Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment of healthy donors with recombinant human granulocyte colony-stimulating factor (rhG-CSF) allows the mobilization and peripheralization into circulating blood of an adequate number of CD34+ cells that can then be collected by leukapheresis (PBSC). This procedure avoids the invasiveness of bone marrow harvest and the risks related to general anesthesia. The main adverse effects of rhG-CSF are: bone pain, 84%, headache, 54%, fatigue, 31%, and nausea, 13%, which are usually scored by the donors as moderate to severe, resolving within 2-3 days after discontinuation of the cytokine. Analgesics, mainly acetaminophen, are sufficient to control the pain. Less than 5% of the donors experience non-cardiac chest pain, a local reaction at the injection site, insomnia, dizziness or a low-grade fever. Discontinuation of the PBSC procedure because of adverse effects of rhG-CSF or leukapheresis is rarely necessary (0.5%) but this good tolerability can be hampered by the need, in 5-20% of cases, for an adequate venous access that requires insertion of a central or venous catheter. There are no absolute contraindications to the stimulation of healthy donors with rhG-CSF but the description of cases of non-traumatic splenic rupture, iritis, cardiac ischemia, and gouty arthritis suggests that further precautionary restrictions are advisable when deciding eligibility for PBSC collection. The main advantages for patients receiving an allogeneic PBSC transplant are the faster hematologic and immunologic recovery and the potential for a greater efficacy in advanced disease by lowering the transplant-related mortality. One of the major concerns regarding the use of rhG-CSF in unrelated healthy donors is the uncertainty about its possible role in triggering malignancy, in particular myelodysplastic syndrome and acute myeloid leukemia. There are no studies with an adequate sample size and follow-up that can answer this question but two recent retrospective studies reported that in the medium term rhG-CSF is not associated with an excess of lymphoproliferative disorders. Currently, caution on the long-term safety of the use of rhG-CSF in healthy donor is still warranted but the data so far accumulated on allogeneic PBSC transplants are encouraging both as far as concerns the good short-medium tolerability profile of G-CSF-stimulation of the donor and the potential major efficacy in leukemia patients.
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PMID:The use of cytokine-stimulated healthy donors in allogeneic stem cell transplantation. 1241 88

Mobilization and recruitment of endothelial progenitor cells (EPC) contributes to vasculogenesis in vivo. So far, applications for cell therapy are limited by the number of available cells. Expansion of EPC or their progeny may, therefore, facilitate its therapeutic use in ischemic disease. The aim of this study was to expand CD34+ EPC-derived progeny from different sources, characterize them, and investigate their potential for use in therapeutic vasculogenesis. CD34+ cells from G-CSF-mobilized peripheral blood (PB) and cord blood (CB) were isolated using immunomagnetic beads and cultured in endothelial cell medium. Cells were expanded up to 16 (PB) and up to 46 (CB) population doublings, respectively. Immunophenotypic and mRNA expression analyses showed a high degree of similarity between the cultured cells and human umbilical vein endothelial cells (HUVEC). By day 14 after transplantation, transplanted human CD31-positive EPC-derived cells were detected. These cells expressed the proliferation marker Ki67 and formed vessel-like structures in ischemic myocardium. Most strikingly, transplantation of EPC-derived cells improved left ventricular function after experimental ischemia, as shown by echocardiography. In conclusion, cells cultured from CD34+ EPC can be expanded in vitro to clinically relevant numbers. In vivo, these cells proliferate, form vascular structures, and improve left ventricular function after experimental myocardial infarction. Therefore, in vitro expanded EPC-derived endothelial cells may be beneficial in the treatment of ischemic disease.
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PMID:Endothelial-like cells expanded from CD34+ blood cells improve left ventricular function after experimental myocardial infarction. 1581 9

G-CSF is a potent hematopoietic factor that enhances survival and drives differentiation of myeloid lineage cells, resulting in the generation of neutrophilic granulocytes. Here, we show that G-CSF passes the intact blood-brain barrier and reduces infarct volume in 2 different rat models of acute stroke. G-CSF displays strong anti-apoptotic activity in mature neurons and activates multiple cell survival pathways. Both G-CSF and its receptor are widely expressed by neurons in the CNS, and their expression is induced by ischemia, which suggests an autocrine protective signaling mechanism. Surprisingly, the G-CSF receptor was also expressed by adult neural stem cells, and G-CSF induced neuronal differentiation in vitro. G-CSF markedly improved long-term behavioral outcome after cortical ischemia, while stimulating neural progenitor response in vivo, providing a link to functional recovery. Thus, G-CSF is an endogenous ligand in the CNS that has a dual activity beneficial both in counteracting acute neuronal degeneration and contributing to long-term plasticity after cerebral ischemia. We therefore propose G-CSF as a potential new drug for stroke and neurodegenerative diseases.
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PMID:The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis. 1600 67

