The Rhyothemis princeps Brain Externalization Project

Someone on a forum asked why iNOS inhibitors (e.g., agmatine, anatabine) would be beneficial and my reply follows: Too much NO generates peroxyynitrite and can cause nitrosative and oxidative stress, causing production of nitrated/oxidized alpha synuclein and oxidized dopamine. NO generated by iNOS in glial cells is particularly problematic for neurons. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408780/ This is in contrast with NO generated by the endothelium during exercise, which acts on the endothelium (autocrine signalling) which in turn produces good things like BDNF (the vascular endothelium can be thought of as an endocrine organ). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2791344/ https://youtu.be/lhZZS6_-Cg4 There are lots of studies on iNOS inhibitors in models of Parkinson's and other neurodegenerative disease. https://pubmed.ncbi.nlm.nih.gov/31192483/ Tobacco use and Solanaceae vegetable consumption are associated with reduced risk of PD. If causal, the relations

Yesterday I watched two excellent presentations on Freidreich ataxia (still trying to use the proper nomenclature convention) from back in 2011: Notes: 5:44 frataxin is essential for muticellular eukaryotes (but not single celled organisms) frataxin is needed for the production of iron-sulfur clusters (aconitase is an important TCA enzyme that includes an iron-sulfur cluster that is particularly vulnerable to oxidation) 13:07 Indeed! & also part of the urea cycle 18:35 Reduction in frataxin leads to iron accumulation in the mitochondrion   38:26 summary of therapeutic approaches in relation to hypothetical vicious cycle in FA EPO - erythropoietin increases expression of genes related to iron utilization (lactoferrin and Wim Hof method breathing increase EPO) HDAC inhibitors increase expression of frataxin (butyrate / tributyrin are HDACi) pioglitozone increases mitochondrial biogenesis (PQQ & urolithin A do the same) I think neuroinflammation should be included as part

Adaptation to flight has a big impact on antioxidant defenses; recently this paper came up in my feed (thank Google): Adaptation of the master antioxidant response connects metabolism, lifespan and feather development pathways in birds [2020] - https://www.nature.com/articles/s41467-020-16129-4 “ Birds (Aves) display high metabolic rates and oxygen consumption relative to mammals, increasing reactive oxygen species (ROS) formation. Although excess ROS reduces lifespan by causing extensive cellular dysfunction and damage, birds are remarkably long-lived. We address this paradox by identifying the constitutive activation of the NRF2 master antioxidant response in Neoaves (~95% of bird species), providing an adaptive mechanism capable of counterbalancing high ROS levels. We demonstrate that a KEAP1 mutation in the Neoavian ancestor disrupted the repression of NRF2 by KEAP1, leading to constitutive NRF2 activity and decreased oxidative stress in wild Neoaves tissues and cells. O

From a  discussion with OS on MedCram (which had gone way OT from sex differences relating to covid-19 pathology - link to discussion thread ): re: AMPK bat genetics - not much yet, but there's this one Positive Selection of Cereblon Modified Function Including Its E3 Ubiquitin Ligase Activity and Binding Efficiency With AMPK - https://pubmed.ncbi.nlm.nih.gov/30836149/ Note the same modification is present in both bats and rodents. Hamsters do seem to have some protection from oxidative stress, but they are not particularly long-lived as are bats. They are what's termed 'r selected' - with a life history characterized by high reproductive rate and short life-span. Here's an article that points out that oxidative stress defenses may be tissue specific and that hamsters may not have as much protection in the brain: Oxidative Damage Does Not Occur in Striped Hamsters Raising Natural and Experimentally Increased Litter Size - https://www.ncbi.

Aconitase (aconitate hydratase) is a tricarboxylic acid cycle (TCA) enzyme that converts citrate to iso-citrate via cis-aconitate. It has an iron sulfur cluster that interacts directly with substrate and is prone to oxidation by superoxide. Inactivation of aconitase has been  implicated in neurodegenerative diseases [1]. A mutation in ACO2 is associated with Infantile Cerebellar-Retinal Degeneration [2]. from [2] : "The active (4Fe-4S) cluster was shown to be extremely sensitive to superoxide-mediated inactivation 10 and a decrease in AH activity was observed in several neurodegenerative diseases associated with the development of oxidative stress, in particular Friedreich ataxia [MIM 229300 ], Parkinson [MIM 168600 ], and Alzheimer disease [MIM 104300 ], 11 as well as in mice lacking mitochondrial superoxide dismutase. 12 The reduced AH activity in endomyocardial biopsies of individuals with Friedreich ataxia was attributed not only to oxidative stress but also to the im