Posted by 石金河, 户瑞丽, 杨亚勤, et al.
on 2014-02-28 00:39:59
Posted by A Ceriello, A Novials, E Ortega, et al.
on 2014-02-28 00:28:10
Background and aims
Hypoglycemia produces thrombosis activation, but little attention has been paid to the effects of hyperglycemia following recovery from hypoglycemia on thrombosis activation.
Methods and results
In both twenty-two healthy subjects and twenty-one matched persons with type 1 diabetes, recovery from a 2-h induced hypoglycemia was obtained by reaching normo-glycemia or hyperglycemia for another 2 h. After this, normal glycemia was maintained for the following 6 h. Hyperglycemia after hypoglycemia was also repeated with the concomitant infusion of vitamin C. In both controls and people with diabetes, the recovery with normo-glycemia was accompanied by a significant improvement of Von Willebrand factor (vWF), prothrombin fragment 1 + 2 (F1 + 2), thrombin–antithrombin III-complexes (TAT), P-selectin, plasminogen activator inhibitor-1 (PAI-1), nitrotyrosine and 8-iso-prostaglandin F2α (8-iso-PGF2α) (p < 0.01 vs hypoglycemia for all the parameters), all directly affected by hypoglycemia itself (p < 0.01 vs baseline for all the parameters). On the contrary, the recovery with hyperglycemia after hypoglycemia worsens all these parameters (p < 0.01 vs normoglycemia for all the parameters), an effect persisting even after the additional 6 h of normo-glycemia. The effect of hyperglycemia following hypoglycemia was partially counterbalanced when vitamin C was infused (p < 0.01 vs hyperglycemia alone for all the parameters), suggesting that hyperglycemia following hypoglycemia may activate thrombosis through the oxidative stress production.
This study shows that, in type 1 diabetes as well as in controls, the way in which recovery from hypoglycemia takes place could play an important role in favoring the activation of thrombosis and oxidative stress, widely recognized cardiovascular risk factors.
Posted by A Gendy, H El-Abhar, AR Mohsen.
on 2014-02-28 00:21:15
Abstract- Cilostazol is an antiplatelet that acts by inhibiting phosphodiesterase-3 and that was proven to be effective in models of ischemia/reperfusion (I/R) injury; however, its possible role in hepatic I/R remains indistinct, which is the aim of the current work. To fulfill this goal, rats were randomized into sham, I/R and cilostazol (60mg/kg, p.o) groups. The hepatic artery and portal vein to the left and median liver lobes were occluded for 30 min and then declamped for reperfusion to establish a model of segmental (70%) warm hepatic ischemia. Pretreatment of animals with cilostazol for two weeks prior to I/R insult significantly decreased serum alanine aminotransferase, and inhibited I/R-induced hepatocytes apoptotic death signified by inhibition of caspase-3. Moreover, cilostazol increased ATP content and lowered the level of lipid peroxidation assessed as malondialdehyde. The drug also elevated the nitric oxide content and decreased that of tumor necrosis factor-α, as well as the myeloperoxidase activity, a marker of neutrophil infiltration. Mechanistic studies revealed that cilostazol protected the liver and enhanced its proliferation ability, where it markedly increased the level of β-catenin and cyclin D1, but blocked the phosphorylation of GSK-3β at Ser9. In conclusion, cilostazol pre-administration protected hepatocytes against I/R insult by virtue of its antioxidant, anti-inflammatory, and antiapoptotic effects; besides, the drug increased hepatocytes proliferation by increasing the level of cyclin D1. It increased also the Wnt/ β-catenin pathway, which aid in its hepatoprotective action along with blocking the GSK-3β phosphorylation at the ser9, which had injurious role in this work.
Posted by P Jurka, L Szulc-D, J Borkowska, et al.
on 2014-02-28 00:09:57
Aglepristone (RU534) is an antiprogestin used for pregnancy termination, parturition induction and conservative pyometra treatment in bitches. Its molecular structure is similar to mifepristone, an antiprogestin used in human medicine. Mifepristone has been shown to suppress proliferation and cytokine production by T cells, whereas the effect of aglepristone on T cell function remains elusive. The purpose of this project was to investigate the in vitro influence of RU534 on IFN-γ and IL-4 synthesis by peripheral blood T cells isolated from healthy bitches (N = 16) in luteal phase. The peripheral blood mononuclear cells (PBMCs) were incubated with three different dosages of aglepristone, or dimethyl sulfoxide (DMSO), with or without mitogen. The production of cytokines by resting or mitogen-activated T cells was determined by intercellular staining and flow cytometry analysis or ELISA assay, respectively.
Our results showed no statistically significant differences in the percentage of IFN-γ and IL-4-synthesizing CD4+ or CD8+ resting T cells between untreated and aglepristone-treated cells at 24 and 48 hours post treatment. Moreover, mitogen-activated PBMCs treated with RU534 displayed similar concentration of IFN-γ and IL-4 in culture supernatants to those observed in mitogen-activated DMSO-treated PBMCs. Presented results indicate that administration of aglepristone for 48 hours has no influence on IFN-γ and IL-4 synthesis by resting and mitogen-activated T cells isolated from diestral bitches.
We conclude that antiprogestins may differentially affect T cell function depending on the animal species in which they are applied.
Posted by EG Findlay, L Danks, J Madden, et al.
on 2014-02-28 00:04:53
An immune response is essential for protection against infection, but, in many individuals, aberrant responses against self tissues cause autoimmune diseases such as rheumatoid arthritis (RA). How to diminish the autoimmune response while not augmenting infectious risk is a challenge. Modern targeted therapies such as anti-TNF or anti-CD20 antibodies ameliorate disease, but at the cost of some increase in infectious risk. Approaches that might specifically reduce autoimmunity and tissue damage without infectious risk would be important. Here we describe that TNF superfamily member OX40 ligand (OX40L; CD252), which is expressed predominantly on antigen-presenting cells, and its receptor OX40 (on activated T cells), are restricted to the inflamed joint in arthritis in mice with collagen-induced arthritis and humans with RA. Blockade of this pathway in arthritic mice reduced inflammation and restored tissue integrity predominantly by inhibiting inflammatory cytokine production by OX40L-expressing macrophages. Furthermore, we identify a previously unknown role for OX40L in steady-state bone homeostasis. This work shows that more targeted approaches may augment the “therapeutic window” and increase the benefit/risk in RA, and possibly other autoimmune diseases, and are thus worth testing in humans.