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Zinc ion binding genes associated with disease progression

PostPosted: Tue Jun 11, 2013 2:52 am
by NHE
Here's an interesting paper. It shows that several zinc ion binding genes are associated with a more progressive disease outcome. For example, in progressive patients, KLF4 is upregulated. In contrast, another zinc ion binding gene, S100B, is downregulated. I believe that this paper illustrates that the role of zinc binding proteins in MS progression is complex and not easily categorized. The full paper is freely available.

Zinc-ion binding and cytokine activity regulation pathways predicts outcome in relapsing–remitting multiple sclerosis ... 9-0235.pdf

Multiple sclerosis (MS) is a demyelinating disease characterized by an unpredictable clinical course with intermittent relapses that lead over time to significant neurological disability. Clinical and radiological variables are limited in the ability to predict disease course. Peripheral blood genome scale analyses were used to characterize MS patients with different disease types, but not for prediction of outcome. Using complementary-DNA microarrays we studied peripheral-blood gene expression patterns in 53 relapsing–remitting MS patients. Patients were classified into good, intermediate and poor clinical outcome established after 2-year follow-up. A training set of 26 samples was used to identify clinical outcome differentiating gene-expression signature. Supervised learning and feature selection algorithms were applied to identify a predictive signature that was validated in an independent group of 27 patients. Key genes within the predictive signature were confirmed by quantitative reverse transcription–polymerase chain reaction in an additional 10 patients. The analysis identified 431 differentiating genes between patients with good and poor clinical outcome (change in neurological disability by the expanded disability status scale was-0•33±0•24 and 1•6±0•35,P=0•0002, total number of relapses were 0 and 1•80±0•35,P=0•00009, respectively). An optimal set of 29 genes was depicted as a clinical outcome predictive gene expression signature and classified appropriately 88•9% of patients. This predictive signature was enriched by genes related biologically to zinc-ion binding and cytokine activity regulation pathways involved in inflammation and apoptosis. Our findings provide a basis for monitoring patients by prediction of disease outcome and can be incorporated into clinical decision-making in relapsing–remitting MS.

The clinical outcome predictive gene expression signature was enriched by zinc-ion binding and cytokine activity pathways. Activation of mononuclear cells in MS involves proinflammatory cytokines such as IFN-g and tumour necrosis factor (TNF)-a that promote disease activity. Conversely, anti-inflammatory cytokines such as TGF-b, interleukin (IL)-4 and IL-10 decrease proinflammatory activation. The molecular transcripts we identified regulate the balance of these opposing effectors and are thus associated with clinical outcome prediction. The zinc-ion binding genes in the predictive signature include KLF4, known to be activated by (signal transducers and activators of transcription (STAT1), which is activated by S100B [25], and increases IFN-g expression [26], a well-known proinflammatory cytokine involved in MS disease activity.

KLF4 is markedly induced in response to IFN-g, lipolpolysaccharide (LPS) or TNF-a. Over-expression of KLF4 is associated with macrophage activation marker inducible nitric-oxide synthase and with TGF-b1 inhibition. KLF4 interacts with the NF-kB family member p65 (RelA), and has an important role as a regulator of key signalling pathways that control macrophage activation [27].

The S100B gene protein is known to be involved in intracellular and extracellular regulatory events within the central nervous system. S100B was found to be elevated in acute brain lesions of RRMS patients [28], and its plasma levels were reported elevated in RRMS patients responding to IFN-b treatment [29]. This is in accordance with our findings, demonstrating decreased S100B expression in patients with poor outcome. Additionally, a novel association of the zinc-ion binding gene CA11 was identified in the network reconstruction.

