Childhood ILD
Muhunthan Thillai, David R Moller, Keith C Meyer in Clinical Handbook of Interstitial Lung Disease, 2017
Disease is due to gain of function mutations. Kindreds with a range of age-related presentations have been described (above). Sp-C chILD is part of the differential diagnosis of RSV bronchiolitis which fails to resolve. Although in the largest series, empirical treatment with systemic corticosteroids, hydroxychloroquine and azithromycin is associated with a good prognosis (3), fatalities are well described. Very prolonged survival with good lung function with just intermittent hydroxychloroquine therapy has been described (41). Interestingly, a Japanese kindred just presenting with UIP in adult life, although containing one child with asymptomatic radiological abnormalities has been described (42). Endoplasmic reticulum stress (BiP, IRE1α, cleaved Caspase-3) was reported to be increased in vitro by the mutant protein. Finding the reasons why the presentation of an inherited abnormality may be delayed may offer avenues for the discovery of new treatments.
Myositis
Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide in Clinical Innovation in Rheumatology, 2023
The degenerative component of IBM can be appreciated in the presence of rimmed vacuoles, cytoplasmic protein aggregates, myonuclear degeneration, and mitochondrial abnormalities.102–104 The protein aggregates are comprised of congophilic amyloid deposits within some fibers that may be intra- or extravacuolar and could prime an immune reaction.105 Degenerative markers, like p62, LC3, and TDP-43, are thought to be a result of endoplasmic reticulum stress resulting in unfolded protein response and autophagy.90, 105 Interestingly, these protein aggregates and markers are also seen in other vacuolar as well as inflammatory myopathies. However, it is still unclear how these proteins aggregate and induce an inflammatory response,13 and it raises the question of whether IBM has a true degenerative component or if this could be a manifestation of an intense autoimmune response. Furthermore, the diseased fibers were found to have upregulated interferon receptor,106 which together with other stressors and pro-inflammatory cytokines lead to further fiber degeneration and, thus, misfolded protein accumulation.
The Silver Lining
David J. Hackam in Necrotizing Enterocolitis, 2021
Cellular death, either unregulated (necrosis) or as regulated, programmed events (apoptosis, autophagy, and necroptosis) (48), is an important aspect of maintaining gut barrier homeostasis. The unregulated form, necrosis, involves a rapid breakdown of the cellular membrane, resulting in the release of intracellular compounds into the extracellular space and damage to surrounding cells. This damage leads to proinflammatory cytokine release and immune system activation (48, 49). In contrast, apoptosis occurs in a signal-specific fashion in response to many events, including DNA damage, nutrient deficiency, endoplasmic reticulum stress, shock, developmental cues, infection, and ligation of death receptors on the cell surface (50). Execution of apoptosis is dependent on caspase signaling (51) and is characterized by membrane blebbing, apoptotic body formation, chromatin condensation, DNA fragmentation, and cell shrinkage (51, 52). Despite its name, NEC has been associated with high epithelial apoptosis rates; however, the other types of cell death mechanisms have not been deeply investigated in the disease.
Bioinformatics analysis of the endoplasmic reticulum stress-related prognostic model and immune cell infiltration in acute myeloid leukemia
Published in Hematology, 2023
Mengya Pan, Junjie Zhou, Changqing Jiao, Jian Ge
Endoplasmic reticulum stress is an imbalance in ER homeostasis characterized by the accumulation of unfolded or misfolded proteins and alterations in the Ca2+ concentration. To alleviate the damage caused by endoplasmic reticulum stress, cells relieve ER stress through biological processes such as the unfolded protein response (UPR), endoplasmic reticulum-associated protein degradation (ERAD), and autophagosome formation [3]. Inositol requiring enzyme 1 (IRE1), protein kinase R-like ER kinase (PERK) and activating transcription factor 6 (ATF6) mediate three classic UPR pathways and play an essential role in relieving ERS and maintaining the homeostasis of the cellular environment [4]. In the absence of endoplasmic reticulum stress, these three sensors are in an inactive state due to their binding to the molecular chaperone protein named glucose-regulated protein 78 (GRP78/BiP) [5]. When ER stress occurs, unfolded proteins or misfolded proteins competitively bind to GRP78/BiP proteins such that GRP78/BiP dissociates from IRE1, PRKR and ATF6, activating downstream signaling pathways [5]. Inhibition of the UPR-mediated pro-survival pathway and induction of the persistent ERS-mediated pro-death pathway are two approaches for ER stress-related antitumor therapy.
Bicyclol alleviates high-fat diet-induced hepatic ER stress- and autophagy-associated non-alcoholic fatty liver disease/non-alcoholic steatohepatitis in mice
Published in Drug Development and Industrial Pharmacy, 2022
Shu Jia, Lianyu Jin, Xiaoyan Cheng, Jingyi Wu, Xiaokun Yao, Jingping Shao, Congcong Zhang, Danwei Cen, Bin Cheng, Jing Wang, Lei Chen, Xiaomin Yao
Endoplasmic reticulum stress is caused by the accumulation of unfolded or misfolded proteins, or changes in the Ca2+ concentration of the internal environment due to various reasons such as nutrient deficiencies, toxin stimulation, and sustained oxidative stress stimulation, resulting in an imbalance in the ER structure and function [17]. The theory of ‘multiple blows’ proposed recently emphasizes the roles of ER stress in the development of NASH [18]. ER stress and its mediated apoptosis are involved in the development of numerous liver diseases [19,20]. In a previous study, sustained and irreversible ER stress activated a number of intracellular signaling pathways associated with the development of NASH pathology, leading to a series of pathological changes, such as liver cell steatosis, inflammatory response, and cell death [21]. In addition, ER stress is also a potent trigger of autophagy, a self-degradative process with an adaptive function [22]. Research has shown that autophagy is involved in the pathogenesis of NAFLD and NASH progression to liver fibrosis [23]. However, no studies on the effect of bicyclol on hepatic autophagy during NASH have been published. Therefore, in-depth investigations on the related mechanisms are required.
The beneficial effect of salubrinal on neuroinflammation and neuronal loss in intranigral LPS-induced hemi-Parkinson disease model in rats
Published in Immunopharmacology and Immunotoxicology, 2022
Fatma Nihan Cankara, Meliha Sümeyye Kuş, Caner Günaydın, Sinan Şafak, Süleyman Sırrı Bilge, Ozlem Ozmen, Emine Tural, Arjan Kortholt
Endoplasmic reticulum stress (ERS) results in impaired protein folding and accumulation of misfolded proteins. This process is detrimental for neuronal survival [9], most likely via neuroinflammation and microglial activation [10,11]. In toxin-induced PD-models several ER-related genes show increased expression, including human ubiquitin ligase HRD1, protein kinase RNA-like ER kinase (PERK), and activating transcription factor 6 (ATF6) [12]. Furthermore, in vivo toxin-based studies and postmortem analysis showed that phosphorylated eukaryotic initiation factor-2α (eIF2α), which is an accepted marker for the ERS, was significantly increased in the PD group compared with the control [13]. This suggest that ERS plays a role in the progression of PD. Increased ERS also has a vital role in protein synthesis, proteostasis, which is fundamental for neuroinflammation. Particularly, proinflammatory cytokines and factors that regulate inflammatory response and cellular survival in neuroinflammation are directly related to PD-related neuronal death.