Vitamin D & zinc fingers

[lyndacarol]

I am not a scientist, but I have been interested in the zinc-vitamin D relationship recently.

Iron, Magnesium, Vitamin D, and Zinc Deficiencies in Children Presenting with Symptoms of Attention-Deficit/Hyperactivity Disorder (2014)
Amelia Villagomez and Ujjwal Ramtekkar
https://www.ncbi.nlm.nih.gov/pubmed/27417479

Abstract: Attention-Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder increasing in prevalence. Although there is limited evidence to support treating ADHD with mineral/vitamin supplements, research does exist showing that patients with ADHD may have reduced levels of vitamin D, zinc, ferritin, and magnesium. These nutrients have important roles in neurologic function, including involvement in neurotransmitter synthesis. The aim of this paper is to discuss the role of each of these nutrients in the brain, the possible altered levels of these nutrients in patients with ADHD, possible reasons for a differential level in children with ADHD, and safety and effect of supplementation. With this knowledge, clinicians may choose in certain patients at high risk of deficiency, to screen for possible deficiencies of magnesium, vitamin D, zinc, and iron by checking RBC-magnesium, 25-OH vitamin D, serum/plasma zinc, and ferritin. Although children with ADHD may be more likely to have lower levels of vitamin D, zinc, magnesium, and iron, it cannot be stated that these lower levels caused ADHD. However, supplementing areas of deficiency may be a safe and justified intervention.


Is the Association between Vitamin D and Metabolic Syndrome Independent of Other Micronutrients. (2016)
International Journal for Vitamin and Nutrition Research
DOI: 10.1024/0300-9831/a000277.
Hossein Khosravi-Boroujeni, Faruk Ahmed, Nizal Sarrafzadegan
https://www.ncbi.nlm.nih.gov/pubmed/27439768
Abstract
The incidence of metabolic syndrome (MetS) has been increasing globally and it is recognized as a major public health problem because MetS is associated with increased risk of diabetes, stroke, cancer, and other chronic diseases. Recently, MetS has been linked to vitamin D deficiency. However, the evidence on the association between vitamin D deficiency and the risk of MetS remains inconclusive. This review therefore aims to depict the existing evidence related to MetS and vitamin D deficiency, and examined some of the possible confounders which may affect the association between vitamin D status and risk of MetS. Earlier studies on the association between vitamin D deficiency and MetS have adjusted for the effect of some confounders including, age, sex, body mass index, race, physical activity, smoking, alcohol consumption, and energy intake. However, these studies failed to consider other potential confounders. There is evidence that vitamin A, zinc (Zn), and magnesium (Mg) play important roles in the activation and function of vitamin D and interact with gene expression. Furthermore, these micronutrients are also related to several components of the MetS including glucose intolerance, dyslipidemia, and obesity. Thus, there could be an interaction between these micronutrients, vitamin D, and MetS. This review highlights the possible interactions of vitamin A, Zn, Mg, and vitamin D with MetS and its components. The findings reinforce the need for further well-designed studies that take into account all potential confounders, including other micronutrients such as vitamin A, Zn, and Mg status, to investigate the independent association of vitamin D status with MetS and its components, and also to scrutinize for possible interactions among other nutrients which may have similar confounding effects.

The incidence of metabolic syndrome (MetS) has been increasing globally and it is recognized as a major public health problem because MetS is associated with increased risk of diabetes, stroke, cancer, and other chronic diseases. Recently, MetS has been linked to vitamin D deficiency. However, the evidence on the association between vitamin D deficiency and the risk of MetS remains inconclusive. This review therefore aims to depict the existing evidence related to MetS and vitamin D deficiency, and examined some of the possible confounders which may affect the association between vitamin D status and risk of MetS. Earlier studies on the association between vitamin D deficiency and MetS have adjusted for the effect of some confounders including, age, sex, body mass index, race, physical activity, smoking, alcohol consumption, and energy intake. However, these studies failed to consider other potential confounders.
There is evidence that

vitamin A,
zinc (Zn), and
magnesium (Mg)

play important roles in the activation and function of vitamin D and interact with gene expression. Furthermore, these micronutrients are also related to several components of the MetS including

glucose intolerance,
dyslipidemia, and
obesity.

