Abstract 017: Hyperglycemia-induced Posttranscriptional Modification Of Proinflammatory Cytokine Mrna Stability Is Mediated Via Hur/PKC-delta Signaling Pathway

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Suresh K Verma ◽  
Alexander R Mackie ◽  
Erin E Vaughan ◽  
Tatiana V Abramova ◽  
Raj kishore ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Cell Line ◽  
Signaling Pathway ◽  
Mrna Stability ◽  
Cardiac Fibrosis ◽  
Diabetic Patients ◽  
Tgf Beta ◽  
Intramyocardial Injection ◽  
Pkc Delta ◽  
Increased Risk

Patients with diabetes are predisposed to increased risk of cardiovascular diseases. Persistent interaction of infiltrating macrophages and resident fibroblasts play a critical role in cardiac fibrosis. However, the signaling mechanism is not clear. We hypothesized that macrophage ELAV1 (mRNA stabilizing protein) modulates profibrotic mediators and extracellular matrix turnover by binding to 3′UTR and regulating the mRNA stability of TGF-beta and MMP-9 in hyperglycemic conditions. Mice receiving intramyocardial injection of HuR-specific shRNA showed significant reduction in infarct size and fibrosis area. Reduced fibrosis was associated with decrease in TGF-beta and MMP-9 expression in the myocardium. Conditioned media (CM) from high glucose (HG) treated macrophages significantly increased profibrogenic response (increased mRNA expression of Col1a1, Col3a1 and fibronectin) in fibroblast cell line as compared to fibroblasts incubated with CM from low glucose (LG)-treated macrophages. Knockdown of ELAV1 in HG-treated macrophages abrogated the profibrotic effects in fibroblasts. Indirect immunofluroscence of bone marrow-derived macrophages (BMM) demonstrated that HG increases nuclear ELAV1 export to the cytoplasm. Pharmacological inhibition of Protein kinase C-delta (PKCd) blocked HG-induced ELAV1 nuclear to cytoplasmic translocation. In vitro, stable knockdown of ELAV1 in mouse macrophage cell line RAW 264.7 reduced mRNA expression of TGF-beta and MMP-9 following LPS challenge, accompanied by a marked reduction in the mRNA stability of these genes. Our study here establishes an ELAV1/TGF-beta/MMP-9/PKC-delta signaling axis in the macrophages controlling the profibrogenic responses in fibroblasts, the major contributor in the pathogenesis of fibrosis. Therefore, targeting this signaling pathway might be of therapy value for cardiac fibrosis in diabetic patients.

Abstract 321: Macrophage Elavl1 Regulates Fibrogenesis Through Post-transcriptional Mechanism Under Diabetic Conditions

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Prince Jeyabal ◽  
Rajarajan A Thandavarayan ◽  
Darukeshwara Joladarashi ◽  
Sahana Suresh Babu ◽  
Shashirekha Krishnamurthy ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Cell Line ◽  
Mrna Stability ◽  
Cardiac Fibrosis ◽  
Critical Role ◽  
Diabetic Patients ◽  
Tgf Beta ◽  
Intramyocardial Injection ◽  
Lps Challenge ◽  
Increased Risk

