Archive September 2015

Zinc, Hedgehog Autoprocesssing, and Chronic Disease!

Zinc is an essential trace mineral with a wide range of biological functions. Hedgehog (Hh) pathway is a key regulator of cell growth and development that helps to establish the body plan of all animals with bilateral symmetry. In many diseases, zinc deficiency and elevated level of Hh ligand co-exist, including prostate cancer, lung cancer, ovarian cancer, and autism. In this study, researchers demonstrate that there is a link between zinc and Hh signaling. The Hh ligand, which is the upstream activator of Hh signaling, originates from Hh autoprocessing. In an in vitro Hh autoprocessing assay, researchers showed that zinc inhibits Hh autoprocessing. They then demonstated that zinc inhibits Hh autoprocessing in a cellular environment. They found that zinc binds the active site residues of the Hh autoprocessing domain to inhibit autopreocessing. In normal physiology, zinc likely acts as a negative regulator of Hh autoprocessing and inhibits the generation of Hh ligand and Hh signaling. According to corresponding author Chunyu Wang, under normal conditions “zinc will inhibit the production of the Hh ligand, and therefore inhibit the Hh pathway, but if there is a zinc deficiency, the pathway can be activated due to enhanced production the Hh ligand.’ Their data suggest a causal relationship between zinc deficiency and the overproduction of Hh ligand.

J Xie, et al. Zinc Inhibits Hedgehog Autoprocessing: Liking Zinc Deficiency with Hedgehog Activation. Journal of Biological Chemistry, 2015; jbc.M114.623264 DOI: 10.1074/jbc.M114.623264

ML Martialay. Zinc Deficiency Linked to Activation of Hedgehog Signaling Pathway. RPI News. Apr 16, 2015

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Zinc deficiency linked to systemic inflammation and chronic disease!

A recent study helps explain how zinc deficiency impacts chronic diseases including cardiovascular disease, diabetes, autism and cancers including prostate, lung, ovarian and breast cancer. Zinc status is especially important for seniors, 40% of whom do not consume enough zinc, and their bodies do not appear to use or absorb zinc efficiently. In one study researchers showed that zinc deficiency induced an increase in inflammatory response in cells, and showed that reducing zinc caused improper immune cell activation and dysregulation of IL-6 cytokine, a protein that affects inflammation in the cell. In an animal model they found that older mice had low zinc levels that corresponded with increased chronic inflammation and decreased IL-6 methylation, an epigenetic mechanism used to control gene expression. They found the same decrease in IL-6 methylation in human immune cells from elderly people. Because the body doesn’t store zinc, adequate intake is crucial. Professor Ho, the lead investigator stated “zinc deficiency is probably a bigger problem that most people realize” and “Preventing that deficiency is important.”

CP Wong,NA rinaldi, E Ho. Zinc deficiency enhanced inflammatory response by increasing immune cell activation and inducing IL6 promoter demethylation. Molecular Nutrition and Food Research, 2015; DOI: 10.1002/mnfr.201400761

Oregon State U. “Zinc deficiency linked to immune system response, particularly in older adults”. ScienceDaily, 23 March 2015

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Vitamin D for Alzheimer’s and Dementia?

Researchers from UC Davis Alzheimer’s Disease Center and Rutgers University wished to assess associations between Vitamin D (VitD) status and trajectories of change in subdomains of cognitive function. They conducted a cohort study of 382 ethnically diverse, older participants in an outpatient clinic (Feb. 2002-Aug. 2010) with baseline assessment and yearly follow-up visits. Serum 25-OHD levels were measured and categorized as deficient (< 12mg/mL), adequate (20 -49 ng/mL) or high (50 ng/mL or higher). Note: to convert to nanomoles per liter, multiply by 2.496. Subdomains of cognitive function were assessed using the Neuropsychological Assessment Scales. Associations were evaluated between 25-OHD levels (as continuous and categorical [deficient, insufficient or adequate]) and trajectories of cognitive decline. Low VitD status was associated with accelerated decline in cognitive function. According to Joshua Miller, professor in the Dept. of Pathology and Laboratory Medicine at the time the research was conducted (currently professor & chair of the Dept. of Nutritional Sciences at Rutgers University), VitD insufficiency was associated with significantly faster declines in both episodic memory and executive function performance. The researchers found that with over five years of follow-up, VitD deficient individuals experienced cognitive declines that were 2 to 3 times faster than those with adequate VitD levels.