The balance between T helper 1 (Th1) and Th2 immune responses plays an important role in the pathogenesis of MS. In addition to the recognition of encephalitogenic epitopes, the ability to produce Th1 cytokines is an important functional requirement by which myelin-reactive T cells mediate the disease, while Th2 cells secreting IL-10 suppress the ongoing inflammation. The cytokine activity-enriched gene family identified in the prediction signature included CCL17, MUC4, PTN and VEGFB. CCL17 displays chemotactic activity for Th2 lymphocytes [30], and its activity is well known to be enhanced by the Th2-related cytokines IL-4 and IL-13, leading to inhibition of inflammation. MUC4 expression is dependent upon IL-4 and IL-13 levels [31–33]. PTN is involved in regulation of cell-mediated immunity [34], and negatively regulates VEGF activity [35]. These findings demonstrate that the poor clinical outcome predictive signature in RRMS is affected mainly by decreased Th2 cytokine activity and aberrant regulation of inflammation.

In conclusion, the predictive outcome gene expression signature is sensitive to RRMS evolution and as such provides a new perspective on disease progression. Moreover, our findings suggest that the co-stimulatory regulatory pathways of zinc-ion binding and cytokine activity-related genes within the predictive signature may serve as new targets for therapeutic interventions. Finally, the predictive signature may enable planning of tailored therapeutic strategies, and allow delineation of patients at high risk who may benefit from early therapy.

Re: Zinc ion binding genes associated with disease progressi

PostPosted: Tue Jun 11, 2013 4:49 am
by jimmylegs
genetic expression is so interesting. found this study:

Gene expression profiling in multiple sclerosis: A disease of the central nervous system, but with relapses triggered in the periphery? (2010) ... f-2009.pdf

I like this bit re variable genetic expression in relapse vs remission:

"We detected a large amount of differentially regulated genes in the CSF when comparing samples from untreated MS patients and controls (939 significant probe sets) whereas the same comparison of PBMC samples detected no significantly altered expression. When samples from MS patients in different stages, i.e., in relapse or remission, were compared, the case was the opposite: large number of regulated genes was seen in PBMCs (266 significant probe sets) but none in CSF. These results are noticeable, since differential expression of numerous genes in PBMCs between active and silent phases of MS have not been convincingly shown before. Moreover, the fact that the simultaneously obtained CSF samples showed lack of differential expression implies that disease bouts in MS may primarily depend on events outside of the CNS not affecting the cells of the CSF. These events may include pathogens and other environmental triggers of disease bouts, although no infections were reported among the included patients at time of sampling."

fortunate that genetic expression can be reprogrammed to some extent, especially where cell turnover rates are high.

ooh I just thought i'd have a go at finding a related study and searched on:
gene expression high cell turnover

found this interesting title instead:

Blood cell gene expression associated with cellular stress defense is modulated by antioxidant-rich food in a randomised controlled clinical trial of male smokers

"The subjects in both intervention groups received food items weekly. In the antioxidant group these included green tea, dog rose juice, cranberry juice, aronia juice, unsweetened bilberry juice, bilberry jam, bilberries, blackberries, strawberries, raspberries, pomegranate, dark blue grapes, Brussels sprouts, broccoli, red cabbage, kale, blue potatoes, tomatoes, dark chocolate, bread with pecan nuts and sunflower seeds, walnuts, olive oil, rosemary, thyme and oregano. The kiwifruit group received a bag of 21 kiwifruits...

Identification of significantly differentially expressed genes
By applying BAMarray, we identified 44 gene transcripts as differentially expressed in the antioxidant-rich diet group as compared to the control group (adjusted for multiple testing). In the kiwifruit group, nine gene transcripts were significantly altered compared to the control group."

Re: Zinc ion binding genes associated with disease progressi

PostPosted: Tue Jun 11, 2013 8:28 am
by Annesse
I think zinc is not only lacking in patients with MS, I think it is also being dysregulated. And--the reason it is lacking is the same reason it is being dysregulated. Zinc is a heavy metal ion and it needs to be tightly controlled.

I believe you can trace every symptom and valid scientific finding in MS directly back to the missing enzymes DNase1 and protease. This can be done with zinc.

Zinc is very much associated with “high protein” foods. According to the National Institutes of Health Office for Dietary Supplements, the main source for zinc is animal–based protein foods, such as poultry, red meat, oysters, eggs, seafood, and milk (National Institutes of Health, 2011). The inability to break down these foods would account for the low levels of zinc found in MS.

Here is some study information on the connection to proteins and zinc absorption.

