Cellular metabolic impairment

Cytotoxicity assays employ mammalian celk in culture to measure cellular metabolic impairment and death resulting from exposure in vitro to soluble and particulate toxicants. Mammalian cells derived from various tissues and organs can be maintained as short term primary cultures or, in some cases, as continuous cell strains or lines. The cytotoxicity assays, incorporated as part of Level 1 analysis, employ primary cultures of rabbit alveolar (lung) macrophages (RAM) and maintenance cultures of strain WI-38 human lung fibroblasts. 

Deprived of their substrate in severe or prolonged hypoxia, some ATPase-driven systems, including ion pumps, may become impaired. Further, with the decrease in the availability of O2 as its terminal electron acceptor, the mitochondrial transport chain becomes increasingly unable to accept reducing equivalents from cellular metabolic processes. Hence the intracellular pH falls, subjecting the cell as a whole to a reductive stress and favouring those enzyme systems with acid pH optima. 

As cellular metabolism increases, the rate of production of carbon dioxide also increases. Typically, increased activity is associated with an increase in ventilation so that the increased amounts of carbon dioxide delivered to the lungs are eliminated. Hypoventilation impairs the elimination of carbon dioxide and causes an increase in alveolar PC02. 

Central nervous system and neuromuscular junction. A remarkable number of alkaloids interfere with the metabolism and activity of neurotransmitters in the brain and nerve cells, a fact known to man for a thousand years (Table IV). The cellular interactions have been discussed above. Disturbance of neurotransmitter metabolism impairs sensory faculties, smell, vision, or hearing, or they may produce euphoric or hallucinogenic effects. 

The frequency of impaired immunocompetence and increased incidence of infection in malnourished patients suggests that certain immune function tests can be used as nutrition status markers. Nutrition affects immune stams either directly, affecting primarily the lymphoid system, or indirectly by affecting cellular metabolism or organ systems that are involved with immune system regulation. Immune fimction tests used in nutrition assessment are the total lymphocyte count (TLC) and DCH reactions. Both tests are simple, readily available, and inexpensive. TLC reflects the number of... 

Biochemical-cellular Toxication Metabolic impairment Cellular damage Detoxication... 

Mechanism of action Fluorouracil is an analogue of uracil. After entry into cells it undergoes conversion to active metabolites fluorodeoxyuridine monophosphate (FdUMP), fluorodeoxyuridine triphosphate (FdUTP) and fluorouridine triphosphate (FUTP). FdUMP directly inhibits thymidy-late synthetase, reducing the availability of thymidine nucleotides, which are required for DNA synthesis, until new enzyme can be synthesized. FUTP is incorporated into RNA and causes impaired RNA processing and functioning, which disrupts cellular metabolism and viability [71 ]. 

Thiamine. Thiamine plays crucial roles in cellular metabolism, and impaired thiamine uptake results in a variety of disorders. 

Biochemical markers may better quantify the initial and on-going magnitude of the shock state [22-26]). Both the base deficit and serum lactic acid level measure the acidosis produced by the anaerobic state during inadequate delivery of substrate to tissues [27]. Shock impairs nutritive blood flow to tissues, shifting cellular metabolism into the less efficient anaerobic glycolysis pathway. The formation of ATP from ADP is slowed, resulting in accumulation of hydrogen ion (H" ) in the cytosol and extracellular fluid. This accumulation of the in the cytosol is quantified by the base deficit measured on the arterial blood gas. Base deficit... 

If future studies prove that GNE/MNK has a role in cellular pathways other than that of sialic acid and possibly more relevant for maintaining skeletal muscle homeostasis, then this will also provide valuable clues to understanding the specific susceptibility of muscle to a generalized metabolic impairment that is peculiar to h-IBM. 

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