UMLS:C0011570 - FACTA Search

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Query: UMLS:C0011570 (depression)
172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fibroblast-mediated cytokine gene therapy has proven to be a promising strategy for restoring hematopoiesis following repeated chemotherapy. Interleukin 3 (IL-3) and interleukin 6 (IL-6) can synergistically promote the recovery of hematopoiesis following chemotherapy. In this investigation, combined use of fibroblast-mediated IL-3 and IL-6 gene therapy was tested for hematopoietic effects on mice with or without 5-fluorouracil administration. The results demonstrated that combined therapy with IL-3 gene-modified NIH3T3 cell (NIH3T3-IL-3) and IL-6 gene-modified fibroblast NIH3T3 cell (NIH3T3-IL-6) implantation achieves obvious stimulation of hematopoiesis in normal mice and accelerates recovery of hematopoiesis. In normal mice the quantities of platelets, neutrophils, and total white blood cells in peripheral blood increased significantly after the combined implantation of NIH3T3-IL-3 and NIH3T3-IL-6 cells. The numbers of colony-forming unit (CFU) granulocyte/macrophage (CFU-GM) and CFU megakaryocyte (CFU-MK) formed by stem cells in bone marrow was significantly higher after the combined implantation of NIH3T3-IL-3 and NIH3T3-IL-6 cells than after the implantation of NIH3T3-IL-3 alone, NIH3T3-IL-6 alone, or neomycin gene-modified NIH3T3 cells. In hematopoiesis-depressed mice induced by preinjection with 5-fluorouracil at the dose of 150 mg/kg before cell implantation, the platelets, neutrophils, and white blood cells showed accelerated recovery, and the numbers of CFU-GM and CFU-MK formed by bone marrow cells were also markedly higher after the combined implantation of NIH3T3-IL-3 and NIH3T3-IL-6 cells than in control groups. Our data show that combined use of fibroblast-mediated IL-3 and IL-6 gene therapy may be of clinical relevance for the recovery of hematopoietic depression for patients after chemotherapy.
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PMID:Effects of fibroblast-mediated interleukin 3 and interleukin 6 gene therapy on hematopoiesis in mice treated with 5-fluorouracil. 982 23

The production and release of granulocytes and macrophages, crucial elements of the host defense system, are significantly impaired after burn injury and sepsis. Prostaglandin E2 (PGE2) is known to be myelosuppressive. We hypothesized that the macrophages contributed to myelopoietic suppression by means of increased PGE2 production, which is induced by thermal injury and sepsis. In this study, peritoneal macrophages were elicited at day 3 from normal mice and from mice who underwent a 15% total body surface area dorsal scald burn with or without Pseudomonas aeruginosa burn wound infection. The macrophages were incubated with or without endotoxin and with or without PGE2 polyclonal antiserum (anti-PGE2) for 18 hours. Macrophage supernatants were then used in co-cultures of bone marrow cells in a clonogenic assay of granulocyte-macrophage colony-forming cells (GM-CFCs) to determine the effect of burn wound infection on the alteration of the proliferative status of the GM-CFCs. Burn wound infection and endotoxin both caused marked reductions in GM-CFC growth in culture (20%-40% as compared with normal, P < .05-.01). The inhibition of GM-CFC growth induced by burn, burn plus infection, or endotoxin was significantly reversed by the addition of anti-PGE2 to the cultures (30%-40% increase in GM-CFC colony growth as compared with cultures without anti-PGE2). These results suggest that PGE2 is a key mediator in the gram-negative sepsis-induced macrophage suppression of granulocyte and macrophage production. The ability of anti-PGE2 to neutralize PGE2 activity may provide a useful means of mitigating myeloid depression that follows postburn sepsis.
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PMID:Macrophage mediated suppression of granulocyte and macrophage growth after burn wound infection reversal by means of anti-PGE2. 1066 41

