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Micronutrients for Improved Management of Huntington’s Disease
Published in Kedar N. Prasad, Micronutrients in Health and Disease, 2019
Using a transgenic HD mouse model, caspase-1 and caspase-3 were found to be transcriptionally upregulated and activated. The degree of activation of caspases correlated with the progression of this disease in HD mice.72 Similar observations were made in autopsied brain samples of HD patients. Activation of caspase-2 cleaves HD protein selectively at amino acid 552, and fragmented HD proteins become aggregated. The aggregated form of HD protein causes selective neuronal cell death in the striatum and cortex of autopsied brain samples of human HD as well as in HD mouse model expressing full length HD gene (YAC72 mice).73 Inhibitors of caspase delayed the onset of symptoms in the transgenic HD mouse model. Treatment of animals with quinolinic acid- and 3-NP increased oxidative stress and induced HD-like changes in the brain.74,75 HD protein also activates microglia causing the release of pro-inflammatory cytokines and reactive oxygen species (ROS).
Basics of Radiation and Radiotherapy
Published in Prakash Srinivasan Timiri Shanmugam, Understanding Cancer Therapies, 2018
Prakash Srinivasan Timiri Shanmugam, Pramila Bakthavachalam
Following exposure to ionizing radiation, cells can undergo apoptosis, mitotic catastrophe, and/or terminal cell arrest. The extent to which one mode of cell death predominates over another is unclear but may be influenced by cell type, radiation dose, and the cell's microenvironment (e.g., relative oxygenation). Depending on the severity of damage, the tumor suppressor protein P53 can trigger cell cycle arrest or initiate apoptosis via transcriptional activation of pro-apoptotic proteins, including those of the Bcl-2 family. P53-induced protein with a death domain, another P53 pro-apoptotic target, also plays a critical role in DNA damage-induced apoptosis, leading to caspase-2 activation and subsequent mitochondrial cytochrome c release.
Animal Models of Vulnerable Plaque
Published in Levon Michael Khachigian, High-Risk Atherosclerotic Plaques, 2004
Harry C. Lowe, Levon M. Khachigian, Leonard Kritharides, Jason L. Johnson
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
Induction of caspase-2 gene expression in carboxyl-functionalized carbon nanotube-treated human T-cell leukemia (Jurkat) cell line
Published in Drug and Chemical Toxicology, 2021
Shirin Lotfipanah, Majid Zeinali, Parichehreh Yaghmaei
Caspase-2 exhibits features of both initiator and effector caspases, but its role in apoptosis is controversial and its function as an initiator/effector caspase is still unknown (Fava et al. 2012, Imre et al. 2017). In contrast to conventional initiator caspases-8/9, caspase-2 does not exert enzymatic activation function on effector caspases-3/6/7. It is shown that during pore-forming toxin (PFT)-mediated apoptosis in different cell type, caspase-2 may function as an initiator caspase (Imre et al. 2017). Fava et al. (2012) believe that caspase-2 does not have a direct role in death, neither as an initiator nor as an effector caspase. A damage-sensing function which will be resulted in limited proteolysis for signaling has been suggested for caspase-2 (Fava et al. 2012). Endoplasmic reticulum (ER) stress or some damages to DNA may be resulted in activation of caspase-2 and regulation of cell death.
Regulation of microRNAs by IRE1α in apoptosis: implications for the pathomechanism of neurodegenerative diseases
Published in International Journal of Neuroscience, 2020
Zhonghao Su, Lanyue Sheng, Ping Yu, Na Ren, Yajuan Li, Zhenxia Qin
UPR miRNAs can act as adaptive or apoptotic, depending on their expression profile changes, specific targets, and diseases model that is involved. It has been reported several pro-apoptotic miRNAs as effector contribute to induction of IRE1α-related apoptosis in non-NDs models such as miR-17 [35,36], miR-34a [36], miR-96 [36], miR-7 [37], miR-216b [38] and miR-125b [36]. Under prolonged stress, accumulating evidence supports the decay of particular miRNAs through RIDD process plays a role in the regulation of apoptosis. It was shown that the induction of a pro-apoptotic protein Caspase-2 [36], thioredoxin-interacting protein (TXNIP) [35], transmembrane E3 ligase RNF183 [37] and c-Jun [38] through IRE1α-dependent specific miRNAs degradation mediated apoptosis in vitro studies. Caspase-2 as an orphan is the most evolutionarily conserved of Caspases identified to date. Although its role in the apoptotic cascade is still elusive, Caspase-2 functions as a tumor suppressor [39]. The endogenous level of RNF183 is most abundant in the testes and kidneys in mouse tissues and may play a role in regulating apoptosis there. RNF183 is implicated in the regulation of colorectal cancer [40]. TXNIP a regulator of ER stress and a tumor suppressor gene play a pro-apoptotic role [41]. c-Jun is a component of the AP-1 transcription factor and JNK has previously been demonstrated to activated and contribute to Ire1α-dependent UPR signaling pathway to induce apoptosis.
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.