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Japanese raisin tree for Alzheimer's disease
Lane Simonian
Posted: Tuesday, August 21, 2018 10:32 AM
Joined: 12/12/2011
Posts: 4713


Sometimes there are some very interesting things out of left field.  Here is one of them.

Traditional Chinese hangover cure seen as potential Alzheimer’s disease treatment

Japanese raisin tree’s leaves may help USC researcher in the fight against Alzheimer’s, Parkinson’s, PTSD, anxiety and other conditions

Jing Liang...has worked with the Japanese raisin tree — the leaves of which were first brewed into a hangover-fighting tea around 660 BC.

https://news.usc.edu/147428/traditional-chinese-cure-potential-alzheimers-disease-treatment/

One of the compounds in the leaves is dihydromyricetin.  Myricetin inhibits the DNA damage (and subsequent inflammation) caused by peroxynitrite in Alzheimer's disease.

 https://www.ncbi.nlm.nih.gov/pubmed/21741426

As a fermented drink, the pseudofruits from the tree have a large number of antioxidants compounds, including eugenol.  Eugenol in some essential oils through aromatherapy helps limit and partially reverse the damage that peroxynitrite does to the brain.  So too may this alcoholic drink.

Furthermore, molecules with reports of therapeutical effects were detected, such as eugenol, a well-known antioxidant and anti-inflammatory. Recently, Prasad et al. (2016) demonstrated the neurorestorative potential of eugenol in terms of its ability to abrogate pre-existing oxidative impairments, mitochondrial dysfunctions and cholinergic deficit in different brain regions. 

 

 


dolor
Posted: Tuesday, September 11, 2018 12:50 PM
Joined: 11/9/2017
Posts: 306


Lane,

I thought this thread would be a good place to post those studies I mentioned on the spouse caregiver forum. The first was sent to me with no link, so I am c&p ing it.


Dementia study links your risk with your fitness level

The study, published Wednesday in the medical journal Neurology, found that women with high cardiovascular fitness, or high stamina, had an 88% lower risk of dementia than women who were moderately fit.
"I was not surprised that there was an association, but I was surprised that it was such a strong association between the group with highest fitness and decreased dementia risk," said Helena Hörder, a professor in the Department of Psychiatry and Neurochemistry at the University of Gothenburg in Sweden, who was first author on the study.
Dementia is the name for a group of symptoms caused by disorders that affect the brain, often leading to memory loss or other problems with brain function. Alzheimer's disease, an irreversible and progressive brain disease, is the most common type of dementia.
About 5.4 million people in the United States are estimated to be living with Alzheimer's disease, and it is the sixth leading cause of death among all adults, according to the US Centers for Disease Control and Prevention.
About 850,000 people in the United Kingdom have dementia as a whole, according to the UK's National Health Service.
Worldwide, about 50 million people have dementia, and there are nearly 10 million new cases every year, according to the World Health Organization.
The new study involved 191 women in Sweden, 38 to 60 years old, who completed an ergometer cycling test to evaluate their cardiovascular fitness.
During the test, the women's workload was measured, based on how much weight or resistance could be added to the bicycle before they became fatigued.
"The level that you are so exhausted that you have to interrupt the test is a measure, in watts, of your work capacity," Hörder said. "Cardiovascular fitness or endurance can also be tested in a submaximal test where you don't push the person to maximal capacity."
Some of the women had to interrupt their cycling test at submaximal workload, before being pushed to maximal capacity, mainly due to changes seen on an electrocardiograph or due to high blood pressure.
Based on their crude peak workload, the women were separated into three groups: Fifty-nine were in the "low fitness" group, 92 were "medium fitness," and 40 were "high fitness."
Those cycling tests were conducted in 1968, and the women were followed over a 44-year period until 2012. During that time, the researchers tracked the women's health, taking a close look at who was diagnosed with dementia and who was not.
The researchers found that among all of the women, 44 of them (or 23%) developed dementia from 1968 to 2012. Yet among those who interrupted their cycling test at submaximal workload, that percentage jumped to 45%.
"Many of those who interrupted the test at submax, very low watt level, probably had indications for a poor cardiovascular health status," Hörder said. "This might indicate that processes in the cardiovascular system might be ongoing many decades before onset of dementia diagnosis."

