Animal Models of Vulnerable Plaque
Levon Michael Khachigian in High-Risk Atherosclerotic Plaques, 2004
A large number of cellular metabolic pathways have been implicated in this process of apoptosis, resulting in medial SMC depletion including the caspase, Bcl-2, and p53 protein families.28 Caspases are members of a cysteine protease group of 14 cytoplasmic proteins.28,29 Although the precise mechanisms by which caspase activation induces cell death is unclear, the caspases can be broadly considered as initiators (caspase-2 and caspase-8) or effectors (caspase-3 and caspase-6) of apoptosis.29 The Bcl-2 family is a second group of cellular proteins involved in apoptosis regulation. Some (Bcl-2, A1) are thought to be anti-apoptotic; others (Bax, Bak) pro-apoptotic, although again, the mechanisms of action of these specific proteins are not yet understood completely.28,30
Pathophysiology of Spinal Shock
Jacques Corcos, Gilles Karsenty, Thomas Kessler, David Ginsberg in Essentials of the Adult Neurogenic Bladder, 2020
There are two main pathways of apoptosis in SCI, extrinsic and intrinsic.11 Extrinsic, or receptor-dependent, apoptosis is evoked by extracellular signals, the most significant of which is tumor necrosis factor. Tumor necrosis factor can rapidly accumulate in the injured spinal cord causing an activation of the Fas receptor of neurons, microglia, and oligodendrocytes, which subsequently induces a sequence of caspase activation involving caspase-8 and caspase-6.20 Activation of these effector caspases results in the demise of the affected cell. Nitric oxide synthase also induces the extrinsic pathway, which brings caspace-3 activation to effect programmed cell death.21
The role of apoptosis in non-mammalian host-parasite relationships
G. F. Wiegertjes, G. Flik in Host-Parasite Interactions, 2004
With regards to the host-parasite interaction, recent studies have revealed that apoptosis is an important component in the immune system of lower vertebrates. Several studies in amphibians have shown that apoptosis is a common occurrence in the lymphocyte component of the immune response. Grant et al. (1995) first reported the time course of mitogen-induced apoptosis in the thymic and splenic lymphocytes of adult Xenopus laevis. Later studies on the splenocytes of this amphibian by Mangurian et al. (1998) indicated that these cells express Fas, which possibly shared both structural and functional homologies with that occurring in humans. In addition, McMahan et al. (2000) revealed that PMA, which sometimes ‘rescues’ mammalian cells from apoptosis, stimulates controlled cell death in the splenocytes of Xenopus. The availability and extensive knowledge of amphibian metamorphosis has meant that this group of animals has served as a useful biological model to investigate the role of apoptosis during morphogenesis of the immune system. Ducoroy et al. (1999) noted that the enterotoxin from the bacterium Staphylococcus aureus, and glucocorticoid treatment induced apoptosis in the thymocytes of the larvae of the urodele amphibian, the axolotl. Studies by Grant et al. (1998) revealed that in Xenopus, apoptosis occurred in the lymphocytes of the thymus and spleen during metamorphosis although the levels differed between the organs and the metamorphic stage. They also noted that the apoptosis observed may not be correlated to plasma glucocorticoid titres. The association of apoptosis and these stress hormones has been extensively studied in fish (e.g. Espelid et al., 1996; Verburg-van Kemenade et al., 1999; Weyts et al., 1997) and has implications when considering the association between parasites and apoptosis (see later). Studies on the sequencing of genes associated with the apoptotic process in lower vertebrates have been somewhat limited. For example, Yabu et al. (2001) cloned and characterized caspase 3 in zebrafish which showed 60% identity with that occurring in Xenopus, chicken and mammals. Recently caspase 6 from rainbow trout has been sequenced and has been shown to be expressed particularly in pronephric cells after exposure to cortisol and LPS and during confinement of the fish (Laing et al., 2001). In addition, we have partially sequenced and cloned Bcl2 and APAF1 from the pronephric cells of carp, Cyprinus carpio.
