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Wild-type mice and AD mice on either H-PUFA or D-PUFA diets perform similarly in fear conditioning tests. (A) Percentage of time that the mice spent freezing on the training day. (B) Percentage of time that the mice spent freezing on day 2, in the absence of a shock (context setting). (C) Percentage of time that the mice spent freezing on day 2, during and after exposure to the same sound used as the cue on the preceding training day. Values are the mean and SEM of 11 wild-type (WT) mice on the H-PUFA diet, 14 AD mice on the H-PUFA diet, and 13 AD mice on the D-PUFA diet. Abbreviations: AD, Alzheimer's disease; D-PUFA, deuterated polyunsaturated fatty acids; SEM, standard error of the mean.
Source publication
Alzheimer's disease (AD) involves progressive deposition of amyloid β-peptide (Aβ), synapse loss, and neuronal death, which occur in brain regions critical for learning and memory. Considerable evidence suggests that lipid peroxidation contributes to synaptic dysfunction and neuronal degeneration, both upstream and downstream of Aβ pathology. Recen...
Contexts in source publication
Context 1
... in the H-PUFA and D-PUFA diet groups entered the platform area less frequently compared to the WT mice (Fig. 3D). There were no significant differences be- tween the AD mice in the H-PUFA and D-PUFA groups in the probe trials (Fig. 3C, D). For the fear conditioning tests, there were no differences between the three groups for the training day (Fig. 4A), contextual test (Fig. 4B), and the cued test (Fig. ...
Context 2
... diet groups entered the platform area less frequently compared to the WT mice (Fig. 3D). There were no significant differences be- tween the AD mice in the H-PUFA and D-PUFA groups in the probe trials (Fig. 3C, D). For the fear conditioning tests, there were no differences between the three groups for the training day (Fig. 4A), contextual test (Fig. 4B), and the cued test (Fig. ...
Context 3
... area less frequently compared to the WT mice (Fig. 3D). There were no significant differences be- tween the AD mice in the H-PUFA and D-PUFA groups in the probe trials (Fig. 3C, D). For the fear conditioning tests, there were no differences between the three groups for the training day (Fig. 4A), contextual test (Fig. 4B), and the cued test (Fig. ...
Citations
... This finding revolutionized the ability of oxidative stress (OS) to be evaluated in human and animal models of disease [6,7]. F 2 -IsoPs are also increased in numerous OS related diseases, including cardiovascular disease [8][9][10], neurodegeneration [11][12][13][14][15], frailty [16][17][18][19], diabetes [20][21][22], and SARS-CoV-2 [23][24][25][26]. F 2 -IsoPs are separated into four sets of regioisomers identified by the position of the hydroxyl group on the side chain ( Fig. 1). ...
UDP-glucuronosyltransferases (UGTs) catalyze the conjugation of glucuronic acid with endogenous and exogenous lipophilic small molecules to facilitate their inactivation and excretion from the body. This represents approximately 35 % of all phase II metabolic transformations. Fatty acids and their oxidized eicosanoid derivatives can be metabolized by UGTs. F2-isoprostanes (F2-IsoPs) are eicosanoids formed from the free radical oxidation of arachidonic acid. These molecules are potent vasoconstrictors and are widely used as biomarkers of endogenous oxidative damage. An increasing body of evidence demonstrates the efficacy of measuring the β-oxidation metabolites of F2-IsoPs rather than the unmetabolized F2-IsoPs to quantify oxidative damage in certain settings. Yet, the metabolism of F2-IsoPs is incompletely understood. This study sought to identify and characterize novel phase II metabolites of 15-F2t-IsoP and 5-epi-5-F2t-IsoP, two abundantly produced F2-IsoPs, in human liver microsomes (HLM). Utilizing liquid chromatography-mass spectrometry, we demonstrated that glucuronide conjugates are the major metabolites of these F2-IsoPs in HLM. Further, we showed that these molecules are metabolized by specific UGT isoforms. 15-F2t-IsoP is metabolized by UGT1A3, 1A9, and 2B7, while 5-epi-5-F2t-IsoP is metabolized by UGT1A7, 1A9, and 2B7. We identified, for the first time, the formation of intact glucuronide F2-IsoPs in human urine and showed that F2-IsoP glucuronidation is reduced in people supplemented with eicosapentaenoic and docosahexaenoic acids for 12 weeks. These studies demonstrate that endogenous F2-IsoP levels can be modified by factors other than redox mechanisms.
