Figure 12.

Impaired folate-mediated one-carbon metabolism (FOCM) and hyperhomocyteinemia (HHCY) are associated with multiorgan damage and multiple clinical diseases via excessive redox stress. Once impaired FOCM develops and goes unchecked, this homocysteine (HCY) wheel begins turning and just keeps on turning, causing damage to the various organs and tissue systems identified, and results in multiple clinical disease states depicted on the HCY wheel (left-hand side of this image). When impaired FOCM and HHCY develops, the elevated HCY is capable of undergoing autoxidation, the formation of Hcy mixed disulfides, the interaction of Hcy thiolactones, and protein homocysteinylation reactions that result in damage and dysfunction to proteins, lipids, and nucleic acids. Note that the asterisks indicate increased importance. These damaging effects result in at least 14 damaging effects enumerated on the right-hand side of this image. This image is provided with permission by CC 4.0 [17]. CHF = congestive heart failure; COVID-19 = coronavirus disease-19; CVD = cerebro-cardiovascular disease; EC = endothelial cell; ecGCx = endothelial cell glycocalyx; eNOS = endothelial nitric oxide synthase; HTN = hypertension; IFNγ = interferon gamma; NO = nitric oxide; LDL = low-density lipoprotein cholesterol; MetS = metabolic syndrome; MMPs = matrix metalloproteinases; NFkappaB = nuclear factor kappa B; NTD = neural tube defects; LC/PASC = long COVID/ post-acute sequelae of SARS-CoV-2; LOAD = late-onset Alzheimer’s disease; Ox = oxidative stress; RBCs = red blood cells; RONS = reactive oxygen nitrogen species; T2DM = type 2 diabetes mellitus. TNFα = tumor necrosis factor alpha.