In the present work we show that acute infection of C3H mice with the CL strain of Trypanosoma cruzi is characterized by an exponential growth of parasites and high mortality accompanied by anemia, thrombocytopenia, leukopenia, and bone marrow hypoplasia. Administration of nifurtimox, a trypanocydal drug currently in clinical use at different days postinfection, modulates parasitemia and prevents mortality. More importantly, none of blood and bone marrow alterations were observed in nifurtimox-treated animals when treatment was initiated early in infection, one or seven days postinoculation. The bone marrow alterations were characterized by a decrease in the total number cells as well in the number of megakaryoblasts and erythroblasts. Transfer experiments of bone marrow cells from infected mice to noninfected lethally irradiated recipients revealed a poor marrow-repopulating activity. The colony forming units-spleen assay confirmed the depression of committed clonal progenitors cells and revealed a decreased number of granulocyte/macrophage, megacariocyte and erythrocyte colonies. In summary, this is the first report showing that acute T. cruzi infection results in profound alterations of the hematopoietic system and that these alterations can be prevented by nifurtimox treatment.
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PMID:Acute Trypanosoma cruzi infection is associated with anemia, thrombocytopenia, leukopenia, and bone marrow hypoplasia: reversal by nifurtimox treatment. 1081 35

Apoptotic death of CD8(+) T cells can be induced by a population of inhibitory myeloid cells that are double positive for the CD11b and Gr-1 markers. These cells are responsible for the immunosuppression observed in pathologies as dissimilar as tumor growth and overwhelming infections, or after immunization with viruses. The appearance of a CD11b(+)/Gr-1(+) population of inhibitory macrophages (iMacs) could be attributed to high levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) in vivo. Deletion of iMacs in vitro or in vivo reversed the depression of CD8(+) T-cell function. We isolated iMacs from the spleens of immunocompromised mice and found that these cells were positive for CD31, ER-MP20 (Ly-6C), and ER-MP58, markers characteristic of granulocyte/monocyte precursors. Importantly, although iMacs retained their inhibitory properties when cultured in vitro in standard medium, suppressive functions could be modulated by cytokine exposure. Whereas culture with the cytokine interleukin 4 (IL-4) increased iMac inhibitory activity, these cells could be differentiated into a nonadherent population of fully mature and highly activated dendritic cells when cultured in the presence of IL-4 and GM-CSF. A common CD31(+)/CD11b(+)/Gr-1(+) progenitor can thus give rise to cells capable of either activating or inhibiting the function of CD8(+) T lymphocytes, depending on the cytokine milieu that prevails during antigen-presenting cell maturation. (Blood. 2000;96:3838-3846)
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PMID:Identification of a CD11b(+)/Gr-1(+)/CD31(+) myeloid progenitor capable of activating or suppressing CD8(+) T cells. 1109 68

Plasma levels of human polymorphonuclear elastase (PMN-E) are considered a marker of granulocyte activation and can potentially complement the peripheral neutrophil count in laboratory and pathophysiological settings. Neutrophilic leukocytosis is a well known effect of lithium therapy, but there is no information about the concomitant behaviour of PMN-E in these patients. The aim of this study was to evaluate both polymorphonuclear leukocyte count and plasma PMN-E levels in depression patients undergoing chronic lithium therapy. Absolute and differential leukocyte count in venous peripheral blood was determined by an automated method, and PMN-E evaluated by enzyme immunoassay. 39 patients (11 males, 28 females; mean age 43. +/- 6.02) with depression disorders were studied, during lithium carbonate therapy. Neutrophilia (neutrophil count > 7.500x10(9) cells per liter) was found in 7 (18%) patients and an increase in plasma PMN-E levels (PMN-E > 56 microg per liter ) in 6 (15%). No correlations were found between neutrophil count, plasma concentration of PMN-E, plasma level of lithium and duration of therapy. The results show that in these patients, not only the PMN count but also elastase levels can exceed the normal range. The absence of correlation between these two parameters suggests that the state of PMN activation is not linked to their number in peripheral blood.
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PMID:Neutrophil peripheral count and human leukocyte elastase during chronic lithium carbonate therapy. 1110 80

