing their preterm birth risk. Toll-like receptors (TLRs) and receptor for advanced glycation end products (RAGE) and their ligands were all found to play a key role in inflammation. In the present study, we reviewed TLR and RAGE expression, their ligands, and signaling in preterm birth.Research Design and Methods. A systematic search was performed in the electronic databases PubMed and ScienceDirect up to July 2010, combining the keywords “preterm birth,” “TLR”, “RAGE”, “danger signal”, “alarmin”, “genomewide,” “microarray,” and “proteomics” with specific expression profiles of genes and proteins.Results. This paper provides data on TLR and RAGE levels and critical downstream signaling events including NF-kappaB-dependent proinflammatory cytokine expression in preterm birth. About half of the genes and proteins specifically present in preterm birth have the properties of endogenous ligands “alarmin” for receptor activation. The interactions between the TLR-mediated acute inflammation and RAGE-mediated chronic inflammation have clear implications for preterm birth via the TLR and RAGE system, which may be acting collectively.Conclusions. TLR and RAGE expression and their ligands, signaling, and functional activation are increased in preterm birth and may contribute to the proinflammatory state.

scholarly journals Dysregulation of Receptor for Advanced Glycation End Products (RAGE) Expression as a Biomarker of Keratoconus

2022 ◽  
Vol 2022 ◽  
pp. 1-11
Author(s):  
Valentin Navel ◽  
Jean Malecaze ◽  
Corinne Belville ◽  
Héléna Choltus ◽  
Fanny Henrioux ◽  
...  
Keyword(s):  
Western Blot ◽  
Advanced Glycation End Products ◽  
Corneal Epithelium ◽  
Controlled Study ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products ◽  
First Time ◽  
Rage Expression ◽  
Corneal Collagen

Background. Because of the implications of Receptor for Advanced Glycation End Products (RAGE) in keratoconus (KC), we describe a differential expression of RAGE transcripts and proteins in corneal tissues and tears of KC and healthy patients. Methods. Using a case-controlled study, corneal epitheliums and tears of KC and healthy subjects were obtained during corneal collagen cross-linking and photorefractive keratectomy (PKR) and during usual consultations. Quantitative reverse transcription (RT-qPCR) and Western-Blot were performed to analyze RAGE transcripts and proteins’ expression in corneal tissues and tears. Results. One hundred and six patients were included in this study. The characteristics of the patients were as follows: 56 KC (25 corneal epithelium and 31 tears) and 50 control subjects (25 corneal epithelium and 25 tears). Transcripts of RAGE, HMGB1, and S100 family ligands were quantified by RT-qPCR, identifying a significantly higher expression of RAGE and HMGB1 in the healthy group than in the KC group ( p = 0.03 and 0.04, respectively). Western Blot showed a significantly higher fl-RAGE expression in KC corneal epithelium than control ( p < 0.001 ) and lower s-RAGE expression in KC tears than control ( p = 0.04 ). Conclusions. Linked with the inflammatory process occurring in KC pathophysiology, we propose for the first time that the RAGE expression (total and truncated forms of receptor and ligands) in KC corneal tissues and tear samples provides viable biomarkers.

scholarly journals The second wave of COVID-19 results in outbreak of mucormycosis: diabetes and immunological perspective

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Ashok kumar Ahirwar ◽  
Kirti Kaim ◽  
Pradeep Ahirwar ◽  
Rajani Kumawat
Keyword(s):  
Adhesion Molecules ◽  
Inflammatory Cells ◽  
Cochrane Library ◽  
Advanced Glycation ◽  
Chronic Hyperglycemia ◽  
Uncontrolled Diabetes ◽  
Tnf Α ◽  
Glycation End Products ◽  
End Products ◽  
Second Wave