J. Nutr. May 1, 2000 vol. 130 no. 5 1378S-1383S
Dietary factors influencing zinc absorption
Protein-quantity and quality.
“…The amount of protein in a meal is positively correlated to zinc absorption (Sandström et al. 1980). When compiling results from several studies with humans to whom various protein sources and amounts had been administered, fractional zinc absorption increased in a linear fashion with increasing protein content (Sandström 1992). It should also be emphasized that protein is a major source of dietary zinc that results in an increased zinc intake with increased protein content of the meal. Thus, in general, increased dietary protein leads to increased zinc intake and a higher bioavailability of the zinc provided.

The type of protein in a meal will also affect zinc bioavailability. Animal protein (e.g., beef, eggs, cheese) has been shown to counteract the inhibitory effect of phytate on zinc absorption from single meals (Sandström and Cederblad 1980), but this may be due to amino acids released from the protein that keep the zinc in solution…”

[Notice the above study references amino acids found in the proteins that "keep zinc in solution". So, not only does zinc come from high protein foods, but the ability to properly bind it also comes from proteins.]

In the following study the researchers stated that their results suggest that mechanisms which govern zinc cellular availability, compartmentalization of zinc or the binding of zinc to cell surface membranes may be altered in patients with MS.

Ann Neurol. 1986 Dec;20(6):712-5.
Zinc in multiple sclerosis. II: Correlation with disease activity and elevated plasma membrane-bound zinc in erythrocytes from patients with multiple sclerosis.
Ho SY, Catalanotto FA, Lisak RP, Dore-Duffy P.
“…Results suggest that mechanisms which govern cellular availability, compartmentalization of Zn, or the binding of Zn to cell surface membranes may be altered in patients with MS, and that these mechanisms vary with disease activity.”

Even though zinc is an essential requirement for a healthy body, zinc, like iron, is a heavy metal ion and must be carefully controlled. Heavy metal ions are toxic to cells. Our bodies take great care to make sure metals go only where they need to and in exactly the right amount.
Scientists have discovered that metals, such as zinc, have special “chaperone” proteins that safely escort the metal through the interior of the cell and deliver it to the specific site where it is needed. Zinc also has “binding proteins” to prevent it from accumulating within the cell and poisoning the cell. The essential amino acid histidine (which MS patients lack) is an essential component of zinc binding proteins, such as ZntR and Zur.

According to Thomas O’Halloran, professor of chemistry at Northwestern University, “The zinc regulatory system is so sensitive and finely tuned-at the femtomolar level-that the metal ions have no chance to float freely in the cell’s cytoplasm before they are bound up in ZntR or Zur. Free floating zinc just doesn’t exist” (Northwestern University, 2001).

Histidine is one of the essential amino acids found lacking in patients with MS. Without histidine the body would not be able to properly bind zinc. We know that patients with MS already lack one of the essential components to prevent zinc toxicity, but science doesn't fully understand the complexities involved in how the body protects itself from zinc, while at the same time benefiting from it.

The following study states that although zinc is an essential trace element, histidine (one of the binding proteins) is necessary to prevent zinc-induced neurotoxicity.

D-Histidine and L-histidine attenuate zinc-induced neuronal death in GT1-7 cells
Masahiro Kawahara,*a Yutaka Sadakane,b Hironari Koyama,c Keiko Konohac and Susumu Ohkawarac

Metallomics, 2013,5, 453-460

“Although zinc (Zn) is an essential trace element, excess Zn causes neuronal death following transient global ischemia and plays a central role in the pathogenesis of vascular-type dementia…both L-histidine and D-histidine exhibit the same neuroprotective activity…that histidine protects against Zn-induced neurotoxicity…”

In the following study the researchers found an association between “subnormal plasma histidine levels and impaired protein hydrolysis" in patients with MS.
(Altern Med Rev 2000;5(3):224-248.)