The researchers also found that the average age at dementia onset was 11 years older in the "high fitness" group than in the "medium fitness" group, and the most pronounced risk reduction was seen among those with the highest fitness: "High compared to medium fitness decreased the risk of dementia by 88%," the researchers wrote.
The study had some limitations, including that it involved a small sample of women in Sweden. More research is needed to determine whether similar findings would occur in a larger, more diverse group.
Also, the findings were not causal. So more research is also needed to determine whether improved fitness could have positive effects on dementia risk and when in life a high fitness level is most important.
For instance, other factors could have influenced the findings to help lower dementia risk, regardless of physical activity habits. Genetics or the cognitive stimulation of fitness could have influenced dementia risk, as well as the social aspects of fitness, as loneliness has been linked to dementia.
"One of the missing pieces of a study like this -- and really the weakness in the literature to date -- is that the kinds of studies that we have mostly seen are association studies. These are studies of correlations, and they can't necessarily talk about causality," said Keith Fargo, director of scientific programs and outreach for the Alzheimer's Association in Chicago, who was not involved in the new study.
Still, he said, "the picture that is really emerging from the literature is a picture about the importance of fitness in midlife, not just old age, when it comes to protecting your brain health and preventing or delaying Alzheimer's disease and other dementias."
The new study adds to that overall growing body of evidence turning a spotlight on dementia and modifiable risk factors, such as poor cardiovascular health, a sedentary lifestyle, poor diet, smoking or excessive alcohol consumption.
So people could try to reduce their risk of cognitive decline by engaging in regular cardiovascular exercise, stopping smoking, eating a healthy diet, getting enough sleep, staying socially engaged, challenging their minds by reading or playing games and of course taking care of their heart health, according to the Alzheimer's Association.
"There's a very strong connection between cardiovascular health -- so the health of your heart and your circulatory system -- and the health of your brain," Fargo said.
"The reason for that is because the brain actually is what we would call a highly vascularized organ, meaning that your brain has many blood vessels," he said. "The demand for nutrient-, oxygen-rich blood in the brain is very high compared to other organs, and so anything a person can do to increase their cardiovascular fitness level is likely to have positive benefits on brain health."
[Gallery] Abandoned Submarines Floating Around the World
dolor
Posted: Tuesday, September 11, 2018 12:53 PM
Joined: 11/9/2017
Posts: 306


Now, for the good news (that's sarcasm).

https://www.medscape.com/viewarticle/899805?src=WNL_infoc_180823_MSCPEDIT_neur&uac=71558MV&impID=1718206&faf=1

"

Can Exercise Worsen Dementia?"

Could exercise worsen dementia? The idea runs against one of the fondest hopes of patients with Alzheimer disease, their caregivers, and physicians. It contradicts some early research and tentative recommendations. But it is a key finding of one of the largest studies yet to examine the question.

In the Dementia And Physical Activity (DAPA) trial, the mean score on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) worsened more for people with dementia who were assigned to a year of vigorous exercise than for people who kept to their usual routines.[1]

The difference was small but statistically significant, says Bart Sheehan MRCPsych, MD, consultant liaison psychiatrist at the Coventry and Warwickshire Partnership Trust in Coventry, United Kingdom. "It does raise the possibility that, at this point, vigorous exercise might be damaging for people."

The finding has experts in the field taking a harder look at what they thought they knew about the way physical activity affects a declining brain. It comes as a particular blow because no one has found a way to halt Alzheimer disease. "People are desperate for a treatment," Sheehan said.

Until the DAPA results came out, exercise was looking like one of the most promising possibilities—if not to stop dementia, then at least to slow its progression. "Among patients with dementia or mild cognitive impairment, randomized controlled trials (RCTs) documented better cognitive scores after 6 to 12 months of exercise compared with sedentary controls," wrote the authors of a 2011 meta-analysis.[2]

Such results were enough to prompt the Mayo Clinic website, a health information website for consumers, to advise that "Exercising several times a week for 30 to 60 minutes may... improve memory, reasoning, judgment and thinking skills (cognitive function) for people with mild Alzheimer's disease or mild cognitive impairment."[3]

But these findings were from relatively small trials. And negative results have also cropped up in the literature for years, including in other reviews of the literature.[1] Funded by the British government, Sheehan and his colleagues set out to settle the question with the most authoritative trial possible.

