• humans are incapable of synthesizing their own vitamin C due to a loss of function mutation in the L-gulono-γ-lactone oxidase (GULO) gene that is required to catalyze the final step of vitamin C formation in the liver
• Vitamin C plays a pivotal role in remodeling the epigenome by enhancing the activity of Jumonji-C domain-containing histone demethylases (JHDMs) and the ten-eleven translocation (TET) proteins. By maintaining differentiation plasticity
• induced pluripotent stem cells (iPSCs)
• vitamin C is a critical cofactor of Fe²⁺⁺ and α-ketoglutarate-dependent dioxygenases (α-KGDDs)
• vitamin C to potentiate the activity of histone and DNA demethylating enzymes also has clinical application in the treatment of cancer.
• Vitamin C deficiency has been widely reported in cancer patients and has recently been shown to accelerate cancer progression in disease models.
• the diverse group of α-KGDDs regulated by vitamin C are erasers of epigenetic modifications, such as the Jumonji-C domain-containing histone demethylases (JHDMs) and the ten-eleven translocation (TET) family of DNA hydroxylases
• Vitamin C, by enhancing the catalytic activity of JHDMs and TETs drive histone and DNA demethylation in somatic cells that allow pluripotency genes to turn on while simultaneously erasing the epigenetic memory of the adult cell state
• Vitamin C-mediated remodeling of the epigenome also has important implications in the treatment of cancer
• Epigenetic dysregulation is a hallmark of cancer initiation and progression, causing aberrant gene expression patterns and genomic instability
• Epigenetic erasers such as JHDMs and TETs are frequently mutated in cancer, resulting in histone and DNA hypermethylation phenotypes that block tumor cells from responding to differentiation cues and provide protection in response to chemotherapy
• Vitamin C treatment at high-doses is now being explored as a novel therapeutic approach to overcome metabolic or epigenetic dysregulation and reprogram the cancer epigenome, allowing cells to regain their ability to differentiate and improve their responsiveness to standard chemotherapies.
• epigenetic memory in iPSCs is evidenced by the tendency for reprogrammed cells to exhibit a differentiation bias toward the donor cell lineage,
• in comparison to other antioxidants such as glutathione, N-acetylcysteine, vitamin E and lipoic acid, vitamin C was found to be substantially more efficient at enhancing proliferation of mouse ESCs and iPSC generation from mouse or human fibroblasts
• Vitamin C is required for the optimal activity and demethylation capacity of several JHDMs
• mechanism by which vitamin C could facilitate reprogramming was through increased histone demethylation
• Vitamin C was also shown to prevent DNA hypermethylation
• The ability of vitamin C to increase the efficiency of reprogramming and improve the quality of iPSCs was therefore attributed to its ability to modulate the epigenome.
• TET expression is essential for reprogramming
• blocked during mesenchymal-to-epithelial transition (MET)
• Vitamin C promotes somatic cell reprogramming by enhancing the activity of α-KGDDs
• Vitamin C can also work synergistically with other factors, such as Vitamin A (retinoic acid, RA), to enhance mouse iPSC reprogramming
• RA has no direct effect on TET enzymatic activity but can increase TET expression levels
• vitamin C enhances the activity of an increased pool of TET protein driven by RA signaling, resulting in greater reprogramming efficiency of primed mouse ESCs to naïve pluripotency
• HIFs are oxygen-sensing transcription factors made up of α and β subunits that dimerize and translocate to the nucleus under conditions of hypoxia to regulate the expression of genes involved in oxygen homeostasis, glucose metabolism, angiogenesis, erythropoiesis and iron metabolism
• During reprogramming, HIF proteins are required to initiate the metabolic switch from oxidative to glycolytic metabolism, an essential step for the initial stages of somatic cell reprogramming
• During hypoxia, the HIFα subunits (HIF1α and HIF2α) are stabilized and help drive the metabolic switch to glycolysis
• vitamin C-mediated reduction in the mRNA expression levels of HIF genes
• Vitamin C, similar to its role in somatic cell reprogramming, has been shown in numerous studies to maintain the proliferation and differentiation potential of ESCs, iPSCs, neural stem cells (NSCs), mesenchymal stem cells (MSCs), epithelial or cardiac progenitors and intestinal stem cells
• Treatment with vitamin C may therefore be important for the maintenance of an epigenetic state that favors enhanced survival of cultured NSCs primed for DA neuron differentiation.
