scholarly journals Cytochrome P450 eicosanoids and cerebral vascular function

2011 ◽  
Vol 13 ◽  
Author(s):  
John D. Imig ◽  
Alexis N. Simpkins ◽  
Marija Renic ◽  
David R. Harder
Keyword(s):  
Blood Flow ◽  
Cytochrome P450 ◽  
Vascular Function ◽  
Therapeutic Targets ◽  
Vascular Diseases ◽  
Cell Types ◽  
Cellular Mechanisms ◽  
Molecular Therapeutic ◽  
Molecular Therapeutic Targets ◽  
Cerebral Vascular

The eicosanoids 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs), which are generated from the metabolism of arachidonic acid by cytochrome P450 (CYP) enzymes, possess a wide array of biological actions, including the regulation of blood flow to organs. 20-HETE and EETs are generated in various cell types in the brain and cerebral blood vessels, and contribute significantly to cerebral blood flow autoregulation and the coupling of regional brain blood flow to neuronal activity (neurovascular coupling). Investigations are beginning to unravel the molecular and cellular mechanisms by which these CYP eicosanoids regulate cerebral vascular function and the changes that occur in pathological states. Intriguingly, 20-HETE and the soluble epoxide hydrolase (sEH) enzyme that regulates EET levels have been explored as molecular therapeutic targets for cerebral vascular diseases. Inhibition of 20-HETE, or increasing EET levels by inhibiting the sEH enzyme, decreases cerebral damage following stroke. The improved outcome following cerebral ischaemia is a consequence of improving cerebral vascular structure or function and protecting neurons from cell death. Thus, the CYP eicosanoids are key regulators of cerebral vascular function and novel therapeutic targets for cardiovascular diseases and neurological disorders.

scholarly journals Key relationships between non-invasive functional neuroimaging and the underlying neuronal activity

2020 ◽  
Vol 376 (1815) ◽  
pp. 20190622
Author(s):  
Anusha Mishra ◽  
Catherine N. Hall ◽  
Clare Howarth ◽  
Ralph D. Freeman
Keyword(s):  
Blood Flow ◽  
Neuronal Activity ◽  
Vascular Function ◽  
Functional Neuroimaging ◽  
Cell Types ◽  
Human Cognition ◽  
Measured Signal ◽  
Bold Signal ◽  
Theme Issue ◽  
Non Invasive

Functional neuroimaging using MRI relies on measurements of blood oxygen level-dependent (BOLD) signals from which inferences are made about the underlying neuronal activity. This is possible because neuronal activity elicits increases in blood flow via neurovascular coupling, which gives rise to the BOLD signal. Hence, an accurate interpretation of what BOLD signals mean in terms of neural activity depends on a full understanding of the mechanisms that underlie the measured signal, including neurovascular and neurometabolic coupling, the contribution of different cell types to local signalling, and regional differences in these mechanisms. Furthermore, the contributions of systemic functions to cerebral blood flow may vary with ageing, disease and arousal states, with regard to both neuronal and vascular function. In addition, recent developments in non-invasive imaging technology, such as high-field fMRI, and comparative inter-species analysis, allow connections between non-invasive data and mechanistic knowledge gained from invasive cellular-level studies. Considered together, these factors have immense potential to improve BOLD signal interpretation and bring us closer to the ultimate purpose of decoding the mechanisms of human cognition. This theme issue covers a range of recent advances in these topics, providing a multidisciplinary scientific and technical framework for future work in the neurovascular and cognitive sciences. This article is part of the theme issue ‘Key relationships between non-invasive functional neuroimaging and the underlying neuronal activity'.

Abstract 14820: Sirt7 Deficiency in Blood Vessel Components Impairs Vascular Function by Inhibiting Cell Cycle- and Inflammatory-Related Protein Expression

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Yuichi Kimura ◽  
Yasuhiro Izumiya ◽  
Satoshi Araki ◽  
Satoru Yamamura ◽  
Yoshiro Onoue ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cells ◽  
Blood Flow ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Vascular Diseases ◽  
Tube Formation ◽  
Hindlimb Ischemia ◽  
Proliferation Assay