They recruited 494 people with mild to moderate dementia according to the criteria in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV). All lived in the community and were able to sit on a chair and walk 10 feet without assistance. The average age was 77. Sixty-one percent were men.

The researchers randomly assigned 329 to exercise and 165 to make no change in their physical activity. The exercisers attended group sessions in a gym twice a week for 4 months under the guidance of physical therapists. Each session lasted 60-90 minutes. The researchers asked them to work out for an additional hour each week at home during this period. The sessions included cycling in place for 25 minutes of moderate to hard intensity, as well as weight training such as biceps curls, shoulder forward raise, lateral raise, and sit-to-stand using a weighted vest or waist belt.

After the 4 months, the researchers prescribed a home-based program of unsupervised exercise of 150 minutes each week. They encouraged the participants to choose activities at home that they preferred and followed up with phone calls to encourage them. Eighty-eight percent reported continuing the exercises at home. Less than 1% of the participants reported doing structured exercise outside of the trial.

The people who evaluated the patients didn't know which ones participated in the exercise programs and which ones did not.

After 12 months, the patients improved their fitness compared with the usual-care group. But when it came to cognitive function, the researchers recorded abysmal results. On the ADAS-cog, where a higher score means worsening function, the usual-care group went from 21.4 to 23.8, a worsening of 2.4 points, as might be expected with the progressive diseases that cause dementia.

But the exercisers fared even worse, going from a mean score of 21.2 to 25.2, a worsening of 4.0. For perspective, a normal score for someone who does not have dementia is 5, while the average score of someone diagnosed with probable Alzheimer's or mild cognitive impairment is 31.2.

The difference was statistically significant (P =.03). It's not clear whether it has clinical significance, Sheehan says. Still, it startled the researchers.

Despite their improved physical fitness, the exercisers did not improve in activities of daily living, behavior, or health-related quality of life.

"It didn't come as a surprise that physical exercise was not effective as a treatment for dementia, because dementia is notoriously difficult to treat," he said. "I think what was a surprise is the very strong signal that it may make dementia worse." They ran the statistics again and again but found no mistake.

And the finding held up regardless of the patients' sex or mobility and regardless of whether they were diagnosed with Alzheimer's versus other kinds of dementia, or whether they had mild versus severe cognitive impairment.

Despite their improved physical fitness, the exercisers did not improve in activities of daily living, behavior, or health-related quality of life.

The finding should influence what clinicians say to people with dementia and their caregivers, said Sheehan, who has treated many such patients. He now tells them that exercise won't help with such core features of dementia as memory or the ability to organize oneself, and that it might actually do damage.

People who are already exercising and enjoying it shouldn't necessarily stop, he added. But they must weigh the enjoyment and other health benefits—which are many—against the risk for harm.

Not everyone interprets the results of the DAPA trial as pessimistically as Sheehan. "We don't have the evidence yet to be able to say that exercise is going to improve cognitive function," said J. Carson Smith, PhD, an associate professor of public health at the University of Maryland. "But there is more evidence of a benefit in mild cognitive impairment and in people at increased risk for dementia."

He is among the researchers whose small studies have suggested that exercise can improve cognitive ability in people with mild cognitive impairment. Epidemiologic studies measuring the benefits of long-term exercise for preventing dementia are even more impressive.

This includes a recent sample of 191 Swedish women who were 38-60 years of age in 1968 when they underwent an ergometer cycling test. Examinations of dementia were done six times up to 2010 and supplemented with information from medical records. Women with high physical fitness at middle age were nearly 90% less likely to develop dementia decades later, compared with women who were moderately fit.[4]

Smith and others have found biological differences between more and less fit people that could explain a difference in dementia risk. Lower cardiovascular fitness is associated with a smaller brain volume two decades later, for example.[5]

It's hard to explain why exercise in healthy people might protect against cognitive decline, but exercise in people with dementia might make it worse. Sheehan theorized that already weakened brains might be too fragile to withstand the temporary loss of oxygen that comes with vigorous exercise. But there isn't much information yet to support or refute such ideas.

Such studies can't prove cause and effect. Not only physical activity but also genes affect physical fitness. And people who exercise may have other healthy behaviors.

