Hypoxia direct effects

Clark and colleagues (27) found evidence of maternal toxicity influencing fetal findings in studies with diflunisal in rabbits, in which fetal axial skeletal defects were observed. Diflunisal was found to produce severe maternal hemolytic anemia and greatly decreased erythrocyte ATP levels. The authors were able to demonstrate that the skeletal malformations resulted from maternal hypoxia secondary to anemia, rather than from a direct effect of the drug on the embryo or fetus. In addition, it was demonstrated that diflunisal had no effects on rat erythrocyte ATP levels, and the compound was categorized as not teratogenic in rats or mice. 

Tobacco use. Cigarette smoke inhaled by a pregnant woman affects the fetus through the direct effects of nicotine and other chemicals, hypoxia associated with increased blood levels of carboxyhemoglobin, nicotine-induced constriction... 

Hypoxia as an Obstacle in Tumor Therapy 276 General Aspects of Hypoxia-Driven Treatment Resistance 276 Direct Effects 278 Indirect Effects Based on Changes in the Transcriptome, in Differential Regulation of Gene Expression and in Alteration of the Proteome 278 Indirect Effects Based on Enhanced Mutagenesis, Genomic Instability and Clonal Selection 279 Tumor Hypoxia as an Obstacle in Radiotherapy 280 Tumor Hypoxia as an Adverse Parameter in Chemotherapy 280 Tumor Hypoxia as an Obstacle in Chemoradiation 281 Tumor Hypoxia as a Barrier for Other Nonsurgical Anticancer Therapies 281 Photodynamic Therapy 281 Immunotherapy 282 Resistance to Hormonal Treatment... 

Hypoxia directly and/or indirectly confers resistance to therapy. Direct effects are mediated through reduced generation of free radicals (some chemotherapy, photodynamic therapy) or lacking fixation of DNA damage (X- and y-rays). 

Hypoxia (low oxygen tension), which can be induced by a blood phase transport limitation, can lead to a breakdown of the endothelial transport barrier either by a direct effect on the endothelial layer or by an indirect mechanism in which hypoxia up-regulates the production of hyperpermeabilizing cytokines from other cells in the arterial wall. A number of recent studies have shown that hypoxia increases macro-molecular transport across endothelial monolayers in culture due to metabolic stress [40-42]. These studies describe direct effects on the endothelial layer since other cells present in the vessel wall were not present in the cell culture systems. 

Changes in PO2 appear to have direct effects on force generation by vascular smooth muscle, and evidence exists that ROS-dependent mechanisms may mediate some of the responses that are observed. The contraction of pulmonary arteries to hypoxia and responses of vascular preparations to posthypoxic reoxygenation are some of conditions for which there is significant evidence for a role for ROS (18,21). The most sensitive signaling mechanisms activated by localized changes in ROS are usually linked to the metabohsm of these species. 

Appheation of DA to the isolated PG in vitro has no direct effect on the activity recorded from both the CSN and the GPB (19,31). Similarly, DA receptor blockade in cocultures of rat carotid body cells and PG neurons affects neither the basal activity of spontaneously active neurons nor the hypoxia-induced responses (23). However, when DA is applied prior to ACh it produces a dose-related modification of the responses induced by the latter. Thus, for a given ACh dose, the lowest DA dose potentiates the response, while the largest dose inhibits the response (19,31). The inhibitory effect of DA on ACh-induced responses is partly reversed by the D2 receptor antagonist spiperone (31). The presence of dopaminergic nemons (32) as well as mRNA for D2 receptors (33) has been shown in a population of PG neurons. These data suggest that DA may act as a modulator of afferent activity in the terminals of PG neurons, and if released at this terminal, it could modulate both the receptor cell and the terminal. 

Arsine poisoning can lead to acute renal tubular necrosis and ultimately to oliguric/anuric renal failure (Rogge et al., 1983). Renal failure can be attributed to direct effect of arsine on renal tissue, heme-pigment nephropathy, or renal hypoxia secondary to massive hemolysis and decreased oxygen carrying capacity of the blood. 

Chemoreceptor response to decreased arterial P02. Hypoxia has a direct depressant effect on central chemoreceptors as well as on the medullary respiratory center. In fact, hypoxia tends to inhibit activity in all regions of the brain. Therefore, the ventilatory response to hypoxemia is elicited only by the peripheral chemoreceptors. 

As the AO with a direct nonspecific mechanism of action we have chosen Hypoxene - sodium poly(2,5-dihydroxiphenyl)-4-thiosulfonate. Besides a direct AO effect as a scavenger of free radicals it exerts an anti-hypoxic effect shunting I and II complexes of mitochondrial respiratory chain, which are inhibited as a consequence of hypoxia (Eropkin et al., 2007). Hypoxene was introduced into cell incubation media before illumination and left during cells further incubation. Hypoxene in the concentration of 40pg/ml, comparable to doses applied in vivo, completely blocked C60-induced phototoxicity (Table 7.3). Cellular viability has completely recovered to control level, which is a convincing evidence of free radical nature of cellular damage in photodynamic effect of fullerene. 

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