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The involvement of acetate, aspartate, butyrate and enzymatic cofactors in the HASD CFS/ME model

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Abstract

Abstract In cells, where mitochondria are utilising glutaminolysis and transamination - whether caused by normal function or when specifically altered by eg. virally induced overexpression of KGA, GLS1, GLUD1 and/or GLUD2 - key enzymatic reactions for energy production are reversed during the transamination of aspartate=>oxaloacetate and α-KG=>glutamate + ammonia, consuming additional pyridoxal 5-phosphate (P5P). Excessive glutaminolysis and transamination increases nitrogen / urea burden, while consuming aspartate, before further consuming acetate and butyrate for increased α-KG=>[..]=>glutamine disposal via the phenylacetylglutamine (PAGN) pathway to urine. Further, this elevates lactate and affects neighbouring cell metabolism via the lactate shuttle. Depletion of acetate could lead to many impaired reactions involving acetyl-CoA, with implications to beta-oxidation pathways, mitochondrial function, pyruvate:lactate balance and any pathways that require an acetyl donor, such as choline=>acetylcholine and carnitine=>acetyl-L-carnitine. Depletion of acetate would cause further dysregulation to the urea cycle (UC), creating an elevation of glutamate, acting as a rate limiting factor for glutaminolysis and further causing impairment of mitochondrial Nicotinamide Adenine Dinucleotide (NAD+):NADH redox, favouring NADH. Aspartate depletion also dysregulates production of reactive oxygen species (ROS), sex hormones, thyroid hormones, alpha-melanocyte-stimulating hormone, GABA and dopamine release. Depletion of butyrate dysregulates immune and mitochondrial apoptotic regulation via Nuclear Factor Kappa B (NF-κB) signalling. It further impacts nitrogen metabolism. The depletion of NAD+ acts as a rate limiting factor for many enzymatic reactions, including glutamate dehydrogenase (GDH), further impairing glutamate<=>α-KG metabolism. We further describe a role for acetate, aspartate, butyrate, P5P and Vitamin B5 in a therapeutic intervention against the HASD model for CFS/ME.
Review:
The involvement of acetate, aspartate,
butyrate and enzymatic cofactors in the
HASD CFS/ME model
Authors: Joshua Leisk, Aline Noçon ©2021
Key words: Epstein-Barr Virus (EBV), hyperlactatemia, chronic fatigue syndrome / myalgic
encephalomyelitis (CFS/ME), fibromyalgia, alpha-ketoglutarate dehydrogenase deficiency,
pyruvate dehydrogenase deficiency, herpesvirus autoimmune spectrum disorder
Abstract
In cells, where mitochondria are utilising glutaminolysis and transamination - whether caused by
normal function or when specifically altered by eg. virally induced overexpression of KGA,
GLS1, GLUD1 and/or GLUD2 - key enzymatic reactions for energy production are reversed
during the transamination of aspartate=>oxaloacetate and α-KG=>glutamate + ammonia,
consuming additional pyridoxal 5-phosphate (P5P).
Excessive glutaminolysis and transamination increases nitrogen / urea burden, while consuming
aspartate, before further consuming acetate and butyrate for increased α-KG=>[..]=>glutamine
disposal via the phenylacetylglutamine (PAGN) pathway to urine. Further, this elevates lactate
and affects neighbouring cell metabolism via the lactate shuttle.
Depletion of acetate could lead to many impaired reactions involving acetyl-CoA, with
implications to beta-oxidation pathways, mitochondrial function, pyruvate:lactate balance and
any pathways that require an acetyl donor, such as choline=>acetylcholine and
carnitine=>acetyl-L-carnitine.
Depletion of acetate would cause further dysregulation to the urea cycle (UC), creating an
elevation of glutamate, acting as a rate limiting factor for glutaminolysis and further causing
impairment of mitochondrial Nicotinamide Adenine Dinucleotide (NAD+):NADH redox, favouring
NADH.
Aspartate depletion also dysregulates production of reactive oxygen species (ROS), sex
hormones, thyroid hormones, alpha-melanocyte-stimulating hormone, GABA and dopamine
release.
