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Inflammatory bowel disease
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Giovanni Monteleone, Markus F. Neurath, Britta Siegmund
Autophagy is a cellular process that is classically responsible for the degradation of damaged organelles or long-lived proteins. It is activated by a variety of conditions associated with starvation and cellular stress such as that associated with the unfolded protein response as a consequence of stress caused by the accumulation of misfolded protein within the endoplasmic reticulum (ER) as well as the presence of cell-associated bacteria. Genes associated with bacterial sensing such as those encoding NOD2 (as discussed) and intelectin-1 have been associated with Crohn's disease, genes associated with autophagy such as autophagy-related gene 16 like-1 (ATG16L1) and that encoding immunity-related guanosine triphosphatase (IRGM) have been associated with Crohn's disease, and genes associated with ER stress such as those encoding X-box binding protein-1 (XBP1) and orsomucoid 1-like 3 (ORMDL3) have also been associated with both Crohn's disease and ulcerative colitis. Although the functional mechanisms for these susceptibilities are incompletely understood, as discussed later, they highlight the primary importance of innate immunity and the intestinal epithelium in the immunopathogenesis of IBD.
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
Endoplasmic reticulum (ER) is an organelle implicated in the secretion and correct folding of proteins, Ca2+ balance, as well as maintaining the quality control of proteins and cell homeostasis. In different situations, such as physiological or pathological conditions, the demand for folding proteins is increased, resulting in an elevation of unfolded or misfolded protein levels in the ER lumen. This burden on the ER is known as the ER stress. To cope with the stress, the unfolded protein response (UPR) is activated. If the URR cannot restore the stress, the UPR mediates apoptosis [38]. The studies have shown that two main pathways, a transcription factor- and a caspase-dependent signaling pathway, mediate ER stress-dependent apoptosis. The UPR mediators, such as transcription factor GADD153/CHOP, can disrupt the balance between BCL-2 and BAX, resulting in the induction of apoptosis. ER stress-induced apoptosis also occurs through the activation of CASP-12, independent of mitochondrial and death receptors pathways (Fig. 3.1) [39]. There is contradictory information about ER stress-mediated apoptosis. Some have demonstrated that UPR mediates apoptosis through CASP-12, while some claimed that CASP-12 is not related to UPR-mediated apoptosis, rather it is dependent on the mitochondrial apoptotic pathway [40, 41]. Interestingly, in most humans, CASP12 appears to be nonfunctional [42], and the ER-resident of CASP-4 is known to be implicated in ER stress-induced apoptosis [43–45].
Nutraceuticals as Supplements for Cancer Prevention
Published in Sheeba Varghese Gupta, Yashwant V. Pathak, Advances in Nutraceutical Applications in Cancer, 2019
Nicholas Micciche, Brianna Choyce, Yashwant V. Pathak
The mechanism of cannabinoids in cancer prevention is predominantly attributed to the inhibition of cancer cell proliferation and the induction of apoptosis. Agonism of CB1 and CB2 receptors cause apoptosis by stimulating ceramide synthesis. Increases in ceramide concentration causes activation of the endoplasmic reticulum (ER) stress-related signaling pathway, an evolutionarily conserved response, termed the unfolded protein response (UPR). This pathway, when activated, causes increased expression of the highly mobile transcriptional regulation factor, p8. The p8 is a key player in the cellular stress response [80]. The expression of p8 mediates early cancer development by stopping the translation of cancer cells and degrading mutated proteins. Activation of p8 results in activation of downstream targets including activating transcription factor 4 (ATF4), C/EBP homologous protein (CHOP), and tribbles homologue 3 (TRIB3). Activation of TRIB3 specifically causes inhibition of Akt, subsequent inhibition of mTORC1, and finally autophagy [70,81] (Figure 2.5).
