Group items tagged

primary hypogonadism (probably the genuine form of LOH) is strongly associated with age

Compensated hypogonadism represents a distinct clinical entity that warrants continued monitoring to prevent or preempt further deterioration

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

whereas the expression of SVCT-2 is ubiquitous

differential sensitivity to VC may result from variations in VC flow into cells, which is dependent on SVCT-2 expression.

high-dose VC significantly impaired both the tumorspheres initiation (Fig. 4d, e) and the growth of established tumorspheres derived from HCC cells (Fig. 4f, g) in a time-dependent and dose-dependent manner.

Hepatocellular carcinoma (HCC)

The antioxidant, N-acetyl-L-cysteine (NAC), preventing VC-induced ROS production (a ROS scavenger), completely restored the viability and colony formation among VC-treated cells

DNA double-strand damage was found following VC treatment

DNA damage was prevented by NAC

Interestingly, the combination of VC and cisplatin was even more effective in reducing tumor growth and weight

Consistent with the in vitro results, stemness-related genes expressions in tumor xenograft were remarkably reduced after VC or VC+cisplatin treatment, whereas conventional cisplatin therapy alone led to the increase of CSCs

VC is one of the numerous common hepatoprotectants.

Interestingly, at extracellular concentrations greater than 1 mM, VC induces strong cytotoxicity to cancer cells including liver cancer cells

we hypothesized that intravenous VC might reduce the risk of recurrence in HCC patients after curative liver resection.

Intriguingly, the 5-year disease-free survival (DFS) for patients who received intravenous VC was 24%, as opposed to 15% for no intravenous VC-treated patients

Median DFS time for VC users was 25.2 vs. 18 months for VC non-users

intravenous VC use is linked to improved DFS in HCC patients.

In this study, based on the elevated expression of SVCT-2, which is responsible for VC uptake, in liver CSCs, we revealed that clinically achievable concentrations of VC preferentially eradicated liver CSCs in vitro and in vivo

Additionally, we found that intravenous VC reduced the risk of post-surgical HCC progression in a retrospective cohort study.

Three hundred thirty-nine participants (55.3%) received 2 g intravenous VC for 4 or more days after initial hepatectomy

As the key protein responsible for VC uptake in the liver, SVCT-2 played crucial roles in regulating the sensitivity to ascorbate-induced cytotoxicity

we also observed that SVCT-2 was highly expressed in human HCC samples and preferentially elevated in liver CSCs

SVCT-2 might serve as a potential CSC marker and therapeutic target in HCC

CSCs play critical roles in regulating tumor initiation, relapse, and chemoresistance

we revealed that VC treatment dramatically reduced the self-renewal ability, expression levels of CSC-associated genes, and percentages of CSCs in HCC, indicating that CSCs were more susceptible to VC-induced cell death

as a drug for eradicating CSCs, VC may represent a promising strategy for treatment of HCC, alone or particularly in combination with chemotherapeutic drugs

In HCC, we found that VC-generated ROS caused genotoxic stress (DNA damage) and metabolic stress (ATP depletion), which further activated the cyclin-dependent kinase inhibitor p21, leading to G2/M phase cell cycle arrest and caspase-dependent apoptosis in HCC cells

we demonstrated a synergistic effect of VC and chemotherapeutic drug cisplatin on killing HCC both in vitro and in vivo

Intravenous VC has also been reported to reduce chemotherapy-associated toxicity of carboplatin and paclitaxel in patients,38 but the specific mechanism needs further investigation

Our retrospective cohort study also showed that intravenous VC use (2 g) was related to the improved DFS in HCC patients after initial hepatectomy

several clinical trials of high-dose intravenous VC have been conducted in patients with advanced cancer and have revealed improved quality of life and prolonged OS

high-dose VC was not toxic to immune cells and major immune cell subpopulations in vivo

high recurrence rate and heterogeneity

tumor progression, metastasis, and chemotherapy-resistance

SVCT-2 was highly expressed in HCC samples in comparison to peri-tumor tissues

high expression (grade 2+/3+) of SVCT-2 was in agreement with poorer overall survival (OS) of HCC patients (Fig. 1c) and more aggressive tumor behavior

SVCT-2 is enriched in liver CSCs

these data suggest that SVCT-2 is preferentially expressed in liver CSCs and is required for the maintenance of liver CSCs.

pharmacologic concentrations of plasma VC higher than 0.3 mM are achievable only from i.v. administration

The viabilities of HCC cells were dramatically decreased after exposure to VC in dose-dependent manner

