Fractionated whole body gamma irradiation modulates the hepatic response in type II diabetes of high fat diet model rats.

HFD animals were exposed to a low rate of different fractionated whole body gamma irradiation doses (0.5, 1 and 2 Gy, three fractions per week for two consecutive months) and the expression of certain genes involved in type 2 diabetes mellitus (T2DM) in livers and brains of HFD Wistar rats was investigated. Additionally, levels of diabetes-related proteins encoded by the studied genes were analyzed. Results indicated that mRNA level of incretin glucagon like peptite-1 receptor (GLP-1R) was augmented in livers and brains exposed to 1 and 2 Gy doses. Moreover, the mitochondrial uncoupling proteins 2 and 3 (UCP2/3) expressions in animals fed on HFD compared to those fed on normal chow diet were significantly increased at all applied doses. GLP-1R and UCP3 protein levels were up regulated in livers. Total protein content increased at 0.5 and 1 Gy gamma irradiation exposure and returned to its normal level at 2 Gy dose. Results could be an indicator of type 2 diabetes delayed development during irradiation exposure and support the importance of GLP-1R as a target gene in radiotherapy against T2DM and its chronic complications. A new hypothesis of brain-liver and intestine interface is speculated by which an increase in the hepatic GLP-1R is influenced by the effect of fractionated whole body gamma irradiation.

Neuroprotection of retinal cells by Caffeic Acid Phenylethyl Ester（CAPE) is mediated by mitochondrial uncoupling protein UCP2.

Oxidative stress due to mitochondrial produced reactive oxygen species is a major cause of damage seen in many retinal degenerative diseases. Caffeic acid phenylethyl ester （CAPE） is protective agent in multiple tissues and is reported to have anti-oxidant properties. Systemically applied CAPE protected retinal ganglion cells from ischemic injury induced by increased intraocular pressure. CAPE provided complete protection for ARPE19 retinal pigment epithelial cells against tert-butyl hydrogen peroxide and reduced both basal and LPS-stimulated ROS production. The major effect of CAPE was mediated by the mitochondrial uncoupling protein UCP2 since both pharmacological inhibition of UCP2 and siRNA-induced knockdown removed the ability of CAPE to block ROS production. Based on common structural features, CAPE may be acting as a mimetic of the natural UCP2 homeostatic regulator 4-hydroxy-2-nonenal. CAPE may provide a valuable tool to treat oxidative stress-related damage in retinal and other degenerative diseases.

Anti-Hypertensive Action of Fenofibrate via UCP2 Upregulation Mediated by PPAR Activation in Baroreflex Afferent Pathway.

Fenofibrate, an agonist for peroxisome proliferator-activated receptor alpha (PPAR-α), lowers blood pressure, but whether this action is mediated via baroreflex afferents has not been elucidated. In this study, the distribution of PPAR-α and PPAR-γ was assessed in the nodose ganglion (NG) and the nucleus of the solitary tract (NTS). Hypertension induced by drinking high fructose (HFD) was reduced, along with complete restoration of impaired baroreceptor sensitivity, by chronic treatment with fenofibrate. The molecular data also showed that both PPAR-α and PPAR-γ were dramatically up-regulated in the NG and NTS of the HFD group. Expression of the downstream signaling molecule of PPAR-α, the mitochondrial uncoupling protein 2 (UCP2), was up-regulated in the baroreflex afferent pathway under similar experimental conditions, along with amelioration of reduced superoxide dismutase activity and increased superoxide in HFD rats. These results suggest that chronic treatment with fenofibrate plays a crucial role in the neural control of blood pressure by improving baroreflex afferent function due at least partially to PPAR-mediated up-regulation of UCP2 expression and reduction of oxidative stress.

Uncoupling Protein 2 Inhibition Exacerbates Glucose Fluctuation-Mediated Neuronal Effects.

Though glucose fluctuations have been considered as an adverse factor for the development of several diabetes-related complications, their impact in the central nervous system is still not fully elucidated. This study was conducted to evaluate the responses of neuronal cells to different glycemic exposures alongside to elucidate the role of uncoupling protein 2 (UCP2) in regulating such responses. To achieve our goals, primary cortical neurons were submitted to constant high (HG)/low (LG) or glucose level variations (GVs), and the pharmacological inhibition of UCP2 activity was performed using genipin. Results obtained show that GV decreased neuronal cells' viability, mitochondrial membrane potential, and manganese superoxide dismutase activity and increased reactive oxygen species (ROS) production. GV also caused an increase in the glutathione/glutathione disulfide ratio and in the protein expression levels of nuclear factor E2-related factor 2 (NRF2), UCP2, NADH-ubiquinone oxidoreductase chain 1 (ND1), and mitochondrially encoded cytochrome c oxidase I (MTCO1), both mitochondrial DNA encoded subunits of the electron transport chain. Contrariwise, genipin abrogated all those compensations and increased the levels of caspase 3-like activity, potentiated mitochondrial ROS levels, and the loss of neuronal synaptic integrity, decreased the protein expression levels of NRF1, and increased the protein expression levels of UCP5. Further, in the control and LG conditions, genipin increased mitochondrial ROS and the protein expression levels of UCP4, postsynaptic density protein 95 (PSD95), ND1, and MTCO1. Overall, these observations suggest that UCP2 is in the core of neuronal cell protection and/or adaptation against GV-mediated effects and that other isoforms of neuronal UCPs can be upregulated to compensate the inhibition of UCP2 activity.