JW Miller, et al. Vitamin D Status and Rates of Cognitive Decline in a Multiethnic Cohort of Older Adults. JAMA Neurology Publishes online Sept 142015 doi:10.1001/jama-neurol.2015.2115
Neuroscience News Sept 14, 2015

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Severe MTHFR deficiency treatment with TMG!

Researchers investigated the effect of trimethylglycine (TMG-also known as betaine) treatment on development and survival in patients with severe methylenetetrahydrofolate reductase (MTHFR) deficiency. Deficiency of (5,10)-MTHFR is a frequent remethylation disorder, and clinical consequences vary greatly depending on the degree of enzyme deficiency. Carriers of the prevalent mild thermolabile variant are at risk for moderate hyperhomocysteinemia, but do not have neurological symptoms. On the other hand, severe MTHFR is rare, and presentation is in infancy or early childhood. The inability to remethylate homocysteine to methionine induces profoundly elevated homocysteine and decreased methionine concentrations in blood. Untreated patients either die or, if they survive, exhibit severe developmental delay and a life-long dependence on care. Researchers identified 15 case reports and case series totaling 36 patients with severe MTHFR deficiency, and compared the outcomes in treated vs. untreated patients, and early vs. late-treated patients. The main outcons and measures was survival and psychomotor development. Results showed that 11 of 36 patients died (31%), all of which occurring in patients who did not receive treatment or in whom treatment was delayed. In contrast, all 5 early-treated patients survived. Additionally, psychomotor development in surviving patients receiving treatment was normal in all 5 early-treated patients, but in none of the surviving patients with delayed treatment. Researchers concluded that early treatment prevents mortality and allows normal psychomotor development in patients with severe MTHFR deficiency, highlighting the importance of timely recognition through newborn screening.

EF Diekman, et al. Survival and Psychomotor Development with Early Betaine Treatment in Patients with Severe Methylenetetrahydrofolate Reductase Deficiency. JAMA Neurol. Feb 2014, Vol 71, No. 2

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Vitamin A Directs Immune Cells to the Intestines!

We know that vitamin A deficiencies lead to increased susceptibility to disease and low concentrations of immune cells in the mucosal barrier lining the intestines. Researchers from Purdue University found that the vitamin A metabolite retinoic acid (RA), is necessary for two of the three types of innate immune cells residing in the intestine (ILC1 and ILC3) to find their proper place. Innate lymphoid cells (ILCs), which are present in barrier tissues, gather in the lymph nodes where RA activates specific receptors upon two of the three subsets, acting as homing devices for the intestines. These immune cells then travel through the circulatory system, the receptor grab onto and bind to molecules in the intestines and keep the cells in place. They need to be concentrated in mucosal barrier tissues, because they are the point of entry from many infections from bacteria, viruses and parasites. These innate immune cells reside under the epithelial cell barrier that lines the intestine in a healthy system. When a pathogen penetrates the epithelial barrier, innate immune cells respond, attacking the pathogen to keep it from penetrating farther into the tissue or reaching the bloodstream. Researchers concluded that distinct programs regulate the migration of ILC subsets to the intestine for regulation of innate immunity. Interestingly, Vitamin D has been shown to work in a similar way to guide immune cells to the skin.

MH Kin, EJ Taparowsky, CH Kim. Retinoic acid differentially regulates the migration of innate lymphoid cell subsets to the gut. Immunity Vol 43, Issue 1, p107-119, 21 July 2015
Purdue study finds vitamin A directs immune cells to the intestines. July 9, 2015. http://www.purdue.edu

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