Depletion of butyrate dysregulates immune and mitochondrial apoptotic regulation via Nuclear
Factor Kappa B (NF-κB) signalling. It further impacts nitrogen metabolism.
The depletion of NAD+ acts as a rate limiting factor for many enzymatic reactions, including
glutamate dehydrogenase (GDH), further impairing glutamate<=>α-KG metabolism.
We further describe a role for acetate, aspartate, butyrate, P5P and Vitamin B5 in a therapeutic
intervention against the HASD model for CFS/ME.
Introduction
In “The true nature of an autoimmune disease” we hypothesised a complex, extensible model of
impaired mitochondrial and metabolic disorders in human herpesvirus (HHV) seropositive
CFS/ME as part of a Herpesvirus Autoimmune Spectrum Disorder (HASD)[1].
Our disease model appears compatible with the “IDO metabolic trap” proposed by Kashi A,
Davis R et al.[14], and the PDH deficiencies reported by Fluge et al.[15].
We previously hypothesised a complex disease model, where a metabolic blockade, or loop,
could be induced, resulting as a simultaneous α-ketoglutarate dehydrogenase (α-KGDH) and
pyruvate dehydrogenase (PDH) deficiency, with dysregulated beta-adrenergic signalling
cascade and impaired hepatic gluconeogenesis, phasic hyperlactatemia and hyperammonemia.
We further described a number of interventions for this blockade and known limitations for this
array of therapeutic interventions, where α-ketoglutarate (α-KG) continues to accumulate, as an
untreated artefact of the original disorder, resulting in elevated Urea Cycle (UC) burden and
further contributing to a state of delayed mitochondrial impairment, proportional to previous
mitochondrial activity.
Further investigation into therapeutically resolving these remaining impairments has uncovered
an extension to our described disease model. This allows for a more complete understanding
and formation of a comprehensive treatment plan.
The HASD CFS/ME model is primarily based around metabolic impairments caused by
alterations to metabolic behaviour in HHV-infected latent hepatic cells, with further complications
associated with any lytic activity[1].
Herein, we further extend the HASD model and examine the roles of aspartate, acetate,
butyrate and enzymatic cofactor depletion as causal factors in achieving and / or maintaining
the metabolic blockade previously described.
Aspartate, or aspartic acid is a key metabolite for many enzymatic reactions, including those in
transamination of α-KG to oxaloacetate[1][60].
Extending the HASD model, we further propose that in the CFS/ME subtype acetate, aspartate
and enzymatic cofactors are depleted through enhanced rates of hepatic glutaminolysis and
transamination, further altering glucose and lactate metabolism[18][60][61][62][63]. This may also be
relevant to other infected tissues, as a secondary complication in HASD CFS/ME.
A sequence for glutaminolysis and transamination to oxaloacetate (and malate) is described
as[60]:
1. [Glutamine] into
[glutamate + ammonia],via
[glutaminase]
Then
2. [Glutamate] into
[α-KG + ammonia],via
[GDH / glutamate pyruvate transaminase (GPT) / glutamate oxaloacetate
transaminase (GOT)]
Then
3. [Aspartate + α-KG] transaminases into
[oxaloacetate + glutamate], via
[P5P, aspartate aminotransferase (AST)].
(Then)
4. [Oxaloacetate + NADH + H+] becomes
[malate + NAD+], via
[malate dehydrogenase (MDH)].
EBV, CMV, HHV-6 and Kaposi's sarcoma-associated herpesvirus (KSHV) have all been
demonstrated to rely on glutaminolysis and glycolysis for maintaining latent and lytic
persistence[1][2][3]. This was previously mentioned as exhibiting similar traits to Warburg-style
cancer cells and senescent cells[1][18][60][61][62][63].
The depletion of aspartate would cause further dysregulation to the UC at argininosuccinate
(ASA), creating an elevation of systemic nitrogen while limiting transamination[1][60].
With Complex V impairment due to elevated α-KG (or α-KGDH deficiency) and transamination,
aspartate deficiency could further cause impairment to Nicotinamide Adenine Dinucleotide
(NAD+):NADH redox, favouring NADH and depleting NAD+[4][7].
