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The Importance of the CXCL12/CXCR4 Axis in Therapeutic Approaches to Diabetes Mellitus Attenuation.

Vidaković M, Grdović N, Dinić S, Mihailović M, Uskoković A, Arambašić Jovanović J - Front Immunol (2015)

Bottom Line: The pleiotropic chemokine (C-X-C motif) ligand 12 (CXCL12) has emerged as a crucial player in several diseases.Diabetes is a metabolic disorder resulting from a failure in glucose regulation due to β-cell loss and/or dysfunction.In view of its ability to stimulate the regeneration, proliferation, and survival of β-cells, as well as its capacity to sustain local immune-isolation, CXCL12 has been considered in approaches aimed at attenuating type 1 diabetes.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology, Institute for Biological Research, University of Belgrade , Belgrade , Serbia.

ABSTRACT
The pleiotropic chemokine (C-X-C motif) ligand 12 (CXCL12) has emerged as a crucial player in several diseases. The role of CXCL12 in diabetes promotion and progression remains elusive due to its multiple functions and the overwhelming complexity of diabetes. Diabetes is a metabolic disorder resulting from a failure in glucose regulation due to β-cell loss and/or dysfunction. In view of its ability to stimulate the regeneration, proliferation, and survival of β-cells, as well as its capacity to sustain local immune-isolation, CXCL12 has been considered in approaches aimed at attenuating type 1 diabetes. However, a note of caution emerges from examinations of the involvement of CXCL12 in the development of diabetes and its complications, as research data indicate that CXCL12 displays effects that range from protective to detrimental. Therefore, as a beneficial effect of CXCL12 in one process could have deleterious consequences in another, a more complete understanding of CXCL12 effects, in particular its functioning in the cellular microenvironment, is essential before CXCL12 can be considered in therapies for diabetes treatment.

No MeSH data available.


Related in: MedlinePlus

Proposed mechanism of the CXCL12/Akt-mediated anti-necrotic effect that leads to pancreatic β-cells survival. Under basal conditions, interaction between activated Akt (pAkt) and PARP-1 leads to PARP-1 phosphorylation that results in partial inhibition of PARP-1 in wild type (wt) and CXCL12 overexpressing Rin-5F cells. After hydrogen peroxide-induced oxidative stress and in response to severe DNA damage in wt cells, the loss of pAkt-PARP-1 interaction allows PARP-1 hyperactivation, followed by extensive PARP-1 auto-poly(ADP-ribosyl)ation, NAD+ and ATP depletion, and final necrotic cell death. In CXCL12 overexpressing cells, pAkt-PARP-1 interaction persists after hydrogen peroxide treatment, maintaining partial inhibition of PARP-1. Consequently, cellular energy depletion is prevented and a switch from the necrotic to the apoptotic cell death is ensured. With CXCL12-mediated suppression of PARP-1 overactivation in stress conditions, cell still operates with the active PARP-1 that is essential player in many cellular processes. The mechanism is based on the findings presented in Ref. (41).
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Figure 1: Proposed mechanism of the CXCL12/Akt-mediated anti-necrotic effect that leads to pancreatic β-cells survival. Under basal conditions, interaction between activated Akt (pAkt) and PARP-1 leads to PARP-1 phosphorylation that results in partial inhibition of PARP-1 in wild type (wt) and CXCL12 overexpressing Rin-5F cells. After hydrogen peroxide-induced oxidative stress and in response to severe DNA damage in wt cells, the loss of pAkt-PARP-1 interaction allows PARP-1 hyperactivation, followed by extensive PARP-1 auto-poly(ADP-ribosyl)ation, NAD+ and ATP depletion, and final necrotic cell death. In CXCL12 overexpressing cells, pAkt-PARP-1 interaction persists after hydrogen peroxide treatment, maintaining partial inhibition of PARP-1. Consequently, cellular energy depletion is prevented and a switch from the necrotic to the apoptotic cell death is ensured. With CXCL12-mediated suppression of PARP-1 overactivation in stress conditions, cell still operates with the active PARP-1 that is essential player in many cellular processes. The mechanism is based on the findings presented in Ref. (41).

Mentions: CXCL12 overexpression considerably improves insulin expression and viability of isolated rat islet cells and Rin-5F pancreatic β-cells after hydrogen peroxide treatment (41). CXCL12 overexpression in pancreatic cells switches hydrogen peroxide-induced cell death from the necrotic to the apoptotic pathway through Akt kinase-mediated reduction of poly(ADP-ribose) polymerase-1 (PARP-1) activity (Figure 1). These findings are in correlation with the documented role of PARP-1 in necrotic cell death (42) and with the observation that pharmacological inhibition or genetic deletion of PARP-1 protects animals against chemically induced and spontaneous diabetes development (43). The anti-necrotic effect of CXCL12 could prevent an additional pro-inflammatory burden of β-cells provoked by necrosis and could therefore be used for diabetes treatment.