... The differences between mean values was indicated for p < 0.05: TBE patients (n = 40) before and after treatment (TBE1 or TBE2) or patients with TBEV + Bb/Ap co-infection (n = 6) before and after treatment (co-infection1 or co-infection2) and control group (n = 20) was signed as "a". TBE patients (n = 40) after (TBE2) and before (TBE1) treatment (n = 40) was signed as "x" cyclization of hydrocarbon chains of fatty acids [29]. Due to the large amount of docosahexaenoic acid in neurons and its greater susceptibility to oxidation than arachidonic acid, neuroprostanes are formed-cyclization products of this acid (DHA), whose level changes can also be observed in the blood. ...
Background
Ticks are vectors of various pathogens, including tick-borne encephalitis virus causing TBE and bacteria such as Borrelia burgdorferi sensu lato and Anaplasma phagocytophilum causing e.g. viral-bacterial co-infections (TBE + LB/HGA), which pose diagnostic and therapeutic problems. Since these infections are usually accompanied by inflammation and oxidative stress causing metabolic modifications, including phospholipids, the aim of the study was to assess the level of polyunsaturated fatty acids and their metabolism (ROS- and enzyme-dependent) products in the blood plasma of patients with TBE and TBE + LB/HGA before and after pharmacotherapy.
Methods
The total antioxidant status was determined using 2,20-azino-bis-3-ethylbenzothiazolin-6-sulfonic acid. The phospholipid and free fatty acids were analysed by gas chromatography. Lipid peroxidation was estimated by measuring small molecular weight reactive aldehyde, malondialdehyde and neuroprostanes. The reactive aldehyde was determined using gas chromatography coupled with mass spectrometry. The activity of enzymes was examined spectrophotometrically. An analysis of endocannabinoids and eicosanoids was performed using a Shimadzu UPLC system coupled with an electrospray ionization source to a Shimadzu 8060 Triple Quadrupole system. Receptor expression was measured using an enzyme-linked immunosorbent assay (ELISA).
Results
The reduced antioxidant status as a result of infection was accompanied by a decrease in the level of phospholipid arachidonic acid (AA) and docosahexaenoic acid (DHA) in TBE, an increase in DHA in co-infection and in free DHA in TBE with an increase in the level of lipid peroxidation products. The enhanced activity of enzymes metabolizing phospholipids and free PUFAs increased the level of endocannabinoids and eicosanoids, while decreased 15-PGJ2 and PGE2 was accompanied by activation of granulocyte receptors before pharmacotherapy and only tending to normalize after treatment.
Conclusion
Since classical pharmacotherapy does not prevent disorders of phospholipid metabolism, the need to support treatment with antioxidants may be suggested.
... The human brain contains high levels of polyunsaturated fatty acids (PFA), therefore it is highly sensitive to oxidative stress compared to other tissues. Also, in the incidence of oxidative stress, lipid peroxidation in the brain occurs to a large extent (29). In this study, it was observed that the cerebral I/R damage increased the ROS production and consequently, lipid peroxidation increased sharply. ...
Objective
Reduction of cerebral ischemia-reperfusion injury (IRI)/re-oxygenation injury, is defined as the paradoxical exacerbation of the cellular dysfunction and death, following restoration of the blood flow to previously ischemic tissues. The re-establishment of blood flow is essential to salvage the ischemic tissues. As a result, the treatment of IRI with novel therapies, which have fewer side effects, are of great importance. Therefore, this study aimed to investigate the effects of curcumin nanoparticle (CN) pre-treatment on the cerebral I/R rat model.