VC and cisplatin combination further caused cell apoptosis in tumor xenograft

These results verify that VC inhibits tumor growth in HCC PDX models and SVCT-2 expression level is associated with VC response

qPCR and IHC analysis demonstrated that expression levels of CSC-associated genes and percentages of CSCs in PDXs dramatically declined after VC treatment, confirming the inhibitory role of VC in liver CSCs

Huperzine A (a natural cholinesterase inhibitor) has been linked to improved memory performance in elderly people with benign forgetfulness, as well as patients with AD and vascular dementia

Cholinesterase inhibitors have been shown to have neuroprotective properties in patients with mild [37] as well as moderate-to-advanced AD

Major Gram-negative bacilli of the human GI-tract, such as the abundant B. fragilis and Escherichia coli (E. coli), are capable of discharging a remarkably complex assortment of pro-inflammatory neurotoxins

(i) bacterial amyloids (10, 21); (ii) endotoxins and exotoxins (5, 12); (iii) LPS (12, 18); and (iv) small non-coding RNAs (sncRNAs)

integral components of the outer leaflet of the outer membrane of Gram-negative bacteria, LPS

LPS, the major molecular component of the outer membrane of Gram-negative bacteria normally serves as a physical barrier providing the bacteria protection from its surroundings

LPS is also recognized by the immune system as a marker for the detection of bacterial pathogen invasion and responsible for the development of inflammatory response is perhaps the most potent stimulator and trigger of inflammation known

AD-affected brains have remarkably large loads of bacterial-derived toxins compared to controls. The transfer of noxious, pro-inflammatory molecules from the GI-tract microbiome to the CNS may be increasingly important during the course of aging when both the GI-tract and blood–brain barriers become significantly more permeable

first evidence of a perinuclear association of LPS with AD brain cell nuclei

LPS-mediated stimulation of chronic inflammation, beta-amyloid accumulation, and episodic memory decline in murine models of AD (39, 40) and a biophysical association of LPS with amyloid deposits and blood vessels in human AD patients

Strong adherence of LPS to the nuclear periphery has recently been shown to inhibit nuclear maturation and function that may impair or block export of mRNA signals from brain cell nuclei, a highly active organelle with extremely high rates of transcription, mRNA processing, and export into the cytoplasm

LPS may be further injurious to the nuclear membrane just as LPS contributes to cerebrovascular endothelial cell membrane injury

high intake of dietary fiber is a strong inhibitor of B. fragilis abundance and proliferation in the intact human GI-tract and as such is a potent inhibitor of the neurotoxic B. fragilis-derived amyloids, LPS, enterotoxins, and sncRNAs.

GI-tract microbiome-derived LPS may be an important initiator and/or significant contributor to inflammatory degeneration in the AD CNS

LPS has been recently localized to the same anatomical regions involved in AD-type neuropathology

a known pro-inflammatory transcription factor complex that triggers the expression of pathogenic pathways involved in neurodegenerative inflammation

pro-inflammatory amyloids, endo- and exotoxins, LPSs, and sncRNAs but also serve as potent sources of membrane-disrupting agents

colocalization of the Bb 23S rRNA probe was not observed in any of the sections of experimental inoculated animals shown to harbor rare persistent spirochetes (Supplemental Figure S1). Previous in vitro work has shown large decreases in Bb rRNA levels when in a stationary phase of growth despite the majority of spirochetes remaining viable

The possibility that the spirochetes were intact but dead also exists, though this may be unlikely given the precedence for viable but non-cultivable B. burgdorferi post-treatment

The doxycycline dose utilized in this study (5mg/kg) was based on a previous pharmacokinetic analysis of oral doxycycline in rhesus macaques proven to be comparable to levels achieved in humans and was meant to mimic treatment of disseminated LD

In addition to the brain of two treated animals, rare morphologically intact spirochetes immunoreactive to OspA were observed in the heart of one treated animal

Although we did not measure the doxycycline levels in the cerebrospinal fluid, they have been found to be 12% to 15% of the amount measured in serum

We and others have demonstrated the development of a drug-tolerant persister population when B. burgdorferi are treated with antibiotics in vitro

The adoption of a dormant or slow-growing phenotype likely allows the spirochetes to survive and re-grow following removal of antibiotic

The basic premise that antibiotic tolerance may be an adaptation of the sophisticated stringent response required for the enzootic cycle by the spirochetes is described in a recent review as well

Although current IDSA guidelines recommend intravenous ceftriaxone (2g daily for 30 days) over oral doxycycline for treatment of neuroborreliosis, a randomized clinical trial failed to show any enhanced efficacy of I.V. penicillin G to oral doxycycline for treatment of Lyme neuroborreliosis (no treatment failures were reported in this study of 54 patients).

we can speculate that the minimal to moderate inflammation that was observed, especially within the CNS and PNS can, in part, explain the breadth of symptoms experienced by late stage Lyme disease patients, such as cognitive impairment and neuralgia.

