scholarly journals NF-κB and FLIP in arsenic trioxide (ATO)-induced apoptosis in myelodysplastic syndromes (MDSs)

Blood ◽  
2005 ◽  
Vol 106 (12) ◽  
pp. 3917-3925 ◽  
Author(s):  
Daniella M. B. Kerbauy ◽  
Vladimir Lesnikov ◽  
Nissa Abbasi ◽  
Sudeshna Seal ◽  
Bart Scott ◽  
...  
Keyword(s):  
Arsenic Trioxide ◽  
Mononuclear Cells ◽  
Nuclear Translocation ◽  
Early Stage ◽  
Single Agent ◽  
Refractory Anemia ◽  
Low Grade ◽  
Death Domain ◽  
Tnf Α ◽  
Induced Apoptosis

Tumor necrosis factor (TNF)-α, a potent stimulus of nuclear factor-κB (NF-κB), is up-regulated in myelodysplastic syndrome (MDS). Here, we show that bone marrow mononuclear cells (BMMCs) and purified CD34+ cells from patients with low-grade/early-stage MDS (refractory anemia/refractory anemia with ring sideroblasts [RA/RARS]) have low levels of NF-κB activity in nuclear extracts comparable with normal marrow, while patients with RA with excess blasts (RAEB) show significantly increased levels of activity (P = .008). Exogenous TNF-α enhanced NF-κB nuclear translocation in MDS BMMCs above baseline levels. Treatment with arsenic trioxide (ATO; 2-200 μM) inhibited NF-κB activity in normal marrow, primary MDS, and ML1 cells, even in the presence of exogenous TNF-α (20 ng/mL), and down-regulated NF-κB-dependent antiapoptotic proteins, B-cell leukemia XL (Bcl-XL), Bcl-2, X-linked inhibitor of apoptosis (XIAP), and Fas-associated death domain (FADD)-like interleukin-1β-converting enzyme (FLICE) inhibitory protein (FLIP), leading to apoptosis. However, overexpression of FLIP resulted in increased NF-κB activity and rendered ML1 cells resistant to ATO-induced apoptosis. These data are consistent with the observed up-regulation of FLIP and resistance to apoptosis with advanced MDS, where ATO as a single agent may show only limited efficacy. However, the data also suggest that combinations of ATO with agents that interfere with other pathways, such as FLIP autoamplification via NF-κB, may have considerable therapeutic activity.

scholarly journals NPI-0052, a novel proteasome inhibitor, induces caspase-8 and ROS-dependent apoptosis alone and in combination with HDAC inhibitors in leukemia cells

Blood ◽  
2007 ◽  
Vol 110 (1) ◽  
pp. 267-277 ◽  
Author(s):  
Claudia P. Miller ◽  
Kechen Ban ◽  
Melanie E. Dujka ◽  
David J. McConkey ◽  
Mark Munsell ◽  
...  
Keyword(s):  
Proteasome Inhibitor ◽  
Histone Deacetylase Inhibitors ◽  
Mononuclear Cells ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Jurkat Cells ◽  
Model Systems ◽  
Caspase 8 ◽  
Death Domain ◽  
Induced Apoptosis

The proteasome has been successfully targeted for the treatment of multiple myeloma and mantle cell lymphoma; however, in other hematologic malignancies, bortezomib has been less effective as a single agent. Here, we describe effects of NPI-0052, a novel proteasome inhibitor, in leukemia model systems. In cell lines, NPI-0052 inhibits all 3 proteolytic activities associated with the proteasome: chymotrypsin-, trypsin-, and caspase-like. NPI-0052 also induces DNA fragmentation in leukemia lines and in mononuclear cells from a Ph + acute lymphoblastic leukemia (ALL) patient. Caspase-3 activation by NPI-0052 was seen in wild-type Jurkat cells, but was significantly lessened in Fas-associated death domain (FADD)–deficient or caspase-8–deficient counterparts. NPI-0052–induced apoptosis was further probed using caspase-8 inhibitors, which were more protective than caspase-9 inhibitors. N-acetyl cysteine (NAC) also conferred protection against NPI-0052–induced apoptosis, indicating a role for oxidative stress by NPI-0052. In support of the drug's in vitro activities, biweekly treatment with NPI-0052 lessened total white blood cell (WBC) burden over 35 days in leukemic mice. Interestingly, combining NPI-0052 with either MS-275 or valproic acid (VPA) induced greater levels of cell death than the combination of bortezomib with these histone deacetylase inhibitors (HDACi). These effects of NPI-0052, alone and in combination with HDACi, warrant further testing to determine the compound's clinical efficacy in leukemia.

