Wedelolactone Mitigates Parkinsonism Via Alleviating Oxidative Stress and Mitochondrial Dysfunction Through NRF2/SKN-1

Sharma, Shruti; Trivedi, Shalini; Pandey, Taruna; Ranjan, Sachin; Trivedi, Mashu; Pandey, Rakesh

doi:10.1007/s12035-020-02080-4

Cited by 27 publications

(13 citation statements)

References 47 publications

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“…He et al reported an increase in ROS and movement disorder in a C. elegans model of PD [66]. Substances with neuroprotective or antioxidant properties reduced ROS and alleviated dyskinesia in C. elegans [67,68]. We found that VB12 treatment reduced ROS levels in parkin-null C. elegans VC1024.…”

Section: Discussionsupporting

confidence: 49%

Vitamin B12 Ameliorates the Pathological Phenotypes of Multiple Parkinson’s Disease Models by Alleviating Oxidative Stress

Zhao

Yang

et al. 2023

Antioxidants

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Parkinson’s disease (PD) is the second most common neurodegenerative disease characterized by progressive loss of dopaminergic neurons in the substantia nigra of the midbrain. The etiology of PD has yet to be elucidated, and the disease remains incurable. Increasing evidence suggests that oxidative stress is the key causative factor of PD. Due to their capacity to alleviate oxidative stress, antioxidants hold great potential for the treatment of PD. Vitamins are essential organic substances for maintaining the life of organisms. Vitamin deficiency is implicated in the pathogenesis of various diseases, such as PD. In the present study, we investigated whether administration of vitamin B12 (VB12) could ameliorate PD phenotypes in vitro and in vivo. Our results showed that VB12 significantly reduced the generation of reactive oxygen species (ROS) in the rotenone-induced SH-SY5Y cellular PD model. In a Parkin gene knockout C. elegans PD model, VB12 mitigated motor dysfunction. Moreover, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse PD model, VB12 also displayed protective effects, including the rescue of mitochondrial function, dopaminergic neuron loss, and movement disorder. In summary, our results suggest that vitamin supplementation may be a novel method for the intervention of PD, which is safer and more feasible than chemical drug treatment.

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Section: Discussionsupporting

confidence: 49%

Vitamin B12 Ameliorates the Pathological Phenotypes of Multiple Parkinson’s Disease Models by Alleviating Oxidative Stress

Zhao

Yang

et al. 2023

Antioxidants

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“…Furthermore, the mitochondria release an amount of ROS, which contributes to oxidative stress through the inactivation of the Nrf2 pathway. Previous studies have demonstrated the effect of WED toward inflammation and oxidative stress in Parkinson’s disease and kidney injury. − Furthermore, WED has attenuated bleomycin-mediated pulmonary fibrosis and protected bronchial epithelial cells from cigarette-smoke-extract-induced damage, , which suggests the potential of WED against inflammation and oxidative stress in ALI. As our expected, these phenomena were all observed by regulating the NF-κB and Nrf2 pathways in LPS-induced macrophages and ALI animals after WED treatment.…”

Section: Discussionmentioning

confidence: 91%

Macrophage Inactivation by Small Molecule Wedelolactone via Targeting sEH for the Treatment of LPS-Induced Acute Lung Injury

Zhang

Huo

et al. 2023

ACS Cent. Sci.

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Soluble epoxide hydrolase (sEH) plays a critical role in inflammation by modulating levels of epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids (EpFAs). Here, we investigate the possible role of sEH in lipopolysaccharide (LPS)-mediated macrophage activation and acute lung injury (ALI). In this study, we found that a small molecule, wedelolactone (WED), targeted sEH and led to macrophage inactivation. Through the molecular interaction with amino acids Phe362 and Gln384, WED suppressed sEH activity to enhance levels of EETs, thus attenuating inflammation and oxidative stress by regulating glycogen synthase kinase 3beta (GSK3β)-mediated nuclear factor-kappa B (NF-κB) and nuclear factor E2-related factor 2 (Nrf2) pathways in vitro. In an LPS-stimulated ALI animal model, pharmacological sEH inhibition by WED or sEH knockout (KO) alleviated pulmonary damage, such as the increase in the alveolar wall thickness and collapse. Additionally, WED or sEH genetic KO both suppressed macrophage activation and attenuated inflammation and oxidative stress in vivo. These findings provided the broader prospects for ALI treatment by targeting sEH to alleviate inflammation and oxidative stress and suggested WED as a natural lead candidate for the development of novel synthetic sEH inhibitors.

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“…A study developing a C. elegans model for neuron-neuron propagation of α-synuclein in vivo demonstrated that RNAi silencing of PD orthologue genes, including lrk-1, pdr-1, pink-1, vps-35 , resulted in increased α-synuclein propagation between neurons [ 254 ]. Furthermore, more complex mechanisms may be at play, as lrk-1 expression at the mRNA level has been shown to significantly increase in nematodes expressing α-synuclein in the muscle in the presence of the apoptosis inducer wedelolactone [ 255 ] and the flavonoid tambulin [ 256 ]. Both of these have been demonstrated to reduce α-synuclein aggregation in C. elegans muscles.…”

Section: Modelling α-Synuclein Pathology In C Elegans To Dissect Pd Gene Functionmentioning

confidence: 99%

Modelling the functional genomics of Parkinson’s disease inCaenorhabditis elegans:LRRK2and beyond

et al. 2021

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For decades, Parkinson’s disease (PD) cases have been genetically categorised into familial, when caused by mutations in single genes with a clear inheritance pattern in affected families, or idiopathic, in the absence of an evident monogenic determinant. Recently, genome-wide association studies (GWAS) have revealed how common genetic variability can explain up to 36% of PD heritability and that PD manifestation is often determined by multiple variants at different genetic loci. Thus, one of the current challenges in PD research stands in modelling the complex genetic architecture of this condition and translating this into functional studies. Caenorhabditis elegans provide a profound advantage as a reductionist, economical model for PD research, with a short lifecycle, straightforward genome engineering and high conservation of PD relevant neural, cellular and molecular pathways. Functional models of PD genes utilising C. elegans, show many phenotypes recapitulating pathologies observed in PD. When contrasted with mammalian in vivo and in vitro models, these are frequently validated, suggesting relevance of C. elegans in the development of novel PD functional models. This review will discuss how the nematode C. elegans PD models have contributed to the uncovering of molecular and cellular mechanisms of disease, with a focus on the genes most commonly found as causative in familial PD and risk factors in idiopathic PD. Specifically, we will examine the current knowledge on a central player in both familial and idiopathic PD, Leucine-rich repeat kinase 2 (LRRK2) and how it connects to multiple PD associated GWAS candidates and Mendelian disease-causing genes.

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Wedelolactone Mitigates Parkinsonism Via Alleviating Oxidative Stress and Mitochondrial Dysfunction Through NRF2/SKN-1

Cited by 27 publications

References 47 publications

Vitamin B12 Ameliorates the Pathological Phenotypes of Multiple Parkinson’s Disease Models by Alleviating Oxidative Stress

Vitamin B12 Ameliorates the Pathological Phenotypes of Multiple Parkinson’s Disease Models by Alleviating Oxidative Stress

Macrophage Inactivation by Small Molecule Wedelolactone via Targeting sEH for the Treatment of LPS-Induced Acute Lung Injury

Modelling the functional genomics of Parkinson’s disease inCaenorhabditis elegans:LRRK2and beyond

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