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Cell Biology for Bioprocessing
Published in Wei-Shou Hu, Cell Culture Bioprocess Engineering, 2020
In addition to their role in energy metabolism, mitochondria also play a key role in the regulation of apoptosis. Some pro-apoptotic proteins are sequestered in the space between the outer and inner membranes of mitochondria. Cytochrome C, a hemeprotein that is an important component of the cytochrome C complex in the electron transport chain, is associated with the inner membrane of mitochondria. The release of cytochrome C and those pro-apoptotic proteins in stressed cells initiates the intrinsic pathway of apoptosis (Figure 2.22). The cytochrome C released into the cytoplasm proceeds to form a complex with APF1, pro-caspase 9, and dATP, known collectively as the apoptosome. In the apoptosome, the inactive pro-caspase 9 becomes activated and subsequently activates downstream caspases.
The Role of Nanoparticles in Cancer Therapy through Apoptosis Induction
Published in Hala Gali-Muhtasib, Racha Chouaib, Nanoparticle Drug Delivery Systems for Cancer Treatment, 2020
Marveh Rahmati, Saeid Amanpour, Hadiseh Mohammadpour
The intrinsic pathway of apoptosis, also known as mitochondrial pathway, is activated by a wide range of stimuli, including DNA-damaging factors, activators of oncogenes, high level of intracellular Ca2+, and oxidative stress. Apoptotic agents, which target mitochondria, may cause mitochondrial swelling through the formation of membrane pores, or may increase the mitochondrial outer membrane permeabilization (MOMP), leading to the release of the apoptotic effectors by a two-step process (Fig. 3.1). This process is initiated by an increase in MOMP, resulting in the release of cytochrome c and other apoptogenic factors into the cytosol. In the cytosol, cytochrome c assembles to a multiprotein complex called “apoptosome,” which consists of apoptotic protease activating factor 1 (apaf1), dATP, cytochrome c, and procaspase-9 (Fig. 3.1). Then, the apoptosome cleaves the procaspase-9 to caspase-9, which in turn activates CASP-3, CASP-6, and CASP-7, respectively [27–29]. The mitochondrial proteins SMACs (Second Mitochondria-derived Activator of Caspases) are also released into the cytosol upon the increase in MOMP. SMAC proteins bind to factors that inhibit apoptosis (IAPs) in order to deactivate them, and in turn, the caspase cascade proceeds to execute apoptosis and create apoptotic hallmarks, such as plasma membrane blebbing and DNA fragmentation. The mitochondrial pathway is strongly under the control of BCL-2 family members. These proteins, which may have either anti-apoptotic or pro-apoptotic functions, mostly regulate mitochondrial permeability [30].
Monitoring Apoptosis and Anticancer Drug Activity in Single Cells Using Nanosensors
Published in Tuan Vo-Dinh, Nanotechnology in Biology and Medicine, 2017
In a study by Vo-Dinh and coworkers, a unique enzyme substrate–based optical nanobiosensor that consists of an enzyme substrate chemically immobilized to a nanotip was used to detect and identify surface-dependent cleavage events of caspase-9 in single live MCF-7 cells [35]. In this work, the application and utility of a unique optical nanobiosensor for monitoring the onset of the mitochondrial pathway of apoptosis within single living cell by detecting enzymatic activities of caspase-9 was demonstrated. The modified sensing format consists of a solid phase for the immobilization of caspase-9 substrate, leucine–glutamic acid–histidine–aspartic acid–7-amino-4-methyl coumarin (LEHD–AMC), which consists of a tetrapeptide, LEHD, coupled to a fluorescent molecule, AMC. LEHD–AMC exists as a nonfluorescent substrate prior to cleavage by caspase-9; however, after cleavage, free AMC fluoresces when excited at 325 nm. Caspase-9 is one of the most important Cysteinyl ASPartate-specific proteASE (caspase) among the caspase family members. It is synthesized as inactive proenzyme that is processed and activated in cells undergoing apoptosis. The processed form consists of large (35 kDa) and small (11 kDa) subunits, respectively, and antibody can be used to detect the 35 kDa protein corresponding to the large subunit to determine whether the cleavage of the inactive proenzyme occurred. Caspase-9 is thought to trigger a caspase-cascade leading to apoptosis [11]. As a result of mitochondrial membrane permeabilization by stimuli such as ROS, which may set the point-of-no-return of the PCD process [36,37], caspase activators, including cytochrome c and caspase-9, are released from the mitochondria intermembrane space into the cytosol. Cytochrome c release triggers the assembly of the cytochrome c/Apaf-A/pro-caspase-9 activation complex, the apoptosome, followed by the processing of caspase-9 [10,38].
