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not a trial
Posted: Saturday, March 28, 2020 9:18 AM
Joined: 12/4/2011
Posts: 18314

but I did ;not  know where to post;

Lane Simonian
Posted: Saturday, March 28, 2020 10:45 AM
Joined: 12/12/2011
Posts: 4751

I did not like it when they changed the name of this forum to clinical trials.  Any study releated to any form of dementia belongs here.

I am in to grand theories these days and this study adds to that thinking.   In Alzheimer's disease and probably lewy body dementia, the ApoE4 gene increases the size of lipid rafts (composed of cholesterol and saturated fats) which are the medium by which the factors that increase the risk for Alzheimer's disease and dementia with lewy bodies are magnified.  The larger the size of the rafts the greater the risk for dementia if the various triggers for dementia are present.  

There are many triggers for dementia but there are four basic results: oxidation, nitration, inflammation, and misfolded proteins (such as amyloid, tau, and alpha synuclein).  The latter two (inflammation and misfolded proteins) further contribute to oxidation and nitration.  Different neurons (cholinergic versus dopamine) and different parts of the brain are damaged (the hippocampus and cortex versus substantia negra), but the processes that lead to this damage may be very similar.

For dementia with lewy bodies for instance:

Neuroinflammation and Oxidation/Nitration of α-Synuclein Linked to Dopaminergic Neurodegeneration

Nitrated/oxidized SYN was detected in these inclusions and abatement of microglia-derived nitric oxide and superoxide provided significant neuroprotection in neuron–glia cultures from M7KO mice

Nitric oxide and superoxide combine to form peroxynitrite; peroxynitrite causes inflammation (via activation of microglia) which in turn produces peroxynitrite.  Peroxynitrite scavengers potentially have a positive role to play in the treatment of lewy body dementia as it does for Alzheimer's disease.

A Role for Activated Microglia and Peroxynitrite in Lewy Body Diseases – Implications for Prevention and Control

Lewy body diseases – encompassing Parkinson’s disease, dementia with Lewy bodies, and Parkinson’s disease with late dementia – may reflect a vicious cycle of neuroinflammation in which aggregated alphasynuclein promotes microglial activation, and the peroxynitrite and cytokines produced by activated microglia in turn promote intraneuronal alpha-synuclein aggregation and neuronal death. If this model is correct, practical measures which dampen microglial activation and lessen peroxynitrite toxicity may aid the prevention and treatment of these disorders. Spirulina, a host of food polyphenols, DHA, astaxanthin, caffeine, a Mediterranean or plant-based diet, and exercise training have potential for blunting microglial activation. Measures which increase intraneuronal levels of urate and of glutathione – such as supplemental inosine, N-acetylcysteine, and phase 2 inducers – should mitigate the toxicity of peroxynitrite. Astaxanthin may suppress intraneuronal generation of superoxide and peroxynitrite by protecting the structure of mitochondrial inner membranes. Hence, it may eventually prove feasible to control or at least slow the progression of these devastating disorders with complex nutraceutical/lifestyle strategies.

I  am a dot connector: the problem is that some of these connections are hard to explain in clear English.

Posted: Tuesday, March 31, 2020 12:50 PM
Joined: 1/25/2020
Posts: 4

What study can you NOT add to your misguided thinking about peroxynitration Lane?  The reason you cannot explain it in clear english is because you have a fundamental misunderstanding of science.  True scientists understand the problems they study for their actual profession so well they can explain it to any audience, from kindergartners to other scientists.
Lane Simonian
Posted: Tuesday, March 31, 2020 1:27 PM
Joined: 12/12/2011
Posts: 4751

Lurker read the following and get back to me.

Also consider the following charts (ONOO- being peroxynitrite):

The reason that I struggle to explain it clearly is due to the complexity of the pathways involved and the variety of damage provoked.

Also this notion that I am somehow inventing things out of whole cloth has to end.  Some of the most respected scientists in the Alzheimer's field have offered an explanation very similar to what I have provided.  

I will repeat this once again: if all the risk factors for Alzheimer's disease lead to oxidation and nitration, if all the putative protective factors reduce oxidation and nitration, if all the features of Alzheimer's disease can be explained either directly or indicectly by oxidation and nitration, and all the trials that have shown effectiveness against Alzheimer's disease partially reverse oxidation and nitration, it is almost impossible to argue that oxidation and nitration have nothing to do with Alzheimer's disease (unless you are heavily invested in another hypothesis such as amyloid or highly disinvested in the use of antioxidants to treat the disease).  Other neurological diseases and conditions are more open to dispute regarding etiology, but some evidence supports the role of oxidation and nitration in these diseases as well.

Posted: Tuesday, April 7, 2020 1:29 PM
Joined: 2/17/2019
Posts: 315

Lurker, if you have a contrasting point of view, by all means, share it. But just insulting someone is not cool.

Lane learned a lot about science to help a family member, his information is invaluable and he keeps sharing it with the community out of a sense of compassion and generosity.

Lane Simonian
Posted: Sunday, April 19, 2020 10:08 AM
Joined: 12/12/2011
Posts: 4751

Thank you for your support HowDoYouDeal.  I don't mind criticism either as long as it is respectful.

I wanted to print this in its entirety because it is right on target.

Oxidative Stress: How has it been Considered in the Design of New Drug Candidates for Neurodegenerative Diseases?

