Despite the progressions in COVID-19 understanding, the optimization of patient-specific therapies remains a challenge. Statins, the most widely prescribed lipid-lowering drugs, received considerable attention due to their pleiotropic effects, encompassing lipid metabolism control and immunomodulatory and anti-thrombotic effects. In COVID-19 patients, statins improve clinical outcomes, reducing Intensive Care Unit admission, the onset of ARDS, and in-hospital death. However, the safety of statins in COVID-19 patients has been debated, mainly for statins’ ability to induce the expression of the ACE2 receptor, the main entry route of SARS-CoV-2. Unfortunately, the dynamic of statins’ mechanism in COVID-19 disease and prevention remains elusive. Using different in vitro models expressing different levels of ACE2 receptor, we investigated the role of lipophilic and hydrophilic statins on ACE2 receptor expression and subcellular localization. We demonstrated that the statin-mediated increase of ACE2 receptor expression does not necessarily coincide with its localization in lipid rafts domains, particularly after treatments with the lipophilic atorvastatin that disrupt lipid rafts’ integrity. Through a proteomic array, we analyzed the cytokine patterns demonstrating that statins inhibit the release of cytokines and factors involved in mild to severe COVID-19 cases. The results obtained provide additional information to dissect the mechanism underlying the protective effects of statin use in COVID-19.

Cystic fibrosis is a monogenic, autosomal, recessive disease characterized by an alteration of chloride transport caused by mutations in the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene. The loss of Phe residue in position 508 (ΔF508-CFTR) causes an incorrect folding of the protein causing its degradation and electrolyte imbalance. CF patients are extremely predisposed to the development of a chronic inflammatory process of the bronchopulmonary system. When the cells of a tissue are damaged, the immune cells are activated and trigger the production of free radicals, provoking an inflammatory process. In addition to routine therapies, today drugs called correctors are available for mutations such as ΔF508-CFTR as well as for others less frequent ones. These active molecules are supposed to facilitate the maturation of the mutant CFTR protein, allowing it to reach the apical membrane of the epithelial cell. Matrine induces ΔF508-CFTR release from the endoplasmic reticulum to cell cytosol and its localization on the cell membrane. We now have evidence that Matrine and Lumacaftor not only restore the transport of mutant CFTR protein, but probably also counteract the inflammatory process by improving the course of the disease.

Most neurodegenerative diseases share a common etiopathogenesis, the accumulation of protein aggregates. An imbalance in homeostasis brought on by the buildup of misfolded proteins within the endoplasmic reticulum (ER) results in ER stress in the cell. Three distinct proteins found in the ER membrane—IRE1α, PERK, and ATF6—control the unfolded protein response (UPR), a signal transduction pathway that is triggered to restore normal physiological conditions. Buildup of misfolded proteins in ER lumen leads to a shunting of GRP78/BiP, thus triggering the UPR. PERK autophosphorylation leads to activation of ATF4, the transcription factor; finally, ATF6 activates the UPR’s target genes, including GRP78/Bip. Accordingly, the UPR is a cellular reaction to an ER stress state that, if left unchecked for an extended period, results in apoptosis and irreversible damage. The identification of caspase 4, which is in the ER and is selectively activated by apoptotic stimuli caused by reticular stress, further demonstrated the connection between reticular stress and programed cell death. Moreover, oxidative stress and ER stress are linked. Oxidative stress is brought on by elevated quantities of radical oxygen species, both mitochondrial and cytosolic, that are not under the enzymatic regulation of superoxide dismutases, whose levels fall with increasing stress. Here, we evaluated the activity of Vx-809 (Lumacaftor), a drug used in cystic fibrosis, in SH-SY5Y neuronal cells, in which an ER stress condition was induced by Thapsigargin, to verify whether the drug could improve protein folding, suggesting its possible therapeutic use in proteinopathies, such as neurodegenerative diseases (NDs). Our data show that Vx-809 is involved in the significant reduction in protein produced under ER stress, particularly in the levels of Bip, ATF4, and ATF6 by Western blotting analysis, the reduction in ROS in the cytosol and mitochondria, and the reduction in the activation of the apoptotic pathway, measured by flow cytofluorimetry analysis and in restoring calcium homeostasis.

Correct protein folding is the basis of cellular well-being; thus, accumulation of misfolded proteins within the endoplasmic reticulum (ER) leads to an imbalance of homeostasis that causes stress to the ER. Various studies have shown that protein misfolding is a significant factor in the etiology of many human diseases, including cancer, diabetes, and cystic fibrosis. Misfolded protein accumulation in the ER triggers a sophisticated signal transduction pathway, the unfolded protein response (UPR), which is controlled by three proteins, resident in ER: IRE1α, PERK, and ATF6. Briefly, when ER stress is irreversible, IRE1α induces the activation of pro-inflammatory proteins; PERK phosphorylates eIF2α which induces ATF4 transcription, while ATF6 activates genes encoding ER chaperones. Reticular stress causes an alteration of the calcium homeostasis, which is released from the ER and taken up by the mitochondria, leading to an increase in the oxygen radical species production, and consequently, to oxidative stress. Accumulation of intracellular calcium, in combination with lethal ROS levels, has been associated with an increase of pro-inflammatory protein expression and the initiation of the inflammatory process. Lumacaftor (Vx-809) is a common corrector used in cystic fibrosis treatment which enhances the folding of mutated F508del-CFTR, one of the most prevalent impaired proteins underlying the disease, promoting a higher localization of the mutant protein on the cell membrane. Here, we demonstrate that this drug reduces the ER stress and, consequently, the inflammation that is caused by such events. Thus, this molecule is a promising drug to treat several pathologies that present an etiopathogenesis due to the accumulation of protein aggregates that lead to chronic reticular stress.