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Inhibition of the prostaglandin D2-GPR44/DP2 axis improves human islet survival and function.

Inhibition of the prostaglandin D2-GPR44/DP2 axis improves human islet survival and function.
Posted by Frank

AIMS / HYPOTHESIS
inflammatory signals and increase the synthesis of prostaglandins play a role during the development of diabetes. The prostaglandin D2 (PGD2) receptor, GPR44 / DP2, is highly expressed in human islets and insulin secretion pathway activation results impaired. GPR44 activation role in the function of small islands and the survival rate for chronic hyperglycaemic conditions are unknown. In this study, we investigated GPR44 GPR44 inhibition by using a selective antagonist (AZ8154) in humans the island both in vitro and in vivo in diabetic mice transplanted with human islets.


METHOD
human islets exposed to PGD2 or proinflammatory cytokines in vitro to determine the effect of GPR44 inhibition on the survival rate of the island. In addition, the molecular mechanism of inhibition of GPR44 investigated in human islets exposed to high concentrations of glucose (HG) and IL-1β.

To the in vivo from this study, human islets are transplanted under the kidney capsule of diabetic rats immunodeficiencies and treated with 6, 60 or 100 mg / kg per day antagonist of GPR44 from the day of transplantation until day 4 short-term (studies) or study days (term long-17) post transplant. IVGTT conducted in rats at 10 days 15 days post transplant. After the termination of the study, metabolic variables, human circulating proinflammatory cytokines, and hepatocyte growth factor (HGF) were analyzed in human islets transplanted.


RESULTS
PGD2 or proinflammatory cytokine-induced apoptosis in human islets, while GPR44 inhibition of reverse these effects. GPR44 inhibition of hate decreased insulin secretion induced by glucose-stimulated HG and IL-1β in human islets. It is accompanied by activation of glycogen synthase kinase-Akt signaling 3β together with the phosphorylation and inactivation of the forkhead box O-1 and upregulation of pancreatic and duodenal homeobox-1 and HGF.

GPR44 antagonist administration up to 17 days for the diabetic mice transplanted with human islets resulted in a marginal reduction in fasting blood glucose and lower glucose fluctuations during IVGTT. improved glucose regulation is supported by an increased level of human C-peptide compared to the vehicle group on day 4 and throughout the treatment period. GPR44 inhibition reduces plasma levels of TNF-α and growth-regulated oncogene-α / chemokine (C-X-C motif) ligand 1 and raise the level of HGF in human islets.


Inhibition of GPR44 in human islets have the potential to improve the functioning of small islands and the survival rate under pressure inflammation and hyperglycaemic. This may have implications for the survival rates were better than the island after transplantation.

Inhibition of the prostaglandin D2-GPR44/DP2 axis improves human islet survival and function.
Inhibition of the prostaglandin D2-GPR44/DP2 axis improves human islet survival and function.

1 Channel Control Pannexin endothelial inflammation by regulating intracellular calcium.

The proinflammatory cytokine IL-1β is a significant risk factor in cardiovascular disease that can be targeted to reduce major cardiovascular events. expression and release of IL-1β is tightly controlled by changes in intracellular Ca2 + ([Ca2 +] i), which has been associated with the release of ATP and purinergic signaling. However, the mechanisms that regulate these changes have not been identified.

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  • 10 ug
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  • 10 ug
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  • 1 mg
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  • EUR 356.00
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  • 1 mg
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  • 1 mg
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  • 10 ug
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  • 200 ug
  • 50 ug

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  • EUR 133.00
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  • 100 ug
  • 10 ug
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  • 200 ug
  • 50 ug

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  • 200 ul
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  • EUR 537.00
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  • EUR 272.00
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  • 200 tests
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  • EUR 133.00
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  • EUR 523.00
  • EUR 300.00
  • 100 ug
  • 10 ug
  • 1 mg
  • 200 ug
  • 50 ug

Interleukin 8 (IL8) Antibody

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  • 1 mg
  • 200 ug

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  • EUR 356.00
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  • EUR 467.00
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  • EUR 272.00
  • 100 ug
  • 1 mg
  • 200 ug
  • 20 ug
  • 50 ug

Dog Interleukin-8 (IL8)

1-CSB-YP011671DO
  • EUR 679.00
  • EUR 335.00
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  • EUR 1051.00
  • EUR 1442.00
  • EUR 435.00
  • 100ug
  • 10ug
  • 1MG
  • 200ug
  • 500ug
  • 50ug
Description: Recombinant Dog Interleukin-8(IL8) expressed in Yeast

Dog Interleukin-8 (IL8)

1-CSB-EP011671DO
  • EUR 611.00
  • EUR 309.00
  • EUR 1827.00
  • EUR 939.00
  • EUR 1218.00
  • EUR 397.00
  • 100ug
  • 10ug
  • 1MG
  • 200ug
  • 500ug
  • 50ug
Description: Recombinant Dog Interleukin-8(IL8) expressed in E.coli

Sheep Interleukin-8 (IL8)

1-CSB-EP011671SH
  • EUR 611.00
  • EUR 309.00
  • EUR 1827.00
  • EUR 939.00
  • EUR 1218.00
  • EUR 397.00
  • 100ug
  • 10ug
  • 1MG
  • 200ug
  • 500ug
  • 50ug
Description: Recombinant Sheep Interleukin-8(IL8) expressed in E.coli

Dog Interleukin-8 (IL8)

1-CSB-MP011671DO
  • EUR 293.00
  • EUR 963.00
  • EUR 409.00
  • EUR 717.00
  • 100ug
  • 1MG
  • 200ug
  • 500ug
Description: Recombinant Dog Interleukin-8(IL8) expressed in Mammalian cell

Eukaryotic Interleukin 8 (IL8)

4-EPA080Bo61
  • EUR 476.32
  • EUR 230.00
  • EUR 1511.20
  • EUR 570.40
  • EUR 1040.80
  • EUR 382.00
  • EUR 3628.00
  • 100 ug
  • 10ug
  • 1 mg
  • 200 ug
  • 500 ug
  • 50ug
  • 5 mg
Description: Recombinant Bovine Interleukin 8 expressed in: 293F cell

Active Interleukin 8 (IL8)

4-APA080Hu01
  • EUR 583.84
  • EUR 259.00
  • EUR 1914.40
  • EUR 704.80
  • EUR 1309.60
  • EUR 454.00
  • EUR 4636.00
  • 100 ug
  • 10ug
  • 1 mg
  • 200 ug
  • 500 ug
  • 50ug
  • 5 mg
Description: Recombinant Human Interleukin 8 expressed in: Available from E.coli, Yeast, Baculovirus and Mammalian cells

Recombinant Interleukin 8 (IL8)

4-RPA080Ca01
  • EUR 440.48
  • EUR 221.00
  • EUR 1376.80
  • EUR 525.60
  • EUR 951.20
  • EUR 358.00
  • EUR 3292.00
  • 100 ug
  • 10ug
  • 1 mg
  • 200 ug
  • 500 ug
  • 50ug
  • 5 mg
Description: Recombinant Dog Interleukin 8 expressed in: E.coli

The pannexin 1 (Panx1) channel has been canonically been involved in the ATP release, particularly during inflammation. We checked Panx1 in human umbilical vein endothelial cells after treatment with proinflammatory cytokines TNF-α. Analysis by the whole transcriptome sequencing and immunoblot Panx1 identified a dramatic increase in mRNA and protein expression were regulated by NF-kB-dependent.

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