Erythema migrans, the clinical hallmark of early localized Lyme disease, was observed in one of the rhesus macaques from this study.

In 2014, a trailblazing study in mice demonstrated a dramatic decline in B. burgdorferi DNA in the tissues for up to eight months after antibiotic treatment followed by the resurgence of B. burgdorferi growth 12 months after treatment

This study provides evidence that the slow-growing spirochetes which persist after treatment, but are not cultivable in standard growth media may remain viable.

The first well-documented indication of Lyme disease (LD) in the United States occurred in the early 1970s

Lyme, Connecticut.

Lyme disease is now known to be caused by multiple closely related genospecies classified within the Bb sensu lato complex, representing the most common tick-borne human disease in the Northern Hemisphere

approximately 30,000 physician-reported cases occur annually in the United States, the annual incidence has been estimated to be 10-fold higher by the Centers for Disease Control and Prevention.6

Current antibiotic therapy guidelines outlined by the Infectious Disease Society of America (IDSA) are successful in the treatment of LD for the majority of LD patients, especially when administered early in disease immediately following identification of erythema migrans (EM)

‘post-treatment Lyme disease syndrome’ (PTLDS)

host-adapted spirochetes that persist in the tissues, probably in small numbers, inaccessible or impervious to antibiotic

inflammatory responses to residual antigens from dead organisms

residual tissue damage following pathogen clearance;

autoimmune responses, possibly elicited by antigenic mimicry

Experimental studies on immunocompetent mice, dogs, and rhesus macaques have provided evidence for the persistence of Bb spirochetes subsequent to antibiotic treatment in the form of residual spirochetes detected within tissue by IFA and PCR, and recovered by xenodiagnoses

Ten male rhesus macaques

half (five) of the NHP received antibiotic treatment, consisting of 5 mg/kg oral doxycycline twice per day.

Minimal and focal lymphoplasmacytic inflammation

inflammation was observed in the leptomeninges overlying a section of temporal cerebral cortex

Minimal localized lymphoplasmacytic choroiditis

Peripheral nerves contained minimal to moderate lymphoplasmacytic inflammation with a predilection for collagen-rich epineurium and perivascular spaces

Inflammation was observed in 56% (5/9) of the NHPs irrespective of treatment group

For all animals, inflammation was reserved to perineural tissue

The treatment lasted 28 days

Minimal to mild lymphoplasmacytic inflammation of either the myocardial interstitium (Figure 2Figure 2A), pericardium (Figure 2Figure 2B), or combination therein was observed in 60% of NHPs

A single morphologically intact spirochete, as indicated by positive red immunofluorescence (Figure 2Figure 2C), was observed in the myocardium of one treated animal

mild, multifocal lymphoplasmacytic inflammation was observed in one doxycycline-treated animal

three animals exhibited minimal to mild lymphoplasmacytic inflammation affecting joint-associated structures

10% to -20% of human patients treated

Multiple randomized placebo-controlled studies which evaluated sustained antimicrobial therapy concluded that there is no benefit in alleviating patients’ symptoms and indicated that long-term antibiotic therapy may even be detrimental to patients due to potential associated complications (ie, catheter infection and/or clostridial colitis)

and the rapid clearance of dead spirochetes in a murine model

higher doses may be needed to combat neuroborreliosis

We first investigated testosterone production after 24 and 48 h of ibuprofen exposure to assess its effects on Leydig cell steroidogenesis. Inhibition of testosterone levels was significant and dose-dependent (β = −0.405, P = 0.01 at 24 h and β = −0.664, P < 0.0001 at 48 h) (Fig. 2A) and was augmented over time

The AMH data show that the hypogonadism affected not only Leydig cells but also Sertoli cells and also occurred as early as 14 d of administration

Sertoli cell activity showed that AMH levels decreased significantly with ibuprofen administration, by 9% (P = 0.02) after 14 d (Fig. 1B) and by 7% (P = 0.05) after 44 d compared with the placebo group

Examination of the effect of ibuprofen exposure on both the ∆4 and ∆5 steroid pathways (Fig. 2B) showed that it generally inhibited all steroids from pregnenolone down to testosterone and 17β-estradiol; the production of each steroid measured decreased at doses of 10−5–10−4 M. Under control conditions, production of androstenediol and dehydroepiandrosterone (DHEA) was below the limit of detection except in one experiment with DHEA

Measuring the mRNA expression of genes involved in steroidogenesis in vitro showed that ibuprofen had a profound inhibitory effect on the expression of these genes (Fig. 3 B–D), consistent with that seen above in our ex vivo organ model. Taken together, these data examining effects on the endocrine cells confirm that ibuprofen-induced changes in the transcriptional machinery were the likely reason for the inhibition of steroidogenesis.

