Apoptosis of Biliary Epithelial Cells
Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso in The Pathophysiology of Biliary Epithelia, 2020
Most of these morphological changes are caused by the caspases, a large family of cysteine proteases.3 These enzymes are highly conserved through the evolution, and can be found not only in mammals, but in insects, nematodes as well.1 Over a dozen caspases have been identified in humans, most of them are known to play role in apoptosis. All known caspases have an active-site cysteine, and cleave substrates at aspartic residues. Caspase-mediated cleavage of specific substrates explains the characteristic features of apoptosis: for example, cleavage of nuclear lamins is required for nuclear shrinking and fragmentation. Caspases are thought to be the central executioners of the apoptotic pathways, indeed, inhibiting caspase activity can prevent apoptosis to occur. Because of the central role of caspases in the apoptotic process, it is important to understand how caspases are activated. Caspases originally are synthesized as enzymatically inert zymogens. During activation, proteolytic cleavage of the zymogen occurs, this exposes caspase substrate sites and results in activation of downstream caspases.3,4 Therefore, the caspase cascade is a useful method to amplify and integrate pro-apoptotic signals. But how the most proximal caspases are activated? There are two major apoptotic pathways identified so far, depending on the initial pro-apoptotic signal: the death receptor or “extrinsic” pathway and the mitochondrial, or “intrinsic” pathway (Fig. 1.).
Testicular germ cell apoptosis and spermatogenesis
Rajender Singh in Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Caspases are the initiators and executioners of apoptosis. They are synthesized in the form of procaspases, which get activated during the apoptotic process (73). These procaspases contain three domains: an NH2 domain and the p20 and p10 domains. Caspases are cysteine proteases that cleave their substrate protein after the aspartic acid residue that leads to cell death (45). The executioner caspases exist in the cytosol in the form of inactive dimers, and their activation is carried out by the initiator caspases through proteolytic cleavage of its catalytic domain to an active scaffold. The proteolytic cleavage allows the rearrangement of its mobile loop conferring it the catalytic activity (74,75). In the cytosol, caspase-3 and caspase-7 exist in their dimeric forms, and activation is through the cleavage within their respective linker segments (76). In human testis biopsies, effector caspase-7 seemed to be absent from normal human testes, whereas procaspase-3 and procaspase-6 were detected in germ cells. Increased germ cell apoptosis in patients with the spermatogenic arrest was associated with increased levels of active caspase-3, which indicates that caspase-3 is the major executioner of apoptosis in human infertility (77). Similarly, in rodents also caspase-3 appears to be the major executioner of apoptosis (78,79).
Micronutrients for Improved Management of Huntington’s Disease
Kedar N. Prasad in 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).
Therapeutic potential of a 2,2’-bipyridine-based vanadium(IV) complex on HepG2 cells: cytotoxic effects and molecular targeting
Published in Egyptian Journal of Basic and Applied Sciences, 2023
Eman Salah El-Shafey, Eslam Samy Elsherbiny
HCC is malignant tumor characterized by high recurrence rate, poor prognosis and increasing levels of chemotherapy resistance [29]. Apoptosis alteration is responsible not only for tumor development and progression but also for tumor resistance to therapies [30]. Caspase-3 is the most important executioner caspase in apoptosis and is activated by both intrinsic and extrinsic pathways [31]. Triggering of caspases is considered as a key regulator in activation of apoptosis and cellular death of tumor cells [32]. In this study, untreated HepG2 cells displayed low percentage of dead cells in sub G peak (8.2%) that represent the apoptotic peak. Moreover, apoptosis analysis by Annexin V/PI method demonstrated the presence of low percentage of cells in early and late apoptotic quadrants. Consequently, lower levels of caspase-3 detected in HepG2 cells may represents the evolved apoptosis resistance.
Modulation of mitochondrial permeability transition pore opening by Myricetin and prediction of its-drug-like potential using in silico approach
Published in Drug and Chemical Toxicology, 2023
Akinwunmi O. Adeoye, John A. Falode, Olabimpe C. Oladipupo, Tajudeen O. Obafemi, Babatunde J. Oso, Ige F. Olaoye
A significant increase in mitochondrial lipid peroxidation was observed in the presence of all the triggering agents which is in agreement with the significant opening of the MMPT pore. Lipid peroxidation may increase the destructive effect of the MMPT in cells since it also promotes mitochondrial swelling and cytochrome c release (Ruberto et al. 2000). Myricetin significantly inhibited mitochondrial lipid peroxidation at the two concentrations tested. It could therefore be suggested that myricetin could play a role in protecting the physicochemical properties of membrane bilayers from free radical-induced severe cellular damage. An increase in cytochrome release in the presence of all the triggering indicated that there was a significant increase in MMPT pore opening. Caspases are responsible for the proteolytic cleavage of a broad spectrum of cellular targets, leading ultimately to cell death. The expression of caspase 3 and 9 activities increased significantly in the presence of all the triggering agents but lowered in myricetin at the two concentrations.
Regulation of the autophagy plays an important role in acute kidney injury induced acute lung injury
Published in Renal Failure, 2022
Ruolin Wang, Siheng Shen, Luyong Jian, Shuhua Liu, Qi Yuan, Huahui Guo, Jiasheng Huang, Penghui Chen, Renfa Huang
Autophagy and apoptosis are two important cellular processes. In many other cases, autophagy and apoptosis develop exclusively. However, autophagy and apoptosis may be triggered by common upstream signals, and sometimes these results in combined autophagy and apoptosis. Apoptosis is a programmed cell death, and its initiation is dependent on the activation of a series of cysteine-aspartic proteases known as Caspases. There are two categories of Caspases, including initiator Caspase and effector Caspase. Caspase-3 is an effector Caspase. Active caspase-3 is responsible for the final execution of proteolytic degradation of a variety of intracellular proteins [39]. Members of the Bcl-2 protein family are responsible for the regulation of apoptosis and are critical to the regulation of both intrinsic and extrinsic apoptotic pathways [40]. As mentioned above, Bcl-2 can combine with Beclin-1 to participate in the process of apoptosis. When autophagy is promoted, the degree of apoptosis will be reduced accordingly. Our results showed that decreased Caspase-3, increased Bcl-2 and Beclin-1, represent the decreased apoptosis in lung and kidney tissues when autophagy was promoted. According to our results, we can speculate that autophagy not only plays a role in the lung-kidney crosstalk through anti-inflammatory and antioxidation, but also plays a protective role in the inhibition of apoptosis.