Apoptosis and

The class III cytokine receptor family includes two TNE receptors, the low affinity NGE receptor and 7-ceU surface recognition sites that appear to play a role in proliferation, apoptosis, and immunodeficiency. TNE-a (- 17, 000 protein) is produced by astrocytes and microglia and can induce fever, induce slow-wave sleep, reduce feeding, stimulate prostaglandin synthesis, stimulate corticotrophin-releasing factor and prolactin secretion, and reduce thyroid hormone secretion. TNE-a stimulates IL-1 release, is cytotoxic to oligodendrocytes, and reduces myelination this has been impHcated in multiple sclerosis and encephalomyelitis. Astrocyte TNE-a receptors mediate effects on IL-6 expression and augment astrocytic expression of MHC in response to other stimulants such as lEN-y. 

Bursch, W. Oberhammer, F., and Schulte-Herrnann, R. (1992). Cell death by apoptosis and its protective role against di.sease. Trends Pharmacol. Set. 1.3(6), 245-251. 

Besides direct apoptosis effectors, there are a number of other diugs which influence the above explained apoptosis pathways more indirectly. This class of diugs includes molecules which inhibit survival pathways like e.g. the Ras/Raf kinase pathway, the NF-kB pathway and many others. Also inhibitors of survival cytokines which are sometimes produced by cancer cells in an autocrine fashion can render cells susceptible to apoptosis and, hence, effective cancer therapy. These include, but are not limited to, ligands for dependence receptors and cytokines like e.g. interleukin-4. 

Many anticancer agents currently in use, including chemotherapeutic drugs and radiation, are potent inducers of apoptosis and cell-cycle arrest. It is believed that induction of these molecular pathways is central to the efficacy of such agents [1]. Genetic and epigenetic alterations that contribute to tumorigenesis... 

The pro- and antiapoptotic members of the Bcl2 family affect cellular sensitivity to apoptosis and thus to many chemotherapeutic agents [4]. For example, overexpression of the antiapoptotic genes Bcl2 and Bcl-XL in some cell lines and tumors can confer resistance to apoptosis triggered by ionizing radiation. Conversely, overexpression of proapoptotic Bax in experimental tumors can induce apoptosis directly or render such tumors more sensitive to cisplatin and 5-FU. 

In the very early phases of the acute inflammatory response most of the cells invading the damaged area are polymorphonuclear neutrophils, also denoted as PMNs, which serve as initial line of defense and source of proinflammatory cytokines. These cells, which usually live for 4-5 days, circulate in the blood until they are attracted by chemokines into injured tissues. Whereas physical injury does not recruit many neutrophils, infections with bacteria or fungi elicit a striking neutrophil response. The characteristic pus of a bacterial abscess is composed mainly of apoptotic (apoptosis) and necrotic PMNs. Emigration of neutrophils from the blood starts with a process denoted as margination where neutrophils come to lie at the periphery of flowing blood cells and adhere to endothelial cells (Fig. 1). L-Selectin is expressed... 

Other, more general effects of insulin on cellular function include stimulation of cell growth (increase in DNA and protein synthesis), inhibition of apoptosis, and modulation of ion-channel activity. 

Acute over-activation of NHE1 results in a marked elevation in intracellular sodium concentration with a subsequent increase in intracellular calcium, via the Na +/Ca++ exchanger. This in turn triggers a cascade of injurious events that can culminate in tissue dysfunction and ultimately apoptosis and necrosis. This is commonly seen in organs such as the heart, brain and kidneys as a consequence of ischemia-reperfusion. 

Inhibitors of Apoptosis and Growth Factor like Molecules... 

Ras is a G protein that cycle between two conformations, an activated Ras-GTP or inactivated form Ras-GDP. Ras, attached to the cell membrane by lipidation, is a key component in many signalling cascades, which couple growth factor receptors to downstream effectors that control such processes as cytoskeletal integrity, proliferation, cell adhesion, apoptosis and cell migration. Mutations and dysregulations of the Ras protein leading to increased invasion and metastasis, and decreased apoptosis are very common in cancers. 

Family of transcription factors that modulate the expression of genes which control immune, inflammatory, and acute-phase responses, as well as cell growth, responses to stress, apoptosis, and oncogenesis. All members of this family have a Rel-homology domain that contains sequences responsible for dimerization and DNA binding. In vertebrates, this family includes NF-kB1 (also known as p50), NF-kB2 (also known as p52), Rel (also known as cRel), Rel-A (also known as p65), and Rel-B. 

Pieters RHH, Bol M, Penninks AH (1994b) Immunotoxic organotins as possible model compounds in studying apoptosis and thymocyte differentiation. Toxicology, 91 (2) 189-202. 

Ohnishi H, Asamoto M, Tujimura K, Hokaiwado N, Takahashi S, Ogawa K, et al. Inhibition of cell proliferation by nobiletin, a dietary phytochemical, associated with apoptosis and characteristic gene expression, but lack of effect on early rat hepatocarcinogenesis in vivo. Cancer Sci 2004 95 936-42. 

Bcl-2 is one of the many factors that control apoptosis, and overexpression of Bcl-2 has been observed in many different cancers. A homology model of Bcl-2 was derived from the NMR 3D structure of the Bcl-XL complex with a Bak BH3 peptide. This model served to search the NCI 3D database of 206,876 organic compounds for potential Bcl-2 inhibitors, which bind to the Bak BH3 binding site of Bcl-2. Full conformational flexibility of the ligands was taken into account in the program DOCK. Thirty-five potential inhibitors were tested, and seven of them had IC50 values from 1.6 to W.OpM. One of... 

Jones GJ, Barsby NL, Cohen EA et al (2007) HIV-1 Vpr causes neuronal apoptosis and in vivo neurodegeneration. J Neurosci 27 3703-3711... 

Zheng J, Thyhn MR, Ghorpade A et al (1999) Intracellular CXCR4 signahng, neuronal apoptosis and neuropathogenic mechanisms of HIV-l-associated dementia. J Neuroimmunol 98 185-200... 

Dasgupta P, Padmanabhan J, CheUappan S (2006) Rb function in the apoptosis and senescence of non-neuronal and neuronal cells role in oncogenesis. Curr Mol Med 6 719-729... 

Utilizing the stark difference in response of wildtype astrocytes (increased apoptosis) and astrocytes (decreased apoptosis), Warrington et al. (2007)... 

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