Dimethyl fumarate (DMF) is an electrophilic compound previously called BG-12 and marketed under the name Tecfidera
. It was approved in 2013 by the US Food and Drug Administration and the European ...Medicines Agency for the treatment of relapsing multiple sclerosis. One mechanism of action of DMF is stimulation of the nuclear factor erythroid 2-related factor 2 (NRF2) transcriptional pathway that induces anti-oxidant and anti-inflammatory phase II enzymes to prevent chronic neurodegeneration. However, electrophiles such as DMF also produce severe systemic side effects, in part due to non-specific S-alkylation of cysteine thiols and resulting depletion of glutathione. This mini-review presents the present status and future strategy for NRF2 activators designed to avoid these side effects. Two modes of chemical reaction leading to NRF2 activation are considered here. The first mode is S-alkylation (covalent reaction) of thiols in Kelch-like ECH-associated protein 1 (KEAP1), which interacts with NRF2. The second mechanism involves non-covalent pharmacological inhibition of protein-protein interactions, in particular domain-specific interaction between NRF2 and KEAP1 or other repressor proteins involved in this transcriptional pathway. There have been significant advances in drug development using both of these mechanisms that can potentially avoid the systemic side effects of electrophilic compounds. In the first case concerning covalent reaction with KEAP1, monomethyl fumarate and monoethyl fumarate appear to represent safer derivatives of DMF. In a second approach, pro-electrophilic drugs, such as carnosic acid from the herb
, can be used as a safe pro-drug of an electrophilic compound. Concerning non-covalent activation of NRF2, drugs are being developed that interfere with the direct interaction of KEAP1-NRF2 or inhibit BTB domain and CNC homolog 1 (BACH1), which is a transcriptional repressor of the promoter where NRF2 binds.
Living cells maintain a balance between oxidation and reduction, and perturbations of this redox balance are thought to contribute to various diseases. Recent attempts to regulate redox state have ...focused on electrophiles (EPs), which activate potent cellular defense systems against oxidative stress. One example of this approach is exemplified by carnosic acid (CA) and carnosol (CS), compounds that are found in the herb rosemary (Rosmarinus officinalis). Importantly, CA and CS themselves are not electrophilic, but in response to oxidation, become electrophilic, and then activate the Keap1/Nrf2/ARE (antioxidant-response element) transcription pathway to synthesize endogenous antioxidant “phase 2” enzymes. As a result of our efforts to develop these compounds as therapeutics for brain health, we have formulated two innovative criteria for drug development: the first concept is the use of pro-electrophilic drugs (PEDs) that are innocuous in and of themselves; and the second concept involves the use of compounds that are pathologically activated therapeutics (PATs);i.e., these small molecules are chemically converted to their active form by the very oxidative stress that they are designed to then combat. The chemical basis for PED and PAT drugs is embodied in the ortho- and para-hydroquinone electrophilic cores of the molecules, which are oxidized by the Cu²⁺/Cu⁺ cycling system (or potentially by other transition metals). Importantly, this cycling pathway is under stringent regulation by the cell redox state. We propose that redox-dependent quinone formation is the predominant mechanism for formation of PED and PAT drugs from their precursor compounds. In fact, redox-dependent generation of the active form of drug from the “pro-form” distinguishes this therapeutic approach from traditional EPs such as curcumin, and results in a decrease in clinical side effects at therapeutic concentrations, e.g., lack of reaction with other thiols such as glutathione (GSH), which can result in lowering GSH and inducing oxidative stress in normal cells. We consider this pro-drug quality of PED/PAT compoundsto be a key factor for generating drugs to be used to combat neurodegenerative diseases that will be clinically tolerated. Given the contribution of oxidative stress to the pathology of multiple neurodegenerative diseases, the Keap1/Nrf2/ARE pathway represents a promising drug target for these PED/PAT agents.
