Anti-TH monoclonal antibody

Although long-studied in the central nervous system, there is increasing evidence that dopamine (DA) has important roles in the periphery including in metabolic regulation. Insulin-secreting pancreatic beta-cells express the machinery for DA synthesis and catabolism, as well as all five DA receptors. In these cells, DA functions as a negative regulator of glucose-stimulated insulin secretion (GSIS), which is mediated by DA D-2-like receptors including D-2(D2R) and D-3(D3R) receptors. However, the fundamental mechanisms of DA synthesis, storage, release, and signaling in pancreatic beta-cells and their functional relevance in vivo remain poorly understood. Here, we assessed the roles of the DA precursorl-DOPA in beta-cell DA synthesis and release in conjunction with the signaling mechanisms underlying DA's inhibition of GSIS. Our results show that the uptake ofl-DOPA is essential for establishing intracellular DA stores in beta-cells. Glucose stimulation significantly enhancesl-DOPA uptake, leading to increased DA release and GSIS reduction in an autocrine/paracrine manner. Furthermore, D2R and D3R act in combination to mediate dopaminergic inhibition of GSIS. Transgenic knockout mice in which beta-cell D2R or D3R expression is eliminated exhibit diminished DA secretion during glucose stimulation, suggesting a new mechanism where D-2-like receptors modify DA release to modulate GSIS. Lastly, beta-cell-selective D2R knockout mice exhibit marked postprandial hyperinsulinemia in vivo. These results reveal that peripheral D2R and D3R receptors play important roles in metabolism through their inhibitory effects on GSIS. This opens the possibility that blockade of peripheral D-2-like receptors by drugs including antipsychotic medications may significantly contribute to the metabolic disturbances observed clinically.

Parkinson's disease (PD) is a long-term degenerative disease of the central nervous system (CNS) that primarily affects the motor system. So far there is no effective treatment for PD, only some drugs, surgery, and comprehensive treatment can alleviate the symptoms of PD. Stem cells derived from human exfoliated deciduous teeth (SHED), mesenchymal stem cells derived from dental pulp, may have promising potential in regenerative medicine. In this study, we examine the therapeutic effect of SHED-derived conditioned medium (SHED-CM) in a rotenone-induced PD rat model. Intravenous administration of SHED-CM generated by standardized procedures significantly improved the PD symptoms accompanied with increased tyrosine hydroxylase amounts in the striatum, and decreased alpha-synuclein levels in both the nigra and striatum, from rotenone-treated rats. In addition, this SHED-CM treatment decreased both Iba-1 and CD4 levels in these brain areas. Gene ontology analysis indicated that the biological process of genes affected by SHED-CM was primarily implicated in neurodevelopment and nerve regeneration. The major constituents of SHED-CM included insulin-like growth factor binding protein-6 (IGFBP-6), tissue inhibitor of metalloproteinase (TIMP)-2, TIMP-1, and transforming growth factor beta 1 (TGF-beta 1). RNA-sequencing (RNA-seq) and Ingenuity Pathway Analysis (IPA) revealed that these factors may ameliorate PD symptoms through modulating the cholinergic synapses, calcium signaling pathways, serotoninergic synapses, and axon guidance. In conclusion, our data indicate that SHED-CM contains active constituents that may have promising efficacy to alleviate PD.