Influence of Stem Cell Therapy on Thyroid Function and Reactive Oxygen Species Production in Diabetic Rats.

Cell therapy with mesenchymal stem cells (MSC) has been proposed for the treatment of diabetes mellitus (DM). It is known that the prevalence of thyroid disease is higher among diabetic patients than in general population. Therefore, our aim was to investigate the effect of the treatment with MSC on thyroid function and ROS generation in an experimental model of type 1 DM. Adult male Wistar rats were divided into the following groups: control, DM (80 mg/kg BW streptozotocin, iv.) and DM+MSC. MSC treatment occurred 4 weeks after DM induction and the animals were euthanized 4 weeks after MSC administration. We also evaluated the effect of co-culture with MSC or extracellular vesicles (EV) obtained from these cells on the rat thyroid cell line PCCL3 exposed to high glucose. Thyroid H2O2 generation was increased in DM, which was reversed by MSC treatment. These changes paralled a significant DuOx1 mRNA increase. The incubation of PCCL3 with high glucose increased extracellular H2O2 generation, which was reversed by both the co-culture with MSC and EV. Even though MSC treatment normalized thyroid ROS generation, serum thyroid hormone (TH) concentration remained low, along with increased serum TSH concentrations. Thyroperoxidase (TPO) activity, was reduced in DM, and MSC treatment did not normalize TPO. Therefore, we conclude that the treatment with MSC was able to reverse the increased thyroid H2O2 generation in diabetic animals and in PCCL3 cells exposed to high glucose, an effect probably mediated by EV produced by these cells, acting in a paracrine fashion.

Rutin Scavenges Reactive Oxygen Species, Inactivates 5'-Adenosine Monophosphate-Activated Protein Kinase, and Increases Sodium-Iodide Symporter Expression in Thyroid PCCL3 Cells.

BACKGROUND: Thyroid iodide uptake, mediated by the sodium-iodide symporter (NIS), is essential for thyroid hormone synthesis and also for treatment of thyroid diseases, such as thyroid cancer, through radioiodine therapy. Therefore, compounds able to increase thyroid iodide uptake could be clinically useful, and it is of great importance to unravel the mechanisms underlying such an effect. It has been shown previously that the flavonoid rutin increases thyroid radioiodide uptake in vivo in rats. This study aimed to investigate the mechanisms involved in the stimulatory effect of rutin on iodide uptake. METHODS: This study evaluated iodide uptake, NIS expression and its subcellular distribution, iodide efflux, reactive oxygen species levels, and the intracellular pathways involved in NIS regulation in a rat thyroid PCCL3 cell line treated with rutin. RESULTS: Similar to previous results found in vivo, rutin increased radioiodide uptake in PCCL3 cells, which was accompanied by increased NIS expression (at both the mRNA and protein levels) and a reduction of radioiodide efflux. Moreover, the results suggest that rutin could regulate NIS subcellular distribution, leading to higher levels of NIS at the cell membrane. In addition, rutin decreased the levels of intracellular reactive oxygen species and phospho-5'-adenosine monophosphate-activated protein kinase. CONCLUSIONS: The flavonoid rutin seems to be an important stimulator of radioiodide uptake, acting at multiple levels, an effect that can be due to decreased oxidative stress, reduced 5'-adenosine monophosphate-activated protein kinase activation, or both. Since thyroid iodide uptake is crucial for effective radioiodine therapy, the results suggest that rutin could be useful as an adjuvant in radioiodine therapy.