Patients with diabetes are predisposed to increased risk of cardiovascular diseases. Persistent interaction of infiltrating macrophages and resident fibroblasts play a critical role in cardiac fibrosis. However, the signaling mechanism is not clear. We hypothesized that macrophage ELAV1 (mRNA stabilizing protein) modulates profibrotic mediators and extracellular matrix turnover by binding to 3′UTR and regulating the mRNA stability of TGF-beta and MMP-9 in hyperglycemic conditions. Mice receiving intramyocardial injection of HuR-specific shRNA showed significant reduction in infarct size and fibrosis area. Reduced fibrosis was associated with decrease in TGF-beta and MMP-9 expression in the myocardium. Conditioned media (CM) from high glucose (HG) treated macrophages significantly increased profibrogenic response (increased mRNA expression of Col1a1, Col3a1 and fibronectin) in fibroblast cell line as compared to fibroblasts incubated with CM from low glucose (LG)-treated macrophages. Knockdown of ELAV1 in HG-treated macrophages abrogated the profibrotic effects in fibroblasts. Indirect immunofluroscence of bone marrow-derived macrophages (BMM) demonstrated that HG increases nuclear ELAV1 export to the cytoplasm. Pharmacological inhibition of Protein kinase C-delta (PKCd) blocked HG-induced ELAV1 nuclear to cytoplasmic translocation. In vitro, stable knockdown of ELAV1 in mouse macrophage cell line RAW 264.7 reduced mRNA expression of TGF-beta and MMP-9 following LPS challenge, accompanied by a marked reduction in the mRNA stability of these genes. Our study here establishes an ELAV1/TGF-beta/MMP-9/PKC-delta signaling axis in the macrophages controlling the profibrogenic responses in fibroblasts, the major contributor in the pathogenesis of fibrosis. Therefore, targeting this signaling pathway might be of therapy value for cardiac fibrosis in diabetic patients.

scholarly journals Advanced Glycation End Products (AGEs), Receptor for AGEs, Diabetes, and Bone: Review of the Literature

2019 ◽  
Vol 3 (10) ◽  
pp. 1799-1818 ◽  
Author(s):  
Kamyar Asadipooya ◽  
Edilfavia Mae Uy
Keyword(s):  
Signaling Pathway ◽  
Advanced Glycation End Products ◽  
Cell Metabolism ◽  
Bone Cell ◽  
Diabetic Patients ◽  
Advanced Glycation ◽  
Soluble Rage ◽  
Increased Risk ◽  
Glycation End Products ◽  
End Products

AbstractDiabetes compromises bone cell metabolism and function, resulting in increased risk of fragility fracture. Advanced glycation end products (AGEs) interact with the receptor for AGEs (RAGE) and can make a meaningful contribution to bone cell metabolism and/or alter function. Searches in PubMed using the key words “advanced glycation end-product,” “RAGE,” “sRAGE,” “bone,” and “diabetes” were made to explain some of the clinical outcomes of diabetes in bone metabolism through the AGE–RAGE signaling pathway. All published clinical studies were included in tables. The AGE–RAGE signaling pathway participates in diabetic complications, including diabetic osteopathy. Some clinical results in diabetic patients, such as reduced bone density, suppressed bone turnover markers, and bone quality impairment, could be potentially due to AGE–RAGE signaling consequences. However, the AGE–RAGE signaling pathway has some helpful roles in the bone, including an increase in osteogenic function. Soluble RAGE (sRAGE), as a ligand decoy, may increase in either conditions of RAGE production or destruction, and then it cannot always reflect the AGE–RAGE signaling. Recombinant sRAGE can block the AGE–RAGE signaling pathway but is associated with some limitations, such as accessibility to AGEs, an increase in other RAGE ligands, and a long half-life (24 hours), which is associated with losing the beneficial effect of AGE/RAGE. As a result, sRAGE is not a helpful marker to assess activity of the RAGE signaling pathway. The recombinant sRAGE cannot be translated into clinical practice due to its limitations.

scholarly journals GDF11 alleviates pathological myocardial remodeling in diabetic cardiomyopathy through SIRT1-dependent regulation of oxidative stress and apoptosis

2021 ◽  
Author(s):  
Hanzhao Zhu ◽  
Liyun Zhang ◽  
Mengen Zhai ◽  
Lin Xia ◽  
Yu Cao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Signaling Pathway ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Dysfunction ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Sirtuin 1 ◽  
H9c2 Cell ◽  
Diabetic Patients ◽  
Intramyocardial Injection

