Glycation End Products Signaling Pathway Research Articles

The Identification of Potential Drugs for Dengue Hemorrhagic Fever: Network-Based Drug Reprofiling Study

Background Dengue fever can progress to dengue hemorrhagic fever (DHF), a more serious and occasionally fatal form of the disease. Indicators of serious disease arise about the time the fever begins to reduce (typically 3 to 7 days following symptom onset). There are currently no effective antivirals available. Drug repurposing is an emerging drug discovery process for rapidly developing effective DHF therapies. Through network pharmacology modeling, several US Food and Drug Administration (FDA)-approved medications have already been researched for various viral outbreaks. Objective We aimed to identify potentially repurposable drugs for DHF among existing FDA-approved drugs for viral attacks, symptoms of viral fevers, and DHF. Methods Using target identification databases (GeneCards and DrugBank), we identified human–DHF virus interacting genes and drug targets against these genes. We determined hub genes and potential drugs with a network-based analysis. We performed functional enrichment and network analyses to identify pathways, protein-protein interactions, tissues where the gene expression was high, and disease-gene associations. Results Analyzing virus-host interactions and therapeutic targets in the human genome network revealed 45 repurposable medicines. Hub network analysis of host-virus-drug associations suggested that aspirin, captopril, and rilonacept might efficiently treat DHF. Gene enrichment analysis supported these findings. According to a Mayo Clinic report, using aspirin in the treatment of dengue fever may increase the risk of bleeding complications, but several studies from around the world suggest that thrombosis is associated with DHF. The human interactome contains the genes prostaglandin-endoperoxide synthase 2 (PTGS2), angiotensin converting enzyme (ACE), and coagulation factor II, thrombin (F2), which have been documented to have a role in the pathogenesis of disease progression in DHF, and our analysis of most of the drugs targeting these genes showed that the hub gene module (human-virus-drug) was highly enriched in tissues associated with the immune system (P=7.29 × 10–24) and human umbilical vein endothelial cells (P=1.83 × 10–20); this group of tissues acts as an anticoagulant barrier between the vessel walls and blood. Kegg analysis showed an association with genes linked to cancer (P=1.13 × 10–14) and the advanced glycation end products–receptor for advanced glycation end products signaling pathway in diabetic complications (P=3.52 × 10–14), which indicates that DHF patients with diabetes and cancer are at risk of higher pathogenicity. Thus, gene-targeting medications may play a significant part in limiting or worsening the condition of DHF patients. Conclusions Aspirin is not usually prescribed for dengue fever because of bleeding complications, but it has been reported that using aspirin in lower doses is beneficial in the management of diseases with thrombosis. Drug repurposing is an emerging field in which clinical validation and dosage identification are required before the drug is prescribed. Further retrospective and collaborative international trials are essential for understanding the pathogenesis of this condition.

Therapeutic targets and signal transduction mechanisms of medicinal plant formula Gancao Xiexin decoction against ulcerative colitis: A network pharmacological study

<b>Background:</b> Ulcerative colitis (UC) is a chronic disease that often presents with abdominal pain, diarrhea, hematochezia, and significant morbidity. Gancao Xiexin decoction (GXD), a traditional Chinese medicine, has been applied for the clinical treatment of UC, while its action mechanisms are unclear. <b>Methods:</b> The active ingredients and their targets of GXD, and UC-related targets, were derived from public databases. Protein-protein interaction, Gene Ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to analyze the important active compounds, key targets, and signaling pathways. Then, molecular docking and animal experiments were performed to verify the findings. A total of 213 active compounds and 89 common targets of GXD for UC were obtained. <b>Results:</b> The hub gene network showed <i>ALB</i>, <i>AKT1</i>, <i>IL6</i>, <i>TNF</i>, <i>VEGFA</i>, <i>TP53</i>, <i>CXCL8</i>, <i>MAPK1</i>, <i>PTGS2</i>, and <i>IL1β</i> may be potential targets of GXD against UC. GO and KEGG pathway enrichment analyses suggested that the action of GXD against UC was mainly related to response to oxygen levels, lipopolysaccharide, and molecule of bacterial origin, etc., and achieved by advanced glycation endproducts/receptors for advanced glycation endproducts signaling pathway in diabetic complications, hypoxia-inducible factor (HIF)-1 signaling pathway, interleukin-17/HIF-1 signaling pathway, TNF signaling pathway, etc. Molecular docking results showed that the GXD had good potency of action with the hub target. <i>In vivo</i> experiments showed that GXD significantly alleviated the symptoms of UC and down-regulated the expression of inflammatory factors, nuclear factor-κB and signal transducer and activator of transcription 3. <b>Conclusions:</b> The anti-UC action of GXD is mainly attributed to its anti-oxidative stress, anti-inflammatory, and immunomodulatory functions.

