Long-chain polyunsaturated fatty acids, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are highly enriched in neuronal synaptosomal plasma membranes and vesicles
The predominant CNS polyunsaturated fatty acid is DHA
effective supplementation and/or increased ingestion of dietary sources rich in EPA and DHA, such as cold-water fish species and fish oil, may help improve a multitude of neuronal functions, including long-term potentiation and cognition.
multiple preclinical studies have suggested that DHA and/or EPA supplementation may have potential benefit through a multitude of diverse, but complementary mechanisms
pre-injury dietary supplementation with fish oil effectively reduces post-traumatic elevations in protein oxidation
The benefits of pre-traumatic DHA supplementation have not only been independently confirmed,[150] but DHA supplementation has been shown to significantly reduce the number of swollen, disconnected and injured axons when administered following traumatic brain injury.
DHA has provided neuroprotection in experimental models of both focal and diffuse traumatic brain injury
potential mechanisms of neuroprotection, in addition to DHA and EPA's well-established anti-oxidant and anti-inflammatory properties
Despite abundant laboratory evidence supporting its neuroprotective effects in experimental models, the role of dietary DHA and/or EPA supplementation in human neurological diseases remains uncertain
Several population-based, observational studies have suggested that increased dietary fish and/or omega-3 polyunsaturated fatty acid consumption may reduce risk for ischemic stroke in several populations
Randomized control trials have also demonstrated significant reductions in ischemic stroke recurrence,[217] relative risk for ischemic stroke,[2] and reduced incidence of both symptomatic vasospasm and mortality following subarachnoid hemorrhage
Clinical trials in Alzheimer's disease have also been largely ineffective
The clinical evidence thus far appears equivocal
curcumin has gained much attention from Western researchers for its potential therapeutic benefits in large part due to its potent anti-oxidant[128,194,236] and anti-inflammatory properties
Curcumin is highly lipophilic and crosses the blood-brain barrier enabling it to exert a multitude of different established neuroprotective effects
in the context of TBI, a series of preclinical studies have suggested that pre-traumatic and post-traumatic curcumin supplementation may bolster the brain's resilience to injury and serve as a valuable therapeutic option
Curcumin may confer significant neuroprotection because of its ability to act on multiple deleterious post-traumatic, molecular cascades
studies demonstrated that both pre- and post-traumatic curcumin administration resulted in a significant reduction of neuroinflammation via inhibition of the pro-inflammatory molecules interleukin 1β and nuclear factor kappa B (NFκB)
no human studies have been conducted with respect to the effects of curcumin administration on the treatment of TBI, subarachnoid or intracranial hemorrhage, epilepsy or stroke
studies have demonstrated that resveratrol treatment reduces brain edema and lesion volume, as well as improves neurobehavioral functional performance following TBI
green tea consumption or supplementation with its derivatives may bolster cognitive function acutely and may slow cognitive decline
At least one population based study, though, did demonstrate that increased green tea consumption was associated with a reduced risk for Parkinson's disease independent of total caffeine intake
a randomized, placebo-controlled trial demonstrated that administration of green tea extract and L-theanine, over 16 weeks of treatment, improved indices of memory and brain theta wave activity on electroencephalography, suggesting greater cognitive alertness
Other animal studies have also demonstrated that theanine, another important component of green tea extract, exerts a multitude of neuroprotective benefits in experimental models of ischemic stroke,[63,97] Alzheimer's disease,[109] and Parkinson's disease
Theanine, like EGCG, contains multiple mechanisms of neuroprotective action including protection from excitotoxic injury[97] and inhibition of inflammation
potent anti-oxidant EGCG which is capable of crossing the blood-nerve and blood-brain barrier,
