Anti-Hypertensive Action of Fenofibrate via UCP2 Upregulation Mediated by PPAR Activation in Baroreflex Afferent Pathway / 神经科学通报·英文版

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.

Protective effect and its mechanism of curcumin on ischemia-reperfusion injury of cerebral cortex in rats / 解放军医学杂志

Objective To investigate the effect of curcumin pretreatment on the expression of uncoupling protein 2 (UCP2) and mitochondrial transcription factor A (MTFA) in rats' cerebral cortex against focal ischemia reperfusion injury. Methods Eighty male SD rats weighed 220g-300g were randomly divided into 4 groups: sham-operated group, ischemia/reperfusion (I/R) group, curcumine 50mg/kg+I/R (low dose) group, and curcumine 100mg/kg+I/R (high dose) group. The common carotid artery, external carotid artery and internal carotid artery on the right side were exposed in the sham-operated group. Animals of the other groups were subjected to a 2-hour period of right middle cerebral artery occlusion, followed by 24 hours of reperfusion, and then they were sacrificed. Curcumin was administered (ip) in a dose of 50mg/kg (low dose group) or 100mg/kg (high dose group) for 5 days, respectively, prior to arterial occlusion. The pathological changes in neurons and their mitochondria in the cerebral cortex supplied by middle cerebral artery were observed with Nissl staining and electron microscope, respectively. The expressions of UCP2 and MTFA in corresponding cotex were assessed by immunohistochemistry and RT-PCR. Results Compared with sham-operated group, animals in I/R group presented edema of neurons in the corresponding cortex, reduction in the number of Nissl bodies, and swelling of mitochondria with broken, even lysis of cristae. Low dose and high dose of curcumin pretreatment before brain ischemia significantly alleviated the loss of neurons and the damage of mitochondria, accompanied with an increase in the expression of UCP2 and TFAM (P<0.05), and the changes appeared a dose-dependent manner (P<0.05). Conclusions Curcumin may prevent neurons from focal cerebral ischemia reperfusion injury by up-regulating UCP2 and MTFA. Regulation of mitochondrial biogenesis may probably be a potential target of curcumin as a neuroprotective drug.

Uncoupling protein 4 and its roles in the central nervous system diseases / 国际脑血管病杂志

Uncoupling protein 4 (UCP4) is a member of the multigenic uncoupling proteins (UCPs), specific expressing in the cerebral cortex and hippocampus. UCP4 plays an important role in Parkinson's disease, multiple sclerosis, epilepsy, stroke, brain trauma and other central nervous system diseases by uncoupling, decreasing mitochondrial membrane potential,regulating Ca2+ homeostasis and oxidative stress. This article reviews UCP4 and its roles in the central nervous system diseases in order to provide certain basis for the development of UCP4targeted medication.

Uncoupling Protein 2 (UCP2) and p53 Expression in Invasive Ductal Carcinoma of Breast

BACKGROUND: Uncoupling protein 2 (UCP2) is a recently identified mitochondrial inner membrane anion carrier and a negative regulator of reactive oxygen species production. In this study, we evaluated the characteristics and relationships of UCP2 and p53 expression in breast cancer tissues. METHODS: Tissue microarray slides from 107 cases of invasive ductal carcinoma of the breast were constructed, UCP2 and p53 immunohistochemical staining was conducted, and clinicopathological correlations were investigated. RESULTS: UCP2 expression in invasive ductal carcinoma was high in 53 cases (49.5%), while p53 expression in invasive ductal carcinoma was high in 37 cases (34.6%). UCP2 expression was correlated significantly with histological grade (p = 0.038) and mitotic count (p = 0.050). UCP2 expression was correlated significantly with p53 expression in invasive ductal carcinoma of the breast (p = 0.045). UCP2 expression (p = 0.8308) and p53 expression (p = 0.3292) showed no significant difference for the overall survival rate in patients with invasive ductal carcinoma. CONCLUSIONS: UCP2 expression in invasive ductal carcinoma increased proportionally with histological grade and mitotic count. High UCP2 expression in invasive ductal carcinoma was observed in conjunction with high p53 expression.

