Role of c-Src and reactive oxygen species in cardiovascular diseases

Hussain, Misbah; Ikram, Wajiha; Ikram, Usama

doi:10.1007/s00438-023-01992-9

Cited by 11 publications

(6 citation statements)

References 182 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is unlikely that taurine blocks the activity of Ang II-activated receptors. On the other hand, as indicated above, it is likely that, at least in part, taurine’s anti-hypertrophic effect in EE is due to its inhibition of Ang II signalization cascades, such as those responsible for activation of the PKA-CREB and intracellular ROS generation pathways [ 17 ]. Thus, the prevention of Ang II-induced hypertrophy in hEECs by taurine could be mainly due to taurine blunting the increase in oxidative stress induced by Ang II [ 17 , 19 ].…”

Section: Discussionmentioning

confidence: 99%

“…This circulating factor has been shown to induce hypertrophy of several cell types; however, nothing is known about the effect of Ang II on EEC hypertrophy, particularly those of human origin. It is reported that Ang II-induced cardiomyocyte hypertrophy is mediated via activation of intracellular signaling, particularly increasing ROS levels or decreasing anti-ROS production [ 17 ]. The increase in intracellular ROS by Ang II was reported to be mediated via the activation of c-Src causing an increase in NOX activity [ 17 ] and, more particularly, the Ca 2+ -dependent NOX5.…”

Section: Introductionmentioning

confidence: 99%

“…It is reported that Ang II-induced cardiomyocyte hypertrophy is mediated via activation of intracellular signaling, particularly increasing ROS levels or decreasing anti-ROS production [ 17 ]. The increase in intracellular ROS by Ang II was reported to be mediated via the activation of c-Src causing an increase in NOX activity [ 17 ] and, more particularly, the Ca 2+ -dependent NOX5. In addition, taurine, a nonessential amino acid, is a well-known endogenous antioxidant and was recently reported to prevent the development of hypertrophy associated with heart failure and early death [ 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Taurine Prevents Angiotensin II-Induced Human Endocardial Endothelium Morphological Remodeling and the Increase in Cytosolic and Nuclear Calcium and ROS

Jacques,

Bkaily

2024

Nutrients

View full text Add to dashboard Cite

Endocardial endothelium (EE) is a layer of cells covering the cardiac cavities and modulates cardiomyocyte function. This cell type releases several cardioactive factors, including Angiotensin II (Ang II). This octopeptide is known to induce cardiac hypertrophy. However, whether this circulating factor also induces EE hypertrophy is not known. Taurine is known to prevent cardiac hypertrophy. Whether this endogenous antioxidant prevents the effect of Ang II on human EE (hEE) will be verified. Using quantitative fluorescent probe imaging for calcium and reactive oxygen species (ROS), our results show that Ang II induces (10−7 M, 48 h treatment) an increase in hEE cell (hEEC) volume and its nucleus. Pretreatment with 20 mM of taurine prevents morphological remodeling and increases intracellular calcium and ROS. These results suggest that the reported Ang II induces cardiac hypertrophy is associated with hEEC hypertrophy. This later effect is prevented by taurine by reducing intracellular calcium and ROS overloads. Thus, taurine could be an excellent tool for preventing Ang II-induced remodeling of hEECs.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Taurine Prevents Angiotensin II-Induced Human Endocardial Endothelium Morphological Remodeling and the Increase in Cytosolic and Nuclear Calcium and ROS

Jacques,

Bkaily

2024

Nutrients

View full text Add to dashboard Cite

show abstract

“…The interaction of the SRC gene and NADPH oxidases serves as a cell type and primary messenger that activates intracellular signaling pathways. The elevated level of ROS species in the environment disturbs vascular homeostasis and causes hypertension, atherosclerosis, and coronary artery disease (64). The MDM2 gene belongs to E3 ubiquitin ligases.…”

Section: Identification Of Shared Gene Signature Between the Scaffold...mentioning

confidence: 99%

Exploring putative drug properties associated with TNF-alpha inhibition and identification of potential targets in cardiovascular disease using Machine Learning-Assisted QSAR Modeling and Virtual Reverse Pharmacology approach

