ABSTRACT
GLP-1 agonists have become increasingly interesting as a new Parkinson's disease (PD) clinical treatment strategy. Additional preclinical studies are important to validate this approach and define the disease stage when they are most effective. We hence characterized the efficacy of PT320, a sustained release formulation of the long acting GLP-1 agonist, exenatide, in a progressive PD (MitoPark) mouse model. A clinically translatable biweekly PT320 dose was administered starting at 5 weeks of age and longitudinally evaluated to 24 weeks, and multiple behavioral/cellular parameters were measured. PT320 significantly improved spontaneous locomotor activity and rearing in MitoPark PD mice. "Motivated" behavior also improved, evaluated by accelerating rotarod performance. Behavioral improvement was correlated with enhanced cellular and molecular indices of dopamine (DA) midbrain function. Fast scan cyclic voltammetry demonstrated protection of striatal and nucleus accumbens DA release and reuptake in PT320 treated MitoPark mice. Positron emission tomography showed protection of striatal DA fibers and tyrosine hydroxylase protein expression was augmented by PT320 administration. Early PT320 treatment may hence provide an important neuroprotective therapeutic strategy in PD.
ABSTRACT
OX40/OX40L pathway plays a very important role in the antigen priming T cells and effector T cells. In the present study, we aimed to examine the involvement of OX40/OX40L pathway in the activation of autoreactive T cells in patients with Grave's disease (GD). We found that OX40 and OX40L were constitutively coexpressed on peripheral CD4(+) T cells from GD patients using flow cytometry analysis. The levels of OX40 and OX40L coexpression on CD4(+) T cells were shown to be correlated with TRAbs. Cell proliferation assay showed that blocking OX40/OX40L signal inhibited T cell proliferation and survival, which suggested that OX40/OX40L could enhance CD4(+) T cell proliferation and maintain their long-term survival in GD by self-enhancing loop of T cell activation independent of APCs. Confocal microscopy and coimmunoprecipitation analysis further revealed that OX40 and OX40L formed a functional complex, which may facilitate signal transduction from OX40L to OX40 and contribute to the pathogenesis of GD.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , Graves Disease/immunology , Graves Disease/metabolism , OX40 Ligand/metabolism , Receptors, OX40/metabolism , Adult , Autoantibodies/immunology , Cell Proliferation , Cell Survival/immunology , Female , Humans , Jurkat Cells , Lymphocyte Activation/immunology , Male , Receptors, Thyrotropin/immunology , Up-RegulationABSTRACT
Drinking deep seawater (DSW) with high levels of magnesium (Mg) decreased serum lipids in animal studies. Therefore the effects of drinking DSW on blood lipids and its antioxidant capacity in hypercholesterolemic subjects were investigated. DSW was first prepared by a process of filtration and reverse osmosis, and then the concentrated DSW with high levels of Mg was diluted as drinking DSW. Forty-two hypercholesterolemic volunteers were randomly divided into three groups: reverse osmotic (RO) water, DSW (Mg: 395 mg/L, hardness 1410 ppm), and magnesium-chloride fortified (MCF) water (Mg: 386 mg/L, hardness 1430 ppm). The subjects drank 1050 mL of water daily for 6 weeks, and blood samples were collected and analyzed on weeks 0, 3, and 6. Drinking DSW caused a decrease in blood total cholesterol levels and this effect was progressively enhanced with time. Serum low-density lipoprotein-cholesterol (LDL-C) was also decreased by DSW. Further, total cholesterol levels of subjects in the DSW group were significantly lower than those in the MCF water or RO water groups. Compared with week 0, the DSW group had higher blood Mg level on weeks 3 and 6, but the Mg levels were within the normal range in all three groups. DSW consumption also lowered thiobarbituric acid-reactive substances (TBARS) values in serum. In conclusion, DSW was apparently effective in reducing blood total cholesterol and LDL-C, and also in decreasing lipid peroxidation in hypercholesterolemic subjects.
