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Autoimmune Lymphoproliferative Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The underlying pathogenesis of ALPS relates to mutations in the FAS, FASLG, and CASP10 genes, which encodes proteins involved in the formation of a death-inducing signaling complex composed of FADD, caspase-8, and caspase-10. This death-inducing signaling complex triggers the downstream effector caspase cascade of the FAS/FASLG signaling pathway, leading to lymphocyte apoptosis. Alterations in the FAS, FASLG, and CASP10 proteins compromise their capacity to induce FAS-mediated apoptosis and result in the accumulation of unwanted lymphocytes and increased autoimmune reactivity.
Imaging of Cardiovascular Disease
Published in George C. Kagadis, Nancy L. Ford, Dimitrios N. Karnabatidis, George K. Loudos, Handbook of Small Animal Imaging, 2018
Aleksandra Kalinowska, Lawrence W. Dobrucki
Cell death can be initiated through two different mechanisms—the intrinsic and extrinsic pathways. The extrinsic pathway is started mainly through extracellular signals and targets cell membrane receptors like Fas, a common mammalian death receptor present in both humans and rodents. The intrinsic one is generated from within the cell through DNA damage, mitochondrial signals, and oncogene activation. Although initial triggers remain separate, upon the activation of a death-inducing signaling complex (DISC), the pathways have been proven to adopt the same effector caspase machinery, involving the activation of multiple caspase proteins (Blankenberg 2008). Molecular imaging takes advantage mainly of the extrinsic pathway as it involves cellmembrane components, such as phosphatidyl serine, which is present outside the cell during apoptosis and form suitable sites for the binding of imaging radiotracers. When cell disintegration progresses, cellular membranes lose potential, and intracellular structures dissipate, exposing proteins, such as histones and other organelle components, which have also been utilized for imaging techniques.
The Molecular and Genetic Effects of Ultraviolet Radiation Exposure on Skin Cells
Published in Henry W. Lim, Herbert Hönigsmann, John L. M. Hawk, Photodermatology, 2007
Marjan Garmyn, Daniel B. Yarosh
The apoptotic process itself is characterized by stereotypical morphological changes such as cell shrinkage, membrane blebbing, chromatin condensation, and DNA fragmentation, leading to a cell with a pycnotic nucleus, and ultimately the formation of apoptotic bodies. Hence, when skin is irradiated with a sufficient high UVB dose, cells with pycnotic nucleus and eosinophilic cytoplasm, a typical apoptotic morphology, also called “the sunburn cell” (SBC), appear in the epidermis. At the biochemical level, the induction of apoptotic cell death is accomplished by specialized cellular machinery where a family of cysteine proteases, the caspases, play a central role. There are two main pathways leading to apoptotic cell death. The intrinsic pathway is activated at the mitochondria. Death-inducing signals (including DNA damage) promote BAX-dependent release of cytochrome C, which together with Apaf- 1 leads to formation of the apoptosome and procaspase 9 activation. In contrast, signaling through the cell surface death receptor (e.g., CD95/Fas, TNF-alphaR) activates the extrinsic pathway, which relies on initiator caspase-8 activation at the death-inducing signaling complex. Both pathways converge into the activation of the effector caspases (caspases-3, -6, and -7) that are directly responsible for the cleavage of cellular proteins resulting in the characteristic morphology of apoptosis. Cleavage of Bid by caspase-8 allows crosstalk between both pathways.
Apoptosis targeted therapies in acute myeloid leukemia: an update
Published in Expert Review of Hematology, 2020
Somedeb Ball, Gautam Borthakur
The extrinsic pathway is triggered by the binding of signal molecules to the transmembrane death receptors, such as Fas, tumor necrosis factor (TNF), and TNF-related apoptosis-inducing ligand (TRAIL). This interaction results in the formation of a death-inducing signaling complex, with the incorporation of Fas-associated death domain (FADD) or TNF receptor type 1-associated death domain protein (TRADD) and procaspase 8, which in turn gets activated to caspase 8. Activation of other downstream effector caspases (caspases 3 and 7) brings about the degradation of cellular substrates. Several inhibitors of apoptosis proteins (IAP), namely X- linked IAP (XIAP), cellular IAP (cIAP), and survivin inhibit apoptosis at different levels of cascade. Among these, XIAP is more specific for the extrinsic pathway [9,10]. However, XIAP can also inhibit the apoptosome in intrinsic pathway through its effect on caspase 9. Several molecules antagonize the action of IAPs, most prominent being the second mitochondrial-derived activator of caspases (SMAC) [11].
Current discovery strategies for hepatocellular carcinoma therapeutics
Published in Expert Opinion on Drug Discovery, 2020
Qiuzi Dai, Cunlong Zhang, Zigao Yuan, Qinsheng Sun, Yuyang Jiang
Significant progress has been made in the development of HDAC inhibitors in recent years. There are five HDAC inhibitors approved as shown in Figure 10(a). Of those, vorinostat (SAHA), romidepsin (FK228) and Belinostat (PXD101) have been approved by FDA in 2006, 2009 and 2014, respectively, for the treatment of patients with cutaneous T-cell lymphoma (CTCL). Vorinostat can activate caspase-3 to promote HCC cells apoptosis and death by TRAIL-DISC activation and autophagy induction. In addition, vorinostat can combat HCC through the immune system [128–132]. Romidepsin can inhibit HCC cells proliferation by inducing cell cycle arrest and apoptosis through ERK/MAPK signaling pathway and c-Jun N-terminal kinase (JNK)/c-Jun signaling pathway. Belinostat can induce apoptosis and tumor regression in HCC cell lines and is undergoing Phase I and Phase II clinical trials in patients with advanced HCC [133–135].
The 70-kDa heat shock protein (Hsp70) as a therapeutic target for stroke
Published in Expert Opinion on Therapeutic Targets, 2018
Jong Youl Kim, Yeonseung Han, Jong Eun Lee, Midori A. Yenari
Extrinsic or cell surface mediated mechanisms of apoptosis involve the engagement of death receptors located on the plasma membrane. This is also referred as the ‘death receptor pathway’. Death receptor ligation causes activation of caspase-8 and caspase-10, which in turn can activate effector caspase-3 [51]. Activation of several death receptors (Fas/CD95, TNFR1, and TRAIL receptor) is promoted by ligands of TNF family, including FASL, TNF, LT-α, LT-β, CD40L, LIGHT, RANKL, and TRAIL, many of which are released as part of the inflammatory response to ischemia [52]. FasL is involved in apoptosis by binding to the Fas receptor, triggering recruitment of the cytoplasmic adaptor protein Fas-associated death domain protein (FADD). FADD contains a ‘death effector domain’ at the N terminus which binds to procaspase-8 by interacting with its death effector domain [53]. This complex is referred to as the death-inducing signaling complex (DISC). This signal complex catalyzes the proteolytic cleavage and transactivation of procaspase-8 to generate activated caspase-8 [53]. Caspase-8 activation is followed by activation of caspases−3 and −10 [54].