Advanced glycation end products modulate electrophysiological remodeling of right ventricular outflow tract cardiomyocytes: A novel target for diabetes-related ventricular arrhythmogenesis.

Diabetes mellitus is associated with cardiovascular disease and cardiac arrhythmia. Accumulation of advanced glycation end products closely correlates with cardiovascular complications through mitochondrial dysfunction or oxidative stress and evoke proliferative, inflammatory, and fibrotic reactions, which might impair cardiac electrophysiological characteristics and increase the incidence of cardiac arrhythmia. This study examined the mechanisms how advanced glycation end products may contribute to arrhythmogenesis of right ventricular outflow tract-a unique arrhythmogenic substrate. A whole-cell patch clamp, conventional electrophysiological study, fluorescence imaging, Western blot, and confocal microscope were used to study the electrical activity, and Ca2+ homeostasis or signaling in isolated right ventricular outflow tract myocytes with and without advanced glycation end products (100 μg/ml). The advanced glycation end products treated right ventricular outflow tract myocytes had a similar action potential duration as the controls, but exhibited a lower L-type Ca2+ current, higher late sodium current and transient outward current. Moreover, the advanced glycation end products treated right ventricular outflow tract myocytes had more intracellular Na+ , reverse mode Na+ -Ca2+ exchanger currents, intracellular and mitochondrial reactive oxygen species, and less intracellular Ca2+ transient and sarcoplasmic reticulum Ca2+ content with upregulated calcium homeostasis proteins and advanced glycation end products related signaling pathway proteins. In conclusions, advanced glycation end products modulate right ventricular outflow tract electrophysiological characteristics with larger late sodium current, intracellular Na+ , reverse mode Na+ -Ca2+ exchanger currents, and disturbed Ca2+ homeostasis through increased oxidative stress mediated by the activation of the advanced glycation end products signaling pathway.

Single-cell transcriptomic, transcriptomic, and metabolomic characterization of human atherosclerosis

Atherosclerosis is the main cause of many cardiovascular and cerebrovascular diseases (CVDs), and gaining a deeper understanding of the intercellular connections and key central genes which mediate formation of atherosclerotic plaques is required. We performed a comprehensive bioinformatics analysis of differential genetic screening, Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway annotation, protein-protein interactions (PPIs), pseudo-timing, intercellular communication, transcription factors on carotid single-cell sequencing data, and aortic bulk transcriptome and metabolomic data. Ten cell types were identified in the data: T cells, monocytes, smooth muscle cells, endothelial cells, B cells, fibroblasts, plasma cells, mast cells, dendritic cells, and natural killer cells. Endothelial, fibroblast, macrophage, and smooth muscle cell subtype differentiation trajectories, interaction networks, and important transcription factors were characterized in detail. Finally, using this information combined with transcriptome and metabolome analyses, we found the key genes and signaling pathways of atherosclerosis, especially the advanced glycation end products and receptor for advanced glycation end products signaling pathway (AGE-RAGE signaling pathway) in diabetic complications, linked the differential metabolites with fibroblasts and atherosclerosis and contributed to it in patients with diabetes. Collectively, this study provides key genes, signaling pathways, cellular communication, and transcription factors among endothelial cells, fibroblasts, macrophages, and smooth muscle cells for the study of atherosclerotic plaques, and provides a basis for the diagnosis and treatment of atherosclerosis-like sclerosis.

Mechanism underlying efficacy of Shugan Sanjie decoction on plasma cell mastitis, based on network pharmacology and experimental verification.