Activation of PPARgamma induces profound multilocularization of adipocytes in adult mouse white adipose tissues

We sought to determine the effects of activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) on multilocularization of adipocytes in adult white adipose tissue (WAT). Male C57BL/6 normal, db/db, and ob/ob mice were treated with agonists of PPAR-gamma, PPAR-alpha, or beta3-adrenoceptor for 3 weeks. To distinguish multilocular adipocytes from unilocular adipocytes, whole-mounted adipose tissues were co-immunostained for perilipin and collagen IV. PPAR-gamma activation with rosiglitazone or pioglitazone induced a profound change of unilocular adipocytes into smaller, multilocular adipocytes in adult WAT in a time-dependent, dose-dependent, and reversible manner. PPAR-alpha activation with fenofibrate did not affect the number of locules or remodeling. db/db and ob/ob obese mice exhibited less multilocularization in response to PPAR-gamma activation compared to normal mice. Nevertheless, all adipocytes activated by PPAR-gamma contained a single nucleus regardless of locule number. Multilocular adipocytes induced by PPAR-gamma activation contained substantially increased mitochondrial content and enhanced expression of uncoupling protein-1, PPAR-gamma coactivator-1-alpha , and perilipin. Taken together, PPAR-gamma activation induces profound multilocularization and enhanced mitochondrial biogenesis in the adipocytes of adult WAT. These changes may affect the overall function of WAT.

Association of UCP1 Genetic Polymorphisms with Blood Pressure among Korean Female Subjects

Recent studies have provided some clues with regard to the relationship existing between uncoupling protein 1 (UCP1) and blood pressure in animal experiments. In an attempt to determine the genetic polymorphisms that are associated with blood pressure in humans, we have analyzed genetic polymorphisms in UCP1 gene. In this study, we assessed the association between UCP1 genotypes and systolic blood pressure (SBP) and diastolic blood pressure (DBP), in a population comprised of 832 Korean female subjects, using a general linear model, which was adjusted for age and body mass index (BMI). Among 4 genetic polymorphisms and the haplotypes constructed from them, haplotype3 of UCP1, UCP1-ht3[GAGA], evidenced significant associations with SBP (p=0.005) and DBP (p=0.013). However, this haplotype was not significantly associated with obesity phenotypes, including BMI or fat mass (p>0.05), thereby suggesting that its association with blood pressure was independent of obesity phenotypes.

Swim training improves leptin receptor deficiency-induced obesity and lipid disorder by activating uncoupling proteins

Leptin receptor deficiency causes morbid obesity and hyperlipidemia in mice. Since physical exercise enhances energy expenditure, it is an important part of successful weight-control regimens. We investigated the mechanism by which swim training regulates leptin receptor deficiency-induced obesity and lipid disorder in a mouse model of obesity (obese db/db mouse). Swim training for 6 weeks significantly decreased body weight gain and adipose tissue mass in both sexes of obese and lean mice, compared to their respective sedentary controls. These effects were particularly evident in obese mice. Swim training also caused significant decreases in serum levels of triglycerides, free fatty acids and total cholesterol in both obese and lean mice. In obese mice, swim training increased the levels of mRNAs and proteins encoding uncoupling protein 1 (UCP1), UCP2 and UCP3 in brown adipose tissue, white adipose tissue and skeletal muscle, respectively. In conclusion, these findings suggest that, in mice, swim training can effectively prevent body weight gain, adiposity and lipid disorders caused by leptin receptor deficiency, in part through activation of UCPs in adipose tissue and skeletal muscle, which may contribute to alleviating metabolic syndromes, such as obesity, hyperlipidemia and type 2 diabetes.