Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Analysis of apoptosis in the human adrenal appears to be of eminent importance in the understanding of adrenal structure, zonation, and function. In this study we investigated the programmed cell death of normal adrenal tissues on the basis of apoptotic index by the nonradioactive in situ end labeling of DNA fragments, proliferating cell nuclear antigen, (PCNA), CD95 (cluster of differentiation), major histocompatibility complex class II immunohistochemistry, and ultrastructural analysis. The highest apoptotic index was detected in the outermost zones of the adrenal cortex, mainly in the zona glomerulosa. A labeling index of 50.46 +/- 5.22% (mean +/- SEM) for zona glomerulosa, 9.36 +/- 1.68% for zona fasciculata, 3.90 +/- 0.78% for zona reticularis, and 7.37 +/- 1.62% for the zona medullaris was found. Immunohistochemistry was used to distinguish between apoptotic and S phase cells. Positive anti-PCNA staining occurred in the inner cortical zones, whereas anti-CD95 signals appeared throughout the whole cortex, albeit at a much weaker level. MHC class II expression, which is known to be associated with programmed cell death, was demonstrated in the inner cortical zone. The data showed that mechanisms of cell death other than necrosis occur in the adrenal. In conclusion, we found a differential regulation of cell death for each zone of the adrenal cortex; the old theories of adrenal zonation (migrational vs. zonal or transformation theory) may, in fact, correlate with each other.
 ...
PMID:Differential regulation of apoptosis in the normal human adrenal gland. 892 71

Major histocompatibility complex (MHC) class II antigens are expressed on adrenocortical cells of the zona reticularis and have been shown to be a marker of dignity. This suggests a correlation to the zellular differentiation of the adrenal cortex. Therefore, we immunohistochemically investigated the MHC class II expression in the context of the ontogenesis of the zonal and cellular differentiation in fetal, postnatal, childhood, and adult adrenals. Cell types and cell turnover were studied using specific immune markers (including expression of CD95/ Fas), in situ end labeling of apoptosis, and electron microscopy. We show that prenatal (fetal and definitive) steroid cells, as well as postnatal adrenals, reveal no expression of MHC class II. In childhood, these antigens first appear by the fourth year, in parallel with the differentiation of reticularis cells. The expression index in childhood was 7.43% +/- 2.78 (mean +/- SEM), in adult adrenals 18.63% +/- 3.14 (third decade), and 15.15% +/- 1.26 (fourth through sixth decade). In conclusion, MHC class II expression and the development of the functional maturation of the adult adrenal cortex occur simultaneously. The expression of MHC class II on steroid cells may thus be involved in potential immune-adrenal interactions.
 ...
PMID:Relevance of major histocompatibility complex class II expression as a hallmark for the cellular differentiation in the human adrenal cortex. 928 58

Cytotoxic T lymphocytes (CTLs) that infiltrate the heart are important immune effectors implicated in heart transplant rejection, myocarditis, and other cardiomyopathies. To investigate the mechanism(s) underlying CTL damage to the myocardium through activation of the Fas receptor (Fas/CD95/Apo-1) by the Fas ligand, we explored the interaction between peritoneal exudate CTLs (PELs), derived from perforin gene-knockout (P-/-) mice, and murine ventricular myocytes. Fas expression on isolated ventricular myocytes was demonstrated immunohistochemically. Action potentials, [Ca2+]i transients, and contractions of myocytes conjugated to P-/- PELs or treated with the apoptosis-inducing anti-Fas monoclonal antibody Jo2 were recorded. Action potential characteristics of nonconjugated myocytes and myocytes conjugated with P-/- PELs were, respectively, as follows: Vm, -73.2+/-1.5 and -53.6+/-6.4 mV (mean+/-SEM); action potential amplitude, 117.9+/-3.9 and 74.3+/-21.2 mV; and action potential duration at 80% repolarization, 17+/-6 and 42+/-13 milliseconds (all P<.05). P-/- PELs also induced early and delayed afterdepolarizations as well as arrhythmogenic activity. Diastolic [Ca2+]i increased during the cytocidal interaction with P-/- PELs, from a fluorescence ratio of 0.82+/-0.05 (n=7) to 1.98+/-0.09 (n=13) (P<.05). All of the effects caused by P-/- PELs were reproduced by incubating the myocytes with Jo2. Heparin (50 microg/mL), an antagonist of inositol trisphosphate (IP3)-operated sarcoplasmic reticulum Ca2+ channels, or U-73122 (2 micromol/L), a phospholipase C inhibitor, but not the inactive agonist U-73343, prevented Fas-mediated myocyte dysfunction. Additionally, intracellular application (through the patch pipette) of the active IP3 analogue, inositol 1,4,5-trisphosphate, but not the inactive analogue, inositol 1,3,4-trisphosphate, caused electrophysiological changes resembling those resulting from P-/- PELs and Jo2, suggesting that CTL-induced Fas-based myocyte dysfunction is mediated by IP3. We conclude that a Fas-based perforin-independent mechanism of CTL action can account for the immunopathology seen in the allotransplanted heart, myocarditis, and dilated cardiomyopathy.
 ...
PMID:Fas (CD95/Apo-1)-mediated damage to ventricular myocytes induced by cytotoxic T lymphocytes from perforin-deficient mice: a major role for inositol 1,4,5-trisphosphate. 950 4

