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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Angiogenesis, a process through which new blood vessels are formed from existing vasculature, begins with the dilatation of preexisting capillaries and venules, followed by an increase of vascular permeability. It plays a crucial role in tissue functional repair, regeneration, and growth, and is stimulated by a wide range of endogenous molecules including growth factors (e.g., VEGF, FGF, EGF, and PIGF), adhesion molecules, proteinases, extracellular matrix proteins, transcription factors, and signaling molecules. Many types of human tumors, especially gliomas and carcinomas, express high levels of VEGF, and so various VEGF isoforms and their cognate tyrosine kinase receptors (i.e., VEGFRs) have been considered as attractive targets for novel anticancer therapies working through the inhibition of angiogenesis. VEGFRs consist of an extracellular component composed of an N-terminal signal sequence and seven immunoglobulin-like domains, a single trans-membrane segment, an intracellular portion containing a juxta membrane (JM) segment, a TK domain (divided into proximal and distal kinase domains by an insert domain of about 70 amino acid residues), and a C-terminal tail (Figure 6.28).
The skin
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
Morphoea is thought to result from three interconnected pathological processes: autoimmunity, altered fibroblast function and vascular damage. The importance of autoimmunity in morphoea is highlighted by the increased prevalence of antibodies to single-stranded DNA, topoisomerase IIa and antinuclear antibodies in patients compared to controls. An unidentified trigger stimulates T-lymphocytes to secrete IL-4, IL-13, and transforming growth factor beta (TGF-β). These cytokines stimulate fibroblasts to produce excess collagen and extracellular matrix proteins. Vessel damage is thought to occur early in pathogenesis, leading to endothelial swelling and release of vascular adhesion molecules, facilitating lymphocyte recruitment.
Role of Engineered Proteins as Therapeutic Formulations
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Khushboo Gulati, Krishna Mohan Poluri
Monobodies are the protein scaffolds based on Fibronectin type III domain. Fibronectin is a large protein that interacts with the extracellular matrix proteins and regulates cell-cell communication. Structurally, it is a large protein containing two 250 kD subunits connected by disulfide bridges. These subunits contain the repeats of three domains (type I, II, III). The first monobody was engineered using the tenth repeat of type III domain of Fibronectin (FNfn10) against ubiquitin using phage display system. FNfn10 is devoid of disulfide bonds, and also contains 7 β-strands and 3 surface loops that can be used to add diversity to the monobodies. Their structural simplicity makes them compatible with any screening method such as phage display, yeast two-hybrid system, and peptide-ribonucleic acid. They can be expressed in large quantities in bacteria and are highly thermo stable (Koide and Koide, 2007). Such properties of monobodies make them ideal candidates for therapeutic protein scaffolds. Monobodies have been engineered for the numerous proteins including EGFR (Hackel et al., 2012), IL-23 (Tang et al., 2012), Ableson (Abl) kinase SH2 domain (Wojcik et al., 2010), etc.
Novel nano-carriers with N-formylmethionyl-leucyl-phenylalanine-modified liposomes improve effects of C16-angiopoietin 1 in acute animal model of multiple sclerosis
Published in Drug Delivery, 2023
Xiao-Xiao Fu, Han Qu, Jing Wang, Hua-Ying Cai, Hong Jiang, Hao-Hao Chen, Shu Han
The fundamental events during the onset of acute EAE include extensive edema and cellular inflammation due to an impaired blood–brain barrier (BBB). Importantly, integrin αVβ3 permits endothelial cells to interact with many extracellular matrix proteins, including laminin. The synthesized peptide C16, a γ1 chain peptide of laminin-1, can selectively bind the αVβ3 and αVβ1 integrins in endothelial cells to block the interaction between leukocytes and endothelial cells, which ultimately inhibits the transmigration of inflammatory cells (Gaillard et al., 2012). A previous study has also verified that C16 had no effect on the total number of leukocytes, suggesting that C16 is not an immunosuppressant (Han S et al., 2010). As a member of the endothelial growth factor family, angiopoietin 1 (Ang-1) has important roles in the establishment and maintenance of the maturation, stabilization, and integrity of the vascular system (Fang et al., 2013). Moreover, C16 and Ang-1 can synergistically alleviate vascular leakage and inflammation and prevent the demyelination and axonal loss in the EAE rat model (Jiang et al., 2014). However, the solubility of C16 is largely affected by the pH of the solvent, which decreases its bioavailability and may limit its clinical application (Han et al., 2010).
Improving therapeutic resistance: beginning with targeting the tumor microenvironment
Published in Journal of Chemotherapy, 2022
Xiao-ying Guan, Xiao-li Guan, Zuo-yi Jiao
Exosomes are a type of nano-sized (approximately 30–150 nanometre in diameter) extracellular vesicles (EVs) secreted by cells and are mainly used for intercellular communication and intracellular homeostasis; furthermore, exosomes have attracted increasing attention as mediators between cancer cells and the TME [54]. Exosomes are secreted by different types of cells in the TME and circulate through bodily fluids, including the blood, ascites, saliva, urine, and amniotic fluid [55]. Recent reports of pancreatic cancer and melanoma have shown that exosomes secreted by tumor cells can change the microenvironment of distant metastatic sites, making colonization easier [56, 57]. Exosomes enter the blood circulation and colonize distant locations, where they can change the extracellular matrix of the host microenvironment by degrading the extracellular matrix and promoting the secretion of specific extracellular matrix proteins [56], such as fibronectin [58]. Exosomes released by melanoma increase the growth and metastasis of primary tumors through tyrosine kinase-mediated signalling, and programme bone marrow-derived cells (BMDCs) at the site before metastasis to promote angiogenesis [57].
Two Useful Umbilical Biomarkers for Therapeutic Hypothermia Decision in Patients with Hypoxic İschemic Encephalopathy with Perinatal Asphyxia: Netrin-1 and Neuron Specific Enolase
Published in Fetal and Pediatric Pathology, 2022
Ufuk Cakir, Burak Ceran, Cuneyt Tayman
The Netrin (NT) system has at least five members of proteins (Netrin-1, -2, -4, G1a and G1b), structurally similar to the laminin family of extracellular matrix proteins. NT-1 stimulates the proliferation, migration, and adhesion of endothelial cells. NT-1 is the first axon guidance molecule discovered as a critical component of embryonic development in vertebrates, and has a strong chemotropic function for cell migration, morphogenesis, angiogenesis, and axonal guidance [10,11]. A previous study has shown that NT-1 reduces the secretion of lipopolysaccharide-derived interleukin-1β and interleukin 12β in astrocyte culture. This information indicates that NT-1 is an important molecule in regulating astrocyte activation and inflammation in cerebral ischemia and may be a potential target for ischemic stroke therapy [12]. NT-1 is an important regulator in maintaining the integrity of the blood-brain barrier during experimental autoimmune encephalomyelitis, traumatic brain injury, and ischemic stroke [12]. Studies are lacking in its use as a biomarker.