Inhibition of ACE2 Expression by Ascorbic Acid Alone and its Combinations with Other Natural Compounds

Abstract

Background: Angiotensin-converting enzyme II or ACE2 is an integral membrane protein present on many types of cells, including vascular endothelial cells and lung alveolar epithelial cells. This receptor serves as the entry point for SARS-coronaviruses (SARS-CoVs), including a novel coronavirus 2019-nCoV. Limited availability of these receptors can thwart cellular entry of this virus. Methods: We tested the effects of ascorbic acid (vitamin C) on cellular expression of ACE2 at the protein and RNA levels in human small alveolar epithelial cells and microvascular endothelial cells. In addition, we investigated whether combinations of ascorbic acid with other natural compounds can affect ACE2 expression. Results: The results show that ascorbic acid itself has moderate but consistent lowering effects on ACE2 expression at the cellular, protein, and RNA levels. Some natural compounds were effective in lowering ACE2 cellular expression, with the highest inhibitory effects observed for baicalin (75%) and theaflavin (50%). Significantly, combinations of these and other test compounds with ascorbic acid further decreased ACE2 expression. The highest impact of ascorbate on ACE2 expression was noted when combined with theaflavin (decrease from 50% to 87%), zinc (decrease from 22% to 62%), and with 10-undecenoic acid (from 18% to 53%). Ascorbic acid showed moderate additional benefits in decreasing ACE2 expression when combined with N-acetylcysteine and baicalin. Conclusion: Our study provides valuable experimental confirmation of the efficacy of micronutrients in controlling ACE2 expression—the coronavirus cellular “entry” point. It further validates the importance of nutrient interactions in various aspects of cellular metabolism and in considering potential therapeutic applications of nutrient-based approaches. The study shows that ascorbic acid and its combination with some natural compounds could be included in developing preventive and therapeutic approaches toward the current pandemic.

Inhibitory effects of specific combination of natural compounds against SARS-CoV-2 and its Alpha, Beta, Gamma, Delta, Kappa, and Mu variants

“…6). These findings further expand on our earlier study using SARS-CoV-2 virion particles, which identified core ingredients in this combination, which were effective in inhibiting viral binding to hACE2 receptor and decreasing expression of ACE2 receptors on human small alveolar epithelial cells [21]. Taking into account immediate availability and high safety profile of these natural compounds, their application as preventive measures, e.g.…”

Imatinib and methazolamide ameliorate COVID-19-induced metabolic complications via elevating ACE2 enzymatic activity and inhibiting viral entry

“…Overexpression of ACE2 enhances viral entry, whereas blockage with ACE2 antibody reduces SARS-CoV-2 infection (Hoffmann et al, 2020). Therefore, inhibition of ACE2 expression has been proposed as a strategy to treat COVID-19 (Ahmad et al, 2021;Ivanov et al, 2021). In contrast, ACE2, as an important component of RAS axis, exerts anti-inflammatory and antioxidative functions and maintains metabolic homeostasis as supported by our current findings.…”

Therapeutic potential of megadose vitamin C to reverse organ dysfunction in sepsis and COVID‐19

“…The known actions of vitamin C indicate that it would also be a plausible adjunct treatment for COVID-19. The findings that plasma vitamin C levels are low in COVID-19 patients (Chiscano-Camon, Ruiz-Rodriguez, Ruiz-Sanmartin, Roca & Ferrer, 2020), and that vitamin C lowers expression of angiotensin converting enzyme 2, the entry point for SARS-CoV-2 into cells (Ivanov, Goc, Ivanova, Niedzwiecki & Rath, 2021), further indicate that it may have beneficial actions in COVID-19. Intravenous vitamin C (1.5-14.0 g) has been investigated in COVID-19 patients with mild beneficial effects (Jamalimoghadamsiahkali et al, 2021;Zhao et al, 2021), but the effects of mega-doses have not been studied.…”