The regulatory effects of IFNgamma on CD95 expression and CD95-mediated cell death were investigated in three high-risk pro-B acute lymphoblastic leukemia (ALL) lines that carry the chromosomal translocation t(4;11)(q21;q23). These leukemias are characteristically refractory to conventional chemotherapeutic treatments operating through the induction of apoptosis. However, the mechanisms leading to increased cell survival and resistance to cell death in these leukemias are largely unknown. Interferon-gamma (IFNgamma), a potent inhibitor of hematopoiesis, acts in part by upregulating CD95 and sensitizing cells to CD95-induced apoptosis. The t(4;11) lines SEM, RS4;11, and MV4;11 expressed low levels of CD95, but were completely resistant to CD95-mediated death. Addition of IFNgamma markedly upregulated CD95 expression in SEM (8-9-fold), RS4;11 (2-3-fold), and MV4;11 (2-3-fold) lines. However, after treatment with IFNgamma, only an 11% increase in sensitivity to CD95-mediated cell death was observed in SEM cells, whereas RS4;11 and MV4;11 cells remained resistant. Cycloheximide, but not actinomycin D or brefeldin A, increased CD95-specific cell death only in IFNgamma-treated RS4;11 cells by approximately 12%. Abundant levels of Bcl-2 and Bcl-XL, known to inhibit CD95-signaling in some cells, were present suggesting a possible role for both molecules in the resistance to CD95-mediated cell death. Resistance of the leukemic blasts to CD95-mediated cell death and the failure of IFNgamma to substantially sensitize the CD95-signaling pathway may contribute to the highly malignant phenotype of pro-B ALL with translocation t(4;11).
 ...
PMID:Regulation of CD95 expression and CD95-mediated cell death by interferon-gamma in acute lymphoblastic leukemia with chromosomal translocation t(4;11). 1051 55

B-lineage acute leukaemia cells are generally resistant to CD95-mediated apoptosis. In this report, the CD95-resistant B-leukaemia lines SEM, RS4;11, and REH were used to investigate the mechanisms of resistance to CD95-signalling. We found that interferon-gamma (IFN-gamma) treatment increased the presence of high molecular weight forms of CD95 in these cells as judged by Western analysis, and treatment of protein extracts with Peptide: N -glycosidase F indicated that the majority of high molecular weight forms were due to N-linked glycosylation. Treatment of whole cells with neuraminidase from Vibrio cholerae substantially reduced the relative molecular mass of CD95 observed after IFN-gamma treatment and partially sensitized the three leukaemia lines to CD95-mediated death. To further characterize the different steps of oligosaccharide processing that may regulate CD95 signalling, the leukaemic cells were treated with IFN-gamma and the glycosidase inhibitors castanospermine, 1-deoxymannojirimycin (DMM), and swainsonine. Treatment with DMM, a mannosidase inhibitor, efficiently reduced the appearance of high molecular weight forms of CD95 after IFN-gamma treatment, and sensitized SEM and REH cells to CD95-mediated death. However, the IFN-gamma-induced increases of CD95 on the cell surface were not altered by treatment with any of the glycosidase inhibitors, suggesting that the generation of complex oligosaccharide structures is not required for trafficking of CD95, but may instead be used as a mechanism of partially blocking CD95 signalling in these cells. In conclusion, IFN-gamma treatment of the B-lineage leukaemia lines provides a novel, inducible system for the further characterization of post-translational modifications involved in modulating sensitivity to CD95-signalling.
 ...
PMID:Interferon-gamma increases the expression of glycosylated CD95 in B-leukemic cells: an inducible model to study the role of glycosylation in CD95-signalling and trafficking. 1209 25