This depletion of NAD+ acts as a rate limiter for many enzymatic reactions, including glutamate
dehydrogenase (GDH), further impairing glutamate<=>α-KG metabolism[1].
The depletion of aspartate could also trigger replenishment from (extracellular) pyruvate via
pyruvate carboxylase, altering lactate:pyruvate balance[16][17]. Pyruvate pathways would be
further confounded by acetyl-CoA depletion, discussed further on, perhaps sustaining
glutaminolysis[26].
Aspartate depletion could also dysregulate production of ROS[21][29][30], sex hormone synthesis,
thyroid hormone synthesis, alpha-melanocyte-stimulating hormone (α-MSH) synthesis,
melatonin, gamma aminobutyric acid (GABA) and dopamine release[21][23].
This may also cause dysregulated energy production, circadian rhythm, unrefreshing sleep,
dysregulation of diurnal cortisol and dysregulation of a-KG levels via compensation by
melatonin-mediated exosome creation[50][51][52][53][64][65].
Skin and hair pigmentation may also be affected, via decreased α-MSH, melatonin, cyclic
adenosine monophosphate cAMP and cyclic guanosine monophosphate (cGMP)[54][58].
With decreased α-MSH, antimicrobial and anti-inflammatory functions may be impaired against
eg. Candida albicans, Escherichia coli, and Staphylococcus aureus[59].
Melatonin has also shown beneficial properties against elevated liver enzymes[55].
Aspartate / aspartic acid exists as both left (L) and right (D) isomers and they each have
different functions in humans. L-aspartate is found in abundance and converted to D-aspartate
on-demand in the liver, heart, lung, stomach, intestines, salivary glands, semen, central nervous
system, knee cartilage, testis, pre-ovulatory ovarian follicle and retinae[33]. A deficiency of
D-aspartate could cause impaired synthesis functions for these organs / tissues.
D-aspartic acid supplementation has yielded mixed results for testosterone production in males.
This suggests a deficiency may act as a rate limiting factor and exogenous dosing to
supraphysiological levels may not have a linear effect for steroidogenesis pathways. However,
the described excitatory effects of D-aspartate against glutamate receptors could prove
problematic in patients with a urea cycle defect, hyperammonemia or HASD CFS/ME[27][33].
Based on these factors, further investigation into L-aspartate and NOT D-aspartate as a
potential treatment for CFS/ME patients (and all diseases / disorders suggested as related to
the HASD disease model) could be warranted[1].
In the HASD CFS/ME model, hyperammonemia (HA) and hepatic encephalopathy (HE) has
been described as partially responsible for encephalomyelitis, with lactatemia being another
cause[1].
Aspartate, in the form of L-ornithine-L-aspartate (LOLA) has been demonstrated to prevent HE,
increasing mental status while decreasing serum and spinal fluid ammonia levels, by increasing
both UC efficiency and glutamine (GLN) synthesis[8].
Acetate, or acetic acid is another common metabolite in many pathways, including regulation of
systemic nitrogen[11]. Phenylacetate (PA) is a key metabolite in an important nitrogen disposal
pathway via incorporation of glutamine into phenylacetylglutamine (PAGN)[5][7]. See “Figure 1”,
(De Las Heras J et al.)[5].
Acetate, in the form of L-ornithine phenylacetate (LOPA), has been demonstrated to prevent HE
via this same pathway[6].
In addition to clinical use for UC disorders, PA and its precursor phenylbutyrate (PB)[31] are
known for being histone deacetylase (HDAC) inhibitors. PA and PB also exhibit inconclusive
results for inhibiting various cancers. Butyrate may decrease C-terminal binding protein (CtBP)
and glutaminolysis via SIRT4[5][9][10][67][68][69][70]. HDAC inhibitors, when used in combination with
aldactone to arrest late-stage EBV (and perhaps other HHV) lytic replication, may assist in
reducing HHV latent cell burden[1][5].