Epigallocatechin-3-gallate also displays neuroprotective properties
More recent research has suggested that vitamin D supplementation and the prevention of vitamin D deficiency may serve valuable roles in the treatment of TBI and may represents an important and necessary neuroprotective adjuvant for post-TBI progesterone therapy
Progesterone is one of the few agents to demonstrate significant reductions in mortality following TBI in human patients in preliminary trials
in vitro and in vivo studies have suggested that vitamin D supplementation with progesterone administration may significantly enhance neuroprotection
Vitamin D deficiency may increase inflammatory damage and behavioral impairment following experimental injury and attenuate the protective effects of post-traumatic progesterone treatment.[37]
emerging evidence has suggested that daily intravenous administration of vitamin E following TBI significantly decreases mortality and improves patient outcomes
high dose vitamin C administration following injury stabilized or reduced peri-lesional edema and infarction in the majority of patients receiving post-injury treatment
it has been speculated that combined vitamin C and E therapy may potentiate CNS anti-oxidation and act synergistically with regards to neuroprotection
one prospective human study has found that combined intake of vitamin C and E displays significant treatment interaction and reduces the risk of stroke
Pycnogenol has demonstrated the ability to slow or reduce the pathological processes associated with Alzheimer's disease
Pcynogenol administration, in a clinical study of elderly patients, led to improved cognition and reductions in markers of lipid peroxidase
One other point of consideration is that in neurodegenerative disease states like Alzheimer's disease and Parkinson's disease, where there are high levels of reactive oxygen species generation, vitamin E can tend to become oxidized itself. For maximal effectiveness and to maintain its anti-oxidant capacity, vitamin E must be given in conjunction with other anti-oxidants like vitamin C or flavonoids
These various factors might account for the null effects of alpha-tocopherol supplementation in patients with MCI and Alzheimer's disease
preliminary results obtained in a pediatric population have suggested that post-traumatic oral creatine administration (0.4 g/kg) given within four hours of traumatic brain injury and then daily thereafter, may improve both acute and long-term outcomes
Acutely, post-traumatic creatine administration seemed to reduce duration of post-traumatic amnesia, length of time spent in the intensive care unit, and duration of intubation
At three and six months post-injury, subjects in the creatine treatment group demonstrated improvement on indices of self care, communication abilities, locomotion, sociability, personality or behavior and cognitive function when compared to untreated controls
patients in the creatine-treatment group were less likely to experience headaches, dizziness and fatigue over six months of follow-up
CNS creatine is derived from both its local biosynthesis from the essential amino acids methionine, glycine and arginine
Studies of patients with CNS creatine deficiency and/or murine models with genetic ablation of creatine kinase have consistently demonstrated significant neurological impairment in the absence of proper creatine, phosphocreatine, or creatine kinase function; thus highlighting its functional importance
chronic dosing may partially reverse neurological impairments in human CNS creatine deficiency syndromes
Several studies have suggested that creatine supplementation may also reduce oxidative DNA damage and brain glutamate levels in Huntington disease patients
Another study highlighted that creatine supplementation marginally improved indices of mood and reduced the need for increased dopaminergic therapy in patients with Parkinson's disease
study finds Testosterone levels <10th percentile compared to men with Testosterone levels in the 11-90th percentile were associated with increased rate of ischemic stroke (34%). The hazard ratio was overweight/obese, and hypertension in men. no correlation was found in women.
transition from catabolism to anabolism is driven by a redox shift
transition from catabolism to anabolism is driven by a redox shift
viral spike protein binds to ACE2 receptor of the host cell [22,23].
