Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0020672 (hypothermia)
17,327 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ability of a retinoid X receptor (RXR) to heterodimerize with many nuclear receptors, including LXR, PPAR, NGF1B and RAR, underscores its pivotal role within the nuclear receptor superfamily. Among these heterodimers, PPAR:RXR is considered an important signalling mediator of both PPAR ligands, such as fatty acids, and 9-cis retinoic acid (9-cis RA), an RXR ligand. In contrast, the existence of an RXR/9-cis RA signalling pathway independent of PPAR or any other dimerization partner remains disputed. Using in vivo chromatin immunoprecipitation, we now show that RXR homodimers can selectively bind to functional PPREs and induce transactivation. At the molecular level, this pathway requires stabilization of the homodimer-DNA complexes through ligand-dependent interaction with the coactivator SRC1 or TIF2. This pathway operates both in the absence and in the presence of PPAR, as assessed in cells carrying inactivating mutations in PPAR genes and in wild-type cells. In addition, this signalling pathway via PPREs is fully functional and can rescue the severe hypothermia phenotype observed in fasted PPARalpha-/- mice. These observations have important pharmacological implications for the development of new rexinoid-based treatments.
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PMID:In vivo activation of PPAR target genes by RXR homodimers. 1510 26

The aim of the present study was to determine the beneficial effect of mild hypothermia during ischemia and/or reperfusion injury in myocardial infarction. Sprague-Dawley rats (400 +/- 20 g) were subjected to 30 min occlusion of the left coronary artery followed by 24 h reperfusion. Rats were divided into normothermic (NT; 37 degrees C) and hypothermic (HT; 34 degrees C) groups. In the HT group hypothermia was maintained during coronary occlusion and continued for 30 min following reperfusion. Histological analysis revealed dead cardiomyocytes and polymorphonuclear neutrophil infiltration after 24 h. Myocardial infarction, measured using an image analyzer, showed that the percentage area of infarction was significantly decreased in the HT group. Immunohistochemical analysis was carried out using antibodies against Bcl-2, Bax and Bak. DNA fragments were labeled in situ using the 3'-OH end-labeling method (TUNEL). In the HT group Bcl-2 was induced in many myocytes, whereas Bax and Bak were induced in only a few myocytes. A higher number of TUNEL-positive cells were recorded in the NT group than in the HT group, but these were more thinly scattered in the HT group. The expression pattern revealed that many myocytes could survive at the border zone in the HT group; in contrast, few myocytes in the NT group were able to survive. Our results suggest that mild hypothermia selectively interferes with, and mitigates, reperfusion injury.
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PMID:Attenuation of ischemia and/or reperfusion injury during myocardial infarction using mild hypothermia in rats: an immunohistochemical study of Bcl-2, Bax, Bak and TUNEL. 1559 11

Apoptosis occurs during the isolation and even short-term storage and culture of hepatocytes, and in the pathogenesis of liver diseases, such as hepatic failure and hepatitis. Therapeutic hypothermia has beneficial effects in experimental models of fulminant hepatic failure. The mechanisms underlying the potential benefits of mild hypothermia on the liver have not been well investigated. We examined the effects of temperature on soluble Fas ligand-induced apoptosis in freshly isolated mouse hepatocytes. Decreasing the culture temperature from 37 degrees C to 32 degrees C produced significant suppression of Fas-mediated apoptosis in cultured hepatocytes over a 12-h period. This observation was supported by cell morphology, flow cytometry analysis of cellular DNA content, and Annexin V-FITC staining of membrane phosphatidylserine translocation. In hypothermic conditions, Fas-mediated cytochrome c release from mitochondria of hepatocytes and the proximate downstream activation of caspase-9 were suppressed under mild hypothermic conditions. Effector caspase-7 activity was also inhibited at 32 degrees C. In contrast, the activation of initiator caspase-8 and cleavage of Bid were not affected after Fas-ligand stimulation. These findings suggest that mild hypothermia suppresses Fas-mediated apoptosis of liver cells by the partial inhibition of signaling events including mitochondrial damage, cytochrome c release, and subsequent apoptosome formation and effector caspase activation.
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PMID:Hypothermia inhibits Fas-mediated apoptosis of primary mouse hepatocytes in culture. 1564 37

