Non-psychotropic cannabinoids as inhibitors of TET1 protein

Antonyová, Veronika; Kejík, Zdeněk; Brogyányi, Tereza; Kaplánek, Robert; Veselá, Kateřina; Abramenko, Nikita; Ocelka, Tomáš; Masařík, Michal; Matkowski, Adam; Gburek, Jakub; Abel, Renata; Goede, Andrean; Preißner, Robert; Novotný, P.; Jakubek, Milan

doi:10.1016/j.bioorg.2022.105793

Cited by 8 publications

(10 citation statements)

References 56 publications

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“…Interestingly, because phenolic and polyphenolic compounds has iron binding affinity ( Horniblow et al, 2017 ; Kejík et al, 2021 ), Antonyová et al reported that CBD stably binds ferrous iron as tested by UV-Vis spectroscopy; it acted as a chelator and strongly inhibited (IC 50 = 4.8 μM) a Fe(II)-dependent protein, ten-eleven translocation methylcytosine dioxygenase 1, which converts 5-methylcytosine to 5- hydroxymethylcytosine ( Antonyová et al, 2022 ). Given its dual action of iron chelation and inhibition of heme oxygenase mentioned in the next part, CBD holds promise as a treatment for iron toxicity or ferroptosis.…”

Section: Inhibition Of Ros/rns Generation By Cbd: Relevance For Ichmentioning

confidence: 99%

Anti-oxidant effects of cannabidiol relevant to intracerebral hemorrhage

Yan,

Zhang,

et al. 2023

Front. Pharmacol.

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Intracerebral hemorrhage (ICH) is a subtype of stroke with a high mortality rate. Oxidative stress cascades play an important role in brain injury after ICH. Cannabidiol, a major non-psychotropic phytocannabinoids, has drawn increasing interest in recent years as a potential therapeutic intervention for various neuropsychiatric disorders. Here we provide a comprehensive review of the potential therapeutic effects of cannabidiol in countering oxidative stress resulting from ICH. The review elaborates on the various sources of oxidative stress post-ICH, including mitochondrial dysfunction, excitotoxicity, iron toxicity, inflammation, and also highlights cannabidiol’s ability to inhibit ROS/RNS generation from these sources. The article also delves into cannabidiol’s role in promoting ROS/RNS scavenging through the Nrf2/ARE pathway, detailing both extranuclear and intranuclear regulatory mechanisms. Overall, the review underscores cannabidiol’s promising antioxidant effects in the context of ICH and suggests its potential as a therapeutic option.

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Section: Inhibition Of Ros/rns Generation By Cbd: Relevance For Ichmentioning

confidence: 99%

Anti-oxidant effects of cannabidiol relevant to intracerebral hemorrhage

Yan,

Zhang,

et al. 2023

Front. Pharmacol.

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“…There is no evidence that THC or CBD can directly interfere with the DNAm machinery, such as DNMTs, despite evidence of changes in stress-induced DNAm activity [ 35 ]. However, recent in silico evidence indicates that CBD can bind to and inhibit TET1, potentially regulating DNA demethylation [ 82 ]. It is, however, possible that the changes in DNAm result from the regulation of neurotransmitter release by cannabinoids, which can indirectly regulate the activity or gene expression levels of enzymes involved with the DNAm process [ 83 , 84 ].…”

Section: Discussionmentioning

confidence: 99%

The Cannabis-Induced Epigenetic Regulation of Genes Associated with Major Depressive Disorder

Sayed

Joca

Starnawska

2022

Genes

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The prevalence of depression is increasing worldwide, as is the number of people suffering from treatment-resistant depression; these patients constitute 30% of those treated. Unfortunately, there have not been significant advances in the treatment of this disorder in the past few decades. Exposure to cannabis and cannabis-derived compounds impacts depression symptomatology in different ways, with evidence indicating that cannabidiol has antidepressant effects; there have been mixed results with medical cannabis. Even though the exact molecular mechanisms of the action underlying changes in depression symptomatology upon exposure to cannabis and cannabis-derived compounds are still unknown, there is strong evidence that these agents have a widespread impact on epigenetic regulation. We hypothesized that exposure to cannabis or cannabis-derived compounds changes the DNA methylation levels of genes associated with depression. To test this hypothesis, we first performed a literature search to identify genes that are differentially methylated upon exposure to cannabis and cannabis-derived compounds, as reported in methylome-wide association studies. We next checked whether genes residing in loci associated with depression, as identified in the largest currently available genome-wide association study of depression, were reported to be epigenetically regulated by cannabis or cannabis-related compounds. Multiple genes residing in loci associated with depression were found to be epigenetically regulated by exposure to cannabis or cannabis-derived compounds. This epigenomic regulation of depression-associated genes by cannabis or cannabis-derived compounds was reported across diverse organisms, tissues, and developmental stages and occurred in genes crucial for neuronal development, functioning, survival, and synapse functioning, as well as in genes previously implicated in other mental disorders.

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“…This indicates an important role for Fe(II) chelators in targeting TET1 and thereby its inhibition. In the our last works, we observed that Fe(II) chelators can display potent inhibition activity against the TET1 protein [32,33].…”

Section: Introductionmentioning

confidence: 91%

Targeting of the Mitochondrial TET1 Protein by Pyrrolo[3,2-b]pyrrole Chelators

Antonyová

Tatar

Brogyányi

et al. 2022

IJMS

Self Cite

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Targeting of epigenetic mechanisms, such as the hydroxymethylation of DNA, has been intensively studied, with respect to the treatment of many serious pathologies, including oncological disorders. Recent studies demonstrated that promising therapeutic strategies could potentially be based on the inhibition of the TET1 protein (ten-eleven translocation methylcytosine dioxygenase 1) by specific iron chelators. Therefore, in the present work, we prepared a series of pyrrolopyrrole derivatives with hydrazide (1) or hydrazone (2–6) iron-binding groups. As a result, we determined that the basic pyrrolo[3,2-b]pyrrole derivative 1 was a strong inhibitor of the TET1 protein (IC50 = 1.33 μM), supported by microscale thermophoresis and molecular docking. Pyrrolo[3,2-b]pyrroles 2–6, bearing substituted 2-hydroxybenzylidene moieties, displayed no significant inhibitory activity. In addition, in vitro studies demonstrated that derivative 1 exhibits potent anticancer activity and an exclusive mitochondrial localization, confirmed by Pearson’s correlation coefficient of 0.92.

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Non-psychotropic cannabinoids as inhibitors of TET1 protein

Cited by 8 publications

References 56 publications

Anti-oxidant effects of cannabidiol relevant to intracerebral hemorrhage

Anti-oxidant effects of cannabidiol relevant to intracerebral hemorrhage

The Cannabis-Induced Epigenetic Regulation of Genes Associated with Major Depressive Disorder

Targeting of the Mitochondrial TET1 Protein by Pyrrolo[3,2-b]pyrrole Chelators

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