Thus, there could be an interaction between these micronutrients, vitamin D, and MetS. This review highlights the possible interactions of vitamin A, Zn, Mg, and vitamin D with MetS and its components. The findings reinforce the need for further well-designed studies that take into account all potential confounders, including other micronutrients such as vitamin A, Zn, and Mg status, to investigate the independent association of vitamin D status with MetS and its components, and also to scrutinize for possible interactions among other nutrients which may have similar confounding effects.
Publisher wants $28 for the PDF

I learned about "zinc fingers:"

On page 3 of this PDF, http://onlinelibrary.wiley.com/doi/10.1016/0307-4412(93%2990125-J/pdf (page 120 of the actual text) of Biochemical Education "Zinc Fingers on the Way" by EJ Wood, 1993, we find in the section, "Zinc Fingers"…

"One might imagine that with a hundred or so enzymes being dependent on zinc, then its deficiency would be somewhat disastrous. However, there is more to it than this, because zinc is shown to have a major role in the action of many hormones (probably all the steroids and thyroid) and and some of the fat-soluble vitamins (A and D). As Klug records in his Scientific American article [Rhodes D and Klug A (1993) 'Zinc Fingers', Scientific American, February 1993, p 32-39, and Further Reading cited therein], since the first zinc finger protein was discovered in 1985, more than 200 proteins, many of them transcription factors, have been shown to contain zinc fingers. This is in addition to the hundreds of zinc enzymes that are known."

On page 6, in the section, "Superfamilies"…
"It became clear in the 1980s the steroid hormones exerted their actions via zinc finger proteins present in cells. This serves to remind us of the general ways in which hormones may act, namely either at a membrane with subsequent transmembrane signaling pathways, or via intracellular receptors.…

The next significant observation, however, was that not only the steroid hormones, but also thyroid hormone, and the fat-soluble vitamins A and D, also appeared to function by interacting with multi-domain, zinc-finger proteins.… What we start to see, however, is that there is a superfamily of receptor proteins, all with zinc-fingers that mediate the actions of these small molecules."

"… the nuclear receptors for thyroid hormone and vitamin D3 also had a similar structure, and a superfamily was born. All have a DNA-binding, four cys type zinc-finger region and a hormone-binding domain, as well as other domains too."




The base of the fingers of the Vitamin D Receptors contain a zinc molecule; i.e., low Zinc results in poor Vitamin D Receptor function.

[jimmylegs]

nice finds LC. there are a few related tidbits under an older thread, which i'll dig up and link over to when i have a sec to go digging.

[lyndacarol]

More mentions of "zinc fingers" – zinc plays a key role!… (But most of this is over my head!)

Mutations in the vitamin D receptor and hereditary vitamin D-resistant rickets (2014)
David Feldman & Peter J Malloy
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4015455/
http://www.nature.com/bonekeyreports/20 ... 20145.html

"Although non-skeletal actions of vitamin D have been found in all tissues harboring a VDR, the most well-recognized actions of vitamin D take place in the intestine, kidney, parathyroid and bone, organs that regulate calcium phosphate metabolism that are responsible for normal mineralization of bone.…

"As discussed by Pike et al,1 the VDR is similar to the other members of the steroid-thyroid-retinoid receptor superfamily.…At the N terminus the VDR has a highly conserved DNA-binding domain (DBD) and in the C-terminal half of the protein, a more variable ligand-binding domain (LBD). The DBD contains two finger-like structures of 12-13 amino acids each. Four cysteine residues bind one zinc atom to form each zinc-finger structure.21 Regions of the DBD are critical both for DNA binding and also serve as a dimerization interface for interaction with the retinoid X receptor α (RXRα).22, 23 "

"In recent years there have been many new actions attributed to vitamin D that mediate important and wide-spread effects on a number of target organs and diseases that are unrelated to calcium bone homeostasis.5 These extra-skeletal effects include actions to reduce the risk of cancer, autoimmune diseases, infection, neurodegeneration, hypertension and cardiac disease, and so on."