Materials and Methods
In this experimental study, CN was administered to rats orally five days before the bilateral common carotid artery occlusion (BCCAO) and continued for three days. The intensity of oxidative stress, the activities of antioxidant enzymes, glutathione (GSH) content, the activity of mitochondrial enzymes, including succinate dehydrogenase (SDH), malate dehydrogenase (MDH) and lactate dehydrogenase (LDH), curcumin bioavailability, pERK/ERK expression ratio and TFEB protein were studied. Data analysis was performed using Graphpad Prism V.8 software, one-way analysis of variance (ANOVA) with the statistical package for the social sciences (SPSS V.26 software).
Results
Cerebral IRI-damage significantly increased the oxidative stress (P=0.0008) and decreased the activity of the antioxidant enzymes including catalase (CAT) (P<0.001), super oxide dismutase (SOD) (P<0.001), reduced GSH (P<0.001), mitochondrial enzymes, pERK/ERK expression ratio (P=0.002) and TEFB protein (P=0.005) in rats’ brains. In addition, the pre-treatment of the rats with CN resulted in a decrease in the reactive oxygen species (ROS), and an increase in the activities of antioxidants and mitochondrial enzymes. This in turn up-regulated the pERK/ERK expression ratio and TEFB expression.
Conclusion
CN has neuroprotective effects on the cerebral IRI condition due to its antioxidant properties and is able to overexpress the pERK and TFEB proteins; thus, it can be considered as a suitable treatment option during and after the incidence of stroke.
... AD is caused by the dysfunction of tau proteins 90 . It was shown that a diet high in deuterated PUFAs (D-PUFAs) can lower levels of A proteins and oxidized AA and DHA in the brain tissue 91 . ...
Lately, substantial exploration and study have focused on natural products, along with their bioactive compounds. Neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) involve progressive neural breakdown and cell loss, culminating in neuronal death. The brain is susceptible to various forms of stress, particularly oxidative stress (OS) caused by the body's oxygen requirements and utilization. The vulnerability of the brain is heightened by the significant presence of unsaturated fatty acids. To gain accurate insights into NDD, various factors such as genetics and environmental risks must be considered, as they can reduce the effectiveness of therapies for NDDs. Addressing oxidative damage and discovering safe and efficient treatments for NDDs are crucial objectives. In this pursuit, bioactive compounds play a vital role in research. Among these compounds, natural elements such as carotenoids, essential oils, essential fatty acids, polyphenols, and phytosterols are captivating due to their potent antioxidant and anti-inflammatory traits. These qualities hold the potential for enhancing brain health. This review centers on assessing how these bioactive compounds can bolster the brain's limited antioxidant and regenerative abilities, foster neurogenesis, offer neuroprotection, and mitigate NDDs.
... The rationale of PUFA deuteration is that hydrogen abstraction can be attenuated or inhibited by substituting hydrogen atoms at bis-allylic positions with deuterium (D-PUFA) [13] with the effect further multiplied by the chain nature of the LPO [14]. The effectiveness of D-PUFA treatment against LPO has been recently demonstrated in multiple cellular and animal models [13][14][15][16][17][18][19], including protection against light-induced lipid peroxidation [20]. Moreover, the active role of D-PUFA against LPO has been confirmed with only a modest contribution of D-PUFA in bilayer membranes (estimated at <20% of total PUFA [14,21]). ...
