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Objective. To investigate the changes of UCP1 protein in brown fat by establishing a model of gestational diabetes mellitus through intervention of high fat and carbohydrate diet. To explore the changes of UCP1 protein in brown fat in gestational diabetic mice, and analyze the characteristics of abnormal glucose metabolism in gestational diabetic mice and its relationship with changes in adipocyte morphology and insulin resistance. Methods. Eighty C57BL/6J pregnant mice were randomly divided into a normal control group and a high-fat and high-sugar feeding group. The normal control group was fed a normal diet, while the high-fat and high-sugar group was fed a high-fat and high-sugar diet to establish a gestational diabetes mellitus (GDM) model. On the pregnancy days 0, 10, and 18, the weight and fasting glucose were measured. On the pregnancy day 18, the triglycerides (TG), the total cholesterol (TC), free fatty acid (FFA), insulin levels, and insulin resistance index (HOMA-IR) were measured or calculated. At the same time, brown fat UCP1 protein of the two groups of pregnant mice were measured using Western blot Observed the Adipose tissue pathological changes by staining HE. The adipocyte was observed, and the correlation was analyzed. Results. Twenty-one pregnant mice reach the level of gestational diabetes diagnosis (FBG ≥ 5.1 mmol/L) in the high-fat and high-sugar diet group. On the pregnancy day 10 and 18, the fasting plasma glucose and the body weight significantly increased (P < 0.05). The total cholesterol, triglycerides, free fatty acid, insulin level, and insulin resistance index of the GDM group were also higher compared with that of the control group (P < 0.05). The adipocyte size significantly increased in the GDM mice. TG, TC, FFA, and body weight at 18 days of gestation were significantly correlated with HOMA-IR and single-adipocyte area in the GDM mice. HOMA-IR was significantly correlated with a single-adipocyte area. Compared with the normal control group, the UCP1 proteins of GDM mice decreased significantly and negatively correlated with body weight increase. Conclusion. Feeding C57BL/6J pregnant mice with high fat and high sugar to establish a gestational diabetes mouse model has good stability and is similar to human gestational diabetes. The reduction of brown fat UCP1 protein in GDM mice has a certain correlation with obesity tendency and obvious insulin resistance. [ABSTRACT FROM AUTHOR]

Bone cancer pain has been reported to have unique mechanisms and is resistant to morphine treatment. Recent studies have indicated that neuron-restrictive silencer factor (NRSF) plays a crucial role in modulating the expression of the μ-opioid receptor (MOR) gene. The present study elucidates the regulatory mechanisms of MOR and its ability to affect bone cancer pain. Using a sarcoma-inoculated murine model, pain behaviors that represent continuous or breakthrough pain were evaluated. Expression of NRSF in the dorsal root ganglion (DRG) and spinal dorsal horn was quantified at the transcriptional and translational levels, respectively. Additionally, chromatin immunoprecipitation assays were used to detect NRSF binding to the promoter of MOR. Furthermore, NRSF was genetically knocked out by antisense oligodeoxynucleotide, and the expression of MOR and the effect of morphine were subsequently analyzed. Our results indicated that in a sarcoma murine model, NRSF expression is upregulated in dorsal root ganglion neurons, and the expression of NRSF mRNA is significantly negatively correlated with MOR mRNA expression. Additionally, chromatin immunoprecipitation analysis revealed that NRSF binding to the neuron-restrictive silencer element within the promoter area of the MOR gene is promoted with a hypoacetylation state of histone H3 and H4. Furthermore, genetically knocking down NRSF with antisense oligodeoxynucleotide rescued the expression of MOR and potentiated the systemic morphine analgesia. The present results suggest that in sarcoma-induced bone cancer pain, NRSF-induced downregulation of MOR is involved in the reduction of morphine analgesia. Epigenetically, up-regulation of MOR could substantially improve the effect of system delivery of morphine. [ABSTRACT FROM AUTHOR]

Substantial evidence implicates 𝛽-amyloid (A𝛽) peptides in the etiology of Alzheimer’s disease (AD). A𝛽 is produced by the proteolytic cleavage of the amyloid precursor protein by 𝛽- and 𝛾-secretase suggesting that 𝛾-secretase inhibition may provide therapeutic benefit for AD. Although many 𝛾-secretase inhibitors have been shown to be potent at lowering A𝛽, some have also been shown to have side effects following repeated administration. All of these side effects can be attributed to altered Notch signaling, another 𝛾-secretase substrate. Here we describe the in vivo characterization of the novel 𝛾-secretase inhibitor SCH 697466 in rodents. Although SCH 697466 was effective at lowering A𝛽, Notch-related side effects in the intestine and thymus were observed following subchronic administration at doses that provided sustained and complete lowering of A𝛽. However, additional studies revealed that both partial but sustained lowering of A𝛽 and complete but less sustained lowering of A𝛽 were successful approaches for managing Notch-related side effects. Further, changes in several Notch-related biomarkers paralleled the side effect observations. Taken together, these studies demonstrated that, by carefully varying the extent and duration of A𝛽 lowering by 𝛾-secretase inhibitors, it is possible to obtain robust and sustained lowering of A𝛽 without evidence of Notch-related side effects. [ABSTRACT FROM AUTHOR]