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Query: UMLS:C0338671 (Steroids)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Murine shock models have employed bolus endotoxin as well as cecal ligation and puncture (CLP) in an attempt to understand the pathophysiologic changes associated with human septic shock. Injection of endotoxin results in a rapid but transient rise in tumor necrosis factor (TNF), with maximal levels between 1 and 2 hr followed by an increase in serum interleukin-1 (IL-1) by 3 hr which remains elevated at 24 hr. CLP animals in contrast do not demonstrate an elevation in serum TNF, and the increase in IL-1 is less significant relative to the endotoxin model. Whereas both models demonstrate comparable increases in serum amyloid A protein and result in host death between 24 and 48 hr, these models respond differently to therapeutic modalities. Steroids and an anti-TNF monoclonal antibody administered prophylactically are effective at preventing death in the endotoxin model and yet had no beneficial effect in antibiotic-treated CLP animals. Experiments with adrenalectomized mice suggest that the absence of serum TNF in the CLP model is in part due to the modulatory effects of endogenous corticosteroids.
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PMID:Differential expression of interleukin-1 and tumor necrosis factor in murine septic shock models. 259 14

The body's response to infection/inflammation is initiated by the elaboration of cytokines, such as tumor necrosis factor, interleukin 1-beta (IL-1-beta), IL-6, and IL-8. Cytokines, in turn, stimulate the pituitary-adrenal axis, and it has been suggested that the corticosteroids elaborated serve as negative feedback signals to diminish inflammatory events. To test this hypothesis, we administered hydrocortisone shortly before endotoxin administration to normal volunteers. Steroids greatly reduced the clinical response to endotoxin and attenuated the appearance of tumor necrosis factor, IL-6, and IL-8 in the circulation. In contrast, IL-1-receptor antagonist, a competitive antagonist of the IL-1 receptor, was unaffected by steroid administration. These data suggest that IL-1-receptor antagonist may act in synergism with corticosteroids to reduce inflammation. Elevation of concentrations of these two factors, corticosteroids and IL-1-receptor antagonist, in plasma appears to be the mechanism used by the body to overcome the effects of inflammatory cytokines.
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PMID:Elaboration of interleukin 1-receptor antagonist is not attenuated by glucocorticoids after endotoxemia. 843 Nov 15

During the second half of the luteal phase, the human corpus luteum becomes responsive to regular luteinizing hormone (LH) pulses. These LH pulses stimulate progesterone secretion tonically, and during this tonic stimulation, additional LH-independent progesterone pulses occur, which are particularly pronounced in women with human chorionic gonadotropin-stimulated luteal function. No progesterone pulses are seen in women suffering from corpus luteum deficiency due to absent LH pulses. The corpus luteum thus has a progesterone pulse generator turned on by gonadotropins but functioning for several hours without further gonadotropic support. This pulse generator appears to be regulated by intraluteal auto-/paracrine mechanisms, which we have investigated in a porcine model using molecular, cellular, and in vivo tools. Luteal oxytocin and progesterone release occurs in tightly coupled pulses. In vivo, oxytocin and prostaglandin F2 alpha(PGF2 alpha) stimulate estradiol and progesterone release and estradiol itself further stimulates progesterone release. Analysis of the different luteal cell compartments (large luteal cells, small luteal cells, fibroblasts) suggests an intraluteal circuit that involves paracrine effects of estradiol, oxytocin, and PGF2 alpha. At the time of luteolysis, the luteotropic effects of estradiol are inhibited by tumor necrosis factor derived from invading macrophages and the intraluteal circuit is thereby disrupted, leading to luteolysis.
Steroids
PMID:Regulation of steroid production and its function within the corpus luteum. 961 90

