Endometrial stromal cells and decidualized stromal cells: Origins,transformation and functions

Decidualization of endometrium, which is characterized by endometrial stromal cell (ESC) decidualization, vascular reconstruction, immune cell recruitment, and plentiful molecule production, is a crucial step for uterus to become receptive for embryo. When implantation takes place, ESCs surround and directly interact with embryo. Decidualized stromal cells (DSCs) are of great importance in endometrial decidualization, having a broad function in regulating immune activity and vascular remodeling of uterus. DSCs are shown to have a higher metabolic level and looser cytoskeleton than ESCs. What's the origin of ESCs and how ESCs successfully transform into DSCs had puzzled scientists in the last decades. Breakthrough had been achieved recently, and many studies had elucidated some of the characters and functions of DSCs. However, several questions still remain unclear. This paper reviews current understanding of where ESCs come from and how ESCs differentiate into DSCs, summarizes some characters and functions of DSCs, analyzes current studies and their limitations and points out research areas that need further investigation.     

Cellular pathways for transport and efflux of ascorbate and dehydroascorbate

The mechanisms allowing the cellular transport of ascorbic acid represent a primary aspect for the understanding of the roles played by this vitamin in pathophysiology. Considerable research effort has been spent in the field, on several animal models and different cell types. Several mechanisms have been described to date, mediating the movements of different redox forms of ascorbic acid across cell membranes. Vitamin C can enter cells both in its reduced and oxidized form, ascorbic acid (AA) and dehydroascorbate (DHA), utilizing respectively sodium-dependent transporters (SVCT) or glucose transporters (GLUT). Modulation of SVCT expression and function has been described by cytokines, steroids and post-translational protein modification. Cellular uptake of DHA is followed by its intracellular reduction to AA by several enzymatic and non-enzymatic systems. Efflux of vitamin C has been also described in a number of cell types and different pathophysiological functions were proposed for this phenomenon, in dependence of the cell model studied. Cellular efflux of AA is mediated through volume-sensitive (VSOAC) and Ca²⁺-dependent anion channels, gap-junction hemichannels, exocytosis of secretory vesicles and possibly through homo- and hetero-exchange systems at the plasma membrane level. Altogether, available data suggest that cellular efflux of ascorbic acid - besides its uptake - should be taken into account when evaluating the cellular homeostasis and functions of this important vitamin.     

Nobiletin protects against insulin resistance and disorders of lipid metabolism by reprogramming of circadian clock in hepatocytes

Scope

Circadian clock plays a principal role in orchestrating our daily physiology and metabolism, and their perturbation can evoke metabolic diseases such as fatty liver and insulin resistance. Nobiletin (NOB) has been demonstrated to possess antitumor and neuroprotective activities. The objective of the current study is to determine potential effects of NOB on modulating the core clock gene Bmal1 regarding ameliorating glucolipid metabolic disorders.

外源性胰岛素对斑马鱼血糖及其转运的影响

斑马鱼（Danio rerio）在糖负荷状态下表现出持续高血糖现象。与对照组（仅腹腔注射灭菌去离子水）相比,葡萄糖组（仅腹腔注射葡萄糖）血浆胰岛素水平无显著差异,胰岛素基因表达显著上调,肝胰脏葡萄糖转运蛋白（glucose transporters,GLUTs）基因表达无显著差异,说明斑马鱼自身胰岛素分泌不足和葡萄糖转运迟缓是导致其在糖负荷状态下持续高血糖的原因。为了观察外源性胰岛素对斑马鱼血糖及其在体内转运的影响,设计低（1.25 IU/kg）、中（12.5 IU/kg）、高（125 IU/kg）3个浓度的胰岛素,分别与葡萄糖溶液（0.1 g/mL）共注射斑马鱼并观察其血糖变化。结果表明,低剂量胰岛素能有效促进斑马鱼血糖的降低,且能直观反映糖负荷后血糖的变化情况,为最适注射浓度。此外,研究显示斑马鱼血糖变化不受性别影响。在胰岛素最适注射浓度下,与葡萄糖组相比,胰岛素组（葡萄糖与胰岛素共注射）可以显著减少斑马鱼血糖恢复到正常水平的时间,进一步分析发现,斑马鱼血浆胰岛素水平增加,肝胰脏葡萄糖转运蛋白基因表达显著上调,但胰岛素基因表达却被显著抑制。综上所述,胰岛素分泌不足和葡萄糖转运迟缓是造成斑马鱼持续高血糖的原因;外源性胰岛素能够促进糖负荷状态下斑马鱼血糖的降低,但是具有反馈抑制斑马鱼肝胰脏胰岛素基因表达的作用。     

SIRT6 Deficiency Results in Severe Hypoglycemia by Enhancing Both Basal and Insulin-stimulated Glucose Uptake in Mice

