4,4′-Dimethoxychalcone regulates redox homeostasis by targeting riboflavin metabolism in Parkinson's disease therapy

Gong, Junhua; Zhang, Wenlong; Ding, Liuyan; Zhang, Mengran; Zheng, Shaohui; Ma, Runfang; Tang, Junyuan; Yi, Wei; Xu, Huaxi; Zhang, Yunlong

doi:10.1016/j.freeradbiomed.2021.07.038

Cited by 9 publications

(13 citation statements)

References 68 publications

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“…Stereotaxic Injection of LV-Rfk shRNA in the Hippocampus: LV-Ctrl and LV-Rfk were packaged by Sunbio Medical Biotechnology (Shanghai, China) and they were stereotaxically injected in the hippocampus according to our recent work. [17] Briefly, mice were anesthetized and placed in a stereotaxic frame. LV-Ctrl and LV-Rfk in 0.5 μL vol were delivered into the bilateral hippocampus at the target site (Bregma AP, −2.0 mm, ML, ±2.0 mm, DV, −2.0 mm).…”

Section: Methodsmentioning

confidence: 99%

Biomimetic Remodeling of Microglial Riboflavin Metabolism Ameliorates Cognitive Impairment by Modulating Neuroinflammation

et al. 2023

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Neuroinflammation, for which microglia are the predominant contributors, is a significant risk factor for cognitive dysfunction. Riboflavin (also known as vitamin B2) ameliorates cognitive impairment via anti‐oxidative stress and anti‐inflammation properties; however, the underlying mechanisms linking riboflavin metabolism and microglial function in cognitive impairment remain unclear. Here, it is demonstrated that riboflavin kinase (RFK), a critical enzyme in riboflavin metabolism, is specifically expressed in microglia. An intermediate product of riboflavin, flavin mononucleotide (FMN), inhibited RFK expression via regulation of lysine‐specific methyltransferase 2B (KMT2B). FMN supplementation attenuated the pro‐inflammatory TNFR1/NF‐κB signaling pathway, and this effect is abolished by KMT2B overexpression. To improve the limited anti‐inflammatory efficiency of free FMN, a biomimetic microglial nanoparticle strategy (designated as MNPs@FMN) is established, which penetrated the blood brain barrier with enhanced microglial‐targeted delivery efficiency. Notably, MNPs@FMN ameliorated cognitive impairment and dysfunctional synaptic plasticity in a lipopolysaccharide‐induced inflammatory mouse model and in a 5xFAD mouse model of Alzheimer's disease. Taken together, biomimetic microglial delivery of FMN may serve as a potential therapeutic approach for inflammation‐dependent cognitive decline.

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Section: Methodsmentioning

confidence: 99%

Biomimetic Remodeling of Microglial Riboflavin Metabolism Ameliorates Cognitive Impairment by Modulating Neuroinflammation

et al. 2023

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“…Open field test (OFT). OFT was performed as described previously [79,80]. Before the OFT, mice were habituated in the testing room for 1 day.…”

Section: Behavioral Testsmentioning

confidence: 99%

“…Pole climbing test. The Pole climbing test was performed as stated previously [80,81]. The mice were placed on the top of a pole with a length of 75 cm and a diameter of 9 cm.…”

Section: Behavioral Testsmentioning

confidence: 99%

“…Grip strength test. The grip strength test was performed as stated previously [80,81]. Mice were suspended on a horizontal metal wire of l mm diameter and placed 30 cm above the ground for 10 s, using the two front paws to test their grasp strength.…”

Section: Behavioral Testsmentioning

confidence: 99%

“…Rotarod test. Rotarod test was performed as stated previously [80,81]. Mice were trained on the rotarod cylinder for 3 days at a constant speed of 5 rpm.…”

Section: Behavioral Testsmentioning

confidence: 99%

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Functional investigation of SLC1A2 variants associated with epilepsy

Zhang

Wang

et al. 2022

Cell Death Dis

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Epilepsy is a common neurological disorder and glutamate excitotoxicity plays a key role in epileptic pathogenesis. Astrocytic glutamate transporter GLT-1 is responsible for preventing excitotoxicity via clearing extracellular accumulated glutamate. Previously, three variants (G82R, L85P, and P289R) in SLC1A2 (encoding GLT-1) have been clinically reported to be associated with epilepsy. However, the functional validation and underlying mechanism of these GLT-1 variants in epilepsy remain undetermined. In this study, we reported that these disease-linked mutants significantly decrease glutamate uptake, cell membrane expression of the glutamate transporter, and glutamate-elicited current. Additionally, we found that these variants may disturbed stromal-interacting molecule 1 (STIM1)/Orai1-mediated store-operated Ca2+ entry (SOCE) machinery in the endoplasmic reticulum (ER), in which GLT-1 may be a new partner of SOCE. Furthermore, knock-in mice with disease-associated variants showed a hyperactive phenotype accompanied by reduced glutamate transporter expression. Therefore, GLT-1 is a promising and reliable therapeutic target for epilepsy interventions.

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Microglial targeted therapy relieves cognitive impairment caused by Cntnap4 deficiency

et al. 2023

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Contactin-associated protein-like 4 (Cntnap4) is critical for GABAergic transmission in the brain. Impaired Cntnap4 function is implicated in neurological disorders, such as autism; however, the role of Cntnap4 on memory processing is poorly understood. Here, we demonstrate that hippocampal Cntnap deficiency in female mice manifests as impaired cognitive function and synaptic plasticity. The underlying mechanisms may involve effects on the pro-inflammatory response resulting in dysfunctional GABAergic transmission and activated tryptophan metabolism. To efficiently and accurately inhibit the pro-inflammatory reaction, we established a biomimetic microglial nanoparticle strategy to deliver FDA-approved PLX3397 (termed MNPs@PLX). We show MNPs@PLX successfully penetrates the blood brain barrier and facilitates microglialtargeted delivery of PLX3397. Furthermore, MNPs@PLX attenuates cognitive decline, dysfunctional synaptic plasticity, and pro-inflammatory response in female heterozygous Cntnap knockout mice. Together, our findings show loss of Cntnap causes pro-inflammatory cognitive decline that is effectively prevented by supplementation with microglia-specific inhibitors; thus validating the targeting of microglial function as a therapeutic intervention in neurocognitive disorders.

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4,4′-Dimethoxychalcone regulates redox homeostasis by targeting riboflavin metabolism in Parkinson's disease therapy

Cited by 9 publications

References 68 publications

Biomimetic Remodeling of Microglial Riboflavin Metabolism Ameliorates Cognitive Impairment by Modulating Neuroinflammation

Biomimetic Remodeling of Microglial Riboflavin Metabolism Ameliorates Cognitive Impairment by Modulating Neuroinflammation

Functional investigation of SLC1A2 variants associated with epilepsy

Microglial targeted therapy relieves cognitive impairment caused by Cntnap4 deficiency

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