http://precedings.nature.com/tags/apoptosis Recently posted documents tagged with 'apoptosis' Nature Publishing Group en Nature Precedings http://precedings.nature.com/images/header_logo.gif http://precedings.nature.com http://precedings.nature.com/documents/3931/version/1 Synthetic "microDNAs (MIDs)"is a new class of ~ 20-25 nucleotide-long DNAs capable of repressing the activity of the target gene at the level of transcription by mechanisms that have not been clarified yet. However they are designed to target non-coding regions of the cancer causing genes, thus interfering with transcription. The inhibition might be possible through the direct binding of MIDs to cis-regulatory sites and/or to some Transcription Factors (TF) that normally activate transcription. Synthetic MIDs in some ways are similar to the newly discovered microRNAs a mechanism by which cell regulates its genetic activities at post-transcriptional level. Synthetic MIDs can provide a powerful tool to prevent massive production of mRNA by undesired gene activities. Therefore drugs are not required to interact with overwhelming number of mRNA and microRNA copies that may present unwanted side effects. In vitro studies suggest that the inhibition of the target gene starts after the first round of DNA replication, usually 24 hours after treatment depending on cell doubling time. Cell growth suppression maximizes at day 6 or 7 and the inhibition effect is sustained for weeks. We have shown that blocking of both bcl-2 and k-ras transcription by their specific microDNA Inhibitors induced apoptosis in HL60 leukemia cells and B-cell lymphomas. http://precedings.nature.com/documents/3931/version/1 Wed, 04 Nov 2009 10:28:46 UTC MicroDNAs and Transcriptional Regulation hdl:10101/npre.2009.3931.1 2009-11-04 Nature Precedings 2009-11-04T10:28:46Z Manuscript Cancer Genetics & Genomics Molecular Cell Biology http://creativecommons.org/licenses/by/3.0/ http://precedings.nature.com/documents/1980/version/2 We introduce a new effective method to control hormone refractory prostate cancer cells by using an activated rubber/resin form (RB), far-infrared ray emitter, with or without sodium butyrate (SB). The growth of three human prostate cancer cell lines (Du145, PC-3 and LNCaP) was suppressed in vitro and in vivo by using RB, and the cells were eradicated with RB + 3 mM SB. G1 arrest and apoptotic pathway proteins were induced by RB with intensified expressions of apoptosis – related mRNA on cDNA microarray. RB radiates far-infrared rays of the 4 to 25 μm wavelengths to an object which exert a favorable influence on a cancer control. These results may render us a new therapeutic modality in hormone refractory prostate cancer. http://precedings.nature.com/documents/1980/version/2 Fri, 20 Mar 2009 12:43:46 UTC Far-infrared rays control prostate cancer cells in vitro and in vivo hdl:10101/npre.2009.1980.2 2009-03-20 Hiroki Shima Nature Precedings 2009-03-20T12:43:46Z Manuscript Cancer http://creativecommons.org/licenses/by/3.0/ http://precedings.nature.com/documents/2870/version/1 Experimental work and theoretical models deduce a “digital” response of the p53 transcription factor when genomic integrity is damaged. The mutual influence of p53 and its antagonist, the Mdm2 oncogene, is closed in feedback. This paper proposes an aerospace architecture for translating the p53/Mdm2/DNA damage network into a digital circuitry in which the optimal control theory is applied for obtaining the requested dynamic evolutions of some considered cell species for repairing a DNA damage. The purpose of this paper is not to improve the analysis of the actual mathematical models but to demonstrate the usefulness of such digital circuitry design capable to predict and detect the cell species dynamics for finding more information regarding the inner mechanism of the cell components.The cell fate is newly conceived by the modified pulsing mechanism of p53 and other apoptotic species when the digital optimal control is applied to an apoptosis wiring diagram. http://precedings.nature.com/documents/2870/version/1 Tue, 17 Feb 2009 16:02:33 UTC Optimal control circuitry design for the digital p53 dynamics in cancer cell and apoptosis hdl:10101/npre.2009.2870.1 2009-02-17 Rosario M. Ardito Marretta Nature Precedings 2009-02-17T16:02:33Z Manuscript Biotechnology Cancer Developmental Biology http://creativecommons.org/licenses/by/3.0/ http://precedings.nature.com/documents/2729/version/1 Background: BPR0L075 [6-methoxy-3-(3’,4’,5’-trimethoxy-benzoyl)-1H-indole] is a novel anti-cancer compound. It inhibits tubulin polymerization and induces mitochondrial-dependent apoptosis in various human cancer cells with different multi-drug resistance (MDR) status. Over-expression of an anti-apoptotic molecule, survivin, causes drug-resistance in various cancers. Survivin inhibits apoptosis by interfering caspase-3 and promotes cell growth by stabilizing microtubule networks. Here, we determined the effects of down-regulation of survivin in BPR0L075 (L075) treatment. Methods: Western blot analysis was used to determine the expression level of survivin in L075-untreated/-treated human oral carcinoma KB and nasopharyngeal carcinoma HONE-1 cancer cells. siRNA was used to down-regulate endogenous survivin. MTT cell viability assay, real-time caspase-3 activity assay and immuno-fluorescence microscopy were used to analyze downstream effects. Results: Survivin expression was up-regulated in both KB and HONE-1 cells in response to L075 treatment. Down-regulation of survivin induced hyper-sensitivity to L075 in KB and re-stored sensitivity to L075 in KB-derived L075-resistant KB-L30 cancer cells. At the molecular level, down-regulation of survivin induced changes in microtubule dynamics in both KB and KB-L30 cells. Surprisingly, down-regulation of survivin did not enhance the activity of caspase-3 in L075 therapy. Instead, down-regulation of survivin induced translocation of the apoptosis-inducing factor (AIF) from cytoplasm to nucleus. Conclusion: Down-regulation of survivin improved drug sensitivity to L075 in both KB and L075-resistant KB-L30 cancer cells, possibly through a tubulin-dependent and caspase-independent mechanism. We suggest that combining BPR0L075 and survivin inhibitor may give better clinical outcome than the use of BPR0L075 monotherapy in future clinical trials. http://precedings.nature.com/documents/2729/version/1 Mon, 29 Dec 2008 12:16:39 UTC Down-regulation of Survivin enhances sensitivity to BPR0L075 in human cancer cells via caspase-independent mechanisms hdl:10101/npre.2008.2729.1 2008-12-29 Chun Hei Antonio Cheung Nature Precedings 2008-12-29T12:16:39Z Manuscript Cancer http://creativecommons.org/licenses/by/3.0/ http://dx.doi.org/10.1038/npre.2008.2453.1 Targeted drug delivery to alveolar macrophages harboring Mycobacterium tuberculosis (Mtb) holds promise of high efficacy against pulmonary tuberculosis (TB). It was investigated whether inhalable microparticles (MP) can rescue macrophages from ‘alternative’ activation induced by pathogenic Mtb in addition to achieving targeted drug delivery. A genome-wide transcription analysis (Affymetrix HG-U133 Plus 2.0 DNA microarray) of THP-1 cell line derived macrophages was undertaken after exposing them to infection with 10 MOI of MTB H37Rv at 0, 12 and 24 hours post infection. The Molecular markers of macrophage bactericidal activity were assayed in THP-1- and primary human peripheral blood mononuclear cell (PBMC)-derived macrophages, in the presence or absence of soluble anti-tuberculosis drugs, drug-containing MP and blank MP. About 1,500 genes were differentially upregulated and about 500 genes differentially downregulated in response to various modes of treatment. Variations were also observed in the kinetics of gene expression. Cluster analysis indicated activation of several pathways related to innate immune response (cytokines, chemokines, receptors and ligands), apoptosis, cytoskeleton and membrane remodeling, general metabolism and general housekeeping. Some of these results were validated at the functional level, by studying caspase activities, concentrations and time-courses of effector molecules , rates/extents of apoptosis and nitrite oxide induction. Production of cytokines and NO, apoptosis, and bacterial survival were studied as pharmacodynamic outcomes. Cytokine responses of THP-1 derived macrophages were estimated. MP reversed suppression of tumor necrosis factor (TNF) induced by infection, and transiently upregulated γ-interferon (IFN-γ). Drug-free MP surprisingly induced IFN-γ, but not TNF. Primary cells responded to MP, regardless of drug content, by upregulation of NO; but THP-1-derived cells did not respond to blank MP. About 19% of infected cells exposed to MP underwent apoptosis as compared to ~11% cells treated with soluble drugs or blank MP. Cell death induced by blank MP was caspase-independent. Only drug-containing MP induced apoptosis through caspase-8 and caspase-9. Bacterial survival after different treatments varied between individuals. In the best case, while untreated infection resulted in survival of 900±141 colony forming units (CFU), treatment with soluble drugs, drug-containing MP and blank MP respectively, reduced CFU counts to 8.5± 0.7, 3±1.4 and 102±138.6. The results suggest a role of the drug delivery system in macrophage activation as a component of therapeutic strategy against