Mammalian hibernation is associated with apnoic breathing patterns and a hypoxia-hypothermia connection has been suggested as part of the mechanism by which body temperature is reduced as animals enter torpor. Hence, we hypothesized that changes in the expression of the hypoxia inducible factor (HIF-1) may potentially be involved in regulating hibernation-responsive gene targets. The expression of the alpha subunit of HIF-1 was quantified at both gene and protein levels in four organs of the thirteen-lined ground squirrel, Spermophilus tridecemlineatus. Reverse transcription-PCR showed no change in hif-1alpha transcript levels in the liver, lung, skeletal muscle or brown adipose tissue of euthermic versus hibernating animals but HIF-1alpha protein levels were elevated by 60-70% in the two organs responsive for thermogenesis (brown adipose and skeletal muscle). Furthermore, assessment of DNA binding by HIF-1 in nuclear extracts from brown adipose revealed 6-fold higher levels in hibernator tissue than in euthermic controls suggesting increased expression of HIF-1 responsive genes during hibernation. The complete nucleotide sequence of hif-1alpha from ground squirrels, the first hif-1alpha sequence amplified from a hibernating mammal, was obtained using PCR amplification and 3' and 5' RACE. Amino acid sequence analysis revealed 90-95% identity with the HIF-1alpha protein from other mammals. Several unique amino acid sequence substitutions were identified that may affect protein conformation and could possibly function to counteract low temperature effects on HIF-1alpha conformation at near 0 degrees C body temperatures during torpor.
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PMID:Cloning and expression of hypoxia-inducible factor 1alpha from the hibernating ground squirrel, Spermophilus tridecemlineatus. 1581 24

Heat stroke-induced death is a major killer worldwide. Mice were subjected to acute heat stress by exposing them to whole-body hyperthermia (WBH) treatment and were used as a model to study heat stroke. Administration of L-arginine (L-arg, 120 mg/kg, i.p) 2 h after the cessation of WBH rescued the mice from heat-induced death and reduced the hypothermia. Heat shock protein 70 levels in the liver were increased significantly in heat-stressed mice administered L-arg compared with the heat-stressed group. WBH induced apoptosis, as indicated by DNA fragmentation, and increased levels of p53 and caspase-3 activity, which were significantly reduced by the administration of L-arg. The levels of inducible nitric oxide synthase in the liver, nitrite, and inflammatory cytokines like interleukin 1beta and tumor necrosis factor-alpha in the serum increased in WBH-treated mice. The levels of the above markers of heat stress significantly decreased in L-arg-treated mice. Kinin-B1 receptor (kinin-B1R) in cardiac tissue that is upregulated in heat stressed mice was significantly lower in L-arg-administered mice. These data suggest the potential use of L-arg, a nonessential amino acid that is used as an enteral diet supplement, to treat heat stroke-related injury when administered at the appropriate dose and time.
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PMID:Therapeutic treatment with L-arginine rescues mice from heat stroke-induced death: physiological and molecular mechanisms. 1620 19

Over the last 50 years deep hypothermia (23 degrees C) has demonstrated to be an excellent neuroprotective agent in cerebral ischemic injury. Mild hypothermia (31-33 degrees C) has proven to have the same neuroprotective properties without the detrimental effects of deep hypothermia. Mechanisms of injury that are exaggerated by moderate hyperthermia and ameliorated by hypothermia include, reduction of oxygen radical production, with peroxidase damage to lipids, proteins and DNA, microglial activation and ischemic depolarization, decrease in cerebral metabolic demand for oxygen and reduction of glycerin and excitatory amino acid (EAA) release. Studies have demonstrated that inflammation potentiates cerebral ischemic injury and that hypothermia can reduce neutrophil infiltration in ischemic regions. To further elucidate the mechanisms by which mild hypothermia produces neuroprotection in ischemia by attenuating the inflammatory response, we provoked inflammatory reaction, in brains of rats, dropping a substance that provokes a heavy inflammatory reaction. Two groups of ten animals underwent the same surgical procedure: the skull bone was partially removed, the duramater was opened and an inflammatory substance (5% carrageenin) was topically dropped. The scalp was sutured and, for the group that underwent neuroprotection, an ice bag was placed covering the entire skull surface, in order to maintain the brain temperature between 29.5-31 degrees C during 120 minutes. After three days the animals were sacrificed and their brains were examined. The group protected by hypothermia demonstrated a remarkable reduction of polymorphonuclear leukocytes (PMNL) infiltration, indicating that mild hypothermia can have neuroprotective effects by reducing the inflammatory reaction.
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PMID:Mild hypothermia reduces polymorphonuclear leukocytes infiltration in induced brain inflammation. 1625 56

