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Combined activation of the energy and cellular-defense pathways may explain the potent anti-senescence activity of methylene blue.

Atamna H, Atamna W, Al-Eyd G, Shanower G, Dhahbi JM - Redox Biol (2015)

Bottom Line: Methylene blue (MB) delays cellular senescence, induces complex-IV, and activates Keap1/Nrf2; however, the molecular link of these effects to MB is unclear.A previous research suggested that the pattern of AMPK activation (i.e., chronic or transient) determines the AMPK effect on cell senescence.Since MB lacked an effect on cell cycle, an MB-dependent change to cell cycle is unlikely to contribute to the anti-senescence activity.

View Article: PubMed Central - PubMed

Affiliation: College of Medicine, California University of Science & Medicine, Colton, CA 92324, USA; Department of Basic Sciences, The Commonwealth Medical College (TCMC), Scranton, PA 18509, USA. Electronic address: atamnah@calmedu.org.

No MeSH data available.


Related in: MedlinePlus

MB interacts with AMPK and Keap1/Nrf2 pathways that oversee energy and cellular defense metabolism, respectively. MB increases the ratio of NAD/NADH, which connects to the cellular energy regulation (pAMPK) and the cytoprotective mechanisms (Keap1/Nrf2). The increase in NAD/NADH, which is fast and transient, is followed by an increase in pAMPK/AMPK. AMPK plays key role in energy metabolism through mitochondrial and complex IV biogenesis (and activity). The biogenesis of complex IV requires SURF1 while PGC1α is important for mitochondrial biogenesis, maintenance, and function. MB also activates the Keap1/Nrf2 pathway, which plays central role in the defense metabolism against oxidants and xenobiotic that may damage DNA, lipids, and proteins. The induction of the cytoprotective mechanism in conjunction with lower levels of oxidants as well as the induction of complex IV and improvement of mitochondrial respiration are likely to enhance genome stability and slow telomeres erosion. Black and gray bars represent mitochondria from young and old cells, respectively. The hexagon represents nucleus from a young cell while dark circle represents the morphological and heterochromatin changes in old cell.
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f0055: MB interacts with AMPK and Keap1/Nrf2 pathways that oversee energy and cellular defense metabolism, respectively. MB increases the ratio of NAD/NADH, which connects to the cellular energy regulation (pAMPK) and the cytoprotective mechanisms (Keap1/Nrf2). The increase in NAD/NADH, which is fast and transient, is followed by an increase in pAMPK/AMPK. AMPK plays key role in energy metabolism through mitochondrial and complex IV biogenesis (and activity). The biogenesis of complex IV requires SURF1 while PGC1α is important for mitochondrial biogenesis, maintenance, and function. MB also activates the Keap1/Nrf2 pathway, which plays central role in the defense metabolism against oxidants and xenobiotic that may damage DNA, lipids, and proteins. The induction of the cytoprotective mechanism in conjunction with lower levels of oxidants as well as the induction of complex IV and improvement of mitochondrial respiration are likely to enhance genome stability and slow telomeres erosion. Black and gray bars represent mitochondria from young and old cells, respectively. The hexagon represents nucleus from a young cell while dark circle represents the morphological and heterochromatin changes in old cell.

Mentions: Scheme 1 reconciles the various effects of MB from this study and from published results (e.g., activation of Keap1/Nrf2). We propose combined activation of energy and cellular defense pathways by MB as possible key factor in MB’s potent anti-senescence activity. MB alters the ratios NAD/NADH and pAMPK/AMPK, which leads to the induction of complex IV and lowering the intracellular oxidants production. In addition, MB activates Keap1/Nrf2 pathway, which enhances cellular resistance to oxidative stress [23,28]. The activity of Keap1/Nrf2 is attenuated with age [50], a factor that enhance the damaging impact of oxidants on macromolecules such DNA and telomeres. Oxidants damage to proteins, lipids, and DNA, enhance telomeres erosion, and mitochondrial dysfunction, all are well-established contributing factors to cell aging [31,58]. These factors are also involved in several age-related disorders (including Alzheimer disease [59], atherosclerosis [60], and Parkinson's disease [61]).


