Loading...
 
Toggle Health Problems and D

High dose vitamin D fights Folate gene changes by COVID, autoimmune, CVD, ALZ – Oct 2022


A Novel Immunomodulatory Mechanism by Which Vitamin D Influences Folate Receptor 3 Expression to Reduce COVID-19 Severity

Anticancer Res . 2022 Oct;42(10):5043-5048. doi: 10.21873/anticanres.16013.
Rosy J Lu 1 , Purusha Shirvani 1 , Michael F Holick 2

Image

Image

Image

Background/aim:
Identify potential mechanisms involving gene expression changes through which vitamin D supplementation could be beneficial in preventing adverse COVID-19 outcomes.

Materials and methods:
We performed a literature review to identify differentially expressed genes (DEGs) in the blood between severe and mild COVID-19 patients. We compared these with the top DEGs induced by6 months of 10,000 IU/day vitamin D supplementation in healthy adults who were vitamin D deficient/insufficient. We used bioinformatic tools to look for a vitamin D response element (VDRE) in DEGs.

Results:
FOLR3, RGS1, GPR84, and LRRN3 were the most significantly altered genes by 6 months of 10,000 IU/day vitamin D supplementation whose expression levels were also involved in COVID-19 severity. FOLR3 and GPR84 were found to be consistently up-regulated and RGS1 and LRRN3 consistently down-regulated in severe COVID-19 infection. FOLR3 and LRRN3 were down-regulated and RGS1 and GPR84 were up-regulated by 10,000 IU/day vitamin D supplementation.

Conclusion:
FOLR3 and RGS1 are expressed in neutrophils and lymphocytes, respectively. Vitamin D supplementation may decrease the neutrophil-lymphocyte ratio as has been reported in patients admitted with severe symptoms. There is evidence that vitamin D directly influences the expression of the RGS1 gene through vitamin D receptor binding. A potential negative VDRE (nVDRE) in an intron of the FOLR3 gene was found, which was homologous with two known nVDREs. Combined with other transcription factor elements near the newly identified nVDRE, these observations may explain the mechanism by which vitamin D regulates these genes, thus influencing COVID-19 outcomes.
 Download the PDF from VitaminDWiki

Clipped from PDF
COVID-19 is not the only disease associated with increased expression of the FOLR3 gene. FOLR3 has been found to be over-expressed in

  • autoimmune diseases, such as rheumatoid arthritis and psoriasis (24),
  • cardiovascular diseases, such as coronary artery disease (25),
  • various cancers (26), and
  • Alzheimer’s disease and mild cognitive impairment (27).

Therefore, decreasing FOLR3 expression could be a way through which being vitamin D sufficient with a 25(OH)D of at least 30 ng/ml has a protective effect against other diseases as well. Indeed, considering how 10,000 IU/day of vitamin D supplementation decreased FOLR3 expression nearly trifold but severe COVID-19 raised it five-fold, further studies should be conducted to determine the effects of higher than 10,000 IU/day of vitamin D supplementation on FOLR3 expression to potentially reduce severity of COVID-19 in at-risk patients.


VitaminDWiki speculates cancellation by 15 ,000 daily. or loading dose >300,000 + 50,000 weekly