Both mild hypothermia (MH) and decompressive craniectomy (CE) have been shown to have neuroprotective effects in brain ischemia. We investigated a possible effect of MH and a combination of CE and MH (CE + MH) on the changes of infarction size, DNA fragmentation, and immunoreactivities for Bcl-2 and Bax after 24 h of permanent middle cerebral artery occlusion (MCAO) in rats. For the estimation of ischemic brain injury, we calculated the infarct size of the MCA region at 24 h after the MCAO. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick labeling (TUNEL) staining was performed for the detection of DNA fragmentation. Immunoreactivities for Bcl-2 and Bax were stained. Infarction size after permanent MCAO was significantly reduced by CE+MH treatment (P < 0.01). Infarction size did not change significantly by application of MH alone (P > 0.05). TUNEL staining was remarkably reduced both in MH-treated animals and in CE + MH-treated animals. Immunoreactivity for Bcl-2 was greatly induced both in MH-treated animals and in CE + MH-treated animals. Induction of immunoreactivity for Bcl-2 was obviously inhibited both in MH-treated animals and in CE + MH-treated animals. It suggests that temporary MH delays infarct evolution and ameliorates neuron apoptosis but does not significantly reduce definite infarction size. CE + MH not only ameliorates neuron apoptosis but also remarkably reduces infarction size.
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PMID:Decompressive craniectomy and mild hypothermia reduces infarction size and counterregulates Bax and Bcl-2 expression after permanent focal ischemia in rats. 1640 75

In this study we describe optimization of polyethylenimine (PEI)-mediated transient production of recombinant protein by CHO cells by facile manipulation of a chemically defined culture environment to limit accumulation of nonproductive cell biomass, increase the duration of recombinant protein production from transfected plasmid DNA, and increase cell-specific production. The optimal conditions for transient transfection of suspension-adapted CHO cells using branched, 25 kDa PEI as a gene delivery vehicle were experimentally determined by production of secreted alkaline phosphatase reporter in static cultures and recombinant IgG4 monoclonal antibody (Mab) production in agitated shake flask cultures to be a DNA concentration of 1.25 microg 10(6) cells(-1) mL(-1) at a PEI nitrogen:DNA phosphate ratio of 20:1. These conditions represented the optimal compromise between PEI cytotoxicity and product yield with most efficient recombinant DNA utilization. Separately, both addition of recombinant insulin-like growth factor (LR3-IGF) and a reduction in culture temperature to 32 degrees C were found to increase product titer 2- and 3-fold, respectively. However, mild hypothermia and LR3-IGF acted synergistically to increase product titer 11-fold. Although increased product titer in the presence of LR3-IGF alone was solely a consequence of increased culture duration, a reduction in culture temperature post-transfection increased both the integral of viable cell concentration (IVC) and cell-specific Mab production rate. For cultures maintained at 32 degrees C in the presence of LR3-IGF, IVC and qMab were increased 4- and 2.5-fold, respectively. To further increase product yield from transfected DNA, the duration of transgene expression in cell populations maintained at 32 degrees C in the presence of LR3-IGF was doubled by periodic resuspension of transfected cells in fresh media, leading to a 3-fold increase in accumulated Mab titer from approximately 13 to approximately 39 mg L(-1). Under these conditions, Mab glycosylation at Asn297 remained essentially constant and similar to that of the same Mab produced by stably transfected GS-CHO cells. From these data we suggest that the efficiency of transient production processes (protein output per rDNA input) can be significantly improved using a combination of mild hypothermia and growth factor(s) to yield an extended "activated hypothermic synthesis".
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PMID:Control of culture environment for improved polyethylenimine-mediated transient production of recombinant monoclonal antibodies by CHO cells. 1673 59

