Figure 4.

Graphical demonstration of predicted SARS-CoV-2 infection, ACE2 blockage, oxidative stress, and RAAS imbalance. (A) Binding of SARS-CoV-2 to ACE2 (1) followed by profuse replication, transcription and translation (2) of SARS-CoV-2 in the host cell leads to endoplasmic reticulum (ER) stress due to accumulation of newly synthesized viral proteins in the ER (3). Protein overload in the ER leads to reactive oxygen species (ROS) generation in the ER (4). Further, ER stress also induces mitochondrial ROS production (5). Together, ER stress and ROS accumulation lead to inflammation and apoptosis. (B) Renin, angiotensin and aldosterone together constitute the Renin-Angiotensin-Aldosterone System (RAAS) and its imbalances in SARS-CoV-2 infection. Angiotensinogen is produced in the liver and cleaved by renin to form angiotensin (I). Angiotensin I is converted to angiotensin II by angiotensin-converting enzyme (ACE). This conversion occurs in the lungs, where ACE is expressed by vascular endothelial and lung epithelial cells. During homeostasis, Angiotensin I is acted upon by ACE2 to generate Angiotensin-(1-9), which is cleaved by ACE to generate Angiotensin-(1-7). Further, ACE2 also cleaves Angiotensin II into Angiotensin-(1-7). Angiotensin-(1-7) via Mas receptor mediates antioxidative and anti-inflammatory responses. Angiotensin II binds to one of two G-protein coupled receptors, the AT₁ and AT₂ receptors. SARS-CoV2 binding to its potent ACE2 receptor diminishes ACE2 function, skewing the ACE/ACE2 equilibrium to a predominant pro-inflammatory ACE-Ang II-AT₁R axis signaling. Imbalances in the RAAS system can alter the AT₂R -MasR pathway, which is very important for vasodilation, angiogenesis, anti-inflammatory, antioxidative, and antiapoptotic activities. In contrast, AT₁R pathway is important for vasoconstriction, inflammation, oxidative stress, and apoptosis. Virus binding to ACE2 dysregulates AT₂R-MasR pathway. Imbalances of ACE and ACE2 generate ROS, leading to oxidative stress, which causes hyperinflammation. In addition, hyperinflammation with cellular oxidative stress imbalances causes disease severity and when reaches its climax leads to respiratory failure as discussed in Figures 1 and 5. Spices could potentially inhibit inflammation and restore homeostasis. Created with BioRender.com.