Caged Dexamethasone/Quercetin Nanoparticles, Formed of the Morphogenetic Active Inorganic Polyphosphate, are Strong Inducers of MUC5AC.

Meik Neufurth,Werner E G Müller,Shunfeng Wang,Xiaohong Wang,Heinz C Schröder

doi:10.3390/md19020064

Abstract

Inorganic polyphosphate (polyP) is a widely distributed polymer found from bacteria to animals, including marine species. This polymer exhibits morphogenetic as well as antiviral activity and releases metabolic energy after enzymatic hydrolysis also in human cells. In the pathogenesis of the coronavirus disease 2019 (COVID-19), the platelets are at the frontline of this syndrome. Platelets release a set of molecules, among them polyP. In addition, the production of airway mucus, the first line of body defense, is impaired in those patients. Therefore, in this study, amorphous nanoparticles of the magnesium salt of polyP (Mg-polyP-NP), matching the size of the coronavirus SARS-CoV-2, were prepared and loaded with the secondary plant metabolite quercetin or with dexamethasone to study their effects on the respiratory epithelium using human alveolar basal epithelial A549 cells as a model. The results revealed that both compounds embedded into the polyP nanoparticles significantly increased the steady-state-expression of the MUC5AC gene. This mucin species is the major mucus glycoprotein present in the secreted gel-forming mucus. The level of gene expression caused by quercetin or with dexamethasone, if caged into polyP NP, is significantly higher compared to the individual drugs alone. Both quercetin and dexamethasone did not impair the growth-supporting effect of polyP on A549 cells even at concentrations of quercetin which are cytotoxic for the cells. A possible mechanism of the effects of the two drugs together with polyP on mucin expression is proposed based on the scavenging of free oxygen species and the generation of ADP/ATP from the polyP, which is needed for the organization of the protective mucin-based mucus layer.

Highlights

Introduction published maps and institutional affilOn the cellular level, both macrophages and dendritic cells are the prime sensors of fungi, bacteria, and viruses that cause infection in humans
Dexamethasone in the form of dexamethasone 21-phosphate disodium salt is added to the Na-polyP solution, the particles increase slightly in size to 100 ± 18 nm (Figure 1B)
The present study shows that caged NP formed of polyP with dexamethasone and QCT display morphogenetic activity and cause an increased expression of mucin, as demonstrated here with MUC5AC

Summary

Introduction

Both macrophages and dendritic cells are the prime sensors of fungi, bacteria, and viruses that cause infection in humans. They are the starting points from where the innate as well as the adaptive immune defense and boosting machineries start [1]. The mucus at the interface to the environment overlays the surfaces of most epithelia. This layer, containing bioactive antimicrobial and antiviral supplements, forms a protective wall against microbes. The mucus with its main structural components, the mucins, physically enwraps the viruses and concomitantly interacts with them by binding and inactivating the surface proteins of the viral envelope [2].

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