星形胶质细胞诱导维持血脑屏障特性

血脑屏障的结构、发生和诱导维持对这神经系统的生理病理研究有重要意义。近年来对星形胶质细胞通过其分泌产物近距离参与对血脑屏障完整性的诱导维持的研究受到重现，对于指导临床实践具有重要作用。     

超生理剂量地塞米松对大鼠胰岛细胞的影响

糖皮质激素广泛应用于治疗多种疾病如自身免疫性疾病、白血病等 ,但大量、长期应用将诱致许多不良反应 ,其中类固醇性糖尿病尤为突出。本研究根据临床地塞米松不同用药量换算成大鼠所用的相应剂量 ,建立接近临床实际的大鼠类固醇性糖尿病模型 ,观察糖皮质激素对α、β、δ、ＰＰ等 4种主要胰岛细胞激素的表达 ,探讨其在发病过程中的作用。一、材料和方法1.材料 :上海ＢＫ公司提供的清洁级Ｓｐｒａｇｕｅ Ｄａｗｌｅｙ(ＳＤ)雄性大鼠 140只 ,体重 (30 0± 2 0 )ｇ ,自由取食进水。饲养温度控制在 (2 0± 2 )℃ ,人工光照每日 12小时。胰岛素(…     

小檗碱对泼尼松性大鼠脑损害的防治作用

目的 观察超生理剂量醋酸泼尼松致大鼠脑损害的特点,并探讨小檗碱对其的防治作用.方法 50只3月龄雄性SD大鼠,随机分成5组,每组10只,分别给予泼尼松与不同剂量小檗碱12w,观察大鼠脑匀浆与神经活动有关的酶含量变化,并对脑组织的形态进行计量学分析.结果 长期超剂量使用糖皮质激素后,脑匀浆中单胺氧化酶(MAO)含量明显增高(P＜0.01);海马CA2区神经元排列无序、分散,有较多的神经细胞变性坏死.小檗碱高、中、低剂量组均可有效预防泼尼松所致的大鼠中枢神经系统功能和结构改变,明显减少糖皮质激素长期应用造成的不良反应.结论 长期应用泼尼松可对大鼠造成脑损害,小檗碱对其有较好的预防作用.     

糖皮质激素的非基因组效应及其在支气管哮喘治疗中的作用

经典理论认为糖皮质激素(glucocorticoid,GC)通过调节基因表达发挥其生理药理作用,该过程耗时长,起效慢.然而,越来越多的证据表明GC可在数秒钟或者数分种内完成对神经内分泌、细胞因子释放、能量代谢及机体行为的调节,该效应被称为GC的快速非基因组效应.深入阐明GC非基因组作用机制将有助于指导GC的临床合理用药并减少其不良反应.以下就GC的非基因组效应机制及其在哮喘治疗中的作用展开综述.     

心理危机及其对老年人生理的影响和危害

类似地震、空难、海啸等各种大型自然灾害,不但造成严重的人员伤亡和财产损失,而且会对老人的心理产生强烈的冲击,尤其对与灾难有牵连的老人陷入心理危机的困扰中,产生一系列的心理生理的不良反应.     

利钠肽生理作用研究进展

利钠肽作为心源性环激素在调节血容量和血管张力方面具有重要作用,近年来研究发现它的作用非常广泛,现对其生理作用研究进展作一综述.     

复方甘草甜素、泼尼松治疗慢性淤胆型乙型肝炎对照研究

慢性淤胆型乙型肝炎是临床常见病,患者以肝内胆汁淤积为主,长期应用糖皮质激素对该病疗效肯定,但常出现严重不良反应,而且大量应用激素后常造成机体免疫抑制,使HBV再激活,导致重型肝炎的发生.复方甘草甜素具有内源性皮质类固醇激素样作用,但不良反应较小.我们应用复方甘草甜素治疗慢性淤胆型乙型肝炎患者,并与泼尼松治疗进行对照分析.     

植物雌激素的心血管保护作用及机制

植物雌激素是一类存在于植物中,在结构和功能上类似于雌激素,并且具有类雌激素或抗雌激素作用的活性物质,但其不良反应明显低于雌激素.现主要总结植物雌激素的分类,并从植物雌激素对心功能、心肌电生理效应等方面阐述其对心脏的作用,通过对调节血脂、血管舒缩功能、血小板和抗氧化的作用阐述其血管保护功能及机制,为心血管疾病的预防和治疗提供新的思路.     

肾素-血管紧张素系统的新成员--血管紧张素转换酶2

肾素-血管紧张素系统在心血管疾病中具有非常重要的作用,近年来,又发现了一个新的成员--血管紧张素转换酶2,现对其生化特征、生理作用及临床意义作一综述.     

