{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T23:29:09Z","timestamp":1785281349728,"version":"3.55.0"},"reference-count":157,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2024,6,24]],"date-time":"2024-06-24T00:00:00Z","timestamp":1719187200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institute of Health (NIH\/NCCIH)","doi-asserted-by":"publisher","award":["5R33AT010637-01A1"],"award-info":[{"award-number":["5R33AT010637-01A1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institute of Health (NIH\/NCCIH)","doi-asserted-by":"publisher","award":["3R33 AT010637-02S1"],"award-info":[{"award-number":["3R33 AT010637-02S1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Malcolm Feist Endowed Chair in Diabetes","award":["5R33AT010637-01A1"],"award-info":[{"award-number":["5R33AT010637-01A1"]}]},{"name":"Malcolm Feist Endowed Chair in Diabetes","award":["3R33 AT010637-02S1"],"award-info":[{"award-number":["3R33 AT010637-02S1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Vitamin D receptors are expressed in many organs and tissues, which suggests that vitamin D (VD) affects physiological functions beyond its role in maintaining bone health. Deficiency or inadequacy of 25(OH)VD is widespread globally. Population studies demonstrate that a positive association exists between a high incidence of VD deficiency and a high incidence of chronic diseases, including dementia, diabetes, and heart disease. However, many subjects have difficulty achieving the required circulating levels of 25(OH)VD even after high-dose VD supplementation, and randomized controlled clinical trials have reported limited therapeutic success post-VD supplementation. Thus, there is a discordance between the benefits of VD supplementation and the prevention of chronic diseases in those with VD deficiency. Why this dissociation exists is currently under debate and is of significant public interest. This review discusses the downregulation of VD-metabolizing genes needed to convert consumed VD into 25(OH)VD to enable its metabolic action exhibited by subjects with metabolic syndrome, obesity, and other chronic diseases. Research findings indicate a positive correlation between the levels of 25(OH)VD and glutathione (GSH) in both healthy and diabetic individuals. Cell culture and animal experiments reveal a novel mechanism through which the status of GSH can positively impact the expression of VD metabolism genes. This review highlights that for better success, VD deficiency needs to be corrected at multiple levels: (i) VD supplements and\/or VD-rich foods need to be consumed to provide adequate VD, and (ii) the body needs to be able to upregulate VD-metabolizing genes to convert VD into 25(OH)VD and then to 1,25(OH)2VD to enhance its metabolic action. This review outlines the association between 25(OH)VD deficiency\/inadequacy and decreased GSH levels, highlighting the positive impact of combined VD+LC supplementation on upregulating GSH, VD-metabolizing genes, and VDR. These effects have the potential to enhance 25(OH)VD levels and its therapeutic efficacy.<\/jats:p>","DOI":"10.3390\/nu16132004","type":"journal-article","created":{"date-parts":[[2024,6,24]],"date-time":"2024-06-24T08:42:03Z","timestamp":1719218523000},"page":"2004","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["The Impact of Vitamin D and L-Cysteine Co-Supplementation on Upregulating Glutathione and Vitamin D-Metabolizing Genes and in the Treatment of Circulating 25-Hydroxy Vitamin D Deficiency"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9574-0436","authenticated-orcid":false,"given":"Sushil K.","family":"Jain","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Louisiana State University Health Sciences Center, Shreveport, LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7905-1887","authenticated-orcid":false,"given":"Jeffrey","family":"Justin Margret","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Louisiana State University Health Sciences Center, Shreveport, LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven A.","family":"Abrams","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Dell Pediatric Research Institute, Dell Medical School at the University of Texas at Austin, Austin, TX 78723, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven N.","family":"Levine","sequence":"additional","affiliation":[{"name":"Department of Medicine, Louisiana State University Health Sciences Center, Shreveport, LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamal","family":"Bhusal","sequence":"additional","affiliation":[{"name":"Department of Medicine, Louisiana State University Health Sciences Center, Shreveport, LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/s11154-017-9424-1","article-title":"The vitamin D deficiency pandemic: Approaches for diagnosis, treatment and prevention","volume":"18","author":"Holick","year":"2017","journal-title":"Rev. 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