NXP032 Ameliorates Aging-Induced Oxidative Stress and Cognitive Impairment in Mice through Activation of Nrf2 Signaling

Lee, Jae-Min; Song, Min Kyung; Kim, Youn Jung

doi:10.3390/antiox11010130

Cited by 11 publications

(11 citation statements)

References 40 publications

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“…GSTA1, GSTO1, and KEAP1 are abundantly present in the hippocampus, a critical brain region crucial for hippocampus-dependent learning tasks [ 72 , 73 ]. Western blot analysis showed that the upregulation of GSTA1 in the CA1 area [ 74 ] and the downregulation of GSTO1 in the hippocampus were linked to cognitive impairment, [ 75 ] commonly seen in aging animals. Other studies showed that these proteins are closely associated with oxidative stress and aging-induced neurodegenerative diseases such as memory impairment [ 76 ].…”

Section: Discussionmentioning

confidence: 99%

Curcumin improves D-galactose and normal-aging associated memory impairment in mice: In vivo and in silico-based studies

et al. 2022

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Aging-induced memory impairment is closely associated with oxidative stress. D-Galactose (D-gal) evokes severe oxidative stress and mimics normal aging in animals. Curcumin, a natural flavonoid, has potent antioxidant and anti-aging properties. There are several proteins like glutathione S-transferase A1 (GSTA1), glutathione S-transferase omega-1 (GSTO1), kelch-like ECH-associated protein 1 (KEAP1), beta-secretase 1 (BACE1), and amine oxidase [flavin-containing] A (MAOA) are commonly involved in oxidative stress and aging. This study aimed to investigate the interaction of curcumin to these proteins and their subsequent effect on aging-associated memory impairment in two robust animal models: D-Gal and normal aged (NA) mice. The aging mice model was developed by administering D-gal intraperitoneally (i.p). Mice (n = 64) were divided into the eight groups (8 mice in each group): Vehicle, Curcumin-Control, D-gal (100mg/kg; i.p), Curcumin + D-gal, Astaxanthin (Ast) + D-gal, Normal Aged (NA), Curcumin (30mg/kg Orally) + NA, Ast (20mg/kg Orally) + NA. Retention and freezing memories were assessed by passive avoidance (PA) and contextual fear conditioning (CFC). Molecular docking was performed to predict curcumin binding with potential molecular targets. Curcumin significantly increased retention time (p < 0.05) and freezing response (p < 0.05) in PA and CFC, respectively. Curcumin profoundly ameliorated the levels of glutathione, superoxide dismutase, catalase, advanced oxidation protein products, nitric oxide, and lipid peroxidation in mice hippocampi. In silico studies revealed favorable binding energies of curcumin with GSTA1, GSTO1, KEAP1, BACE1, and MAOA. Curcumin improves retention and freezing memory in D-gal and nature-induced aging mice. Curcumin ameliorates the levels of oxidative stress biomarkers in mice. Anti-aging effects of curcumin could be attributed to, at least partially, the upregulation of antioxidant enzymes through binding with GSTA1, GSTO1, KEAP1, and inhibition of oxidative damage through binding with BACE1 and MAOA.

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Section: Discussionmentioning

confidence: 99%

Curcumin improves D-galactose and normal-aging associated memory impairment in mice: In vivo and in silico-based studies

et al. 2022

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“…Many of recent studies have shown that neurovascular damage in the aged brain is caused by oxidative stress, which leads to the accumulation of various toxic substances, that leads to decreased brain function, especially, cognitive impairment 36,37 . In our previous study, we showed that had increased oxidative stress markers, reduced expression of SOD-1 and GSTO1/2, neuronal loss and cognitive impairment in aged mice 24 . The increased oxidative damage along with aging has detrimental effects on cells and contributes to the pathogenesis of cerebrovascular diseases such as hypertension and atherosclerosis 38 .…”

Section: Discussionmentioning

confidence: 92%

“…We have developed Aptamin® C320, a DNA aptamer that speci cally binds to vitamin C and inhibits the oxidation of vitamin C. Aptamers are single-stranded DNA-based oligonucleotides, and Aptamin® C320 can inhibit the oxidation of vitamin C and maintain antioxidant activity in the body system 23 . NXP032 (vitamin C/DNA Aptamin® C320 complex) can induce effective ROS removal and increase of antioxidant enzymes with stable antioxidant effect by inhibiting oxidative stress induced by activation of the ARE pathway in aged mice 24 .…”

Section: Introductionmentioning

confidence: 99%

NXP032 ameliorates cognitive impairment by alleviating of neurovascular aging process in aged mice brain