Abstract Background Diabetic cardiomyopathy (DCM) is characterized by cardiac dysfunction and cardiomyocyte injury, which induced by metabolic disorder. Nowadays, there is still a lack of drugs for the treatment of DCM. Growth differentiation factor 11 (GDF11) is a novel member of the transforming growth factor β superfamily that alleviates cardiac hypertrophy, myocardial infarction, and vascular injury by regulating oxidative stress, inflammation, and cell survival. However, the roles and underlying mechanisms of GDF11 in DCM remain largely unknown. Methods In this study, we sought to determine whether GDF11 could prevent DCM. The mouse model of diabetes was established by administering a high-fat diet and intraperitoneal injecting streptozotocin. After that, intramyocardial injection of an adeno-associated virus carrying GDF11 gene was used to achieve myocardium-specific overexpression. Results Our data showed that GDF11 overexpression remarkably improved cardiac dysfunction and interstitial fibrosis by reducing the levels of reactive oxygen species and protecting against cardiomyocyte loss. Mechanistically, decreased sirtuin 1 (SIRT1) expression was observed in diabetic mice, which was significantly increased after GDF11 overexpression. To further explore how SIRT1 mediates the role of GDF11, the selective inhibitor EX527 was used to block SIRT1 signaling pathway, which abolished the protective effects of GDF11 against DCM. In vitro studies confirmed that GDF11 protected against H9c2 cell injury in high glucose and palmitate by attenuating oxidative injury and apoptosis, and these effects were also eliminated by SIRT1 depletion. Conclusion Our results demonstrated for the first time that GDF11 protected against DCM by regulating SIRT1 signaling pathway, and GDF11 had the potential to become a novel target for reversing cardiac dysfunction in diabetic patients.

The Capacity of a Specific Anti-Streptococcus Mutans Monoclonal Antibodies Test to Identify the Diabetic Patients with Increased Risk of Periodontal Disease

2017 ◽  
Vol 68 (11) ◽  
pp. 2556-2559
Author(s):  
Mona Ionas ◽  
Sebastian Ioan Cernusca Mitariu ◽  
Adela Dancila ◽  
Tiberiu Horatiu Ionas ◽  
Raluca Monica Comaneanu ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Periodontal Disease ◽  
Streptococcus Mutans ◽  
Mutans Streptococci ◽  
Diabetic Patients ◽  
A Value ◽  
Salivary Level ◽  
Increased Risk ◽  
The Status

By means of a specific anti-Streptococcus mutans monoclonal antibodies test we want to identify the diabetic patients which have an increased risk to develop the periodontal disease. The highest percentage, of 88.1% of all patients included in this study represents the subjects with a level greater than 500,000 cfu / mL of streptococcus mutans. The Kruskal-Wallis test reveals a value of p = 0.283 resulted from the status of diabetes in patients and the level of streptococcus mutans in saliva. In conclusion, the status of diabetes in patients seems not to influence the salivary level of mutans streptococci determined with the method used in our study.

Circulating Stem/Progenitor Cells as Prognostic Biomarkers in Macro- and Microvascular Disease: A Narrative Review of Prospective Observational Studies

2018 ◽  
Vol 25 (35) ◽  
pp. 4507-4517 ◽  
Author(s):  
Mauro Rigato ◽  
Gian Paolo Fadini
Keyword(s):  
Cardiovascular Disease ◽  
Progenitor Cells ◽  
Cardiovascular Events ◽  
Observational Studies ◽  
English Language ◽  
Microvascular Disease ◽  
Patient Characteristics ◽  
Diabetic Patients ◽  
Increased Risk ◽  
Cell Phenotypes