Fruit vinegars contain acetic acid. They have also been shown to contain unique organic acids,
such as succinic acid. These vinegars have been demonstrated to reduce oxidative stress,
improve metabolism, aid recovery and reduce fatigue by enhancing glycogen repletion in both
rat liver and skeletal muscle post-exercise[11[12]][13].
With a surprising nod towards claims made by alternative health practitioners, these specific
vinegars which contain organic acids (and other compounds) relate to the therapeutic
interventions previously described. Depending on the fermentation process, these can contain
variable and/or suboptimal amounts to elicit a response[1][11][12][13][24][28]][36][37].
The fermentation process for each vinegar requires normal activity from the same families of
bacteria which inhabit our gut microbiome. The relationship between the end-products from both
gut microbiome fermentation and vinegar fermentation processes are direct. In both microbial
fermentation processes, depending on the prebiotics, bacteria and nutrient cofactors, the
end-products are highly variable, yet predictable[24][28]][36][37].
Relative to these fermentation variables, a healthy gut microbiome and/or commercial vinegar
may create appropriate organic acid profiles suitable for therapeutic use in HASD CFS/ME. A
more concentrated, powdered vinegar may warrant further investigation for inclusion in a pilot
study. It was shown that 1L of finished apple cider vinegar may contain between 1-1600mg of
succinic acid, typically 5000mg of acetic acid, along with variable amounts of pyruvate, malic
acid, butyric acid, aspartic acid and many other compounds[24][28][36][37][56].
Unlike the poorly-understood and chaotic conditions surrounding the human gut microbiome,
creating vinegars is a highly controlled process which uses specific prebiotics (fruits) and a
controlled microbial environment. This leads to a consistent end-product which is analogous to
key activities of a healthy gut microbiome[24][28]][36][37].
High levels of lactate are created as a symptom in the HASD CFS/ME model[1]. Lactatemia
could increase species of gut bacteria such as Escherichia, Klebsiella, Serratia, Vibrio and
Pseudomonas, while also decreasing species of gut bacteria such as Firmicutes, Bacteroidetes,
Faecalibacterium, Roseburia and Eubacterium. This may cause a reduction of circulating
butyrate[38]. Butyrate notably inhibits NF-κB and assists with regulation of systemic
nitrogen[5][7][41].
NF-κB is both a proapoptotic and antiapoptotic regulatory factor[42]. Inhibiting NF-κB has been
shown to reverse the Warburg effect, induces apoptosis in both EBV-infected cells[40] and some
cancer cells, as well as decreasing tumorigenesis[43].
NF-κB controls mitochondrial gene expression, including cAMP response element (CREB)
binding protein (CBP) transcriptional co-activators. NF-κB functions as a catalytic subunit in
Complex IV and can influence enzymatic activity in respiratory electron transport chain (ETC)
complexes[43]. cAMP has also been indicated in the HASD CFS/ME model to have relevance to
hepatic gluconeogenesis and lactate metabolism[1].
In Alzheimer’s Disease, NF-κB signalling controls amyloid β-induced mitochondrial dysfunction
and was somewhat modulated by creatine[43].
As butyrate and aspartate are both metabolites for nitrogen disposal via PB=>PA=>PAGN, a
depletion of either could lead to dysregulation of NF-κB signalling and further alterations to
B-cells and CD4+, CD8+T cells. A deficiency of acetate can influence these same
alterations[5][7][39].
A deficiency of aspartate could also impair microbial secretion of acetic acid, as recently
indicated in the pathogenesis of type 1 diabetes. Dietary intake of high-amylose maize starch
(HAMS) that has been acetylated (HAMSA) or butyrylated (HAMSB) was shown to alter
microbial diversity and affect disease progression[39].
It was further shown that succinate, acetate and butyrate secretion dramatically increased when
a high-amylose diet was combined with casein, soy or potato proteins, respectively[47]. A
high-amylose and soy protein diet was also shown to reduce blood urea by 42% in rats[49].
These combined results suggest that an appropriate dietary intake of these food items may
provide beneficial microbiome alterations in HASD CFS/ME and related diseases[44][45][46][47][49].
