The Impact of SARS-CoV-2 on the Human Body and the Therapeutic Potential of N-acetylcysteine (NAC) and Sulodexide

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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has emerged as a global health crisis, affecting not only the respiratory system but also extending its impact to various other organs in the human body. Studies by Raman et al. (2021) and Bonaventura et al. (2021) have highlighted the virus’s mechanism of invasion, primarily through endothelial cells, leading to a cascade of bodily reactions.

These reactions include hyperinflammation, activation of neutrophils, monocytes, and platelets, and triggering of the coagulation cascade, potentially causing intravascular thrombosis. This information is crucially supported by the research of Bermejo-Martin et al. (2020), Evans et al. (2020), and Teuwen et al. (2020).

The virus’s impact at the cellular level is profound, especially on the endothelium, characterized by a lack of nitric oxide, oxidative stress, and damaged glycocalyx structure. COVID-19-related myocarditis, a notable complication, exacerbates endothelial cell dysfunction, as outlined by Bonaventura et al. (2021) and further supported by Fogarty et al. (2021), Yin et al. (2021), and Bogdanov and Khirmanov (2022). These complications can lead to long-COVID-19 syndrome, affecting a significant percentage of patients (Davis et al., 2021; Ceban et al., 2022).

A ray of hope in mitigating these effects is found in N-acetylcysteine (NAC) and Sulodexide. Studies by Ciszewicz et al. (2007), Sosińska-Zawierucha et al. (2018, 2019), and others have demonstrated their potential in reducing endothelial damage and dysfunction. NAC, in particular, has shown efficacy in inhibiting pro-inflammatory cytokines and reducing viral replication in various viruses, including HIV (ho and Douglas, 1992) and RSV (Mata et al., 2012), as well as potentially in SARS-CoV-2 (Ibrahim et al., 2020; Nasi et al., 2020; Poe and Corn, 2020; du Preez et al., 2022b). Moreover, Sulodexide’s effectiveness in the acute phase of COVID-19 has been documented (Gonzalez-Ochoa et al., 2021; Bednarz et al., 2022; Melkumyants et al., 2022), with ongoing studies into their long-term effects (Charfeddine et al., 2022).

Our study delves into the effects of serum isolated from post-COVID-19 patients on human coronary endothelial cells in vitro. The findings revealed significant differences in blood inflammatory parameters between the post-COVID-19 group and the control group. Intracellular generation of free radicals and synthesis of IL-6 and vWF were markedly higher in cells exposed to post-COVID-19 serum, indicating increased stress and inflammation. Notably, the addition of NAC or Sulodexide to the post-COVID-19 serum significantly reduced these effects, highlighting their potential therapeutic value.

Discussion

Endothelial Injury and Long-term Consequences of COVID-19

The post-COVID-19 syndrome presents a complex, multifaceted challenge with long-term implications for numerous bodily systems and organs. One critical area of concern is the endothelial cell injury sustained during the acute phase of the infection. Research by Haffke et al. (2022) underscores the persistence of endothelial injury markers well beyond the acute phase, sometimes up to 8 months post-infection.

Our study builds upon this understanding, demonstrating that inflammation in endothelial cells during SARS-CoV-2 infection may not be solely a direct consequence of the virus but can also develop much later, as evidenced by the inflammatory potential of convalescent serum. This observation is particularly noteworthy in the context of increased oxidative stress and the production of pro-inflammatory cytokines such as IL-6, vWF, tPA, and PAI-1 in coronary artery endothelial cells (CAEC) exposed to post-COVID-19 serum.

Sulfation, Glycocalyx, and SARS-CoV-2 Susceptibility

The role of heparan sulfate sulfation within the glycocalyx emerges as a significant factor in susceptibility to SARS-CoV-2 (Clausen et al., 2020; Liu et al., 2021; du Preez et al., 2022a, 2022b). Oxidative stress and proteolysis, induced by SARS-CoV-2, lead to rapid depletion of sulfur amino acids, as noted by Bourgonje et al. (2021) and du Preez et al. (2022b).

This underscores the potential impact of undersulfation on infection response. Sulfur donors, such as NAC and Sulodexide, could be crucial in counteracting endothelial cell injury, a hypothesis supported by our findings that demonstrate the restoration of sulfur amino acid levels and a reduction in endothelial dysfunction biomarkers following NAC supplementation.

Thromboembolic Complications and COVID-19

The thromboembolic complications associated with COVID-19 are an area of particular concern, often monitored through elevated levels of D-dimers, fibrinogen, and vWF against standard ranges of PT, aPTT, and platelet count (Helms et al., 2020; Iba et al., 2020). Goshua et al. (2020) and Rovas et al. (2021) have noted an increase in endothelial dysfunction biomarkers like vWF and PAI-1 in COVID-19 patients, correlating with more severe disease manifestations and higher mortality. Our study echoes these findings, revealing sustained endothelial damage and increased secretion of endothelial factors such as vWF and PAI-1 even months post-infection, as also supported by Fogarty et al. (2021).

Therapeutic Potential of NAC and Sulodexide

NAC has been recognized for its capacity to reduce virus binding and replication, coupled with anti-inflammatory and antioxidant properties (Mohanty et al., 2021; Wong et al., 2021; du Preez et al., 2022b). In our study, NAC exhibited a protective role for CAEC exposed to post-COVID-19 serum, reducing pro-inflammatory cytokine levels. This aligns with previous findings on the use of NAC in the acute phase of SARS-CoV-2 infection, particularly in managing cytokine storms.

Sulodexide, a mixture of glycosaminoglycans, emerges as another potential therapeutic agent, especially for mild COVID-19 cases (Charfeddine et al., 2022; Melkumyants et al., 2022). Its multifaceted effects, including arterial and venous anticoagulant activity, anti-inflammatory properties, and the inhibition of IL-6 production (Coccheri and Mannello, 2013; Sosinska-Zawierucha et al., 2019), make it a promising candidate for treating endothelial cells in various conditions. Our findings indicate that Sulodexide inhibits IL-6 secretion from endothelial cells in later stages of COVID-19, albeit with less significant effects on other tested factors, warranting further investigation.

Concluding Insights

The lingering risk of endothelial cell injury months after COVID-19 highlights the importance of targeted therapeutic strategies. NAC shows potential in reducing myocardial injury associated with post-COVID-19 syndrome by alleviating coronary artery endothelial injury. Similarly, Sulodexide could play a vital role in protecting endothelial cells during and after COVID-19 infection. As we continue to navigate the complexities of post-COVID-19 syndrome, these findings underscore the need for ongoing research and therapeutic innovation in addressing the long-term impacts of this global health crisis.


reference link : https://www.frontiersin.org/articles/10.3389/fcimb.2023.1268016/full

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