Abstract Objectives To evaluate the potential relationship between COVID-19 pandemic and mucormycosis outbreak. Methods PubMed, Embase, Cochrane Library and Google Scholar were searched for the term “COVID-19 and mucormycosis” up to May 31, 2021. Results After the second wave of COVID-19, the mucormycosis outbreak complicates the natural course of COVID-19. COVID-19 patients with uncontrolled diabetes mellitus with diabetic ketoacidosis, excessive glucocorticoid use, prolonged neutropenia, malnutrition and any underlying immunocompromised conditions are at risk of developing mucormycosis. Conclusions Hyperglycaemia impairs the motility of phagocytes and also decreases the oxidative and non-oxidative mechanism of killing the causative pathogen. Chronic hyperglycemia also leads to the formation of advanced glycation end-products (AGE), which leads to cross-linking between key proteins of inflammation and connective tissue such as collagen which makes tissue susceptible to immunological dysregulation. The receptor for AGE (RAGE) is expressed on various inflammatory cells including neutrophils and its activation by AGEs leads to activation of many down signaling pathways which ultimately leads to impairment of the inflammatory response. Hyperglycemia also increases serum Nitric Oxide (NO), which decreases neutrophil motility and reduces the synthesis and release of various inflammatory mediators such as TNF-α and IL-1β, IL-6. It also decreases the expression of adhesion molecules such as LFA-1 and ICAM-2, on neutrophils. Steroids cause immunosuppression majorly by inhibiting the NF-κB pathway which is a transcription factor involved in the synthesis of many immunological mediators such as Interleukins, cytokines, chemokines, etc., and various adhesion molecules.

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 &amp; 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 Advanced glycation end-products accelerate telomere attrition and increase pro-inflammatory mediators in human WIL2-NS cells

Mutagenesis ◽  
2020 ◽  
Vol 35 (3) ◽  
pp. 291-297
Author(s):  
Permal Deo ◽  
Varinderpal S Dhillon ◽  
Wai Mun Lim ◽  
Emma L Jaunay ◽  
Leigh Donnellan ◽  
...  
Keyword(s):  
Advanced Glycation End Products ◽  
No Production ◽  
Dependent Manner ◽  
Advanced Glycation ◽  
Telomere Attrition ◽  
Tnf Α ◽  
Glycation End Products ◽  
End Products ◽  
Increasing Trend ◽  
Dietary Sugars

Abstract This study investigated the effect of dietary sugars and advanced glycation end-products (AGE) on telomere dynamics in WIL2-NS cells. Dietary sugars [glucose (Glu) and fructose (Fru); 0.1 M each] were incubated with bovine serum albumin (BSA) (10 mg/ml) at 60 ± 1°C for 6 weeks to generate AGE-BSA. Liquid chromatography-mass spectrometry (LC-MS/MS) analysis showed total AGE levels as 87.74 ± 4.46 nmol/mg and 84.94 ± 4.28 nmol/mg respectively in Glu-BSA and Fru-BSA model. Cell treatment studies using WIL2-NS cells were based on either glucose, fructose (each 2.5–40 mM) or AGE-BSA (200–600 µg/ml) in a dose-dependent manner for 9 days. Telomere length (TL) was measured using qPCR. Nitric oxide (NO) production and tumour necrosis factor-α (TNF-α) levels were measured in WIL2-NS culture medium. An increasing trend for TNF-α and NO production was observed with higher concentration of glucose (R2 = 0.358; P = 0.019; R2 = 0.307; P = 0.027) and fructose (R2 = 0.669; P = 0.001; R2 = 0.339; P = 0.006). A decreasing trend for TL (R2 = 0.828; P = 0.000), and an increasing trend for NO production (R2 = 0.352; P = 0.031) were observed with increasing Glu-BSA concentrations. Fru-BSA treatment did not show significant trend on TL (R2 = 0.135; P = 0.352) with increasing concentration, however, a significant reduction was observed at 600 µg/ml (P &lt; 0.01) when compared to BSA treatment. No trends for TNF-α levels and a decreasing trend on NO production (R2 = 0.5201; P = 0.019) was observed with increasing Fru-BSA treatment. In conclusion, this study demonstrates a potential relationship between dietary sugars, AGEs and telomere attrition. AGEs may also exert telomere shortening through the production of pro-inflammatory metabolites, which ultimately increase the risk of diabetes complications and age-related disease throughout lifespan.

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