redox signaling plays an important role in regulating immune function and inflammation, and disruptions in this signaling can lead to excessive cytokine production and immune system activation
Aging is associated with a poor control of the redox balance
thiol/disulfide homeostasis
reduced extracellular environment in the elderly and the increased susceptibility to Covid-19 infection
reduced extracellular environment in the elderly and the increased susceptibility to Covid-19 infection
Redox signaling tightly modulates the inflammatory response and oxidative stress has been reported in acute Covid-19
People at high risk are the elderly, patients suffering from metabolic syndrome such as obesity, or those suffering from chronic diseases such as cancer or inflammation
COVID-19 patients with severe disease have higher levels of oxidative stress markers and lower antioxidant levels
oxidative stress can activate the NLRP3 inflammasome, which is a protein complex that plays a key role in the cytokine storm
inflammation leads to the formation of ROS and RNS, while redox iMeBalance results in cellular damage, which in turn triggers an inflammatory response
persistently elevated mtROS triggers endothelial dysfunction and inflammation, which results in a vicious loop involving ROS, inflammation, and mitochondrial dysfunction
Damaged mitochondria releasing ROS induce inflammation via the NLRP3 inflammasome
Damaged mitochondria releasing ROS induce inflammation via the NLRP3 inflammasome
reduced environment during the cytokine storm
IL-2 is highly up-regulated in Covid-19 patients [37], and IL-2 is known to significantly stimulate the generation of NO in patients
Nitric acid is also the key mediator of IL-2-induced hypotension and vascular leak syndrome
mitochondrial dysfunction has been linked to the pathogenesis of Covid-19
mitochondrial dysfunction triggered by SARS-CoV-2 leads to damage to the mitochondria
mitochondrial dysfunction triggered by SARS-CoV-2 leads to damage to the mitochondria
As catabolism is decreased, entropy is released through anabolism
Elevated levels of lactate, a characteristic of the Warburg effect, were also reported in the high-risk Covid-19
elevated levels of ventricular lactic acid consistent with oxidative stress
A decrease of ΔΨm is implicated in several inflammation-related diseases
decrease in ΔΨm in leucocytes from Covid-19 patients
vaccinated with RNA or DNA vaccines triggering the synthesis of the viral spike protein in human cells
viral reactivation in varicella-zoster virus [55] or hepatitis [56], coagulopathy and resulting stroke and myocarditis following both DNA-based vaccines [57] and RNA-based vaccines
Covid-19, mitochondrial impairment
characteristic of the Warburg effect is present in almost every disease and appears to be a central feature in most of the hallmarks of cancer
inflammation, mitochondrial dysfunction and increased lactate concentrations in the extracellular fluid
In Covid-19, like any inflammation, there is a metabolic rewiring where cells rely on glycolysis
As the mitochondria are impaired, the infected cell cannot catabolize efficiently. It will release lactic acid in the blood stream
Striking similarities are seen between cancer, Alzheimer's disease and Covid-19, all related to the Warburg effect
Cancer, inflammation, Alzheimer's, and Parkinson's diseases share a common peculiarity, the inability of the cell to export entropy outside the body in the harmless form of heat
Entropy: lack of order or predictability; gradual decline into disorder.
MEB relieves the Warburg effect [87], improves memory [77], is active in the treatment of depressive episodes [79,80] and reduces the importance of ischemic strokes
MEB relieves the Warburg effect [87], improves memory [77], is active in the treatment of depressive episodes [79,80] and reduces the importance of ischemic strokes
MEB has been shown to inhibit SARS-Cov-2 replication in vitro
MEB has been shown to inhibit SARS-Cov-2 replication in vitro
It has been shown that Covid-19-patients treated with MEB, have a significant reduction in hospital stay duration and mortality
MeB is an acceptor-donor molecule
MeB + can take a pair of electrons (of H atoms) and MeBH can release this pair easily, so that MeB is partially recycled like a catalyst
MeB acts as an electron bridge between a donor (FADH2, FMNH, NADH) and an acceptor (complex IV of ETC or oxygen itself)
As a coenzyme of pyruvate dehydrogenase (PDH), alpha-lipoic acid (ALA) initiates the formation of acetyl-CoA to feed the TCA cycle
ALA enhances the catabolism of carbon. cycle and therefore may reduce the Warburg effect and consequently, lactate production
Methylene Blue plays a similar role after the TCA cycle, by carrying electrons to complex IV of the electron transport chain
Drugs such as lipoic acid and MeB, which target the metabolism, decrease the redox shift by increasing catabolism
low Estradiol and high Total Testosterone associated with high risk of ischemic heart disease. This study looked at endogenous levels in women. This data as well as others really brings into question the massive prescription Testosterone push in women.
nice review, older, of ischemic stroke risk and ways to prevent/heal in a more integrative approach. Good review of risk associated with hs-CRP and homocysteine as well.