New prebiotics by ketone donation Satoh, Takumi
Trends in endocrinology and metabolism,
07/2023, Volume:
34, Issue:
7
Journal Article
Peer reviewed
Disorder of the gut microbiome is related to progression of chronic inflammation-related gut diseases. Classical prebiotics do not show significant inhibition of these diseases; thus, new prebiotics ...are urgently needed.Poly-hydroxybutyrate (PHB), which increases 3-hydroxybutyrate (3HB) in the large intestinal lumen, can be used as a prebiotic to donate 3HB to microbiota.PHB alters the composition and restores the integrity of the microbiome i.e., increases butyrate-producing bacteria and release of short-chain fatty acids, which activate regulatory T cells (Tregs), resulting in anti-inflammatory effects. Although Tregs are activated in the gut epithelium, they can enter systemic circulation and may ease systemic chronic diseases.
Integrity of the microbiome is an essential element for human gut health. 3-Hydroxybutyrate (3HB) secreted into the gut lumen has gained attention as a regulator of gut physiology, including stem cell expansion. In this opinion, I propose new prebiotics leading to gut health by use of a ketone (3HB) donor. When exogenous 3HB is supplied through ketone donation, it has the potential to markedly improve gut health by altering the gut microbiome and systemic metabolic status. Poly-hydroxybutyrate (PHB) donates 3HB and primarily influences microbiota, making it an effective prebiotic for improving the gut environment. Thus, exogenous 3HB donation to the lumen of the gut may aid gut health by maintaining the integrity of microbiome.
Rosemary (
family Lamiaceae), an herb of economic and gustatory repute, is employed in traditional medicines in many countries. Rosemary contains carnosic acid (CA) and carnosol (CS), abietane-type ...phenolic diterpenes, which account for most of its biological and pharmacological actions, although claims have also been made for contributions of another constituent, rosmarinic acid. This review focuses on the potential applications of CA and CS for Alzheimer's disease (AD), Parkinson's disease (PD), and coronavirus disease 2019 (COVID-19), in part via inhibition of the NLRP3 inflammasome. CA exerts antioxidant, anti-inflammatory, and neuroprotective effects via phase 2 enzyme induction initiated by activation of the KEAP1/NRF2 transcriptional pathway, which in turn attenuates NLRP3 activation. In addition, we propose that CA-related compounds may serve as therapeutics against the brain-related after-effects of SARS-CoV-2 infection, termed "long-COVID." One factor that contributes to COVID-19 is cytokine storm emanating from macrophages as a result of unregulated inflammation in and around lung epithelial and endovascular cells. Additionally, neurological aftereffects such as anxiety and "brain fog" are becoming a major issue for both the pandemic and post-pandemic period. Many reports hold that unregulated NLRP3 inflammasome activation may potentially contribute to the severity of COVID-19 and its aftermath. It is therefore possible that suppression of NLRP3 inflammasome activity may prove efficacious against both acute lung disease and chronic neurological after-effects. Because CA has been shown to not only act systemically but also to penetrate the blood-brain barrier and reach the brain parenchyma to exert neuroprotective effects, we discuss the evidence that CA or rosemary extracts containing CA may represent an effective countermeasure against both acute and chronic pathological events initiated by SARS-CoV-2 infection as well as other chronic neurodegenerative diseases including AD and PD.
