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  • Senescence induction in human fibroblasts and hematopoietic progenitors by leukemogenic fusion proteins. 20421454

    Hematologic malignancies are typically associated with leukemogenic fusion proteins, which are required to maintain the oncogenic state. Previous studies have shown that certain oncogenes that promote solid tumors, such as RAS and BRAF, can induce senescence in primary cells, which is thought to provide a barrier to tumorigenesis. In these cases, the activated oncogene elicits a DNA damage response (DDR), which is essential for the senescence program. Here we show that 3 leukemogenic fusion proteins, BCR-ABL, CBFB-MYH11, and RUNX1-ETO, can induce senescence in primary fibroblasts and hematopoietic progenitors. Unexpectedly, we find that senescence induction by BCR-ABL and CBFB-MYH11 occurs through a DDR-independent pathway, whereas RUNX1-ETO induces senescence in a DDR-dependent manner. All 3 fusion proteins activate the p38 MAPK pathway, which is required for senescence induction. Our results reveal diverse pathways for oncogene-induced senescence and further suggest that leukemias harbor genetic or epigenetic alterations that inactivate senescence induction genes.
    Tipo de documento:
    Referencia
    Referencia del producto:
    S7100
    Nombre del producto:
    ApopTag® Peroxidase In Situ Apoptosis Detection Kit

  • Thrombin-sensitive dual fluorescence imaging and therapeutic agent for detection and treatment of synovial inflammation in murine rheumatoid arthritis. 22959919

    We have developed a thrombin-sensitive polymeric photosensitizer prodrug (T-PS) to selectively image and eradicate inflammatory lesions in rheumatoid arthritis (RA). Thrombin is a serine protease up-regulated in synovial tissues of rheumatoid arthritis (RA) patients. T-PS consists of a polymeric backbone, to which multiple photosensitizer (PS) units are tethered via short thrombin-cleavable peptide linkers. Fluorescence emission and phototoxicity of the prodrug are efficiently quenched due to the interaction of neighboring photosensitizer units. The prodrug is passively delivered to the inflammation site via the enhanced permeability and retention (EPR) effect. Subsequent site-selective proteolytic cleavage of the peptide linkers restores its photoactivity by increasing the mutual distance between PS. Whole animal imaging in murine collagen-induced arthritis, an experimental model of RA revealed a dose-dependent fluorescence increase in arthritic paws after systemic prodrug injection. In addition, administration of T-PS resulted in much higher fluorescence selectivity for arthritic joints as compared to the free PS. Irradiation of the arthritic joints induced light dose dependent phototoxic effects such as apoptosis, vascular damage and local hemorrhage. Long-term observations showed complete regression of the latter. Irradiated non-arthritic tissues or non-irradiated arthritic tissues showed no histological effects after photodynamic therapy with T-PS. This illustrates that T-PS can localize inflammatory lesions with excellent selectivity and induce apoptosis and vascular shut down after irradiation.
    Tipo de documento:
    Referencia
    Referencia del producto:
    S7100
    Nombre del producto:
    ApopTag® Peroxidase In Situ Apoptosis Detection Kit

  • Helicobacter pylori accelerates hepatic fibrosis by sensitizing transforming growth factor-beta1-induced inflammatory signaling. 20531291