Acetic acid was demonstrated to alleviate dextran sulfate sodium (DSS)-induced colitis in mice,
by inhibiting both interferon (IFN)-γ-producing T helper (Th)1 and IL-17-producing CD4+ effector
cell lineage (Th17) responses, as well as NOD-like receptor protein3 (NLRP3) inflammasomes.
It also activates the mitogen-activated protein kinase (MAPK) signal pathway[11].
Vinegar / acetic acid was shown to increase AMP-activated protein kinase (AMPK), peroxisome
proliferator-activated receptor γ (PPARγ) and PPARγ coactivator-1α (PGC-1α) in male rats,
modulating spontaneous hypertension[11]. This could have additional relevance for metabolism in
HASD CFS/ME.
Acetic acid has been demonstrated to selectively induce apoptosis in gastric cancer cells[22].
Further investigation of acetic acid against latent cell viability may be warranted.
In humans, consumption of vinegar decreased obesity, total cholesterol and triglycerides. It
further improved insulin sensitivity in diabetics and lowered gastric emptying. Additionally, acetic
acid enhanced muscle blood flow and glucose uptake in humans with impaired glucose
tolerance and hypertriglyceridemia. Melanoidins from fruits vinegars reduced ROS in normal
human liver cells, protecting them from oxidative stress through a mitophagy-dependent
pathway[11].
Acetic acid can be bound to coenzyme A to produce acetyl-CoA. When acetyl-CoA is combined
with aspartate by neuronal aspartate N-acetyltransferase (NAT8L), N-acetylaspartate is formed.
Acetyl-CoA is also used to create acetylcholine from choline[19]. A reduction of acetylcholine
could impair muscle activation and cognition.
These are just two examples. Impaired acetyl-CoA production could have significant
consequences for the synthesis of the many products requiring acetylation, such as
acetyl-L-carnitine or N-acetylserotonin. Acetyl-L-carnitine is essential for the beta-oxidation of
fatty acids[31]. An impairment to this pathway could result in decreased mitochondrial efficiency
and potentially cause a compensatory effect of increased catecholamine secretion, leading to
postural orthostatic tachycardia syndrome (POTS), dysautonomia and cortisol dysregulation.
Acetyl-CoA can also be synthesised from pyruvate by PDH. Where PDH is also impaired, by eg.
PDH Kinase, an acetyl-CoA deficiency can occur[1]. When combined with an acetate shortage,
deficiencies of N-acetylaspartate and acetylcholine may result, causing cognitive impairment.
In pigs, it has been shown that Acetyl-CoA derived from inflammation-induced fatty acid
oxidation promotes hepatic malate-aspartate shuttle activity and glycolysis. This was
demonstrated via hepatic injections of lipopolysaccharide (LPS), suggesting the existence of a
further extension and additional input to our HASD CFS/ME disease model. This input would
consist of circulating LPS, as secreted from LPS-positive bacteria, and subsequent bowel
permeability issues. Circulating LPS would induce or complicate the same metabolic blockade
via hepatic metabolic alterations and further impair immune response via decreased
CD4+/CD25+ and CD4+/Foxp3[1][20][34][35][66].
Figure 1- Flowchart for HASD CFS/ME Model v1.1
(High-resolution available in supplemental files)
Discussion
Here we have explored a notion that administration of buyrate, aspartate / aspartic acid and
acetate / acetic acid, along with enzymatic cofactors P5P (preferred form of Vitamin B6) and the
CoA precursor, pantothenic acid (Vitamin B5) may alleviate metabolic deficiencies capable of
inducing or sustaining key symptoms described in the HASD CFS/ME disease model
hypothesis.
We have further explored how vinegar fermentation processes closely resemble helpful gut
microbiome fermentation processes and how HASD CFS/ME symptoms could negatively impact
the gut microbiome, complicating the disorder.
Specific dietary alterations - increased hydration, reduced protein intake, increased amylose
starch, potatoes, rice, soy and casein may provide long term benefits to HASD CFS/ME
outcomes - moreso, if combined with repopulation of beneficial gut bacteria.
