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Therapeutic potential of pterostilbene against pancreatic beta-cell apoptosis mediated through Nrf2
Elango Bhakkiyalakshmi1, Devibalan Shalini, Thillai Veerapazham Sekar
1Department of Biotechnology, School of Bioengineering, SRM University, Kattankulathur, Tamilnadu, India.
Background And Purpose:
Nuclear factor erythroid 2-related factor 2 (Nrf2) is considered to be a 'master regulator' of the antioxidant response as it regulates the expression of several genes including phase II metabolic and antioxidant enzymes and thus plays an important role in preventing oxidative stress-mediated disorders, including diabetes. In this study, for the first time, we investigated the protective properties of a naturally available antioxidant, pterostilbene (PTS), against pancreatic beta-cell apoptosis and the involvement of Nrf2 in its mechanism of action.
Experimental Approach:
Immunoblotting and quantitative reverse transcriptase (qRT)-PCR analysis were performed to identify PTS-mediated nuclear translocation of Nrf2 protein and the following activation of target gene expression, respectively, in INS-1E cells. In addition, an annexin-V binding assay was carried out to identify the apoptotic status of PTS-treated INS-1E cells, while confirming the anti-apoptotic potential of Nrf2 by qRT-PCR analysis of the expressions of both pro- and anti-apoptotic genes.
Key Results:
PTS induced significant activation of Nrf2, in dose- and time-dependent manner, in streptozotocin-treated INS-1E rat pancreatic beta-cells. Furthermore, PTS increased the expression of target genes downstream of Nrf2, such as heme oxygenase 1 (HO1), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), that confer cellular protection. PTS also up-regulated the expression of anti-apoptotic gene, Bcl-2, with a concomitant reduction in pro-apoptotic Bax and caspase-3 expression.
Conclusion And Implications:
Collectively, our findings indicate the therapeutic potential of Nrf2 activation by PTS as a promising approach to safeguard pancreatic beta-cells against oxidative damage in diabetes.
Insights
Pterostilbene (PTS) protects pancreatic beta-cells from oxidative damage by activating the antioxidant response regulator Nrf2 (Nuclear factor erythroid 2-related factor 2). This activation upregulates protective genes and inhibits apoptosis, offering a potential therapy for diabetes.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of cellular antioxidant defense mechanisms.
- Oxidative stress plays a significant role in the pathogenesis of diabetes and related complications.
- Pancreatic beta-cell dysfunction and apoptosis contribute to impaired insulin production in diabetes.
Purpose of the Study:
- To investigate the protective effects of pterostilbene (PTS) against apoptosis in pancreatic beta-cells.
- To elucidate the role of Nrf2 activation in the mechanism of PTS-mediated cytoprotection.
- To assess the potential of PTS as a therapeutic agent for diabetes-related pancreatic beta-cell damage.
Main Methods:
- INS-1E rat pancreatic beta-cells were treated with streptozotocin and/or PTS.
- Immunoblotting and qRT-PCR were used to analyze Nrf2 translocation and target gene expression.
- Annexin-V binding assays and analysis of pro-/anti-apoptotic gene expression determined the apoptotic status.
Main Results:
- Pterostilbene (PTS) dose- and time-dependently activated Nrf2 in pancreatic beta-cells.
- PTS increased the expression of Nrf2 downstream antioxidant enzymes (HO1, SOD, CAT, GPx).
- PTS reduced apoptosis by upregulating Bcl-2 and downregulating Bax and caspase-3.
Conclusions:
- Nrf2 activation by PTS confers significant protection to pancreatic beta-cells against oxidative stress.
- Pterostilbene demonstrates therapeutic potential for preventing diabetes-associated pancreatic beta-cell damage.
- Targeting Nrf2 with compounds like PTS may be a viable strategy for managing diabetes.
