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Chemopreventive Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Apoptosis, also known as Programmed Cell Death, is induced in cells in response to physiological or pathological changes in order to eliminate aged cells, or those with extensive genetic mutations that might pose a risk of transforming into cancer cells if not eradicated. There are two predominant apoptotic pathways, the first being the intrinsic/mitochondrial pathway which is regulated by the Bcl protein family. This initially results in various stimuli which trigger increased mitochondrial membrane permeability to release apoptogenic factors, leading to membrane disruption and mitochondrial dysfunction. This results in activation of apoptogenic proteases including caspase-3 and -9, and also the expression of Death Receptors (i.e., DR4 and DR5) on the cell surface. Caspase enzymes also play vital regulatory roles in cell protein turnover via several activating and deactivating mechanisms, with nine different caspases involved in apoptotic pathways. The extrinsic apoptotic pathway is stimulated via binding of a ligand from the TNF superfamily to a Death Receptor on the cell surface. Once bound, the ligand undergoes trimerization which stimulates recruitment of adaptor proteins to their cytosolic Death Domains, such as FasL/FasR, TNFα/TNFR1, and TRAIL/TRAILR1 or TRAILR2.
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
It has been found that genetic deficiencies in apoptosis pathways can lead to developmental abnormalities and disease.12 One of the major breakthroughs in determining the physiological relevance of lymphocyte apoptosis and autoimmune disorders came from the identification of genetic mutations of CD95 (Fas) in Ipr mice and CD95 ligand (FasL) in gld mice.121,122 The Ipr stands for “lymphoproliferative response” and the gld for “generalized lymphoproliferative disease”. In Ipr mice, a transposable element insertion in the 2nd intron of CD95 gene disrupts transcription of the gene while in gld mice, a point mutation in the CD95L gene produces a mutant protein that fails to bind CD95. In both cases, peripheral lymphocytes escape from CD95-mediated cell death. Over their lifetime, these mice develop progressive lymphoadenopathy, splenomegaly, and autoimmune disease.123 These data indicate that death receptor-mediated apoptosis is important for shaping the immune system by limiting lymphocyte accumulation.
Effects of Retinoids at the Cellular Level (Differentiation, Apoptosis, Autophagy, Cell Cycle Regulation, and Senescence)
Published in Ayse Serap Karadag, Berna Aksoy, Lawrence Charles Parish, Retinoids in Dermatology, 2019
An extrinsic apoptosis pathway is activated upon binding of extracellular ligands, such as TNF-α, Fas cell surface death receptor (FAS), and TRAIL, to the corresponding death receptors localized on cell membrane. Activation of death receptors and recruitment of adaptor proteins activate effectors of apoptosis such as procaspase 8 and induce downstream apoptotic signaling (53).
Ramelteon and mechanism of its restorative effect in an experimental lung disease model
Published in Toxicology Mechanisms and Methods, 2023
İlkay Armağan, Halil Aşcı, Yalçın Erzurumlu, Songül Özkula, Nursel Hasseyid, Duygu Kumbul Doğuç, Gözde Okuyucu, Ahmetcan Varel
A considerable feature of apoptosis is its effects mainly through a kind of serine protease which is known as caspase. A death signal is transmitted via signaling pathways causing to activate the caspases destroying cell. Apoptosis can be initiated by both intrinsic and extrinsic stimuli combined with intrinsic and extrinsic apoptosis pathways (Xu et al. 2019). Cas-8 is a canonical cysteine protease that is needed for the execution and initiation of apoptosis. It is an important factor in programmed cell death induced by death receptor, and it should be activated for this pathway’s functionality (Fianco et al. 2018). The MTX group had significantly higher Cas-8 level indicating that the increase in Cas-8 is associated with apoptosis in inflammatory cells, alveolar, bronchiolar and bronchial epithelial cells. RML treatment, on the other hand, regressed apoptosis by reducing the level of Cas-8 and exhibited antiapoptotic properties. The fact that increasing Cas-8 levels are inversely related to decreasing AQP levels indicates that the AQP levels, especially in cell membranes, decrease along with dying cells. Agents that can prevent inflammation or apoptosis may contribute to the maintenance or increase in AQP levels. At the same time, the observation after routine histochemical examination that the general tissue toxicity findings, including inflammation, observed in the injury group, changed significantly with RML. These histopathological changes support immunohistochemistry and other molecular findings.
Development of an immune-related prognostic biomarker for triple-negative breast cancer
Published in Annals of Medicine, 2022
Yan Zhang, Quan Wang, Wei-Kang Yang, Yong-Si Wang, Qiao Zhou, Jie Lin, Xu-Xuan Wei, Tian Liang, Tongtong Liu, Wen-Tao Fan, Li Liang, You-Nian Xu
Increasing evidence indicates that tumorigenesis is tightly associated with the immunological surveillance and defense during the disease course, and these functions play a key role in mediating response to therapy [5]. The tumour immune microenvironment (TIME) in TNBC is a highly complicated, heterogeneous construct consisting of diverse cell types and disordered gene expression. Importantly, the rapid expansion of tumour tissue induces hypoxia and necrosis, reprogramming the TIME gene expression landscape to radically affect immune cell survival, recognition, and anti-tumour function. In comparison to other breast cancers, the TIME in TNBC is associated with higher expression of vascular endothelial growth factors and other molecules promoting growth and migration of tumour cells, as well as tumour-infiltrating lymphocytes and tumour-associated macrophages [6,7]. It has been shown that the presence of tumour-infiltrating lymphocytes is correlated with a better prognosis and an improved response to neoadjuvant chemotherapy in TNBC [8–10]. Furthermore, the interaction between death receptor 1 on T cells and programmed cell death ligand 1 on tumour cells, suppresses the immune system, resulting in tumour cell immune escape [11]. As such, gaining a better understanding of the pathological impact and dynamics of different TNBC immune cells is essential for developing an effective TIME-related prognostic biomarker.
The prognostic and therapeutic potentials of CTLA-4 in hematological malignancies
Published in Expert Opinion on Therapeutic Targets, 2022
Mohammad Sadeghi, Atefeh Khodakarami, Armin Ahmadi, Mehrdad Fathi, Jamshid Gholizadeh Navashenaq, Hamed Mohammadi, Mehdi Yousefi, Mohammad Hojjat-Farsangi, Ali Akbar Movasaghpour Akbari, Farhad Jadidi-Niaragh
As discussed earlier, Laurent et al. reported that 80% of AML cells expressed CTLA-4. Subsequently, they evaluated the possibility of apoptosis induction in leukemic cells by targeting CTLA-4 with recombinant B7 (rB7). Leukemic cells were cultured in the presence or absence of rB7 at different concentrations in vitro. Then, cell apoptosis was evaluated. The apoptosis induction occurred in a dose-dependent manner with an optimal effect at the highest concentration, followed by the cleavage of procaspase-8. It has been reported that a common cause of AML chemoresistance includes defects in cell apoptosis pathways. The main reason relies on death receptor-mediated apoptosis. CTLA-4-induced apoptosis does not seem to be a Fas-Associated protein with Death Domain (FADD) mediated. Thus, this might represent a new way to induce apoptosis and efficiently kill chemo-resistant AML cells [15]. By clarifying the exact mechanism of induction of this apoptosis, it can be evaluated in other leukemias in which malignant cells express CTLA-4.