关附甲素抗氧化和抗房颤作用

研究关附甲素(Guanfu base A,GFA)的抗房颤和抗氧化作用。大鼠尾静脉注射乙酰胆碱-氯化钙混合液(Ca Cl210 mg/m L,Ach 66μg/m L),连续7 d建立房颤模型。SD大鼠分为正常组、模型组、GFA治疗组(6 mg/kg,12 mg/kg)、胺碘酮(Amiodarone,Ami)治疗组(50 mg/kg)以及洛伐他汀(Lovastatin,Lov)治疗组(10 mg/kg)。测定大鼠房颤持续时间和有效不应期(AERP),用实时荧光定量PCR方法和Western blot方法测定氧化应激相关基因表达,试剂盒测定抗氧化酶的活性。结果显示:与模型组相比,GFA(6 mg/kg,12 mg/kg,po)治疗4 d后能缩短房颤持续时间,延长AERP,超氧化物歧化酶的活力提高,丙二醛含量明显下降。心房肌p22phox、p47phox、p67phox、gp91phox表达下调,膜Rac-1与胞浆Rac-1比值显著下降,缝隙连接蛋白(connexin40)表达升高。提示GFA(6 mg/kg,12 mg/kg)能有效抑制房颤引起的大鼠心房氧化应激损害,抑制房颤发生。     

Analysis of serum soluble CD40 ligand (sCD40L) in the patients undergoing allogeneic stem cell transplantation: platelet is a major source of serum sCD40L

CD40 ligand (CD40L) is expressed not only on activated T cells but also on activated platelets. A soluble CD40 ligand (sCD40L) is released from the activated T cells and platelets by ill-defined proteolytic process in vitro. It has been reported that sCD40L is elevated in the serum of patients with systemic lupus erythematosus, unstable angina, essential thrombocythemia, and autoimmune thrombocytopenic purupura. However, source of sCD40L in vivo remains to be elucidated. We investigated the serial sCD40L in the serum in patients undergoing allogeneic stem cell transplantation and compared with the platelets number and soluble IL2R, which is a marker of activated T cells. The value of sCD40L was well correlated with platelet number or thrombopoiesis. In cases of severe graft vs. host disease with markedly increased sIL2R, sCD40L was not increased in vivo. These results indicate that sCD40L in vivo is released mainly from the platelets or in the process of platelet production but not from the activated T cells.     

Erythromycin ameliorates renal injury via anti-inflammatory effects in experimental diabetic rats

Aims/hypothesis Recent studies have shown that the inflammatory process is involved in the pathogenesis of diabetic nephropathy. Fourteen-membered ring macrolides, including erythromycin, have anti-inflammatory, as well as antibacterial effects. The aim of this study was to investigate the renoprotective effects of erythromycin in streptozotocin (STZ)-induced diabetic rats.Methods STZ-induced diabetic rats were treated orally with erythromycin (5 mg/kg body weight) or vehicle every day for 8 weeks. To evaluate the effect of erythromycin treatment, we measured urinary albumin excretion, and examined the following in the kidney: histological changes, the expression of intercellular adhesion molecule-1 (ICAM-1), macrophage infiltration, and nuclear factor-kappa B (NF-B) activity.Results Erythromycin significantly reduced urinary albumin excretion without affecting blood glucose levels and blood pressure. Erythromycin also attenuated glomerular hypertrophy, mesangial expansion, macrophage infiltration and ICAM-1 expression in renal tissues. The expression of the gene encoding TGFB1 (also known as TGF-1), type IV collagen protein production and NF-B activity in renal tissues were increased in diabetic rats and reduced by erythromycin treatment.Conclusions/interpretation Erythromycin prevented renal injuries without changes of blood glucose levels and blood pressure in experimental diabetic rats. These results suggest that the renoprotective effects of erythromycin are based on its anti-inflammatory effect via suppression of NF-B activation. Modulation of microinflammation with erythromycin may provide a new approach for diabetic nephropathy.     

CD40-mediated immune cell activation enhances response to anti-PD-1 in murine intrahepatic cholangiocarcinoma

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Implications of IL-13Rα2 in atopic skin inflammation

Atopic dermatitis (AD) is a common eczematous skin disorder characterized by skin inflammation, barrier disruption, chronic pruritus and marked scratching. Th2 cytokines, especially IL-13, play a pathogenic role in AD. IL-13 signals via a heterodimeric receptor composed of IL-4Rα and IL-13 Rα1. A second receptor, IL-13 Rα2, binds to IL-13 with high affinity, but it works as a decoy receptor. IL-13 Rα2 is overexpressed in the lesional skin of AD. Notably, mechanical scratching, as well as IL-13 itself, also upregulates IL-13 Rα2 expression. The scratch-induced IL-13 Rα2 upregulation may attenuate the IL-13-mediated epidermal barrier dysfunction and dermal fibrosis. Recent studies stress an importance of another IL-13 Rα2 ligand, chitinase 3-like 1 or YKL-40 in Th2 differentiation. However, the implications of increased IL-13 Rα2 levels remain elusive in AD. In this review, we summarize the recent topics on IL-13 Rα2 in atopic skin inflammation.     

Toll‐like receptors and CD40 modulate each other's expression affecting Leishmania major infection

Toll‐like receptors (TLRs) recognize pathogen‐associated molecular patterns and results in innate immune system activation that results in elicitation of the adaptive immune response. One crucial modulator of the adaptive immune response is CD40. However, whether these molecules influence each other's expression and functions is not known. Therefore, we examined the effects of TLRs on CD40 expression on macrophages, the host cell for the protozoan parasite L eishmania major. While polyinosinic‐polycytidylic acid [poly (I:C)], a TLR‐3 ligand, lipopolysaccharide (LPS), a TLR‐4 ligand, imiquimod, a TLR‐7/8 ligand and cytosine–phosphate–guanosine (CpG), a TLR‐9 ligand, were shown to enhance CD40 expression, CD40 stimulation enhanced only TLR‐9 expression. Therefore, we tested the synergism between CD40 and CpG in anti‐leishmanial immune response. In L eishmania‐infected macrophages, CpG was found to reduce CD40‐induced extracellular stress‐regulated kinase (ERK)1/2 activation; with the exception of interleukin (IL)‐10, these ligands had differential effects on CD40‐induced IL‐1α, IL‐6 and IL‐12 production. CpG significantly enhanced the anti‐leishmanial function of CD40 with differential effects on IL‐4, IL‐10 and interferon (IFN)‐γ production in susceptible BALB/c mice. Thus, we report the first systematic study on CD40–TLR cross‐talk that regulated the experimental L . major infection.