But even Sheehan has not given up on the idea that physical activity can help people in their declining years. Some kinds of exercise can improve balance, for example. "People say, 'I wish my father could recognize me,' but they also say, 'I wish my father didn't fall over,'" he points out.


dolor
Posted: Tuesday, September 11, 2018 1:01 PM
Joined: 11/9/2017
Posts: 306


Also articles found on Medscape:

Faulty Lipid Metabolism Linked to Alzheimer's

 

More Evidence for Gut-Brain Link in Alzheimer's Disease

Finally, a Winner for Alzheimer's?

Anti-amyloid Agent Shows Promise

This is fu***ng exhausting.


Lane Simonian
Posted: Tuesday, September 11, 2018 3:45 PM
Joined: 12/12/2011
Posts: 4713


Thank you for all the posts, Dolor.  Almost all the people who use to provide me with new information, puzzles, and important clues are gone from this forum.  I don't want to put too much pressure on you to take their place.

I had never heard of low levels of plasmalogens in Alzheimer's disease before, but here is a possible explanation.

Lipids play an important role as risk or protective factors in Alzheimer’s disease, which is characterized by amyloid plaques composed of aggregated amyloid‐beta. Plasmalogens are major brain lipids and controversially discussed to be altered in Alzheimer’s disease (AD) and whether changes in plasmalogens are cause or consequence of AD pathology. Here, we reveal a new physiological function of the amyloid precursor protein (APP) in plasmalogen metabolism. The APP intracellular domain was found in vivo and in vitro to increase the expression of the alkyl‐dihydroxyacetonephosphate‐synthase (AGPS), a rate limiting enzyme in plasmalogen synthesis. Alterations in APP dependent changes of AGPS expression result in reduced protein and plasmalogen levels. Under the pathological situation of AD, increased amyloid‐beta level lead to increased reactive oxidative species production, reduced AGPS protein and plasmalogen level. Accordingly, phosphatidylethanol plasmalogen was decreased in the frontal cortex of AD compared to age matched controls. Our findings elucidate that plasmalogens are decreased as a consequence of AD and regulated by APP processing under physiological conditions.

In regards to the Biogen results, they were inflated by the fact of people who dropped out or were required by regulators to drop out due to the occurrence or risk of occurrence of adverse effects (mainly brain swelling) had the ApoE4 gene.  People with the Apoe4 gene progress more rapidly during the early stages of Alzheimer's disease so not taking into account the dropouts made it look like the high dose group was declining less rapidly than it actually was.  The drug may still have some benefit but not as much as the drug makers would have you believe.

The beneficial effects of exercise is via the phosphatidylinositol 3-kinase/Akt pathway which is a neuroprotective pathway but this pathway is blocked by nitration in Alzheimer's disease.  So either strenuous exercise or exercise during Alzheimer's disease may actually increase the formation of peroxynitrite.

https://www.ncbi.nlm.nih.gov/pubmed/15857681 

https://www.ncbi.nlm.nih.gov/pubmed/16410804  

www.webmd.com/fitness-exercise/news/20090715/strenuous-exercise-linked-to_memory-loss#1

In Alzheimer's disease, the combination of superoxide with nitric oxide is the main route to peroxynitrite formation and the production of each is increasesd by factors that activate protein kinase C and NMDA receptors.  

Here are some early articles about peroxynitrite and Alzheimer's disease.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4692346/

https://www.ncbi.nlm.nih.gov/pubmed/9092586

https://www.ncbi.nlm.nih.gov/pubmed/9185121 (although Vitamin C can make the disease worse early on because it can breakdown into hydrogen peroxide).

https://pdfs.semanticscholar.org/b00a/30ed1acfb7119b1c6cfb1e4fcd89f8d9c720.pdf

When peroxynitrite is scavenged (by compounds in CBD oil, essential oils via aromatherapy, and panax ginseng, for instance) it produces water and water is a de-nitrating agent.

This disease can make your head spin with seemingly contradictory studies, but after awhile it begins to make sense.

 

 


dolor
Posted: Tuesday, September 11, 2018 4:46 PM
Joined: 11/9/2017
Posts: 306


More good news!