In each estrous cycle, only one follicle, the dominant follicle, reaches full maturation while the other recruited follicles become atretic in a process characteristic of programmed cell death. Moreover, the old corpus luteum formed in a previous cycle undergoes luteolysis by a mechanism also characteristic of programmed cell death. Granulosa cells comprise the largest cell population of the ovarian follicle and are the main source of estradiol and progesterone in the ovary. Their cyclic nature of differentiation and death determines the cyclic secretion of female sex hormones and therefore serve as an excellent model for steroid regulation during apoptosis. The characteristics of granulosa cell apoptosis, as in other cell types, are cell membrane blebbing, DNA degradation and protease activation. In addition, there are specific characteristics of steroidogenic granulosa cell apoptosis, as follows: 1) The trigger for apoptosis may be exerted by different effectors and signal transduction mechanisms during follicle development. For example, tumor necrosis factor (TNF) may trigger granulosa cell apoptosis at early stage of follicular development, while cAMP/p53 signals may trigger this process only in mature preovulatory granulosa cells. 2) cross-talk between paracrine and endocrine signals, and between death genes and tumor suppressor genes, may determine the fate of the granulosa cell. 3) in the mature follicle the follicular basement membrane plays an important role in transmitting survival signals and in prevention of apoptosis. 4) during the initial steps of apoptosis, steroidogenesis may be increased due to clustering of the steroidogenic organelles in the perinuclear region and their exclusion from the apoptotic blebs. 5) Actin cytoskeleton reorganization plays an important role in this compartmentalization as well as in transmitting survival signals exerted by basement membrane, laminin and growth factors which activate tyrosine kinase receptors.
Steroids
PMID:Steroid regulation during apoptosis of ovarian follicular cells. 961 93

In ovariectomized (Ovx) mice, collagenolytic cysteine protease (CCP) activity in calvaria significantly increased 7 days after ovariectomy and was about 50% of that observed in sham-operated (Sham) mice 3 weeks later. In Ovx mice, subcutaneously (s.c.) administered estradiol-17beta (E2) (10 microg/kg) for 2 weeks led to a decrease in CCP activity in calvaria to the level observed in Sham mice. In Ovx mice, though the amount of cathepsin L increased more than that of cathepsin K, cathepsin K and cathepsin L content increased by 200-400% compared with the Sham mice; cathepsin K was detected in larger amounts than cathepsin L in calvaria from both Sham and Ovx mice. The amounts of cathepsin K and cathepsin L in Ovx mice were reduced to the values seen with Sham mice after administration (s.c.) of E2 (10 microg/kg) for 2 weeks. In mouse calvarial organ culture, the increase of CCP activity and release of hydroxyproline, an indicator of degradation of type-I collagen, in the presence of 1alpha,25-(OH)(2)D(3), parathyroid hormone, interleukin (IL)-1alpha, IL-6, or tumor necrosis factor-alpha was suppressed by E2 (10(-9)-10(-7) M). In all cases, secretion of both cathepsin K and cathepsin L were suppressed by E2. In osteoclasts, expression of cathepsin K and cathepsin L was suppressed by E2 at the mRNA level. Cathepsin B was detected faintly or not at all. These results suggest that synthesis of cathepsin K and cathepsin L was negatively regulated by E2 at the mRNA level. In Ovx mice, deficiency of E2 resulted in an augmentation of cathepsin K and cathepsin L synthesis, and the cathepsins might share roles in bone resorption in vivo.
Steroids 2000 Jul
PMID:Regulation of collagenolytic cysteine protease synthesis by estrogen in osteoclasts. 1089 36