When possibly combined with some of the previously described therapeutic interventions[1],
these additions may address and ameliorate all hypothesised gaps in the array of discussed
treatment options and therefore allow for a complete remission of HASD CFS/ME symptoms, in
a non-lytic viral state, where the root cause matches the scope of the model.
In veterinary sciences, acetic acid and enhanced hydration has also been mentioned as an
acute intervention for hyperammonemia symptoms, by conversion to a non-toxic form[25]. This
could also prove worthy of investigation for decreasing or arresting acute HE-like symptoms of
post-exercise malaise in HASD CFS/ME.
Further research is needed. Case reports and a pilot study to follow.
Acknowledgements
With special thanks to J Carlson, S Asnani and M Kaczmarek.
Data Availability Statement
All materials used have been cited. Images were created in Draw.IO and source files to extend
this model are available upon request to the corresponding author.
Author Contributions
JL conceived the design and authored the manuscript. AN reviewed methodology, provided
oversight and guidance, expert lab experience, analysis skills, audited / validated citations and
edited the manuscript. All authors critically reviewed the final manuscript.
Funding
This work was unfunded and conducted out of human interest.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or
financial relationships that could be construed as a potential conflict of interest. Authors have
previously joint-filed a patent relating to the formulation of a treatment protocol.
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Supplementary resource (1)

... We recently shared our novel understanding of a rather complicated disease model by submitting a few articles for peer-review and journal publication purposes [1] [2] . This model appears to accurately describe the pathophysiology of a very large number of diseases and disorders in a way that allows them to be treated and potentially cured [1] [2] . ...
... We recently shared our novel understanding of a rather complicated disease model by submitting a few articles for peer-review and journal publication purposes [1] [2] . This model appears to accurately describe the pathophysiology of a very large number of diseases and disorders in a way that allows them to be treated and potentially cured [1] [2] . Largescale testing has not yet been performed. ...
... There have been some early challenges in communicating our understanding of this model, as the language used was unfortunately as complicated as the disease model itself [1] [2] . ...
Preprint
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Here we describe the root cause of Chronic Fatigue Syndrome / Myalgic Encephalomyelitis, the growing list of related diseases in the proposed spectrum, related cancers, senescent cells, their previously described mitochondrial / metabolic disturbances and their related pattern of metabolite depletions and compensations as being virally-induced by upregulated expression of protein levels for “GLS1 - KGA, GAC” and “GLUD1”, “GLUD2”. We further describe some practical solutions to this problem, in plain language. [PLEASE NOTE: This is a "special edition", intended for a wider audience and hyperbole contained here may not be present in the final version.] {Errata, second paragraph on Page 9 of 39 should read: First, if α-KG levels are low - converting glutamate into α-KG (while importantly making ammonia and NADH) - this was incorrectly written as NAD+}
Preprint
Full-text available
Abstract Here we propose a hypothetical model seeking to map the pathogenesis of a herpesviridae-positive serology subtype of Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME) as a simultaneous α-ketoglutarate dehydrogenase (α-KGDH) and pyruvate dehydrogenase (PDH) deficiency, with degraded beta-adrenergic signalling cascade and impaired hepatic gluconeogenesis, phasic hyperlactatemia and hyperammonemia - as caused by herpesviridae-mediated antibodies and latent cell burden. For example, “M37GO37” targets dihydrolipoamide succinyltransferase from the α-ketoglutarate dehydrogenase complex (α-KGDC), creating an acute deficiency of α-KGDH, impairing Citric Acid Cycle (CAC) metabolites from succinyl-CoA / Complex V through malate, accumulating α-ketoglutarate (α-KG), reducing adenosine triphosphate (ATP), NAD+ and respiration. “M18GP8”, “M82GP8”, “M37GPl1” antibodies to pyruvate dehydrogenase complex (PDC), plus hypoxia, low physical activity and/or antibodies creating beta-adrenergic dysregulation can each cause a decrease in PDH, Cori Cycle efficiency and insulin resistance. When combined with succinate and argininosuccinate (ASA) deficiency, plus elevated α-KG, nitrogen disposal shunts to nitrogen retention via metabolism to L-glutamate and L-glutamine, triggering glutaminolysis. Sleeping, fasting and respiration decrease lactate and nitrogen retention via metabolic shunting, partially rescuing succinate availability for CAC, urea cycle metabolism via GABA. Each of these α-KGDH, PDH and beta-adrenergic cascade deficiencies are able to cause both of the others, adding additional complexity to diagnosis and treatment. These phases can be accompanied by debilitating symptoms associated with hyperammonemia, GABA deficiency, glutamate-induced excitotoxicity, uremia, hyperlactatemia, adrenergic and cortisol dysregulation, with accompanying hair, skin, GI, collagen, immune, sphingolipid, endocrine, sleep and neurological disorders. This further suggests investigating the herpesvirus family as causal for numerous disorders.