Alzheimer’s Disease - From Basic Research to Clinical Applications

I can't control font size here. Anyway, it's on google books too, but it won't let me copy and paste, and a link won't open.

"The term 'risk factor' would be a light-hearted euphemism for the preseniline-and APP mutations which are autosomal dominant and show near complete penetrance."

 

That was like typing a foreign language, and...did he really just say that???

Looks like genetic testing should be on the old bucket list.



Lane Simonian
Posted: Wednesday, September 12, 2018 10:26 AM
Joined: 12/12/2011
Posts: 4713


Funny, I was wondering yesterday how the Japanese raisin tree had suddenly become so popular.

It has been bothering me for awhile why different forms of dementia have different features.  Your question may have given me a partial answer.  Peroxynitrite levels appears to be much higher in Alzheimer's disease than in other forms of dementia.  This may be due to the "fact" that NMDA receptors (ionotropic glutamate receptors) appear to be more heavily concentrated in the hippocampus and cortex--the two parts of the brain most affected by Alzheimer's disease.  

Glutamate-stimulated peroxynitrite production in a brain-derived endothelial cell line is dependent on N-methyl-d-aspartate (NMDA) receptor activation

But glutamate release (maybe as a result of metabotropic glutamate receptor alterations) appears to be even higher in other forms of dementia than in Alzheimer's disease (at least where hallucinations are not present).  This might explain the sharper decline in cognition in those with Alzheimer's disease compared to other forms of dementia but why other forms of dementia often come with more severe neuropsychiatric problems (which may be due to higher levels of norepinephrine following glutamate release).  

Whatever the case, ferulic acid which reduces glutamate levels appears to help with behavioral and neuropyschiatric problems in Alzheimer's disease, dementia with lewy bodies, and frontotemporal lobe dementia.

Ferulic Acid: A Novel Inhibitor of Presynaptic Glutamate Release

Feru-guard (ferulic acid in Angelica archangelica and rice bran oil) is now part of a larger trial at the Oregon Health and Science University.





Lane Simonian
Posted: Wednesday, September 12, 2018 10:34 AM
Joined: 12/12/2011
Posts: 4713


Efforts to reduce superoxide levels in Alzheimer's disease have not worked particularly well perhaps because superoxide levels are higher than levels of inducible nitric oxide.  In mice, ending the production of inducible nitric oxide stops disease progression of an Alzheimer's-like disease but mice are subject to much less oxidative stress than humans and some levels of peroxynitrite are needed to kill certain pathogens.

Protection from Alzheimer's-like disease in the mouse by genetic ablation of inducible nitric oxide synthase

The best scavengers of peroxynitrite are compounds that are excellent hydrogen donors (this includes eugenol in various essential oils via aromatherapy; terpenes, cannabidiol, and THC in CBD oil, and ferulic acid, syringic acid, vanillic acid, p-coumaric acid, maltol, and ginsenosides in panax ginseng).

ONOO- + 2H+ + 2e-=H20 + NO2-


dolor
Posted: Wednesday, September 12, 2018 12:23 PM
Joined: 11/9/2017
Posts: 306


"Angelica archangelica... Leaves, stems, roots and seeds (all with a taste of licorice) (my note: yuk) have been cultivated for many years for both culinary and medicinal purposes. Culinary uses include: (1) leaves may be added to mixed salads; (2) stalks and young shoots may be used like celery or crystallized in sugar for cake decorations or snacks; (3) leaves, seeds and roots may be used for making tea; (4) seed is commercially used for flavoring liqueurs (as Chartreuse). Plants also have a long folk history in Europe and Asia for medicinal uses.

Genus name was formerly Herba angelica and so named because an angel pointed out the medicinal qualities of the plant."

http://www.missouribotanicalgarden.org/PlantFinder/PlantFinderDetails.aspx?kempercode=e399 

I'm starting to believe that angel part.

Anyway, I see extracts are commercially available.

" Peroxynitrite levels appears to be much higher in Alzheimer's disease than in other forms of dementia."

 This is not encouraging, Lane! I know, know and know that there is no single factor. But I'm equally terrified of FTD and Parkinsons, Vascular dementia,

 I'm not learning--and retaining!--enough fast enough, in what little time I have.

 Next task: back to 10th grade to review diagrams of the brain, sigh.