• vitamin C also promotes the transcription of collagen genes and increases the stability of collagen mRNA in multiple cell types
• Vitamin C has been shown to up-regulate the expression of extracellular matrix type-I collagen, fibronectin, integrin β1, and promote intercellular junctions that lead to enhanced sheet formation in both in vivo animal models and in vitro cultured human MSCs
• vitamin C has also been shown to increase telomerase activity and the expression of genes encoding telomerase-related RNA and protein components that protect telomere stability
• The ability of vitamin C to suppress senescence and reverse aging phenotypes may be of therapeutic value in the treatment of premature aging.
• Impaired α-KGDD function leads to histone and DNA hypermethylation that is a hallmark of several cancers
• Treatment with vitamin C slows down telomere shortening in WS MSCs, and causes down-regulation of p16/Ink4a and decreases the expression of the pro-inflammatory cytokines IL-6 and IL-8 that are associated with a senescence phenotype
• Vitamin C-mediated suppression of accelerated aging in WS MSCs is most likely a direct effect of enhanced activity of epigenetic regulators
• loss of TET function occurs in a variety of hematologic malignancies
• Vitamin C could therefore be considered a rejuvenating epigenetic cofactor, capable of reversing aging phenotypes, such as those observed in patients with WS, and could also be useful in preventing the premature aging of normal differentiated adult cell types.
• enhancing any residual amount of functional wild-type TET or JHDM activity, even in the presence of inhibitory oncometabolites, could be sufficient to restore epigenetic differentiation cues and erase aberrant DNA and histone hypermethylation phenotype
• Vitamin C deficiency modeled in Gulo^–/– mice increases the frequency of HSCs in bone marrow and causes a loss of 5hmC in their genome that resembles the effect of TET deficiency (Anthony and Schorah, 1982). Importantly, the suppression of TET activity in HSCs was reversible and could be restored to normal levels upon dietary vitamin C administration
• Vitamin C treatment in mouse models of leukemia was shown to mimic genetic restoration of Tet2 function, causing an increase in 5hmC formation, global DNA hypomethylation, a block in aberrant self-renewal and suppression of disease progression in Tet2-deficient mice
• The majority of patients with hematologic malignancies (up to 58%) are vitamin C deficient compared to normal healthy controls (Huijskens et al., 2016; Liu et al., 2016) and chemotherapy or HSC transplantation can cause vitamin C levels to decrease even further in these patients
• vitamin C deficiency could fuel increased disease aggressiveness or risk of relapse even in non-TET mutant cancer patients.
• promoter CpG island DNA hypermethylation in the context of global DNA hypomethylation
• Restoring TET function in cancer cells by vitamin C administration, in combination with other targeted epigenetic therapies and hypomethylating agents, may help to erase the epigenetic memory of the cancerous cell state and reprogram the epigenome of these cells that allows them to re-acquire normal differentiation potential and tumor suppressive gene expression programs
• Genome-wide DNA hypo-methylation induced by vitamin C in ESCs is also observed upon treatment of human leukemia cell lines and correlates with increased TET2 activity
• Vitamin C can synergize with decitabine in a TET2-dependent manner to increase 5hmC, drive DNA hypo-methylation and up-regulate the expression of endogenous retroviral genes that triggers an innate viral mimicry response leading to apoptosis of several human cancer cells lines including AML
• Vitamin C treatment in combination with the PARP inhibitor Olaparib, enhances the killing of human AML cells greater than either agent alone (Cimmino et al., 2017), suggesting that TET-mediated DNA oxidation induced by vitamin C can create a targetable synthetic lethality.
• By forcing AML cells to undergo increased active DNA demethylation, vitamin C treatment renders them hypersensitive to PARP inhibition that can be exploited as a novel combination therapy for the treatment of leukemia.
• In patients with glioblastoma, small pre-clinical and clinical case studies have shown that the combination of conventional treatments with intravenous (i.v.) high-dose vitamin C therapy improved quality of life, progression-free and overall survival
• the therapeutic mechanism of action in glioma has been attributed to increased intracellular labile-iron toxicity and the prooxidant effects of high-dose vitamin C, an epigenetic response and role for increased TET or JHDM activity in these patients was not investigated.
