Development apoptosis

As described earlier, superoxide is a well-proven participant in apoptosis, and its role is tightly connected with the release of cytochrome c. It has been proposed that a switch from the normal four-electron reduction of dioxygen through mitochondrial respiratory chain to the one-electron reduction of dioxygen to superoxide can be an initial event in apoptosis development. This proposal was supported by experimental data. Thus, Petrosillo et al. [104] have shown that mitochondrial-produced oxygen radicals induced the dissociation of cytochrome c from bovine heart submitochondrial particles supposedly via cardiolipin peroxidation. Similarly, it has been found [105] that superoxide elicited rapid cytochrome c release in permeabilized HepG2 cells. In contrast, it was also suggested [106] that it is the release of cytochrome c that inhibits mitochondrial respiration and stimulates superoxide production. 

Wang J, Lenardo MJ. Roles of caspases in apoptosis, development, and cytokine maturation revealed by homozygous gene deficiencies. J Cell Sci 2000 113 753-757. 

A rather close relationship between the apoptosis induced by microcystin-LR and caspase-3 activity was observed. Hepatocytes are extremely sensitive to microcystins and nodularin, as can be deduced from the quick apparition of cellular apoptotic changes such as superficial budding and shrinkage of cytosol and nucleus. Analogous findings were obtained in other kinds of cells, like Swiss 3T3 fibroblasts or promyelocytic IPC.81 cells, provided that the toxins were microinjected. However, in caspase-3 deficient MCF-7 cells, apoptosis developed slowly and was independent of the ZVAD, a compound that ordinarily inhibited apoptosis without affecting the hyperphosphorylation caused by PP inhibition [147]. 

Persistent net ROS formation in thiamine deficiency can also initiate a cascade of cell death pathways via intracellular messengers, e.g. intracellular cas-pase-3-mediated apoptosis. Development of oxidative stress also leads to other disturbances in brain function, including an inhibition of glutamate uptake due to transporter protein nitrosylation following peroxynitrite formation (Hazell et al. 2003 Trotti et al. 1996 Volterra et al. 1994). Under conditions of oxidative stress, levels of HO-1, cNOS, iNOS, ICAM-1 and microglial activation are increased. Thus, oxidative stress can lead to profound neuropathological consequences in thiamine deficiency and WE. 

Domingos PM, Steller H (2007) Pathways regulating apoptosis during patterning and development. Curr Opin Genet Dev 17 294—299... 

Apart from these two Vertex compounds, only one other caspase inhibitor, BDN-6556, has been used in clinical trials. This compound belongs to the class of oxamyl dipeptides and was originally developed by Idun Pharmaceuticals (taken over by Pfizer). It is the only pan-caspase inhibitor that has been evaluated in humans. BDN-6556 displays inhibitory activity against all tested human caspases. It is also an irreversible, caspase-specific inhibitor that does not inhibit other major classes of proteases, or other enzymes or receptors. The therapeutic potential of BDN-6556 was first evaluated in several animal models of liver disease because numerous publications suggested that apoptosis contributes substantially to the development of some hepatic diseases, such as alcoholic hepatitis, hepatitis B and C (HBV, HCV), non-alcoholic steato-hepatitis (NASH), and ischemia/reperfusion injury associated with liver transplant. Accordingly, BDN-6556 was tested in a phase I study. The drug was safe and... 

In contrast, UCN-01, a staurosporine derivative, acts as a potent inhibitor of the Chkl kinase and efficiently abrogates the G2 checkpoint upon DNA damage. Die forced entry into mitosis in the presence of DNA damage results in a mitotic form of apoptosis. Several clinical trials are currently exploring a combined treatment with UCN-01 and various DNA damaging diugs. In the same vein, inhibitors of Chk2 are developed and tested in clinical trials. 

This class of lymphocytes differentiates from immuno-logically incompetent hematopoietic stem cells of the bone marrow within the thymus - hence, the name thymus-dependent (T-) lymphocytes. Two major subclasses develop simultaneously, T-helper lymphocytes (Th) and cytotoxic effector lymphocytes (Tc). The cytotoxic T-lymphocytes (carrying on the surface the differentiation marker CD8) destroy cells, which cany their cognate antigen bound to MHC class I molecules on the surface by inducing apoptosis. From an evolutionary point of view Tc cells appear to have developed predominantly to cope with vims infections. As vituses can only replicate within cells, Tc eliminate them by destroying their producers. 

Radu CG, Cheng D, Nijagal A et al (2006) Normal immune development and glucocorticoid-induced thymocyte apoptosis in mice deficient for the T-cell death-associated gene 8 receptor. Mol Cell Biol 26 668-677... 

Visual imaging of cell population in vitro) using low signal-to-noise ratio phase contrast microscopy can enable systematic monitoring measurements of cell quality, development and apoptosis. In the present study, microscopic evaluations as seen in Fig. 11 did not reveal any significant alteration in cellular morphology upto 1000 ng/ml. 

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