糖皮质激素抗支气管哮喘治疗的药物基因组学研究进展

支气管哮喘(简称哮喘)是全世界范围儿童最常见的慢性呼吸道疾病.糖皮质激素是哮喘治疗中最有效最常见的药物.临床发现哮喘患者对糖皮质激素的治疗反应存在个体差异和不良反应.药物基因组学研究发现,糖皮质激素通路及相关通路基因、药物代谢酶基因、哮喘易感基因的单核苷酸多态性与糖皮质激素在哮喘治疗中的反应有关.文中主要综述了近年糖皮质激素抗哮喘治疗的药物基因组学研究进展.     

Modulation of Dickkopf-1 attenuates glucocorticoid induction of osteoblast apoptosis, adipocytic differentiation, and bone mass loss

Long-term glucocorticoid treatment impairs the survival and bone formation of osteogenic cells, leading to bone mass loss. The Wnt inhibitor Dickkopf-1 (DKK1) acts as a potent bone-remodeling factor that mediates several types of skeletal disorders. Whereas excess glucocorticoid is known to disturb Wnt signaling in osteogenic cells, modulation of the skeletally deleterious effects of DKK1 to alleviate glucocorticoid induction of bone loss has not been tested. In this study, knockdown of DKK1 expression by end-capped phosphorothioate DKK1 antisense oligonucleotide (DKK1-AS) abrogated dexamethasone suppression of alkaline phosphatase activity and osteocalcin expression in MC3T3-E1 preosteoblasts. Exogenous DKK1-AS treatment alleviated dexamethasone suppression of mineral density, trabecular bone volume, osteoblast surface, and bone formation rate in bone tissue and ex vivo osteogenesis of primary bone-marrow mesenchymal cells. The DKK1-AS inhibited adipocyte volume in the marrow cavity of steroid-treated bone tissue. Immunohistochemical observation revealed that DKK1-AS abrogated dexamethasone-induced DKK1 expression and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling of osteoblasts adjacent to trabecular bone. Knocking down DKK1 abrogated dexamethasone-modulated expression of nuclear beta-catenin and phosphorylated Ser(473)-Akt and survival of osteoblasts and adipocytic differentiation of mesenchymal progenitor cell cultures. Taken together, knocking down DKK1 alleviated the deleterious effect of glucocorticoid on bone microstructure. The DKK1-AS treatment appeared to protect bone tissue by modulating beta-catenin and Akt-mediated survival as well as the osteogenic and adipogenic activities of glucocorticoid-stressed osteoprogenitor cells. Interference with the osteogenesis-inhibitory action of DKK1 has therapeutic potential for preventing glucocorticoid induction of osteopenia.     

The role of 11 beta-hydroxysteroid dehydrogenase in central obesity and osteoporosis

Both central obesity and osteoporosis are common findings in states of glucocorticoid excess. In many tissues, including adipose tissue, hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyses the inter-conversion of active glucocorticoid, cortisol (F) and inactive cortisone (E) and regulates exposure to the glucocorticoid receptor. As such, factors which regulate 11beta-HSD1 are likely to have an important role in adipose tissue and bone physiology. Using primary cultures of human adipose stromal cells we have investigated the effect of various factors present within the adipocyte microenvironment for their effects on 11beta-HSD1 expression. IGF-1 caused a dose dependant inhibition of 11beta-HSD1 activity in both subcutaneous and omental stromal cells. Additionally, TNFalpha treatment increased 11beta-HSD1 reductase activity and mRNA expression. In adult human bone, 11beta-HSD1, but not 11beta-HSD2, expression was demonstrated using enzyme activity studies, RT-PCR and immunohistochemistry. In contrast to liver and adipose tissues, where reductase activity predominates, both reductase and dehydrogenase activities of 11beta-HSD1 were evident in bone chips and primary cultures of human osteoblasts. The action of growth factors and cytokines on glucocorticoid sensitive tissues such as adipose tissue and bone may be mediated by modulation of local glucocorticoid metabolism at a pre-receptor level.     

Effect of glucocorticoids on bone mineral density in patients with idiopathic thrombocytopenic purpura

To elucidate the effects of glucocorticoid on bone mineral density in idiopathic thrombocytopenic purpura (ITP) patients, we retrospectively evaluated the relationship between bone mineral density (BMD) and the total dose of glucocorticoid or the mean daily dose given. We found decreased BMD in 66.7% of the patients with ITP to whom glucocorticoid was given, though rather normal bone BMD was observed in 28.6% of ITP patients treated without steroids. The mean level of BMD was markedly decreased in steroid-treated patients compared with steroid non-treated patients (p < 0.01). The relationship between BMD and the total dose of glucocorticoid (p = 0.023) or the mean daily dose revealed a negative correlation (p = 0.022). This study showed that glucocorticoid-induced osteoporosis was observed in patients with ITP, similar to other diseases already reported. When we think of this disease, many cases tend to be followed for a long time, and as the majority of ITP patients is female, we should pay particular attention in the prevention of glucocorticoid-induced osteoporosis.     

