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Polyphenol Stilbenes: Molecular Mechanisms of Defence against Oxidative Stress and Aging-Related Diseases.

Reinisalo M, Kårlund A, Koskela A, Kaarniranta K, Karjalainen RO - Oxid Med Cell Longev (2015)

Bottom Line: There is convincing data that stilbene compounds, a diverse group of natural defence phenolics, abundant in grapes, berries, and conifer bark waste, may confer a protective effect against aging-related diseases.The impact of stilbenes on the nuclear factor-erythroid-2-related factor-2 (Nrf2) mediated cellular defence against oxidative stress as well as the potential roles of SQSTM1/p62 protein in Nrf2/Keap1 signaling and autophagy will be summarized.The therapeutic potential of stilbene compounds against the most common aging-related diseases is discussed.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.

ABSTRACT
Numerous studies have highlighted the key roles of oxidative stress and inflammation in aging-related diseases such as obesity, type 2 diabetes, age-related macular degeneration (AMD), and Alzheimer's disease (AD). In aging cells, the natural antioxidant capacity decreases and the overall efficiency of reparative systems against cell damage becomes impaired. There is convincing data that stilbene compounds, a diverse group of natural defence phenolics, abundant in grapes, berries, and conifer bark waste, may confer a protective effect against aging-related diseases. This review highlights recent data helping to clarify the molecular mechanisms involved in the stilbene-mediated protection against oxidative stress. The impact of stilbenes on the nuclear factor-erythroid-2-related factor-2 (Nrf2) mediated cellular defence against oxidative stress as well as the potential roles of SQSTM1/p62 protein in Nrf2/Keap1 signaling and autophagy will be summarized. The therapeutic potential of stilbene compounds against the most common aging-related diseases is discussed.

No MeSH data available.


Related in: MedlinePlus

The Nrf2/ARE pathway and cAMP second messenger system together are the key regulators of cellular antioxidant defence. These pathways can be modulated by stilbenes. Stilbenes can activate nuclear localization of Nrf2 and activation of Nrf2 target genes associated with antioxidant defence and autophagy. Autophagy related protein p62 and Nrf2 form a regulatory loop where p62 enables the release of Nrf2 from cytoplasmic Keap1 complex. When cells are not stressed, the excess of cytoplasmic Nrf2 is eliminated by proteasomal degradation. In addition, stilbenes are capable of activating cAMP response element-binding protein (CREB) target genes and the AMPK pathway by PDE inhibition mediated increase of cellular cAMP levels.
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fig2: The Nrf2/ARE pathway and cAMP second messenger system together are the key regulators of cellular antioxidant defence. These pathways can be modulated by stilbenes. Stilbenes can activate nuclear localization of Nrf2 and activation of Nrf2 target genes associated with antioxidant defence and autophagy. Autophagy related protein p62 and Nrf2 form a regulatory loop where p62 enables the release of Nrf2 from cytoplasmic Keap1 complex. When cells are not stressed, the excess of cytoplasmic Nrf2 is eliminated by proteasomal degradation. In addition, stilbenes are capable of activating cAMP response element-binding protein (CREB) target genes and the AMPK pathway by PDE inhibition mediated increase of cellular cAMP levels.

