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This and other notions make it difficult to explain the pathogenicity of Hcy because: (i) lowering tHcy does not improve pathological outcomes; (ii) damage due to HSH usually emerges at supraphysiological doses; and (iii) it is not known why tiny increments in plasma concentrations of HSH can be pathological.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Critical Issues:<\/jats:title>\n                    <jats:p>\n                      Albumin may have a role in Hcy toxicity, because HSS-ALB could release toxic HSH\n                      <jats:italic toggle=\"yes\">via<\/jats:italic>\n                      thiol-disulfide (SH\/SS) exchange reactions in cells. Similarly, thiol-disulfide exchange processes of reduced albumin (albumin with free SH group of Cys34 [HS-ALB]) or\n                      <jats:italic toggle=\"yes\">N<\/jats:italic>\n                      -homocysteinylated albumin are plausible alternatives for initiating Hcy pathological events. Adverse effects of albumin and other data reviewed here suggest the hypothesis of a role of albumin in Hcy toxicity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:italic toggle=\"yes\">Future Directions<\/jats:italic>\n                      :\n                    <\/jats:title>\n                    <jats:p>\n                      HSS-ALB might be involved in disruption of the antioxidant\/oxidant balance in critical tissues (brain, liver, kidney). Since homocysteine-albumin mixed disulfide is a possible intermediate of thiol-disulfide exchange reactions, we suggest that homocysteinylated albumin could be a new pathological factor, and that studies on the redox role of albumin and mixed disulfide production\n                      <jats:italic toggle=\"yes\">via<\/jats:italic>\n                      thiol-disulfide exchange reactions could offer new therapeutic insights for reducing Hcy toxicity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" orientation=\"portrait\" position=\"float\" xlink:href=\"10.1089_ars.2021.0269-img51001.jpg\"\/>\n                    <\/jats:p>\n                  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