    Our earlier report has shown that Helicobacter pylori promoted hepatic fibrosis in a murine model. Herein, in order to elucidate the mechanism by which H. pylori accelerate liver fibrosis, the authors investigated the changes in expression levels of mitogen-activated protein kinases (MAPKs), p53-related proteins, antioxidants, and proinflammatory cytokines in liver samples. H. pylori infection enhanced CCl(4)-induced MAP kinase activation and p53 signaling pathway as well as Bax- and proliferating-cell nuclear antigen expressions, whereas H. pylori alone induced neither of these expressions nor hepatic fibrosis. Moreover, mRNA expressions of inflammatory cytokines, glutathione peroxidase expression, and the proliferative index were strongly augmented in livers of the H. pylori with CCl(4) treatment group compared with those of the CCl(4)-alone treatment group, whereas there was no difference in apoptotic index between the two groups. Interestingly, H. pylori treatment increased the number of alpha-fetoprotein-expressing hepatocytes independently of CCl(4) intoxication. In vitro analyses, using an immortalized rat hepatic stellate cell (HSC) line, revealed that H. pylori lysates increased the proliferation of HSCs, which was boosted by the addition of transforming growth factor-beta1 (TGF-beta1). Furthermore, the treatment of H. pylori lysates promoted the translocation of nuclear factor kappa-light-chain enhancer of activated B cells (NF-kappaB) into the nucleus based on an increase in the degradation of NF-kappaB inhibitor alpha, in the presence of TGF-beta1, as did H(2)O(2) treatment. In conclusion, H. pylori infection along with an elevated TGF-beta1 may accelerate hepatic fibrosis through increased TGF-beta1-induced pro-inflammatory signaling pathways in HSCs. Moreover, H. pylori infection might increase the risk of TGF-beta1-mediated tumorigenesis by disturbing the balance between apoptosis and proliferation of hepatocytes.Laboratory Investigation advance online publication, 7 June 2010; doi:10.1038/labinvest.2010.109 published online 7 June 2010.
    Tipo de documento:
    Referencia
    Referencia del producto:
    S7100
    Nombre del producto:
    ApopTag® Peroxidase In Situ Apoptosis Detection Kit

  • The p53 Inhibitor MDM2 Facilitates Sonic Hedgehog-Mediated Tumorigenesis and Influences Cerebellar Foliation. 21437245

    Disruption of cerebellar granular neuronal precursor (GNP) maturation can result in defects in motor coordination and learning, or in medulloblastoma, the most common childhood brain tumor. The Sonic Hedgehog (Shh) pathway is important for GNP proliferation; however, the factors regulating the extent and timing of GNP proliferation, as well as GNP differentiation and migration are poorly understood. The p53 tumor suppressor has been shown to negatively regulate the activity of the Shh effector, Gli1, in neural stem cells; however, the contribution of p53 to the regulation of Shh signaling in GNPs during cerebellar development has not been determined. Here, we exploited a hypomorphic allele of Mdm2 (Mdm2(puro)), which encodes a critical negative regulator of p53, to alter the level of wild-type MDM2 and p53 in vivo. We report that mice with reduced levels of MDM2 and increased levels of p53 have small cerebella with shortened folia, reminiscent of deficient Shh signaling. Indeed, Shh signaling in Mdm2-deficient GNPs is attenuated, concomitant with decreased expression of the Shh transducers, Gli1 and Gli2. We also find that Shh stimulation of GNPs promotes MDM2 accumulation and enhances phosphorylation at serine 166, a modification known to increase MDM2-p53 binding. Significantly, loss of MDM2 in Ptch1(+/-) mice, a model for Shh-mediated human medulloblastoma, impedes cerebellar tumorigenesis. Together, these results place MDM2 at a major nexus between the p53 and Shh signaling pathways in GNPs, with key roles in cerebellar development, GNP survival, cerebellar foliation, and MB tumorigenesis.
    Tipo de documento:
    Referencia
    Referencia del producto:
    S7100
    Nombre del producto:
    ApopTag® Peroxidase In Situ Apoptosis Detection Kit

  • Vascular smooth muscle Jak2 deletion prevents angiotensin II-mediated neointima formation following injury in mice. 21420414

    The in vitro treatment of vascular smooth muscle cells (VSMC) with angiotensin II (Ang II) causes Janus kinase 2 (Jak2) to interact with the Ang II type 1 receptor (AT(1)-R) resulting in enhanced cell growth. However, the role that Jak2 plays in AT(1)-R-mediated vascular cell growth and remodeling in vivo is less clear. We hypothesized that in vivo, Jak2 plays a rate-limiting role in Ang II-mediated neointima formation following vascular injury. Using the Cre-loxP system, we conditionally ablated Jak2 from the VSMC of mice. We found that these mice are protected from Ang II-mediated neointima formation following iron chloride-induced vascular injury. In addition, the VSMC Jak2 null mice were protected from injury-induced vascular fibrosis and the pathological loss of the contractile marker, smooth muscle α-actin. Finally, when compared to controls, the VSMC Jak2 null mice exhibited significantly less Ang II-induced VSMC proliferation and migration in vitro and in vivo and more apoptosis. These results suggest that Jak2 plays a central role in the causation of Ang II-induced neointima formation following vascular injury and may provide a novel target for the prevention of neointima formation.Copyright © 2011 Elsevier Ltd. All rights reserved.
    Tipo de documento:
    Referencia
    Referencia del producto:
    S7100
    Nombre del producto:
    ApopTag® Peroxidase In Situ Apoptosis Detection Kit

