Naringin Chelates Excessive Iron and Prevents the Formation of Amyloid-Beta Plaques in the Hippocampus of Iron-Overloaded Mice

Jahanshahi, Mehrdad; Khalili, Masoumeh; Margedari, Asra

doi:10.3389/fphar.2021.651156

Cited by 22 publications

(22 citation statements)

References 46 publications

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“…Then, sections were rinsed with distilled water three times and the nuclei were counterstained with nuclear fast red (Beyotime Biotechnology, China). Finally, the sections were photographed under a fluorescence microscope at 400× and 100× magnification (Nikon, Japan) (Jahanshahi et al 2021 ).…”

Section: Methodsmentioning

confidence: 99%

Eriodictyol ameliorates cognitive dysfunction in APP/PS1 mice by inhibiting ferroptosis via vitamin D receptor-mediated Nrf2 activation

Zheng

et al. 2022

Mol Med

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Background Alzheimer’s disease (AD) is the most common type of neurodegenerative disease in the contemporary era, and it is still clinically incurable. Eriodictyol, a natural flavonoid compound that is mainly present in citrus fruits and some Chinese herbal medicines, has been reported to exert anti-inflammatory, antioxidant, anticancer and neuroprotective effects. However, few studies have examined the anti-AD effect and molecular mechanism of eriodictyol. Methods APP/PS1 mice were treated with eriodictyol and the cognitive function of mice was assessed using behavioral tests. The level of amyloid-β (Aβ) aggregation and hyperphosphorylation of Tau in the mouse brain were detected by preforming a histological analysis and Western blotting. HT-22 cells induced by amyloid-β peptide (1–42) (Aβ1–42) oligomers were treated with eriodictyol, after which cell viability was determined and the production of p-Tau was tested using Western blotting. Then, the characteristics of ferroptosis, including iron aggregation, lipid peroxidation and the expression of glutathione peroxidase type 4 (GPX4), were determined both in vivo and in vitro using Fe straining, Western blotting and qPCR assays. Additionally, the expression level of vitamin D receptor (VDR) and the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling pathway were tested using Western blotting and qPCR assays. Afterward, HT-22 cells with VDR knockout were used to explore the potential mechanisms, and the relationship between VDR and Nrf2 was further assessed by performing a coimmunoprecipitation assay and bioinformatics analysis. Results Eriodictyol obviously ameliorated cognitive deficits in APP/PS1 mice, and suppressed Aβ aggregation and Tau phosphorylation in the brains of APP/PS1 mice. Moreover, eriodictyol inhibited Tau hyperphosphorylation and neurotoxicity in HT-22 cells induced by Aβ1–42 oligomer. Furthermore, eriodictyol exerted an antiferroptosis effect both in vivo and in vitro, and its mechanism may be associated with the activation of the Nrf2/HO-1 signaling pathway. Additionally, further experiments explained that the activation of Nrf2/HO-1 signaling pathway by eriodictyol treatment mediated by VDR. Conclusions Eriodictyol alleviated memory impairment and AD-like pathological changes by activating the Nrf2/HO-1 signaling pathway through a mechanism mediated by VDR, which provides a new possibility for the treatment of AD.

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Section: Methodsmentioning

confidence: 99%

Eriodictyol ameliorates cognitive dysfunction in APP/PS1 mice by inhibiting ferroptosis via vitamin D receptor-mediated Nrf2 activation

Zheng

et al. 2022

Mol Med

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“…Both Hesperidin and coumarin have antioxidant activity and can decrease free radical production (Lin et al, 2008;Nakao et al, 2011). Some natural products have metal chelation and antioxidant activities such as citrus fruits, hesperidin, coumarin, naringin, coumarin, resveratrol, quercetin, naringin, and silymarin (Mokni et al, 2007;Cui et al, 2014;Dong et al, 2014;Wang et al, 2014;Ebrahimzadeh et al, 2015Ebrahimzadeh et al, , 2016Filipsky et al, 2015;Khalili et al, 2015a;Zou et al, 2016;Chen et al, 2018;Jahanshahi et al, 2021). Our results show that hesperidin and coumarin have potential iron chelation activities.…”

Section: Discussionmentioning

confidence: 56%

“…Tocotrienol-rich fraction, as a natural product, had some dose-dependent effects on serum total cholesterol and LDL-cholesterol (Qureshi et al, 2002). Our previous study demonstrated that naringin could chelate excessive iron from the brain tissues and serum of the iron-overloaded mice (Jahanshahi et al, 2021). Iron accumulation in the brain occurs with aging.…”