Image


References
  1. Holick MF: Vitamin D deficiency. N Engl J Med 357(3): 266281,2007. PMID: 17634462. DOI: 10.1056/NEJMra070553
  2. Kaufman HW, Niles JK, Kroll MH, Bi C and Holick MF: SARS-CoV-2 positivity rates associated with circulating 25- hydroxyvitamin D levels. PLoS One 15(9): e0239252, 2020. PMID: 32941512. DOI: 10.1371/journal.pone.0239252
  3. Charoenngam N, Shirvani A and Holick MF: Vitamin D and its potential benefit for the COVID-19 pandemic. Endocr Pract 27(5): 484-493, 2021. PMID: 33744444. DOI: 10.1016/j.eprac.2021.03.006
  4. Maghbooli Z, Sahraian MA, Ebrahimi M, Pazoki M, Kafan S, Tabriz HM, Hadadi A, Montazeri M, Nasiri M, Shirvani A and Holick MF: Vitamin D sufficiency, a serum 25-hydroxyvitamin D at least 30 ng/mL reduced risk for adverse clinical outcomes in patients with COVID-19 infection. PLoS One 15(9): e0239799, 2020. PMID: 32976513. DOI: 10.1371/journal.pone.0239799
  5. Liu X, Baylin A and Levy PD: Vitamin D deficiency and insufficiency among US adults: prevalence, predictors and clinical implications. Br J Nutr 119(8): 928-936, 2018. PMID: 29644951. DOI: 10.1017/S0007114518000491
  6. Shirvani A, Kalajian TA, Song A and Holick MF: Disassociation of vitamin D’s calcemic activity and non-calcemic genomic activity and individual responsiveness: a randomized controlled double-blind clinical trial. Sci Rep 9(1): 17685, 2019. PMID: 31776371. DOI: 10.1038/s41598-019-53864-1
  7. Manne BK, Denorme F, Middleton EA, Portier I, Rowley JW, Stubben C, Petrey AC, Tolley ND, Guo L, Cody M, Weyrich AS, Yost CC, Rondina MT and Campbell RA: Platelet gene expression and function in patients with COVID-19. Blood 136(11): 13171329, 2020. PMID: 32573711. DOI: 10.1182/blood.2020007214
  8. Aschenbrenner AC, Mouktaroudi M, Krämer B, Oestreich M, Antonakos N, Nuesch-Germano M, Gkizeli K, Bonaguro L, Reusch N, Baßler K, Saridaki M, Knoll R, Pecht T, Kapellos TS, Doulou S, Kröger C, Herbert M, Holsten L, Horne A, Gemünd ID, Rovina N, Agrawal S, Dahm K, van Uelft M, Drews A, Lenkeit L, Bruse N, Gerretsen J, Gierlich J, Becker M, Händler K, Kraut M, Theis H, Mengiste S, De Domenico E, Schulte- Schrepping J, Seep L, Raabe J, Hoffmeister C, ToVinh M, Keitel V, Rieke G, Talevi V, Skowasch D, Aziz NA, Pickkers P, van de Veerdonk FL, Netea MG, Schultze JL, Kox M, Breteler MMB, Nattermann J, Koutsoukou A, Giamarellos-Bourboulis EJ, Ulas T and German COVID-19 Omics Initiative (DeCOI): Disease severity-specific neutrophil signatures in blood transcriptomes stratify COVID-19 patients. Genome Med 13(1): 7, 2021. PMID: 33441124. DOI: 10.1186/s13073-020-00823-5
  9. Jackson H, Rivero Calle I, Broderick C, Habgood-Coote D, D’Souza G, Nichols S, Vito O, Gomez-Rial J, Rivero-Velasco C, Rodriguez-Nunez N, Barbeito-Castineiras G, Pérez-Freixo H, Barreiro-de Acosta M, Cunnington AJ, Herberg JA, Wright VJ, Gomez-Carballa A, Salas A, Levin M, Martinon-Torres F, Kaforou M, PERFORM consortium and GEN-COVID (www.gencovid.eu) study group: Characterisation of the blood RNA host response underpinning severity in COVID-19 patients. Sci Rep 12(1): 12216, 2022. PMID: 35844004. DOI: 10.1038/s41598-022-15547-2
  10. Li Y, Duche A, Sayer MR, Roosan D, Khalafalla FG, Ostrom RS, Totonchy J and Roosan MR: SARS-CoV-2 early infection signature identified potential key infection mechanisms and drug targets. BMC Genomics 22(1): 125, 2021. PMID: 33602138. DOI: 10.1186/s12864-021-07433-4
  11. Sfikakis PP, Verrou KM, Ampatziadis-Michailidis G, Tsitsilonis O, Paraskevis D, Kastritis E, Lianidou E, Moutsatsou P, Terpos E, Trougakos I, Chini V, Manoloukos M, Moulos P, Pavlopoulos GA, Kollias G, Hatzis P and Dimopoulos MA: Blood transcriptomes of anti-SARS-CoV-2 antibody-positive healthy individuals who experienced asymptomatic versus clinical infection. Front Immunol 12: 746203, 2021. PMID: 34675930. DOI: 10.3389/fimmu.2021.746203Disanto G, Sandve GK, Berlanga-Taylor AJ, Ragnedda G, Morahan JM, Watson CT, Giovannoni G, Ebers GC and Ramagopalan SV: Vitamin D receptor binding, chromatin states and association with multiple sclerosis. Hum Mol Genet 21(16): 3575-3586, 2012. PMID: 22595971. DOI: 10.1093/hmg/dds189
