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Cardiovascular Disease and Oxidative Stress
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Marco Fernandes, Alisha Patel, Holger Husi
Consecutive monocyte differentiation into macrophages and their local accumulation in the adipose tissue is recognized as a key event in insulin resistance (IR) (Patsouris et al., 2014). The local deposition of insulin resistant macrophages up-regulates the scavenger receptor class B member 1 (SCARB1), which promotes foam cell formation and then the establishment of an atherosclerotic lesion (Chistiakov et al., 2017). In case of activation of the peroxisome proliferator-activated receptor gamma (PPARG), the latter described processes can be overturned by transcriptionally regulation of the macrophage insulin signalling activation (Chawla, 2010) (Fig. 7.1). ROS accumulation enduring IR and long-term hyperglycaemia adds-up to both cardiac and structural defects such as endothelial dysfunction and tissue remodelling.
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Published in Chad A. Mirkin, Spherical Nucleic Acids, 2020
Chung Hang J. Choi, Liangliang Hao, Suguna P. Narayan, Evelyn Auyeung, Chad A. Mirkin
We previously reported a role for scavenger receptors (SRs) in mediating the endocytosis of SNAs using fucoidan (FCD) and polyinosinic acid (Poly I) as pharmacological inhibitors [16]. Here, we verified that the pretreatment of C166 cells with FCD and Poly I resulted in 80–90% reduction in the uptake of SNAs. As FCD and Poly I can bind to more than one member of the SR family [17, 18], they do not allow for the determination of the specific SR member(s) responsible for the endocytosis of SNAs. Based on this result, we can only speculate that class B SRs are not responsible, because FCD and Poly I are not ligands for this receptor subclass [18]. To test this claim, we prepared stable C166 cells that have a deficient expression level of class B scavenger receptor type I, a representative member of the receptor subclass (denoted “SCARB1-DF”) by lentiviral trans-fection of shRNAs targeting the SCARB1 gene. Compared with nontargeting pGIPZ-control cells, SCARB1-DF cells revealed only 25% reduction in uptake of SNAs (Fig. 19.4C). To explore the involvement of other SRs, we devised a modified ELISA to measure the binding affinity of SNAs to SRs. Class A SR (SR-A) demonstrates high affinity toward SNAs, netting an apparent binding dissociation constant of ~5 nM (Fig. 19.4D). By contrast, SR-BI does not exhibit appreciable binding to SNAs, in agreement with the uptake data from the use of pharmacological inhibitors (i.e., FCD and Poly I) and SCARB1-DF cells. These data led us to hypothesize the importance of SR-A in mediating the endocytosis of SNAs. We prepared C166 cells deficient in SR-A by lentiviral transfection of shRNAs targeting the macrophage scavenger receptor 1 (MSR1) gene (denoted “MSR1-DF”). Upon incubation with SNAs, pellets collected from MSR1-DF cells are markedly less red than those from pGIPZ-control cells. Ensuing ICP-MS analysis of the same pellets revealed ~80% decrease in uptake of SNAs by MSR1-DF cells in contrast to nontargeting pGIPZ-control cells (Fig. 19.4C). Since such a degree of decrease matches with that achievable via the use of FCD and Poly I, we conclude that SR-A is an important receptor subclass that mediates the endocytosis of SNAs. To confirm the ability of SR-A to recognize oligonucleotides anchored on SNAs as specific ligands, we incubated SNAs as well as AuNPs that are covalently attached with poly(ethylene glycol) chains (PEG– AuNPs) to different ELISA wells immobilized with recombinant SR-A in parallel. SNAs clearly demonstrate dose-dependent binding to SR-As, whereas PEG–AuNPs do not. We also compared the ability of SNAs and ssDNAs of the same sequence to engage SR-A immobilized on the ELISA plate. Under conditions where the total amount of oligonucleotide is held constant, SNAs can bind to SR-A at least 10 times more strongly than ssDNAs, in agreement with the results from the competitive binding assay conducted using C166 cells (Fig. 19.4B). These data confirm that the 3D oligonucleotide shell, not the NP core, dictates the binding of SNAs to SR-A.
HCV NS5B RdRp mutations and their effects on ligand binding affinity
Published in International Journal of Modelling and Simulation, 2022
Ahmed Emam, Khaled R. A. Abdellatif, Noha H. Amin, Khaled M. Elokely
The development of a vaccine for HCV is challenging because the HCV envelope glycoproteins (E1, E2) are genetically variable by up to 80% among HCV genotypes, and even among different subtypes of the same genotype [10]. As an alternative strategy, host cell surface factors were targeted for HCV prophylaxis by ITX 5061 (Figure 1) which binds scavenger receptor B1 (SCARB1) [11].