Background: Circulating progenitor cells (CPCs) and endothelial progenitor cells (EPCs) are immature cells involved in vascular repair and related to many aspects of macro and microvascular disease. <p> Objective: We aimed to review studies reporting the prognostic role of CPCs/EPCs measurement on development of cardiovascular disease and microangiopathy. <p> Methods and Results: We reviewed the English language literature for prospective observational studies reporting the future development of cardiovascular disease or microangiopathy in patients having a baseline determination of CPCs/EPCs. We retrieved 34 studied reporting on cardiovascular outcomes and 2 studies reporting on microvascular outcomes. Overall, a reduced baseline level of CPCs/EPCs was associated with a significant increased risk of cardiovascular events, all-cause death, and onset/progression of microangiopathy. The most predictive phenotypes were CD34+ and CD34+CD133+. The main limitation was related to the high heterogeneity among studies in terms of patient characteristics and cell phenotypes. <p> Conclusion: The present review shows that a reduced level of circulating progenitor cells is a risk factor for the development of future cardiovascular events and death. In addition, low CPCs/EPCs levels predict the onset or worsening of microalbuminuria and retinopathy in diabetic patients.

scholarly journals Identification of a juvenile-hormone signaling inhibitor via high-throughput screening of a chemical library

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Takumi Kayukawa ◽  
Kenjiro Furuta ◽  
Keisuke Nagamine ◽  
Tetsuro Shinoda ◽  
Kiyoaki Yonesu ◽  
...  
Keyword(s):  
Juvenile Hormone ◽  
Cell Line ◽  
Signaling Pathway ◽  
High Throughput ◽  
High Throughput Screening ◽  
Large Scale ◽  
Ex Vivo ◽  
Agricultural Field ◽  
Chemical Library ◽  
Field Development

Abstract Insecticide resistance has recently become a serious problem in the agricultural field. Development of insecticides with new mechanisms of action is essential to overcome this limitation. Juvenile hormone (JH) is an insect-specific hormone that plays key roles in maintaining the larval stage of insects. Hence, JH signaling pathway is considered a suitable target in the development of novel insecticides; however, only a few JH signaling inhibitors (JHSIs) have been reported, and no practical JHSIs have been developed. Here, we established a high-throughput screening (HTS) system for exploration of novel JHSIs using a Bombyx mori cell line (BmN_JF&AR cells) and carried out a large-scale screening in this cell line using a chemical library. The four-step HTS yielded 69 compounds as candidate JHSIs. Topical application of JHSI48 to B. mori larvae caused precocious metamorphosis. In ex vivo culture of the epidermis, JHSI48 suppressed the expression of the Krüppel homolog 1 gene, which is directly activated by JH-liganded receptor. Moreover, JHSI48 caused a parallel rightward shift in the JH response curve, suggesting that JHSI48 possesses a competitive antagonist-like activity. Thus, large-scale HTS using chemical libraries may have applications in development of future insecticides targeting the JH signaling pathway.

scholarly journals Risk of Typical Diabetes-Associated Complications in Different Clusters of Diabetic Patients: Analysis of Nine Risk Factors

2021 ◽  
Vol 11 (5) ◽  
pp. 328
Author(s):  
Michael Leutner ◽  
Nils Haug ◽  
Luise Bellach ◽  
Elma Dervic ◽  
Alexander Kautzky ◽  
...  
Keyword(s):  
Risk Factors ◽  
Liver Disease ◽  
Diabetic Patients ◽  
Complication Risk ◽  
Increased Risk ◽  
Icd 10 ◽  
Healthy Control ◽  
Design And Methods ◽  
The Relationship ◽  
Observation Period