  12. Holm J and Hansen SI: Characterization of soluble folate receptors (folate binding proteins) in humans. Biological roles and clinical potentials in infection and malignancy. Biochim Biophys Acta Proteins Proteom 1868(10): 140466, 2020. PMID: 32526472. DOI: 10.1016/j.bbapap.2020.140466
  13. Kehrl JH: The impact of RGS and other G-protein regulatory proteins on Gai-mediated signaling in immunity. Biochem Pharmacol 114: 40-52, 2016. PMID: 27071343. DOI: 10.1016/j.bcp.2016.04.005
  14. Simadibrata DM, Calvin J, Wijaya AD and Ibrahim NAA: Neutrophil-to-lymphocyte ratio on admission to predict the severity and mortality of COVID-19 patients: A meta-analysis. Am J Emerg Med 42: 60-69, 2021. PMID: 33453617. DOI: 10.1016/j.ajem.2021.01.006
  15. Maghbooli Z, Sahraian MA, Jamalimoghadamsiahkali S, Asadi A, Zarei A, Zendehdel A, Varzandi T, Mohammadnabi S, Alijani N, Karimi M, Shirvani A and Holick MF: Treatment with 25- hydroxyvitamin D3 (Calcifediol) is associated with a reduction in the blood neutrophil-to-lymphocyte ratio marker of disease severity in hospitalized patients with COVID-19: a pilot multicenter, randomized, placebo-controlled, double-blinded clinical trial. Endocr Pract 27(12): 1242-1251, 2021. PMID: 34653608. DOI: 10.1016/j.eprac.2021.09.016
  16. Carlberg C: Vitamin D: a micronutrient regulating genes. Curr Pharm Des 25(15): 1740-1746, 2019. PMID: 31298160. DOI: 10.2174/1381612825666190705193227
  17. White JH: Vitamin D metabolism and signaling in the immune system. Rev Endocr Metab Disord 13(1): 21-29, 2012. PMID: 21845364. DOI: 10.1007/s11154-011-9195-z
  18. Alroy I, Towers TL and Freedman LP: Transcriptional repression of the interleukin-2 gene by vitamin D3: direct inhibition of NFATp/AP-1 complex formation by a nuclear hormone receptor. Mol Cell Biol 15(10): 5789-5799, 1995. PMID: 7565732. DOI: 10.1128/MCB.15.10.5789
  19. Takeuchi A, Reddy GS, Kobayashi T, Okano T, Park J and Sharma S: Nuclear factor of activated T cells (NFAT) as a molecular target for 1alpha,25-dihydroxyvitamin D3-mediated effects. J Immunol 160(1): 209-218, 1998. PMID: 9551973.
  20. Field MS, Szebenyi DM, Perry CA and Stover PJ: Inhibition of 5,10-methenyltetrahydrofolate synthetase. Arch Biochem Biophys 458(2): 194-201, 2007. PMID: 17250800. DOI: 10.1016/j .abb .2006.12.023
  21. Joshi MB, Baipadithaya G, Balakrishnan A, Hegde M, Vohra M, Ahamed R, Nagri SK, Ramachandra L and Satyamoorthy K: Elevated homocysteine levels in type 2 diabetes induce constitutive neutrophil extracellular traps. Sci Rep 6: 36362, 2016. PMID: 27811985. DOI: 10.1038/srep36362
  22. Ackermann M, Anders HJ, Bilyy R, Bowlin GL, Daniel C, De Lorenzo R, Egeblad M, Henneck T, Hidalgo A, Hoffmann M, Hohberger B, Kanthi Y, Kaplan MJ, Knight JS, Knopf J, Kolaczkowska E, Kubes P, Leppkes M, Mahajan A, Manfredi AA, Maueröder C, Maugeri N, Mitroulis I, Muñoz LE, Narasaraju T, Naschberger E, Neeli I, Ng LG, Radic MZ, Ritis K, Rovere-Querini P, Schapher M, Schauer C, Simon HU, Singh J, Skendros P, Stark K, Stürzl M, van der Vlag J, Vandenabeele P, Vitkov L, von Köckritz-Blickwede M, Yanginlar C, Yousefi S, Zarbock A, Schett G and Herrmann M: Patients with COVID- 19: in the dark-NETs of neutrophils. Cell Death Differ 28(11): 3125-3139, 2021. PMID: 34031543. DOI: 10.1038/s41418-021- 00805-z
  23. Tan Y, Qi Q, Lu C, Niu X, Bai Y, Jiang C, Wang Y, Zhou Y, Lu A and Xiao C: Cytokine imbalance as a common mechanism in both psoriasis and rheumatoid arthritis. Mediators Inflamm 2017: 2405291,2017. PMID: 28239238. DOI: 10.1155/2017/2405291
  24. Sivapalaratnam S, Basart H, Watkins NA, Maiwald S, Rendon A, Krishnan U, Sondermeijer BM, Creemers EE, Pinto-Sietsma SJ, Hovingh K, Ouwehand WH, Kastelein JJ, Goodall AH and Trip MD: Monocyte gene expression signature of patients with early onset coronary artery disease. PLoS One 7(2): e32166, 2012. PMID: 22363809. DOI: 10.1371/journal.pone.0032166
  25. Bin-Alee F, Arayataweegool A, Buranapraditkun S, Mahattanasakul P, Tangjaturonrasme N, Hirankarn N, Mutirangura A and Kitkumthorn N: Transcriptomic analysis of peripheral blood mononuclear cells in head and neck squamous cell carcinoma patients. Oral Dis 27(6): 1394-1402, 2021. PMID: 32892371. DOI: 10.1111/odi.13639
  26. Cohen D, Pilozzi A and Huang X: Network medicine approach for analysis of Alzheimer’s disease gene expression data. Int J Mol Sci 21(1): 332, 2020. PMID: 31947790. DOI: 10.3390/ijms21010332

