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Neuroprotective mechanisms of ?-viniferin in a rotenone-induced cell model of Parkinson's disease: significance of SIRT3-mediated FOXO3 deacetylation.

ABSTRACT: Trans-(-)-?-viniferin (?-viniferin) has antioxidative and anti-inflammatory effects. It also has neuroprotective effects in Huntington's disease by activating the SIRT3/LKB1/AMPK signaling pathway; however, it remains unknown whether ?-viniferin also has a neuroprotective role in Parkinson's disease. A Parkinson's disease cell model was induced by exposing SH-SY5Y cells to 3.0 ?M rotenone for 24 hours, and cells were then treated with 1.0 ?M ?-viniferin for 24 hours. Treatment with ?-viniferin upregulated SIRT3 expression, which promoted FOXO3 deacetylation and nuclear localization. ?-Viniferin also increased ATP production and decreased reactive oxygen species production. Furthermore, ?-viniferin treatment alleviated rotenone-induced mitochondrial depolarization and reduced cell apoptosis, and restored the expression of mitochondrial homeostasis-related proteins. However, when cells were transfected with SIRT3 or FOXO3 shRNA prior to rotenone and ?-viniferin treatment, these changes were reversed. The results from the present study indicate that ?-viniferin enhances SIRT3-mediated FOXO3 deacetylation, reduces oxidative stress, and maintains mitochondrial homeostasis, thus inhibiting rotenone-induced cell apoptosis. ?-Viniferin may therefore be a promising treatment strategy for Parkinson's disease.

SUBMITTER: Zhang S

PROVIDER: S-EPMC7716051 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Neuroprotective mechanisms of ε-viniferin in a rotenone-induced cell model of Parkinson's disease: significance of SIRT3-mediated FOXO3 deacetylation.

Zhang Shuo S Ma Yan Y Feng Juan J

Neural regeneration research 20201101 11

Trans-(-)-ε-viniferin (ε-viniferin) has antioxidative and anti-inflammatory effects. It also has neuroprotective effects in Huntington's disease by activating the SIRT3/LKB1/AMPK signaling pathway; however, it remains unknown whether ε-viniferin also has a neuroprotective role in Parkinson's disease. A Parkinson's disease cell model was induced by exposing SH-SY5Y cells to 3.0 μM rotenone for 24 hours, and cells were then treated with 1.0 μM ε-viniferin for 24 hours. Treatment with ε-viniferin u ...[more]

PMID: 32394973

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Project description:Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra (SN) pars compacta. Dopamine (DA) replacement therapy is one of the most effective drug treatments for PD; however, long-term levodopa treatment can lead to various side effects that negatively impact the quality of life of patients. Therefore, finding safe and effective alternative drugs to treat PD is of clinical importance. The Bushen-Jianpi decoction (BSJPD) was derived from classic traditional Chinese medicine and has been shown to be effective in the treatment of PD. This study explored the effects and mechanisms of action of BSJPD in PD. In our study, rats were randomly divided into six groups: the vehicle group, rotenone (ROT) + Saline group, ROT + low-dose BSJPD group, ROT + high-dose BSJPD group, ROT + Madopar group, and ROT + low-dose BSJPD + Madopar group. Treatment was administered to the rats once a day for 28 days, and behavioral tests were assessed. Tyrosine hydroxylase (TH), catechol-O-methyltransferase (COMT), monoamine oxidase B (MAO-B), dopa decarboxylase (DDC), alpha-synuclein (α-syn), and heme oxygenase-1 (HO-1) levels were detected. Our results show that BSJPD increases the body weight of rats, improves their motor coordination, reverses decreasing TH levels in the SN, and increases the expression level of DDC and HO-1 in the striatum (ST), but it fails to affect TH levels in the ST in the PD model. In addition, BSJPD reduced the expression of MAO-B in the ST in the PD model, but it did not have a significant effect on COMT. Rather, COMT in the plasma and liver increased in the low-dose BSJPD treatment group. Upregulation of α-syn in the PD model was also observed, but BSJPD has shown no obvious effect to clear it. Our results suggest that BSJPD exhibits a therapeutic effect on PD and may play a neuroprotective role by regulating HO-1 expression and participating in the metabolic process of DA.

Project description:Salmonella typhimurium (S. typhimurium) infection of macrophage induces NLRC4 inflammasome-mediated production of the pro-inflammatory cytokines IL-1β. Post-translational modifications on NLRC4 are critical for its activation. Sirtuin3 (SIRT3) is the most thoroughly studied mitochondrial nicotinamide adenine dinucleotide (NAD+) -dependent deacetylase. We wondered whether SIRT3 mediated-deacetylation could take part in NLRC4 inflammasome activation. Methods: We initially tested IL-1β production and pyroptosis after cytosolic transfection of flagellin or S. typhimurium infection in wild type and SIRT3-deficient primary peritoneal macrophages via immunoblotting and ELISA assay. These results were confirmed in SIRT3-deficient immortalized bone marrow derived macrophages (iBMDMs) which were generated by CRISPR-Cas9 technology. In addition, in vivo experiments were conducted to confirm the role of SIRT3 in S. typhimurium-induced cytokines production. Then NLRC4 assembly was analyzed by immune-fluorescence assay and ASC oligomerization assay. Immunoblotting, ELISA and flow cytometry were performed to clarify the role of SIRT3 in NLRP3 and AIM2 inflammasomes activation. To further investigate the mechanism of SIRT3 in NLRC4 activation, co-immunoprecipitation (Co-IP), we did immunoblot, cellular fractionation and in-vitro deacetylation assay. Finally, to clarify the acetylation sites of NLRC4, we performed liquid chromatography-mass spectrometry (LC-MS) and immunoblotting analysis. Results: SIRT3 deficiency led to significantly impaired NLRC4 inflammasome activation and pyroptosis both in vitro and in vivo. Furthermore, SIRT3 promotes NLRC4 inflammasome assembly by inducing more ASC speck formation and ASC oligomerization. However, SIRT3 is dispensable for NLRP3 and AIM2 inflammasome activation. Moreover, SIRT3 interacts with and deacetylates NLRC4 to promote its activation. Finally, we proved that deacetylation of NLRC4 at Lys71 or Lys272 could promote its activation. Conclusions: Our study reveals that SIRT3 mediated-deacetylation of NLRC4 is pivotal for NLRC4 activation and the acetylation switch of NLRC4 may aid the clearance of S. typhimurium infection.

Dataset Information

Neuroprotective mechanisms of ?-viniferin in a rotenone-induced cell model of Parkinson's disease: significance of SIRT3-mediated FOXO3 deacetylation.

Publications

Neuroprotective mechanisms of ε-viniferin in a rotenone-induced cell model of Parkinson's disease: significance of SIRT3-mediated FOXO3 deacetylation.

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