 Also, in search of the collective nose on our faces--

 1) what sorts of common and uncommon drugs contribute to causing dementia (ie sleeping pills!)

 2) why are women more susceptible? Is it only down to hormones? Do any of the massive amounts of chemicals (cosmetics, lotions, etc.) we put on our faces and bodies trigger anything?

 3) while #2 may sound far fetched, we KNOW that pesticides in sufficient amount cause Parkinson's and other disorders such as schizophrenia.  And we still use them. I've seen the effects, on a young son of a farmer who "got into some pesticides."

 


Lane Simonian
Posted: Wednesday, September 12, 2018 12:36 PM
Joined: 12/12/2011
Posts: 4713


To follow up on a few more points.  The book looks interesting although hopefully the passage you quoted is not indicative of the writing for all the sections of the book.

Certain genetic mutation guarantee the onset of Alzheimer's disease, but even here there are variations.  The presenilin gene 1 mutations increases oxidative stress by cutting off the neuroprotective phosphatidyinositol 3-kinase/Akt pathway.  

Wild-Type But Not FAD Mutant Presenilin-1 Prevents Neuronal Degeneration by Promoting Phosphatidylinositol 3-Kinase Neuroprotective Signaling

Together, our data indicate that the neuroprotective role of PS1 depends on its ability to activate the PI3K/Akt signaling pathway and that PS1 FAD [familial alzheimer's disease] mutations increase GSK-3 activity and promote neuronal apoptosis by inhibiting the function of PS1 in this pathway. These observations suggest that stimulation of PI3K/Akt signaling may be beneficial to FAD patients.

All of the genes associated with early onset Alzheimer's disease produce overwhelming levels of oxidative stress.

Mutations in amyloid precursor protein and presenilin-1 genes increase the basal oxidative stress in murine neuronal cells and lead to increased sensitivity to oxidative stress mediated by amyloid beta-peptide (1-42), HO and kainic acid: implications for Alzheimer's disease.

The results are consonant with the hypothesis that Abeta(1-42)-associated oxidative stress and increased vulnerability to oxidative stress may contribute significantly to neuronal apoptosis and death in familial early onset AD.

But other factors which increase or decrease oxidative stress affects the age of onset.  For example, people in Japan with the exact same presenilin 1 gene mutation develop Alzheimer's nearly a decade later on average (late 50s) than people with the exact same presenilin 1 gene mutation in Colombia.  The drinking of green tea and eating rice bran decrease oxidative stress for the individuals with the gene in Japan whereas high levels of mercury exposure (due to mining operations) increase the amount of oxidative stress for individuals with the gene in Colombia.

Turning to the gut biome and Alzheimer's disease, here is an interesting one:

 2017 Jul 19;8(7):1438-1447. doi: 10.1021/acschemneuro.7b00176. Epub 2017 Jul 7.

Gut Microbiota, Nitric Oxide, and Microglia as Prerequisites for Neurodegenerative Disorders.

Abstract

Regulating fluctuating endogenous nitric oxide (NO) levels is necessary for proper physiological functions. Aberrant NO pathways are implicated in a number of neurological disorders, including Alzheimer's disease (AD) and Parkinson's disease. The mechanism of NO in oxidative and nitrosative stress with pathological consequences involves reactions with reactive oxygen species (e.g., superoxide) to form the highly reactive peroxynitrite, hydrogen peroxide, hypochloride ions and hydroxyl radical. NO levels are typically regulated by endogenous nitric oxide synthases (NOS), and inflammatory iNOS is implicated in the pathogenesis of neurodegenerative diseases, in which elevated NO mediates axonal degeneration and activates cyclooxygenases to provoke neuroinflammation. NO also instigates a down-regulated secretion of brain-derived neurotrophic factor, which is essential for neuronal survival, development and differentiation, synaptogenesis, and learning and memory. The gut-brain axis denotes communication between the enteric nervous system (ENS) of the GI tract and the central nervous system (CNS) of the brain, and the modes of communication include the vagus nerve, passive diffusion and carrier by oxyhemoglobin. Amyloid precursor protein that forms amyloid beta plaques in AD is normally expressed in the ENS by gut bacteria, but when amyloid beta accumulates, it compromises CNS functions. Escherichia coli and Salmonella enterica are among the many bacterial strains that express and secrete amyloid proteins and contribute to AD pathogenesis. Gut microbiota is essential for regulating microglia maturation and activation, and activated microglia secrete significant amounts of iNOS. Pharmacological interventions and lifestyle modifications to rectify aberrant NO signaling in AD include NOS inhibitors, NMDA receptor antagonists, potassium channel modulators, probiotics, diet, and exercise.

