Glucocorticoid Receptor Changes Associate with Age in the Paraventricular Nucleus of Type II Diabetic Rat Model

Diabetes is a metabolic disorder that is associated with the dysregulation of a number of systems within the body. In the present study, we investigated glucocorticoid receptor (GR) immunoreactivity and its protein levels in the paraventricular nuclei of 4-, 12-, 20- and 30-week-old Zucker diabetic fatty (fa/fa, ZDF) and in Zucker lean control (fa/+ or +/+, ZLC) rats, because the progressive induction of diabetes is detectable in this model after 7 weeks of age and chronic diabetic conditions are maintained after 12 weeks of age. GR immunoreactivity was detected in parvocellular paraventricular nuclei and this and GR protein levels were exponentially increased according to the ages. In particular, GR immunoreactivities and protein levels were markedly more increased in 30-week-old ZDF rats than in age-matched ZLC group and in younger ZDF group. The present study suggests that GR immunoreactivity and its protein level is associated with a degenerative phenotype in the hypothalamus of from 12-weeks old in the ZDF rat type II diabetes model.     

Glucocorticoid receptors on and in a unicellular organism,Cryptobia salmositica

This is the first report to our knowledge that demonstrates a functional steroid hormone receptor in a protozoon. The study used Cryptobia salmositica, a pathogenic haemoflagellate found in salmonid fishes. It has been previously shown that cortisol and dexamethasone (a synthetic glucocorticoid) enhanced the multiplication of C. salmositica under in vitro conditions indicating the presence of glucocorticoid receptors on/in the parasite. Also, the glucocorticoid receptor antagonist, mifepristone (RU486), inhibited the stimulatory effect of the two glucocorticoids on parasite multiplication. In the present study, we used an antibody (produced in a rabbit against glucocorticoid receptor protein) agglutination test and confocal microscopy with immunohistofluorescence staining to demonstrate cortisol-glucocorticoid receptor-like protein receptors on the plasma membrane and in the cytoplasm of the parasite. In two in vitro studies, the addition of 50 ng ml⁻¹ of RU486 was more effective in inhibiting parasite replication in cultures with 7,000 parasites ml⁻¹ than in cultures with 14,000 parasites ml⁻¹. Also, 100 ng ml⁻¹ of RU486/ml was more effective than 50 ng ml⁻¹ in inhibiting parasite multiplication in the 14,000 parasites ml^-1 cultures. These in vitro studies indicate that the number of binding sites on/in the parasite is finite. The findings may be important in future studies especially on steroid receptor signalling pathways and dissection of ligand–receptor interactions, and for evaluating the adaptations that develop in pathogens as part of the host–parasite interaction.     

Increased expression and activity of 11beta-HSD-1 in diabetic islets and prevention with troglitazone

To determine if increased local production of glucocorticoids by the pancreatic islets might play a role in the spontaneous noninsulin-dependent diabetes mellitus of obesity, we compared islet 11beta-HSD-1 mRNA and activity in islets of obese prediabetic and diabetic Zucker Diabetic Fatty (ZDF) (fa/fa) rats and lean wild-type (+/+) controls. In diabetic rat islets, both mRNA and enzymatic activity of the enzyme were increased in proportion to the hyperglycemia. Troglitazone (TGZ) treatment, beginning at 6 weeks of age, prevented the hyperglycemia, the hyperlipidemia, and the increase in 11beta-HSD-1. To determine if the metabolic abnormalities had caused the 11beta-HSD-1 increase, prediabetic islets were cultured in high or low glucose or in 2:1 oleate:palmitate for 3 days. Neither nutrient enhanced the expression of 11beta-HSD-1. We conclude that 11beta-HSD-1 expression and activity are increased in islets of diabetic, but not prediabetic ZDF rats, and that TGZ prevents both the increase in 11beta-HSD-1 and the diabetes.     

