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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
When cells are infected by viruses, the perforin/granzyme apoptosis pathway is initiated by cytotoxic lymphocytes to remove the infected cells. Perforin, also known as cytoplasmic granule toxin, is a kind of protein with a pore-forming ability in mitochondrial membrane. Granzyme is a serine protease protein, which contains cytotoxic granules of cytotoxic lymphocytes (CLs). Although, Granzyme is required for triggering apoptosis, it should be delivered appropriately by perforin. In humans, there are numerous granzymes including A, B, H, K, and M, but the Granzymes A and B are the most abundant enzymes that are involved in apoptosis. This pathway is initiated when granzymes could enter into target cells. This internalization is facilitated by perforin. Granzyme B activates pro-apoptotic BH3-interacting domain death agonist Bid, leading to the activation of CASP-3. Activated CASP-3 is subsequently able to proceed with executive apoptosis. Granzyme B can also inactivate MCL-1, which is a member of the anti-apoptotic BCL-2 family [36]. The granzyme A pathway is also involved in apoptosis via activating a parallel, caspase-independent cell death pathway through single-stranded DNA damage [37].
Recent Advances of Nanotechnologies for Cancer Immunotherapy Treatment
Published in Loutfy H. Madkour, Nanoparticle-Based Drug Delivery in Cancer Treatment, 2022
Immune system activation toward cancer cells leads to a competition wherein immune cells inhibit fast cellular proliferation and mutation fosters tumor growth, but the formation of a detectable tumor is often the result of the failure of body immunity to tumor cells. If the immunity could not eradicate all the tumor cells at the beginning, it usually forms a selective force to tumor cell clones that can alter the composition of tumors and gradually leave and promote the growth of tumor cell clones with the least immunogenicity. Ultimately, the immunoediting effect often gives rise to the most invasive and uncontrolled tumors formed by the most insensitive cells [25]. Tumor cells have several mechanisms that assist in evading from being detected and eliminated by the immune system: Downregulation of MHC-I on tumor cells as a consequence of mutations of MHC genes or molecules involved in TAA antigen processing and presentation can reduce immunogenicity of tumor cells and evade cytotoxic T-lymphocyte-mediated lysis [26].Tumor cells could suppress immunity by expressing programmed death-ligand 1 (PD-L1) that binds to the negative costimulator programmed death (PD)-1 on lymphocyte’s membrane, or by secreting immunosuppression cytokines that suppress the activation and differentiation of APCs and lymphocytes, such as transforming growth factor (TGF)-β [27,28].Tumor cells could resist cytotoxic T-lymphocyte-mediated killing effects by expressing granzyme serine proteases to inhibit the perforin/granzyme pathway that mediates tumor cell lysis, and decoy receptors for cell death including soluble Fas, osteoprotegerin, and decoy receptor-3, 4. In addition, increased expression of oncogenic and antiapoptotic molecules such as the signal transducer and activator of transcription 3 and B-cell lymphoma 2 (Bcl2) also resists T-lymphocyte-mediated lysis [29].Immunoregulatory cells with immunosuppressive effects, such as myeloid-derived suppressor cells and M2-type tumor-associated macrophages, could be recruited by tumor cells in the tumor microenvironment, which could produce immunosuppressive cytokines and also secrete the vascular endothelial growth factor and matrix metalloproteinases that favor tumor angiogenesis for tumor growth and invasion [30,31].A physical barrier around the tumor could be generated by tumor cells through secreting a series of molecules such as collagen, thus forming an immune privilege area and preventing the lymphocytes and APCs from entering the tumor area [32].
Intraoperative storage of saphenous vein grafts in coronary artery bypass grafting
Published in Expert Review of Medical Devices, 2019
Catherine J. Pachuk, Sophie K. Rushton-Smith, Maximilian Y. Emmert
A key question is how much damage has occurred within 45 minutes? This is particularly relevant given that vascular grafts are kept in a storage solution for between 30 minutes and 2 − 3 hours, depending upon the complexity of the surgery. To help answer this question, PMVs were stained with a caspase-3 specific immunohistochemistry reagent. Caspase-3 is involved the granzyme B apoptotic pathway of cell death, and positive staining would suggest that the cells were ‘committed to dying’ by apoptosis [27]. However, neither saline-exposed PMV nor DuraGraft-exposed PMV stained positive for caspase-3, indicating that the granzyme B apoptotic pathway was unlikely to be active in these PMVs. There are, however, other ‘committed death pathways’, including the granzyme A apoptotic and necrotic pathways [27]. Studies to determine if these pathways are active in the PMVs were beyond the scope of this work.
Mathematical model for the in-host malaria dynamics subject to malaria vaccines
Published in Letters in Biomathematics, 2018
Titus Okello Orwa, Rachel Waema Mbogo, Livingstone Serwadda Luboobi
Due to intracellular infections, P. falciparum parasites are susceptible to immune-mediated control by CD8+ T cells, which target intracellular pathogens (Villarino, 2013). The CD8+ T cells have both direct and indirect effector pathways for parasite elimination at the liver stage. The indirect mechanism includes the production of IFN-γ and TNF, whereas the direct mechanism involves the release of perforin and granzymes (Nganou-Makamdop, van Gemert, Arens, Hermsen, & Sauerwein, 2012). IFN-γ suppresses parasite development through direct impairment of parasite differentiation in hepatocytes (Mellouk et al., 1987). Moreover, IFN-γ increases the expression of nitric oxide synthase which leads to subsequent increase in nitric oxide that confers protection against P. falciparum (Seguin et al., 1994). Although CD8+ T cells are sufficiently primed during blood stage malaria, they offer very minimal contribution to protective immunity. It is thought in Villarino (2013) that vascular endothelial cells that acquire antigen from IRBCs stimulate CD8+ T cells to release perforin and granzyme B during blood stage malaria. The capacity of CD8+ T cells to eradicate malaria parasites and infected cells both at the liver stage and at the blood stage is therefore considered in this paper.
A mathematical model of cytotoxic and helper T cell interactions in a tumour microenvironment
Published in Letters in Biomathematics, 2018
Heidi Dritschel, Sarah L. Waters, Andreas Roller, Helen M. Byrne
While immunosurveillance should, in theory, rid the body of pre-cancerous and/or cancerous cells, in practice this does not always occur. If, for example, immunogeneic cells are removed by the immune system then a poorly immunogeneic and antigenic population of tumour cells remains (DuPage et al., 2012; Pardoll, 2003; Vicari et al., 2002). As these tumour cells proliferate, they mutate, creating cells that present low levels of tumour antigen and, consequently, evade recognition by T cells (Vesely and Schreiber, 2013). Cancer cells also manipulate the local microenvironment by producing immunosuppressive cytokines such as TGF- and IL-10 that promote differentiation of helper T cells to a regulatory phenotype (Kawamura et al., 2002). Cancer cells may also produce cytolytic molecules such as Granzyme B that induce apoptosis of immune cells (Igney and Krammer, 2002).