When cows develop endometritis after birth, Escherichia coli and Arcanobacterium pyogenes are usually the most prominent bacteria present in bovine uterine lochial secretions. A. pyogenes alone is rarely found in the course of a disturbed puerperium. This was confirmed in this study, since average and high-grade uterine contaminations were always associated with the presence of both bacteria. The contamination grade was positively correlated with uterine polymorphonuclear granulocyte (PMN) numbers and negatively correlated with blood PMN numbers. Whether E. coli and A. pyogenes affect the phenotype and function of bovine PMN in a similar or differential way was subject to in vitro studies. PMN were tested in the presence of washed bacterial fragments or culture supernatants taken as a source for soluble and/or secreted bacterial products. Fragments and soluble products differed only quantitatively in their effects on PMN. Usually, long-time exposure (24h) of PMN to fragments induced the strongest effects. Accelerated death of granulocytes was only moderately induced by both E. coli and A. pyogenes products. Both E. coli and A. pyogenes products induced the enhanced expression of a membrane molecule detected by mAb IL-A110 and of CD11b. Expression of other surface structures remained largely unchanged (MHC class I, CD11c). Functional parameters of PMN (phagocytosis; generation of reactive oxygen species, ROS; antibody-independent cellular cytotoxicity, AICC) generally declined after pre-incubation for 24h with products of E. coli or A. pyogenes. Interestingly, soluble products of A. pyogenes stimulated the phagocytosis of PMN. However, co-incubation with E. coli products abrogated this stimulatory effect. The results supply evidence for similar modes of action of the gram-negative E. coli and the gram-positive A. pyogenes on bovine PMN. Alterations in PMN function and phenotype are mainly triggered by direct contact between bacterial fragments and PMN. Inhibition experiments with polymyxin B demonstrated that E. coli-mediated effects were not solely due to the action of lipopolysaccharide. The dominant functional depression of neutrophils by E. coli products strengthens the suggestion that the earlier appearance of E. coli in the uterus may support the co-infection of this organ by A. pyogenes at later times.
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PMID:Influence of Escherichia coli and Arcanobacterium pyogenes isolated from bovine puerperal uteri on phenotypic and functional properties of neutrophils. 1126 94

TaqMan real time PCR was used to study the transcriptional activity of the bovine IL-2, IL-6, IL-12p40, IFN-gamma, TNF-alpha and granulocyte-monocyte colony stimulating factor of whole milk cells in bovine mammary gland experimentally infected with Staphylococcus aureus. Cytokine transcriptional activity was monitored at 7, 24 and 32 h Post-infection (Pi). IL-12 and TNF-alpha levels were significantly elevated at 24 h Pi followed by sharp decrease at 32 h pi. IL-2 level was decreased at 32 h pi. IL-12 and IFN-gamma showed a significant interaction at 24 h pi. The significant elevations of the IL-12 and TNF-alpha transcriptional level most likely indicate their important role in regulation of the immune responses of bovine mammary gland in S. aureus infection. Depression of IL-2 could reflect the suppressive nature of the S. aureus mastitis.
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PMID:The cytokine markers in Staphylococcus aureus mastitis of bovine mammary gland. 1266 86

Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor with neuroprotective and antiinflammatory properties. By real-time polymerase chain reaction we show that G-CSF transcripts are induced 485-fold at 4 h and 65-fold at 16 h in ischemic lesions after middle cerebral artery occlusion compared to control brains. Further analysis in photochemically induced focal ischemia revealed that G-CSF induction involved both the infarct area and remote nonischemic brain regions. Remote responses could be blocked by the noncompetitive NMDA receptor antagonist MK-801, suggesting periinfarct depolarizations as a trigger. To further confirm this notion, cortical spreading depression (CSD) was induced by focal application of KCl to the brain surface. CSD led to a 90-fold increase in G-CSF mRNA. Contrastingly, the induction of granulocyte-monocyte (GM)-CSF, another member of the hematopoietic growth factor family, was only moderate (sixfold) and restricted to ischemic brain lesions. In conclusion, G-CSF induction in the brain may be part of an intrinsic stress response aimed at limitation of neuronal damage.
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PMID:Induction of granulocyte colony-stimulating factor mRNA by focal cerebral ischemia and cortical spreading depression. 1553 Jun 54