5 Feldman D, Pike JW, Adams JS (eds). Vitamin D. Third Edn Elsiever: San Diego, CA, USA, 2011.
The VDR is present in selected cell types in most if not all tissues in the body and 1,25(OH)2D3/VDR complexes regulate multiple target genes in tissues containing the VDR.5 in article There is no doubt that vitamin D has important actions on bone and parathyroid cells,5 as discussed in many chapters in special issue.78, 79, 80 in article In recent years there have been many new actions attributed to vitamin D that mediate important and wide-spread effects on a number of target organs and diseases that are unrelated to calcium and bone homeostasis.5 in article



The T-box near the zinc fingers of the human vitamin D receptor is required for heterodimeric DNA binding and transactivation. (1995)
JC Hsieh, PW Jurutka, SH Selznick, MC Reeder, CA Haussler, GK Whitfield, MR Haussler
https://www.ncbi.nlm.nih.gov/pubmed/7575575

"The T-box mediates binding of retinoid X receptor (RXR) homodimers to DNA while the P- and D-box in the zinc fingers of steroid hormone receptors play roles in DNA-binding specificity and homodimerization, respectively. We investigated the function of these elements in the human vitamin D receptor (hVDR)…"

[jimmylegs]

here's one
Is there a link between premature ovarian failure and serum concentrations of vitamin D, zinc, and copper?
http://journals.lww.com/menopausejourna ... re.15.aspx
"Most women with POI [primary ovarian insufficiency] are deficient in vit D. Zinc, copper, and vit D seem to correlate with hormonal status in the participants. The present study may generate hypotheses for future studies that will investigate the possible mechanisms behind alterations in trace elements and vit D deficiency in women with POI and whether these changes could be used to screen for the risk of developing POI."

still don't have time to track down the relevant discussion from i think a couple yrs back. at some point will do.

[jimmylegs]

The essential role of zinc in growth
http://www.sciencedirect.com/science/ar ... 1795000038
Zinc is known to play a relevant role in growth and development. The basic mechanisms of action of this trace element are intimately linked to the structure and action of countless enzymes involved in many different metabolic processes. In this respect, when zinc specifically acts on cartilage growth it is involved in multiple enzymatic reactions which make this a multifactorial event. Thus, we may divide the actions of zinc into three distinct types:
1) action on taste and smell acuity, appetite regulation, and food consumption and regulation;
2) action on DNA and RNA synthesis stimulating a) cell replication and differentiation of chondrocytes, osteoblasts and fibroblasts; b) cell transcription culminating in the synthesis of somatomedin-C (liver), alkaline phosphatase, collagen and osteocalcin (bone), and c) protein, carbohydrate and lipid metabolism, that is intimately related to the mechanisms of smell, taste, appetite, and food consumption and utilization;
3) action on hormonal mediation by participating in a) GH synthesis and secretion is somatomammotroph cells, b) the action of GH on liver somatomedin-C production, and c) somatomedin-C activation in bone cartilage.
In addition to these multiple functions, zinc also interacts with other hormones somehow related to bone growth such as testosterone, thyroid hormones, insulin, and vitamin D3
On the basis of the above considerations, we conclude that the integration of these mechanisms contributes to the perfect physiological functioning of bone. In the presence of zinc deficiency, this homeostasis is impaired, causing the weight-height deficiency detected in several species studied, the human species in particular.

[jimmylegs]

Impaired recovery from peritoneal inflammation in a mouse model of mild dietary zinc restriction (Phillips et al, 2016)
https://www.ncbi.nlm.nih.gov/pubmed/26627196
abstract excerpts
"SCOPE:
Mild dietary zinc (Zn) deficiency is wide-spread in human populations, but the effect on Zn-dependent processes of immune function and healing are not well understood. The consequences of mild dietary Zn restriction were examined in two mouse models of inflammation and recovery
METHODS AND RESULTS:
Male C57BL/6 mice were fed a Zn adequate diet (ZA, 30 mg Zn/kg diet), or diets containing sub-optimal Zn levels (ZM, 15 mg Zn/kg diet; ZD, 10 mg Zn/kg diet) for 30 days before a thioglycollate peritonitis challenge. Plasma lipid profiles were distinct, with greater Zn restriction resulting in a greater impact on metabolites. The milder ZM diet was selected for immune studies.
CONCLUSION:
Mild Zn deficiency enhances local inflammatory responses, amplifying macrophage functions and delaying recovery from acute insults within the peritoneum."