Mild hypothermia, applied either during or soon after cerebral ischemia, has been shown to confer robust neuroprotection against brain injury in experimental stroke and in patients recovering from cardiac arrest. However, the mechanism underlying hypothermic neuroprotection is not completely understood. In this study, the effect of mild hypothermia on the induction of oxidative DNA damage, an early harmful event during post-ischemic reperfusion that triggers both necrotic and apoptotic cell death in the brain, was studied using the rat model of middle cerebral artery occlusion (MCAO) and reperfusion. Rats were subjected to 2-hr MCAO and reperfusion of various durations up to 3 days. Selective brain hypothermia (33 degrees C) was induced at the onset of ischemia and terminated at the beginning of reperfusion, and this significantly decreased infarct volume 72 hr later. Correlated with this protective effect, intraischemic mild hypothermia markedly attenuated the nuclear accumulations of several oxidative DNA lesions, including 8-oxodG, AP sites, and DNA single-strand breaks, after 2-hr MCAO. Consequently, harmful DNA damage-dependent signaling events, including NAD depletion, p53 activation, and mitochondrial translocation of PUMA and NOXA, were reduced during post-ischemic reperfusion in hypothermia-treated brains. These results suggest that the attenuation of oxidative DNA damage and DNA damage-triggered pro-death signaling events may be an important mechanism underlying the neuroprotective effect of mild hypothermia against ischemic brain injury.
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PMID:Mild hypothermia diminishes oxidative DNA damage and pro-death signaling events after cerebral ischemia: a mechanism for neuroprotection. 1712 18

Cerebral ischemia and reperfusion induces rapid accumulation of oxidative DNA lesions in the brain, which, if not repaired promptly, may trigger cell death. The base-excision repair (BER) pathway is the main mechanism employed by neurons to repair various types of oxidative DNA damage. Recent studies have suggested that the cellular activity of BER is highly regulated (up- or down-regulated) after ischemic brain injury, and this regulation may contribute to the outcome of cell injury. The mechanism through which cellular BER is regulated in response to neuronal injury is currently poorly understood. In the present study, we have examined BER regulation in the rat model of focal ischemic brain injury induced by 2 hr of middle cerebral artery occlusion and 0-72 hr of reperfusion. As determined using cerebral nuclear extracts, focal ischemia resulted in a marked reduction in BER activities, including the overall BER activity, AP endonuclease activity and DNA polymerase-beta activity, indicating functional impairment of the BER pathway. BER reduction occurred as early as 0.5 hr after the onset of reperfusion. Thereafter, BER activity failed to recover, and there were persistent accumulations of apurinic/apyrimidinic abasic sites and DNA single-strand breaks in ischemic tissues. The reduction in BER during the early reperfusion phase (less than 6 hr) was not accompanied by any alterations in the levels of essential BER enzymes in brain extracts. However, increased serine- and threonine-specific phosphorylation was detected for both AP endonuclease and DNA polymerase-beta after ischemia, with the time course of serine phosphorylation closely correlated to that of changes in BER activity. Furthermore, dephosphorylation of nuclear extracts with alkaline phosphatase largely restored AP endonuclease and DNA polymerase-beta activities. Taking advantage of the neuroprotective effect of mild hypothermia (33 degrees C), which was induced in the brain during the first 2 hr of reperfusion, we found that the post-ischemic suppression of BER activity is a reversible event. Hypothermic treatment diminished the serine-specific phosphorylation of AP endonuclease and DNA polymerase-beta, promoted BER activities, and attenuated the levels of oxidative DNA lesions after ischemia. These results suggest that the functional impairment of the BER pathway after severe focal cerebral ischemia is due to the loss-of-function post-translational modifications of repair enzymes. Further investigations elucidating the precise mechanism underlying the post-translational regulation of BER enzymes may lead to novel therapeutic strategies for cerebral ischemia.
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PMID:Impaired DNA repair via the base-excision repair pathway after focal ischemic brain injury: a protein phosphorylation-dependent mechanism reversed by hypothermic neuroprotection. 1712 26


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