Glucocorticoid-induced osteoporosis: recent findings

The clinical features, pathogenesis and management of bone involvement in Cushing's syndrome are briefly reviewed. Personal data on bone mineral density and markers of bone turnover in Cushing's syndrome and adrenal incidentalomas are also reported. As long ago as 1932, Harvey Cushing recognized osteoporosis as a serious consequence of endogenous hypercortisolism. The introduction of cortisone in the therapy of autoimmune, rheumatic, allergic or dermatologic disorders was followed by several reports of detrimental effects on bone of patients who had undergone prolonged glucocorticoid treatment. Due to the rarity of Cushing's syndrome, most of the studies in the literature on glucocorticoid-induced osteoporosis refer to exogenous over-exposure to cortisone and its synthetic derivatives. Only a small number of works concern endogenous hypercortisolism, even if the characteristics of bone damage seem qualitatively the same. Finally, very few data are reported on the hypothetical detrimental effect on bone in the condition of the silent hypercortisolism of adrenal incidentalomas. Glucocorticoid-induced osteoporosis in Cushing's syndrome often results in vertebral fractures, and bone loss is more evident in trabecular than in cortical bone. Notwithstanding some distinctive features in osteoporosis induced by endogenous and exogenous glucocorticoid excess, the common eventual picture is notable bone damage that involves mainly the trabecular bone. Prompt and effective therapy is mandatory to reduce the risk of fractures. The present options include calcium and vitamin D supplementation, estrogen replacement therapy, bisphosphonates, either oral or parenteral. A novel approach to the clinical problem of glucocorticoid-induced osteoporosis might, in the future, be based on studies on selective glucocorticoid receptor modulators, a new class of synthetic glucocorticoids that exhibit significant anti-inflammatory and immunosuppressive activities, with reduced side effects on bone.     

Glucocorticoid-induced osteoporosis: pathogenesis,prevention and treatment,with special regard to the rheumatic diseases

Abstract. Objectives. To review factors associated with development of osteoporosis in patients with rheumatic diseases, as well as the preventive and therapeutic measures. Design. A MEDLINE literature search. Results. 1 Pathogenesis. Rheumatoid arthritis in itself causes reduction of bone mass; this process can be aggravated by glucocorticoid treatment. With glucocorticoid treatment, bone mineral density decrease is most pronounced during the first months of treatment. There is no agreement on the effects of daily dose, cumulative dose, and duration of glucocorticoid treatment on the rate of bone loss. However, with treatment by low doses (< 10 mg of prednisone equivalent per day), bone loss appears to be minimal or even undetectable compared to controls. Alternate day treatment, or treatment with steroid ‘pulses’ have not been shown to protect from bone loss. 2 Prevention and treatment. Prophylactic and therapeutic measures for glucocorticoid-induced osteoporosis include calcium supplementation, vitamin D in physiological doses and oestrogen in perimenopausal female patients. Efficacy has not always been shown in this particular indication but is extrapolated from other forms of osteoporosis. Limited data exist on treatment with anabolic steroids, calcitonin (with an additional analgesic effect) and biphosphonates and reduction of fracture rates has not yet been investigated. At present, there is insufficient evidence to show that altered steroid molecules can dissociate adverse effects on bone from clinically desirable effects. Conclusion. In view of the paucity of study data, prophylaxis and therapy of glucocorticoid-induced osteoporosis should receive more attention in future clinical studies.     

Glucocorticoid-induced osteoporosis

Glucocorticoid-induced osteoporosis is the most frequent cause of secondary osteoporosis. Glucocorticoids cause a rapid bone loss in the first few months of use, but the most important effect of the drug is suppression of bone formation. The administration of oral glucocorticoid is associated with an increased risk of fractures at the spine and hip. The risk is related to the dose, but even small doses can increase the risk. Patients on glucocorticoid therapy lose more trabecular than cortical bone and the fractures are more frequent at the spine than at the hip. Calcium, vitamin D and activated forms of vitamin D can prevent bone loss and antiresorptive agents are effective for prevention and treatment of bone loss and to decrease fracture risk. Despite the known effects of glucocorticoids on bone, only a few patients are advised to take preventive measures and treat glucocorticoid-induced osteoporosis.     

