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Apoptosis Inhibitor (apoptosi + inhibitor)
Selected AbstractsApoptosis-inhibiting activities of BIR family proteins in Xenopus egg extractsFEBS JOURNAL, Issue 9 2005Yuichi Tsuchiya In many animal species including Xenopus, ovulated eggs possess an intrinsic apoptotic execution system. This program is inhibited for a limited time by some maternal apoptosis inhibitors, although their molecular properties remain uncharacterized. Baculovirus IAP repeat (BIR) family proteins contain evolutionarily conserved BIR domains and play important roles in apoptosis suppression, and are therefore good candidates as maternal apoptosis inhibitors. We identified four maternal BIR family proteins in Xenopus eggs and, using the biochemical advantages of egg extracts, examined their physiological functions. These molecules included two survivin-related proteins, xEIAP/XLX, and a possible ortholog of XIAP named xXIAP. The addition of recombinant xXIAP greatly delayed apoptotic execution, whereas the immunodepletion of endogenous xXIAP significantly accelerated the onset of apoptosis. In contrast, xEIAP/XLX was a poor apoptosis inhibitor, and neither of the survivin orthologs showed anti-apoptotic activity in our assay. Both xEIAP/XLX and xXIAP were degraded by activated caspases, and also by a novel proteolytic system that required the presence of C-terminal RING finger domain but was insensitive to proteasome inhibition. Our data suggest that the regulation of endogenous xXIAP concentration is important for the survival of Xenopus eggs. [source] Efficacy of ultraviolet A1 phototherapy on the expression of bcl-2 in atopic dermatitis and cutaneous T-cell lymphoma in vivo: a comparison studyPHOTODERMATOLOGY, PHOTOIMMUNOLOGY & PHOTOMEDICINE, Issue 5 2002F. Breuckmann Background/Purpose: Atopic dermatitis (AD) is characterized immunohistochemically by a high number of skin infiltrating T-helper cells (CD4 + ). In most cases cutaneous T-cell lymphoma (CTCL) is characterized by a malignant proliferation of CD4 + T-helper lymphocytes. The purpose of our study was to evaluate the extent of anti-apoptotic effects in patients suffering from AD or CTCL, respectively, which may contribute to the prolonged inflammation. Furthermore, we investigated whether medium-dose ultraviolet A1 (UVA1) phototherapy is able to modulate the expression of bcl-2 within the dermal inflammatory infiltrate. Methods: In order to enumerate bcl-2+ cells pre- and post-therapeutic punch skin biopsies of ten patients with AD and five patients with CTCL were stained immunohistochemically for features of apoptosis using a monoclonal antibody detecting bcl-2. Results: Both AD and CTCL sections revealed a high percentage of bcl-2+ cells within the dermal perivascular infiltrate before therapy. After the successful treatment using medium-dose UVA1 phototherapy this percentage could be decreased significantly. Conclusion: Both T-cell-derived skin diseases exhibit an increased pre-therapeutic number of bcl-2+ cells. After medium-dose UVA1 phototherapy the substantial improvement of the skin condition was linked to a significant decrease of the dermal bcl-2+ cell count. Moreover, we could demonstrate a remarkable correlation referring to the decrease and staining pattern of bcl-2 between these two groups as well as within each group. Because the bcl-2 protein is known to act as an apoptosis inhibitor, its pre-therapeutic increase may provide the persistent cutaneous inflammatory reaction in T-cell-derived skin diseases. Additionally, the post-therapeutic reduction of bcl-2+ cells might represent a key mechanism of medium-dose UVA1 phototherapy. [source] AM-111 prevents hearing loss from semicircular canal injury in otitis media,THE LARYNGOSCOPE, Issue 1 2010Tyler C. Grindal MD Abstract Objectives/Hypothesis: Iatrogenic semicircular canal (SC) transection during mastoidectomy for chronic otitis media often leads to profound hearing loss. AM-111, an apoptosis inhibitor, has been shown to mitigate hearing loss resulting from a variety of inner ear injuries. The goal of this study was to determine if round window application of AM-111 following SC transection in the presence of Pseudomonas aeruginosa otitis media (PA-OM) may reduce the associated hearing loss. Study Design: Prospective, randomized, controlled study in an animal model. Methods: PA-OM was induced bilaterally in 34 guinea pigs. After 3 days, both bullae were opened and the lateral SC of one ear was transected. AM-111 or vehicle was applied topically to the round window of the ear that had undergone SC transection. Hearing was assessed with auditory brainstem responses. Results: The mean change in hearing thresholds was significantly less in transected ears treated with AM-111 than those receiving vehicle alone when testing with clicks (22.1 dB vs. 35.0 dB; P = .019) and at 4kHz (11.3 dB vs. 40.0 dB; P = .021). A similar trend was shown with 16 kHz tone pips (27.7 dB vs. 41.1 dB; P = .119). Conclusions: AM-111 prevents hearing loss from SC transection in the guinea pig model of PA-OM. Laryngoscope, 2010 [source] Overexpression of caspase recruitment domain (CARD) membrane-associated guanylate kinase 