Molecular dynamics of ultradian glucocorticoid receptor action

In recent years it has become evident that glucocorticoid receptor (GR) action in the nucleus is highly dynamic, characterized by a rapid exchange at the chromatin template. This stochastic mode of GR action couples perfectly with a deterministic pulsatile availability of endogenous ligand in vivo. The endogenous glucocorticoid hormone (cortisol in man and corticosterone in rodent) is secreted from the adrenal gland with an ultradian rhythm made up of pulses at approximately hourly intervals. These two components - the rapidly fluctuating ligand and the rapidly exchanging receptor - appear to have evolved to establish and maintain a system that is exquisitely responsive to the physiological demands of the organism. In this review, we discuss recent and innovative work that questions the idea of steady state, static hormone receptor responses, and replaces them with new concepts of stochastic mechanisms and oscillatory activity essential for optimal function in molecular and cellular systems.     

Glucocorticoid and proteasome inhibitor impact on the leukemic lymphoblast: multiple, diverse signals converging on a few key downstream regulators

Twenty years ago a proteasome inhibitor was suggested as therapy for glucocorticoid-resistant multiple myeloma, a disease that involves terminally differentiated B cells. Since then, research has proven that it has utility on a number of tumors resistant to chemotherapy. Hematologic malignancy, however, often involves lesser differentiated cells, which have a high potential to modulate their intrinsic machinery and thereby activate alternative rescue pathways. A corresponding multiplicity of therapies is not always practical. One approach to conditions with heterogeneous physiology is to identify key biochemical mediators, thereby reducing the number of treatment targets. Results from several ongoing studies indicate convergence of genomically diverse signal pathways to a limited number of key downstream regulators of apoptosis. Convergence of pathways can be exploited to address the problem of genetic heterogeneity in acute leukemia: this would mean treating multiple molecular aberrations with fewer drugs and enhanced therapeutic benefit.     

Clinicopathologic features and prednisone therapeutic effect of 50 cases of proliferative sclerosing IgA nephropathy

Objective To analyze the clinicopathologic features of proliferative sclerosing IgA nephropathy and the efficacy of prednisone therapy. Methods A retrospective analysis was conducted, enrolling 50 patients with biopsy-proven primary proliferative sclerosing IgA nephropathy who were admitted in the Hospital from January 2005 to June 2015 - 26 males and 24 females, mean age (36.8±10.4) years. Clinicopathologic features and prednisone therapeutic effect were analyzed. Results The clinical manifestations of 50 cases were nephritis syndrome with varying degrees of renal insufficiency, including 32 cases (64.0%) with hypertension, 15 cases (30.0%) with microscopic hematuria. Renal biopsy showed the incidence of glomerular global sclerosis was 17.0%-47.2%, tubular atrophy/ interstitial fibrosis outstanding (T0 50%, T1 32%, T2 18%). After prednisone treatment, compared with sustained remission group and relapse group, invalid patients had higher incidence of hypertension (P＜0.05), relatively lower Hb (P＜0.01) and serum albumin, more significant renal dysfunction (P＜0.01), more severe glomerular global sclerosis, segmental sclerosis, tubular atrophy/interstitial fibrosis, while the lower interstitial inflammatory cell infiltration. During the follow-up, which lasted from 6 to 132 months (median 27.3 months), the effective rate of treatment was 74.0% after sufficient prednisone or half dose prednisone therapy. Repeated recurrence rate was 32.0%. At the end of the follow-up period, 13(26.0%) patients entered the stage of uremia. Conclusions Application of glucocorticoids in the treatment of proliferative sclerosing IgA nephropathy can protect renal function and delay the progression of renal impairment. The efficacy of glucocorticoids therapy is significantly associated with the presence or absence of hypertension, the degree of renal function impairment, and the severity of the onset of renal pathology.     

糖皮质激素诱导的亮氨酸拉链蛋白在糖皮质激素作用中的角色及分子机制

糖皮质激素（glucocorticoids,GCs）因具有强大的抗炎和免疫抑制作用,在临床上广泛用于自身免疫性疾病和炎症相关性疾病的治疗。然而,长期使用或者大剂量使用会导致较多的不良反应,降低其应用价值。因此,为了既保留GCs的抗炎作用、又减轻GCs的免疫抑制作用,深入研究GCs的分子作用机制对寻找新的药物靶点或者具有GCs作用的小分子化合物具有重要意义。糖皮质激素诱导的亮氨酸拉链蛋白（glucocorticoid-induced leucine zipper protein,GILZ）是GCs调控的靶分子,是GCs的重要下游执行分子,但GILZ效应又不完全等同于GCs通过糖皮质受体（glucocorticoids receptor,GR）发挥的生理和药理效应,具有替代GCs用于临床的可能性。因此,本文就GILZ在GCs的抗炎、免疫抑制中的作用、分子机制以及在自身免疫系统疾病模型中的应用进行综述。     

基于“少火生气,壮火食气”理论治疗硬皮病

硬皮病是临床难治性自身免疫性疾病,常累及全身多个系统,其发病机制尚不明确,且进展迅速,预后多不良,目前尚缺乏特效治疗药物,治疗棘手。本病隶属于中医学中“皮痹”范畴,中医对其病因病机有着深入的认识,治疗效果显著,不良反应较小。现阐述《内经》中“少火生气、壮火食气”的理论内涵,浅析中医对硬皮病认识,探讨该理论对中医治疗硬皮病的指导作用,并举汤小虎教授临床验案1例,以期为临床多角度认识和治疗硬皮病提供有价值的思路。     

重症肌无力患儿糖皮质激素治疗前后血清皮质醇水平的初步探讨

目的：探讨重症肌无力（MG）患儿在使用糖皮质激素（GC）治疗前、后血清皮质醇的变化。方法：选取新发MG患儿43例和健康儿童微量元素抽查群体19例,取静脉血上清液用化学发光法测定其血清皮质醇水平,MG患儿抽血时间为治疗前及治疗后2个月时。结果：新发MG患儿治疗前血清皮质醇水平明显高于正常对照组（P〈0.05）和GC治疗后（P〈0.01）,而正常对照组血清皮质醇水平与GC治疗后患儿的血清皮质醇水平比较差异无统计学意义（P〉0.05）。结论：外源性GC对改善MG患儿由于异常应激状态及免疫功能紊乱等导致体内血清皮质醇升高有较好的纠正作用。