Cytotoxic stress

Based on the triggering stimulus and the nature of the components involved, at least two apoptotic signaling pathways can be differentiated that lead to activation of the effector caspases. On the one hand, receptor systems may be involved on the other hand, activation may be triggered by cytotoxic stress. The two pathways differ in the mechanism of activation of the initiator caspase but use the same effector caspase at least partially. 

Fig. 5.5. A summary of our current knowledge how integrin signaling critically modifies certain cellular response pathways upon radiation- or drug-induced cytotoxic stress. Cascades in green mediate prosurvival signals from transmembrane located integrins and RTKs via Ras/MEK/MAPK, Akt, or FAK/Src/Cas in a cell type- and/or context-dependent manner. The cascade in red transduces anti-survival signals via ILK, caspase-8 and cas-pase-3 to promote apoptosis...

Proteasomal inhibition represents a novel strategy in cancer treatment and the small molecule Bortezomid (PS-341, Velcade ) has been approved for the treatment of refractory and relapsed multiple myeloma, a proliferative disease of plasma cells. Bortezomid inhibits an active site in a proteasome subunit and remarkably shows selective cytotoxicity to cancer cells. Although the underlying mechanisms are not completely understood bortezomid apparently induces a cell stress response in these tumor cells followed by caspase-dependent apoptosis. Whether bortezomid is beneficial for the treatment of other proliferative disease is currently being tested in clinical trials. 

Another study showed that a mixture of oxidative metabolites of P-carotene, but not P-carotene, was able to increase the binding of benzo[a]pyrene to DNA. Other mixtures of P-carotene cleavage products have been shown to induce oxidative stress in vitro,exert cytotoxic and genotoxic effects, and inhibit gap junction intercellular communications. It has been suggested that these detrimental effects could possibly occur in vivo following the intake of high doses of carotenoids. 

Aluminium toxicity is a major stress factor in many acidic soils. At soil pH levels below 5.0, intense solubilization of mononuclear A1 species strongly limits root growth by multiple cytotoxic effects mainly on root meristems (240,241). There is increasing evidence that A1 complexation with carboxylates released in apical root zones in response to elevated external Al concentration is a widespread mechanism for Al exclusion in many plant species (Fig. 10). Formation of stable Al complexes occurs with citrate, oxalate, tartarate, and—to a lesser extent— also with malate (86,242,243). The Al carboxylate complexes are less toxic than free ionic Al species (244) and are not taken up by plant roots (240). This explains the well-documented alleviatory effects on root growth in many plant species by carboxylate applications (citric, oxalic, and tartaric acids) to the culture media in presence of toxic Al concentrations (8,244,245) Citrate, malate and oxalate are the carboxylate anions reported so far to be released from Al-stressed plant roots (Fig. 10), and Al resistance of species and cultivars seems to be related to the amount of exuded carboxylates (246,247) but also to the ability to maintain the release of carboxylates over extended periods (248). In contrast to P deficiency-induced carboxylate exudation, which usually increases after several days or weeks of the stress treatment (72,113), exudation of carboxylates in response to Al toxicity is a fast reaction occurring within minutes to several hours... 

Byrnes, D. M., M. H. Antoni, K. Goodkin, j. Efantis-Potter, D. Asthana, T. Simon et al., Stressful Events, Pessimism, Natural Killer Cell Cytotoxicity, and Cytotoxic/Suppressor T Cells in Hiv+ Black Women at Riskfor Cervical Cancer , Psychosomatic Medicine 60 (1998) 714-22... 

Numerous studies have demonstrated that degradation products of (3-carotene exhibit deleterious effects in cellular systems (Alija et al., 2004, 2006 Hurst et al., 2005 Salerno et al., 2005 Siems et al., 2003). A mixture of (3-carotene degradation products exerts pro-apoptotic effects and cytotoxicity to human neutrophils (Salerno et al., 2005 Siems et al., 2003), and enhances the geno-toxic effects of oxidative stress in primary rat hepatocytes (Alija et al., 2004, 2006), as well as dramatically reduces mitochondrial activity in a human leukaemic cell line, K562, and RPE 28 SV4 cell line derived from stably transformed fetal human retinal pigmented epithelial cells (Hurst et al., 2005). As a result of degradation or enzymatic cleavage of (3-carotene, retinoids are formed, which are powerful modulators of cell proliferation, differentiation, and apoptosis (Blomhoff and Blomhoff, 2006). 

Variation of the content of impurities in the different CNT preparations [21] offers additional challenges in the accurate and consistent assessment of CNT toxicity. As-produced CNTs generally contain high amounts of catalytic metal particles, such as iron and nickel, used as precursors in their synthesis. The cytotoxicity of high concentrations of these metals is well known [35, 36], mainly due to oxidative stress and induction of inflammatory processes generated by catalytic reactions at the metal particle surface [37]. Another very important contaminant is amorphous carbon, which exhibits comparable biological effects to carbon black or relevant ambient air particles. 

MWNTs were found to be cytotoxic in human skin fibroblasts (HSF42) and human epidermal keratinocytes (HEK) [42-44], whereas SWNTs were toxic in human keratinocyte (HaCaT) cultures [25, 26, 45]. Reduced cell proliferation and oxidative stress were reported also in epithelial (HeLa) cells [45] and murine epidermal cells (JB6 P + ) [46] upon incubation with SWNTs. 

Butyl rubber - This material generally had the least endurance in fatigue tests, but it may be adequate for some cardiovascular applications. Advantages include less sensitivity to stress concentrators than Pellethane, a very low permeability to fluids, a moderate creep resistance and widespread availability at low cost. Disadvantages include a relatively low fatigue resistance compared to the elastomers specifically designed for these applications. The rubber tested was not designed for medical applications and had standard rubber additives and modifiers that were cytotoxic unless the material was extracted after manufacture. 

Oxidative stress Lipid oxidation Oxygen absorption Manometric, polarographic Diene conjugation HPLC, spectrophotometry (234 nm) Lipid hydroperoxides HPLC, GC-MS, chemiluminescence, spectrophotometry Iodine liberation Titration Thiocyanate Spectrophotometry (500 nm) Hydrocarbons GC Cytotoxic aldehydes LPO-586, HPLC, GC, GC-MS Hexanal and related end products Sensory, physicochemical, Cu(II) induction method, GC TBARS Spectrophotometry (532-535 nm), HPLC Rancimat Conductivity F2-iP GC/MS, HPLC/MS, immunoassays... 

The products formed during lipid peroxidation include unsaturated aldehydes, such as 4-hydroxynonenal. Their quantification is of great interest because of their extremely reactive and cytotoxic properties. This extreme reactivity and metabolic conversion, however, may make them unsuitable as test analytes for in vivo antioxidant activity studies except at high levels of oxidative stress. Furthermore, simple chemical tests such as the TBARS (thiobarbituric acid reactive substances) and LPO-586 (colorimetric... 

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