Keep contributing when you can.


dolor
Posted: Wednesday, September 12, 2018 1:22 PM
Joined: 11/9/2017
Posts: 306


Hi Lane,

Am working my way slowly through your post (at work and subject to interruption)

but--people in Japan eat white rice. However, with some high speed googling, I found more info. I was initially going to cut off at the oil part but found the rest far too relevant!

"The outer layer of the grain (bran) and the oil made from the bran are used for medicine. Rice bran oil is popular as a “healthy oil” in Japan, Asia, and particularly India. Be careful not to confuse rice bran with other forms of bran such as oat and wheat bran.

Rice bran is used for treating diabetes, high blood pressure, high cholesterol, alcoholism, obesity, and AIDS; for preventing stomach and colon cancer; for preventing heart and blood vessel (cardiovascular) disease; for strengthening the immune system; for increasing energy and improving athletic performance; for improving liver function; and as an antioxidant.

Rice bran oil is also used for high cholesterol.

Some people apply rice bran directly to the skin for an allergic skin rash called eczema (ectopic dermatitis)."

https://www.webmd.com/vitamins/ai/ingredientmono-852/rice-bran

 


dolor
Posted: Wednesday, September 12, 2018 1:50 PM
Joined: 11/9/2017
Posts: 306


I should add that Japan has a high rate of stomach and gastric cancers, despite the alleged benefits of rice bran as noted on web.md.
Lane Simonian
Posted: Wednesday, September 12, 2018 3:29 PM
Joined: 12/12/2011
Posts: 4713


Thank you for posting some of the benefits or rice bran and rice bran oil.

The following may apply to Japan as well as Korea (although may be not as much nitrites and nitrates from meat):

Nitrates and nitrites are substances commonly found in cured meats. They can be converted by certain bacteria, such as H pylori, into compounds that have been shown to cause stomach cancer in lab animals.

The high rates of stomach cancer are thought to have two causes. One is chronic infection with Helicobacter pylori bacteria, which is common in developing countries and treatable with antibiotics. Stomach cancer rates in the United States plummeted as refrigeration came into use. In Koreans, diet is also blamed, specifically foods that are preserved with nitrates and nitrites.

Mechanisms of the bactericidal effects of nitrate and nitrite in cured meats.

For cured meat products, nitrite is recognized for its antimicrobial effects against pathogenic bacteria, even though the specific inhibitory mechanisms are not well known. Nitrite contributes to oxidative stress by being the precursor of peroxynitrite (ONOO-), which is the major strong oxidant. Thus, bacterial stress (highly pH-very low partial pressure of oxygen-dependent) is enhanced by the nitrate-nitrite-peroxynitrite system which is also highly pH- and low partial pressure of oxygen-dependent.


Nitrosamines are chemical compounds, most of which are carcinogenic...

Nitrosamines are produced when nitrites and amines combine in acidic places like the human stomach. High temperatures and frying can increase the formation of these nitrosamines. Significant levels can be found in beer, fish, non-fat dry milk and cured meats (primarily bacon and hot dogs) and cheese preserved with nitrite pickling salt.

Originally they were added as preservatives to prevent salmonella infection from contaminated meat. Nitrites are added to some processed foods to increase the shelf life. For example, sodium nitrate is responsible for the pink colour in bologna. They are often used to transport fish across the Pacific Ocean and added to preserve flavor and colouring. Nitrites can also be found in fertilizers which end up on our produce like potatoes and beets.

Some researchers believe nitrosamines can play a part in Alzheimer's brain degeneration. Adding high fat to the diet makes things worse.


Reactive nitrogen species, including nitrogen oxides (N(2)O(3) and N(2)O(4)), peroxynitrite (ONOO(-)), and nitryl chloride (NO(2)Cl), have been implicated as causes of inflammation and cancer. We studied reactions of secondary amines with peroxynitrite and found that both N-nitrosamines and N-nitramines were formed...Nitrated secondary amines, e.g., N-nitroproline, could be identified as specific markers for endogenous nitration mediated by reactive nitrogen species.