Polyunsaturated fatty acids (PUFA) are particularly susceptible to free radical-induced lipid peroxidation (LPO).Specific deuteration at bis-allylic positions of PUFA (D-PUFA) has been recently proposed as a way to inhibit theLPO. Here, a high mass resolution untargeted lipidomic analysis protocol was applied to examine the changes inthe lipidome of keratinocytes supplemented with bis-allylic deuterated linoleic acid (D2-LA). Incorporation of D2-LA occurs preferentially in membrane phospholipids such as phosphatidylcholine and phosphatidylethanolamine,followed by triglycerides. However, the relative contribution of D2-LA among membrane lipids is highest incardiolipin (60%) followed by its precursor phosphatidylglycerol (50%). Cardiolipins are enriched in PUFA andexclusively located in mitochondrial membranes, thus representing major targets for lipid peroxidation. Thesefindings indicate that D2-LA supplementation is linked to the preservation of mitochondrial function underoxidative stress. Finally, our study highlights the suitability of high mass resolution lipidomic analysis to inves-tigate lipid metabolism at the level of individual molecular species in stable isotope tracing experiments.
... In contrast, heavier deuterium atoms at the same sites slow this abstraction sufficiently to block peroxide propagation 35,36 . The potent anti-peroxidation activity of these compounds has been demonstrated in vitro as well as in vivo 17,24,[35][36][37][38] . Here, we aimed to use these D-PUFAs as a chemical tool, hypothesizing that the observed sites of accumulation may point to essential protection points against ferroptosis. ...
Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, provides a potential treatment avenue for drug-resistant cancers and may play a role in the pathology of some degenerative diseases. Identifying the subcellular membranes essential for ferroptosis and the sequence of their peroxidation will illuminate drug discovery strategies and ferroptosis-relevant disease mechanisms. In this study, we employed fluorescence and stimulated Raman scattering imaging to examine the structure–activity–distribution relationship of ferroptosis-modulating compounds. We found that, although lipid peroxidation in various subcellular membranes can induce ferroptosis, the endoplasmic reticulum (ER) membrane is a key site of lipid peroxidation. Our results suggest an ordered progression model of membrane peroxidation during ferroptosis that accumulates initially in the ER membrane and later in the plasma membrane. Thus, the design of ER-targeted inhibitors and inducers of ferroptosis may be used to optimally control the dynamics of lipid peroxidation in cells undergoing ferroptosis.
... Studies have shown that iron accumulation in the brain is associated with the formation of senile plaques and neurofibrillary tangles, elevated iron levels in the brain increase the risk of Alzheimer's disease, and ferritin levels in cerebrospinal fluid predict the progression from mild cognitive impairment to Alzheimer's disease [59][60][61]. The chronic inflammation, neuronal degeneration, and lack of downstream apoptosis indicators associated with Alzheimer's disease suggest the existence of other cell death manners such as ferroptosis in Alzheimer's disease [62][63][64]. ...
... Another study found that overexpression or hyperphosphorylation of tau protein can induce ferroptosis in neurons, while α-lipoic acid can rescue neurons by downregulating TfR1, reducing p38 phosphorylation level, and upregulating the expression of Slc7a11 and Gpx4 [63]. In addition, feeding with a deuterated polyunsaturated fatty acid in a mouse model of Alzheimer's disease can alleviate the lipid peroxidation of tissues and reduces β-amyloid deposition [64,65]. ...
Ferroptosis, an iron-dependent novel type of cell death, has been characterized as an excessive accumulation of lipid peroxides and reactive oxygen species. A growing number of studies demonstrate that ferroptosis not only plays an important role in the pathogenesis and progression of chronic diseases, but also functions differently in different diseases. As a double-edged sword, activation of ferroptosis could potently inhibit tumor growth and increase sensitivity to chemotherapy and immunotherapy in various cancer settings. Therefore, the development of more efficacious ferroptosis agonists or inhibitors remains the mainstay of ferroptosis-targeting strategy for cancer therapeutics or cardiovascular and cerebrovascular diseases and neurodegenerative diseases therapeutics.