Study finds that "midrange" Testosterone and DHT associated with a reduced ischemic heart disease and death rate. No association was found with Estradiol. One flaw of this study is in their use of serum.
Small study of 154 men post 1rst stroke finds a reduction in a second ischemic stroke with Testosterone therapy. That equals a 7.1% risk of secondary stroke in the Testosterone treated group (diagnosed with low T) versus 16.6% in the untreated group. Testosterone was started one week after the first stroke event.
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T3 in the post MI individual decreases the MI infarct size and the progression to heart failure. What is really interesting about this study is that the T3 induced mitochondrial biogenesis and activity which is a great thing in recovery of MI and also in disease i.e. cancer. However, it appears to increase HIF-1alpha and angiogenesis which is stimulated by retrograde signaling. There is a muddied picture here. Because T3 stimulates oxidative phosphorylation and mitochondria biogenesis which is favorable for health. However, in this study of rats, it induced HIF-1alpha and angiogenesis in post MI, which is favorable to recovery, yet this is unfavorable for cancer. Yet oxidative phosphorylation is favorable to cancer prevention/elimination and MI recovery.
Testosterone shown to have vasodilatory effect in men. In this small study, the short course of IV testosterone reduced exercise induced heart ischemia. This was in men with pre-existing CAD.
Levels of SHBG are higher in older men, therefore levels of free T decline more steeply than total T as men's age increases.
calculations based on mass action equations may not reflect precisely free T measured using a reference method
free T declines more steeply with age than total T in both cross-sectional [35] and longitudinal studies, [36] as does free E2 in comparison to total E2
T may slow development of or progression of atherosclerosis by modulating effects on insulin resistance, inflammation, endothelial function, preclinical atherosclerosis or the vasculature.
these cross-sectional and longitudinal studies support a relationship between low circulating T with CIMT and higher E2 with its progression
lower levels of T are biomarkers for aortic vascular disease
circulating free T was negatively associated with the presence of AAA
luteinizing hormone (LH) was positively associated.
low levels of total or bioavailable T were associated with aortic atherosclerosis manifested as calcified deposits detected by radiography
Men with total or free T in the lowest quartile had increased adjusted ORs for PAD defined as ABI <0.90, as did men with free E2 in the highest quartile of values
The apparent association of SHBG with intermittent claudication reflects the correlation of total T with SHBG, while the contribution of E2 to risk of PAD remains unclear
men with total T in the lowest quartile of values (<11.7 nmol l−1 ) experienced an increased incidence of stroke or transient ischemic attack
lower total T with increased incidence of CVD events
cohort studies in mostly older men have supported the association of lower androgen levels with higher mortality
lower total or free T levels were associated with mortality in older men, but with discordant results for cause-specific mortality and for associations of E2
several large studies identifying lower endogenous levels of total or free T as independent predictors of all-cause or CVD-related deaths in middle-aged and older men
T exhibits anti-inflammatory effects, enhances flow-mediated brachial artery reactivity, and reduces arterial stiffness
Short-term T therapy had a beneficial effect on exercise-induced myocardial ischemia in middle-aged men with coronary artery disease or chronic stable angina, [95],[96],[97] and reduced angina frequency in older men with diabetes and coronary artery disease
T therapy resulted in an increase in treadmill test duration and time to ST segment depression
there are interventional studies supporting a protective effect of exogenous T against myocardial ischemia in men with coronary artery disease
This dosing is 100 fold higher then peak production of a young man at 20-22.
Observational studies indicate that lower levels of endogenous T in older men are associated with the presence of carotid atherosclerosis, aortic and peripheral vascular disease, and incidence of CVD events and mortality
Interventional studies have shown beneficial effects of exogenous T on vascular function and on exercise-induced myocardial ischemia in men with coronary artery disease