full text excerpts:
"3.3 Influence of mild dietary Zn restriction on macrophage activities following peritoneal inflammation
Observations summarized above indicate that even the mildest dietary Zn restriction results in a reduction of circulating retinoic acid, vitamin D metabolite 3-Deoxyvitamin D3, and increased PA O-36:5, while a greater zinc restriction altered a larger number of metabolites with greater amplitude.
4 Discussion
Among the lipids that could be identified, a general pattern emerged that indicated a low-grade systemic state of inflammation and oxidative stress, with evidence that some vitamins are depleted even in the mildest state of Zn restriction.
Our study suggests that even mild Zn restriction can lead to such disturbances, implicating Zn as a potential driver of disturbances in other micronutrients. Reports in the literature suggest that disturbances in systemic inflammation and oxidative stress may be a characteristic throughout the spectrum of Zn deficiency [5, 24, 25]. Our observations suggest that even in milder states of Zn deficiency, protocols of repletion may fail without attention to imbalances in other micronutrients or products of metabolism that are generated by chronic low-grade inflammation and oxidative stress."

[jimmylegs]

again not quite zinc *fingers*, but interconnection stuff
The effect of toxic doses of cholecalciferol (vitamin D3) on the serum zinc levels in rats (Guven et al, 1993)
https://www.ncbi.nlm.nih.gov/pubmed/7682831
abstract excerpt:
"In this study, toxic doses of vitamin D3 were injected subcutaneously (25 micrograms/d) to rats for 5 wk. It caused a significant increase in serum zinc levels (p < 0.02). On the other hand, no significant increase was detected in the other groups. Excessive amounts of vitamin D3 caused bone breakdown and increased the levels of zinc in blood."

[lyndacarol]

More mentions of "zinc fingers" – zinc plays a key role!… (But most of this is over my head!)

Mutations in the vitamin D receptor and hereditary vitamin D-resistant rickets (2014)
David Feldman & Peter J Malloy
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4015455/
http://www.nature.com/bonekeyreports/20 ... 20145.html

"Although non-skeletal actions of vitamin D have been found in all tissues harboring a VDR, the most well-recognized actions of vitamin D take place in the intestine, kidney, parathyroid and bone, organs that regulate calcium phosphate metabolism that are responsible for normal mineralization of bone.…

"As discussed by Pike et al,1 the VDR is similar to the other members of the steroid-thyroid-retinoid receptor superfamily.…At the N terminus the VDR has a highly conserved DNA-binding domain (DBD) and in the C-terminal half of the protein, a more variable ligand-binding domain (LBD). The DBD contains two finger-like structures of 12-13 amino acids each. Four cysteine residues bind one zinc atom to form each zinc-finger structure.21 Regions of the DBD are critical both for DNA binding and also serve as a dimerization interface for interaction with the retinoid X receptor α (RXRα).22, 23 "

"In recent years there have been many new actions attributed to vitamin D that mediate important and wide-spread effects on a number of target organs and diseases that are unrelated to calcium bone homeostasis.5 These extra-skeletal effects include actions to reduce the risk of cancer, autoimmune diseases, infection, neurodegeneration, hypertension and cardiac disease, and so on."

5 Feldman D, Pike JW, Adams JS (eds). Vitamin D. Third Edn Elsiever: San Diego, CA, USA, 2011.
The VDR is present in selected cell types in most if not all tissues in the body and 1,25(OH)2D3/VDR complexes regulate multiple target genes in tissues containing the VDR.5 in article There is no doubt that vitamin D has important actions on bone and parathyroid cells,5 as discussed in many chapters in special issue.78, 79, 80 in article In recent years there have been many new actions attributed to vitamin D that mediate important and wide-spread effects on a number of target organs and diseases that are unrelated to calcium and bone homeostasis.5 in article

Here is Dr. David Feldman, the author above, with mention again of zinc fingers:

Vitamin D: It's Not Just For Bones Anymore (34 minutes), Dec 12, 2007
David Feldman, MD, Stanford School of Medicine Medcast lecture series


Historic understanding of vitamin D: necessary to prevent rickets (in children) and osteomalacia (in adults)
Rickets/osteomalacia is vitamin D deficiency disease; it is soft bones because the osteoid, the collagen matrix, is not mineralized and hardened.
@4:10 Excellent Diagram of physiology of the vitamin D metabolic pathways
@8:26 Vitamin D action on calcium balance and bone homeostasis (explanation of PTH)
@10:17 New idea: Vit D involved with alopecia
@14:39 ( ) Zinc Fingers