Dipyridamole decreases inflammatory metalloproteinase-9 expression and release by human monocytes

2013 ◽  
Vol 109 (02) ◽  
pp. 280-289 ◽  
Author(s):  
Maria Annunziata Carluccio ◽  
Mariangela Pellegrino ◽  
Nadia Calabriso ◽  
Carlo Storelli ◽  
Giuseppe Martines ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Mononuclear Cells ◽  
Nuclear Translocation ◽  
Human Peripheral Blood ◽  
Antiplatelet Agent ◽  
Guanosine Monophosphate ◽  
Human Monocytes ◽  
Peripheral Blood Mononuclear ◽  
Tnf Α ◽  
Anti Inflammatory

SummaryMatrix metalloproteinase (MMP)-9 plays an important role in stroke by accelerating matrix degradation, disrupting the blood-brain barrier and increasing infarct size. Dipyridamole is an antiplatelet agent with recognised benefits in ischaemic stroke prevention. In addition to its antiplatelet properties, recent studies have reported that dipyridamole also features anti-inflammatory and anti-oxidant properties. We therefore investigated whether dipyridamole can ameliorate the proinflammatory profile of human monocytes, a source of MMP-9 in stroke, in terms of regulation of MMP-9 activity and expression, and explored underlying mechanisms. Human peripheral blood mononuclear cells (PBMC) and U937 cells were treated with increasing concentrations of dipyridamole (up to 10 µg/ml) for 60 minutes before stimulation with tumour necrosis factor (TNF)-α or phorbol myristate acetate (PMA). Exposure of PBMC and U937 to dipyridamole reduced TNF-α- and PMA-induced MMP-9 activity and protein release as well as MMP-9 mRNA, without significantly affecting the release of TIMP-1. This inhibitory effect was independent of dipyridamole-induced cyclic adeno-sine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) increase. Correspondingly, dipyridamole also significantly inhibited TNF-α-induced nuclear factor (NF)-κB activation and nuclear translocation of the p65 NF-κB subunit through a mechanism involving the inhibition of IkBα degradation and p38 MAPK activation. In conclusion, dipyridamole, at therapeutically achievable concentrations, reduces the expression and release of MMP-9 through a mechanism involving p38 MAPK and NF-κB inhibition. These results indicate that dipyridamole exerts anti-inflammatory properties in human monocytes that may favourably contribute to its actions in the secondary prevention of stroke, independent of its antiplatelet properties.

scholarly journals Endometrial Cancer: What Is New in Adjuvant and Molecularly Targeted Therapy?

2010 ◽  
Vol 2010 ◽  
pp. 1-11 ◽  
Author(s):  
Flora Zagouri ◽  
George Bozas ◽  
Eftichia Kafantari ◽  
Marinos Tsiatas ◽  
Nikitas Nikitas ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Metastatic Disease ◽  
Cancer Biology ◽  
Early Stage ◽  
Single Agent ◽  
Postoperative Management ◽  
Low Grade ◽  
Early Stage Disease ◽  
High Risk Factors ◽  
Staging Surgery

Endometrial cancer is the most common gynaecological cancer in western countries. Radiotherapy remains the mainstay of postoperative management, but accumulating data show that adjuvant chemotherapy may display promising results after staging surgery. The prognosis of patients with metastatic disease remains disappointing with only one-year survival. Progestins represent an effective option, especially for those patients with low-grade estrogen and/or progesterone receptor positive disease. Chemotherapy using the combination of paclitaxel, doxorubicin, and cisplatin is beneficial for patients with advanced or metastatic disease after staging surgery and potentially for patients with early-stage disease and high-risk factors. Toxicity is a point in question; however, the combination of paclitaxel with carboplatin may diminish these concerns. In women with multiple medical comorbidities, single-agent chemotherapy may be better tolerated with acceptable results. Our increased knowledge of the molecular aspects of endometrial cancer biology has paved the way for clinical research to develop novel targeted antineoplastic agents (everolimus, temsirolimus, gefitinib, erlotinib, cetuximab, trastuzumab, bevacizumab, sorafenib) as more effective and less toxic options. Continued investigation into the molecular pathways of endometrial cancer development and progression will increase our knowledge of this disease leading to the discovery of novel, superior agents.

