Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0599766 (functional recovery)
 13,441 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have examined the efficacy of various drugs in 44 patients with MDS and found the different effectiveness which depends on the type of MDS. Namely, RA appears to respond to steroid hormone, androgen, and/or vitamin D3, regardless of single or combined use. In particular, it is obvious in androgen, and as our previous reports, high content of acidic ferritin in RBC with RA have changed to more basic ones by treatment with androgen. On the contrary, these drugs were not effective on RAEB, RAEB-T, and CMML. A long-term observation is needed to determine whether the prolonged or decreased occurrence of leukemia could be obtained in the effective cases with RA. Most of the cases who did not develop overt leukemia during this study died of bleeding or infections due to thrombocytopenia or leukocytopenia, thus indicating that supportive therapies are important in patients with MDS. Since it has recently been reported that recombinant G-CSF or GM-CSF is helpful to increase the number of leucocyte and to enhance their functional recovery in MDS, these factors may be powerful agents against infections when they are carefully used with regard to the activation of leukemic clones.
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PMID:[Therapy of the preleukemic state: effect of androgens on refractory anemia]. 283 1

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 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

The clinical application of G-CSF is broadening. In addition to treating neutropenia and in bone marrow transplants, it is now being considered for functional recovery after myocardial infarction and stroke. It is thus very important that the effects of extended G-CSF administration on the skeleton are investigated. To simulate this potential clinical use of G-CSF in postmyocardial infarction or cerebral vascular accident, a 2-week course of administration was selected. Ten C57BL/6 mice at 22 weeks of age were given intraperitoneal injection of saline, and another nine of the same age were given G-CSF. Four weeks later, femurs were harvested and three-point-bend tests were performed until fracture. From the load-displacement curve recorded during the test, the stiffness, Young's modulus, fracture strength of the bone, fracture energy, and the total energy to break the femur were determined. The test data show that mice treated with G-CSF have significantly lower modulus in their femurs when compared to the controlled mice treated with saline. The stiffness demonstrates the largest decrease, by as much as 25%. As its clinical use increases, G-CSF effects on the mechanical properties of the skeleton become increasingly more important because many of these diseases occur in older patients with already compromised skeleton by osteopenia or osteoporosis. How G-CSF administration achieves these alterations in skeletal biomechanical properties is unclear. Although the current findings confirm its known temporary catabolic effects on bone homeostasis, it also suggests that a transient state of higher bone compliance following the end of G-CSF administration can be achieved that may have clinical benefits.
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PMID:Granulocyte colony-stimulating factor administration alters femoral biomechanical properties in C57BL/6 mice. 1825 84

Several lines of evidence have demonstrated beneficial effects of the hematopoietic factor G-CSF in experimental stroke. A conclusive demonstration of this effect in G-CSF deficient mice is, however, lacking. We therefore investigated the effect of G-CSF deficiency on infarct volumes, functional recovery, mRNA and protein expression of the matrix metalloproteinase 9 (MMP-9) after stroke. Furthermore we tested the efficacy of G-CSF substitution in G-CSF deficient animals to prevent the potential consequences of G-CSF deficiency. In the present study experimental stroke was induced in female non-treated wildtype (wt), G-CSF deficient mice and G-CSF substituted G-CSF deficient mice followed by assessment of infarct volumes, neurological outcome and sensorimotor function. In addition, immunohistochemistry and real-time PCR of the peri-ischemic area were performed. G-CSF deficient mice showed increased infarct volumes, whereas G-CSF substituted mice had a remarkable reduction in lesion size compared to wt mice. These findings are accompanied by an improvement in neurological and sensorimotor function. G-CSF deficiency resulted in an upregulation of MMP-9 in the direct peri-ischemic tissue. Treatment with G-CSF suppressed the upregulation of MMP-9. Taken together, G-CSF deficiency clearly resulted in enlarged infarct volumes, and worsened neurological outcome. G-CSF substitution abolished these negative effects, led to significant reduced lesion volumes, and improved neurological outcome. G-CSF mediated suppression of MMP-9 further demonstrates that endogenous G-CSF plays a significant role in brain protective mechanisms. We have shown for the first time that endogenous G-CSF is required for brain recovery mechanisms after stroke.
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PMID:Endogenous brain protection by granulocyte-colony stimulating factor after ischemic stroke. 1933 60

The nervous system regulates immunity through hormonal and neuronal routes as part of host defense and repair mechanism. Here, we review the emerging evidence for regulation of human hematopoietic stem and progenitor cells (HSPC) by the nervous system both directly and indirectly via their bone marrow (BM) niche-supporting stromal cells. Functional expression of several neurotransmitter receptors was demonstrated on HSPC, mainly on the more primitive CD34(+)/CD38(-/low) fraction. The myeloid cytokines, G-CSF and GM-CSF, dynamically upregulate neuronal receptor expression on human HSPC. This is followed by an increased response to neurotransmitters, leading to enhanced proliferation and motility of human CD34(+) progenitors, repopulation of the murine BM and their egress to the circulation. Importantly, recent observations showed rapid mobilization of human HSPC to high SDF-1 expressing ischemic tissues of stroke individuals followed by neoangiogenesis, neurological and functional recovery. Along with decreased levels of circulating immature CD34(+) cells and SDF-1 blood levels found in patients with early-stage Alzheimer's disease, these findings suggest a possible involvement of human HSPC in brain homeostasis and thus their potential clinical applications in neuropathology.
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PMID:Blood-forming stem cells are nervous: direct and indirect regulation of immature human CD34+ cells by the nervous system. 1934 92

