Neuroprotective effects of kukoamine A on 6-OHDA-induced Parkinson's model through apoptosis and iron accumulation inhibition

Li, Xin; Jiang, Xiaowen; Chu, Hai-Xiao; Ding, Huaiwei; Cai, Chen

doi:10.1016/j.chmed.2020.12.004

Cited by 17 publications

(6 citation statements)

References 44 publications

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“…Apoptotic pathways can be roughly divided into the mitochondrial pathway and death receptor pathway, among which the mitochondrial pathway is a response to cell stress and can lead to the activation of proapoptotic protein Bim, which can directly or indirectly activate apoptotic factor Bax and lead to apoptosis. 33,34 In this study, RTK, IRS, and PDK1 proteins in the insulin signaling pathway were predicted, while Bim proteins were downstream of the insulin signaling pathway. Effector proteins PI3K, Akt, and FOXO1 were verified in the western blotting experiment, and the callback trend in the results could prove that TMYXP reduced the apoptosis of cardiomyocytes through the PI3K/FOXO1/Bim/ Bax axis.…”

Section: Discussionmentioning

confidence: 83%

Integrating Metabolomics and Network Pharmacology to Explore the Mechanism of Tongmai Yangxin Pills in Ameliorating Doxorubicin-Induced Cardiotoxicity

et al. 2023

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Doxorubicin (DOX) is a broad-spectrum chemotherapeutic drug used in clinical treatment of malignant tumors. It has a high anticancer activity but also high cardiotoxicity. The aim of this study was to explore the mechanism of Tongmai Yangxin pills (TMYXPs) in ameliorating DOX-induced cardiotoxicity through integrated metabolomics and network pharmacology. In this study, first, an ultrahigh-performance liquid chromatography−quadrupole-time-of-flight/mass spectrometry (UPLC−Q-TOF/MS) metabonomics strategy was established to obtain metabolite information and potential biomarkers were determined after data processing. Second, network pharmacological analysis was used to evaluate the active components, drug−disease targets, and key pathways of TMYXPs to alleviate DOX-induced cardiotoxicity. Targets from the network pharmacology analysis and metabolites from plasma metabolomics were jointly analyzed to select crucial metabolic pathways. Finally, the related proteins were verified by integrating the above results and the possible mechanism of TMYXPs to alleviate DOX-induced cardiotoxicity was studied. After metabolomics data processing, 17 different metabolites were screened, and it was found that TMYXPs played a role in myocardial protection mainly by affecting the tricarboxylic acid (TCA) cycle of myocardial cells. A total of 71 targets and 20 related pathways were screened out with network pharmacological analysis. Based on the combined analysis of 71 targets and different metabolites, TMYXPs probably played a role in myocardial protection through regulating upstream proteins of the insulin signaling pathway, MAPK signaling pathway, and p53 signaling pathway, as well as the regulation of metabolites related to energy metabolism. They then further affected the downstream Bax/Bcl-2−Cyt c−caspase-9 axis, inhibiting the myocardial cell apoptosis signaling pathway. The results of this study may contribute to the clinical application of TMYXPs in DOX-induced cardiotoxicity.

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Section: Discussionmentioning

confidence: 83%

Integrating Metabolomics and Network Pharmacology to Explore the Mechanism of Tongmai Yangxin Pills in Ameliorating Doxorubicin-Induced Cardiotoxicity

et al. 2023

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“… 29 Since iron is involved in PD progression due to its pro-oxidant nature, the interruption of iron homeostasis by 6-OHDA could cause neuronal damage, especially in the substantia nigra (SN). 30 , 31 Our previous study found that 6-OHDA regulated the expression of iron-related proteins, increased cellular iron uptake and retention in N27 cells. 6 Here, we further confirmed the involvement of oxidative stress with 6-OHDA showing the increased intracellular ROS as a result of exposure to 6-OHDA for 6 hours in N27 cells..…”

Section: Discussionmentioning

confidence: 96%

The Protection of EGCG Against 6-OHDA-Induced Oxidative Damage by Regulating PPARγ and Nrf2/HO-1 Signaling

