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The Fight Against Cancer
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
In normal cells, vascular growth factors are usually released when tissues have been damaged. Angiogenesis helps repair the injuries and is regulated by angiogenesis inhibitors, such as angiostatin and thrombospondin. Matrix metalloproteinases are enzymes that break down the membrane around the blood vessels to allow endothelial cells to migrate towards the tumour and enable the release of angiogenesis factors. Tumours are able to receive the blood supply they require due to a disruption to this balance. Furthermore, this increases the risk of cancer cells escaping from the primary source and metastasizing because of the increased availability of blood and newly developing endothelial cells can release proteins such as interleukin-6 that stimulates metastasis. The angiogenesis promoted by cancer cells result in the production of abnormal blood vessels, which are dilated, permeable, and have a disorganised structure. Also, integrin molecules are displayed on the cell surface membrane, which are usually absent from mature cells, so prevent apoptosis.
Pathogenesis
Published in Aparna Palit, Arun C. Inamadar, Systemic Sclerosis, 2019
The upregulation of angiostatic factors like angiostatin and endostatin is greater than that of angiogenic factors.9 Epidermal growth factor-like domain 7 (EGFL7) regulates angiogenesis by promoting endothelial cell proliferation, migration, sprouting, and invasion. It plays an important role in the normal process of microvascular repair following vascular or ischemic injury. Significantly higher serum levels of EGFL7 have been reported in patients with SSc, correlating with the severity of nailfold capillary abnormalities and digital ulcers. The downregulation of EGFL7 expression on endothelial cells and mesodermal derived endothelial progenitor cells (EPC) has been demonstrated in SSc. Hence, loss of endothelial EGFL7 expression in patients with SSc plays an important role in peripheral microvascular disease and defective angiogenesis.12
Micronutrients in Improvement of the Standard Therapy in Cancer
Published in Kedar N. Prasad, Micronutrients in Health and Disease, 2019
NAC at therapeutic doses reduced the growth of several rodent and human cancer cells in culture by inducing apoptosis.94,95 Apoptosis was preceded by increased production of reactive oxygen species (ROS), activation of tumor suppressor gene, increased expression of Bax, release of cytochrome C from mitochondria, caspase activation, induction of pro-apoptotic signaling (i.e., JNK), and inhibition of anti-apoptotic signaling (i.e. PKB/Akt) pathways.95 Therapeutic doses of NAC treatment inhibited tumor growth by increasing the expressions of TNF-alpha in T-cell lymphocytes and TNF-RI and TNF-RII on tumor cells and on T-cell lymphocytes.96 NAC treatment also reduced incidence and multiplicity of lymphoma in Atm (AT-mutated) deficient mice, and increased their lifespan.97 It has been reported that NAC treatment for 8 weeks induced anti-angiogenesis by increasing the production of angiostatin that resulted in endothelial apoptosis and vascular collapse in the tumor.98 Others have also reported that NAC treatment inhibited angiogenesis and reduced growth of tumor cells in vitro and in animal models.99
Targeted urine proteomics in lupus nephritis – a meta-analysis
Published in Expert Review of Proteomics, 2020
Ting Zhang, Valeria Duran, Kamala Vanarsa, Chandra Mohan
Among the 23 common proteins identified using both targeted proteomic platforms, the second largest category of biomarkers is associated with angiogenic process. Serum angiogenic activity is increased in SLE patients compared with healthy controls, associated with renal complications [60]. Angiostatin, a bioactive fragment of plasminogen, is a potent angiogenesis inhibitor, which specifically inhibits proliferation and induces apoptosis of vascular endothelial cells. It is also anti-inflammatory by inhibiting activation and migration of neutrophils. Urinary angiostatin was significantly elevated in active LN, particularly in class IV LN, and correlated with renal SLEDAI and the histologic chronicity index [6,61]. Angiopoietin-like protein 4 (Angptl4), or angiopoietin-related protein 4, is a multifunctional cytokine regulating vascular permeability, angiogenesis, and inflammation [62]. It has been considered as a novel antiangiogenic modulatory factor, which markedly inhibited proliferation, chemotaxis, and tubule formation of endothelial cells. Addition of Angptl4 significantly inhibited both vascular endothelial growth factor-induced in vivo angiogenesis and vascular leakiness [63]. Urinary Angptl4 easily differentiated active LN from active non-renal or inactive SLE patients, and was strongly correlated with renal SLEDAI [26]. Angiogenin is also implicated in angiogenesis [64]. However, serum angiogenin was not significant different in SLE patients from that of healthy subjects, and its role in LN remains unknown [65].
Innovative therapies for neovascular age-related macular degeneration
Published in Expert Opinion on Pharmacotherapy, 2019
Hasenin Al-Khersan, Rehan M. Hussain, Thomas A. Ciulla, Pravin U. Dugel
Retinostat (Oxford Biomedica) is a lentivector platform based on the recombinant equine infectious anemia virus (EIAV). It is delivered by subretinal injection and encodes the anti-angiogenic proteins endostatin and angiostatin [77]. A bicistronic expression cassette leads to production of both molecules from one lentivirus vector. This approach derives from preclinical work demonstrating that direct intravitreal injections of either AAV-endostatin, AAV-angiostatin, or lentiviral vector-angiostatin significantly inhibited a neonatal murine model of proliferative retinopathy [78,79]. The phase 1 ‘Gene transfer of Endostatin/angiostatin for Macular degeneration’ (GEM) trial (NCT01301443) enrolled 21 patients with advanced nAMD (poorly responsive to anti-VEGF-A therapy) to receive three dosing cohorts over a 48-week period. Overall, there were no adverse effects related to the lentivector platform. There were sustained high levels of angiostatin and endostatin expressed in the eye throughout the study, as determined by direct sampling from the anterior chamber. A reduction in leakage on FA occurred in 71% of patients, but only one patient showed a significant reduction in intraretinal/subretinal fluid compared to baseline [80]. These results may have been limited by advanced nAMD disease.
Granzyme B as a therapeutic target for wound healing
Published in Expert Opinion on Therapeutic Targets, 2019
Christopher T. Turner, Sho Hiroyasu, David J. Granville
Granzyme B cleaves plasmin [60], von Willebrand factor [59], plasminogen [60] and fibrinogen [59], leading to an expected reduction in angiogenesis. Granzyme B-mediated cleavage of plasmin generates angiostatin, an endogenous angiogenesis inhibitor, and [60] during tissue repair, the overall serum concentration of plasmin is reduced (as reported in systemic sclerosis) [60]. While VEGF is known to be pro-angiogenic [64], granzyme B was found to disrupt endothelial adhesion, migration and capillary tube formation [65], whilst also promoting endothelial permeability in a VEGF-dependent manner [55]. Moreover, in a model of cardiac fibrosis, endothelial permeability was reduced in granzyme B knockout mice [54]. Cleavage of von Willebrand factor, occurring in the specific domains required for platelet interaction, is expected to interfere with clotting by preventing cell tethering, adhesion, spreading and aggregation [59], although in vivo studies are required to confirm. Taken together, the capacity of granzyme B to increase vascular permeability, impair hemostasis and impede normal angiogenesis is expected to augment efficient wound repair.