Stroke is one of the leading causes of unnatural death and disability. No effective therapy is available. Recombinant human granulocyte colony-stimulating factor (rhG-CSF), as a mobilizing agent for bone marrow stem cells, can promote stem cell mobilization, homing to brain after cerebral ischemia. In the present study, the administration of G-CSF significantly increased number of CD34(+) cells in the marginal zone of the infarction. Rats receiving G-CSF had higher survival rate and lower infarction volume. Neurological behavior was improved, and the expression of fibronectin in the ischemic brain was increased, as compared to rats treated with vehicle. To mimic the ischemia-reperfusion injury in experimental animals, we employed hippocampal slice cultures that were first treated with oxygen and glucose deprivation (OGD) and then with oxygen-glucose resupply, finding that fibronectin significantly increased the neurite outgrowth of OGD hippocampal slices, upregulated the expression of Bcl-2 protein, and ameliorated the ultrastructure damage of OGD hippocampal slices.
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PMID:Fibronectin and neuroprotective effect of granulocyte colony-stimulating factor in focal cerebral ischemia. 1681 50

Severe thrombocytopenia in association with G-CSF therapy is extremely rare. Here we report a case of profound thrombocytopenia in a 57-year-old male with refractory cardiac ischemia, who received G-CSF during an angiogenesis trial. After 5 days of G-CSF therapy (10 microg/kg/day) the platelet count fell progressively to a nadir of 5x10(9)/L. The patient received steroid, immunoglobulin and platelet support and recovered without sequelae. Subsequent investigations suggested an underlying immune-mediated thrombocytopenia, which we hypothesize was exacerbated by G-CSF therapy.
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PMID:Profound thrombocytopenia related to G-CSF. 1703 24

We present a patient with critical limb ischemia who was successfully treated with the injection of autologous peripheral blood (PB) CD133+ purified stem cells (SC) into the gastrocnemius muscle. No serious adverse events related to G-CSF administration, mononuclear cells harvest or CD133+ SC administration was observed. After 17 months of follow-up, our patient has experienced limb salvage, symptomatic relief and functional improvement. Moreover, we have observed the appearance of flow in the right posterior tibial artery that was absent before the procedure. To our knowledge, this is the first case of critical limb ischemia treated with PB CD133+ SC.
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PMID:Peripheral endothelial progenitor cells (CD133 +) for therapeutic vasculogenesis in a patient with critical limb ischemia. One year follow-up. 1735 5

We have recently provided evidence that transplantation of G-CSF mobilized peripheral blood mononuclear cells (M-PBMNCs) improves limb ischemia in diabetic patients. This method represents a simple, safe, effective, and novel therapeutic approach for diabetic ischemia. Here we investigated the mechanisms by which mobilized blood cells transplantation improves limb ischemia. Unilateral hindlimb ischemia was surgically induced in streptozotocin-induced diabetic nude mice, and they were intramuscularly injected 10(6) M-PBMNCs, or human umbilical vein endothelial cells (HUVECs), PBS controls. We compared their blood-flow restoration via laser Doppler perfusion image (LDPI), angiogenesis via histological determination of capillary density. Physiological and histological assessment revealed an acceleration of ischemia recovery and increase in capillary density with less apoptosis in M-PBMNCs group, compared with those in HUVECs and PBS groups. In vivo noninvasive imaging and immunofluorescence revealed the survival, migration, proliferation, differentiation, and incorporation of M-PBMNCs into foci of vessel networks. More angioblasts were from blood cells after mobilization, and they also produced a number of antiapoptotic and proagniogenic factors that promoted angiogenesis in vivo. M-PBMNCs and its conditioned medium augmented the vessel formation in matrigel plugs in vivo. Thus, transplantation of M-PBMNCs achieved therapeutic neovascularization via supply of abundant angioblasts and angiogenic factors.
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PMID:Enhancement of neovascularization with mobilized blood cells transplantaion: supply of angioblasts and angiogenic cytokines. 1739 Mar 42