Cortisol increases the activities of intestinal apical membrane hydrolases and nutrient transporters before weaning in mink (Mustela vison)

Glucocorticoids from endogenous and exogenous sources accelerate maturation of brush-border membrane (BBM) hydrolases in omnivorous laboratory rodents and pigs. Less is known for carnivores, and whether the route of administration (oral or systemic) has an influence. The present study examined the influence of administering cortisol (hydrocortisone succinate, 5 mg/kg-day) to mink during postnatal week 4, just prior to weaning, on small intestine glucose and amino acid (aspartate, leucine, lysine, methionine, proline) absorption and on the activities of BBM disaccharidases and peptidases. Kits treated with cortisol were smaller (P<0.05), but had small intestines that were proportionally larger (P<0.05 for length and mass per kg body weight, but not for mucosal mass) than control kits with higher rates of absorption for most nutrients, except leucine, and increased activities of most BBM hydrolases, except lactase. As a consequence, cortisol increased hydrolytic and absorptive capacities of the entire small intestine, with the responses more pronounced when the cortisol was given orally. These findings indicate administration of cortisol stimulates growth of the developing mink small intestine, but does not accelerate the postnatal declines in nutrient transport, and may be a dam-to-kit signal that prepares suckling mink to digest and absorb the adult diet.     

Morphine withdrawal modifies antinociceptive effects of acute morphine in rats

Repeated opioid use is known to cause tolerance of antinociceptive effects. Whether opioid abstinence modifies antinociceptive effects is unknown. Here we reported that morphine withdrawal for 18 h and 4 days after repeated morphine treatment largely reduced tail-flick latencies compared with control, while the rats showed severe withdrawal syndromes. However, the latencies and withdrawal syndromes were restored to control level at 20 days withdrawal. Similarly, antinociceptive effects of acute morphine were decreased at 18 h and further decreased at 4 days but restored to control level at 20 days withdrawal. Behavioral stress that was given to the rats at 18 h withdrawal further reduced tail-flick latencies and antinociceptive effects. Conversely, the glucocorticoid receptor antagonist RU38486 increased tail-flick latencies and antinociceptive effects at 4 days withdrawal. These results suggest that morphine withdrawal could evoke behavioral stress to modify antinociceptive effects, implicating a significant influence of opioid abstinence on chronic pain treatment.     

前列腺素E1 联合糖皮质激素治疗药物性重症肝炎的临床效果*

目的:探讨前列腺素E1联合糖皮质激素治疗药物性重症肝炎的临床效果。方法:前瞻性研究我院药物性重症肝炎患者68例,随机分为实验组与对照组,每组34例。对照组患者给予糖皮质激素治疗,实验组患者给予糖皮质激素联合前列腺素E1治疗。观察并比较治疗前后两组患者血清谷丙转氨酶(ALT)、谷草转氨酶(AST)、总胆红素(TBIL)水平的变化情况,以及临床疗效和并发症的发生率。结果:与治疗前相比,两组患者治疗后血清ALT,AST,TBIL水平均降低,差异具有统计学意义(P0.05);与对照组相比,实验组患者治疗后血清ALT,AST及TBIL水平较低,差异具有统计学意义(P0.05);实验组患者并发症发生率(41.18%)明显低于对照组(52.94%),差异具有统计学意义(P0.05)。实验组患者临床总有效率(91.18%)显著高于对照组(73.53%),差异具有统计学意义(P0.05)。结论:前列腺素E1联合糖皮质激素能够提高药物性重症肝炎的临床总有效率,降低并发症发病率,值得在临床上推广应用。     

Novel mechanism of miRNA‐365‐regulated trophoblast apoptosis in recurrent miscarriage

Clinical pregnancies increasingly end in recurrent miscarriage (RM) during the first trimester, with genetic factors shouldering the main responsibility. MicroRNAs (miRNAs) regulate gene expression in a wide array of important biological processes. We examined the potential role of dysregulated miRNAs in RM pathogenesis and trophoblast development as an approach to elucidate the molecular mechanism behind RM. miRNA profiles from clinical specimens of RM and induced abortion (IA) were compared, and several miRNAs were found to be aberrantly expressed in RM samples. Among the miRNAs, miR‐365 was significantly differentially expressed in RM decidual tissues. Furthermore, our results demonstrate that miR‐365 functions as an upstream regulator of MDM2/p53 expression, cell cycle progression and apoptosis in trophoblasts. Bioinformatic prediction and experimental validation assays identified SGK1 as a direct target of miR‐365; consistently, its protein levels were low in decidual tissues. Additionally, functional studies revealed that SGK1 silencing elicits cell cycle arrest and apoptosis in trophoblasts and that SGK1 overexpression attenuates the effects of miR‐365 on apoptosis and MDM2/p53 expression. Collectively, our data provide evidence that the up‐regulation of miR‐365 may contribute to RM by decreasing SGK1 expression, which suggests its potential utility as a prognostic biomarker and therapeutic target for RM.