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The Role of Vascular Development in the Pathogenesis of Necrotizing Enterocolitis
Published in David J. Hackam, Necrotizing Enterocolitis, 2021
Isabelle G. De Plaen, Elizabeth Managlia, Xiaocai Yan
Administration of VEGFR2-specific kinase inhibitors increased the severity of experimental NEC and pup mortality while decreasing endothelial cell proliferation and intestinal microvascular density (11). While these studies suggest a role for VEGF/VEGFR2 signaling in NEC, further studies are needed to better define the mechanism involved.
Regulation of Reproduction by Dopamine
Published in Nira Ben-Jonathan, Dopamine, 2020
Because D2R was expressed in an ectopic human endometrium [73], the effects of DA agonists on animal models of endometriosis were examined [74]. Human uterine fragments were implanted in the peritoneal cavity of immune-deficient female mice and the mice were treated with the D2R agonist cabergoline. D2R activation decreased the number of active endometriotic lesions and suppressed cell proliferation. The effects were attributed to the suppression of angiogenesis via the reduced expression and phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR-2). The authors concluded that these data support the testing of peripheral DA agonists as novel therapeutic approaches for peritoneal endometriosis in humans. A recent review on effective treatments of endometriosis listed D2R agonists among the most promising drugs [75].
Tyrosine Kinase Inhibitors: Targets Other Than FLT3, BCR-ABL, and c-KIT
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Suzanne R. Hayman, Judith E. Karp
The VEGF family members bind with different affinities to three receptor TKs belonging to the “7-Ig” or FLT gene family, FLT-1 [VEGF receptor (VEGFR)-1], KDR/Flk-1 (VEGFR-2), and FLT-4 (VEGFR-3), each of which contains seven extracellular immunoglobulin-like domains, one membrane-spanning segment, and a consensus TK sequence domain interrupted by a kinase-insert domain (54). The receptors are expressed primarily on vascular ECs with many of their actions mediated through PI3-kinase and activation of EC-derived NOS, and by bone marrow-derived cells as well (54). VEGF-A activity primarily is mediated through VEGFR-1 and VEGFR-2. Both VEGFRs are expressed in all adult vascular ECs, with the exception of the brain (58). VEGR-1 is also expressed on HSCs, leukemic blasts, vascular smooth muscle cells, and monocytes. An alternatively spliced soluble form of VEGFR-1 (s-FLT-1) is an inhibitor of VEGF. The functions of VEGFR-1 have not been characterized fully, and they appear to vary depending on cell type and maturational stage (55). VEGFR-2 activates vascular EC differentiation, proliferation, and migration and also induces vascular permeability (55). Most studies have found that VEGFR-1 is more commonly expressed in hematological malignancies than VEGFR-2 (55). VEGFR-1, not VEGFR-2, is associated with inhibition of HSC cycling, differentiation, and hematopoietic recovery in adults (55).
1,3,4-Oxadiazole-naphthalene hybrids as potential VEGFR-2 inhibitors: design, synthesis, antiproliferative activity, apoptotic effect, and in silico studies
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Mohamed Hagras, Marwa A. Saleh, Rogy R. Ezz Eldin, Abdelrahman A. Abuelkhir, Emad Gamil Khidr, Ahmed A. El-Husseiny, Hesham A. El-Mahdy, Eslam B. Elkaeed, Ibrahim H. Eissa
In embryonic vasculogenesis, VEGFR1 plays a critical function. VEGFR2 is a protein that controls embryonic and tumour angiogenesis. VEGFR2 has mostly overexpressed in tumour vasculature endothelial cells, with reduced expression in normal endothelial cells14. Overexpressed VEGFR-2 is found in a variety of malignancies, including hepatocellular carcinoma and breast cancer15–17. Blocking VEGFR2 is a viable method for the identification of novel therapies for angiogenesis-dependent cancers18. VEGFR2 is now the most significant target of antiangiogenic therapy. During development, VEGFR3 is found in all endothelium, but it is only found in the lymphatic endothelium in adults19. It is up-regulated in the microvasculature of tumours and wounds20.
A blockade of microRNA-155 signal pathway has a beneficial effect on neural injury after intracerebral haemorrhage via reduction in neuroinflammation and oxidative stress
Published in Archives of Physiology and Biochemistry, 2022
Wenwen Zhang, Luping Wang, Ruimin Wang, Zongsheng Duan, Hushan Wang
It should be noted that VEGF regulates vascular development, angiogenesis and lymphangiogenesis by binding to a number of VEGFRs (Holmes et al., 2007, Stuttfeld and Ballmer-Hofer, 2009). There are three main subtypes of VEGFR, numbered 1, 2 and 3. The function of VEGFR-1 is less defined, although it is required for the recruitment of haematopoietic stem cells and the migration of monocytes and macrophages (Holmes et al., 2007, Stuttfeld and Ballmer-Hofer, 2009). VEGFR-2 appears to mediate almost all of the known cellular responses to VEGF and it is critical for vascular endothelial cell development and regulates vascular endothelial function (Holmes et al., 2007). VEGFR-3 regulates lymphatic endothelial cell function and mediates lymphangiogenesis in response to VEGF (Holmes et al., 2007, Stuttfeld and Ballmer-Hofer, 2009). Considerable evidence shows that VEGFR-2 is specific intracellular signal cascades leading to proliferation, migration, survival and increased permeability, each of which contributes to the angiogenic response (Holmes et al., 2007). In the previous study, the involvement of VEGF and its subtype receptor VEGFR-2 in the process of neurological deficits after ICH has been described [49]. It is well reasoned that VEGFR-2 is likely to mediate the effects of VEGF in the parietal cortex and hippocampus in improving neurological functions induced by ICH after a blockade of miR-155 signal.
An updated patent review of VEGFR-2 inhibitors (2017-present)
Published in Expert Opinion on Therapeutic Patents, 2021
Thoraya A. Farghaly, Wedian A. Al-Hasani, Hanan Gaber Abdulwahab
Angiogenesis is a vital process for cellular functions in both physiological and pathophysiological conditions and is one of the hallmarks of cancer progression and metastasis. VEGF/VEGFR-2 signaling pathway has been recognized as the most critical factor in promoting angiogenesis. Hence, several VEGFR-2 inhibitors have been clinically tested and/or approved for the treatment of angiogenesis-related diseases. In this review, we summarized the reports in the patent literature in the period from 2017 to the end of 2020 on the small-molecule inhibitors and antibodies of VEGFR-2 and their potential use as therapeutics for several types of cancers, angiogenesis-related disorders, and Parkinson’s and Alzheimer’s diseases. Several series of substantial inhibitors were found to be potent against several types of cancers.