Mentions: Nuclear factor-erythroid-2-related factor-2 (Nrf2), a member of the basic leucine zipper (bZIP) transcription factor family, is an essential transcription factor for cellular detoxification and defence against oxidative stress. In the cell nucleus, Nrf2 is able to recognize the antioxidant response element (ARE) with the specific nucleotide binding sequence (5′-TGACnnnGC-3′) positioned in regulatory region of target genes [51, 52]. Role of other members of the Nrf-family such as Nrf1 and Nrf3 has not been so thoroughly studied but current evidence suggests that these genes have partially different functions, target genes, and tissue-specificities although they recognize the same ARE sequence as Nrf2 [51, 53]. By acting through the ARE element, Nrf2 has a central role in the regulation of a large group of phase II metabolite conjugation and antioxidant genes (Figure 2) as well as in influencing some of the genes involved in proteasome pathway and inflammation [52, 54–57]. Until now, several Nrf2 target genes (see Table 2) such as heme oxygenase-1 (HO-1) [58] and NAD(P)H dehydrogenase, quinone 1 (NQO1) [59], have been verified. Under basal conditions, the Nrf2/ARE pathway is suppressed since Nrf2 is trapped in the cytosol as it forms a protein complex with Kelch-like ECH-associated protein 1 (Keap1) [55]. Keap1 acts as a molecular switch sensing cellular electrophile and oxidant homeostasis [60]. With assistance of Cullin-3 (CUL3), the Nrf2-Keap1-CUL3 protein complexes are constantly exposed to ubiquitin conjugation and proteasomal degradation [55, 61]. In condition of stress or exposure to electrophiles, Nrf2 dissociates from the Keap1-CUL3 complex and translocates into the nucleus. The dissociation of Nrf2 is mediated via modification of specific Keap1 cysteine residues by electrophiles, oxidants, and dietary supplements such as stilbenes [62]. Alternatively, dissociation of Nrf2 from cytoplasmic Nrf2-Keap1-CUL3 complex is enabled by p62 involved in autophagy process (see Section 4.2). In the nucleus, Nrf2 heterodimerizes with small Maf (sMaf) proteins which seems to be indispensable partners required for ARE binding and subsequent transactivation of target genes [52]. In contrast, in the nucleus, the transcriptional repressor BACH1 seems to have an important role as an antagonist for Nrf2 mediated activation by binding ARE-like elements in Nrf2 target genes [63]. It should be noted that Keap1 has the capability to undergo nuclear localization and to shuttle back to cytoplasm; this suggests that Keap1 is also involved in the regulation of Nrf2 in the cell nucleus [64]. Interestingly, in different species, ARE elements are also found in the regulatory regions of Nrf2 itself as well as in several regulators of the Nrf2/ARE pathway such as Keap1, sMaf, and p62 [65, 66]. In addition, it has been shown that the acetylation-deacetylation status of Nrf2 in the nucleus is also important for Nrf2 binding and target gene activation [67]. Auxiliary mechanisms such as the cAMP/CREB pathway [68] and the aryl hydrocarbon receptor (AhR) pathway [69] interacting with the Nrf2/ARE pathway will be discussed later in this review (see Section 4.3).


Polyphenol Stilbenes: Molecular Mechanisms of Defence against Oxidative Stress and Aging-Related Diseases.

Reinisalo M, Kårlund A, Koskela A, Kaarniranta K, Karjalainen RO - Oxid Med Cell Longev (2015)

The Nrf2/ARE pathway and cAMP second messenger system together are the key regulators of cellular antioxidant defence. These pathways can be modulated by stilbenes. Stilbenes can activate nuclear localization of Nrf2 and activation of Nrf2 target genes associated with antioxidant defence and autophagy. Autophagy related protein p62 and Nrf2 form a regulatory loop where p62 enables the release of Nrf2 from cytoplasmic Keap1 complex. When cells are not stressed, the excess of cytoplasmic Nrf2 is eliminated by proteasomal degradation. In addition, stilbenes are capable of activating cAMP response element-binding protein (CREB) target genes and the AMPK pathway by PDE inhibition mediated increase of cellular cAMP levels.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4477219&req=5