• The relevance of vitamin C as a therapeutic agent will ultimately be dependent on its mode of administration, plasma concentration and capacity for uptake by tumor cells
• Pharmacokinetic studies comparing dietary vs. i.v. administration of high dose vitamin C revealed striking differences in the plasma levels of ascorbate
• Less than 50% of an oral dose of 1.25 g is absorbed, resulting in maximum peak plasma concentrations of ∼100 μM that fall back to a baseline of ∼70 μM after 4 h
• intravenous administration of the same 1.25 g dose of ascorbate can generate a peak plasma level of 1 mM concentration
• The difference in circulating plasma levels between dietary and i.v. administration have been attributed to the homeostatic down-regulation of the sodium dependent vitamin C transporter 1 (SVCT1) on intestinal epithelial cells in the presence of elevated ascorbate levels
• Brain tissue has been reported to have the highest intracellular requirements for vitamin C
• Vitamin C is able to pass from the blood into the endothelial cells of the blood-brain barrier in its oxidized form, DHA, through glucose transporters (GLUT1) where it can then be reduced back to ascorbate for uptake via SVCT2 that is highly expressed in brain cortex and cerebellar stem cells, neurons and neuroblastoma cell
• The same mechanisms underlying the erasure of epigenetic memory during reprogramming can also be harnessed in cancer therapy to reverse aberrant epigenetic signatures and allow tumor cells to regain their potential to differentiate or die
• vitamin C represents a natural, non-toxic, epigenetic therapy that can be used in the prevention and treatment of cancer
• loss of function in epigenetic regulators is a hallmark of malignant transformation and a driver of cancer progression
• the ability of vitamin C to enhance the activity of epigenetic erasers such as JHDM and TET proteins

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• precursor molecules olivetolic acid and geranyl-pyrophosphate, which combine to form cannabigerolic acid (CBGA)
• CBGA serves as the precursor to most other cannabinoids and is converted to Δ9-tetrahydrocannabinolic acid (Δ9-THCA), cannabidiolic acid (CBDA), and cannabichromenic acid
• it is normally found in very low quantities in Cannabis
• 2018 Farm Bill
• in spite of having CBG as a common precursor, Δ9-THC, CBD, and CBC have dramatically different physiologic effects
• cannabinoids other than Δ9-THC and CBD have had little exploration and characterization.
• CBG is distinct from Δ9-THC and CBD in its pharmacological profile
• CBG seems to reside, pharmacologically, in between Δ9-THC and CBD
• CBG is more like Δ9-THC at the CB1/CB2 receptors than CBD, but with a lower affinity (by a factor of between 5-fold and 27-fold)
• negligible binding affinities for CBG at CB1 and CB2 receptors
• CBD and CBG are very comparable at six transient receptor potential cation channels (TRPA1, TRPV1, TRPV2. TRPV3, TRPV4, and TRPM8) with relatively minor differences in affinity (generally less than 5-fold differences)
• for GPR55 (the potential nonhomologous CB3 receptor), there is no information on CBG binding
• CBG appears to be a very potent (nanomolar to sub-nanomolar affinity) agonist at the α-2 adrenoceptor
• clear differentiation of CBG and CBD at the 5-HT_1A receptor, in which the former is reported to be an antagonist, whereas the latter is an indirect agonist
• CBG is a potent agonist at the α-2 recepto
• the α-2 receptor class is best known as a presynaptic receptor
• this autoregulatory receptor has shown its ability to dampen sympathetic nervous system activity through its Gi (inhibitory) activity that is triggered when synaptic norepinephrine binds to the presynaptic receptor
• reduced sympathetic activity
• three receptor subtypes—α-2A, α-2B, and α-2C—
• In the brain, 2A receptors are widely distributed and abundant in the locus coeruleus and in brainstem regions with homeostatic functions. The α-2B receptors are found in the thalamic nuclei, whereas 2C is found in the basal ganglia, olfactory tubercle, hippocampus, and cerebral cortex
• The 2A and 2C receptors are the primary contributors of α-2 receptor function in the central nervous system
• 2A is found in platelets, beta cells of the pancreas, adrenal glands, intestinal epithelia, vascular endothelium, and smooth muscle cells
• peripheral α-2 agonism effects center around their antihypertensive, sedative, and analgesic functions
• α-2 agonists are used to improve working memory and planning ability in ADHD in children and adults, along with tic disorders and reduction of opiate withdrawal symptom severit
• 5-HT_1A receptor, which has previously been shown to interact with endogenous and exogenous cannabinoid ligands.
• The receptor is located both pre- and postsynaptically,
• CBG has been reported to be a potent (50 nM) 5-HT_1A antagonist.
• CBG and CBD have neuroprotective effects against oxidative neurotoxicity through a 5-HT_1A receptor–mediated mechanism.
• The effects of CBG on serotonin signaling or availability have not yet been thoroughly studied
• PPARα, PPARβ, and PPARγ
• regulate lipid metabolism, hepatic metabolic functions, and inflammation.
• CBG exhibits stronger affinity to the PPARγ receptor than Δ9-THC and CBD.
