Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002874 (aplastic anemia)
 5,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stem cells are believed to be closely associated with tissue degeneration during aging. Studies of human genetic diseases and gene-targeted animal models have provided evidence that functional decline of telomeres and deregulation of cell cycle checkpoints contribute to the aging process of tissue stem cells. Telomere dysfunction can induce DNA damage response via key cell cycle checkpoints, leading to cellular senescence or apoptosis depending on the tissue type and developmental stage of a specific stem cell compartment. Telomerase mutation and telomere shortening have been observed in a variety of hematological disorders, such as dyskeratosis congenital, aplastic anemia, myelodysplastic syndromes and leukemia, in which the hematopoietic stem cells (HSC) are a major target during the pathogenesis. Moreover, telomere dysfunction is able to induce both cell-intrinsic checkpoints and environmental factors limiting the self-renewal capacity and differentiation potential of HSCs. Crucial components in the cascade of DNA damage response, including ataxia telangiectasia mutated, CHK2, p53, p21 and p16/p19(ARF), play important roles in HSC maintenance and self-renewal in the scenarios of both sufficient telomere reserve and dysfunctional telomere. Therefore, a further understanding of the molecular mechanisms underlying HSC aging may help identity new therapeutic targets for stem cell-based regenerative medicine.
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PMID:Telomere dysfunction and cell cycle checkpoints in hematopoietic stem cell aging. 2167 Oct 44

Fanconi anemia is a genetic bone marrow failure syndrome. The current treatment options are suboptimal and do not prevent the eventual onset of aplastic anemia requiring bone marrow transplantation. We previously showed that resveratrol, an antioxidant and an activator of the protein deacetylase Sirt1, enhanced hematopoiesis in Fancd2 mutant mice and improved the impaired stem cell quiescence observed in this disease. Given that Sirt1 is important for the function of hematopoietic stem cells, we hypothesized that Sirt1 activation may improve hematopoiesis. Indeed, Fancd2(-/-) mice and wild-type mice treated with the selective Sirt1 activator SRT3025 had increased numbers of hematopoietic stem and progenitor cells, platelets and white blood cells. SRT3025 was also protective against acetaldehyde-induced hematopoietic damage. Unlike resveratrol, however, SRT3025 did not affect stem cell quiescence, suggesting distinct mechanisms of action. Conditional deletion of Sirt1 in hematopoietic cells did not abrogate the beneficial effects of SRT3025, indicating that the drug did not act by directly stimulating Sirt1 in stem cells, but must be acting indirectly via extra-hematopoietic effects. RNA-Seq transcriptome analysis revealed the down-regulation of Egr1-p21 expression, providing a potential mechanism for improved hematopoiesis. Overall, our data indicate that SRT3025 or related compounds may be beneficial in Fanconi anemia and other bone marrow failure syndromes.
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PMID:The Sirt1 activator SRT3025 expands hematopoietic stem and progenitor cells and improves hematopoiesis in Fanconi anemia mice. 2604 30

Aplastic anemia is the bone marrow failure condition characterized by the development of hypocellularity in both marrow and peripheral blood compartments. Anti-tumor chemotherapeutic agents often exert secondary effect on hematopoietic system leading to aplastic anemia by marrow failure. The precise mechanisms behind the marrow ablative effects of the drugs remain yet to be established. The present study holds a mechanistic approach to unveil the mystery. Aplastic anemia was generated in mice with the administration of busulfan and cyclophosphamide followed by the characterization of the disease with peripheral blood hemogram, histopathological and cytochemical examinations of bone marrow. To gain deep knowledge about the molecular mechanisms of the hematopoietic disruption, cytotoxicity assay, DNA damage measurement, apoptosis study, replicative senescence analysis, redox balance study, mitochondrial membrane potential change assessment, flowcytometric expressional analysis of p21, p53, ATM, Chk-2, Necdin, Gfi-1, c-myc, KU-80 and Sod-2 were done with marrow hematopoietic stem/ progenitor cells (HSPCs). Severe blood pancytopenia and marrow hypocellularity was found in aplastic mice. Proliferative hindrance and apoptosis of marrow cells were identified as the cause behind the hematopoietic catastrophe. The genotoxic effects of the drugs triggered chromatin damage and induced replicative senescence in aplastic HSPCs by upregulating p21 in a p53 independent manner. Moreover, accumulation of genomic insults also caused apoptotic elimination of marrow cells due to disruption of mitochondrial membrane potential by generating redox imbalance. The study established the underlying mechanisms behind hematopoietic disruption during drug induced marrow aplasia. Outcome of the study may be helpful in successful designing of therapeutic strategies for the disease concerned.
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PMID:Genomic insult oriented mitochondrial instability and proliferative hindrance in the bone marrow of aplastic mice including stem/progenitor population. 3068 72