Stroke remains a leading cause of death and disability worldwide. An increasing number of animal studies and preclinical trials have, however, provided evidence that regenerative cell-based therapies can lead to functional recovery in stroke patients. Stem cells can differentiate into neural lineages to replace lost neurons. Moreover, they provide trophic support to tissue at risk in the penumbra surrounding the infarct area, enhance vasculogenesis, and help promote survival, migration, and differentiation of the endogenous precursor cells after stroke. Stem cells are highly migratory and seem to be attracted to areas of brain pathology such as ischemic regions. The pathotropism may follow the paradigm of stem cell homing to bone marrow and leukocytes migrating to inflammatory tissue. The molecular signaling therefore may involve various chemokines, cytokines, and integrins. Among these, stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor-4 (CXCR4) signaling is required for the interaction of stem cells and ischemia-damaged host tissues. SDF-1 is secreted primarily by bone marrow fibroblasts and is required for BMSC homing to bone marrow. Overexpression of SDF-1 in ischemic tissues has been found to enhance stem cell recruitment from peripheral blood and to induce neoangiogenesis. Furthermore, SDF-1 expression in the lesioned area peaked within 7 days postischemia, in concordance with the time window of G-CSF therapy for stroke. Recent data have shown that SDF-1 expression is directly proportional to reduced tissue oxygen tension. SDF-1 gene expression is regulated by hypoxic-inducible factor-1 (HIF-1), a hypoxia-dependent stabilization transcription factor. Thus, ischemic tissue may recruit circulating progenitors regulated by hypoxia through differential expression of HIF-lalpha and SDF-1. In addition to SDF-1, beta2-integrins also play a role in the homing of hematopoietic progenitor cells to sites of ischemia and are critical for their neovascularization capacity. In our recent report, increased expression of beta1-integrins apparently contributed to the local neovasculization of the ischemic brain as well as its functional recovery. Identification of the molecular pathways involved in stem cell homing into the ischemic areas could pave the way for the development of new treatment regimens, perhaps using small molecules, designed to enhance endogeneous mobilization of stem cells in various disease states, including chronic stroke and other neurodegenerative diseases. For maximal functional recovery, however, regenerative therapy may need to follow combinatorial approaches, which may include cell replacement, trophic support, protection from oxidative stress, and the neutralization of the growth-inhibitory components for endogenous neuronal stem cells.
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PMID:Regenerative therapy for stroke. 1747 98

In the past few years, the dogma that the heart is a terminally differentiated organ has been challenged. Evidence from preclinical investigations emerged that there are cells, even in the heart itself, that may be able to restore impaired cardiac function after myocardial infarction. Although the exact mechanisms by which the infarcted heart can be repaired by stem cells are not yet fully defined, there is a new optimism among cardiologists that this treatment will prove successful in addressing the cause of heart failure after myocardial infarction-myocyte loss. Despite the promising preliminary data of human myocardial stem cell trials, scientists have also focused on the possibility of enhancing the underlying mechanisms of stem cell repair to gain healthier myocardial tissue. Attempts to induce neo-angiogenesis by transfecting stem cells with signaling factors (such as VEGF), to raise the number of endothelial progenitor cells with medical treatments (such as statins), to transfect stem cells with heat shock protein 70 (as a cardioprotective agent against ischemia) and to enhance the healing process after myocardial infarction with the use of various forms of stimulating factors (G-CSF, SCF, GM-CSF) have been made with notable results. In this article, we summarize the evidence from preclinical and clinical myocardial stem cell studies that have addressed the possibility of enhancing the regenerative capacity of cells used after myocardial infarction.
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PMID:Drugs, gene transfer, signaling factors: a bench to bedside approach to myocardial stem cell therapy. 1766 19

We proposed here that mobilized progenitor cells (MPCs) from the bone marrow are special cell types which carry cytoprotective proteins for cardiac repair following ischemia. Myocardial ischemia was induced by ligation of the left anterior descending coronary artery (LAD) in mice. Progenitor cells in peripheral blood were analyzed by fluorescence-activated cell sorting (FACS). The expression of cytoprotective genes was assayed by ELISA, RT-PCR, and/or real-time PCR. G-CSF was markedly up-regulated in the ischemic myocardium. A good correlation was observed between serum G-CSF and progenitor cells in circulation following LAD ligation. MPCs overexpressed cardiac transcription factor, GATA-4, and anti-apoptotic factor, Bcl-2, besides expression of the surface markers of bone marrow stem cells (BMSCs). Transplantation of cultured MPCs into the ischemic border area significantly improved cardiac function by reducing infarction size. More importantly, MPCs significantly protected cardiomyocytes against apoptosis when co-cultured with cardiomyocytes. The cardiac protection by MPCs was blocked by Bcl-2 neutralizing antibody and GATA-4 siRNA. In contrast, transfection of BMSCs with GATA-4 provided increased protection of myocytes against apoptosis. It is concluded that MPCs are highly cytoprotective and carry protective genes responsible for cardiac repair.
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PMID:Mobilized bone marrow progenitor cells serve as donors of cytoprotective genes for cardiac repair. 1822 54


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