Suppression of gene expression concerned the initial conversion of cholesterol to the final testosterone synthesis. Hence, expression of genes involved in cholesterol transport to the Leydig cell mitochondria was impaired

A previous study reported androsterone levels decreased by 63% among men receiving 400 mg of ibuprofen every 6 h for 4 wk

We next examined the gene expression involved in testicular steroidogenesis ex vivo and found that levels of expression of every gene that we studied except CYP19A1 decreased after exposure for 48 h compared with controls

the changes in gene expression indicate that the transcriptional machinery behind the endocrine action of Leydig cells was most likely impaired by ibuprofen exposure.

Together, these data show that ibuprofen also directly impairs Sertoli cell function ex vivo by inhibiting transcription

ibuprofen use in men led to (i) elevation of LH; (ii) a decreased testosterone/LH ratio and, to a lesser degree, a decreased inhibin B/FSH ratio; and (iii) a reduction in the levels of the Sertoli cell hormone AMH

The decrease in the free testosterone/LH ratio resulted primarily from the increased LH levels, revealing that testicular responsiveness to gonadotropins likely declined during the ibuprofen exposure. Our data from the ex vivo experiments support this notion, indicating that the observed elevation in LH resulted from ibuprofen’s direct antiandrogenic action

AMH levels were consistently suppressed by ibuprofen both in vivo and ex vivo, indicating that this hormone is uncoupled from gonadotropins in adult men. The ibuprofen suppression of AMH further demonstrated that the analgesic targeted not only the Leydig cells but also the Sertoli cells, a feature encountered not only in the human adult testis but also in the fetal testis

ibuprofen displayed broad transcription-repression abilities involving steroidogenesis, peptide hormones, and prostaglandin synthesis

a chemical compound, through its effects on the signaling compounds, can result in changes in the testis at gene level, resulting in perturbations at higher physiological levels in the adult human

The analgesics acetaminophen/paracetamol and ibuprofen have previously been shown to inhibit the postexercise response in muscles by repressing transcription

Previous ex vivo studies on adult testis have indeed pointed to an antiandrogenicity, only on Leydig cells, of phthalates (41), aspirin, indomethacin (42), and bisphenol A (BPA) and its analogs

ibuprofen’s effects were not restricted to Leydig and Sertoli cells, as data showed that the expression of genes in peritubular cells was also affected

short-term exposure

In the clinical setting, compromised Leydig cell function resulting in increased insensitivity to LH is defined as compensated hypogonadism (4), an entity associated with all-cause mortality

compensated hypogonadic men present with an increased likelihood of reproductive, cognitive, and physical symptoms

an inverse relationship was recently reported between endurance exercise training and male sexual libido

AMH concentrations are lower in seminal plasma from patients with azoospermia than from men with normal sperm levels

inhibin B is a key clinical marker of reproductive health (32). The function of AMH, also secreted by Sertoli cells, and its regulation through FSH remain unclear in men

the striking dual effect of ibuprofen observed here on both Leydig and Sertoli cells makes this NSAID the chemical compound, of all the chemical classes considered, with the broadest endocrine-disturbing properties identified so far in men.

after administration of 600 mg of ibuprofen to healthy volunteers

14 d or at the last day of administration at 44 d

The cytokine storm is a consequence of mitochondrial dysfunction

The cytokine storm is a consequence of mitochondrial dysfunction

The cytokine storm is a consequence of mitochondrial dysfunction

The cytokine storm is a consequence of mitochondrial dysfunction

Lipoic acid, Methylene Blue and Chlorine dioxide relieve COVID-19 spike protein toxicity

Lipoic acid, Methylene Blue and Chlorine dioxide relieve COVID-19 spike protein toxicity

Lipoic acid, Methylene Blue and Chlorine dioxide relieve COVID-19 spike protein toxicity