Bird evolution by insulin resistance Satoh, Takumi
Trends in endocrinology and metabolism,
October 2021, 2021-10-00, 20211001, Volume:
32, Issue:
10
Journal Article
Peer reviewed
Open access
Drift of oxygen concentrations in the atmosphere was one of the main drivers of the evolution of vertebrates. The drop in oxygen concentrations at the Permian–Triassic (PT) boundary may have been the ...biggest challenge to vertebrates. This hypoxic condition forced theropods to lose certain genes to maximize their efficiency of oxygen usage. Recent studies show that omentin and insulin-sensitive glucose transporter 4 (GLUT4) are missing in the bird genome. Since these gene products play essential roles in maintaining insulin sensitivity, this loss forced theropods to become insulin resistant. Insulin resistance may have been the key to allowing theropods to become hyperathletic under hypoxic conditions and to outcompete mammals during the Triassic period. A second challenge was the gradual increase in oxygen concentrations during the late Jurassic, Cretaceous, and Tertiary periods when reactive oxygen species (ROS) leakage from mitochondria became a problem. Since the simplest solution was the expansion of body size, some theropods became bigger to reduce ROS leakage per volume. Another solution was the development of a constitutively active countermeasure against ROS. A recent study shows that Neoaves have constitutively active nuclear factor erythroid 2-related factor 2 (NRF2) due to deletion of the C-terminal part of the KEAP1 protein, thus allowing Neoaves to express antioxidant enzymes to overcome ROS leakage.
Birds are well known to have long lifespans despite their high oxygen consumption. In mammals, high oxygen consumption induces reactive oxygen species (ROS) leakage and shortens the lifespan. By contrast, birds have high oxygen consumption without this ROS leakage, a phenomenon termed the ‘Bird Paradox’. This paradox has attracted many investigators to speculate about the protective mechanisms at work to overcome this ROS leakage.I propose that theropods developed insulin resistance to adapt themselves to the low-oxygen environment of the Triassic period. This insulin resistance may have allowed theropods to maximize the efficiency of oxygen usage, almost outcompeting mammals during the Triassic period.Another epoch-making event was constitutive nuclear factor erythroid 2-related factor 2 (NRF2) activation induced by deletion of the C-terminal part of Kelch-like ECH-associated protein (KEAP1), preventing ROS leakage, just in Neoaves but not in the Palaeognathae, thus suggesting that this deletion may have occurred during the early Tertiary period.
Background
Carnosic acid (CA), found in rosemary, has been reported to have antioxidant and anti-adipogenic properties. We recently demonstrated that CA protects against steatosis in
ob
/
ob
mice. In ...the present report, we investigated the molecular mechanism by which CA inhibits lipids accumulation both in vivo and in vitro
.
Methods
In the in vivo study,
ob
/
ob
mice were fed a standard chow diet with or without CA for 5 weeks, then their hepatocyte lipid accumulation was determined. The serum concentrations of cytokines, the levels of lipid regulatory mediators, and the hepatic metabolic and signaling molecules were also evaluated. In the in vitro study, HepG2 cells were used to further clarify the effects of CA on cellular lipid accumulation and to confirm the signaling pathways involved in these effects.
Results
CA significantly reduced hepatocyte lipid accumulation. This effect was associated with repressed levels of hepatic PPARγ, reduced expression of inflammatory cytokines such as IL-1β, IL-12, IL-17, IFN-γ, MCP-1, and MIP-1β, and increased ATP, acetyl CoA, NAD(P)
+
, and NAD(P)H. Other signaling molecules, such as EGFR, MAPK, AMPK, and ACC, which regulate lipid metabolism, were activated in mice fed the CA diet. CA inhibited palmitate-induced cellular lipid accumulation and stimulated the phosphorylation of both EGFR and MAPK. Pretreatment with either the EGFR inhibitor AG1478 or the MEK-specific inhibitor U0126 abolished the effects of CA on cellular lipid accumulation and decreased both the protein expression and activity of PPARγ.
Conclusions
EGFR/MAPK signaling plays an important role in the inhibitory effect of CA on hepatocyte lipid accumulation.
The importance of phosphorylation of key threonine, serine and tyrosine residues is a well known essential feature of many signal transduction pathways. A similar, highly conserved redox reaction ...involving cysteine thiols is now emerging as an important regulator of protein function. An example of this redox regulation is S -nitrosylation (the transfer of a nitric oxide group to a key protein thiol). Here, we review the chemical biology of an additional class of drugs, electrophiles (electron-deficient carbon centers), that react with key protein thiols, and provide insights into a broader class of reactions implicated in redox signaling. Interestingly, certain electrophilic compounds, including endogenous metabolites and natural products, seem to have neuroprotective effects, and this has resulted in the development of neuroprotective electrophilic drugs, including prostaglandin derivatives and hydroquinones, that exert their action through activating antioxidant-signaling cascades.