The secretion of cortisol, a principle homeostatic regulator in humans, shows a circadian rhythm, with high concentrations in the morning and low levels in the evening and at night. Tissue response to hormones is dependent on hormone concentrations but also on a variety of cellular factors, such as hormone receptors, transcription factors, and activators. In this report, we evaluated whether cell sensitivity to glucocorticoids (GCs) is also subject to diurnal variation using a whole cell system (whole blood samples) stimulated by lipopolysacharide to induce the production of tumor necrosis factor (TNF-alpha); the induction of TNF-alpha is inhibited by dexamethasone. Blood samples obtained in the morning (08.30-09.00 h) and in the evening (22.30-23.00 h) from 37 healthy individuals (18 males, 19 females) aged 29+/-3 years were treated with lipopolysacharide in the presence or absence of 10(-6) M dexamethasone, and the percentage of inhibition of TNF-alpha production was used as an index of sensitivity to GCs. The mean +/- SD in morning samples was 43.5+/-13.8% for the general population, 42.3+/-14.0% for males and 44.6+/-13.8% for females, whereas that in the evening samples was 36.5+/-15.7%, 35.6+/-13.8% and 37.4+/-17.7%, respectively. The results support a significantly increased sensitivity to GCs in the morning hours compared with that in the evening in the general population (P<0.001) as well as in males (P<0.001) and in females (P<0.001). No sex related differences in sensitivity to GCs were observed in the morning or in the evening hours. The sensitive and reproducible assay utilized in this study could also be used to investigate the sensitivity to GCs in various diseases characterized by resistance to GCs and/or alterations in glucocorticoid receptor function.
Steroids 2000 Dec
PMID:Diurnal changes in glucocorticoid sensitivity in human peripheral blood samples. 1107 82

Induction of apoptosis is a feature of the anti-tumor effects of certain vitamin D analogs. The aim of this study was to identify if common effectors are involved in cell death mediated by serum starvation, vitamin D analogs and tumor necrosis factor (TNF) alpha in 3 human breast cancer cell lines: MCF-7, T47-D and Hs578T. Incubation of cells in serum-free medium induced apoptosis as assessed by loss of cell viability and increased DNA fragmentation. Addition of IGF-I (30 ng/ml) protected against loss of cell viability in MCF-7 cells and co-treatment with two synthetic analogs (CB1093 and EB1089, 50 nM for 4 days) prevented these anti-apoptotic effects of IGF-I. Pretreatment of MCF-7 and Hs578T cells with the vitamin D analogs substantially potentiated the cytotoxic effects of TNFalpha. This cytokine was not cytotoxic for T47-D cells but co-incubation with CB1093 led to loss of cell viability. Potentiation by CB1093 of TNFalpha-induced apoptosis in MCF-7 cells was accompanied by increased activation of cytosolic phospholipase A2 and arachidonic acid release, which was partially inhibited by AACOCF3, a specific cPLA2 inhibitor. The broad-spectrum caspase inhibitor z-VAD-fmk prevented TNFalpha but not CB1093 mediated cell death and activation of cPLA2. Serum starvation induced apoptosis was accompanied by cPLA2 activation, which was inhibited by IGF-I and by z-VAD-fmk. However, the ability of these agents to suppress cPLA2 activation was abrogated by co-treatment with CB1093, suggesting a role for arachidonic acid release in the caspase-independent mechanism by which vitamin D analogs prevent the protective effects of IGF-I on breast cancer cell survival.
Steroids
PMID:Interaction of vitamin D analogs with signaling pathways leading to active cell death in breast cancer cells. 1117 39