... Knockout of the Gpx4 gene in mice was lethal and displayed prominent cell death in motor neurons [6]. Deuterated-PUFAs, a specific inhibitor of ferroptosis [7], reduced brain damage in mouse models of Parkinson's disease [8] and Alzheimer's disease [9]. These data suggest that the ferroptosis pathway should be explored in the neuronal context to understand the diverse mechanisms of neuronal cell death and develop an alternative strategy for treating neurodegenerative diseases. ...
Ferroptosis is a regulated form of cell death driven by the lethal accumulation of lipid peroxides in cell membranes. Several regulators of ferroptosis have been identified using cancer cell lines. However, the cellular pathways of ferroptosis in neurons remain poorly characterized. In this study, we used a mouse embryonic stem cell-derived motor neuron model to investigate how motor neurons respond to ferroptosis inducers. Pharmacological and genetic inhibition of glutathione peroxidase 4 (GPx4) induced ferroptosis in motor neurons, while system xc - inhibition by erastin had no effect. RNA-seq analysis showed that the expression levels of several genes were altered during RSL3-induced ferroptosis. Subsequent bioinformatic analysis revealed alterations in several biological pathways during ferroptosis, including synaptogenesis and calcium signaling. Finally, we found that edaravone, an FDA-approved drug for treating amyotrophic lateral sclerosis (ALS) disease, rescued motor neurons from RSL3-induced ferroptosis. Our data highlight the crucial role of GPx4 in ferroptosis regulation, and demonstrate that stem cell-derived motor neuron culture is a valuable model to study ferroptosis at the single-cell level in a neuronal context.
... 95 It was determined that the deuterated PUFA (D-PUFA) diet can decrease the concentration of Aβ proteins and oxidation products of both DHA and AA in the brain tissue. 96 3.1.5. Phytosterols and AD. ...
The brain is vulnerable to different types of stresses, particularly oxidative stress as a result of oxygen requirements/ utilization in the body. Large amounts of unsaturated fatty acids present in the brain increase this vulnerability. Neurodegenerative diseases (NDDs) are brain disorders that are characterized by the gradual loss of specific neurons and are attributed to broad evidence of cell-level oxidative stress. The accurate characterization of neurological disorders relies on several parameters along with genetics and environmental risk factors, making therapies less efficient to fight NDDs. On the way to tackle oxidative damage and discover efficient and safe therapies, bioactives are at the edge of NDD science. Naturally occurring bioactive compounds such as polyphenols, carotenoids, essential fatty acids, phytosterols, essential oils, etc. are particularly of interest owing to their potent antioxidant and anti-inflammatory activities, and they offer lots of brain-health-promoting features. This Review focuses on probing the neuroefficacy and bioefficacy of bioactives and their role in supporting relatively low antioxidative and low regenerative capacities of the brain, neurogenesis, neuroprotection, and ameliorating/treating NDDs.
... The activation of ferroptosis will produce excessive lipid peroxides, an early event in the pathology of AD [32,33]. Deuterated polyunsaturated fatty acids can mitigate lipid peroxidation in the AD brain and reduce Aβ [34]. Besides, lipid peroxidation induced by accumulated iron can subsequently enhance apoptosis, which can also cause neuronal cell death, by initiating several apoptotic signaling pathways in neurons [35]. ...
Ferroptosis is newly identified as a non-apoptotic form of programmed cell death. It is characterized by iron-dependent intracellular accumulation of lipid peroxides which ultimately leads to oxidative stress and cell death. Ferroptosis has been identified in several diseases, such as cancer, renal failure, liver injury, and ischemia–reperfusion injury. Besides, it has been reported to be involved in the pathological mechanism of neurodegenerative diseases (NDD). In addition, interventions targeting ferroptosis can influence the course of NDD, making it a potential therapeutic target for NDD. By summarizing the current research on ferroptosis and its impact on many neurological diseases, we hope to provide valuable strategies for the underlying mechanisms and treatment of these neurological diseases.