The Impact of GM-CSF on Arsenic Trioxide (As2O3, Trisenox) Therapy in Patients with Myelodysplastic Syndrome (MDS): Preliminary Results of a Phase II Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4856-4856 ◽  
Author(s):  
Blanche H. Mavromatis ◽  
Craig M. Kessler ◽  
Bruce D. Cheson ◽  
Aung Sein ◽  
Stewart A. Sharp
Keyword(s):  
Arsenic Trioxide ◽  
Phase Ii ◽  
Single Agent ◽  
Patient Characteristics ◽  
Refractory Anemia ◽  
International Prognostic Scoring System ◽  
Clinical Activity ◽  
Gm Csf ◽  
Pre Treatment ◽  
The Impact

Abstract Background: Arsenic trioxide(As2O3) has proven clinical efficacy in relapsed acute promyelocytic leukemia, and is currently being studied in the upfront setting. At micromolar doses, As2O3 induces apoptosis and cellular differentiation, promotes histone acetylation, and inhibits tumor angiogenesis. In preclinical MDS studies, As2O3 inhibits proliferation of malignant hematopoietic cells, and increases rates of apoptosis in short term cultures. Notably, pre-treatment with GM-CSF increases sensitivity of cells to the effect of As2O3. Single agent clinical activity has also been demonstrated in MDS and multiple myeloma. Methods: As2O3 was combined with GM-CSF in pts with MDS in a phase II trial. Eligible patients included those with Low/Int-1 and Int-2/High risk disease. Pts received treatment with As2O3 0.25 mg/Kg d1–d5 the first week, then twice a week for 9 weeks, then 2 weeks off. The cycle was repeated if a response was observed. GM-CSF was administered twice a week for the entire cycle. Pt characteristics are summarized in the table below. Toxicity: Grade 3 and 4 study related AEs included peripheral neuropathic pain (1/7), febrile neutropenia (2/7), infection (4/7), abdominal pain (2/7), thrombocytopenia (2/7), hypoxia (1/7), chills associated with infusion (1/7), VT despite normal electrolytes (1/7), AV block (1/7). Results. 7 pts were enrolled (5M/2F), RA (1), RARS (3) and RAEB (3). A minor hematologic response was seen in one patient with RARS. One patient with RAEB2 showed a reduction of marrow blast count from 15% to < 5% after one cycle. 3 pts completed less than one cycle and response could not be assessed. Conclusion: The data suggest that As2O3 with GM-CSF is active in MDS, however with significant side effects. The study of As2O3 with the newer approved agents such as 5-azacitidine or lenalidomide should be undertaken, but done sequentially in order to minimize any overlapping toxicities. Patient Characteristics and Results Patient Age MDS Subtype Cytogenetics IPSS Number of Cycles Response Overall Survival months) Nl: normal, RA: refractory anemia; RARS: refractory anemia with ringed sideroblasts; RAEB1: refractory anemia with excess blasts 1; Int risk: intermediate risk; IPSS: international prognostic scoring system 1 76 RARS Nl Int risk-1 3 Minor HI-E 28+ 2 75 RAEB1 Nl Int risk-2 2 PR 10 3 78 RA Nl Int risk-1 1 SD 7 4 69 RAEB1 Nl Int risk-1 <1 NA NA 5 58 RARS Nl Int risk-1 1 SD 25+ 6 65 RARS 7 del, 20 del Int risk-2 1 SD NA 7 62 RAEB1 Complex: 3q-, abn ch 12, 5q-, -7, 2 ring ch8, trisomy 22 Int risk-2 <1 NA NA

Disulfiram, an Clinically Used Anti-Alcoholism Drug Has the Potential to Target Leukemia Stem and Progenitor Cells in a Copper-Dependent Manner

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4088-4088
Author(s):  
Bing Xu ◽  
Shiyun Wang ◽  
Feili Chen ◽  
Pengcheng Shi ◽  
Jie Zha ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mononuclear Cells ◽  
Nuclear Translocation ◽  
Conflicts Of Interest ◽  
Therapeutic Option ◽  
Flow Cytometric Analysis ◽  
Dependent Manner ◽  
Induced Apoptosis ◽  
Acute Myeloid