It is well established that 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)), the active metabolite of vitamin D, plays a role in regulating proliferation and differentiation of cells, in addition to its classic function in mineral homeostasis. Recent studies have also provided evidence for the involvement of 1alpha,25(OH)(2)D(3) in regulating the immune system. However, therapeutic application of 1alpha,25(OH)(2)D(3) to hyperproliferative diseases such as cancer, or for immunologic purposes, is thwarted by its hypercalcemic activity. In order to overcome this obstacle, analogs of 1alpha,25(OH)(2)D(3) have been produced that exhibit decreased hypercalcemic activity while retaining the growth and immunologic regulating properties. In the present study, the efficacy of 1alpha,24(S)-dihydroxyvitamin D(2) (1alpha,24(S)(OH)(2)D(2)), a vitamin D(2) analog, in restraining cell proliferation was compared to that of 1alpha,25(OH)(2)D(3). In parallel studies, cancer cell lines were grown in increased concentrations (10(-10)-10(-7) M) of each compound for various incubation periods (1-4 days). Growth was assessed by measuring [(3)H]thymidine incorporation. The results revealed that 1alpha,24(S)(OH)(2)D(2) significantly inhibits proliferation to an extent similar to that observed for 1alpha,25(OH)(2)D(3). Moreover, incubating the human leukemia cell line, HL-60, with 1alpha,24(S)(OH)(2)D(2) resulted in an induction of differentiation of these promyelomonocyte cells into monocyte-macrophage-like cells, in a manner similar to that observed with 1alpha,25(OH)(2)D(3). Using a Western procedure, it was also shown that 1alpha,24(S)(OH)(2)D(2) like 1alpha,25(OH)(2)D(3) enhances the expression of vitamin D receptors (VDR) in the rat osteosarcoma cell line, ROS 17/2.8. The expression of tumor necrosis factor (TNF) alpha (TNF-alpha) in human peritoneal macrophages (HPM) obtained from uremic patients treated with continuous ambulatory peritoneal dialysis (CAPD) was found to be regulated by 1alpha,25(OH)(2)D(3) as well as by 1alpha,24(S)(OH)(2)D(2). Incubations of HPM with 1alpha,25(OH)(2)D(3) or 1alpha,24(S)(OH)(2)D(2), have inhibited the expression of TNF-alpha on both mRNA and protein levels. These results suggest that 1alpha,25(OH)(2)D(3) has a role in controlling the rate of inflammation in the peritoneal cavity of CAPD treated patients. Since 1alpha,24(S)(OH)(2)D(2) does not cause hypercalcemia, the present results encourage the possible use of this vitamin D(2) analog in the treatment of cancer and hyper-inflammatory diseases.
Steroids
PMID:The effects of 1alpha,24(S)-dihydroxyvitamin D(2) analog on cancer cell proliferation and cytokine expression. 1117 40

Cerebral malaria is the main cause of death in severe Plasmodium falciparum infection and is one of the most important medical emergencies. No conclusive theory exists on the pathogenesis of cerebral malaria, although it has been shown that the level of tumor necrosis factor correlates well with the severity of symptoms. Involvement of the intracerebral capillaries by the malaria parasites interferes with microcirculation in the brain, leading to cerebral anoxia, oedema, and cell death. Cerebral oedema is not, however, consistently found in all cases. The condition is more commonly seen in nonimmune people, children below five years old, and in pregnancy. Nonetheless, any degree of impairment of cerebral functions given infection with P. falciparum warrants clinical consideration of cerebral malaria unless proved otherwise. Basic principles of management should include maintenance of patent airways, care of bowel, bladder, skin; regular blood sugar estimation; intravenous or oral Quinine 10 mg per body weight every eight hours for 5-10 days; intravenous glucose; daily parasite count; exchange transfusion and hemodialysis when indicated. Steroids should never be used.
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PMID:Cerebral malaria -- its management. 1228 4

Crohn's disease and ulcerative colitis, both chronic inflammatory bowel diseases, have become an important health problem in the US and in Northern Europe. Both diseases require significant medical therapy for treatment and prevention of relapses. Traditional treatment is based on aminosalicylates and steroids. Steroids are associated with major complications and many patients are either dependent upon or refractory to steroids. The development of new drugs is therefore very important. This is possible because of a better knowledge of the pathogenetic mechanisms of the diseases. Many of the new drugs belong to the family of biologic therapies. Because of the expense of production and the parenteral delivery systems needed for most of them, these therapies must prove to be significantly more effective than traditional drugs. Many biologic agents are still under investigation. Therapeutic strategies directed against tumor necrosis factor (TNF)-alpha, including monoclonal antibodies, such as infliximab and CDP-571 and the human recombinant TNF receptor fusion protein, etanercept, have already been proven to be beneficial, especially in treating Crohn's disease. Treatment with infliximab induces even endoscopic and histologic healing. The benefit of additional immunosuppressive therapy is under investigation. New treatment strategies that might change the natural course of the disease can be considered for Crohn's disease. The experience with biologic agents for ulcerative colitis is still limited. A preliminary study with antegren, a recombinant humanized antibody against integrins is promising. The initial safety experience with infliximab is favorable but, ultimately, evaluation of large populations of patients over many years is required to define the relative safety of biologic agents.
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PMID:Biological therapies in IBD: an international course. 1602 80


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