VitaminDWiki pages with FOLATE in title (16 as of Oct 2022)

This list is automatically updated

Items found: 16
Title Modified
High dose vitamin D fights Folate gene changes by COVID, autoimmune, CVD, ALZ – Oct 2022 06 Oct, 2022
Folate and Vitamin B6 decrease mortality – May 2022 27 May, 2022
Important Role of Micronutrients during COVID-19 (Zinc, Vitamin D, C, Folate) – May 5, 2021 06 May, 2021
Higher vitamin D is associated with higher Folate or higher Vitamin B-12 – June 2020 13 Jul, 2020
Sweat types, folate, binding protein, lighter skin in females and Vitamin D – Jan 2020 19 Jan, 2020
Glyphosate (Roundup) kills both weeds and the microbes in your gut that produce Folate – July 2019 11 Jul, 2019
Dr. Coimbra interview covering Vitamin D, Magnesium, Folate, Vaccines - Oct 2018 24 Nov, 2018
Neural tube defects more likely due to low vitamin D than low Folate – April 2017 15 Sep, 2018
Off topic – Folate can be produced by micro-organisms, can avoid synthetic Folic Acid – Aug 2018 02 Aug, 2018
First-Episode Psychosis associated with low Vitamin D, Vitamin C and Folate – meta-analysis Nov 2017 22 Dec, 2017
Increased cows milk allergy if Folic acid or Folate added to vitamin D during pregnancy – June 2016 05 Apr, 2017
Autism 17 times more likely with excessive Folate and B-12 (now added to bread) – May 2016 09 Jun, 2016
Autism 17X more likely when have excessive levels of Folate and B-12 – May 2016 12 May, 2016
Vitamin D and Folate fortification of foods - April 2012 25 Apr, 2015
Neural tube defects of pregnant mice reduced by Vitamin D (perhaps less Folate needed) – April 2015 25 Apr, 2015
Hypothesis – Increasing Folate or vitamin D decreases probability of skin cancer – July 2012 02 Aug, 2012

See also web

  • Folate receptors and transporters: biological role and diagnostic/therapeutic targets in cancer and other diseases - 2019 PDF

Image


Created by admin. Last Modification: Thursday October 6, 2022 16:14:35 GMT-0000 by admin. (Version 8)

Attached files

ID Name Comment Uploaded Size Downloads
18577 FR cancer.jpg admin 06 Oct, 2022 16:12 53.47 Kb 58
18576 Folate receptors and transporters_CompressPdf.pdf admin 06 Oct, 2022 16:02 654.34 Kb 23
18575 Cancel increase.jpg admin 06 Oct, 2022 15:24 43.54 Kb 55
18574 FOLR3 expressipn.jpg admin 06 Oct, 2022 15:08 17.04 Kb 57
18573 10K down highlight.jpg admin 06 Oct, 2022 15:07 63.19 Kb 52
18572 10K up.jpg admin 06 Oct, 2022 15:07 64.94 Kb 60
18571 10K folate.pdf PDF 2022 admin 06 Oct, 2022 15:06 598.68 Kb 28
See any problem with this page? Report it (WORKS NOV 2021)