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Human herpesvirus 6 (HHV-6) is an important immunosuppressive and immunomodulatory virus worldwide. However, whether and how HHV-6 infection influences the metabolic machinery of the host cell to provide the energy and biosynthetic resources for virus propagation remains unknown. In this study, we identified that HHV-6A infection promotes glucose metabolism in infected T cells, resulting in elevated glycolytic activity with an increase of glucose uptake, glucose consumption and lactate secretion. Furthermore, we explored the mechanisms involved in HHV-6A-mediated glycolytic activation in the infected T cells. We found increased expressions of the key glucose transporters and glycolytic enzymes in HHV-6A-infected T cells. In addition, HHV-6A infection dramatically activated AKT-mTORC1 signaling in the infected T cells and pharmacological inhibition of mTORC1 blocked HHV-6A-mediated glycolytic activation. We also found that direct inhibition of glycolysis by 2-Deoxy-D-glucose (2-DG) or inhibition of mTORC1 activity in HHV-6A-infected T cells effectively reduced HHV-6 DNA replication, protein synthesis and virion production. These results not only reveal the mechanism of how HHV-6 infection affects host cell metabolism, but also suggest that targeting the metabolic pathway could be a new avenue for HHV-6 therapy.
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The C-terminal binding protein (CtBP) is an NADH-dependent dimeric family of nuclear proteins that scaffold interactions between transcriptional regulators and chromatin-modifying complexes. Its association with poor survival in several cancers implicates CtBP as a promising target for pharmacological intervention. We employed computer-assisted drug design to search for CtBP inhibitors, using quantitative structure-activity relationship (QSAR) modeling and docking. Functional screening of these drugs identified 4 compounds with low toxicity and high water solubility. Micro molar concentrations of these CtBP inhibitors produces significant de-repression of epigenetically silenced pro-epithelial genes, preferentially in the triple-negative breast cancer cell line MDA-MB-231. This epigenetic reprogramming occurs through eviction of CtBP from gene promoters; disrupted recruitment of chromatin-modifying protein complexes containing LSD1, and HDAC1; and re-wiring of activating histone marks at targeted genes. In functional assays, CtBP inhibition disrupts CtBP dimerization, decreases cell migration, abolishes cellular invasion, and improves DNA repair. Combinatorial use of CtBP inhibitors with the LSD1 inhibitor pargyline has synergistic influence. Finally, integrated correlation of gene expression in breast cancer patients with nuclear levels of CtBP1 and LSD1, reveals new potential therapeutic vulnerabilities. These findings implicate a broad role for this class of compounds in strategies for epigenetically targeted therapeutic intervention.
