scholarly journals Contribution of “Omic” Studies to the Understanding of Cadasil. A Systematic Review

2021 ◽  
Vol 22 (14) ◽  
pp. 7357
Author(s):  
Elena Muiño ◽  
Israel Fernández-Cadenas ◽  
Adrià Arboix
Keyword(s):  
Growth Factor ◽  
Protein Misfolding ◽  
Drug Targets ◽  
Transforming Growth Factor ◽  
Small Vessel Disease ◽  
Transforming Growth Factor Β ◽  
Small Vessel ◽  
Vessel Disease ◽  
Extracellular Matrix Components ◽  
Recurrent Strokes

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a small vessel disease caused by mutations in NOTCH3 that lead to an odd number of cysteines in the epidermal growth factor (EGF)-like repeat domain, causing protein misfolding and aggregation. The main symptoms are migraines, psychiatric disorders, recurrent strokes, and dementia. Omic technologies allow the massive study of different molecules for understanding diseases in a non-biased manner or even for discovering targets and their possible treatments. We analyzed the progress in understanding CADASIL that has been made possible by omics sciences. For this purpose, we included studies that focused on CADASIL and used omics techniques, searching bibliographic resources, such as PubMed. We excluded studies with other phenotypes, such as migraine or leukodystrophies. A total of 18 articles were reviewed. Due to the high prevalence of NOTCH3 mutations considered pathogenic to date in genomic repositories, one can ask whether all of them produce CADASIL, different degrees of the disease, or whether they are just a risk factor for small vessel disease. Besides, proteomics and transcriptomics studies found that the molecules that are significantly altered in CADASIL are mainly related to cell adhesion, the cytoskeleton or extracellular matrix components, misfolding control, autophagia, angiogenesis, or the transforming growth factor β (TGFβ) signaling pathway. The omics studies performed on CADASIL have been useful for understanding the biological mechanisms and could be key factors for finding potential drug targets.

scholarly journals Small vessel disease and biomarkers of endothelial dysfunction after ischaemic stroke

2018 ◽  
Vol 4 (2) ◽  
pp. 119-126 ◽  
Author(s):  
Francesco Arba ◽  
Alessio Giannini ◽  
Benedetta Piccardi ◽  
Silvia Biagini ◽  
Vanessa Palumbo ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Endothelial Dysfunction ◽  
Adhesion Molecule ◽  
Small Vessel Disease ◽  
Small Vessel ◽  
Intercellular Adhesion Molecule ◽  
Vascular Endothelial ◽  
Vessel Disease ◽  
Endothelial Growth Factor

Introduction Although pathogenesis of small vessel disease is poorly understood, increasing evidence suggests that endothelial dysfunction may have a relevant role in development and progression of small vessel disease. In this cross-sectional study, we investigated the associations between imaging signs of small vessel disease and blood biomarkers of endothelial dysfunction at two different time points in a population of ischaemic stroke patients. Patients and methods In stroke patients treated with intravenous thrombolysis, we analysed blood levels of von Willebrand factor, intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and vascular endothelial growth factor. Three reviewers independently assessed small vessel disease features using computed tomography. At baseline and 90 days after the index stroke, we tested the associations between single and combined small vessel disease features and levels of blood biomarkers using linear regression analysis adjusting for age, sex, hypertension, diabetes, smoke. Results A total of 263 patients were available for the analysis. Mean age (±SD) was 69 (±13) years, 154 (59%) patients were male. We did not find any relation between small vessel disease and endothelial dysfunction at baseline. At 90 days, leukoaraiosis was independently associated with intercellular adhesion molecule-1 (β = 0.21; p = 0.016) and vascular cell adhesion molecule-1 (β = 0.22; p = 0.009), and lacunes were associated with vascular endothelial growth factor levels (β = 0.21; p = 0.009) whereas global small vessel disease burden was associated with vascular endothelial growth factor (β = 0.26; p = 0.006). Discussion Leukoaraiosis and lacunes were associated with endothelial dysfunction, which could play a key role in pathogenesis of small vessel disease. Conclusions Small vessel disease features and total burden were associated with endothelial dysfunction 90 days after the stroke, whereas there was no relation during the acute phase. Our results suggest that endothelial dysfunction, particularly vascular endothelial growth factor, is involved in pathological process of small vessel disease.

scholarly journals GPCR transactivation signalling in vascular smooth muscle cells: role of NADPH oxidases and reactive oxygen species

2019 ◽  
Vol 1 (1) ◽  
pp. R1-R11 ◽  
Author(s):  
Raafat Mohamed ◽  
Reearna Janke ◽  
Wanru Guo ◽  
Yingnan Cao ◽  
Ying Zhou ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Growth Factor ◽  
Drug Targets ◽  
Protein Tyrosine Kinase ◽  
Transforming Growth Factor ◽  
Growth Factor Receptor ◽  
Reactive Oxygen ◽  
Transforming Growth Factor Β ◽  
Oxygen Species