Seaweed-origin electrophilic compounds are proposed as a class of neuroprotective compounds that provide neuroprotection through activation of the Nrf2/ARE pathway. Electrophilic hydroquinones are of ...particular interest due to their ability to become electrophilic quinones upon auto-oxidation. Although many marine plants produce a variety of electrophilic compounds, the detailed mechanism of action of these compounds remain unknown. Here, we focused on the neuroprotective effects of zonarol (ZO), a para-hydroquinone-type pro-electrophilic compound from the brown algae Dictyopteris undulata. We show that ZO activates the Nrf2/ARE pathway, induces phase-2 enzymes, and protects neuronal cells from oxidative stress. ZO is the first example of a neuroprotective pro-electrophilic compound obtained from brown algae.
•Zonarol activates Nrf2.•It protects neurons.•It is a brain drug lead from seaweed.
Alzheimer's disease (AD) is characterized by synaptic and neuronal loss, which occurs at least partially through oxidative stress induced by oligomeric amyloid-β (Aβ)-peptide. Carnosic acid (CA), a ...chemical found in rosemary and sage, is a pro-electrophilic compound that is converted to its active form by oxidative stress. The active form stimulates the Keap1/Nrf2 transcriptional pathway and thus production of phase 2 antioxidant enzymes. We used both in vitro and in vivo models. For in vitro studies, we evaluated protective effects of CA on primary neurons exposed to oligomeric Aβ. For in vivo studies, we used two transgenic mouse models of AD, human amyloid precursor protein (hAPP)-J20 mice and triple transgenic (3xTg AD) mice. We treated these mice trans-nasally with CA twice weekly for 3 months. Subsequently, we performed neurobehavioral tests and quantitative immunohistochemistry to assess effects on AD-related phenotypes, including learning and memory, and synaptic damage. In vitro, CA reduced dendritic spine loss in rat neurons exposed to oligomeric Aβ. In vivo, CA treatment of hAPP-J20 mice improved learning and memory in the Morris water maze test. Histologically, CA increased dendritic and synaptic markers, and decreased astrogliosis, Aβ plaque number, and phospho-tau staining in the hippocampus. We conclude that CA exhibits therapeutic benefits in rodent AD models and since the FDA has placed CA on the 'generally regarded as safe' (GRAS) list, thus obviating the need for safety studies, human clinical trials will be greatly expedited.
Zonarol, which was discovered in the brown algae
has antibiotic, antioxidative, anti-inflammatory, and neuroprotective hydroquinone properties. Additionally, a daily treatment of zonarol taken orally ...has been proven to prevent ulcerative colitis and nonalcoholic fatty liver disease in experimentally induced mice models. In this study, to elucidate the physiological behavior of zonarol in vivo, the establishment of quantitative methods for the determination of zonarol in biological samples and basic pharmacokinetics parameters after oral or intravenous administration with purified zonarol to mice were investigated. The zonarol (20-600 ng/mL) in this study was dose-dependently detected using an HPLC-FI system as a single peak on the ODS column with 80% aqueous methanol at 332 nm with an excitation of 293 nm. The pharmacokinetic parameters were derived from a non-compartment analysis of the plasma concentration of zonarol following oral or intravenous treatment in mice. The absolute bioavailability of zonarol was calculated as 25.0%. Interestingly, the maximal distribution of zonarol in the brain (2.525 ± 1.334 µg/g tissue) at 30 min was observed to be higher and slower than that in the liver and kidney at 15 min after bolus intravenous administrations to the mice (10 mg/kg BW). Based on these results, zonarol might be a candidate for a potential drug, an effective tool for drug delivery, or enhancing the treatment of cerebral disease.
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