Shah,

Arumugam

2024

Preprint

View full text Add to dashboard Cite

Introduction Cardiovascular disease is a chronic inflammatory disease with several categories of risk factors that impart a high mortality rate. Despite TNF-alpha being a prominent pro-inflammatory cytokine associated with chronic inflammation within cardiovascular disease, the adverse effects of current TNF-alpha based medications prompt an urgent need to identify efficient inhibitors as alternatives. This study not only explores the quantitative structural activity relationship (QSAR) of TNF-alpha inhibitors but also identifies potential drug targets to treat cardiovascular disease. Materials and Methods A GitHub Repository-based pipeline was used to curate data from the ChEMBL database. This was followed by pre-processing to exclude remove TNF-alpha inhibitors with missing bioactivity values and identify significant properties of molecules using exploratory data analysis (EDA). The extracted molecules were subjected to PubChem (PC) and SubStructure (SS) fingerprint descriptors, and a QSAR-based Random Forest model (QSAR-RF) was generated using the WEKA tool. QSAR-RF was validated using FDA drugs and molecules from PubChem and ZINC databases and used to predict the pIC50 value of the molecules selected from the docking study followed by molecular dynamic simulation with a time step of 100ns. Through virtual reverse pharmacology, we determined the main drug targets for the top four hit compounds obtained via molecular docking study. Our analysis included an integrated bioinformatics approach to pinpoint potential drug targets, as well as a PPI network to investigate critical targets. To further elucidate the findings, we utilized g:Profiler for GO and KEGG pathway analysis, ultimately identifying the most relevant cardiovascular disease-related pathway for the hub genes involved. Results A unique pipeline was used to create QSAR-RF a machine-learning model that identifies TNF-alpha inhibitors based on molecular features. It distinctly used PC and SS fingerprints, which show strong correlation coefficients of 0.993 and 0.992 respectively, with 0.607 and 0.716 as the respective 10-fold cross-validation scores. The VIP method extracts important features for each model. The QSAR-RF model was built using SS-fingerprints, and validated by docking study and small molecule bioactivity prediction. Irinotecan showed strong binding to TNF-alpha, with three important inhibitory features identified using a comprehensive variance importance plot (VIP). MD simulation confirmed the structural stability of the Irinotecan-TNF-alpha complex. For, the reverse network pharmacology approach, we identified four scaffolds namely, Tirilazad, Irinotecan, Diosgenin, and Gitogenin with higher binding scores. As a result, a total of 289 potential drug targets were identified for cardiovascular diseases (CVD). PPI network analysis identified EGRF, HSP900A1, STAT3, SRC, AKT1, MDM2, and other possible CVD targets. The treatment of CVD using four different scaffold drug targets was found to involve in oxidative stress, smooth muscle proliferation, organonitrogen compound, and multiple pathways such as PI3K-AKT signaling, lipid and atherosclerosis, among others. Conclusion In conclusion, Our study applies a ligand-based drug design approach to generate a SubStructure-based QSAR-RF prediction model to unravel the structural inhibitory feature of TNF-alpha inhibitors. And also identified multiple targets to treat CVD through a reverse network pharmacology approach.

show abstract

“…It plays key roles in cell proliferation, differentiation, division, migration, and survival [1,2] . Activation of c‐Src is associated with increased risk of acute and chronic kidney diseases, [3,4] cardiovascular diseases (e. g., cardiac hypertrophy, atherosclerosis, and hypertension), [5] neurological diseases (e. g., Parkinson disease, Alzheimer's disease), [6] and cancers [2] . Notably, recent studies show that inhibition of c‐Src alone or c‐Src together with other cancer targets (e. g., epidermal growth factor receptor [EGFR]), is a promising therapeutic approach for various cancers [7,8] …”

Section: Introductionmentioning

confidence: 99%

Activated tyrosine kinase c‐Src‐responsive artificial gene carrier: in vitro and in vivo evaluation

Terada,

Asai,

Kang

et al. 2024

ChemistrySelect

View full text Add to dashboard Cite

The proto‐oncogene c‐Src is a protein‐tyrosine kinase that is associated with increased risk of acute and chronic kidney diseases, cardiovascular diseases, neurological diseases, and cancers. The purpose of this study was to develop a gene delivery carrier responding to activated c‐Src and to evaluate its efficacy in vitro and in vivo. The polymeric gene carrier consists of a neutral main chain bearing a peptide substrate of c‐Src or negative control peptide. Complexes of the polymer containing c‐Src‐targeting peptides and DNA were phosphorylated in the presence of c‐Src, resulting in release of the DNA. Green fluorescent protein (GFP) expression was observed after microinjection of complexes of polymer containing c‐Src‐targeting peptides and GFP‐encoding DNA into A431 cells at the nitrogen/phosphate (N/P) ratio of 1.0. GFP was not expressed in cells microinjected with negative control polymer/DNA complex. Direct injection of complexes of polymer containing c‐Src‐targeting peptides and luciferase‐encoding DNA at N/P ratios of 1.0 and 2.0 into tumor‐bearing mice resulted in luciferase expression in A431 tumors but not in normal skin tissues. No luciferase expression was observed in A431 tumors or skin tissues after injection of control polymer/DNA complex. These results indicate that our gene delivery carrier enables activated c‐Src‐specific gene expression.

show abstract

Role of c-Src and reactive oxygen species in cardiovascular diseases

Cited by 11 publications

References 182 publications

Taurine Prevents Angiotensin II-Induced Human Endocardial Endothelium Morphological Remodeling and the Increase in Cytosolic and Nuclear Calcium and ROS

Taurine Prevents Angiotensin II-Induced Human Endocardial Endothelium Morphological Remodeling and the Increase in Cytosolic and Nuclear Calcium and ROS

Exploring putative drug properties associated with TNF-alpha inhibition and identification of potential targets in cardiovascular disease using Machine Learning-Assisted QSAR Modeling and Virtual Reverse Pharmacology approach

Activated tyrosine kinase c‐Src‐responsive artificial gene carrier: in vitro and in vivo evaluation

Contact Info

Product

Resources

About