Royal jelly arranges apoptotic and oxidative stress pathways and reduces damage to liver tissues of rats by down-regulation of Bcl-2, GSK3 and NF-κB and up-regulation of caspase and Nrf-2 protein signalling pathways
Published in Biomarkers, 2023
Abdullah Aslan, Ozlem Gok, Seda Beyaz, Gozde Parlak, Muhammed Ismail Can, Ramazan Gundogdu, Serpil Baspinar, Ibrahim Hanifi Ozercan, Akif Evren Parlak
Apoptosis is a gene-regulated event involved in various cellular processes such as chromatin condensation, cell contraction and DNA damage. The two main families of proteins, including the caspase 3, 8, and 9 enzymes and the cysteine proteases called the Bcl-2 family play significant roles in apoptosis. caspase 3, 8 and 9 enzymes are effective in the apoptotic process of the liver. As one of the most significant member of the caspase family, caspase-3 is responsible for the biochemical mechanism of apoptosis leading to chromatin condensation, DNA fragmentation and apoptotic bodies. Members of the Bcl-2 protein family, which have anti-apoptotic or pro-apoptotic effects, may prevent the apoptotic activity by blocking the release of cytochrome-c from mitochondria (Karadeniz et al. 2011, Aslan et al. 2022b). Pro-apoptotic proteins such as Bax, commonly found in mitochondria and endoplasmic reticulum, promote apoptosis (Cao et al. 2013, Almeer et al.2019). ATP with the addition of a complex called apoptosome leads to the conversion of inactive procaspase 9to active caspase-9 and activation of other effector caspases. Following its activation, caspase-9 initiates the caspase cascade, significantly activating procaspase 3 and procaspase 7. Caspase-3 then continues to activate the terminating procaspase 6 and procaspase 2. Caspase-6 continues to divide and activate procaspase-8 and procaspase-10, initiating the remaining caspase cascade leading to irreversible cell suicide (Atagun et al. 2011, Aslan et al. 2022a).
Design, synthesis, and in vitro evaluation of aza-peptide aldehydes and ketones as novel and selective protease inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Thomas S. Corrigan, Leilani M. Lotti Diaz, Sarah E. Border, Steven C. Ratigan, Kayla Q. Kasper, Daniel Sojka, Pavla Fajtova, Conor R. Caffrey, Guy S. Salvesen, Craig A. McElroy, Christopher M. Hadad, Özlem Doğan Ekici
Compounds 6 and 7 were designed as tetrapeptides to target human caspase-3 with the ideal sequence Asp-Glu-Val-Asp and compound 8 targets human caspase-6 with its optimal sequence Ile-Glu-Thr-Asp as caspases require a minimum of four amino acids in their recognition sequence26. Compounds 6, 7, and 8 show low-to-mid µM range inhibition with their target enzyme, where the best inhibitor is ketone 6 with an IC50 value of 7.74 µM against caspase-3 (Table 2). As expected, the caspase-3 specific compounds 6 and 7 show less activity against caspase-6; however, due to the strict P1 Asp requirement for cleavage for all caspases, it is a challenge to obtain highly selective inhibition among different caspase family members. Likewise, compound 8 inhibits caspase-6 with an IC50 value of 9.08 µM, 13 times more effectively than it inhibits caspase-3, emphasising the importance of the preference in caspase-3 for the P4 Asp residue. Within caspase-3 and -6, the benzyl compound 7 demonstrates the lowest inhibition for both enzymes, with IC50 values of 13.36 and 64.23 µM, respectively.
The aminopeptidase inhibitor, z-L-CMK, is toxic and induces cell death in Jurkat T cells through oxidative stress
Published in Toxicology Mechanisms and Methods, 2018
E. H. Yeo, W. L. Goh, S. C. Chow
Our results suggest that caspases are activated only in Jurkat T cells treated with 10 µM and not with 50 µM of z-L-CMK. We next examined the caspases activated in Jurkat T cells exposed to 10 µM or 50 µM of z-L-CMK using Western blotting. As shown in Figure 6, all the caspases (-2, -3, -6, -8, and -9) examined remained intact in their pro-form in control untreated cells. Following treatment with 10-µM z-L-CMK, there was a marked reduction of these pro-form caspases in Jurkat T cells. The pro-form of the initiator caspases (-2, -8, and -9) was markedly reduced, where caspase-8 and caspase-9 were cleaved into their p43/41 and p37/35 subunits, respectively. On the other hand, effector caspases, such as caspase-3, were processed to the catalytically active p17 subunit while the pro-form of caspase-6 was markedly decreased. The caspase-3 substrate, PARP (116 kDa), was cleaved to the 85 kDa fragment. In the presence of 50 µM z-VAD-FMK, the processing of caspase-3, caspase-6, and caspase-8 was inhibited whereas processing of caspase-2 and caspase-9 was only partially blocked. The cleavage of PARP was also completely abrogated in the presence of z-VAD-FMK. Collectively, these results demonstrated that cell death mediated by low concentration of z-L-CMK is caspase-dependent and via apoptosis. In sharp contrast, the processing of caspases and PARP in Jurkat T cells exposed to 50 μM of z-L-CMK remained intact in the absence or presence of z-VAD-FMK.
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