The Importance of the CXCL12/CXCR4 Axis in Therapeutic Approaches to Diabetes Mellitus Attenuation.

Vidaković M, Grdović N, Dinić S, Mihailović M, Uskoković A, Arambašić Jovanović J - Front Immunol (2015)

Proposed mechanism of the CXCL12/Akt-mediated anti-necrotic effect that leads to pancreatic β-cells survival. Under basal conditions, interaction between activated Akt (pAkt) and PARP-1 leads to PARP-1 phosphorylation that results in partial inhibition of PARP-1 in wild type (wt) and CXCL12 overexpressing Rin-5F cells. After hydrogen peroxide-induced oxidative stress and in response to severe DNA damage in wt cells, the loss of pAkt-PARP-1 interaction allows PARP-1 hyperactivation, followed by extensive PARP-1 auto-poly(ADP-ribosyl)ation, NAD+ and ATP depletion, and final necrotic cell death. In CXCL12 overexpressing cells, pAkt-PARP-1 interaction persists after hydrogen peroxide treatment, maintaining partial inhibition of PARP-1. Consequently, cellular energy depletion is prevented and a switch from the necrotic to the apoptotic cell death is ensured. With CXCL12-mediated suppression of PARP-1 overactivation in stress conditions, cell still operates with the active PARP-1 that is essential player in many cellular processes. The mechanism is based on the findings presented in Ref. (41).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4528295&req=5

Figure 1: Proposed mechanism of the CXCL12/Akt-mediated anti-necrotic effect that leads to pancreatic β-cells survival. Under basal conditions, interaction between activated Akt (pAkt) and PARP-1 leads to PARP-1 phosphorylation that results in partial inhibition of PARP-1 in wild type (wt) and CXCL12 overexpressing Rin-5F cells. After hydrogen peroxide-induced oxidative stress and in response to severe DNA damage in wt cells, the loss of pAkt-PARP-1 interaction allows PARP-1 hyperactivation, followed by extensive PARP-1 auto-poly(ADP-ribosyl)ation, NAD+ and ATP depletion, and final necrotic cell death. In CXCL12 overexpressing cells, pAkt-PARP-1 interaction persists after hydrogen peroxide treatment, maintaining partial inhibition of PARP-1. Consequently, cellular energy depletion is prevented and a switch from the necrotic to the apoptotic cell death is ensured. With CXCL12-mediated suppression of PARP-1 overactivation in stress conditions, cell still operates with the active PARP-1 that is essential player in many cellular processes. The mechanism is based on the findings presented in Ref. (41).
Mentions: CXCL12 overexpression considerably improves insulin expression and viability of isolated rat islet cells and Rin-5F pancreatic β-cells after hydrogen peroxide treatment (41). CXCL12 overexpression in pancreatic cells switches hydrogen peroxide-induced cell death from the necrotic to the apoptotic pathway through Akt kinase-mediated reduction of poly(ADP-ribose) polymerase-1 (PARP-1) activity (Figure 1). These findings are in correlation with the documented role of PARP-1 in necrotic cell death (42) and with the observation that pharmacological inhibition or genetic deletion of PARP-1 protects animals against chemically induced and spontaneous diabetes development (43). The anti-necrotic effect of CXCL12 could prevent an additional pro-inflammatory burden of β-cells provoked by necrosis and could therefore be used for diabetes treatment.

Bottom Line: The pleiotropic chemokine (C-X-C motif) ligand 12 (CXCL12) has emerged as a crucial player in several diseases.Diabetes is a metabolic disorder resulting from a failure in glucose regulation due to β-cell loss and/or dysfunction.In view of its ability to stimulate the regeneration, proliferation, and survival of β-cells, as well as its capacity to sustain local immune-isolation, CXCL12 has been considered in approaches aimed at attenuating type 1 diabetes.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology, Institute for Biological Research, University of Belgrade , Belgrade , Serbia.

ABSTRACT
The pleiotropic chemokine (C-X-C motif) ligand 12 (CXCL12) has emerged as a crucial player in several diseases. The role of CXCL12 in diabetes promotion and progression remains elusive due to its multiple functions and the overwhelming complexity of diabetes. Diabetes is a metabolic disorder resulting from a failure in glucose regulation due to β-cell loss and/or dysfunction. In view of its ability to stimulate the regeneration, proliferation, and survival of β-cells, as well as its capacity to sustain local immune-isolation, CXCL12 has been considered in approaches aimed at attenuating type 1 diabetes. However, a note of caution emerges from examinations of the involvement of CXCL12 in the development of diabetes and its complications, as research data indicate that CXCL12 displays effects that range from protective to detrimental. Therefore, as a beneficial effect of CXCL12 in one process could have deleterious consequences in another, a more complete understanding of CXCL12 effects, in particular its functioning in the cellular microenvironment, is essential before CXCL12 can be considered in therapies for diabetes treatment.

No MeSH data available.


Related in: MedlinePlus