Section: Discussionmentioning

confidence: 99%

“…Iron-overloaded animals are one way to study diseases related to the iron accumulation (Khalili et al, 2015a;Ebrahimzadeh et al, 2016;Jahanshahi et al, 2021). Using the metal chelation agents is an important way to decrease the iron-overload's side effect (Jahanshahi et al, 2021). Hesperidin is a flavonoid, which can be found in the C. sinensis Osbeck, C. limon Burm.…”

Section: Discussionmentioning

confidence: 99%

“…injection of iron-dextran could lead to iron deposition in the liver, brain, and plasmas of the mice (Khalili et al, 2015a,b;Ebrahimzadeh et al, 2016). Additionally, naringin, as a natural product and an iron chelation agent, could chelate iron from the brain and serum of the iron-overloaded mice (Jahanshahi et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

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Comparison Between Hesperidin, Coumarin, and Deferoxamine Iron Chelation and Antioxidant Activity Against Excessive Iron in the Iron Overloaded Mice

et al. 2022

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ObjectiveIron accumulation in the brain leads to the development of Alzheimer’s and Parkinson’s diseases. Nowadays, iron chelation therapy is the best way to decrease the side effects of iron and amyloid plaques accumulation. Iron chelators are commonly used for the treatment of Alzheimer’s disease. Previous studies have shown that natural products such as phenol and flavonoid compounds could chelate heavy metals. In the current study, we examined the iron chelation activity of hesperidin and coumarin on the brain tissue of iron-overloaded mice.Methods48 NMRI male mice were divided into eight groups (n = 6). Six groups were treated with iron dextran (100 mg/kg/day) four times a week for 6 weeks. After stopping the injections for a month, five groups of iron-overloaded mice were treated with hesperidin, coumarin, and desferal four times a week subsequent for four subsequent weeks. Finally, the mice were anesthetized, and blood samples were collected from the ventricle of the heart for subsequent examination. The brain tissues were isolated and fixed in the 4% paraformaldehyde solution for Perl’s staining.ResultsThe results show that hesperidin and coumarin could strongly chelate excessive iron from the serum and deposit iron from the brain tissue compared to desferal group. Catalase and super oxidase activity were decreased in the iron-overloaded group, but in the treated group by hesperidin and coumarin, the enzyme’s activity was increased significantly.ConclusionHesperidin and coumarin, as natural products, are powerful options to chelate iron ions and increase the activity of antioxidant enzymes.

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Iron homeostasis imbalance and ferroptosis in brain diseases

Long

Zhu

Wei

et al. 2023

MedComm

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Brain iron homeostasis is maintained through the normal function of blood–brain barrier and iron regulation at the systemic and cellular levels, which is fundamental to normal brain function. Excess iron can catalyze the generation of free radicals through Fenton reactions due to its dual redox state, thus causing oxidative stress. Numerous evidence has indicated brain diseases, especially stroke and neurodegenerative diseases, are closely related to the mechanism of iron homeostasis imbalance in the brain. For one thing, brain diseases promote brain iron accumulation. For another, iron accumulation amplifies damage to the nervous system and exacerbates patients’ outcomes. In addition, iron accumulation triggers ferroptosis, a newly discovered iron‐dependent type of programmed cell death, which is closely related to neurodegeneration and has received wide attention in recent years. In this context, we outline the mechanism of a normal brain iron metabolism and focus on the current mechanism of the iron homeostasis imbalance in stroke, Alzheimer's disease, and Parkinson's disease. Meanwhile, we also discuss the mechanism of ferroptosis and simultaneously enumerate the newly discovered drugs for iron chelators and ferroptosis inhibitors.

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Naringin Chelates Excessive Iron and Prevents the Formation of Amyloid-Beta Plaques in the Hippocampus of Iron-Overloaded Mice

Cited by 22 publications

References 46 publications

Eriodictyol ameliorates cognitive dysfunction in APP/PS1 mice by inhibiting ferroptosis via vitamin D receptor-mediated Nrf2 activation

Eriodictyol ameliorates cognitive dysfunction in APP/PS1 mice by inhibiting ferroptosis via vitamin D receptor-mediated Nrf2 activation

Comparison Between Hesperidin, Coumarin, and Deferoxamine Iron Chelation and Antioxidant Activity Against Excessive Iron in the Iron Overloaded Mice

Iron homeostasis imbalance and ferroptosis in brain diseases

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