Background: Oxidative stress is considered as one of the key players in the aetiology and progression of various neurodegenerative disorders (NDs). These pathologies include common and debilitating disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Although the clinical and neuropathological aspects of these disorders are distinct and most have their onset attributted to abnormal protein deposits as a crucial factor, all have a common and characteristic pattern of neuronal degeneration in anatomically or functionally related regions. To date, no cure is available for these diseases and the available therapies are symptomatic, being unable to change the course or progression of the underlying disease.

In recent years, we have observed a significant increase of interest to investigate antioxidative and anti-inflammatory effects of diverse classes of natural and synthetic compounds as promising drug candidates for the treatment of NDs. This interest is supported by many pathological conditions associated with overproduction of reactive oxygen species (ROS) and reactive nitrogen species (RNS), such as superoxide anion, hydroxyl radicals, hydrogen peroxide, lipid peroxyl radicals, nitric oxide and peroxynitrite. These species are commonly generated in many cellular systems, through enzymatic and nonenzymatic reactions, but in excess these species can attack key proteins, lipids and DNA, affect signal transduction pathways, destroy membranes and subcellular organelles, and cause subsequent apoptosis and cell death. Abundant literature data suggest that oxidative stress (OS) may induce not only cellular and membrane damage, but also DNA repair system breakdown or mitochondrial disfunction, contributing to a complex network of events related to energy supply, neurodegeneration and aging, a phenomena observed in AD or PD, for example. Increased ROS levels is a crucial and prompt consequence of oxidative stress and it is related to down-regulated by several defence systems including antioxidant enzymes or endogenous small-molecule antioxidants (e.g. superoxide dismutase, glutathione peroxidase, catalase, peroxiredoxins, tri-peptide glutathione, vitamins E and C). Conversely, decline in ROS levels has been evidenced in many other physiological processes like cellular signalling, pro-survival pathways or activation of transcription factors regulating cellular response to ROS. In this context, a number of hypotheses have been proposed recently to explain the complexity and multifactorial pathogenesis of AD, including oxidative stress as a pivotal player and, maybe, one of the major causative factors of NDs, unifying a number of other sequential or individual pathophysiological events. By this consensus, oxidative damage in the brain of patients is a result of excessive production of free radicals induced by insoluble and/or overproduced protein fragments, such as Aβ, α-synuclein, tau and hungtintin, with functional alteration in mitochondria, inadequacy in energy supply, production of inflammatory mediators, and alteration of antioxidante defenses. Thus, modulation of cellular oxidative process should lead to a novel concept in drug design and possibly a novel way for searching more effective disease modifying chemical entities, reinforcing the hope for, at least, a real clinical relief, if the cure still remains not possible.

Posted: Monday, April 20, 2020 4:23 PM
Joined: 1/25/2020
Posts: 4

Lane studies science as a hobby. An important distinction is Lane is not a scientist, and does not have any formal training as a researcher.  Lane has proven in other forums that he cannot properly critically evaluate scientific literature.  Lane has been asked to stop these types of posts in multiple other forums for this exact reason.

I do not doubt that Lane's heart is in the right place, in that he wants to help patients and their families.  However, he continues to ignore people with much more scientific knowledge and experience than he and insist he knows best, while posting these complicated scientific diagrams to make it seem like he knows what he's talking about while promoting unproven, ineffective, and potentially dangerous treatments to vulnerable patients and their caregivers.

The problem with countering Lane's bogus claims, any bogus claims really, is to do it properly takes much more time and effort than it took to make the original claim. Lane can mutate this actually very interesting post about the intersection of Parkinson's and Alzheimer's in five minutes by posting the top hit from his "peroxynitration+alpha-synuclein+Alzheimer's" search. Meanwhile, to critically read his posts, do some research, and formulate a lay explanation of why his posts are bunk could take hours. With my full-time job as an actual scientist and other responsibilities, I do not have this time. I wish I did.

I have watched Lane post his nonsense here for a while, all the time biting my tongue, but upon seeing him try and jam this square piece of scientific evidence into the round hole that is his pet project, I could not stay silent any more.  

My number one priority is the health and safety of patients.  I have harsh words for Lane because while his heart may be in the right place, he is acting irresponsibly in the material he posts on these boards and the "therapeutic" strategy he promotes.

Lane Simonian
Posted: Monday, April 20, 2020 6:10 PM
Joined: 12/12/2011
Posts: 4751

This is your best post yet.  My heart is in the right place and my mind is mostly in the right place.

I am not a scientist, although I have studied biology (starting with my father who was a high school biology teacher and then several excellent biology teachers in college).  Perhaps more to the point, I have studied Alzheimer's disease for sixteen years.  My aunt and cousin died from Alzheimer's disease.  My mother had Alzheimer's disease but died from heart failure.  I still feel I have an obligation to them, but even more so I feel I have an obligation to help others like I was able to help my mother.

It often does take time to respond to me.  A few have and I have greatly appreciated their input.  It is too easy to say he is just copying and pasting, that it is just a hobby, that it is all pseudosience, that every single clinical trial that I post is garbage (they all have faults, some were considerably worse designed than others).  But to actually engage in the science is a more time-consuming task and I understand when some scientists don't have the time to take the time that I have to understand the science in the first place.