Objectives: Diabetic patients are often diagnosed with several comorbidities. The aim of the present study was to investigate the relationship between different combinations of risk factors and complications in diabetic patients. Research design and methods: We used a longitudinal, population-wide dataset of patients with hospital diagnoses and identified all patients (n = 195,575) receiving a diagnosis of diabetes in the observation period from 2003–2014. We defined nine ICD-10-codes as risk factors and 16 ICD-10 codes as complications. Using a computational algorithm, cohort patients were assigned to clusters based on the risk factors they were diagnosed with. The clusters were defined so that the patients assigned to them developed similar complications. Complication risk was quantified in terms of relative risk (RR) compared with healthy control patients. Results: We identified five clusters associated with an increased risk of complications. A combined diagnosis of arterial hypertension (aHTN) and dyslipidemia was shared by all clusters and expressed a baseline of increased risk. Additional diagnosis of (1) smoking, (2) depression, (3) liver disease, or (4) obesity made up the other four clusters and further increased the risk of complications. Cluster 9 (aHTN, dyslipidemia and depression) represented diabetic patients at high risk of angina pectoris “AP” (RR: 7.35, CI: 6.74–8.01), kidney disease (RR: 3.18, CI: 3.04–3.32), polyneuropathy (RR: 4.80, CI: 4.23–5.45), and stroke (RR: 4.32, CI: 3.95–4.71), whereas cluster 10 (aHTN, dyslipidemia and smoking) identified patients with the highest risk of AP (RR: 10.10, CI: 9.28–10.98), atherosclerosis (RR: 4.07, CI: 3.84–4.31), and loss of extremities (RR: 4.21, CI: 1.5–11.84) compared to the controls. Conclusions: A comorbidity of aHTN and dyslipidemia was shown to be associated with diabetic complications across all risk-clusters. This effect was amplified by a combination with either depression, smoking, obesity, or non-specific liver disease.

scholarly journals The potential regulatory role of hsa_circ_0004104 in the persistency of atrial fibrillation by promoting cardiac fibrosis via TGF-β pathway

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yuanfeng Gao ◽  
Ye Liu ◽  
Yuan Fu ◽  
Qianhui Wang ◽  
Zheng Liu ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Expression Patterns ◽  
In Silico Analysis ◽  
Significant Negative Correlation ◽  
Circular Rnas ◽  
Tgf Beta ◽  
Rt Pcr ◽  
Derivation Cohort ◽  
Tgf Β1

Abstract Introduction The progression of paroxysmal AF (PAF) to persistent AF (PsAF) worsens the prognosis of AF, but its underlying mechanisms remain elusive. Recently, circular RNAs (circRNAs) were reported to be associated with cardiac fibrosis. In case of the vital role of cardiac fibrosis in AF persistency, we hypothesis that circRNAs may be potential regulators in the process of AF progression. Materials and methods 6 persistent and 6 paroxysmal AF patients were enrolled as derivation cohort. Plasma circRNAs expressions were determined by microarray and validated by RT-PCR. Fibrosis level, manifested by serum TGF-β, was determined by ELISA. Pathways and related non-coding RNAs involving in the progression of AF regulated were predicted by in silico analysis. Results PsAF patients showed a distinct circRNAs expression profile with 92 circRNAs significantly dysregulated (fold change ≥ 2, p < 0.05), compared with PAF patients. The validity of the expression patterns was subsequently validated by RT-PCR in another 60 AF patients (30 PsAF and PAF, respectively). In addition, all the 5 up and down regulated circRNAs were clustered in MAPK and TGF-beta signaling pathway by KEGG pathway analysis. Among the 5 circRNAs, hsa_circ_0004104 was consistently downregulated in PsAF group (0.6 ± 0.33 vs 1.46 ± 0.41, p < 0.001) and predicted to target several AF and/or cardiac fibrosis related miRNAs reported by previous studies. In addition, TGF-β1 level was significantly higher in the PsAF group (5560.23 ± 1833.64 vs 2236.66 ± 914.89, p < 0.001), and hsa_circ_0004104 showed a significant negative correlation with TGF-β1 level (r = − 0.797, p < 0.001). Conclusion CircRNAs dysregulation plays vital roles in AF persistency. hsa_circ_0004104 could be a potential regulator and biomarker in AF persistency by promoting cardiac fibrosis via targeting MAPK and TGF-beta pathways.

Sign in / Sign up

Export Citation Format

Share Document