Baicalein Attenuates Brain Iron Accumulation through Protecting Aconitase 1 from Oxidative Stress in Rotenone-Induced Parkinson’s Disease in Rats

Liu, Runzhe; Zhang, Sen; Zhang, Wen; Zhao, Xiaoyue; Du, Guanhua

doi:10.3390/antiox12010012

Cited by 15 publications

(6 citation statements)

References 59 publications

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“…Protection and repair of iron‐sulfur clusters have received some study [ 152 ] and factors governing the transcription, translation, and protein stability of HIF‐1 have been identified. [ 153–155 ]…”

Section: Discussionmentioning

confidence: 99%

“…Protection and repair of iron-sulfur clusters have received some study [152] and factors governing the transcription, translation, and protein stability of HIF-1 have been identified. [153][154][155] The decline in PEPCK expression with age presumably reflects, as does its suppression in embryo, methylation of its gene promoter region.…”

Section: Consideration Of the Tca Cycle Integrates Disparate Mechanis...mentioning

confidence: 99%

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The Tricarboxylic Acid Cycle as a Central Regulator of the Rate of Aging: Implications for Metabolic Interventions

Borkum

2023

Advanced Biology

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Certain metabolic interventions such as caloric restriction, fasting, exercise, and a ketogenic diet extend lifespan and/or health span. However, their benefits are limited and their connections to the underlying mechanisms of aging are not fully clear. Here, these connections are explored in terms of the tricarboxylic acid (TCA) cycle (Krebs cycle, citric acid cycle) to suggest reasons for the loss of effectiveness and ways of overcoming it. Specifically, the metabolic interventions deplete acetate and likely reduce the conversion of oxaloacetate to aspartate, thereby inhibiting the mammalian target of rapamycin (mTOR) and upregulating autophagy. Synthesis of glutathione may provide a high‐capacity sink for amine groups, facilitating autophagy, and prevent buildup of alpha‐ketoglutarate, supporting stem cell maintenance. Metabolic interventions also prevent the accumulation of succinate, thereby slowing DNA hypermethylation, facilitating the repair of DNA double‐strand breaks, reducing inflammatory and hypoxic signaling, and lowering reliance on glycolysis. In part through these mechanisms, metabolic interventions may decelerate aging, extending lifespan. Conversely, with overnutrition or oxidative stress, these processes function in reverse, accelerating aging and impairing longevity. Progressive damage to aconitase, inhibition of succinate dehydrogenase, and downregulation of hypoxia‐inducible factor‐1α, and phosphoenolpyruvate carboxykinase (PEPCK) emerge as potentially modifiable reasons for the loss of effectiveness of metabolic interventions.

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Section: Discussionmentioning

confidence: 99%

Section: Consideration Of the Tca Cycle Integrates Disparate Mechanis...mentioning

confidence: 99%

The Tricarboxylic Acid Cycle as a Central Regulator of the Rate of Aging: Implications for Metabolic Interventions

Borkum

2023

Advanced Biology

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Section: Discussionmentioning

confidence: 99%

“…It is known that hydrogen peroxide or nitric oxide can disrupt the iron-sulfur cluster of ACO1 activating its iron regulatory protein 1 (IRP1) conformation. This promotes intracellular iron accumulation by increasing TFR1 and DMT1 mRNA stability (Liu et al, 2022). Furthermore, superoxide anion, which we found increased upon dopamine treatment, was shown to inactivate ACO2 (Liang and Patel, 2004), suggesting that oxidative stress may decrease the activity of this enzyme, leading to a predicted repercussion on the cellular metabolism.…”

Section: Discussionmentioning

confidence: 99%

Dopamine-iron homeostasis interaction rescues mitochondrial fitness in Parkinson’s disease

Buoso,

Seifert,

Lang

et al. 2023

Preprint

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Imbalances of iron and dopamine metabolism along with mitochondrial dysfunction have been linked to the pathogenesis of Parkinson’s disease (PD). We have previously suggested a direct link between iron homeostasis and dopamine metabolism, as dopamine can increase cellular uptake of iron into macrophages thereby promoting oxidative stress responses. In this study, we investigated the interplay between iron, dopamine, and mitochondrial activity in neuroblastoma SH-SY5Y cells and human induced pluripotent stem cell (hiPSC)-derived dopaminergic neurons differentiated from a healthy control and a PD patient with a mutation in the α-synuclein (SNCA) gene. In SH-SY5Y cells, dopamine treatment affected the expression of transmembrane iron transporters and cellular iron accumulation. Furthermore, dopamine supplementation led to decreased mitochondrial respiration and reduced mitochondrial fitness, including reduced mtDNA copy number and citrate synthase activity, increased oxidative stress and impaired aconitase activity. In dopaminergic neurons derived from a healthy control individual, dopamine showed comparable effects as observed in SH-SY5Y cells. The hiPSC-derived PD neurons harboring an endogenousSNCAmutation demonstrated altered mitochondrial iron homeostasis, reduced mitochondrial capacity along with increased oxidative stress and alterations of tricarboxylic acid cycle linked metabolic pathways compared with control neurons. Importantly, dopamine treatment of these PD neurons promoted a rescue effect by increasing mitochondrial respiration, activating antioxidant stress response, and normalizing altered metabolite levels linked to mitochondrial function. These observations provide evidence that dopamine affects iron homeostasis, intracellular stress responses and mitochondrial function in healthy cells, while dopamine supplementation can restore this disturbed regulatory network in PD cells.