The discovery and extension of G-protein-coupled receptor (GPCR) transactivation-dependent signalling has enormously broadened the GPCR signalling paradigm. GPCRs can transactivate protein tyrosine kinase receptors (PTKRs) and serine/threonine kinase receptors (S/TKRs), notably the epidermal growth factor receptor (EGFR) and transforming growth factor-β type 1 receptor (TGFBR1), respectively. Initial comprehensive mechanistic studies suggest that these two transactivation pathways are distinct. Currently, there is a focus on GPCR inhibitors as drug targets, and they have proven to be efficacious in vascular diseases. With the broadening of GPCR transactivation signalling, it is therefore important from a therapeutic perspective to find a common transactivation pathway of EGFR and TGFBR1 that can be targeted to inhibit complex pathologies activated by the combined action of these receptors. Reactive oxygen species (ROS) are highly reactive molecules and they act as second messengers, thus modulating cellular signal transduction pathways. ROS are involved in different mechanisms of GPCR transactivation of EGFR. However, the role of ROS in GPCR transactivation of TGFBR1 has not yet been studied. In this review, we will discuss the involvement of ROS in GPCR transactivation-dependent signalling.

scholarly journals Chemical pleurodesis – a review of mechanisms involved in pleural space obliteration

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Michal Mierzejewski ◽  
Piotr Korczynski ◽  
Rafal Krenke ◽  
Julius P. Janssen
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Early Response ◽  
Mesothelial Cells ◽  
Pleural Space ◽  
Coagulation Cascade ◽  
Chemical Pleurodesis ◽  
Sclerosing Agents ◽  
Extracellular Matrix Components

Abstract Chemical pleurodesis is a therapeutic procedure applied to create the symphysis between the parietal and visceral pleura by intrapleural administration of various chemical agents (e.g. talk, tetracycline, iodopovidone, etc.). The two major clinical conditions treated with chemical pleurodesis are recurrent pleural effusion (PE) and recurrent spontaneous pneumothorax. Although the history of chemical pleurodesis began over a century ago, detailed data on the mechanisms of action of sclerosing agents are highly incomplete. The following article aims to present the state of knowledge on this subject. It is believed that mesothelial cells are the main structural axis of pleurodesis. In response to sclerosing agents they secrete a variety of mediators including chemokines such as interleukin 8 (IL-8) and monocyte chemoattractant protein (MCP-1), as well as growth factors - vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF) and transforming growth factor- β (TGF-β). Numerous data suggest that intact mesothelial cells and the above cytokines play a crucial role in the initiation and maintenance of different pathways of pleural inflammation and pleural space obliteration. It seems that the process of pleurodesis is largely nonspecific to the sclerosant and involves the same ultimate pathways including activation of pleural cells, coagulation cascade, fibrin chain formation, fibroblast proliferation and production of collagen and extracellular matrix components. Of these processes, the coagulation cascade with decreased fibrinolytic activity and increased fibrinogenesis probably plays a pivotal role, at least during the early response to sclerosant administration. A better understanding of various pathways involved in pleurodesis may be a prerequisite for more effective and safe use of various sclerosants and for the development of new, perhaps more personalized therapeutic approaches.

scholarly journals Serum Hepatocyte Growth Factor Is Associated with Small Vessel Disease in Alzheimer’s Dementia

2018 ◽  
Vol 10 ◽  
Author(s):  
Yanan Zhu ◽  
Saima Hilal ◽  
Yuek L. Chai ◽  
M. K. Ikram ◽  
Narayanaswamy Venketasubramanian ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Small Vessel Disease ◽  
Alzheimer’S Dementia ◽  
Small Vessel ◽  
Alzheimer's Dementia ◽  
Vessel Disease ◽  
Hepatocyte Growth

Molecular embryology of the lung: then, now, and in the future

1999 ◽  
Vol 276 (5) ◽  
pp. L697-L704 ◽  
Author(s):  
David Warburton ◽  
Jingsong Zhao ◽  
Mary Anne Berberich ◽  
Merton Bernfield
Keyword(s):  
Growth Factor ◽  
Transcriptional Activation ◽  
Transforming Growth Factor ◽  
Gene Families ◽  
Transforming Growth Factor Β ◽  
Branching Morphogenesis ◽  
Limb Bud ◽  
Loss Of Function ◽  
New Therapeutic Approaches ◽  
Extracellular Matrix Components

Complementary molecular and genetic approaches are yielding information about gain- versus loss-of-function phenotypes of specific genes and gene families in the embryonic, fetal, neonatal, and adult lungs. New insights are being derived from the conservation of function between genes regulating branching morphogenesis of the respiratory organs in Drosophila and in the mammalian lung. The function of specific morphogenetic genes in the lung are now placed in context with pattern-forming functions in other, better understood morphogenetic fields such as the limb bud. Initiation of lung morphogenesis from the floor of the primitive foregut requires coordinated transcriptional activation and repression involving hepatocyte nuclear factor-3β, Sonic hedgehog, patched, Gli2, and Gli3 as well as Nkx2.1. Subsequent inductive events require epithelial-mesenchymal interaction mediated by specific fibroblast growth factor ligand-receptor signaling as well as modulation by other peptide growth factors including epidermal growth factor, platelet-derived growth factor-A and transforming growth factor-β and by extracellular matrix components. A scientific rationale for developing new therapeutic approaches to urgent questions of human pulmonary health such as bronchopulmonary dysplasia is beginning to emerge from work in this field.

scholarly journals Cerebral small vessel disease genomics and its implications across the lifespan

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Muralidharan Sargurupremraj ◽  
◽  
Hideaki Suzuki ◽  
Xueqiu Jian ◽  
Chloé Sarnowski ◽  
...  
Keyword(s):  
White Matter ◽  
Drug Targets ◽  
Small Vessel Disease ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
Older Individuals ◽  
Brain Images ◽  
Vessel Disease ◽  
Genetic Stratification ◽  
Insight Into

AbstractWhite matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.

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