It appears that there are a variety of ways in which nitrites, nitrates, and nitrosamines can contribute to cancer and Alzheimer's disease and some of these ways are related to peroxynitrite formation.


dolor
Posted: Wednesday, September 12, 2018 3:45 PM
Joined: 11/9/2017
Posts: 306


Beer???

Well, we've heard the bacon and hot dog warnings for ages, haven't we? And grilling meat (or possibly any food). But it's back to the medieval demon-sounding peroxynitrite. I need to review the oxidant and the free radicals which make it several times before it is going to sink in, I'm afraid. I'm still curious about ways to kill off the free rads, as well as the peroxynitrite.

It's useful to consider other dietary influences as a reminder. I'll need to peruse this info more slowly as well.

I realize I am ALL OVER the place trying to grasp this, and some focus is in order (still don't have that diagram of brain done) but I found this, with great dismay:

"In two separate large population studies, both benzodiazepines (a category that includes medications for anxiety and sleeping pills) and anticholinergics (a group that encompasses medications for allergies and colds, depression, high blood pressure, and incontinence) were associated with an increased risk of dementia in people who used them for longer than a few months. In both cases, the effect increased with the dose of the drug and the duration of use."

https://www.health.harvard.edu/mind-and-mood/two-types-of-drugs-you-may-want-to-avoid-for-the-sake-of-your-brain

The article does go on to discuss the studies, so it isn't a blanket reference.

Quitting benzos is no walk in the park.

 


Lane Simonian
Posted: Wednesday, September 12, 2018 5:46 PM
Joined: 12/12/2011
Posts: 4713


On the other hand, beer contains compounds that are peroxynitrite scavengers.

And then there is this:

 2018 Sep;118:59-67. doi: 10.1016/j.mehy.2018.06.019. Epub 2018 Jun 20.

How chronic administration of benzodiazepines leads to unexplained chronic illnesses: A hypothesis.

Abstract

It is thought that an ill defined biochemical cascade may lead to protracted withdrawal symptoms subsequent to discontinuance of routine use of benzodiazepine class drugs and establish chronic illness in some patients. In this review, published findings are presented that support the novel concept that withdrawal from benzodiazepine class drugs can trigger elevated and sustained levels of a potent oxidant called peroxynitrite via potentiation of the L-type voltage-gated calcium channels, and in the later stages of withdrawal, via excessive N-methyl-D-aspartate receptor activity, as well. Potentiation of L-type voltage-gated calcium channels and excessive N-methyl-D-aspartate receptor activity both result in calcium influx into the cell that triggers nitric oxide synthesis. In pathophysiological conditions, such increased nitric oxide synthesis leads to peroxynitrite formation. The downstream effects of peroxynitrite formation that may occur during withdrawal ultimately lead to further peroxynitrite production in a system of overlapping vicious cycles collectively referred to as the NO/ONOO(-) cycle. Once triggered, the elements of the NO/ONOO(-) cycle perpetuate pathophysiology, perhaps including reduced GABAA receptor functioning, that may explain protracted withdrawal associated symptoms while the vicious cycle nature of the NO/ONOO(-) cycle may explain how withdrawal becomes a chronic state. Suboptimal levels of tetrahydrobiopterin may be one risk factor for the development of the protracted withdrawal syndrome as this will lead to partial nitric oxide uncoupling and resultant peroxynitrite formation. Nitric oxide uncoupling results in superoxide production as calcium-dependent nitric oxide synthases attempt to produce nitric oxide in response to L-type voltage-gated calcium channel-mediated calcium influx that is known to occur during withdrawal. The combination of nitric oxide and superoxide produced, as when partial uncoupling occurs, react together in a very rapid, diffusion limited reaction to form peroxynitrite and thereby trigger the NO/ONOO(-) cycle. The NO/ONOO(-) cycle may explain the nature of the protracted withdrawal syndrome and the related constellation of symptoms that are also common in other illnesses characterized as NO/ONOO(-) disorders such as myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia.

I am throwing fourteen years of research at you (including today), so take your time looking at it.