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A large body of literature supports the idea that nuclear factor kappa B (NF-κB) signaling contributes to not only immunity, but also inflammation, cancer, and nervous system function. However, studies on NF-κB activity in mitochondrial function are much more limited and scattered throughout the literature. For example, in 2001 it was first published that NF-κB subunits were found in the mitochondria, including not only IkBα and NF-κB p65 subunits, but also NF-κB pathway proteins such as IKKα, IKKβ, and IKKγ, but not much follow-up work has been done to date. Upon further thought the lack of studies on NF-κB activity in mitochondrial function is surprising given the importance and the evolutionary history of both NF-κB and the mitochondrion. Both are ancient in their appearance in our biological record where both contribute substantially to cell survival, cell death, and the regulation of function and/or disease. Studies also show NF-κB can influence mitochondrial function from outside the mitochondria. Therefore, it is essential to understand the complexity of these roles both inside and out of this organelle. In this review, an attempt is made to understand how NF-κB activity contributes to overall mitochondrial function – both inside and out. The discussion at times is speculative and perhaps even provocative to some, since NF-κB does not yet have defined mitochondrial targeting sequences for some nuclear-encoded mitochondrial genes and mechanisms of mitochondrial import for NF-κB are not yet entirely understood. Also, the data associated with the mitochondrial localization of proteins must be yet further proved with additional experiments.
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Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating noncommunicable disease brandishing an enormous worldwide disease burden with some evidence of inherited genetic risk. Absence of measurable changes in patients’ standard blood work has necessitated ad hoc symptom-driven therapies and a dearth of mechanistic hypotheses regarding its etiology and possible cure. A new hypothesis, the indolamine-2,3-dioxygenase (IDO) metabolic trap, was developed and formulated as a mathematical model. The historical occurrence of ME/CFS outbreaks is a singular feature of the disease and implies that any predisposing genetic mutation must be common. A database search for common damaging mutations in human enzymes produces 208 hits, including IDO2 with four such mutations. Non-functional IDO2, combined with well-established substrate inhibition of IDO1 and kinetic asymmetry of the large neutral amino acid transporter, LAT1, yielded a mathematical model of tryptophan metabolism that displays both physiological and pathological steady-states. Escape from the pathological one requires an exogenous perturbation. This model also identifies a critical point in cytosolic tryptophan abundance beyond which descent into the pathological steady-state is inevitable. If, however, means can be discovered to return cytosolic tryptophan below the critical point, return to the normal physiological steady-state is assured. Testing this hypothesis for any cell type requires only labelled tryptophan, a means to measure cytosolic tryptophan and kynurenine, and the standard tools of tracer kinetics.
Chapter
Carnitine serves an important role in the burning of fat for energy, and ferrying fatty acids across the walls of the mitochondria, where they are oxidized and turned into energy. Carnitine's role in fat metabolism leads it to affect, in some degree, all the other energy metabolism in the cell, including the burning of carbohydrate. In this way it can be linked to glucose metabolism, insulin and Metabolic Syndrome. There is compelling evidence that 1.5–3 g a day of acetyl-carnitine can improve cognitive function of individuals in the milder, early stages of Alzheimer's disease. Acetylcholine levels are decreased in many forms of dementia, and most of the drugs used for treatment of Alzheimer's disease increase the availability of acetylcholine by preventing its enzymatic destruction in the brain. Carnosine is useful in helping prevent damage caused by too much sugar in the body. Sugars, such as glucose or fructose, can bind with proteins. This binding not only damages the protein, but the glycosylated protein can stimulate secondary inflammatory processes. Increasing levels of carnosine in the brain may have a protective effect from Alzheimer's disease. Consumption of chocolate tends to inhibit synthesis of leukotrienes. Leukotrienes act to constrict blood vessels, promote inflammation, and activate platelets. There are many other nutritional supplements that play an important role in Metabolic Syndrome.
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Vinegar has been widely used as acidic condiment worldwide for thousands of years. Vinegar contains various nutrients and bioactive components, which are brewed by liquid-state and solid-state fermentation techniques. This review highlights the nutrients and bioactive components in different types of vinegars and their functional properties. Nutrients in vinegar include amino acids, sugars, vitamins, and minerals. The functions of these nutrients were providence energy, regulation of cell metabolism regulation, immunoregulation, antioxidation, anticoagulation and improvement of brain development. In addition, the bioactive components in vinegar include organic acids, polyphenols, melanoidins, and tetramethylpyrazine, which have the functions of antioxidative activity, regulation of lipid metabolism, liver protection, blood pressure and glucose control, anti-fatigue and anti-tumor. However, further studies are needed to explore the novel functional compounds in vinegars and their molecular mechanisms on health benefits in future.