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Karlberg T.,Karolinska Institutet | Thorsell A.-G.,Karolinska Institutet | Kallas A.,Karolinska Institutet | Kallas A.,Cebix AB | Schuler H.,Karolinska Institutet
Journal of Biological Chemistry | Year: 2012

ADP-ribosylation is involved in the regulation of DNA repair, transcription, and other processes. The 18 human ADP-ribose transferases with diphtheria toxin homology include ARTD1/ PARP1, a cancer drug target. Knowledge of other family members may guide therapeutics development and help evaluate potential drug side effects. Here, we present the crystal structure of human ARTD15/PARP16, a previously uncharacterized enzyme. ARTD15 features an α-helical domain that packs against its transferase domain without making direct contact with the NAD+-binding crevice or the donor loop. Thus, this novel domain does not resemble the regulatory domain of ARTD1. ARTD15 displays auto-mono(ADP-ribosylation) activity and is affected by canonical poly(ADP-ribose) polymerase inhibitors. These results add to a framework that will facilitate research on a medically important family of enzymes. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.


Wahren J.,Karolinska Institutet | Wahren J.,Cebix AB | Larsson C.,Cebix AB
Diabetes Research and Clinical Practice | Year: 2015

Much new information on C-peptide physiology has appeared during the past 20 years. It has been shown that C-peptide binds specifically to cell membranes, elicits intracellular signaling via G-protein and Ca2+-dependent pathways, resulting in activation and increased expression of endothelial nitric oxide synthase, Na+, K+-ATPase and several transcription factors of importance for anti-inflammatory, anti-oxidant and cell protective mechanisms. Studies in animal models of diabetes and early clinical trials in patients with type 1 diabetes demonstrate that C-peptide in replacement doses elicits beneficial effects on early stages of diabetes-induced functional and structural abnormalities of the peripheral nerves, the kidneys and the retina. Much remains to be learned about C-peptide's mechanism of action and long-term clinical trials in type 1 diabetes subjects will be required to determine C-peptide's clinical utility. Nevertheless, even a cautious evaluation of the available evidence presents the picture of a bioactive endogenous peptide with therapeutic potential. © 2015 Elsevier Ireland Ltd.


Jolivalt C.G.,University of California at San Diego | Rodriguez M.,University of California at San Diego | Wahren J.,Karolinska Institutet | Wahren J.,Cebix AB | Calcutt N.A.,University of California at San Diego
Diabetes, Obesity and Metabolism | Year: 2015

Aims: To investigate the efficacy of a pegylated C-peptide (Peg-C-peptide) against indices of peripheral neuropathy in a mouse model of type 1 diabetes and to compare efficacy of this C-peptide analogue against that of the native molecule. Methods: C57Bl/6 mice were injected with two consecutive doses of streptozotocin (STZ) to induce type 1 diabetes. Mice were treated twice daily with native C-peptide [0.4-1.3mg/kgsubcutaneously (s.c.)] or twice weekly with Peg-C-peptide (0.1-1.3mg/kgs.c.) for 20weeks. Motor and sensory nerve conduction velocities, thermal and tactile responses and rate dependent H-wave depression were assessed after 20weeks of diabetes. Foot skin intraepidermal fibres and corneal nerves were counted, and sciatic nerve substance P and plasma C-peptide levels were also determined. Results: After 5months of STZ-induced diabetes, mice exhibited significant motor and sensory nerve conduction slowing, thermal hypoalgesia, tactile allodynia and attenuation of rate-dependent depression of the H reflex. These functional disorders were accompanied by nerve substance P depletion but not loss of small sensory fibres in the hind paw epidermis or the cornea. The efficacy of twice-daily treatment with native C-peptide in preventing these disorders was matched or exceeded by twice-weekly treatment with Peg-C-peptide. Both native and Peg-C-peptide also increased corneal nerve occupancy in the sub-basal nerve plexus of control rats. Conclusions: These data identify actions of C-peptide against novel and clinically pertinent aspects of diabetic neuropathy in mice and also establish Peg-C-peptide as a long-acting therapeutic method of potential clinical value. © 2015 John Wiley & Sons Ltd.


PubMed | Karolinska Institutet and Cebix AB
Type: Journal Article | Journal: Diabetes research and clinical practice | Year: 2015

Much new information on C-peptide physiology has appeared during the past 20 years. It has been shown that C-peptide binds specifically to cell membranes, elicits intracellular signaling via G-protein and Ca2+ -dependent pathways, resulting in activation and increased expression of endothelial nitric oxide synthase, Na+, K+ -ATPase and several transcription factors of importance for anti-inflammatory, anti-oxidant and cell protective mechanisms. Studies in animal models of diabetes and early clinical trials in patients with type 1 diabetes demonstrate that C-peptide in replacement doses elicits beneficial effects on early stages of diabetes-induced functional and structural abnormalities of the peripheral nerves, the kidneys and the retina. Much remains to be learned about C-peptides mechanism of action and long-term clinical trials in type 1 diabetes subjects will be required to determine C-peptides clinical utility. Nevertheless, even a cautious evaluation of the available evidence presents the picture of a bioactive endogenous peptide with therapeutic potential.

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