Toxicity of thallium at low doses: A review

A mini review of the toxicity of Thallium (Tl) at low doses is herein presented. Thallium has severe toxicity. Although its acute biological effects have been widely investigated and are well known, its biological effects on human health and in cell cultures at low doses (<100 µg/L) due, for example, to Tl chronic exposure via consumption of contaminated water or foods, have often been overlooked or underestimated. Relatively few papers have been published on this topic and are herein reviewed to provide a focused scientific opinion in the light of current worldwide regulatory issues

Sphingolipid metabolites in neural signalling and function

Sphingolipid metabolites, such as ceramide, sphingosine, sphingosine-1-phosphate (S1P) and complex sphingolipids (gangliosides), are recognized as molecules capable of regulating a variety of cellular processes. The role of sphingolipid metabolites has been studied mainly in non-neuronal tissues. These studies have underscored their importance as signals transducers, involved in control of proliferation, survival, differentiation and apoptosis. In this review, we will focus on studies performed over the last years in the nervous system, discussing the recent developments and the current perspectives in sphingolipid metabolism and functions

Role of mitochondria in serum withdrawal-induced apoptosis of immortalized neuronal precursors

Abstract The intracellular mechanisms controlling apoptosis in immature neurons are still largely unknown. Taking immortalized hippocampal neuronal precursors (mouse cell line HN9.10e) as a model, we have analyzed the cellular events associated to apoptosis induced by serum deprivation. We observed translocation of Bax from cytosol to mitochondria after 1 h of serum withdrawal followed, 2 h later, by cytochrome c release from mitochondria. These events occurred without mitochondrial membrane potential loss nor mitochondrial calcium raise. As calcium is implicated in several cell death pathways, we analyzed intracellular calcium levels after longer periods of 21 21 serum deprivation. After 6 h, an increase of cytosolic Ca was detected in HN9.10e cells loaded with the Ca indicator Fluo3-AM. This increase of calcium preceded morphological signs of apoptosis such as cell shrinkage and nuclear fragmentation, and was followed by a more pronounced raise that persisted until the terminal phases of the apoptotic process. Cells serum-deprived for 4 h and then grown in complete medium for 20 h fully recovered viability. Summarizing, in HN9.10e cells, calcium deregulation occurs in the late phases of apoptosis; earlier events involve translocation of Bax, release of cytochrome c, and maintenance of mitochondrial functionality. This allows an enlargement of the temporal window in which commitment to death is reversible

Serum-withdrawal-dependent apoptosis of hippocampal neuroblasts involves Ca(++) release by endoplasmic reticulum and caspase-12 activation

Apoptotic death caused by diseases or toxic insults is preceded and determined by endoplasmic reticulum dysfunction and altered intraluminar calcium homeostasis in many different cell types. With the present study we have explored the possibility that the ER stress could be involved also in apoptotic death induced by serum deprivation in neuronal cells. We have chosen as a model of study the cell line HN9.10e, constituted by immortalized hippocampal neuroblasts. The Ca(++) concentration in the lumen of the ER has been evaluated by using the low affinity Ca(++) probe Mag-fluo-4. We show that serum deprivation lowers the ER Ca(++) concentration with a time course closely related to the increase of apoptosis incidence. Serum deprivation also enhances the expression of a well-known marker of ER stress, the glucose-regulated protein-78 (GRP-78), a member of the heat shock/stress response protein family. Moreover, in serum-deprived neuroblasts, following GRP-78 up-regulation, the ER-associated procaspase-12 is cleaved with a time course which parallels the ER calcium loss while activation of caspase-3 is a later event. Depletion of ER Ca(++) by thapsigargin, a specific inhibitor of the ER-associated Ca(++) ATPase, also produces caspase-12 processing and apoptotic cell death, whereas agents capable of reducing the ER calcium loss protect the cells from serum-deprivation-induced apoptosis. These findings indicate that, in hippocampal neuroblasts, Ca(++) mobilization from ER and caspase-12 activation are components of the molecular pathway that leads to apoptosis triggered by serum deprivation and may constitute an amplifying loop of the mitochondrial pathway