TB. http://dx.doi.org/10.1038/npre.2008.2453.1 Tue, 04 Nov 2008 15:17:57 UTC Genome-wide transcription analysis of interaction between the human macrophage and Mycobacterium tuberculosis during concurrent drug administration by conventional and novel methods doi:10.1038/npre.2008.2453.1 2009-04-20 Awadh Bihari Yadav Nature Precedings 2008-11-04T15:17:57Z Poster Pharmacology http://creativecommons.org/licenses/by/3.0/ http://dx.doi.org/10.1038/npre.2008.1758.1 VEGF and TGF-β1 induce angiogenesis but have opposing effects on endothelial cells. VEGF protects endothelial cells from apoptosis; TGF-β1 induces apoptosis. We have previously shown that VEGF / VEGF receptor-2 (flk-1) signaling mediates TGF-β1 induction of apoptosis. This finding raised an important question: Does this mechanism stimulate or inhibit angiogenesis? Here we report that VEGF-mediated apoptosis is required for TGF-β1 induction of angiogenesis. In vitro the apoptotic effect of TGF-β1 on endothelial cells is rapid and followed by a long period in which the cells are refractory to apoptosis induction by TGF-β1. Inhibition of VEGF / flk-1 signaling abrogates formation of vessel-like structures by TGF-β1 with an effect comparable to that of z-VAD, an apoptosis inhibitor. Similarly, genetic deficiency of VEGF abolishes TGF-β1 upregulation of endothelial cell differentiation and formation of vascular structures in embryoid bodies. In vivo TGF-β1 induces endothelial cell apoptosis as rapidly as in vitro. Inhibition of VEGF blocks TGF-β1 induction of both apoptosis and angiogenesis, an effect similar to that of z-VAD. Thus, TGF-β1 induction of angiogenesis requires rapid and transient endothelial cell apoptosis mediated by VEGF/flk-1. This novel, unexpected role of VEGF and flk-1 indicates VEGF-mediated apoptosis as a potential target to control angiogenesis. http://dx.doi.org/10.1038/npre.2008.1758.1 Thu, 03 Apr 2008 20:16:15 UTC Transforming growth factor-beta 1 (tgf-β1) induces angiogenesis through vascular endothelial growth factor (vegf)-mediated apoptosis doi:10.1038/npre.2008.1758.1 2008-04-03 Giovanni Ferrari Nature Precedings 2008-04-03T20:16:15Z Manuscript Cancer http://creativecommons.org/licenses/by/3.0/ http://dx.doi.org/10.1038/npre.2008.1561.1 Introduction: Cervical cancer remains a global health concern for females. Thus, in order to control cervical cancer, attempts are being made by researchers globally to somehow induce programmed cell death in the said cancerous cells. Wide spectrums of molecules are being probed for its ability to induce apoptosis in cervical cancer cells. Focus has now shifted in exploring natural compounds having antioxidant and anti-inflammatory molecules that may induce apoptosis in cancerous cells. Thus, we have employed allicin from garlic- a natural antioxidant, to probe the above in the present study.Objective: To probe whether or not allicin from garlic, a natural antioxidant, induces apoptosis in monocytes from patients with cervical cancer.Results: Allicin (500 ng/ml) reduced cell viability to 27% after 24 hours of treatment. Moreover, allicin-induced apoptosis was ascertained by measuring the activity of caspase-3, caspase-8 and caspase-9-like proteases in allicin treated and untreated monocytes from cervical cancer patients. Monocyte co-cultured with allicin for 24 hrs exhibited higher activity of caspase-3 followed by caspase-8 and caspase-9 like proteases, thereby indicating that the activation of caspase-3 like proteases was associated with reduced cell survival and apoptotic death of allicin-treated cervical cancer monocytes. This was ascertained by pre-treatment of cancer cells with cell permeable inhibitor Z-VAD-FMK (caspase-3 inhibitor), Z-IETD-FMK (caspase-8 inhibitor) and Z-LEHD-FMK (caspase-9 inhibitor) followed by allicin for 24 hrs (pConclusion: Allicin from garlic may act as an adjunct in the chemotherapy of cervical cancer. http://dx.doi.org/10.1038/npre.2008.1561.1 Fri, 01 Feb 2008 19:18:49 UTC Beneficial role of allicin from garlic in cervical cancer doi:10.1038/npre.2008.1561.1 2008-02-01 Najmul Islam Nature Precedings 2008-02-01T19:18:49Z Poster Cancer Molecular Cell Biology http://creativecommons.org/licenses/by/3.0/ http://dx.doi.org/10.1038/npre.2008.1549.1 Pain initiated or caused by a primary lesion or dysfunction in the nervous system is defined as neuropathic pain. It results from direct injury to nerves in the peripheral or central nervous system and is associated with several clinical symptoms. Neuropathic pain treatment is extremely difficult, as it is a very complex disease, involving several molecular pathways. Excitatory or inhibitory pathways controlling neuropathic pain development show altered gene expression, caused