Static electric field exposure decreases white blood cell count in peripheral blood through activating hypothalamic–pituitary–adrenal axis
Published in International Journal of Environmental Health Research, 2022
Jiahong Wu, Li Dong, Junli Xiang, Guoqing Di
As mentioned above, the elevation of CORT levels in peripheral blood could raise the concentration of CORT-GR complex in lymphocytes. Bim, a pro-apoptotic protein, is another target gene regulated by the CORT-GR complex (Wang et al. 2003; Dong et al. 2015; Dong and Vaux 2020). Bim can activate downstream pro-apoptotic proteins, especially Bax (Dong et al. 2015). Activated Bax could translocate from cytoplasm to outer mitochondrial membrane (OMM) and mediate the formation of permeability pores on OMM (Banuelos et al. 2016). After the permeability of OMM increases, cytochrome c, located between OMM and inner mitochondrial membrane, is released into the cytoplasm (Distelhorst 2002). In the cytoplasm, cytochrome c forms the apoptosome together with pro-caspase-9 and Apaf. The apoptosome could further activate caspase-3, which ultimately cleaves the majority of intracellular proteins to execute irreversible apoptosis (Smith and Cidlowski 2010). Therefore, the additional reason for the significant decrease of total WBC count and lymphocyte count in this study is that a SEF exposure of 7d and 14d can activate HPA axis. CORT, the end-product of HPA axis, induces the apoptosis of lymphocytes by upregulating Bim gene expression. To present the process in which the SEF exposure of 7d and 14d induce the apoptosis of lymphocytes more clearly, the discussion above is visually summarized in Figure 4(b).
Ceramide pathway: A novel approach to cancer chemotherapy
Published in Egyptian Journal of Basic and Applied Sciences, 2018
Mahdi Mashhadi Akbar Boojar, Masoud Mashhadi Akbar Boojar, Sepide Golmohammad
In the intrinsic pathway, factors such as environmental stress, heat, hypoxia, lack of growth factors, infections from intracellular masses and caspase-8 which activated in the external pathway of apoptosis results in increased expression of pro-apoptotic proteins of the B-cell lymphoma family such as BAX, BAK, BID, BAD and nitric oxide and attenuation of the anti-apoptosis proteins such as Bcl-2 and Bcl-XL [5,9,12] . The total of these events leads to increased permeability of the mitochondrial membrane and the formation of pores in its surface, resulting in the release of factors such as Cytochrome C and SMAC from mitochondria into the cytoplasm [13]. The release of these agents by generating the apoptosome complex activates Caspase-9, and the activation of Caspase-9 induces caspase 3 which leads to apoptosis [14].
Chlorogenic acid potentiates antitumor effect of doxorubicin through upregulation of death receptors in solid Ehrlich carcinoma model in mice
Published in Egyptian Journal of Basic and Applied Sciences, 2019
Nesma A. Abd Elrazik, Mohamed El-Mesery, Amro El-Karef, Laila A. Eissa, Amal M El Gayar
The Bcl-2 gene family which includes anti-apoptotic Bcl-2 is significant in the regulation of cell apoptosis [37]. Here, we found that Bcl-2 gene expression in tumor tissue was reduced by CGA. In addition, the combination of CGA and DOX significantly decreased the Bcl-2 gene expression level in comparison with each treatment alone. Thus, the reduction in gene expression of Bcl-2 leads to disruption of mitochondrial outer membrane permeability and the release of cytochrome-c into the cytoplasm. Cytochrome-c triggers the formation of apoptosome by binding to apoptosis protease activating factor-1 (Apaf-1) and pro-caspase-9, allowing the release of caspase-9. This process in turn activates downstream executor caspases-3, caspase-6 and caspase-7 [38,39].