To investigate the mechanism underpinning the effeicay of Shugan Sanjie decoction (, SGSJD) on plasma cell mastitis (PCM) based on network pharmacology, and to verify it through . Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform and Bioinformatics Analysis Tool for Molecular mechanism of Traditional Chinese Medicine were used to screen effective compounds and drug targets; Online Mendelian Inheritance in Man and GeneCards were used to search for PCM targets. The potential targets of SGSJD in treating PCM were obtained after the drug targets and disease targets were crossed. Cytoscape software was used to establish and analyze the network of Chinese medicines-active compounds-targets-disease; STRING database platform was used to analyze Protein Protein Interaction network; Bioconductor software package was used to perform Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment for potential targets. Western blot analysis was used to verify the janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway . (a) 47 potential pharmacological components of SGSJD treatment of PCM were screened including quercetin, luteolin, kaempferol and others; 20 common targets were obtained, including interleukin-6 (IL-6), epidermal growth factor receptor, estrogen receptor 1, nitric oxide synthase 3 and others; a number of signal pathways were available, of which advanced glycation end product/ receptor for advanced glycation end products signaling pathway in diabetic complications, hypoxia-inducible factor 1 signaling pathway and janus tyrosine kinase-signal transducer and transcription activator (JAK-STAT) signaling pathway were the main signal pathways related to PCM. (b) Compared with the Blank group, the expressions of p-JAK2/JAK2, p-STAT3/STAT3 and IL-6 protein in the Model group were significantly increased ( < 0.01); Compared with the Model group, the expression of p-JAK2/JAK2, p-STAT3/STAT3, and IL-6 protein in the treatment group were significantly reduced in a dose-dependent manner ( < 0.05). Compared with the Model group, the dexamethasone significantly reduced the expression of p-JAK2/JAK2, p-STAT3/STAT3, and IL-6 ( < 0.01). The SGSJD may regulate the JAK-STAT signaling pathway to achieve the effect of treating PCM by reducing the expression of p-JAK2/JAK2, p-STAT3/STAT3 and IL-6 in a dose-dependent manner.

Correction to: Activation of the High-Mobility Group Box 1 Protein-Receptor for Advanced Glycation End-Products Signaling Pathway in Rats During Neurogenesis After Intracerebral Hemorrhage.

Correction to: Activation of the High-Mobility Group Box 1 Protein-Receptor for Advanced Glycation End-Products Signaling Pathway in Rats During Neurogenesis After Intracerebral Hemorrhage.

Network pharmacology study on the mechanism of the Chinese medicine Radix Isatidis (Banlangen) for COVID-19.

Radix Isatidis (Banlangen) is a well-known traditional Chinese medicine for the treatment of different diseases and prevention of many body disorders. Besides, it also plays a pivotal role in novel coronavirus pneumonia, coronavirus disease 2019 (COVID-19). However, few researchers know its active ingredients and mechanism of action for COVID-19. To find whether Banlangen has a pharmacological effect on COVID-19. In this research, we systematically analyze Banlangen and COVID-19 through network pharmacology technology. A total of 33 active ingredients in Banlangen, 92 targets of the active ingredients, and 259 appropriate targets of COVID-19 were obtained, with 11 common targets. The analysis of the biological process of gene ontology and the enrichment of Kyoto Encyclopedia of Genes and Genomes signaling pathway suggests that Banlangen participated in the biological processes of protein phosphatase binding, tetrapyrrole binding, the apoptotic process involving cysteine-type endopeptidase activity, etc. The COVID-19 may be treated by regulating advanced glycation end products/a receptor for advanced glycation end products signaling pathway, interleukin-17 signaling pathway, tumor necrosis factor signaling pathway, sphingolipid signaling pathway, and p53 signaling pathway. Banlangen has a potential pharmacological effect on COVID-19, which has the value of further exploration in the following experiment and clinical application.

The unique molecular mechanism of diabetic nephropathy: a bioinformatics analysis of over 250microarray datasets.

Background/AimsDiabetic nephropathy (DN) is one of the main causes of end-stage kidney disease worldwide. Emerging studies have suggested that its pathogenesis is distinct from nondiabetic renal diseases in many aspects. However, it still lacks a comprehensive understanding of the unique molecular mechanism of DN.MethodsA total of 255 Affymetrix U133 microarray datasets (Affymetrix, Santa Calra, CA, USA) of human glomerular and tubulointerstitial tissues were collected. The 22 215 Affymetrix identifiers shared by the Human Genome U133 Plus 2.0 and U133A Array were extracted to facilitate dataset pooling. Next, a linear model was constructed and the empirical Bayes method was used to select the differentially expressed genes (DEGs) of each kidney disease. Based on these DEG sets, the unique DEGs of DN were identified and further analyzed using gene ontology and pathway enrichment analysis. Finally, the protein–protein interaction networks (PINs) were constructed and hub genes were selected to further refine the results.ResultsA total of 129 and 1251 unique DEGs were identified in the diabetic glomerulus (upregulated n = 83 and downregulated n = 203) and the diabetic tubulointerstitium (upregulated n = 399 and downregulated n = 874), respectively. Enrichment analysis revealed that the DEGs in the diabetic glomerulus were significantly associated with the extracellular matrix, cell growth, regulation of blood coagulation, cholesterol homeostasis, intrinsic apoptotic signaling pathway and renal filtration cell differentiation. In the diabetic tubulointerstitium, the significantly enriched biological processes and pathways included metabolism, the advanced glycation end products–receptor for advanced glycation end products signaling pathway in diabetic complications, the epidermal growth factor receptor (EGFR) signaling pathway, the FoxO signaling pathway, autophagy and ferroptosis. By constructing PINs, several nodes, such as AGR2, CSNK2A1, EGFR and HSPD1, were identified as hub genes, which might play key roles in regulating the development of DN.ConclusionsOur study not only reveals the unique molecular mechanism of DN but also provides a valuable resource for biomarker and therapeutic target discovery. Some of our findings are promising and should be explored in future work.