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“…This study suggested that isoliquiritigenin counteracted the rise in NOS2 and COX-2 in the mouse substantia nigra and lessened PD phenotypes ( Bai et al, 2023 ). Liu et al (2023) demonstrated that baicalein effectively decreased ROS-induced oxidative stress in rotenone-treated human neuroblastoma cells. Additionally, baicalein prevented lipid peroxidation in the brain and improved motor coordination in a rotenone-induced rat model of PD ( Liu et al, 2023 ).…”

Section: Introductionmentioning

confidence: 96%

Virtual screening of flavonoids as potential RIPK1 inhibitors for neurodegeneration therapy

Bepari,

Shatabda,

Reza

2024

PeerJ

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Background Global prevalence of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease is increasing gradually, whereas approvals of successful therapeutics for central nervous system disorders are inadequate. Accumulating evidence suggests pivotal roles of the receptor-interacting serine/threonine-protein kinase 1 (RIPK1) in modulating neuroinflammation and necroptosis. Discoveries of potent small molecule inhibitors for RIPK1 with favorable pharmacokinetic properties could thus address the unmet medical needs in treating neurodegeneration. Methods In a structure-based virtual screening, we performed site-specific molecular docking of 4,858 flavonoids against the kinase domain of RIPK1 using AutoDock Vina. We predicted physicochemical descriptors of the top ligands using the SwissADME webserver. Binding interactions of the best ligands and the reference ligand L8D were validated using replicated 500-ns Gromacs molecular dynamics simulations and free energy calculations. Results From Vina docking, we shortlisted the top 20 flavonoids with the highest binding affinities, ranging from −11.7 to −10.6 kcal/mol. Pharmacokinetic profiling narrowed down the list to three orally bioavailable and blood-brain-barrier penetrant flavonoids: Nitiducarpin, Pinocembrin 7-O-benzoate, and Paratocarpin J. Next, trajectories of molecular dynamics simulations of the top protein-ligand complexes were analyzed for binding interactions. The root-mean-square deviation (RMSD) was 1.191 Å (±0.498 Å), 1.725 Å (±0.828 Å), 1.923 Å (±0.942 Å), 0.972 Å (±0.155 Å) for Nitiducarpin, Pinocembrin 7-O-benzoate, Paratocarpin J, and L8D, respectively. The radius of gyration (Rg) was 2.034 nm (±0.015 nm), 2.0.39 nm (± 0.025 nm), 2.053 nm (±0.021 nm), 2.037 nm (±0.016 nm) for Nitiducarpin, Pinocembrin 7-O-benzoate, Paratocarpin J, and L8D, respectively. The solvent accessible surface area (SASA) was 159.477 nm2 (±3.021 nm2), 159.661 nm2 (± 3.707 nm2), 160.755 nm2 (±4.252 nm2), 156.630 nm2 (±3.521 nm2), for Nitiducarpin, Pinocembrin 7-O-benzoate, Paratocarpin J, and L8D complexes, respectively. Therefore, lower RMSD, Rg, and SASA values demonstrated that Nitiducarpin formed the most stable complex with the target protein among the best three ligands. Finally, 2D protein-ligand interaction analysis revealed persistent hydrophobic interactions of Nitiducarpin with the critical residues of RIPK1, including the catalytic triads and the activation loop residues, implicated in the kinase activity and ligand binding. Conclusion Our target-based virtual screening identified three flavonoids as strong RIPK1 inhibitors, with Nitiducarpin exhibiting the most potent inhibitory potential. Future in vitro and in vivo studies with these ligands could offer new hope for developing effective therapeutics and improving the quality of life for individuals affected by neurodegeneration.

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Baicalein Attenuates Brain Iron Accumulation through Protecting Aconitase 1 from Oxidative Stress in Rotenone-Induced Parkinson’s Disease in Rats

Cited by 15 publications

References 59 publications

The Tricarboxylic Acid Cycle as a Central Regulator of the Rate of Aging: Implications for Metabolic Interventions

The Tricarboxylic Acid Cycle as a Central Regulator of the Rate of Aging: Implications for Metabolic Interventions

Dopamine-iron homeostasis interaction rescues mitochondrial fitness in Parkinson’s disease

Virtual screening of flavonoids as potential RIPK1 inhibitors for neurodegeneration therapy

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