Introduction: Aging is a well-established cardiovascular risk factor and associated with vascular dysfunction. Sirt7, one of the members of mammalian sirtuin family, is thought to be involved in age-related diseases. However, little is known about the relative contribution of Sirt7 in vascular dysfunction. Hypothesis: Sirt7 maintains vascular cell functions and its deficiency plays a critical role in vascular diseases. Methods: Sirt7 loss- and gain-of-function experiments were performed with human aortic smooth muscle cells (HAoSMCs) and human umbilical vein endothelial cells (HUVECs). In vivo, blood flow recovery was evaluated by hindlimb ischemia model in homozygous Sirt7 deficient (Sirt7-/-) and wild-type (WT) mice. Irradiated WT mice were intravenously received bone marrow (BM) cells from WT or Sirt7 -/- mouse to achieve BM transfer. Results: An RNAi-medicated Sirt7 knockdown resulted in a significant inhibition of HAoSMCs proliferation following serum or Platelet-derived growth factor BB (PDGF-BB) stimulation as determined by cell count, BrdU cell proliferation assay and MTS proliferation assay. Knockdown of endogenous Sirt7 also reduced cell migration as revealed by Boyden chamber migration assay. The Cyclin D1 and Cyclin dependent kinase 2 (CDK2) protein levels were significantly decreased in Sirt7 siRNA-treated HAoSMCs in response to serum or PDGF-BB stimulation. In endothelial cells, knockdown of Sirt7 attenuated tube formation, proliferation and migration. These changes were accompanied by reduced ERK activation and VCAM-1 mRNA and protein expression in Sirt7 siRNA-treated HUVECs. Conversely, overexpression of Sirt7 by adenovirus enhanced tube formation and cell proliferation. In vivo, blood flow recovery in response to hindlimb ischemia was significantly attenuated in Sirt7-/- mice compared with WT mice. There was no difference in blood flow recovery between WT mice transplanted with WT or Sirt7-/- BM cells suggesting that Sirt7 deficiency in vascular cells have a predominant effect on attenuated blood flow recovery in response to hindlimb ischemia. Conclusions: Sirt7 in blood vessel components have an important role in maintenance of vascular function. Sirt7 could be a promising therapeutic target for vascular diseases.

scholarly journals Rac Guanosine Triphosphatases Represent Integrating Molecular Therapeutic Targets for BCR-ABL-Induced Myeloproliferative Disease

Cancer Cell ◽  
2007 ◽  
Vol 12 (5) ◽  
pp. 467-478 ◽  
Author(s):  
Emily K. Thomas ◽  
Jose A. Cancelas ◽  
Hee-Don Chae ◽  
Adrienne D. Cox ◽  
Patricia J. Keller ◽  
...  
Keyword(s):  
Therapeutic Targets ◽  
Myeloproliferative Disease ◽  
Molecular Therapeutic ◽  
Molecular Therapeutic Targets

scholarly journals Molecular genetics of medullary thyroid carcinoma: the quest for novel therapeutic targets

2009 ◽  
Vol 43 (4) ◽  
pp. 143-155 ◽  
Author(s):  
Aniello Cerrato ◽  
Valentina De Falco ◽  
Massimo Santoro
Keyword(s):  
Thyroid Carcinoma ◽  
Medullary Thyroid Carcinoma ◽  
Therapeutic Targets ◽  
C Cells ◽  
Rare Tumour ◽  
Medullary Thyroid ◽  
Early Evidence ◽  
Molecular Therapeutic ◽  
Molecular Therapeutic Targets ◽  
Novel Therapeutic

Medullary thyroid carcinoma (MTC) is a rare tumour arising from neural crest-derived parafollicular C-cells. Metastatic MTC patients are incurable because the cancer does not respond to radiotherapy or chemotherapy. The REarranged during Transfection (RET) proto-oncogene plays a key role in the development of MTC. However, one-half of the sporadic MTC do not carry RET mutations. Mice models and early evidence obtained in human samples suggest that other genes, including those encoding components of the RB1 (retinoblastoma) and TP53 tumour-suppressor pathways, may be involved in MTC formation. Here, we review the data on the involvement of genes acting in the RET and RB1/TP53 pathways in MTC. Understanding genetic lesions that occur in MTC is a prerequisite to identifying molecular therapeutic targets in MTC and in improving the efficacy of RET-targeted therapies.

DUAL SPECIFICITY PROTEIN PHOSPHATASES: Therapeutic Targets for Cancer and Alzheimer's Disease

2005 ◽  
Vol 45 (1) ◽  
pp. 725-750 ◽  
Author(s):  
Alexander P. Ducruet ◽  
Andreas Vogt ◽  
Peter Wipf ◽  
John S. Lazo
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Discovery ◽  
Therapeutic Targets ◽  
Dual Specificity ◽  
Complete Sequencing ◽  
Dual Specificity Phosphatases ◽  
Molecular Therapeutic ◽  
Specificity Protein ◽  
Molecular Therapeutic Targets

The complete sequencing of the human genome is generating many novel targets for drug discovery. Understanding the pathophysiological roles of these putative targets and assessing their suitability for therapeutic intervention has become the major hurdle for drug discovery efforts. The dual-specificity phosphatases (DSPases), which dephosphorylate serine, threonine, and tyrosine residues in the same protein substrate, have important roles in multiple signaling pathways and appear to be deregulated in cancer and Alzheimer's disease. We examine the potential of DSPases as new molecular therapeutic targets for the treatment of human disease.

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