Molecular basis of degenerative spinal disorders from a proteomic perspective (Review)

Intervertebral disc degeneration (IDD) and ligamentum flavum hypertrophy (LFH) are major causes of degenerative spinal disorders. Comparative and proteomic analysis was used to identify differentially expressed proteins (DEPs) in IDD and LFH discs compared with normal discs. Subsequent gene ontology term enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis of the DEPs in human IDD discs or LFH samples were performed to identify the biological processes and signaling pathways involved in IDD and LFH. The PI3K-AKT signaling pathway, advanced glycation endproducts-receptor for advanced glycation endproducts signaling pathway, p53 signaling pathway, and transforming growth factor-b signaling pathway were activated in disc degeneration. This review summarizes the recently identified DEPs, including prolargin, fibronectin 1, cartilage intermediate layer protein, cartilage oligomeric matrix protein, and collagen types I, II and IV, and their pathophysiological roles in degenerative spinal disorders, and may provide a deeper understanding of the pathological processes of human generative spinal disorders. The present review aimed to summarize significantly changed proteins in degenerative spinal disorders and provide a deeper understanding to prevent these diseases.

Effects of vitamin D supplementation on advanced glycation end products signaling pathway in T2DM patients: a randomized, placebo-controlled, double blind clinical trial

BackgroundSeveral researches have recommended vitamin D possible health benefits on diabetic complications development, but a few number of studies have been accomplished on the molecular and cellular mechanisms. Certain cellular pathways modification and also some transcription factors activation may protect cells from hyperglycemia condition induced damages. This study purpose was to determine the vitamin D supplementation effect on some key factors [advanced glycation end products (AGEs) signaling pathway] that were involved in the diabetic complications occurrence and progression for type-2 diabetes participants.Methodology48 type-2 diabetic patients (T2DM) randomly divided into two groups (n = 24 per group), receiving: 100-µg vitamin D or placebo for 3 months. At this study beginning and the end, the receptor expression for advanced glycation end products (RAGE) and glyoxalase I (GLO1) enzyme from peripheral blood mononuclear cells (PBMCs) and AGEs and tumor necrosis factor-α (TNF-α) serum levels were measured by the use of real-time PCR and ELISA methods, respectively.ResultsThis study results demonstrated that vitamin D supplementation could down-regulate RAGE mRNA [fold change = 0.72 in vitamin D vs. 0.95 in placebo) P = 0.001)]. In addition, no significant changes were observed for GLO1 enzyme expression (P = 0.06). This study results also indicated that vitamin D serum level significantly increased in vitamin D group (P < 0.001). Moreover, AGES and TNF-α serum levels significantly reduced in vitamin D group, but they were remained unchanged in the placebo group.ConclusionIn conclusion, vascular complications are more frequent in diabetic patients, and vitamin D treatment may prevent or delay the complications onset in these patients by AGEs serum level and RAGE gene expression reducing.Trial registration NCT03008057. Registered December 2016

Si-TP73-AS1 suppressed proliferation and increased the chemotherapeutic response of GC cells to cisplatin.

Previous studies have revealed that long noncoding RNAs (lncRNAs) function as crucial regulators in various biological processes, including tumorigenesis. Although the expression of lncRNA TP73-antisense RNA1 (AS1) has been identified in hepatocellular carcinoma and glioma, the biological function of TP73-AS1 in gastric cancer (GC) remains unclear. Thus, the present study employed a comprehensive analysis on the function of lncRNA TP73-AS1 in GC. The aim of the present study was to determine the clinical significance and biological function of TP73-AS1 in human GC tissues and cells. Additionally, the expression of TP73-AS1 was increased in GC tissues and cell lines and increased expression level of TP73-AS1 was associated with poor prognosis in patients with GC. Functional assays revealed that silencing of TP73-AS1 may suppress cell proliferation and enhance the chemotherapeutic response of GC cells to cisplatin through targeting the high mobility group 1/receptor for advanced glycation endproducts signaling pathway. Collectively, the results of the present study demonstrated that TP73-AS1 may be a novel lncRNA for the clinical prognosis of GC and a potential therapeutic target for the treatment of GC.