• PPARγ will regulate adipocyte differentiation, insulin sensitivity, and inflammatory states
• affinities of CBG at these receptors (in the tens of nanomolars to sub-nanomolar range)
• neuroprotective potential in vitro and in animal models
• mediated through PPARγ
• CBG and VCE-003.2 have been shown to reduce the inflammatory molecules TNF-α, IL-1β, IL-6, Macrophage Inflammatory Protein (MIP-1α), and Prostaglandin E2 (PGE2) in rat microglial cells treated with lipopolysaccharide (LPS), and both compounds reduce glutamate-induced oxidative cell death in mouse hippocampal cells
• VCE-003.2 reduced the inflammatory markers TNF-α, IL-1β, and inducible nitric oxide synthase (iNOS), and this response was mediated through PPARγ
• suggests that the protective effects of CBG and CBD against oxidative neurotoxicity are derived from a 5-HT_1A receptor–mediated process
• reduced expression of glutamate release genes, enhanced expression of GABA release genes, and upregulated dopamine D4 receptor and its downstream effectors
• CBG was also effective as a treatment to prevent colitis-associated damage
• cannabigerol reduced tumor formation in the azoxymethane model of colorectal cancer and reduced xenograft tumor growth
• Orally administered CBG reduced colonic inflammation as measured by significantly reducing myeloperoxidase (MPO) activity, IL-1b levels
• Adding fish oil to the treatment paradigm increased the CBG-induced reduction in myeloperoxidase activity, IL-1b levels
• CBD on its own did not induce significant changes to these metrics
• CBG has also been shown to increase feeding in rats and to reduce weight loss associated with cisplatin chemotherapy
• CBG has not been found to have antiemetic effects and appears to oppose the antiemetic effects of CBD
• role for cannabigerol in chemotherapy-associated weight loss and loss of appetite
• CBG lacks the potential euphoric side effect of these medications.
• Hypertension, one component of metabolic syndrome, can be modestly reduced with α-2 agonist therapy
• CBG is currently the only known cannabinoid that is an agonist at the adrenergic receptor
• CBG and its derivatives are shown to act on PPARγ receptors in its role on neuroinflammation.
• CBG and the CBG/CBD combinations provided similar effects in vivo as rosiglitazone and additive effects to improve adipogenesis
• Renewed adipogenesis and insulin sensitization improve both symptoms and pathology of metabolic syndrome; therefore, CBG could be explored as a potential therapeutic for this devastating disease.
• CBG was found to be among the most potent cannabinoids tested against antibiotic resistant strains of Staphylococcus aureus
• CBG had a lower minimum inhibitory concentration than norfloxacin in five of the six strains tested and was more potent than er
• cycline, and oxacillin in at least one resistant strain
• CBG was as effective at reducing colony forming units as vancomycin.
• CBG was effective against Gram negative bacteria
• rigorously tested for safety and unintended effects.
• CBG has potent activity at the α-2 receptor, and this unique property could also induce unintended cardiovascular consequences such as hypotension, bradycardia, and xerostomia
• reported hypertension as a counterintuitive adverse effect in high doses of α-2 agonists, which appears to be mediated by the α-2B receptor subtype
• CBG, since its activity at different α-2 receptor subtypes has yet to be studied.
• CBG may have therapeutic potential among neurologic, gastrointestinal, and metabolic disorders,
• companies are making unsubstantiated claims and overselling the benefits and underselling the risks
• companies are already touting CBG as the “mother of all cannabinoids,”
• What they fail to point out, however, is that only the Cannabis plant goes on to convert CBG to the other molecules—the human body does not.
• very few Cannabis strains actually harbor large concentrations of CBG, so there is not much prior reporting (and virtually no documentation) of human side effects of CBG
• mind. In a couple of recent reports on CBD oil, it has been reported that not all CBD oil preparations had concentrations of CBD close to what the manufacturer claims
• recalls for CBD preparations that contained unacceptable concentrations of lead
• very real risk of inducing drug-drug interactions when over-the-counter preparations like CBD oil or CBG oil are taken by a patient on other (prescription) medications

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• Enterococcus species have been noted to promote responses to immune checkpoint immunotherapy (ICI)
• Bifidobacterium pseudolongum and Akkermansia muciniphila were observed to produce the metabolite inosine, which enhances ICI through T_h1 activation

• pentose phosphate pathway (PPP), which branches from glycolysis at the first committed step of glucose metabolism, is required for the synthesis of ribonucleotides and is a major source of NADPH
• PPP plays a pivotal role in helping glycolytic cancer cells to meet their anabolic demands and combat oxidative stress

• hypoxia and cell proliferation are associated to lactic acid production
• Lactate exchanges are at the core of tumor metabolism
• Transmembrane lactate trafficking depends on monocarboxylate transporters (MCTs)
• MCTs are implicated in tumor development and aggressiveness
• MCTs is a therapeutic option for cancer treatment

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• i.v. administration of 20 mg
• mean half-life (t_1/2) of CBD was reported as 1.1 and 2.4 h following nebuliser and aerosol administration (20 mg)

• Tumor hypoxia develops due to the structural and functional abnormalities of the tumor vasculature since cancer growth often overrides the ability of the cancer vasculature to adapt to the increasing oxygen demand.