The malononitrilamide FK778 is a leflunomide analogue with a shorter half-life than leflunomide. Groups of cynomolgus monkeys were treated orally with various doses of FK778 once daily for 7 days: group A, 10 mg/kg ( n=4); group B, 5 mg/kg ( n=3); and group C, one single loading dose of 20 mg/kg followed by 5 mg/kg once daily ( n=2). Trough plasma concentration of FK778 was measured by HPLC. Lymphocyte proliferation and expression of T-cell activation surface antigens were assessed by flow cytometry. In group A, trough plasma concentration of FK778 reached steady state at 48 h. After 7 days, lymphocyte proliferation was 23+/-7.4% (mean +/- SEM) and expression of CD71, CD25, CD11a and CD95 on T cells was less than 50% of pre-treatment baseline values. In group B, trough plasma levels of FK778 did not reach steady state, but dropped to near-zero levels after 3 days and on day 7 and lymphocyte proliferation and T-cell surface antigen expression were not different from pre-treatment baseline values. In group C, FK778 trough levels did not reach steady state, but drug exposure was evident over the entire period of treatment, and on day 7, lymphocyte proliferation was 11.4+/-8.6% of pre-treatment baseline values. We conclude that FK778 inhibits lymphocyte proliferation and expression of T-cell activation antigens in vivo in non-human primates after 1 week of treatment. These effects are related to the total drug exposure over the time of treatment. At doses lower than 10 mg/kg daily, FK778 is cleared from the circulation between the dosing intervals, thus failing to exert its inhibitory effects on immune functions.
 ...
PMID:In vivo pharmacokinetic and pharmacodynamic evaluation of the malononitrilamide FK778 in non-human primates. 1271 38

A beryllium (Be)-ferritin adduct containing 270 pm of Be stimulated proliferation of bronchoalveolar lavage (BAL) lymphocytes from subjects with chronic beryllium disease (CBD) at concentrations 5-6 logs lower than the amounts of beryllium sulfate (BeSO4) needed to induce proliferation. We observed increased apoptotic CBD BAL macrophages after exposure to both BeSO4 (50 +/- 6%, mean +/- SEM, P <0.05 versus unstimulated controls) and Be-ferritin (40 +/- 2%), whereas only 2.0 +/- 0.2% of BAL lymphocytes underwent activation-induced cell death. Be-ferritin also induced apoptosis in BAL macrophages from subjects with Be sensitization (25 +/- 3%) and in the H36.12j hybrid macrophage cell line (15 +/- 2%). Be-ferritin induced lung macrophage CD95 (Fas) expression and the activation of intracellular caspase-3, -8 and -9. Thus, lung macrophages take up Be-ferritin, delivering physiologically relevant levels of Be that promote Be antigen presentation and macrophage apoptosis. Be-ferritin thereby serves as a "Trojan Horse," triggering proliferation of Be-ferritin-specific CBD BAL T cells. We hypothesize that Be-ferritin exposure may result in persistent antigen exposure inducing Be-specific T cell clonal expansion and T cell helper type 1-type cytokine production and potentially explains the chronicity of CBD and its development years after environmental Be exposure has ceased.
 ...
PMID:Beryllium-ferritin: lymphocyte proliferation and macrophage apoptosis in chronic beryllium disease. 1525 86

