The present study was designed to test the hypothesis that a pneumotoxin, 3-methylindole, alters the basic metabolic pathways involved in phospholipid and neutral lipid synthesis in cultured fibroblasts. Rat skin fibroblasts were obtained from day-old pups. Confluent monolayers were preincubated for up to 24 h with a range of concentrations (0–0.76 mM) of 3-methylindole. Following these treatments, the cell lipids were labelled by incubation for 6 h with [ 14 C]glycerol. The lipids were extracted, separated by thin layer chromatography, and the radioactivity in each fraction was determined. 3-Methylindole had no effect on the total incorporation of [ 14 C]glycerol into lipids, but significantly altered the the distribution among lipid fractions. Incubation with 3-methylindole caused a decrease in the incorporation of [ 14 C]glycerol into phosphatidylcholine, while radioactivity accumulated in the neutral lipid fraction. The other lipid fractions responded variably. Similarity, Flow 2000 human diploid lung fibroblasts were incubated for 24 h with 3-methylindole followed by treatment with [ 14 C]glycerol, resulting in a 74% decrease in the incorporation of [ 14 C]glycerol into phosphatidylcholine and a 50% increase in its accumulation in neutral lipid. The results indicate that 3-methylindole inhibits the synthesis of phosphatidylcholine from diacylglycerol precursors on the endoplasmic reticulum in cultured fibroblasts. This is an important observation as it shows that 3-methylindole affects the synthesis of phospholipids required for membrane turnover in cells that are not specialized for the production of phospholipids for surfactant.
Dietary niacin deficiency, and pharmacological excesses of nicotinic acid or nicotinamide, have dramatic effects on cellular NAD pools, ADP-ribose metabolism, tissue function and health. ADP-ribose metabolism is providing new targets for pharmacological intervention, and it is important to consider how the supply of vitamin B3 may directly influence ADP-ribosylation reactions, or create interactions with other drugs designed to influence these pathways. In addition to its redox roles, NAD+ is used as a substrate for mono-, poly- and cyclic ADP-ribose formation. During niacin deficiency, not all of these processes can be maintained, and dramatic changes in tissue function and clinical condition take place. Conversely, these reactions may be differentially enhanced by pharmacological intakes of vitamin B3, and potentially by changing expression of specific NAD generating enzymes. A wide range of metabolic changes can take place following pharmacological supplementation of nicotinic acid or nicotinamide. As niacin status decreases towards a deficient state, the function of other types of pharmaceutical agents may be modified, including those that target ADP-ribosylation reactions, apoptosis and inflammation. This article will explore what is known and yet to be learned about the response of tissues, cells and subcellular compartments to excessive and limiting supplies of niacin, and will discuss the etiology of the resulting pathologies.
Abstract Medical contraindications and complications pose challenges for electroconvulsive therapy (ECT). Most published reports are scattered across various physiological systems and individual disease conditions. This review aimed to evaluate the literature on physiological and medical complexities during ECT and discuss risk mitigation strategies in a comprehensive review. We searched PubMed and Embase for contraindications and precautions during ECT with relevant MeSH terms and appraised previous reviews on the same topic. The results suggest that mortality directly attributed to ECT is extremely rare. Instances of fatalities, including fetal deaths, have been reported after ECT in the presence of recent myocardial infarction, deep vein thrombosis, intracranial aneurysm and tumors, pheochromocytoma, sepsis, and pregnancy. However, there are no definite conclusions or consensus on attributions of the outcomes to ECT in all cases because of the time lag between the treatment and deaths and confounding factors. The risks can be mitigated with safety protocols, adequate stakeholder communication, collaboration with anesthetists and specialists, consultation‐liaison services, and ECT education. Overall, ECT remains a relatively safe treatment even in the presence of medical and physiological complexities. In rare instances, certain medical conditions may indicate a high risk for ECT, where practitioners avoid the treatment or administer it with precautions if the risk‐benefit ratio favors its use.
Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme which has been shown to play a role in the differentiation of haematopoietic cells. We report here that neutrophils are the first nucleated mammalian cell type demonstrated to be devoid of immunoreactive PARP. Both NB4 acute promyelocytic leukaemia and HL-60 (acute myelocytic leukaemia) cells were differentiated into non-malignant neutrophils with all-trans-retinoic acid (ATRA). Western blot analysis demonstrated that ATRA had no effect on PARP expression in HL-60 cells. However, PARP was completely down-regulated in NB4 cells within 36 h of treatment initiation. This decrease in PARP polypeptide coincided with growth arrest and preceded the appearance of neutrophilic differentiation features. NB4 cells require a combination of 1,25-dihydroxyvitamin D3 (1,25-D3) and phorbol 12-myristate 13-acetate (PMA) to differentiate completely into monocyte/macrophages, whereas HL-60 cells can be made to differentiate by combined or single agents. PARP expression was up-regulated 90-fold when NB4 cells were treated with PMA and 1,25-D3 together, and this increase accompanied expression of the monocyte/macrophage phenotype. Only modest changes in PARP expression were observed when each agent was used alone in NB4 cells or when HL-60 cells were differentiated along the monocyte/macrophage pathway. In addition, PARP activity was modulated in a pattern similar to protein levels when NB4 cells were induced to differentiate along the neutrophilic and monocyte/macrophage pathways. This suggests that the activity of PARP may be controlled through regulation of protein levels during NB4 cell differentiation. We conclude that PARP levels are dramatically modulated during monocyte/macrophage and neutrophilic differentiation. On the basis of the tremendous changes in PARP polypeptide and total activity during myeloid differentiation, we propose that modulation of PARP gene expression is required for cellular maturation in both lineages.
This chapter contains sections titled: Introduction Summary Niacin Structure and Nomenclature Assessment and Maintenance of Niacin Nutriture NAD Metabolism Physiological Functions of NAD NAD-utilizing Proteins Niacin and Disease Physiological Concentrations of NAD Precursors Future Directions