1 (CARMA1) and CARD9 in primary gastric B-cell lymphomaCANCER, Issue 9 2005Shigeo Nakamura M.D. Abstract BACKGROUND Although caspase recruitment domain (CARD) membrane-associated guanylate kinase (MAGUK) protein 1 (CARMA1) and CARD9 play important roles in lymphocyte activation, the significance of CARMA1 and CARD9 in the pathogenesis of gastric mucosa-associated lymphoid tissue (MALT) lymphoma remains to be elucidated. METHODS By using reverse transcription-polymerase chain reaction analysis, the expression levels of mRNA of CARMA1, CARD9, Bcl10, and the apoptosis inhibitor 2 (API2)-MALT1 chimeric transcript were determined in tissue specimens from 65 patients with primary gastric B-cell lymphoma (43 patients with low-grade MALT lymphoma, 16 patients with MALT lymphoma plus diffuse large B-cell lymphoma [DLBL], and 6 patients with DLBL without MALT lymphoma) and in tissue specimens from 18 patients with chronic gastritis. The expression levels of CARMA1 and BCL10 were examined immunohistochemically in 30 patients with lymphoma. RESULTS CARMA1 mRNA was detected in 55% of lymphoma patients but in only 17% of chronic gastritis patients. The positive rates for CARD9, Bcl10, and API2-MALT1 chimeric transcript in the lymphoma patients were 48%, 98%, and 8%, respectively, whereas the 3 molecules were not detected in any specimens from patients with chronic gastritis. The expression of CARMA1 and CARD9 was frequent in the Helicobacter pylori -negative patients (100% and 86%, respectively), in the API2-MALT1 chimeric transcript-positive patients (100% and 100%, respectively), and in the specimens from patients who did not respond to H. pylori eradication (76% and 71%, respectively). In addition, CARMA1 expression was positive more frequently in patients of DLBL without MALT lymphoma (100%) than in patients of MALT lymphoma (51%). CARMA1 protein expression was correlated significantly with the expression of CARMA1 mRNA and also with the expression of nuclear BCL10. CONCLUSIONS The overexpression of CARMA1 and CARD9 presumably is associated with the development or progression of gastric B-cell lymphoma, especially among patients who have disease in which the pathogenesis is not related to H. pylori. Cancer 2005. © 2005 American Cancer Society. [source] Apoptosis-inhibiting activities of BIR family proteins in Xenopus egg extractsFEBS JOURNAL, Issue 9 2005Yuichi Tsuchiya In many animal species including Xenopus, ovulated eggs possess an intrinsic apoptotic execution system. This program is inhibited for a limited time by some maternal apoptosis inhibitors, although their molecular properties remain uncharacterized. Baculovirus IAP repeat (BIR) family proteins contain evolutionarily conserved BIR domains and play important roles in apoptosis suppression, and are therefore good candidates as maternal apoptosis inhibitors. We identified four maternal BIR family proteins in Xenopus eggs and, using the biochemical advantages of egg extracts, examined their physiological functions. These molecules included two survivin-related proteins, xEIAP/XLX, and a possible ortholog of XIAP named xXIAP. The addition of recombinant xXIAP greatly delayed apoptotic execution, whereas the immunodepletion of endogenous xXIAP significantly accelerated the onset of apoptosis. In contrast, xEIAP/XLX was a poor apoptosis inhibitor, and neither of the survivin orthologs showed anti-apoptotic activity in our assay. Both xEIAP/XLX and xXIAP were degraded by activated caspases, and also by a novel proteolytic system that required the presence of C-terminal RING finger domain but was insensitive to proteasome inhibition. Our data suggest that the regulation of endogenous xXIAP concentration is important for the survival of Xenopus eggs. [source] Molecular targeted therapies for diffuse large B-cell lymphoma based on apoptosis profiles,THE JOURNAL OF PATHOLOGY, Issue 5 2010Saskia AGM Cillessen Abstract Diffuse large B-cell lymphoma (DLBCL) is the most common type of adult non-Hodgkin lymphoma and is treated with chemotherapy in combination with rituximab. Despite this aggressive therapy, the disease is fatal in 30,40% of patients. Inhibition of the apoptosis signalling pathways is strongly related to response to chemotherapy and eventual clinical outcome. In order to survive, lymphoma cells depend on disruption of the apoptosis pathway by mutations in apoptosis inducing genes or by continuous expression of anti-apoptotic proteins. The development of molecules targeting these apoptosis inhibitors provides a very promising opportunity to specifically target tumour cells without toxicity to non-malignant cells in DLBCL patients. Sensitivity for most of these antagonists can be predicted based on biological markers, suggesting the possibility of pre-defining patients who will most likely benefit from these targeted therapies. Experimental therapies aimed at restoring the upstream apoptosis pathway or targeting apoptosis inhibitors are currently being tested in clinical trials and are expected to be effective particularly in chemotherapy-refractory DLBCL, providing hope for patients who are refractory to current therapies. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] | ||||||||||