  • Genotoxic and cytotoxic effects induced by aluminum in the lymphocytes of the common carp (Cyprinus carpio). 20883821

    Few studies have been made in regard to the effect of aluminum on the molecular and cellular structure and function of aquatic organisms; therefore, in the present report we determined the genotoxic and cytotoxic effects induced by the metal on the lymphocytes of carp (Cyprinus carpio). Three groups of fish were exposed to 0.05, 120, and 239mg/L of aluminum (Al), respectively, by using Al(2) (SO(4))(3)·7H(2)O, and another group was included as control. The cells obtained were studied with the comet assay, flow cytometry, and the TUNEL method. With the first method we found a concentration and time dependent, significant increase in the amount of DNA damage induced by Al, and a higher damage when we evaluated the level of oxidized DNA. By applying flow cytometry we established that the metal induced a DNA content increase and ploidy modifications as well as apoptosis and disturbances of the cell cycle progression. With the last method we determined a significant increase in the amount of apoptotic cells, mainly in the 72-96h period. Our results established that Al caused deleterious DNA and cellular effects in the tested organism, and they suggested the pertinence of evaluating toxicity induced by the metal in organisms living in contaminated water bodies.
    Tipo de documento:
    Referencia
    Referencia del producto:
    S7100
    Nombre del producto:
    ApopTag® Peroxidase In Situ Apoptosis Detection Kit

  • Tooth-bone morphogenesis during postnatal stages of mouse first molar development. 21418206

    The first mouse molar (M1) is the most common model for odontogenesis, with research particularly focused on prenatal development. However, the functional dentition forms postnatally, when the histogenesis and morphogenesis of the tooth is completed, the roots form and the tooth physically anchors into the jaw. In this work, M1 was studied from birth to eruption, assessing morphogenesis, proliferation and apoptosis, and correlating these with remodeling of the surrounding bony tissue. The M1 completed crown formation between postnatal (P) days 0-2, and the development of the tooth root was initiated at P4. From P2 until P12, cell proliferation in the dental epithelium reduced and shifted downward to the apical region of the forming root. In contrast, proliferation was maintained or increased in the mesenchymal cells of the dental follicle. At later stages, before tooth eruption (P20), cell proliferation suddenly ceased. This withdrawal from the cell cycle correlated with tooth mineralization and mesenchymal differentiation. Apoptosis was observed during all stages of M1 postnatal morphogenesis, playing a role in the removal of cells such as osteoblasts in the mandibular region and working together with osteoclasts to remodel the bone around the developing tooth. At more advanced developmental stages, apoptotic cells and bodies accumulated in the cell layers above the tooth cusps, in the path of eruption. Three-dimensional reconstruction of the developing postnatal tooth and bone indicates that the alveolar crypts form by resorption underneath the primordia, whereas the ridges form by active bone growth between the teeth and roots to form a functional complex.© 2011 The Authors. Journal of Anatomy © 2011 Anatomical Society of Great Britain and Ireland.
    Tipo de documento:
    Referencia
    Referencia del producto:
    S7100
    Nombre del producto:
    ApopTag® Peroxidase In Situ Apoptosis Detection Kit

  • Severity of doxorubicin-induced small intestinal mucositis is regulated by the TLR-2 and TLR-9 pathways. 21960132