Abstract Abstract 4088 Backgrounds Acute myeloid leukemia(AML) is a hierarchical disease initiating from a rare population of cells known as leukemia stem cells (LSCs), which are typically enriched in CD34+CD38- cells and presumed responsible for the relapse and refractory of AML. Moreover, current regimens may not effectively discriminate between normal and malignant cells. For this reason, it is important to identify therapies that can specifically target the LSC population without affecting normal cells. Disulfiram (DS) is an anti-alcoholism drug that has recently been indicated to show cytotoxic to multiple cancers including acute myeloid leukemia (AML) and the antineoplastic activity was enhanced in the present of copper (Cu). In the present study, we investigated the effect of DS/Cu on LSCs and further explored its mechanism. Methods and Results CD34+CD38- leukemia stem cell (LSC) enriched subpopulations were sorted from both KG1a cell lines and primary AML bone marrow or peripheral blood mononuclear cells (n=6) by fluoresce-activated cell sorting (FACS) analysis. Using MTT cell proliferation assay and Annexin-V/PI staining assay, We demonstrated that DS/Cu inhibited proliferation and induced apoptosis in CD34+CD38−KG1a cells (IC50= 0.788± 0.451 μM at 24h). With the increasing concentrations of DS (DS=0.05, 0.5, 5, 50μM), the apoptotic proportion increased from 7.2% to 89.5% at 24h. Apoptosis was also observed in CD34+CD38- primary AML cells and the exposure to DS/Cu (DS=0.01, 0.1, 1μM;Cu=0.5μM clearly inhibited the growth of AML-colony-forming units (CFUs) for both CD34+CD38-LSC enriched subpopulations (AML-CFUs decreased from 34.2% to 0% in KG1a cells), but was relatively sparing to normal hematopoietic progenitors. Further more, using flow cytometric analysis, western blot and RT-PCR, we identified that the change in redox status and redox-dependent signaling events play a crucial role in DS/Cu-induced apoptosis. We showed that DS/Cu(DS= 0.625,1.25,2.5,5μM, Cu=1μM) increased reactive oxygen species (ROS) and activated its downstream apoptosis-related SAPK/JNK pathway in association with blockade translocation of Nrf2 and expression of Nrf2-regulated genes in CD34+CD38−KG1a cells. Notably, blockade of ROS by glutathione precursor N-acetylcysteine (NAC)(10mM) strongly diminished DS/Cu mediated lethality and restored Nrf2 nuclear translocation and blocked JNK activation. Additionally, consistent with the ROS accumulation, we also seen that translocation of RelA/p65 and the expression of NF-κb-related gene, associated with abnormal apoptotic response of LSCs, were significantly inhibited by DS/Cu. Conclusion Taken together, we concluded that DS/Cu might selectively eradicate LSCs by induction of oxidatibe stress and blockade the NF-κb pathway and offers a potential therapeutic option in AML. Disclosures: No relevant conflicts of interest to declare.

TRAIL/Apo2L ligand selectively induces apoptosis and overcomes drug resistance in multiple myeloma: therapeutic applications

Blood ◽  
2001 ◽  
Vol 98 (3) ◽  
pp. 795-804 ◽  
Author(s):  
Constantine S. Mitsiades ◽  
Steven P. Treon ◽  
Nicholas Mitsiades ◽  
Yoshihito Shima ◽  
Paul Richardson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Mononuclear Cells ◽  
Nuclear Translocation ◽  
Death Receptor 5 ◽  
Therapeutic Applications ◽  
Trail Receptors ◽  
Induced Apoptosis

Abstract Multiple myeloma (MM) remains incurable and novel treatments are urgently needed. Preclinical in vitro and in vivo evaluations were performed to assess the potential therapeutic applications of human recombinant tumor necrosis factor (TNF)–related apoptosis-inducing ligand/Apo2 ligand (TRAIL/Apo2L) in MM. TRAIL/Apo2L potently induced apoptosis of MM cells from patients and the majority of MM cell lines, including cells sensitive or resistant to dexamethasone (Dex), doxorubicin (Dox), melphalan, and mitoxantrone. TRAIL/Apo2L also overcame the survival effect of interleukin 6 on MM cells and did not affect the survival of peripheral blood and bone marrow mononuclear cells and purified B cells from healthy donors. The status of the TRAIL receptors (assessed by immunoblotting and flow cytometry) could not predict TRAIL sensitivity of MM cells. The anti-MM activity of TRAIL/Apo2L was confirmed in nu/xid/bg mice xenografted with human MM cells; TRAIL (500 μg intraperitoneally daily for 14 days) was well tolerated and significantly suppressed the growth of plasmacytomas. Dox up-regulated the expression of the TRAIL receptor death receptor 5 (DR5) and synergistically enhanced the effect of TRAIL not only against MM cells sensitive to, but also against those resistant to, Dex- or Dox-induced apoptosis. Nuclear factor (NF)-κB inhibitors, such as SN50 (a cell-permeable inhibitor of the nuclear translocation and transcriptional activity of NF-κB) or the proteasome inhibitor PS-341, enhanced the proapoptotic activity of TRAIL/Apo2L against TRAIL-sensitive MM cells, whereas SN50 reversed the TRAIL resistance of ARH-77 and IM-9 MM cells. Importantly, normal B lymphocytes were not sensitized to TRAIL by either Dox, SN50, or PS-341. These preclinical studies suggest that TRAIL/Apo2L can overcome conventional drug resistance and provide the basis for clinical trials of TRAIL-based treatment regimens to improve outcome in patients with MM.

