Identification of a potent activator of Akt phosphorylation from a novel series of phenolic, picolinic, pyridino, and hydroxamic zinc(II) complexes

Georgiades, Savvas N.; Mak, Lok Hang; Angurell, Inmaculada; Rosivatz, Evelyn; Mustapa, M.F. Mohd; Polychroni, Christoulla; Woscholski, Rüdiger; Vilar, Ramón

doi:10.1007/s00775-010-0716-0

Cited by 10 publications

(5 citation statements)

References 41 publications

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“…Zn-induced prevention of the diabetic upregulation of PTEN and PTP1B is most likely due to Zn’s ability to negatively regulate them both [48–51] However, we do not have the answer as to why Zn supplementation had no effect on PTEN and PTP1B regulation under normal conditions. Although both are important Akt negative mediators, Zn-induced Akt and GSK-3β activation is not always mediated by Zn inhibition of PTEN and PTPs [22,52]. Consistent with these findings, here Zn stimulated Akt and GSK-3β phosphorylation not only in diabetic conditions, but also in normal kidney tissue.…”

Section: Discussionsupporting

confidence: 82%

“…The role of Akt3 is less clear, though it seems to be important for the brain [17,18]. Reportedly, Zn has an insulin-like function allowing it to stimulate Akt phosphorylation and activate glucose metabolism [20–22]. Therefore, because of the important role of Akt2 in insulin-mediated glucose metabolism, we assume that Zn-mediated protection from diabetes-induced renal damage may be predominantly dependent on Akt2.…”

mentioning

confidence: 99%

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Renal improvement by zinc in diabetic mice is associated with glucose metabolism signaling mediated by metallothionein and Akt, but not Akt2

Sun

Wang

Miao

et al. 2014

Free Radical Biology and Medicine

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Human epidemiological and animal studies have shown the beneficial effect of zinc supplementation on mitigating diabetic nephropathy. However, the mechanism by which zinc protects the kidney from diabetes remains unknown. Here we demonstrate the therapeutic effects of zinc on diabetes-induced renal pathological and functional changes. These abnormalities were found in both transgenic OVE26 and Akt2-KO diabetic mouse models, accompanied by significant changes in glucose-metabolism-related regulators. The changes included significantly decreased phosphorylation of Akt and GSK-3β, increased phosphorylation of renal glycogen synthase, decreased expression of hexokinase II and PGC-1α, and increased expression of the Akt negative regulators PTEN, PTP1B, and TRB3. All of these were significantly prevented by zinc treatment for 3 months. Furthermore, zinc-stimulated changes in glucose metabolism mediated by Akt were actually found to be metallothionein dependent, but not Akt2 dependent. These results suggest that the therapeutic effects of zinc in diabetic nephropathy are mediated, in part, by the preservation of glucose-metabolism-related pathways via the prevention of diabetes-induced upregulation of Akt negative regulators. Given that zinc deficiency is very common in diabetics, this finding implies that regularly monitoring zinc levels in diabetic patients, as well as supplementing if low, is important in mitigating the development of diabetic nephropathy.

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Section: Discussionsupporting

confidence: 82%

mentioning

confidence: 99%

Renal improvement by zinc in diabetic mice is associated with glucose metabolism signaling mediated by metallothionein and Akt, but not Akt2

Sun

Wang

Miao

et al. 2014

Free Radical Biology and Medicine

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“…They exhibit more specific functions, such as the inhibition of caspase-3 activity and promotion of ErbB1-ErbB2 heterodimerization by Zinc pyrithione [17], inhibition of cyclin-dependent kinase CDK1 [18]and inhibition of parathyroid hormone activity [13]. Induction of phosphorylation of the Akt downstream effector glycogen synthase kinase 3 and thus proposed to serve as lead structures for developing antidiabetic drugs and useful tools for regulating glucose metabolism to name but a few examples [19]. Zn 2+ complexes are also known to exhibit antibacterial/antimicrobial, anticancer activities, interacting with DNA and the inducing protein aggregation [20][21][22][23][24][25][26].…”

Section: Highlightmentioning

confidence: 99%

A small-molecule acts as a ‘roadblock’ on DNA, hampering its fundamental processes

Kumar

2017

Journal of Inorganic Biochemistry

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DNA replication, RNA and protein synthesis are the most fundamental housekeeping processes involved in an organism's growth. Failure or dysregulation of these pathways are often deleterious to life. Therefore, selective inhibition of such processes can be crucial for the inhibition of the growth of any cell, including cancer cells, pathogenic bacteria or other deadly microbes. In the present study, a Zn complex is shown to act as a roadblock of DNA. The Zn complex inhibited DNA taq polymerase activity under the in vitro conditions of polymerase chain reaction (PCR). Under in vivo conditions, it readily crosses the cell wall of gram-negative bacteria (Escherichia coli), leading to the reduction of RNA levels as well as protein content. Growth of pathogenic bacteria (e.g., Staphylococcus aureus and Pseudomonas aeruginosa) was also significantly retarded. The Zn complex binds to the grooves of the DNA without inducing conformational changes or exhibiting chemical nuclease activity. To the best current knowledge, this is first coordination complex exhibiting a 'roadblock' property under both in vitro and in vivo conditions (show at all three levels - DNA, RNA and protein). The label-free approach used in this study may offer an alternative route towards fighting pathogenic bacteria or cancer cells by hampering fundamental cellular processes.

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“…Studies have shown that Zn may play a similar role to that of insulin, causing it to stimulate Akt phosphorylation and activate glucose metabolism [63][64][65] and a recent study on podocytes showed the protective effects of Akt2 against damage induced by chronic kidney disease [66]. Therefore the importance of Akt2 for glucose metabolism led to the assumption that the protective effect of Zn was dependent on this enzyme.…”

Section: Improvements In Diabetic Glucose Metabolism After Zinc Supplmentioning

confidence: 99%

The Role of Zinc in Renal Pathological Changes in Diabetic Status

Fern¹,

Zhou²

2015

J Nutr Disorders Ther

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Identification of a potent activator of Akt phosphorylation from a novel series of phenolic, picolinic, pyridino, and hydroxamic zinc(II) complexes

Cited by 10 publications

References 41 publications

Renal improvement by zinc in diabetic mice is associated with glucose metabolism signaling mediated by metallothionein and Akt, but not Akt2

Renal improvement by zinc in diabetic mice is associated with glucose metabolism signaling mediated by metallothionein and Akt, but not Akt2

A small-molecule acts as a ‘roadblock’ on DNA, hampering its fundamental processes

The Role of Zinc in Renal Pathological Changes in Diabetic Status

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