High-mobility group box 1 facilitates migration of neural stem cells via receptor for advanced glycation end products signaling pathway

High-mobility group box 1 (HMGB1) facilitates neural stem cells (NSCs) proliferation and differentiation into neuronal linage. However, the effect of HMGB1 on NSCs migration is still elusive. The present study is to investigate the corelation between HMGB1 and NSCs migration and the potential mechanism. The results indicated that 1 ng/ml HMGB1 promoted NSCs proliferation using CCK8 assays. Moreover, data showed that 1 ng/ml HMGB1 facilitated NSCs migration via filopodia formation using phase-contrast and transwell assays. Furthermore, 1 ng/ml HMGB1 upregulated the expression of RAGE, one of the HMGB1 receptor, using western blotting assays and immunofluorescence staining. In addition, 1 ng/ml HMGB1 increased the percentage of filopodia formation using phalloidin staining. Meanwhile, the enhanced migration effect could be abrogated by 50 nM FPS-ZM1, one of the RAGE antagonist, and RAGE-specific siRNA through immunofluorescence and phalloidin staining. Together, our data demonstrate that HMGB1/RAGE axis facilitates NSCs migration via promoting filopodia formation, which might serve as a candidate for central nervous system (CNS) injury treatment and/or a preconditioning method for NSCs implantation.

Effect of morroniside on glomerular mesangial cells through AGE-RAGE pathway.

Diabetes mellitus is an endocrine and metabolic disease characterized by high blood glucose. Diabetic nephropathy (DN) is one of the most typical diabetic complications. Cornus officinalis is a type of traditional Chinese medicine that replenishes the liver and kidney. Morroniside is one of the main characteristic components of C. officinalis. In this study, an in vitro model for simulating DN damage was established by stimulating rat glomerular mesangial cells by the advanced glycation end products. The protective mechanism and effect of morroniside in regulating receptor for advanced glycation end products signaling pathway in DN was investigated to provide experimental evidence for the prevention and treatment of DN.

Activation of the high-mobility group box 1 protein-receptor for advanced glycation end-products signaling pathway in rats during neurogenesis after intracerebral hemorrhage.

Following intracerebral hemorrhage (ICH), high-mobility group box 1 protein (HMGB1) may promote neurogenesis that supports functional recovery. How HMGB1 regulates or participates in this process is unclear, as are the pattern recognition receptors and signaling pathways involved. ICH was induced by injection of collagenase in Sprague-Dawley rats, which were treated 3 days later with saline, with the HMGB1 inhibitor ethyl pyruvate or with FPS-ZM1, an antagonist of the receptor for advanced glycation end-products. A Sham group was treated with saline solution instead of collagenase and then treated 3 days later with saline again or with ethyl pyruvate or N-benzyl-4-chloro-N-cyclohexylbenzamide (FPS-ZM1). Expression of the following proteins was measured by Western blot, immunohistochemistry, or immunofluorescence: HMGB1, receptor for advanced glycation end-products, toll-like receptor (TLR)-2, TLR4, brain-derived neurotrophic factor, and matrix metalloproteinase-9. The number of cells positive for 5-bromo-2-deoxyuridine or doublecortin was determined by immunohistochemistry and immunofluorescence. Levels of HMGB1, receptor for advanced glycation end-products, TLR4, TLR2, brain-derived neurotrophic factor, and matrix metalloproteinase-9 were significantly higher 14 days after ICH than at baseline, as were the numbers of 5-bromo-2-deoxyuridine- or doublecortin-positive cells. At the same time, HMGB1 moved from the nucleus into the cytoplasm. Administering ethyl pyruvate significantly reduced all these ICH-induced increases, except the increase in TLR4 and TLR2. Administering FPS-ZM1 reduced the ICH-induced increases in the expression of brain-derived neurotrophic factor and matrix metalloproteinase-9 and in the numbers of 5-bromo-2-deoxyuridine- or doublecortin-positive cells. These findings suggest that HMGB1 acts via the receptor for advanced glycation end-products signaling pathway to promote neurogenesis in later phases of ICH.