scholarly journals Arsenic trioxide induces macrophage autophagy and atheroprotection by regulating ROS-dependent TFEB nuclear translocation and AKT/mTOR pathway

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Shaohong Fang ◽  
Xin Wan ◽  
Xiaoyi Zou ◽  
Song Sun ◽  
Xinran Hao ◽  
...  
Keyword(s):  
Arsenic Trioxide ◽  
Signaling Pathway ◽  
Nuclear Translocation ◽  
Early Stage ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Pi3k Inhibitor Ly294002 ◽  
Vascular Stents ◽  
Atherosclerotic Lesions

AbstractInducing autophagy and inhibiting apoptosis may provide a therapeutic treatment for atherosclerosis (AS). For the treatment of progressive AS, arsenic trioxide (ATO) has been used to coat vascular stents. However, the effect of ATO on autophagy of macrophages is still unknown. Therefore, the aims of this study were to characterize the effects and the mechanism of actions of ATO on autophagy in macrophages. Our results showed that ATO-induced activation of autophagy was an earlier event than ATO-induced inhibition of the expression of apoptosis markers in macrophages and foam cells. Nuclear transcription factor EB (TFEB) prevents atherosclerosis by activating macrophage autophagy and promoting lysosomal biogenesis. Here, we report that ATO triggered the nuclear translocation of TFEB, which in turn promoted autophagy and autophagosome-lysosome fusion. Both the latter events were prevented by TFEB knockdown. Moreover, ATO decreased the p-AKT and p-mTOR in the PI3K/AKT/mTOR signaling pathway, thus inducing autophagy. Correspondingly, treatment with the autophagy inhibitor 3-methyladenine (3-MA) abolished the autophagy-inducing effects of ATO. Meanwhile, PI3K inhibitor (LY294002) and mTOR inhibitor (rapamycin) cooperated with ATO to induce autophagy. Furthermore, reactive oxygen species (ROS) were generated in macrophages after treatment with ATO. The ROS scavenger N-acetyl-1-cysteine (NAC) abolished ATO-induced nuclear translocation of TFEB, as well as changes in key molecules of the AKT/mTOR signaling pathway and downstream autophagy. More importantly, ATO promoted autophagy in the aorta of ApoE−/− mice and reduced atherosclerotic lesions in early AS, which were reversed by 3-MA treatment. In summary, our data indicated that ATO promoted ROS induction, which resulted in nuclear translocation of TFEB and inhibition of the PI3K/AKT/mTOR pathway. These actions ultimately promoted macrophage autophagy and reduced atherosclerotic lesions at early stages. These findings may provide a new perspective for the clinical treatment of early-stage atherosclerosis and should be further studied.

scholarly journals Protein Kinase Cϵ Is Required for Macrophage Activation and Defense Against Bacterial Infection

2001 ◽  
Vol 194 (9) ◽  
pp. 1231-1242 ◽  
Author(s):  
Antonio Castrillo ◽  
Daniel J. Pennington ◽  
Florian Otto ◽  
Peter J. Parker ◽  
Michael J. Owen ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Bacterial Infection ◽  
Nuclear Translocation ◽  
Early Stage ◽  
Gram Positive Bacteria ◽  
Iκb Kinase ◽  
Tnf Α ◽  
Oxide Synthase ◽  
Necrosis Factor