Lee

Kim

Sim

et al. 2023

Preprint

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Vascular aging is well known to be associated with breakdown of the neurovascular unit (NVU) that is essential for maintaining brain homeostasis and has been linked to higher cognitive dysfunction. Oxidative stress is believed to be a major cause of the vascular aging process, and damages cerebral parenchymal cells in aged brain. Vitamin C is easily oxidized under human physiologic conditions and loses its potent antioxidant activity. To overcome this limitation, we have developed a DNA aptamer that enhances function of vitamin C; NXP032 is binding form of Aptamer and vitamin C. We investigated microvascular damage, blood-brain barrier (BBB) disruption, glial activation, and cognitive function in 20-month-old mice to confirm the protective effect of NXP032 on vascular aging. NXP032 was treated orally for 8 weeks every day. In this study, we found that aged mice showed obvious cognitive impairment through Y-maze and passive avoidance tests. The microvascular damage was manifested through the decreased length of PECAM-1, lectin. BBB disruption was confirmed through the expression of PDGFR-β, ZO-1 and laminin. Aged mice also showed activation of microglia and astrocytes in the motor cortex and hippocampal CA1 region. These changes were significantly alleviated after the NXP032 treatment in aged mice. Based on the results, we suggest that the NXP032 reduces vascular aging which may be a novel intervention for aging-induced cognitive impairment.

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“…Highly reactive oxygen free radicals generated during high metabolic activity in the brain are toxic to neuronal cells; thus, believed to be involved in the etiology of the disease. Aging increases chronic oxidative stress, a major risk factor for Alzheimer's (Lee et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Effect of Date Palm (Phoenix dactylifera) Phytochemicals on Aβ1−40 Amyloid Formation: An in-silico Analysis

Zia

Rehman²,

Hashmi³

et al. 2022

Front. Neurosci.

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Alzheimer's disease (AD) is a neurodegenerative disease and the most prevalent form of dementia. The generation of oxygen free radicals and oxidative damage is believed to be involved in the pathogenesis of AD. It has been suggested that date palm, a plant rich in phenolic compounds and flavonoids, can provide an alternative treatment to fight memory loss and cognitive dysfunction due to its potent antioxidant activity. Thus, we studied the effect of flavonoids present in date palm on Aβ1−40 amyloid formation using molecular docking and molecular dynamics simulation. AutoDock. Myricetin was used as a positive control drug. The flavonoids Diosmetin, Luteolin, and Rutin were found to be potent inhibitors of aggregation (docking energies ≤ −8.05 kcal mol−1) targeting Aβ1−40 fibrils (both 2LMO and 6TI5), simultaneously. Further screening by physicochemical properties and drug-likeness analysis suggested that all flavonoids except Rutin followed Lipinski's rule of five. Rutin was, thus, taken as a negative control (due to its violation of Lipinski's rule) to compare its dynamics with Diosmetin. Diosmetin exhibited the highest positive scores for drug likeness. Since Luteolin exhibited moderate drug-likeness and better absorption properties, it was also included in molecular dynamics simulation. Molecular dynamics of shortlisted compounds (Rutin, Diosmetin, and Luteolin) were performed for 200 ns, and the results were analyzed by monitoring root mean square deviations (RMSD), root mean square fluctuation (RMSF) analysis, the radius of gyration (Rg), and solvent accessible surface area (SASA). The results proved the formation of a stable protein-compound complex. Based on binding energies and non-bonded interactions, Rutin and Luteolin emerged as better lead molecules than Diosmetin. However, high MW (610.5), lowest absorption rate (16.04%), and more than one violation of Lipinski's rule make Rutin a less likely candidate as an anti-amyloidogenic agent. Moreover, among non-violators of Lipinski's rule, Diosmetin exhibited a greater absorption rate than Luteolin as well as the highest positive scores for drug-likeness. Thus, we can conclude that Diosmetin and Luteolin may serve as a scaffold for the design of better inhibitors with higher affinities toward the target proteins. However, these results warrant in-vitro and in-vivo validation before practical use.

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NXP032 Ameliorates Aging-Induced Oxidative Stress and Cognitive Impairment in Mice through Activation of Nrf2 Signaling

Cited by 11 publications

References 40 publications

Curcumin improves D-galactose and normal-aging associated memory impairment in mice: In vivo and in silico-based studies

Curcumin improves D-galactose and normal-aging associated memory impairment in mice: In vivo and in silico-based studies

NXP032 ameliorates cognitive impairment by alleviating of neurovascular aging process in aged mice brain

Effect of Date Palm (Phoenix dactylifera) Phytochemicals on Aβ1−40 Amyloid Formation: An in-silico Analysis

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