Zinc improves Akt and Nrf2 signalling Zinc increases Akt phosphorylation (results in increased activity) Akt inhibits Fyn - the nuclear exporter of Nrf2 Zn supplement prevented the effects of TPEN and also increased Akt and GSK-3β phosphorylation with a decrease in Nrf2 nuclear exporter, Fyn. All these effects of Zn were abolished by Akt inhibitor. Therefore, Zn up-regulates Nrf2 function via activating Akt-mediated inhibition of Fyn function. (R1)

What is RET? RET stands for Reverse Electron Transport. RET is produced when electrons from ubiquinol are transferred back to respiratory complex I, reducing NAD+ to NADH. This process generates a significant amount of ROS. (R1) Recent studies have highlighted an important role for reverse electron transport (RET) in producing mtROS. RET occurs when the pool of coenzyme Q (CoQ) is over‐reduced with electrons from respiratory complex II.

Activation of HIF1 Cofactors and substrates involved in HIF1 activation: TODO (succinate, iron, lack of oxygen) Changes initiated by HIF-1 Highlights HIF-1 stops Fe-S clusters assembly by reducing expression of ISCU1/2 and NDUFA4L2 (via miR-201) Decreased Fe-S clusters assembly represses mito respiration and ETC, by decreasing Complex I activity Import of glucose is increased Lactate level increases because of the shift to glycolysis mitochondrial-selective autophagy is induced All these changes allow to reduce ROS Several studies have shown that HIF-1 reduces cellular ROS production by switching energy production from oxidative phosphorylation to glycolysis via multiple pathways (6).

Disorders that have PPI in common Thus, as reviewed in some detail in Braff et al. (2001), studies prior to 2001 demonstrated that PPI deficits are also evident in patients with schizotypal personality disorder, Obsessive Compulsive Disorder (OCD), Tourette’s Syndrome, and Huntington’s Disorder, and under some experimental conditions PTSD. This group of disorders has been suggested to reflect a family of disorders which can be characterized as having deficits in the gating of motor (Huntington’s, Tourette’s), sensory (schizophrenia), and/or cognitive information (OCD).

Valve-role to reduce SAMe/SAH ratio The primary role of GNMT is to methylate glycine, to produce sarcosine. GNMT enzyme serves a role of pressure-release valve that reduces the level of SAMe and it’s controlled by the level of pentaglutamated 5-MTHF. S-adenosylmethionine was decreased significantly (GNMT– versus GNMT+ cells = 3,195.8 ± 114.1 versus 2,313.4 ± 134.0 [pmol/mg protein], P < 0.001) and S-adenosylhomocysteine increased (GNMT– versus GNMT+ cells = 18.

CSE in the brain However, recent studies have demonstrated that CSE is both present and active in the brain (17, 18) and that H2S is in fact detected in the brains of transgenic mice lacking CBS (19). The major role of CSE in H2S biogenesis in the peripheral system has been convincingly demonstrated in CSE knock-out mice, which exhibit significantly reduced H2S levels in the serum and lower H2S production rates in aorta and heart (20).

Co-activator of PPAR-gamma PGC-1α is a co-activator of the nuclear receptor PPARγ, and it is highly expressed when energy requirements are high. PGC-1α is not expressed in tissues such as myocardium, skeletal muscle, nervous system, liver, kidney, and adipose tissue, and mainly regulates the synthesis of mitochondrial proteins (including respiratory chain complex subunits) by activating the nuclear transcription factor NRF1. (R6) Regulation (from Wikipedia) PGC-1α is thought to be a master integrator of external signals.

Typical lab tests I would do to figure out why a person may have tics or Tourette syndrome Blood tests Plasma Homocysteine (blood, fasting) Ferritin (blood) Active B12 / Transcobalamin II (blood) Complete Blood Count (CBC) Folate (blood, fasting) Vitamin D (at least the active 1,25-OH-D3. Ideally both active and inactive forms) Plasma amino acids (blood, fasting) Essential Fatty Acids (finger prick at home, mailed to the lab) Plasma (or serum) total porphyrins Urine Organic acids test (morning urine) Metals in urine (urine) Hair Hair Mineral Tissue Analysis (hair) These allow to check several things: mineral deficiencies, heavy metals presence, status of amino acids, vitamin deficiencies and state of iron and methionine cycle.

WORK IN PROGRESS Regulation of VDR Human cytomegalovirus induces Vitamin D resistance Vitamin-D supplementation is considered to play a beneficial role against multiple viruses due to its immune-regulating and direct antimicrobial effects. In contrast, the human cytomegalovirus (HCMV) has shown to be resistant to treatment with vitamin D in vitro by downregulation of the vitamin-D receptor. (R6) Impairment from low Methylation potential Low methylation potential inactivates vitamin D signalling by disrupting interaction between VDR and PGC1a, and by increased destruction of VDR due to over-expression of HSP90:

Hepcidin is a peptide hormone secreted by the liver in response to iron loading and inflammation, it controls the export of iron from duodenal epithelial cells, hepatocytes and macrophages and consequently influences the level of serum iron available for the bone marrow and other tissues heavily dependent on iron supply (R1) Hepcidin in Iron overload and iron deficiency Hepcidin is the central regulator of systemic iron homeostasis. Dysregulation of hepcidin production results in a variety of iron disorders.