Transdermal histamine in multiple sclerosis,
part two: A proposed theoretical basis for its use.
George Gillson, MD, PhD,
Jonathan V. Wright, MD, Elaine DeLack, RN,
and George Ballasiotes, BSc, Pharm

“…Here we include preliminary findings on the impairments of digestion and assimilation in MS patients seen in a private clinic. Although only a small number of patients was surveyed, an association was found between impaired gastric acid production, impaired protein hydrolysis, and subnormal plasma histidine levels in patients with MS. Impaired digestion might, therefore, impair the ability of MS patients to synthesize histamine…Various mechanisms of action are suggested, including: enhanced gastric acid and pancreatic enzyme secretion…We also discuss the observed failure of digestive function in MS…”

By restoring your body's ability to digest proteins, you will be able to not only properly absorb zinc, but you will also be able to properly regulate it.

Re: Zinc ion binding genes associated with disease progressi

PostPosted: Tue Jun 11, 2013 8:48 am
by Annesse
Here is an additional study on zinc and histidine.

Effects of amino acids on zinc transport in rat erythrocytes.
S P Aiken, N M Horn, and N R Saunders
“A significant proportion of plasma zinc exists complexed with amino acids…These properties suggest that zinc is being transported as a zinc-histidine complex, utilizing an amino acid carrier system…”

Re: Zinc ion binding genes associated with disease progressi

PostPosted: Tue Jun 11, 2013 10:04 am
by jimmylegs
I think we have to consider primary zinc deficiency as well, not just secondary. poor zinc status could affect the expression of relevant genes and protease activity

Large doses of zinc oxide increases the activity of hydrolases in rats.
"ZnO supplementation dose dependently increased the plasma Zn concentration and significantly increased amylase, lipase, trypsin and total protease activity in pancreatic homogenates and small intestinal contents."
(since the dose is measured in mgs per kg of diet, that's a bit tough to translate into dose per kg of rat, or per kg of person for that matter. still.)

there are diverse explanations for the lower zinc status seen in many ms patients. in my case it was a long history of veganism. I had quite seriously deficient zinc status, and there wasn't much in the way of protein going on either.

question re histidine. "The essential amino acid histidine (which MS patients lack)" can you provide a research link for this statement? I wouldn't mind checking that out. on reading that the foods highest in histidine include beef, turkey, lamb, chicken, and so on, I wouldn't be surprised if I was low in this essential amino acid upon diagnosis!

Re: Zinc ion binding genes associated with disease progressi

PostPosted: Tue Jun 11, 2013 2:11 pm
by Annesse
Hi Jimmy~I posted the histidine info in my post. Here is some additional information on the lack of essential amino acids in MS.

Studies confirm that MS patients lack numerous essential amino acids. In the following study entitled “Plasma and cerebrospinal fluid tryptophan in multiple sclerosis and degenerative diseases” researchers found that MS patients had diminished levels of the essential amino acids tryptophan, leucine, isoleucine, valine, and phenylalanine. Leucine, isoleucine, and valine are the three branched chain amino acids (BCAAs). The term “branched chain” refers to their molecular structure. The BCAAs are used by the muscles for energy and in the regulation of protein synthesis. The patients also lacked the amino acid tyrosine. Tyrosine is an amino acid the body makes from the essential amino acid phenylalanine.

J Neurol Neurosurg Psychiatry. 1979 July; 42(7): 640–641.
Plasma and cerebrospinal fluid tryptophan in multiple sclerosis and degenerative diseases.
F Monaco, S Fumero, A Mondino, and R Mutani
“…Tryptophan and competing neutral amino acid levels were found to be diminished in the plasma of patients with multiple sclerosis and degenerative diseases…Tryptophan, leucine, isoleucine, valine, tyrosine, and phenylalanine were all diminished in the plasma of patients with multiple sclerosis…”

In the following study the researchers found that patients with MS had lower levels of the essential amino acids methionine (Met), valine (Val), phenylalanine (Phe), and lysine (Lys).

J Chromatogr. 1988 Dec 28;459:237-44.
Quantitation of free amino acids in biological samples by high-performance liquid chromatography. Application of the method in evaluating amino acid levels in cerebrospinal fluid and plasma of patients with multiple sclerosis.
Qureshi GA, Baig MS.
“…lower levels of Met, Val, Phe and Lys in plasma of MS patients.”