China
Africa
Explore chapters and articles related to this topic
Autoimmune Lymphoproliferative Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The CASP10 (caspase 10) gene on chromosome 2q33.1 is of 48 kb in length with 11 exons, and encodes caspase 10, which participates in the FAS/FASLG signaling pathway through formation of a death-inducing signaling complex composed of FAS-associated death domain protein (FADD), caspase-8, and caspase-10, which triggers downstream caspase cascade, and apoptosis.
Immunology (primary Immunodeficiency Syndromes
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Stephan Strobel, Alison M. Jones
The clinical history is usually suggestive, and there may be a positive family history. Laboratory abnormalities include elevated ‘double negative’ (CD4+/CD8+) T-cells, defective in vitro Fas-mediated apoptosis, and elevated ‘biomarkers’ (soluble Fas-ligand, plasma IL-10, plasma or serum Vitamin B12, plasma IL-18). Definitive diagnosis is confirmed by demonstration of mutation in Fas, Fas-L or caspase 10.
Death Receptor-Mediated Apoptosis and Lymphocyte Homeostasis
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Lixin Zheng, Richard M. Siegel, Jagan R. Muppidi, Felicita Hornung, Michael J. Lenardo
Members of the TNF receptor family that contain a death domain (DD) in their cytoplasmic tail are termed death receptors. Apoptosis induced through death receptors is believed to be triggered by formation of the death inducing signaling complex (DISC)102 (Fig. 4). The components of the DISC vary because a number of different receptors, adaptor proteins and downstream signaling molecules can participate in this signaling complex. In the case of CD95-induced apoptosis, there are at least 3 core components that come together to form the DISC;102 they are CD95, an adapter molecule FADD/Mort-1, and caspase-8 and/or -10. CD95/FAS/APO-1 is a type-I membrane protein with a cytoplasmic tail that harbors a death domain (DD).102FADD/Mort-1 is a cytoplasmic adapter protein that has a C-terminal DD and an N-terminal death effector domain (DED).103 Under appropriate conditions, cross-linking surface CD95 for example, FADD is recruited to the cytoplasmic tail of CD95 through homotypic associations between the DDs of CD95 and FADD. Caspase-8/ FLICE and caspase-10/Mch-4 are two cysteine aspartate proteases (caspases). Caspase-8 and -10 are each composed of two DED domains at their N-terminus and one caspase domain with two subunits each at their C-terminus. Again, through homophilic interactions between the homologous DEDs of FADD and caspase-8/-10, these caspases are recruited into the DISC which triggers autoactivation of the enzymes104-106 (Fig. 4). The aggregation of caspase-8 and -10 appears to be sufficient to initiate enzymatic auto-processing and activation of the enzymes. Our group and others have demonstrated that dimerization of the enzymatic domains of caspase 8 is sufficient to activate the pro-enzyme and induce apoptosis in transfected cells.107,108
Primary Immunodeficiency and Thrombocytopenia
Published in International Reviews of Immunology, 2022
Maryam Mohtashami, Azadehsadat Razavi, Hassan Abolhassani, Asghar Aghamohammadi, Reza Yazdani
Some immune deficiencies are closely related to decrease platelet generation in this category. For example, FOXP3 gene disruption in T- cell signaling pathway causes immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, which affects T- cells regulatory function [267]. This gene has important roles in immune regulation. It has been demonstrated that PRKCD and IPEX deficiency not only decrease platelet activation, but also reduces platelet production derived from megakaryocytes, which ultimately lead to thrombocytopenia [268–272]. Additionally, the ALPS-FASLG signaling pathway, as the first one deficiency, describes a condition that autoimmune lymph proliferative syndrome (ALPS) result from FASLG deficiency [273]. The majority effect of FAS-associated death domain (FADD) deficiency on T and B cells is stimulated by apoptosis via FAS molecule. Furthermore, FADD is accompanied by proliferative responses in B cells via TLR3- and TLR4 [274]. On the other hand, the interaction between Caspases 8, 10 and FAS-associated protein with the death domain of FAS has an essential function in platelet production. Despite regulating the apoptosis pathway, previous studies have demonstrated that FAS and FAS-associated proteins with the death domain are capable to induce necrosis when caspases inhibit. Thus, in ALPS and FADD deficiency, caspase-8 and caspase 10 absence or reduction of caspases can lead to necrosis in megakaryocytes, consequently, platelet count decreased [275–277].
