Oxidized LDL receptors: a recent update.

PURPOSE OF REVIEW: LDL in its oxidized form, or 'oxLDL', is now generally acknowledged to be highly proatherogenic and to play a significant role in atherosclerotic plaque formation. Therefore, there has been increasing interest in understanding the significance of oxLDL and its receptors in different phases of atherosclerosis, leading to the accumulation of additional data at the cellular, structural, and physiological levels. This review focuses on the most recent discoveries about these receptors and how they influence lipid absorption, metabolism, and inflammation in various cell types. RECENT FINDINGS: Two crystal structures of lectin-like oxLDL receptor-1 (LOX-1), one with a small molecule inhibitor and the other with a monoclonal antibody have been published. We recently demonstrated that the 'surface site' of LOX1, adjacent to the positively charged 'basic spine region' that facilitates oxLDL binding, is a targetable site for drug development. Further, recent human studies showed that soluble LOX-1 holds potential as a biomarker for cardiovascular disease diagnosis, prognosis, and assessing the efficacy of therapy. SUMMARY: Receptor-mediated oxLDL uptake results in cellular dysfunction of various cell types involved in atherogenesis and plaque development. The current advancements clearly demonstrate that targeting oxLDL-LOX-1 axis may lead to development of future therapeutics for the treatment of atherosclerotic cardiovascular and cerebrovascular diseases.

Exploring the druggability of oxidized low-density lipoprotein (ox-LDL) receptor, LOX-1, a proatherogenic drug target involved in atherosclerosis.

Lectin-like oxidized low-density lipoprotein (ox-LDL) receptor 1 (LOX-1) is a vital scavenger receptor involved in ox-LDL binding, internalization, and subsequent proatherogenic signaling leading to cellular dysfunction and atherosclerotic plaque formation. Existing data suggest that modulation of ox-LDL - LOX-1 interaction can prevent or slow down atherosclerosis. Therefore, we utilized computational methods such as multi-solvent simulation and characterized two top-ranked druggable sites. Using systematic molecular docking followed by atomistic molecular dynamics simulation, we have identified and shortlisted small molecules from the NCI library that target two key binding sites. We demonstrate, using surface plasmon resonance (SPR), that four of the shortlisted molecules bind one-on-one to the purified C-terminal domain (CTLD) of LOX-1 receptor with high affinity (KD), ranging from 4.9 nM to 20.1 µM. Further, we performed WaterMap analysis to understand the role of individual water molecules in small molecule binding and the LOX-1-ligand complex stability. Our data clearly show that LOX-1 is druggable with small molecules. Our study provides strategies to identify novel inhibitors to attenuate ox-LDL - LOX-1 interaction.

Does Silver in Different Forms Affect Bacterial Susceptibility and Resistance? A Mechanistic Perspective.

The exceptional increase in antibiotic resistance in past decades motivated the scientific community to use silver as a potential antibacterial agent. However, due to its unknown antibacterial mechanism and the pattern of bacterial resistance to silver species, it has not been revolutionized in the health sector. This study deciphers mechanistic aspects of silver species, i.e., ions and lysozyme-coated silver nanoparticles (L-Ag NPs), against E. coli K12 through RNA sequencing analysis. The obtained results support the reservoir nature of nanoparticles for the controlled release of silver ions into bacteria. This study differentiates between the antibacterial mechanism of silver species by discussing the pathway of their entry in bacteria, sequence of events inside cells, and response of bacteria to overcome silver stress. Controlled release of ions from L-Ag NPs not only reduces bacterial growth but also reduces the likelihood of resistance development. Conversely, direct exposure of silver ions, leads to rapid activation of the bacterial defense system leading to development of resistance against silver ions, like the well-known antibiotic resistance problem. These findings provide valuable insight on the mechanism of silver resistance and antibacterial strategies deployed by E. coli K12, which could be a potential target for the generation of aim-based and effective nanoantibiotics.

Zinc2+ ion inhibits SARS-CoV-2 main protease and viral replication in vitro.

Zinc deficiency is linked to poor prognosis in COVID-19 patients while clinical trials with zinc demonstrate better clinical outcomes. The molecular targets and mechanistic details of the anti-coronaviral activity of zinc remain obscure. We show that zinc not only inhibits the SARS-CoV-2 main protease (Mpro) with nanomolar affinity, but also viral replication. We present the first crystal structure of the Mpro-Zn2+ complex at 1.9 Å and provide the structural basis of viral replication inhibition. We show that Zn2+ coordinates with the catalytic dyad at the enzyme active site along with two previously unknown water molecules in a tetrahedral geometry to form a stable inhibited Mpro-Zn2+ complex. Further, the natural ionophore quercetin increases the anti-viral potency of Zn2+. As the catalytic dyad is highly conserved across SARS-CoV, MERS-CoV and all variants of SARS-CoV-2, Zn2+ mediated inhibition of Mpro may have wider implications.

Controlling Surfactant Adsorption on Highly Charged Nanoparticles to Stabilize Bijels.

Bicontinuous particle-stabilized emulsions (bijels) are networks of interpenetrating oil/water channels with applications in catalysis, tissue engineering, and energy storage. Bijels can be generated by arresting solvent transfer induced phase separation (STrIPS) via interfacial jamming of nanoparticles. However, until now, STrIPS bijels have only been formed with silica nanoparticles of low surface charge densities, limiting their potential applications in catalysis and fluid transport. Here, we show how strongly charged silica nanoparticles can stabilize bijels. To this end, we carry out a systematic study employing dynamic light scattering, zeta potential, acid/base titrations, turbidimetry, surface tension, and confocal microscopy. We find that moderating the adsorption of oppositely charged surfactants on the particles is crucial to facilitate particle dispersibility in the bijel casting mixture and bijel stabilization. Our results potentially introduce a general understanding for bijel fabrication with different inorganic nanoparticle materials of variable charge density.

Utilizing metal tolerance potential of soil fungus for efficient synthesis of gold nanoparticles with superior catalytic activity for degradation of rhodamine B.

In recent years, the surging demand of nanomaterials has boosted unprecedented expansion of research for the development of high yielding and sustainable synthesis methods which can deliver nanomaterials with desired characteristics. Unlike the well-established physico-chemical methods which have various limitations, biological methods inspired by mimicking natural biomineralization processes have great potential for nanoparticle synthesis. An eco-friendly and sustainable biological method that deliver particles with well-defined shape, size and compositions can be developed by selecting a proficient organism followed by fine tuning of various process parameter. The present study revealed high metal tolerance ability of a soil fungus Cladosporium oxysporum AJP03 and its potential for extracellular synthesis of gold nanoparticles. The morphology, composition and crystallinity of nanoparticles were confirmed using standard techniques. The synthesized particles were quasi-spherical in shape with fcc packing and an average particle size of 72.32 ± 21.80 nm. A series of experiments were conducted to study the effect of different process parameters on particle size and yield. Biomass: water ratio of 1:5 and 1 mM precursor salt concentration at physiological pH (7.0) favoured the synthesis of well-defined gold nanoparticles with maximum yield. The as-synthesized nanoparticles showed excellent catalytic efficiency towards sodium borohydride mediated reduction of rhodamine B (2.5 × 10(-5) M) within 7 min of reaction time under experimental conditions. Presence of proteins as capping material on the nanoparticle surface was found to be responsible for this remarkable catalytic efficiency. The present approach can be extrapolated to develop controlled and up-scalable process for mycosynthesis of nanoparticles for diverse applications.