Combined activation of the energy and cellular-defense pathways may explain the potent anti-senescence activity of methylene blue.

Atamna H, Atamna W, Al-Eyd G, Shanower G, Dhahbi JM - Redox Biol (2015)

MB interacts with AMPK and Keap1/Nrf2 pathways that oversee energy and cellular defense metabolism, respectively. MB increases the ratio of NAD/NADH, which connects to the cellular energy regulation (pAMPK) and the cytoprotective mechanisms (Keap1/Nrf2). The increase in NAD/NADH, which is fast and transient, is followed by an increase in pAMPK/AMPK. AMPK plays key role in energy metabolism through mitochondrial and complex IV biogenesis (and activity). The biogenesis of complex IV requires SURF1 while PGC1α is important for mitochondrial biogenesis, maintenance, and function. MB also activates the Keap1/Nrf2 pathway, which plays central role in the defense metabolism against oxidants and xenobiotic that may damage DNA, lipids, and proteins. The induction of the cytoprotective mechanism in conjunction with lower levels of oxidants as well as the induction of complex IV and improvement of mitochondrial respiration are likely to enhance genome stability and slow telomeres erosion. Black and gray bars represent mitochondria from young and old cells, respectively. The hexagon represents nucleus from a young cell while dark circle represents the morphological and heterochromatin changes in old cell.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4588422&req=5

f0055: MB interacts with AMPK and Keap1/Nrf2 pathways that oversee energy and cellular defense metabolism, respectively. MB increases the ratio of NAD/NADH, which connects to the cellular energy regulation (pAMPK) and the cytoprotective mechanisms (Keap1/Nrf2). The increase in NAD/NADH, which is fast and transient, is followed by an increase in pAMPK/AMPK. AMPK plays key role in energy metabolism through mitochondrial and complex IV biogenesis (and activity). The biogenesis of complex IV requires SURF1 while PGC1α is important for mitochondrial biogenesis, maintenance, and function. MB also activates the Keap1/Nrf2 pathway, which plays central role in the defense metabolism against oxidants and xenobiotic that may damage DNA, lipids, and proteins. The induction of the cytoprotective mechanism in conjunction with lower levels of oxidants as well as the induction of complex IV and improvement of mitochondrial respiration are likely to enhance genome stability and slow telomeres erosion. Black and gray bars represent mitochondria from young and old cells, respectively. The hexagon represents nucleus from a young cell while dark circle represents the morphological and heterochromatin changes in old cell.
Mentions: Scheme 1 reconciles the various effects of MB from this study and from published results (e.g., activation of Keap1/Nrf2). We propose combined activation of energy and cellular defense pathways by MB as possible key factor in MB’s potent anti-senescence activity. MB alters the ratios NAD/NADH and pAMPK/AMPK, which leads to the induction of complex IV and lowering the intracellular oxidants production. In addition, MB activates Keap1/Nrf2 pathway, which enhances cellular resistance to oxidative stress [23,28]. The activity of Keap1/Nrf2 is attenuated with age [50], a factor that enhance the damaging impact of oxidants on macromolecules such DNA and telomeres. Oxidants damage to proteins, lipids, and DNA, enhance telomeres erosion, and mitochondrial dysfunction, all are well-established contributing factors to cell aging [31,58]. These factors are also involved in several age-related disorders (including Alzheimer disease [59], atherosclerosis [60], and Parkinson's disease [61]).

Bottom Line: Methylene blue (MB) delays cellular senescence, induces complex-IV, and activates Keap1/Nrf2; however, the molecular link of these effects to MB is unclear.A previous research suggested that the pattern of AMPK activation (i.e., chronic or transient) determines the AMPK effect on cell senescence.Since MB lacked an effect on cell cycle, an MB-dependent change to cell cycle is unlikely to contribute to the anti-senescence activity.

View Article: PubMed Central - PubMed

Affiliation: College of Medicine, California University of Science & Medicine, Colton, CA 92324, USA; Department of Basic Sciences, The Commonwealth Medical College (TCMC), Scranton, PA 18509, USA. Electronic address: atamnah@calmedu.org.

No MeSH data available.


Related in: MedlinePlus