Azathioprine (AZA) is a cytotoxic immunosuppressive drug used in the prevention of rejection in organ transplants and the treatment of auto-immune diseases. However, AZA is haemotoxic causing significant bone marrow depression. The present studies were to characterize the haemotoxicity of AZA in the female CD-1 mouse. In Experiment 1, a dose-ranging study, with AZA gavaged daily for 10 days, clinical evidence of toxicity was evident at 125 mg/kg and above. Experiment 2 was a dose-response study with AZA gavaged daily for 10 days at 40-120 mg/kg. At day 1 after the final dose, AZA induced a dose-related pancytopaenia, reduced femoral marrow cellularity, increases in serum levels of the cytokine fms-like tyrosine kinase 3 ligand, reduction in granulocyte-monocyte colony-forming units and erythroid colonies, and increased bone marrow apoptosis. Histology demonstrated hepatocyte hypertrophy, thymic atrophy, reduced splenic extramedullary haemopoiesis, and reduced cellularity of sternal bone marrow. In Experiment 3, AZA was dosed for 10 days at 100 mg/kg with autopsies at 1, 3, 9, 22, 29, 43 and 57 days postdosing. At 1, 3 and 9 days, haematological parameters reflected changes in Experiment 2. At 22/29 days, many blood parameters were returning towards normal; at 43/57 days, most parameters compared with controls. However, there was some evidence of a persistent (i.e. residual/late-stage) mild reduction in RBC and erythroid progenitor cell counts at day 43/57. We conclude that the CD-1 mouse provides an acceptable model for the haemotoxicity of AZA in man.
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PMID:The haemotoxicity of azathioprine in repeat dose studies in the female CD-1 mouse. 1833 31

In this subacute toxicity study, ethyl methanesulfonate (EMS) was administered daily by oral gavage to SPF-bred Wistar rats of both sexes at dose levels of 20, 60 and 180/120 mg/kg body weight (bw)/day for a period of 28 days (for 19 days in the high-dose group). A control group was treated similarly with the vehicle, bidistilled water, only. The groups comprised 10 animals per sex, which were sacrificed after 28 days, respectively 19 days in the high-dose group, of treatment. Additional five rats per sex and group were treated accordingly and then allowed a 14 days treatment-free recovery period. Additional six rats per sex and group (three rats per sex in the control group) were treated accordingly and used for hemoglobin adduct analysis after EMS exposure. All animals survived until their scheduled necropsy. Treatment with EMS had a direct dose-dependent effect on food consumption and consequently on body weight at doses > or =20mg/kgbw/day in male rats and at > or =60 mg/kgbw/day in females rats. Hence, treatment with the high dose of 180 mg/kgbw/day had to be interrupted for 9 days after which, the animals were re-dosed at 120 mg/kgbw/day. This dose was also poorly tolerated over the remaining two treatment weeks causing again a marked reduction in food consumption and body weight. A dose of 60 mg/kgbw/day was moderately tolerated over 4 weeks treatment with mean daily food consumption and body weight distinctly lower than in controls. Primary targets of systemic toxicity were the hematopoietic system, thymolymphatic system and sexual organs. Characteristic changes in hematology parameters were decreased red blood cell counts, hematocrit, and hemoglobin concentration. White blood cell counts were also decreased due to reduced lymphocyte and granulocyte populations of each fraction. The corresponding histopathology findings were fatty atrophy of bone marrow and minimal hypocellularity of the white pulp of the spleen. Similarly, treatment with EMS caused an involution of the thymolymphatic system characterized by decreased organ weight of thymus, lymph nodes, and spleen microscopically associated with atrophy of the thymus and hypocellularity of Peyer's patches, lymph nodes and the white pulp of the spleen. The effects on sexual organs included lower organ weight/reduced size for testes, epididymides, seminal vesicles, prostate, and uterus. Tubular atrophy, single cell necrosis of the germ cells and in epididymides reduced spermatozoa were recorded microscopically. The described findings occurred at doses of 60 and 180/120 mg/kgbw/day and were dose-dependent with regard to incidence and severity. Other target organs were the pancreas (acinar cell vacuolation), thyroid gland (follicular cell hypertrophy), and salivary gland (secretory depletion of convoluted ducts). The systemic exposure to EMS was monitored by hemoglobin ethylvaline adduct measurement. The concentration of hemoglobin ethylvaline adducts was linear with the dose and accumulated 11-26-fold over the treatment period. In summary, decreases in food consumption and body weight were the dose-limiting effects of treatment with EMS. Organ toxicity was characterized by depression of cell proliferation (hematopoiesis and spermatogenesis) and changes suggestive of reduced metabolism and/or physiological imbalances (e.g. thymolymphatic system and thyroid gland) without signs of inflammatory or necrotic lesions. For some findings, especially the effects on the thymolymphatic system and sexual organs, it cannot be excluded that starvation-like condition contributed to the occurrence of such changes. The low dose of 20 mg/kgbw/day was basically free of adverse effects despite of a clear evidence for hemoglobin adducts.
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PMID:General 4-week toxicity study with EMS in the rat. 1944 10

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