Cryopreservation increases the rate of apoptotic spermatozoa with decreased capability to fertilise oocytes. In order to optimise the fertilisation rates, especially in assisted reproduction the use of apoptotic sperms should be avoided. Early events of apoptosis in cryopreserved spermatozoa are not detectable by conventional methods. However, the surface of apoptotic spermatozoa is characterised by externalisation of phosphatidylserine (PS), which has a high affinity to Annexin V. Therefore, colloid paramagnetic Annexin-V-conjugated microbeads (AN-MB) were tested for their ability to eliminate apoptotic spermatozoa from a total of 40 fresh and in TEST yolk buffer cryopreserved semen samples which were provided by 15 healthy volunteers. By passing through a magnetic field (MiniMACS, Miltenyi Biotec) the sperm suspensions were divided into 2 sperm fractions depending on bound magnetic Annexin V-microbeads (AN-MB) to spermatozoa. As additional markers of apoptosis CD95 (Fas, APO-1) on the sperm surface and activated caspases in the cytosol were detected in both fractions. Supplementary investigations comprised eosin-supravital staining and computer assisted sperm motion analysis. The separation was supervised by flow cytometric analysis of spermatozoa labelled with FITC-conjugated anti Annexin V-antibodies. Analyses of the magnetic inactive sperm fraction (AN-MB-negative) showed CD95 on 0.6 +/- 0.3% (X +/- SEM) of spermatozoa and only 3.2 +/- 0.5% were stainable with eosin, whereas, 40.6 +/- 6.7% of the remaining cells in the column appeared to be CD95 positive and 99.8 +/- 0.1% stainable with eosin after cryopreservation. Indeed the overall amount of CD95 positive spermatozoa did not significantly increase after cryopreservation (2.5 +/- 0.5% vs. 4.3 +/- 1.2%; p > 0.05). Activated caspases were found in 21.8 +/- 2.6% of the spermatozoa in fresh and in 47.7 +/- 5.8% of cryopreserved semen samples (p < 0.01). The separation procedure of the cryopreserved spermatozoa reduced significantly the quantity of those containing activated caspases to 9.3 +/- 2.2% within the AN-MB-negative fraction. In contrast 89.1 +/- 2.3% of AN-MB-positive sperms showed activation of these proteolytic enzymes. Flow cytometric analyses using FITC-conjugated anti Annexin V-antibodies for monitoring of AN-MB-binding to spermatozoa showed 5.2 +/- 1.0% labelled spermatozoa in the AN-MB negative fraction and 72.6 +/- 2.7% labelled spermatozoa in the AN-MB positive one. There was no significant influence of the separation column and the magnetic field on the sperm functions. The passage through the column led to a sperm loss of 0.8 +/- 1.2%. Conclusion: The binding of paramagnetic Annexin V-conjugated microbeads is an excellent method to eliminate spermatozoa at early apoptotic stages from cryopreserved semen samples. A deleterious influence of the separation column and the magnetic field on the spermatozoa was not observed.
 ...
PMID:Enrichment of non-apoptotic human spermatozoa after cryopreservation by immunomagnetic cell sorting. 1525 10

Cigarette smoking enhances apoptosis rate of alveolar macrophages. However, little is known about the appearance and extension of apoptosis in bronchoalveolar lavage (BAL) lymphocytes originating from smoker individuals, both in pulmonary sarcoidosis (the disease characterized by lymphocytic alveolitis) and in controls. BAL was carried out in 60 nontreated patients with pulmonary sarcoidosis, subdivided acc. smoking status and in 22 control persons, free of any lung pathology. BAL (alveolar) lymphocytes were a) stained for TUNEL; b) permeabilized and stained with PI for late apoptosis/cell cycle analyses; c) immunophenotyped, including CD95, CD95 Ligand, Bcl-2, Bcl-XL, Bak and insulin-like growth factor-I (IGF-I) expression. BD FACSCalibure flow cytometer, PC Lysys and ModFit software were applied. The low number of AL entered apoptosis, which was confirmed by both techniques. Cigarette smokers were characterized by higher AL apoptosis percentage in respective subgroups (sarcoidosis: 0.6 +/- 0.13 in nonsmokers vs 0.9 +/- 0.23 in smokers; controls: 0.85 +/- 0.23 in nonsmokers vs 1.5 +/- 0.35 smokers, median +/- SEM, p < 0.05); the proliferation rate was lower. Decreased IGF-I expression in AL of sarcoidosis smokers was observed (13.5 +/- 9.2 vs 46.0 +/- 6.0 in nonsmokers, p < 0.05). No differences were found between studied groups in expression of Bcl-2, Fas and FasL molecules (except significantly declined ratio of CD8+FasL+ cells in sarcoidosis nonsmokers). AL apoptosis rate was positively correlated with respective alveolar macrophage results (Rs = +0.59, p < 0.00001) and negatively with CD4/CD8 ratio (Rs = -0.32, p < 0.001); no correlation was found with lung function test results and with Bcl-2, Fas and FasL expression in BAL cells. Apoptosis of alveolar lymphocytes was more frequent in nonsmokers both in pulmonary sarcoidosis and in controls; lower AL percentage proliferates. These phenomena seem to participate in lower AL percentage, observed in smoker subgroup of sarcoidosis. Some mechanisms of local apoptosis alterations in smokers may be common for alveolar lymphocytes and macrophages.
 ...
PMID:[Apoptosis of alveolar lymphocytes in sarcoidosis and in control group is more frequent in smokers than in nonsmoking persons]. 1728 68