• hypoxia has proven to be a causative factor in many pathophysiological events, including cancer progression
• decreased oxygen tension selects for more malignant cells and induces multiple cellular adaptations, which again sustains and fosters cancer progression
• induction of angiogenesis
• increased glycolysis
• upregulation of genes involved in cell survival/apoptosis
• increase genetic instability
• activate invasive growth
• preserve the undifferentiated cell state
• resistance to conventional therapy
• epithelial-to-mesenchymal transition
• Hyperbaric oxygen can be used to overcome hypoxia.
• administration of 100 % oxygen at higher than normal atmospheric pressure.
• increasing O₂ tissue delivery independent of hemoglobin
• tumor oxygen pressure has been shown to be preserved clinically for approximately 30 min after HBO exposure
• conclusion in both reviews was that HBO did not promote cancer growth, and that the use of HBO in patients with malignancies was considered safe.
• evidence implies that cancer tissue might differ in response from normal tissue
• Chen et al. [20] observed activation of the pro-apoptotic pathway MAPK and downregulation of the anti-apoptotic ERK pathway in hematopoetic cells after HBO
• study of HBO using osteosarcoma cells also demonstrated induction of apoptosis
• demonstrated induction of cell death after HBO treatment
• reduced cell proliferation
• inhibition of cell division after HBO treatment.
• HBO has been shown to induce an antiangiogenic effect in two mammary tumor models [22, 24, 37], in addition to one glioma model
• difference between cancer tissue and wounds and concluded that HBO is not likely to enhance tumor angiogenesis.
• important to distinguish between normal or injured tissue and tumor tissue when it comes to the effect of HBO and angiogenesis since there is no evidence for enhanced angiogenesis in cancerous tissue
• None of the studies reviewed showed induced metastasis after HBO
• hypoxia-mediated chemoresistance has been ascribed to: (1) altered cellular metabolism reducing drug cytotoxicity; (2) the redox state, meaning that oxygen is required to generate ROS to be maximally cytotoxic; and (3) genetic instability, which can lead to more rapid development of drug-resistant cells
• HBO could improve and help overcome chemotherapeutic resistance by increasing both tumor perfusion and cellular sensitivity
• uptake of chemotherapy is increased for the duration of, and immediately after, HBO treatment.
• potentiation of chemotherapy can probably not occur unless the chemotherapeutic agent is administered during or immediately after the HBO session, when the pO₂ is elevated.
• HBO indicating a change to less tumorigenic metabolism
• prolongs the biological residence time
• Mayer et al. [53] list up five chemotherapeutic agents (doxorubicin, bleomycin, disulfiram, cisplatin, and mafenide acetate); all of which are strongly contradictory in combination with HBO due to potential potentiation of toxicity
• Radiotherapy in combination with HBO has been used clinically in two different applications: (1) as a therapeutic agent for treating late radiation injury and (2) as a radiosensitizer
• will improve the results of radiotherapy
• irradiation should be administered immediately after and not concurrently to HBO treatment.
• none of the studies reported a cancer-promoting effect of HBO
• HBO treatment alone had a strong antiproliferative effect on different mammary cancer cells in vitro
• clinically relevant HBO protocols
• significant inhibitory effect of HBO as a stand-alone treatment on mammary tumor growth in vivo
• antiangiogenic effect
• increase in cell death and reduced cell proliferation
• less aggressive tumor type
• HBO restricts the growth of large tumor cell colonies
• HBO did reduce the hypoxic state of the tumors
• HBO did not have any tumor stimulatory effect and does not promote formation of distal metastases, and secondly that HBO therefore can safely be used in combination with other therapies
• older experimental and clinical studies have demonstrated that HBO improves the effect of photodynamic therapy
• increased levels of pO₂, using both normobaric and moderate HBO, significantly reduced tumor growth, possibly by increasing cell death and reducing the vascular density.
• HBO therapy prolongs the biological residence time of carboplatin
• HBO promotes apoptosis in leukemia cells,
• HBO can decrease the rate of growth and increase the sensitivity to the anticancer agents taxol and doxorubicin in in vitro experiments, by accumulating prostate cancer cells in the chemosensitive portion of the cell cycle

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