Lipoic acid, Methylene Blue and Chlorine dioxide relieve COVID-19 spike protein toxicity

most diseases display a form of anabolism due to mitochondrial impairment

most diseases display a form of anabolism due to mitochondrial impairment

most diseases display a form of anabolism due to mitochondrial impairment

infection by Covid-19 follows a similar pattern

chronic inflammation

Long-term effects include redox shift and cellular anabolism as a result of the Warburg effect and mitochondrial dysfunction

Long-term effects include redox shift and cellular anabolism as a result of the Warburg effect and mitochondrial dysfunction

Long-term effects include redox shift and cellular anabolism as a result of the Warburg effect and mitochondrial dysfunction

Long-term effects include redox shift and cellular anabolism as a result of the Warburg effect and mitochondrial dysfunction

infection by Covid-19 follows a similar pattern

unrelenting anabolism leads to the cytokine storm,

unrelenting anabolism leads to the cytokine storm,

unrelenting anabolism leads to the cytokine storm,

chronic inflammation

chronic inflammation

infection by Covid-19 follows a similar pattern

Lipoic acid and Methylene Blue have been shown to enhance the mitochondrial activity, relieve the Warburg effect and increase catabolism

Lipoic acid and Methylene Blue have been shown to enhance the mitochondrial activity, relieve the Warburg effect and increase catabolism

Lipoic acid and Methylene Blue have been shown to enhance the mitochondrial activity, relieve the Warburg effect and increase catabolism

Methylene Blue, Chlorine dioxide and Lipoic acid may help reduce long-term Covid-19 effects by stimulating the catabolism

Methylene Blue, Chlorine dioxide and Lipoic acid may help reduce long-term Covid-19 effects by stimulating the catabolism

Methylene Blue, Chlorine dioxide and Lipoic acid may help reduce long-term Covid-19 effects by stimulating the catabolism

direct consequence of redox iMeBalance, itself a consequence of decreased energy yield by the mitochondria

direct consequence of redox iMeBalance, itself a consequence of decreased energy yield by the mitochondria

mitochondrial dysfunction and increased levels of lactate, which are important characteristics of metabolic shift and Warburg effect in many diseases

mitochondrial dysfunction and increased levels of lactate, which are important characteristics of metabolic shift and Warburg effect in many diseases

increased lactate dehydrogenase activity (LDH) was observed in COVID-19 patients

increased lactate dehydrogenase activity (LDH) was observed in COVID-19 patients

almost every disease presents an increased anabolism

almost every disease presents an increased anabolism

cell division is the most sophisticated way to release entropy

cell division is the most sophisticated way to release entropy

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

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

pharmacologic ascorbate as a prooxidant drug for therapeutic use.

Recently we reported that pharmacologic ascorbic acid concentrations produced H2O2 concentrations of ≥25 μM, causing cancer cell death in vitro

We found that H2O2 concentrations generated in vivo were those that caused cancer cell death in vitro

When ascorbate was given parenterally, Asc•−, the product of a loss of one electron from ascorbate, was detected preferentially in extracellular fluid compared with blood

Asc•− generation in extracellular fluid depended on the ascorbate dose and the resulting concentrations

With i.v. administration of ascorbate, Asc•− concentrations were as much as 12-fold greater in extracellular fluid compared to blood and approached 250 nM

In blood, such Asc•− concentrations were never produced and were always <50 nM

These data are all consistent with the hypothesis that pharmacologic ascorbate concentrations in vivo serve as a prodrug for selective delivery of H2O2 to the extracellular space

After oral ingestion, control of intracellular and extracellular ascorbate concentrations is mediated by three mechanisms: intestinal absorption, tissue transport, and renal reabsorption

intestinal absorption, or bioavailability, declines at doses >200 mg

corresponding to plasma concentrations of ≈60 μM

at approximately this concentration, the ascorbate tissue transporter SVCT2 approaches Vmax, and tissues appear to be saturated

also at ≈60 μM, renal reabsorption approaches saturation, and excess ascorbate is excreted in urine

Parenteral administration bypasses tight control

When tight control is bypassed, H2O2 forms in the extracellular space

in vivo validation of ascorbate as a prodrug for selective H2O2 formation

Temporarily bypassing tight control with parenteral administration of ascorbate allows H2O2 to form in discrete time periods only, decreasing likelihood of harm, and provides a pharmacologic basis for therapeutic use of i.v. ascorbate

H2O2 formation results in selective cytotoxicity

Tumor cells are killed with exposure to H2O2 for ≤30 min

In vitro, killing is mediated by H2O2 rather than Asc•−

In addition to cancer treatment, another potential therapeutic use is for treatment of infections. H2O2 concentrations of 25–50 μM are bacteriostatic

virally infected cells may also be candidates