by peripheral nerve injury.This study used several experimental pain models to demonstrate the occurrence of programmed cell death in the centers controlling pain induction and maintenance, such as spinal cord and pre-frontal cortex. We combined behavioural, molecular and morphological approaches to assess the involvement of bcl-2 gene family and caspases in neuropathic pain. Chronic constriction injury (CCI) and spared nerve injury (SNI) of rodent sciatic nerve induced the appearance of pain-like behaviours, such as hyperalgesia and allodynia. An early (2-3 days post-CCI) apoptosis appeared in the spinal cord neurons as the pro-apoptotic bax gene increased (320±19%). The incidence of apoptosis appeared to be limited to the first few days following nerve injury. Subsequently, increased expression of anti-apoptotic bcl-2 family genes may inhibit further neuron loss. SNI triggered apoptotic pathway and caspases activation in pre-frontal cortex 7, 14, and 21 days post-injury. Among the time-points analyzed, RT-PCR analysis showed increased expression of the bax/bcl-2 ratio (40±2%), bid (16±2%), caspase-1 (84±3%), caspase-8 (53±6%), caspase-9 (25±6%), caspase-12 (58±2%), TNF (32±2%) genes in the cortex by 7 days post-injury. Western blot analysis showed increased active Caspase-3 protein levels in the cortex at 3, 7, 14, and 21 post-surgery. This study shows that apoptotic genes could be an useful pharmacological target in neuropathic pain controlling. http://dx.doi.org/10.1038/npre.2008.1549.1 Wed, 30 Jan 2008 17:25:02 UTC Apoptotic gene expression in neuropathic pain doi:10.1038/npre.2008.1549.1 2008-01-30 Dario Siniscalco Nature Precedings 2008-01-30T17:25:02Z Poster Pharmacology http://creativecommons.org/licenses/by/3.0/ http://dx.doi.org/10.1038/npre.2007.1347.1 One form of plant immunity against pathogens involves a rapid host programmed cell death at the site of infection accompanied by resistance, termed the hypersensitive response (HR). Here it is shown that the HR programmed cell death program initiated by the bacterial type III secretion system dependent proteinaceous elicitor harpin from Erwinia amylovora can be reversed till very late in the process by the plant growth regulator auxin. Early inhibition or late reversal of this cell death program does not affect marker genes tightly correlated with local and systemic resistance. Cross-regulation between cell death programs and growth regulators is prevalent in different kingdoms. Thus, the concept that cell death program can be reversed till late provides a framework for further investigation of such phenomena, in addition to having utility in choosing better targets and strategies for treating mammalian and agricultural diseases. http://dx.doi.org/10.1038/npre.2007.1347.1 Mon, 19 Nov 2007 17:02:49 UTC Reversal of an immunity associated plant cell death program by the growth regulator auxin doi:10.1038/npre.2007.1347.1 2007-11-26 Suresh Gopalan Nature Precedings 2007-11-19T17:02:49Z Manuscript Biotechnology Microbiology Molecular Cell Biology Plant Biology http://creativecommons.org/licenses/by/3.0/ http://dx.doi.org/10.1038/npre.2007.1190.1 We compared the effects of microparticles (MP) containig anti-tubercular drugs and those of the drugs themselves on the host macrophage (MΦ) response to infection with Mycobacterium tuberculosis H37Ra (Mtb). Mice infected intravenously with M. tb. were either administered rifampicin and isoniazid by oral gavage or through inhalation of biodegradable MP containing the two anti-tubercular drugs. Bronchoalveolar lavage (BAL) was perfomed to recover lung MΦ, which were cultured and the supernatant analysed for TNFα by ELISA. The murine MΦ cell line J774 or the human monocyte line THP-1 differentiated with phorbol myristate were infected in vitro and treated with MP or soluble drugs. The kinetics of secretion of TNFα were determined. Caspase-3 activity after infection and treatment was assesed using a substrate cleavage detection kit.MP, but not soluble drugs, strongly induced TNFα in infected cells. Uninfected cells also responded to MP, although less strongly. Caspase-3 was observed to be upregulatedWe conclude that MP treatment induces infected MΦ to upregulate the Th1 cytokine TNFα and Caspase-3, creating conditions for induction of apoptosis in these cells as a strategy to overcome infection. http://dx.doi.org/10.1038/npre.2007.1190.1 Sun, 30 Sep 2007 20:17:49 UTC Tumor necrosis factor and caspase in response to soluble or microparticle-incorporated drugs in Mycobacterium tuberculosis infection doi:10.1038/npre.2007.1190.1 2007-09-30 Amit Misra Nature Precedings 2007-09-30T20:17:49Z Poster Immunology Pharmacology http://creativecommons.org/licenses/by/2.5/