    Intestinal mucositis is a serious complication of cancer chemotherapy and radiotherapy; it frequently compromises treatment and dramatically reduces the quality of life of patients. Different approaches to limit the damage to the intestine during anti-cancer therapy have been largely ineffective due to insufficient knowledge of the mechanism of mucositis development. This study aimed to define the role of TLR-2 and TLR-9 in the modulation of small intestinal damage in a model of doxorubicin-induced mucositis. Doxorubicin-induced intestinal damage was verified by a histological score (HS), analysis of leukocyte influx into the lamina propria, and determination of the number of apoptotic cells. Additionally, the activation status of glycogen synthase kinase 3? (GSK-3?) was assessed. Wild-type (WT) mice injected with doxorubicin demonstrated severe intestinal damage (HS 8.0 ± 0.81), reduction of villus length to 43.9% ± 13.7% of original length, and increased influx of leukocytes as compared to vehicle-injected mice (HS 1.33 ± 1.15). The protective effect of TLR-2 or TLR-9 deficiency was associated with a significant decrease of the HS as compared to WT mice. In the ileum, a minor reduction of villus length and a decreased number of infiltrating leukocytes and TUNEL-positive cells was observed. We demonstrate that the TLR-9 antagonist ODN2088 reduces doxorubicin-induced intestinal damage. Furthermore, we show that GSK-3? activity is inhibited in the absence of TLR-2. The protective capacity of GSK-3? suppression was observed in WT mice by inhibiting it with the specific inhibitor SB216763. Overall, our findings demonstrate that the TLR-2/GSK-3? and TLR-9 signalling pathways play a central role in the development of intestinal mucositis and we suggest a new therapeutic strategy for limiting doxorubicin-induced intestinal inflammation. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
    Tipo de documento:
    Referencia
    Referencia del producto:
    S7100
    Nombre del producto:
    ApopTag® Peroxidase In Situ Apoptosis Detection Kit

  • Intermittent hypoxia promotes hippocampal neurogenesis and produces antidepressant-like effects in adult rats. 20861371

    Increasing evidence indicates that stimulating hippocampal neurogenesis could provide novel avenues for the treatment of depression, and recent studies have shown that in vitro neurogenesis is enhanced by hypoxia. The aim of this study was to investigate the potential regulatory capacity of an intermittent hypobaric hypoxia (IH) regimen on hippocampal neurogenesis and its possible antidepressant-like effect. Here, we show that IH promotes the proliferation of endogenous neuroprogenitors leading to more newborn neurons in hippocampus in adult rats. Importantly, IH produces antidepressant-like effects in multiple animal models screening for antidepressant activity, including the forced swimming test, chronic mild stress paradigm, and novelty-suppressed feeding test. Hippocampal x-ray irradiation blocked both the neurogenic and behavioral effects of IH, indicating that IH likely produces antidepressant-like effects via promoting neurogenesis in adult hippocampus. Furthermore, IH stably enhanced the expression of BDNF in hippocampus; both the antidepressant-like effect and the enhancement of cell proliferation induced by IH were totally blocked by pharmacological and biological inhibition of BDNF-TrkB (tyrosine receptor kinase B) signaling, suggesting that the neurogenic and antidepressant-like effects of IH may involve BDNF signaling. These observations might contribute to both a better understanding of physiological responses to IH and to developing IH as a novel therapeutic approach for depression.
    Tipo de documento:
    Referencia
    Referencia del producto:
    S7100
    Nombre del producto:
    ApopTag® Peroxidase In Situ Apoptosis Detection Kit

  • In vivo efficacy of the histone deacetylase inhibitor suberoylanilide hydroxamic acid in combination with radiotherapy in a malignant rhabdoid tumor mouse model. 22458853

    Histone deacetylase inhibitors are promising new substances in cancer therapy and have also been shown to sensitize different tumor cells to irradiation (XRT). We explored the effect as well as the radiosensitizing properties of suberoylanilide hydroxamic acid (SAHA) in vivo in a malignant rhabdoid tumor (MRT) mouse model.
    Tipo de documento:
    Referencia
    Referencia del producto:
    S7100
    Nombre del producto:
    ApopTag® Peroxidase In Situ Apoptosis Detection Kit