Targeting of keloid with TRAIL and TRAIL-R2/DR5
Published in Journal of Dermatological Treatment, 2021
Pengfei Sun, Zhensheng Hu, Bo Pan, Xiaosheng Lu
In humans, TRAIL works by binding to five types of receptors, such as TRAIL-R1/death receptor (DR)4,TRAIL-R2/DR5,TRAIL-R3/DcR1,TRAIL-R4/DcR2,TRAIL-R5/Osteoprotegerin(OPG) (40) (Figure 2). Among them, TRAIL-R1/DR4 and TRAIL-R2/DR5 mediated apoptosis through cytoplasmic death domain (DD), but DD was incomplete or absent in TRAIL-R3/DcR1 and TRAIL-R4/DcR2, so it can not induce apoptosis. TRAIL-R5/OPG is a decoy receptor of TRAIL, which can inhibit apoptosis. AT the physiological conditions of cells, TRAIL is more inclined to interact with TRAIL-R2/DR5. Park et al. (41) proved that TRAIL-R2/DR5 is highly expressed in tumor cells, and its high expression can increase the sensitivity of TRAIL and increase the effect of inducing apoptosis of tumor cells. Therefore, TRAIL-R2/DR5 is more capable of mediating apoptosis and it is an important anticancer target. The specific process of action of TRAIL is that the ligand binds to the receptor (TRAIL-R1/DR4,TRAIL-R2/DR5), which activates the intracellular DD and binds to the C-terminal of the Fas related protein death domain (FADD) in the cytoplasm. The death response domain (DED) on the N-terminal of FADD is combined with the DED on Pro-Caspase8 to form the death-induced signal complex (DISC). Thus caspase-8 and caspase-10 were activated, and then downstream caspases 3, 6, 7 were activated, which resulted in apoptosis. In addition, caspase-8 promotes the release of cytochrome c and induced endophytic apoptosis of type II cells through mitochondrial pathway (42) (Figure 3).
Exploration of novel heterofused 1,2,4-triazine derivative in colorectal cancer
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Justyna Magdalena Hermanowicz, Anna Szymanowska, Beata Sieklucka, Robert Czarnomysy, Krystyna Pawlak, Anna Bielawska, Krzysztof Bielawski, Joanna Kalafut, Alicja Przybyszewska, Arkadiusz Surazynski, Adolfo Rivero-Muller, Mariusz Mojzych, Dariusz Pawlak
Stimulation of the extrinsic pathway starts with the activation of death receptors. After binding the appropriate death ligand, the receptors accumulate in clusters in the cell membrane and promote the recruitment of adapter proteins. These proteins have the death effector domain (DED), through which they interact with procaspase-8 and procaspase-10. The receptor, adapter protein, and procaspase form the complex DISC, that led to the activation of caspase-8 and caspase-10, and subsequently cell death. The activation of caspase-8 and caspase-10 was determined after 24-h treatment with RSC, 5-FU, and MM-129 by FLICA Caspase-8 Assay Kit (Supplementary Figure 3Sa, 3Sb) and FLICA Caspase-10 Assay Kit (Supplementary Figure 4Sa, 4Sb). It was shown that tested compound increased the expression of the active form of caspase-8 and caspase-10 in both cell lines. The highest percent of cells with the active form of caspase 8 was observed for MM-129 at a 3 µM concentration, and it was 81.2% on DLD-1 cell line and 67.8% on HT-29 cell (Figure 8(c,d)). Similar effect on the activation of caspase-10 in DLD-1 was also exhibited by MM-129 at a 3 µM concentration; the percentage of cells with the active form of initiator caspase-10 was 42.9%. The highest percentage of HT-29 cells expressing active caspase-10 was also evoked by compound MM-129, and it was 37.9% (Figure 8(e,f)).