Xu,

Chen,

Chen

et al. 2024

Nutr Metab Insights

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6-Hydroxydopamine (6-OHDA) is a classic neurotoxin that has been widely used in Parkinson’s disease research. 6-OHDA can increase intracellular reactive oxygen species (ROS) and can cause cell damage, which can be attenuated with (-)-Epigallocatechin-3-gallate (EGCG) treatment. However, the mechanism by which EGCG alters the 6-OHDA toxicity remains unclear; In this study, we found 6-OHDA (25 μM) alone increased intracellular ROS concentration in N27 cells, which was attenuated by pretreating with EGCG (100 μM). We evaluated the intracellular oxidative damage by determining the level of thiobarbituric acid reactive substances (TBARS) and protein carbonyl content. 6-OHDA significantly increased TBARS by 82.7% ( P < .05) and protein carbonyl content by 47.8 ( P < .05), compared to the control. Pretreatment of EGCG decreased TBARS and protein carbonyls by 36.4% ( P < .001) and 27.7% ( P < .05), respectively, compared to 6-OHDA alone treatment. Antioxidant effect was tested with E2-related factor 2 (Nrf2), heme oxygenase-1(HO-1) and peroxisome-proliferator activator receptor γ (PPARγ) expression. 6-OHDA increased Nrf2 expression by 69.6% ( P < .001), HO-1 by 173.3% ( P < .001), and PPARγ by 122.7% ( P < .001), compared with untreatment. EGCG pretreatment stabilized these alterations induced by 6-OHDA. Our results suggested that the neurotoxicity of 6-OHDA in N27 cells was associated with ROS pathway, whereas pretreatment of EGCG suppressed the ROS generation and deactivated the Nrf2/HO-1 and PPARγ expression.

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“…Zeng et al demonstrated that unilateral 6-OHDA increased the mRNA expression of α-synuclein in the SN, and levodopa had no effect on its mRNA expression [51]. Li et al also reported that 6-OHDA up-regulated α-synuclein protein levels in PC12 cells [52]. The aggregation of αsynuclein is linked to impaired lipid metabolism and hence mitochondrial dysfunction in dopaminergic neurons [53][54][55].…”

Section: Discussionmentioning

confidence: 99%

Hydroxychloroquine attenuated motor impairment and oxidative stress in a rat 6-hydroxydopamine model of Parkinson’s disease

Athari

Farajdokht

Sadigh-Eteghad

et al. 2022

International Journal of Neuroscience

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Background: Parkinson's disease (PD) is associated with the destruction of dopaminergic neurons in the substantia nigra (SN). Hydroxychloroquine (HCQ) has the capability to cross the blood-brain barrier and promote a neuroprotective potential. This study evaluated the effects of HCQ on the 6-hydroxydopamine (6-OHDA)-induced PD model in rats.Methods: Wistar rats were randomly divided into sham, PD, PD+levodopa, and PD+HCQ groups. The PD model was induced by a stereotactic administration of 6-OHDA into the left SN pars compacta (SNpc) and con rmed by rotation and the Murprogo's tests. HCQ (100 mg/kg, p.o.) and levodopa (12 mg/kg, p.o.)were administered once a day for 21 days. Three weeks after surgery, the behavioral tests were performed. Brain lipid peroxidation index (MDA), glutathione peroxidase activity (GPx), total antioxidant capacity (TAC) levels, and α-synuclein protein expression in the SN were also measured.Results: The behavioral tests demonstrated that induction of PD increased the muscle rigidity and the number of rotations, which were reversed by HCQ treatment. Also, induction of PD was associated with an increase in α-synuclein protein levels and MDA and decreased TAC levels and GPx activity. However, HCQ decreased α-synuclein and MDA levels while increased TAC levels and GPx activity. Additionally, histopathological data showed that HCQ protects dopaminergic neurons against 6-OHDA-induced toxicity.Conclusion: According to the results, HCQ has a bene cial effect in improving PD-related pathophysiology, in part, by mitigating oxidative stress and protecting the dopaminergic neurons in the SN.

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Neuroprotective effects of kukoamine A on 6-OHDA-induced Parkinson's model through apoptosis and iron accumulation inhibition

Cited by 17 publications

References 44 publications

Integrating Metabolomics and Network Pharmacology to Explore the Mechanism of Tongmai Yangxin Pills in Ameliorating Doxorubicin-Induced Cardiotoxicity

Integrating Metabolomics and Network Pharmacology to Explore the Mechanism of Tongmai Yangxin Pills in Ameliorating Doxorubicin-Induced Cardiotoxicity

The Protection of EGCG Against 6-OHDA-Induced Oxidative Damage by Regulating PPARγ and Nrf2/HO-1 Signaling

Hydroxychloroquine attenuated motor impairment and oxidative stress in a rat 6-hydroxydopamine model of Parkinson’s disease

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