Glucose homeostasis in mammals is mainly regulated by insulin signaling. It was previously shown that SIRT6 mutant mice die before 4 weeks of age, displaying profound abnormalities, including low insulin, hypoglycemia, and premature aging. To investigate mechanisms underlying the pleiotropic phenotypes associated with SIRT6 deficiency, we generated mice carrying targeted disruption of SIRT6. We found that 60% of SIRT6^−/− animals had very low levels of blood glucose and died shortly after weaning. The remaining animals, which have relatively higher concentrations of glucose, survived the early post-weaning lethality, but most died within one year of age. Significantly, feeding the mice with glucose-containing water increased blood glucose and rescued 83% of mutant mice, suggesting that the hypoglycemia is a major cause for the lethality. We showed that SIRT6 deficiency results in more abundant membrane association of glucose transporters 1 and 4, which enhances glucose uptake. We further demonstrated that SIRT6 negatively regulates AKT phosphorylation at Ser-473 and Thr-308 through inhibition of multiple upstream molecules, including insulin receptor, IRS1, and IRS2. The absence of SIRT6, consequently, enhances insulin signaling and activation of AKT, leading to hypoglycemia. These data uncover an essential role of SIRT6 in modulating glucose metabolism through mediating insulin sensitivity.     

Continuous stress-induced dopamine dysregulation augments PAP-I and PAP-II expression in melanotrophs of the pituitary gland

We studied the acquisition of dehydroascorbic acid by rat hepatocytes, H4IIE rat hepatoma cells and Xenopus laevis oocytes. Transport kinetics and competition and inhibition studies revealed that rat hepatocytes transport oxidized dehydroascorbic acid through a single functional component possessing the functional and kinetic properties expected for the glucose transporter GLUT2. On the other hand, rat hepatoma cells showed expression of at least two dehydroascorbic acid transporters with the expected functional and kinetic properties expected for GLUT1 and GLUT2. Expression studies of GLUT2 in X. laevis oocytes followed by transport kinetics and competition and inhibition studies revealed that GLUT2 is a low affinity dehydroascorbic transporter whose kinetic and functional properties match those observed for the endogenous GLUT2 transporter in rat hepatocytes and rat hepatoma cells. Therefore, GLUT2, a transporter known as a low affinity transporter of glucose and fructose and a high affinity transporter of glucosamine is also a low affinity dehydroascorbic acid transporter.     

The effect of age on glucose uptake and GLUT1 and GLUT4 expression in rat skeletal muscle

During the life span, phenotypic and structural modifications on skeletal muscle contribute to a reduction on glucose uptake either in basal state or triggered by insulin, but the underlying mechanisms for this decline are not entirely identified. A reduction in the expression of skeletal muscle glucose transporters (GLUTs), glucose transporter type 1 (GLUT1) and glucose transporter type 4 (GLUT4), has been associated to such phenomena, but unlike the case of insulin, only few studies have addressed the effect of age on muscle-contraction-induced glucose uptake. The aim of the study was to investigate the influence of age on GLUT1 and GLUT4 expression in skeletal muscle and its relation to the glucose uptake induced by muscle contraction. For this purpose, soleus muscle from Wistar rats aged 4, 10, 22 and 42 weeks were isolated and electrically stimulated (30 min, 10 Hz, 20 V, 0.2 ms). After stimulation, glucose uptake and GLUT1 and GLUT4 expression and localisation were evaluated. Muscle contraction caused an increase in glucose uptake in all studied groups. In addition, the absolute rates of glucose uptake were negatively correlated with age. The expression of GLUT4 was lower in older animals, whereas no relation between age and GLUT1 expression was found. Immunohistochemistry confirmed the ontogenic effect on GLUT4 expression and suggested an age-related modification on GLUT1 distribution within the muscle fibres; for instance, this protein seems to be present mainly out of the sarcoplasm. The present findings demonstrate that the ability of muscle contraction to increase glucose uptake is not influenced by age, whereas glucose uptake under basal conditions decreases with age.     

Expression of glucose transporters in cancers

It has been known for 80 years that cancer cell growth in an energy-related process supported by an increased glucose metabolism. This phenomenon suggests a need for a corresponding increased uptake of glucose across the plasma membrane through an enhancement in the glucose transporter proteins, SGLT proteins as well as GLUT proteins. The results of many studies have demonstrated that the expression of glucose transporters, especially GLUT1, is increased in a variety of malignancies. GLUT1 overexpression has been found to be associated with tumor progression. It was found that GLUT1 overexpression is associated with poor overall survival in various malignant tumors.     

Decreased glucose transporters correlate to abnormal hyperphosphorylation of tau in Alzheimer disease

Brain glucose uptake/metabolism is impaired in Alzheimer disease (AD). Here, we report that levels of the two major brain glucose transporters (GLUT1 and GLUT3) responsible for glucose uptake into neurons were decreased in AD brain. This decrease correlated to the decrease in O-GlcNAcylation, to the hyperphosphorylation of tau, and to the density of neurofibrillary tangles in human brains. We also found down-regulation of hypoxia-inducible factor 1, a major regulator of GLUT1 and GLUT3, in AD brain. These studies provide a possible mechanism by which GLUT1 and GLUT3 deficiency could cause impaired brain glucose uptake/metabolism and contribute to neurodegeneration via down-regulation of O-GlcNAcylation and hyperphosphorylation of tau in AD.