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Pathophysiology of Spinal Shock
Published in Jacques Corcos, Gilles Karsenty, Thomas Kessler, David Ginsberg, Essentials of the Adult Neurogenic Bladder, 2020
Siobhán M. Hartigan, Elizabeth A. Rourke, Roger R. Dmochowski
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
Designing Smart Nanotherapeutics
Published in Suresh C. Pillai, Yvonne Lang, Toxicity of Nanomaterials, 2019
A. Joseph Nathanael, Tae Hwan Oh, Vignesh Kumaravel
A supra-molecular peptide nano-sponge of (cholesterol-(K/D)n DEVDGC)3-trimaleimide units with a trigonal maleimide linker was designed for the rapid uptake by leukocytes and neural stem cells (Yapa et al. 2018). Here, ‘K’ and ‘D’ are lysine and aspartic acid. 5(6)-carboxyfluorescein was used as a model drug. The therapeutic efficacy of the nano-sponge was tested for the caspase-6 mediated release of 5(6)-carboxyfluorescein drug. The N-terminal of the peptides were capped with cholesterol and the peptides were further connected to a trimaleimide scaffold through Michael-addition (Wang et al. 2017b). It was found that the nano-sponges were efficiently taken up by the leukocytes in the peripheral blood flow. The cytotoxicity was assessed in neural progenitor cells (C17.2) by the MTT assay. The results revealed that DK20 nano-sponges are non-toxic up to 100 μM. However, a slight increase in cell proliferation is noted at low concentrations of DK20.
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
Alzheimer’s disease: phenotypic approaches using disease models and the targeting of tau protein
Published in Expert Opinion on Therapeutic Targets, 2020
Elisabetta Lauretti, Domenico Praticò
Numerous studies have shown that tau can be also a substrate for different proteases including calpain, cathepsin, and several caspases in AD and related tauopathies (i.e. CBD, PiD, FTD, and PSP). Like phosphorylation, tau truncation inhibits its biological function and promotes tau conformational changes and subsequent aggregation. Supporting this concept, a study showed that there is an inverse correlation between the abundance of tau cleavage products and cognitive performance [30]. Specifically, tau can be cleaved at Asp421 by caspase 3 and 6, at Asp314 by caspase 2 and at Asp402 and Asp13 by caspase 6 [31–34]. Caspase-3 can also modulate tau phosphorylation indirectly by cleavage of the protein kinase B (Akt) which in turn regulates the activation of the GSK3β kinase pathway. This was demonstrated in vitro in neuro-2A neuroblastoma (N2A) neuronal cells stably expressing human APP carrying the K670N, M671L Swedish mutation (APPswe) [35] as well as in vivo, in the 3xTg transgenic mouse model of AD [33]. Additionally, proteolytic cleavage of tau at glutamic acid 391 (E391) was also observed in AD brain, as a component of NFTs [36]. To study the biological consequences of this truncation, McMillian et al. generated a mouse model expressing E391-truncated tau and found that indeed, the E391 peptide promotes tau cellular mis-localization, phosphorylation, and tau conformational change confirming the relevance of tau truncated species in the development of these pathologies [36].
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.
Caspase inhibitors: a review of recently patented compounds (2013-2015)
Published in Expert Opinion on Therapeutic Patents, 2018
Hyemin Lee, Eun Ah Shin, Jae Hee Lee, Deoksoo Ahn, Chang Geun Kim, Ju-Ha Kim, Sung-Hoon Kim
Accumulating evidence indicates that caspase-6 plays a critical role in the execution phase of cell apoptosis [11] and regulates B cell activation and differentiation [109]. Thus, Estaquier [110] invented synthetic caspase-6 inhibitors for regulating immune disorders induced by T cell activation and/or proliferation. These compounds were claimed to work as immunosuppressive agents against graft rejection [110] and include synthetic compounds such as Z- Val-Glu(OMe)-Ile-Asp(OMe)-CH2F, also known as Z-VEID-FMK [111], FMK or CH2F [39] and difluorophenoxyl (OPH) [112]. Of note, this invention reveals that spectrum caspase inhibitors (zVAD-FMK and Boc-D-fmk) and specific synthetic caspase-6 and -8 inhibitors prevent T cell proliferation [110], leading to suppression of graft rejection. However, caspase-6 inhibitors were more effective in T cell activation and proliferation compared to caspase-3 and caspase-8 inhibitors without causing undesirable effects on inflammation or interferon secretion, supporting the potency of caspase-6 inhibitors as immunosuppressive agents against graft rejection.