Effects of 4-phenylbutyric acid on the development of diabetic retinopathy in diabetic rats: regulation of endoplasmic reticulum stress-oxidative activation
Published in Archives of Physiology and Biochemistry, 2023
Amany Abdel-Ghaffar, Ghada G. Elhossary, Atef M. Mahmoud, Amany H. M. Elshazly, Olfat A. Hassanin, Anisa Saleh, Sahar M. Mansour, Fatma G. Metwally, Laila K. Hanafy, Sawsan H. Karam, Neveen Darweesh, Ahmed Mostafa Ata
The UPR signal transduction across the ER membrane is performed by three transmembrane proteins; inositol-requiring protein-1 (IRE-1), protein kinase RNA (PKR)-like ER kinase (PERK), and activating transcription factor-6 (ATF6). The UPR is kept in an inactive state in the unstressed cells by the binding of BiP/GRP78 to the luminal domains of these three proteins. Under conditions of accumulated unfolded or misfolded proteins inside the ER lumen, Bip protein is dissociated from the three proteins and signal transmission is initiated through the IRE1, PERK, and ATF6 pathways (Hu et al.2012). Activated IRE1 results in up-regulation of UPR target genes, including ER-associated degradation genes (ERAD) and chaperone genes, that code for folding proteins (Calfon et al.2002, Lee et al.2003). The pathway of the PERK action is through PERK-mediated phosphorylation of eukaryotic translation initiation factor-2α (eIF2α), with subsequent translational attenuation. This protects cells from ER stress-mediated apoptosis (Schroder 2008). As regards ATF6, it transits to the Golgi then cleaved by proteases and further translocated to the nucleus to act as a transcription factor to activate UPR target genes responsible for protein folding and ERAD by regulating important targets such as CCAAT-enhancer-binding protein (C/EBP) homologous protein (CHOP) (Rajan et al.2007).
Protective role of PERK-eIF2α-ATF4 pathway in chronic renal failure induced injury of rat hippocampal neurons
Published in International Journal of Neuroscience, 2023
Qi Chen, Jingjing Min, Ming Zhu, Zhanqin Shi, Pingping Chen, Lingyan Ren, Xiaoyi Wang
The endoplasmic reticulum is one of the most important organelles in eukaryotic cells. It is not only the site for protein translation and synthesis as well as calcium ion storage, but also a participant in the transmission and processing of various cell signals. In addition, one of the major functions of the endoplasmic reticulum is to serve as a site for synthesizing secretory and integral membrane proteins.5,6 When cells are stimulated by hypoxia, an imbalance of calcium ions or a change in their concentration occurs in the internal environment, accompanied with the accumulation of some unfolded proteins in the endoplasmic reticulum, resulting in an imbalance between the structure and function of the endoplasmic reticulum. At this time, the corresponding signal pathway is activated to further trigger the endoplasmic reticulum stress (ERS) response.7 Unfolded protein response activation can be triggered in the following three ways: (1) inhibition of protein translation to prevent the production of more folded proteins; (2) induction of the folding of unfolded proteins by the endoplasmic reticulum chaperone; (3) activation of endoplasmic reticulum associated degradation pathways to remove unfolded proteins accumulated in the endoplasmic reticulum.8 However, under prolonged or severe stress, the unfolded protein response initiates programmed cell death.
Molecular mechanisms of ferroptosis and their role in inflammation
Published in International Reviews of Immunology, 2023
Feng Wang, Jingya He, Ruxiao Xing, Tong Sha, Bin Sun
The unfolded protein reaction (UPR) pathway can be triggered by ER stress or ER homeostasis disorder, preliminarily restoring homeostasis by activating genes related to protein folding and antioxidant mechanisms [43]. In addition, it has been reported in recent studies that the inflammatory response caused by excessive ROS is effectively inhibited by UPR-mediated activation of Nrf2 [44,45]. It has been determined previously that phosphorylated eIF2α inhibits senescence, more than inflammation regulation, thereby protecting cells from ROS. It also inhibits cell ferroptosis caused by abnormal ROS levels [46]. Lipid regulation of TMEM16 is highly correlated with the regulation of inflammation and cell death (e.g., apoptosis and hypertrophy). During ferroptosis, the TMEM16 protein is modulated by altering the membrane phospholipid profile’ for greater specificity and readability [47]. In addition to regulatory protein molecules, lncRNA molecules have also been shown to be involved in inflammation and ferroptosis. In pulmonary fibrosis, fibroblast activation, inflammation, and lipid peroxidation induced by TGF-β1 are significantly reduced by lncRNA zinc finger antisense 1 (ZFAS1). Collectively, the lncRNA ZFAS1/miR-150-5p/SLC38A1 axis plays an important role in cellular inflammation and ferroptosis induced by lipid peroxidation [48].