Several recent studies demonstrated beneficial effects of G-CSF treatment (granulocyte colony-stimulating factor) in various CNS disease. Possible mechanisms underlying this activity are neuroprotection, anti-apoptosis, angiogenesis and anti-inflammation. Hence, we investigated the efficacy of G-CSF administration in experimental stroke by determining infarct volume and neurological score in wildtype, G-CSF-deficient and G-CSF-treated G-CSF-deficient mice. Besides, cerebral ischemia is followed by an upregulation of endothelial adhesion molecules which promote leukocyte recruitment to the injured area. In combination with G-CSF-induced leukocytosis, increased peripheral neutrophils could aggregate within microvasculature and additionally impair blood perfusion of the ischemic tissue. Therefore, we analyzed the neutrophil counts in both vessel and tissue compartment 2 and 5 days post-stroke by immunohistochemistry. Here we show that G-CSF deficiency leads to increased infarct volumes, whereas G-CSF substitution revokes detrimental effects by reducing lesion size and enhancing neurological outcome compared to untreated animals. Administration of G-CSF is accompanied by significant increase of circulating neutrophils 2 days post-ischemia but leukocytosis is restricted to the vessel compartment and has no deleterious effect on lesion formation and functional recovery. These observations are likely to be important for therapeutic targeting of G-CSF-mediated neuroprotection in stroke.
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PMID:Effects of G-CSF treatment on neutrophil mobilization and neurological outcome after transient focal ischemia. 2002 12

G-CSF is widely employed for the treatment of chemotherapy-induced neutropenia. Recently, neuroprotective effects of G-CSF in animal stroke models were discovered including infarct size reduction and enhancement of functional recovery. The underlying mechanisms of action of G-CSF in ischemia appear to be a direct anti-apoptotic activity in neurons and a neurogenesis inducing capacity. Additional effects may be based on the stimulation of new blood-vessel formation, the stimulation of immunocompetence and -modulation as well as on bone marrow mobilization. In addition to a discussion of these mechanisms, we will review the available preclinical studies and analyze their impact on the overall efficacy of G-CSF in experimental stroke.
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PMID:Granulocyte-colony stimulating factor for stroke treatment: mechanisms of action and efficacy in preclinical studies. 2014 89

Fatty acid epoxides are important lipid signaling molecules involved in the regulation of vascular tone and homeostasis. Tissue and plasma levels of these mediators are determined by the activity of cytochrome P450 epoxygenases and the soluble epoxide hydrolase (sEH), and targeting the latter is an effective way of manipulating epoxide levels in vivo. We investigated the role of the sEH in regulating the mobilization and proliferation of progenitor cells with vasculogenic/reparative potential. Our studies revealed that sEH down-regulation/inhibition impaired the development of the caudal vein plexus in zebrafish, and decreased the numbers of lmo2/cmyb-positive progenitor cells therein. In mice sEH inactivation attenuated progenitor cell proliferation (spleen colony formation), but the sEH products 12,13-dihydroxyoctadecenoic acid (12,13-DiHOME) and 11,12- dihydroxyeicosatrienoic acid stimulated canonical Wnt signaling and rescued the effects of sEH inhibition. In murine bone marrow, the epoxide/diol content increased during G-CSF-induced progenitor cell expansion and mobilization, and both mobilization and spleen colony formation were reduced in sEH(-/-) mice. Similarly, sEH(-/-) mice showed impaired functional recovery following hindlimb ischemia, which was rescued following either the restoration of bone marrow sEH activity or treatment with 12,13-DiHOME. Thus, sEH activity is required for optimal progenitor cell proliferation, whereas long-term sEH inhibition is detrimental to progenitor cell proliferation, mobilization, and vascular repair.
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PMID:Soluble epoxide hydrolase regulates hematopoietic progenitor cell function via generation of fatty acid diols. 2266 95

Stem cell transplantation has been used to improve neural function in intracerebral hemorrhage (ICH). However, reports on bone marrow-derived mesenchymal stem cell (MSC) transplantation in ICH are limited. We aimed to explore the therapeutic effect and related mechanisms by transplantation of MSCs in rats with ICH. An experimental rat ICH model was established by intrastriatal administration of collagenase. The rats were randomly divided to receive either rat MSCs or PBS solution intravenously. In addition, behavioral tests using the modified neurological severity score (mNSS) were performed following ICH. Immunohistochemistry was performed to detect the Brdu-labeled MSCs and the protein expression of caspase 2, NF200 and GFAP in neural tissues. Western blotting and ELISA were performed to measure the protein expression of Akt and bcl-2 or the protein content of G-CSF and BDNF. The MSC-transplanted group demonstrated better neural function on the mNSS test following ICH compared with the control group (P<0.05). The MSC-transplanted group also showed reduced hemorrhage volume at 24 and 72 h following ICH. In the perihematomal regions of rat brain with ICH, a substantial number of Brdu-labeled MSCs were observed, and a high protein expression of caspase 3, NF200 and GFAP was found in the MSC-transplanted group. The protein content of Akt, Bcl-2, G-CSF and BDNF were all elevated by MSC transplantation. Intravenously transplanted MSCs are capable of improving functional recovery and restoring neurological deficits in experimental ICH. The mechanisms are associated with enhanced survival and differentiation of neural cells, and increased expression of anti-apoptotic proteins and trophic factors.
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PMID:Therapeutic effect of mesenchymal stem cells in rats with intracerebral hemorrhage: reduced apoptosis and enhanced neuroprotection. 2282 63


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