fig2: The Nrf2/ARE pathway and cAMP second messenger system together are the key regulators of cellular antioxidant defence. These pathways can be modulated by stilbenes. Stilbenes can activate nuclear localization of Nrf2 and activation of Nrf2 target genes associated with antioxidant defence and autophagy. Autophagy related protein p62 and Nrf2 form a regulatory loop where p62 enables the release of Nrf2 from cytoplasmic Keap1 complex. When cells are not stressed, the excess of cytoplasmic Nrf2 is eliminated by proteasomal degradation. In addition, stilbenes are capable of activating cAMP response element-binding protein (CREB) target genes and the AMPK pathway by PDE inhibition mediated increase of cellular cAMP levels.
Mentions: Nuclear factor-erythroid-2-related factor-2 (Nrf2), a member of the basic leucine zipper (bZIP) transcription factor family, is an essential transcription factor for cellular detoxification and defence against oxidative stress. In the cell nucleus, Nrf2 is able to recognize the antioxidant response element (ARE) with the specific nucleotide binding sequence (5′-TGACnnnGC-3′) positioned in regulatory region of target genes [51, 52]. Role of other members of the Nrf-family such as Nrf1 and Nrf3 has not been so thoroughly studied but current evidence suggests that these genes have partially different functions, target genes, and tissue-specificities although they recognize the same ARE sequence as Nrf2 [51, 53]. By acting through the ARE element, Nrf2 has a central role in the regulation of a large group of phase II metabolite conjugation and antioxidant genes (Figure 2) as well as in influencing some of the genes involved in proteasome pathway and inflammation [52, 54–57]. Until now, several Nrf2 target genes (see Table 2) such as heme oxygenase-1 (HO-1) [58] and NAD(P)H dehydrogenase, quinone 1 (NQO1) [59], have been verified. Under basal conditions, the Nrf2/ARE pathway is suppressed since Nrf2 is trapped in the cytosol as it forms a protein complex with Kelch-like ECH-associated protein 1 (Keap1) [55]. Keap1 acts as a molecular switch sensing cellular electrophile and oxidant homeostasis [60]. With assistance of Cullin-3 (CUL3), the Nrf2-Keap1-CUL3 protein complexes are constantly exposed to ubiquitin conjugation and proteasomal degradation [55, 61]. In condition of stress or exposure to electrophiles, Nrf2 dissociates from the Keap1-CUL3 complex and translocates into the nucleus. The dissociation of Nrf2 is mediated via modification of specific Keap1 cysteine residues by electrophiles, oxidants, and dietary supplements such as stilbenes [62]. Alternatively, dissociation of Nrf2 from cytoplasmic Nrf2-Keap1-CUL3 complex is enabled by p62 involved in autophagy process (see Section 4.2). In the nucleus, Nrf2 heterodimerizes with small Maf (sMaf) proteins which seems to be indispensable partners required for ARE binding and subsequent transactivation of target genes [52]. In contrast, in the nucleus, the transcriptional repressor BACH1 seems to have an important role as an antagonist for Nrf2 mediated activation by binding ARE-like elements in Nrf2 target genes [63]. It should be noted that Keap1 has the capability to undergo nuclear localization and to shuttle back to cytoplasm; this suggests that Keap1 is also involved in the regulation of Nrf2 in the cell nucleus [64]. Interestingly, in different species, ARE elements are also found in the regulatory regions of Nrf2 itself as well as in several regulators of the Nrf2/ARE pathway such as Keap1, sMaf, and p62 [65, 66]. In addition, it has been shown that the acetylation-deacetylation status of Nrf2 in the nucleus is also important for Nrf2 binding and target gene activation [67]. Auxiliary mechanisms such as the cAMP/CREB pathway [68] and the aryl hydrocarbon receptor (AhR) pathway [69] interacting with the Nrf2/ARE pathway will be discussed later in this review (see Section 4.3).

Bottom Line: There is convincing data that stilbene compounds, a diverse group of natural defence phenolics, abundant in grapes, berries, and conifer bark waste, may confer a protective effect against aging-related diseases.The impact of stilbenes on the nuclear factor-erythroid-2-related factor-2 (Nrf2) mediated cellular defence against oxidative stress as well as the potential roles of SQSTM1/p62 protein in Nrf2/Keap1 signaling and autophagy will be summarized.The therapeutic potential of stilbene compounds against the most common aging-related diseases is discussed.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.

ABSTRACT
Numerous studies have highlighted the key roles of oxidative stress and inflammation in aging-related diseases such as obesity, type 2 diabetes, age-related macular degeneration (AMD), and Alzheimer's disease (AD). In aging cells, the natural antioxidant capacity decreases and the overall efficiency of reparative systems against cell damage becomes impaired. There is convincing data that stilbene compounds, a diverse group of natural defence phenolics, abundant in grapes, berries, and conifer bark waste, may confer a protective effect against aging-related diseases. This review highlights recent data helping to clarify the molecular mechanisms involved in the stilbene-mediated protection against oxidative stress. The impact of stilbenes on the nuclear factor-erythroid-2-related factor-2 (Nrf2) mediated cellular defence against oxidative stress as well as the potential roles of SQSTM1/p62 protein in Nrf2/Keap1 signaling and autophagy will be summarized. The therapeutic potential of stilbene compounds against the most common aging-related diseases is discussed.

No MeSH data available.


Related in: MedlinePlus