Skeletal involvement in adult patients with endogenous hypercortisolism

Overt endogenous glucocorticoid excess is a well-recognized cause of bone loss and osteoporotic fractures. Cortisol excess inhibits bone formation, increases bone resorption, impairs calcium absorption from the gut, and affects the secretion of several hormones (in particular gonadotropins and GH), cytokines, and growth factors, influencing bone metabolism. The glucocorticoid excess mainly affects trabecular bone, leading to vertebral fractures in up to 70% of patients. Osteoporotic fractures may be the presenting symptom of an otherwise silent glucocorticoid excess and can precede the diagnosis of hypercortisolism by up to 2 yr. The removal of glucocorticoid excess leads to a recovery of bone mass which is, however, often incomplete and delayed, although it reduces the risk of osteoporotic fractures. Bisphosphonate therapy has been suggested to be useful in maintaining bone mass in these patients. Subclinical hypercortisolism, a condition of impaired hypothalamic- adrenal-axis homeostasis without the classical signs and symptoms of glucocorticoid excess, is a recently defined entity, which has been shown to be associated to increased bone resorption, bone loss, and high prevalence of vertebral fractures regardless of gonadal status. However, data about the effect of this subtle glucocorticoid excess on bone are still scarce and conflicting. Moreover, it is not yet known whether removing the cause of subclinical hypercortisolism leads to a recovery of bone mass and reduces the risk of osteoporotic fractures. Finally, recent data suggest that subclinical hypercortisolism is a common and underrated finding in patients with established osteoporosis. In summary, it is crucial to evaluate the risk of osteoporosis and fractures in patients with glucocorticoid excess; on the other hand, it also seems advisable to screen for glucocorticoid excess patients with osteoporotic fractures without known secondary causes of osteoporosis.     

First‐line treatment with bortezomib rapidly stimulates both osteoblast activity and bone matrix deposition in patients with multiple myeloma,and stimulates osteoblast proliferation and differentiation in vitro

Objectives: The aim of the study was to investigate the effect of bortezomib on osteoblast proliferation and differentiation, as well as on bone matrix deposition for the first time in bisphosphonate‐naïve, previously untreated patients with myeloma. Methods: Twenty newly diagnosed patients received four cycles of bortezomib treatment, initially as monotherapy and then combined with a glucocorticoid from cycle two to four. Bone remodeling markers were monitored closely during treatment. Furthermore, the effects of bortezomib and a glucocorticoid on immature and mature osteoblasts were also studied in vitro. Results: Treatment with bortezomib caused a significant increase in bone‐specific alkaline phosphatase and pro‐collagen type I N‐terminal propeptide, a novel bone formation marker. The addition of a glucocorticoid resulted in a transient decrease in collagen deposition. In vitro bortezomib induced osteoblast proliferation and differentiation. Differentiation but not proliferation was inhibited by glucocorticoid treatment. Conclusions: Bortezomib used as first‐line treatment significantly increased collagen deposition in patients with multiple myeloma and osteolytic lesions, but the addition of a glucocorticoid to the treatment transiently inhibited the positive effect of bortezomib, suggesting that bortezomib may result in better healing of osteolytic lesions when used without glucocorticoids in patients that have obtained remission with a previous therapy. The potential bone‐healing properties of single‐agent bortezomib are currently being explored in a clinical study in patients who have undergone high‐dose therapy and autologous stem cell transplantation.     

The skeletal effects of glucocorticoid excess override those of orchidectomy in mice

Hypogonadism has been implicated as a contributing factor in glucocorticoid-induced osteoporosis, but evidence for this is limited. Hypogonadism and glucocorticoid excess both cause bone loss, but the cellular mechanisms responsible are distinct. Loss of gonadal steroids causes an increase in bone remodeling by up-regulating osteoblastogenesis and osteoclastogenesis. Glucocorticoid excess, conversely, suppresses remodeling by down-regulating osteoblastogenesis and osteoclastogenesis. Nonetheless, both conditions increase osteoblast apoptosis and decrease osteoclast apoptosis, and both cause bone loss due to an undersupply of osteoblasts relative to the need for cavity repair. To investigate their interactions, we compared the effects of orchidectomy, glucocorticoid excess, or both combined in mice. After 28 d, serum unbound testosterone concentration and seminal vesicle weight were not diminished when prednisolone was administered alone. Vertebral bone mineral density and compression strength decreased to the same extent in animals receiving prednisolone or after orchidectomy, but the changes were not additive. Orchidectomy induced the expected up-regulation of osteoblast and osteoclast progenitors, but these changes were prevented in orchidectomized mice simultaneously receiving glucocorticoids. Likewise, the increase in cancellous osteoid, osteoblasts, osteoclasts, bone formation, and activation frequency caused by orchidectomy were prevented by prednisolone. The prevalence of osteoblast apoptosis increased in the mice receiving prednisolone or after orchidectomy, but the increases were not additive. These data demonstrate that hypogonadism does not occur in or contribute to glucocorticoid-induced osteoporosis and that the adverse skeletal effects of glucocorticoid excess override those of orchidectomy.