To assess directly the role of protein kinase C (PKC)ϵ in the immune system, we generated mice that carried a homozygous disruption of the PKCϵ locus. PKCϵ−/− animals appeared normal and were generally healthy, although female mice frequently developed a bacterial infection of the uterus. Macrophages from PKCϵ−/− animals demonstrated a severely attenuated response to lipopolysaccharide (LPS) and interferon (IFN)γ, characterized by a dramatic reduction in the generation of NO, tumor necrosis factor (TNF)-α, and interleukin (IL)-1β. Further analysis revealed that LPS-stimulated macrophages from PKCϵ−/− mice were deficient in the induction of nitric oxide synthase (NOS)-2, demonstrating a decrease in the activation of IκB kinase, a reduction in IκB degradation, and a decrease in nuclear factor (NF)κB nuclear translocation. After intravenous administration of Gram-negative or Gram-positive bacteria, PKCϵ−/− mice demonstrated a significantly decreased period of survival. This study provides direct evidence that PKCϵ is critically involved at an early stage of LPS-mediated signaling in activated macrophages. Furthermore, we demonstrate that in the absence of PKCϵ, host defense against bacterial infection is severely compromised, resulting in an increased incidence of mortality.

scholarly journals Disturbances in the functioning of the immune system as a consequence of a prolonged expоsure to low dosages of depleted uranium

2018 ◽  
pp. 73-79
Author(s):  
K. I. Stosman ◽  
K. V. Sivak ◽  
T. N. Savateeva-Ljubimova
Keyword(s):  
Chronic Exposure ◽  
Mononuclear Cells ◽  
Early Stage ◽  
Experimental Studies ◽  
Relative Number ◽  
Uranyl Acetate ◽  
Depleted Uranium ◽  
Delayed Type Hypersensitivity ◽  
Industrial Facilities ◽  
Tnf Α

Relevance. Depleted uranium (DU) is actively used in many industries. The problems of the safety of personnel employed at industrial facilities of this kind continue to remain relevant. Experimental studies have shown the toxicity of uranium compounds, especially its soluble forms.Intention.  To identify immunological disorders developing after chronic exposure to low-dose depleted uranium.Methods. The study involved 30 outbred rats and 60 mice CBA. Uranyl acetate dehydrate was used as a toxicant and administered intragastrically for 120 days. The relative number of T-lymphocytes, apoptotic and necrotic cells, the production of TNF-α, IL-1, -4, -6-β, the level of circulating immune complexes, the phagocytic activity of neutrophils, delayed-type hypersensitivity reactions, and production of immunoglobulins were assessed.Results and Discussion.  According to the tests on rats, phagocytic-metabolic activity of neutrophils as well as TNF-α production increased, CD4+/CD8+ ratio decreased, and the early stage apoptosis of mononuclear cells was activated after chronic exposure to uranium salts. Most detected changes were dose-dependent. In experiments on mice it was shown that uranyl acetate dehydrate at a dose of 5 mg/kg had no effect on the functional activity of immunocytes, while the index of the delayed-type hypersensitivity reaction and IgG titers increased in animals which were administered DU at a dose of 10 mg/kg.Conclusion. The results can be used to provide specialized medical care after chronic exposure to depleted uranium.

scholarly journals Dap-Kinase Participates in TNF-α–And FAS-Induced Apoptosis and Its Function Requires the Death Domain

1999 ◽  
Vol 146 (1) ◽  
pp. 141-148 ◽  
Author(s):  
Ofer Cohen ◽  
Boaz Inbal ◽  
Joseph L. Kissil ◽  
Tal Raveh ◽  
Hanna Berissi ◽  
...  
Keyword(s):  
Cell Death ◽  
Dominant Negative ◽  
Protein Domain ◽  
Dominant Negative Mutant ◽  
Death Domain ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Dap Kinase ◽  
Tnf Α ◽  
Induced Apoptosis

Death-associated protein (DAP)–kinase is a calcium/calmodulin regulated serine/threonine kinase that carries ankyrin repeats, a death domain, and is localized to the cytoskeleton. Here, we report that this kinase is involved in tumor necrosis factor (TNF)-α and Fas-induced apoptosis. Expression of DAP-kinase antisense RNA protected cells from killing by anti–Fas/APO-1 agonistic antibodies. Deletion of the death domain abrogated the apoptotic functions of the kinase, thus, documenting for the first time the importance of this protein domain. Overexpression of a fragment encompassing the death domain of DAP-kinase acted as a specific dominant negative mutant that protected cells from TNF-α, Fas, and FADD/MORT1–induced cell death. DAP-kinase apoptotic function was blocked by bcl-2 as well as by crmA and p35 inhibitors of caspases, but not by the dominant negative mutants of FADD/MORT1 or of caspase 8. Thus, it functions downstream to the receptor complex and upstream to other caspases. The multidomain structure of this serine/threonine kinase, combined with its involvement in cell death induced by several different triggers, place DAP-kinase at one of the central molecular pathways leading to apoptosis.

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