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Introduction to Cancer, Conventional Therapies, and Bionano-Based Advanced Anticancer Strategies
Published in D. Sakthi Kumar, Aswathy Ravindran Girija, Bionanotechnology in Cancer, 2023
Necrosis is a death mechanism, in which cells die accidently in response to an acute insult such as snake biting, trauma or lack of blood supply, etc. In the case of necrosis, the cells undergo plasma membrane permeabilization, swelling, and rupture, and by that the necrotic cells spill out the cellular contents over their neighbors, which invite the damage associated molecular patterns (DAMPs) and may initiate inflammation. Necrosis is also termed as necroptosis and it is mediated by death receptor TNFR1 (tumor necrosis factor receptor). On TNF stimulation, TNFR1 goes through a confirmation change and recruits TNFR-associated death domain protein (TRADD), TRARF2, cellular inhibitor of apoptosis protein 1 (cIAP1), cIAP2, and receptor interacting protein kinase 1 (RIPK1), to form complex 1. RIPK1 is polyubiquinated by cIPA1 and c1PA2 activates NFkB. Caspase 8 cleavage induces apoptosis, in certain condition, and caspase 8 inhibition will induce necroptosis. Necroptosis involves several factors such as ROS production, lysosomal permeabalization, AIF release, and PARP activation. When caspase activation is not involved, necroptosis is associated with the formation of autophagic vesicles.
Oxidative Stress and Inflammation
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
Varsha Rana, Dey Parama, Sosmitha Girisa, Choudhary Harsha, Ajaikumar B. Kunnumakkara
Neuroinflammation mediates neurodegeneration by inducing the release of excessive ROS and RNS, thereby causing oxidative stress and further inflammation. TNF, an inflammatory cytokine and one of the vital players of the inflammatory response, further enhances inflammation by activating the immune cells. The local production of TNF in the CNS induces the apoptosis of oligodendrocyte and demyelination in experimental autoimmune encephalomyelitis model (Taupin et al., 1997; Kunnumakkara et al., 2018). The binding of TNF to tumor necrosis factor receptor 1 (TNFR1) also induces oxidative stress by activating specific ROS and RNS-producing enzymes (Fischer and Maier, 2015; Kunnumakkara et al., 2019). Additionally, overproduction of the pro-inflammatory cytokines induces neuronal damage and death (Chitnis and Weiner, 2017).
Japanese Encephalitis Virus and Human CNS Infection
Published in Sunit K. Singh, Daniel Růžek, Neuroviral Infections, 2013
Kallol Dutta, Arshed Nazmi, Anirban Basu
JEV infection has been reported to initiate apoptotic death in neurons. The tumor necrosis factor receptor (TNFR)-associated death domain (TRADD) has been suggested to be the crucial signal adaptor that mediates all intracellular responses from TNFR-1. Using an in vitro approach it has been shown that the altered expression of TNFR-1 and TRADD following JEV infection regulates the downstream apoptotic cascades (Swarup et al. 2007, 2008). However, even though the infected neurons eventually die, recent evidences suggests that a possible intracellular innate immune response against the virus is mounted following viral recognition through the retinoic-acid-inducible gene I (RIG-I) (Nazmi et al. 2011).
Novel immune targets for the treatment of triple-negative breast cancer
Published in Expert Opinion on Therapeutic Targets, 2021
Chiara Corti, Eleonora Nicolò, Giuseppe Curigliano
Although pharmacological research mainly focused on co-inhibitory molecules, broad investigations aimed at targeting co-stimulatory antigens as well, especially 4–1BB (CD137), glucocorticoid-induced tumor necrosis factor receptor (GITR), OX40 and Inducible Co-Stimulator (ICOS). Since the first three immune targets belong to the Tumor Necrosis Factor Receptor (TNFR) superfamily, drug design needs to take into account their particular structure, evolved along with receptor multimerization [25]. Moreover, GITR, OX40, and ICOS are not only expressed on T effector cells but they are also constitutively expressed on Tregs [25]. Although such differential expression further complicates the interpretation of any research findings, its exploitation lies in bispecific agents able to both activate final effectors and reduce Tregs [25,68,69].
MiR-199a-5p regulates rat liver regeneration and hepatocyte proliferation by targeting TNF-α TNFR1/TRADD/CASPASE8/CASPASE3 signalling pathway
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Chunyan Zhang, Bingyu Ye, Jiaojiao Wei, Qiwen Wang, Cunshuan Xu, Guoying Yu
TNF-α is a kind of pleiotropic cytokine, which was discovered by Carswell in 1975 and secreted by a variety of cells in various inflammatory and immune responses [36]. There are two types of tumour necrosis factor receptor (TNFR) families, TNFR1 and TNFR2, but most of the biological activity of TNF-alpha is through binding to TNFR1 [37]. TNFR1 is universally expressed in all cell types, playing an important role in NF-kB pathway activation. TNFR1 ligation could trigger receptor trimerization, which subsequently recruits TRADD, the latter actives caspase-8 and induce cell apoptosis by binding with a specific death domain (DD) in cytoplasmic domain of TNFR1 [38]. In turn, activated caspase-8 could activate effector caspases, including caspase-3, to trigger cell apoptosis via digesting upwards of hundreds of proteins [39]. The molecular context of TNFR1 activation is thought to determine whether it promotes regeneration or contributes to hepatocyte death [40]. Studies have shown that cell populations, involved in normal liver physiology, including hepatocytes, endothelial cells as well as neutrophils, undergo apoptosis through TNF/TNFR1-induced death signals [41]. Our outcomes implicated that decreased expression of TNF-α reversed the inhibitory effect of miR-199a inhibitor on hepatocytes.
Tetravalent biepitopic targeting enables intrinsic antibody agonism of tumor necrosis factor receptor superfamily members
Published in mAbs, 2019
Yanli Yang, Sherry H. Yeh, Shravan Madireddi, Wadim L. Matochko, Chen Gu, Patricia Pacheco Sanchez, Mark Ultsch, Gladys De Leon Boenig, Seth F. Harris, Brandon Leonard, Suzie J. Scales, Jing W. Zhu, Erin Christensen, Julie Q. Hang, Randall J. Brezski, Scot Marsters, Avi Ashkenazi, Siddharth Sukumaran, Henry Chiu, Rafael Cubas, Jeong M. Kim, Greg A. Lazar
Receptors of the tumor necrosis factor receptor superfamily (TNFRSF) are central regulators of immunity, cell proliferation and death, and other important biological processes. Because of these essential roles, targeted agonism of this receptor class is an active therapeutic approach for the treatment of cancer, autoimmunity, and other diseases.1–4 Because cognate ligands of these receptors generally make suboptimal drugs due to poor production, stability, or pharmacokinetics (PK), the monoclonal antibody has been the most common drug modality advanced for this receptor class. A significant challenge for the pharmacologic agonism of these receptors by antibodies is the general requirement for high-order receptor clustering,5,6 whereby a multiplicity of receptors are brought together in close proximity on the cell surface. Antibodies achieve this mechanism in pre-clinical in vivo models via extrinsic cross-linking from Fc engagement with Fc gamma receptors (FcγRs) on immune cells.7–9 Despite the advancement of a large pipeline of TNFRSF agonist antibodies into development, as yet none have been approved or reached late-stage clinical trials, and several have been withdrawn.1,3,4,10–12 While a diverse host of factors may be responsible, the lack of intrinsic potency represents a major deficiency of this class of agents, and it remains a question as to whether a native antibody is capable of sufficiently driving receptor signaling in a therapeutic setting.