Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.99.3 (heme oxygenase)
 4,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An increased expression of the inducible form of heme oxygenase (HO), HO-1, is found in the hippocampus after kainate injection, but thus far it is unclear whether the HO-1 is enzymatically active. The present study was carried out, using monoclonal antibodies to bilirubin and HO-1 and histochemical staining for iron, to compare the products of HO enzymatic activity, bilirubin and iron, with HO-1 expression in the kainate-lesioned hippocampus. There was a close correlation between bilirubin and HO-1 expression, and both bilirubin and HO-1 were observed in damaged neurons at early times, and astrocytes at later times (weeks), after kainate injection. These results indicate that the increased HO-1 in the hippocampus is enzymatically active. Too determine whether HO-1 activity after kainate could have a protective or, perhaps, destructive effect, kainate-injected rats were injected intraperitoneally with a blood-brain barrier-permeable inhibitor of HO, tin protoporphyrin (SnPP), and the effects of such treatment were compared with effects in rats that received kainate and saline injection. It was found that SnPP treatment did not improve neuronal survival. Instead, increased mortality was observed in rats treated with SnPP. Four SnPP-injected rats vs. one saline-injected rats died after kainate treatment. The surviving SnPP-treated rats showed significantly less hippocampal field that containing Nissl or MAP2 staining (an indicator of surviving neurons) compared with the saline-injected rats. These results indicate that HO-1 induction had a net protective effect on neurons in the kainate model of excitotoxic injury.
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PMID:Heme oxygenase-1 activity after excitotoxic injury: immunohistochemical localization of bilirubin in neurons and astrocytes and deleterious effects of heme oxygenase inhibition on neuronal survival after kainate treatment. 1575 Oct 16

Cerebral ischemia and neurodegenerative diseases lead to impairment or death of neurons in the central nervous system. Stem cell based therapies are promising strategies currently under investigation. Carbon monoxide (CO) is an endogenous product of heme degradation by heme oxygenase (HO) activity. Administration of CO at low concentrations produces several beneficial effects in distinct tissues, namely anti-apoptotic and anti-inflammatory. Herein the CO role on modulation of neuronal differentiation was assessed. Three different models with increasing complexity were used: human neuroblastoma SH-S5Y5 cell line, human teratocarcinoma NT2 cell line and organotypic hippocampal slice cultures (OHSC). Cell lines were differentiated into post-mitotic neurons by treatment with retinoic acid (RA) supplemented with CO-releasing molecule A1 (CORM-A1). CORM-A1 positively modulated neuronal differentiation, since it increased final neuronal production and enhanced the expression of specific neuronal genes: Nestin, Tuj1 and MAP2. Furthermore, during neuronal differentiation process, there was an increase in proliferative cell number (ki67 mRNA expressing cells) and a decrease in cell death (lower propidium iodide (PI) uptake, limitation of caspase-3 activation and higher Bcl-2 expressing cells). CO supplementation did not increase the expression of RA receptors. In the case of SH-S5Y5 model, small amounts of reactive oxygen species (ROS) generation emerges as important signaling molecules during CO-promoted neuronal differentiation. CO's improvement of neuronal differentiation yield was validated using OHSC as ex vivo model. CORM-A1 treatment of OHSC promoted higher levels of cells expressing the neuronal marker Tuj1. Still, CORM-A1 increased cell proliferation assessed by ki67 expression and also prevented cell death, which was followed by increased Bcl-2 expression, decreased levels of active caspase-3 and PI uptake. Likewise, ROS signaling emerged as key factors in CO's increasing number of differentiated neurons in OHSC. In conclusion, CO's increasing number of differentiated neurons is a novel biological role disclosed herein. CO improves neuronal yield due to its capacity to reduce cell death, promoting an increase in proliferative population. However, one cannot disregard a direct CO's effect on specific cellular processes of neuronal differentiation. Further studies are needed to evaluate how CO can potentially modulate cell mechanisms involved in neuronal differentiation. In summary, CO appears as a promising therapeutic molecule to stimulate endogenous neurogenesis or to improve in vitro neuronal production for cell therapy strategies.
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PMID:Carbon Monoxide Releasing Molecule-A1 (CORM-A1) Improves Neurogenesis: Increase of Neuronal Differentiation Yield by Preventing Cell Death. 2714 88