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The Indispensable Soma Hypothesis in Aging
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
In addition to the above studies, it could be possible to evaluate biomarkers which indicate if the stress response has been activated. Following exposure to meaningful information, there is neural expression of factors such as the endoplasmic reticulum stress response factor IRE-1 [93] mentioned above, which may then interfere with normal germline function, as in Figure 4.1. Thus, evaluating this and similar biomarkers may prove an effective way of studying some basic premises of the Indispensable Soma Hypothesis. Other stress response factors in neurons are PERK (protein kinase RNA-like endoplasmic reticulum kinase [145], ATF6 (activating-transcription-factor-6) [146], c-Jun N-terminal kinase 1 (JNK) [147], and ATF4 [148]. These may initiate apoptosis depending on the level of sensed damage [149] and can thus be used as biomarkers of a cognitive stress response, which may then affect germline function.
Immunomodulatory Activities of Silver Nanoparticles (AgNPs) in Human Neutrophils
Published in Huiliang Cao, Silver Nanoparticles for Antibacterial Devices, 2017
Both intrinsic and extrinsic pathways of cell apoptosis are known to be activated during spontaneous human neutrophil apoptosis as evidenced by several parameters, including caspase-9 (intrinsic) and caspase-8 (extrinsic) activation (Bruno et al. 2005; Cross et al. 2008; Ge and Rikihisa 2006). More recently, we were the first to determine that the ER stress-induced cell apoptotic pathway is also operational in human PMNs (Binet et al. 2010). Indeed, PMNs were found to express inositol-requiring protein-1 (IRE1), activating transcription factor-6 (ATF6) and protein kinase RNA (PKR)–like ER kinase (PERK), the three major sensors of protein folding status in the ER (Ron and Walter 2007; Todd et al. 2008).
Mechanisms of Hepatitis C Virus Clearance by Interferon and Ribavirin Combination
Published in Satya Prakash Gupta, Cancer-Causing Viruses and Their Inhibitors, 2014
Srikanta Dash, Partha K. Chandra, Kurt Ramazan, Robert F. Garry, Luis A. Balart
In order to explain why an HCV persistently infected cell culture is resistant to IFN-α and RBV combination treatment, we have examined activation of ER stress and autophagy in HCV cell culture (Chandra et al. 2014). ATF6 luciferase activity shows that persistently infected HCV culture also induces a chronic ER stress response. It is known that cellular autophagy response is activated secondary to ER stress as a cell survival defense mechanism. Induction of an autophagy response in the persistently infected HCV culture was verified by a number of autophagy assays including the processing of LC3-I into LC3-II by Western blotting and the induction of the key autophagy gene, Beclin1, in the persistently infected culture. The expression of p62 was reduced significantly in the infected cells in a time-dependent manner, which indicated that HCV replication induced an autophagy response. We also investigated whether persistent HCV replication could induce autophagosomes, which then progress to autophagolysosomes through fusion with acidic lysosomes detectable by using acridine orange staining. Considerably higher numbers of membrane localized autophagic vacuoles were observed in the persistently infected cells as compared to uninfected cells. We further verified our hypothesis that the lack of cell surface expression of IFNAR1 is the cause of IFN-α resistance by analysis of HCV-positive and HCV-negative cell populations after flow sorting. These results showed that the IFN-α-resistant cells had a notably lower level of IFNAR1 than the IFN-α-sensitive cells.
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
The malignant growth and proliferation capacity of tumor cells create an unfavorable microenvironment characterized by hypermetabolic hypoxia nutrient restriction and acidosis, which in turn disrupts the homeostasis of calcium and lipids of the various cell types that inhabit this environment [20]. In these cases, the unfolded protein response (UPR) is then activated in an attempt to restore intracellular endoplasmic reticulum homeostasis and adapt to tumor development [20]. The PERK/ATF4/CHOP, IRE-1/XBP1 and ATF6 signaling pathways are three classic UPR pathways that play a pivotal role in relieving ER stress and maintaining cellular homeostasis [21]. Related studies have demonstrated that sustained activation of PERK and prolonged expression of ATF4 under constant stress could induce cell apoptosis by promoting the transcription of CHOP [6]. The IRE-1-XBP1 signaling pathway can suppress antitumor immune responses and provide opportunities for tumor formation [22]. ATF6 expression is high in cervical cancer cells, and inhibition of ATF6 expression can reduce cell viability and migration and promote cell apoptosis by inhibiting Bcl-2 and increasing caspase-3 [23]. These results suggest that ER stress has an essential role in cell survival and remodeling of the tumor microenvironment, and it is a potential novel target for AML therapy.
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).
Activating transcription factor 6 reduces Aβ1–42 and restores memory in Alzheimer’s disease model mice
Published in International Journal of Neuroscience, 2020
Yayun Du, Xiaoli Liu, Xilin Zhu, Ying Liu, Xinru Wang, Xiaopan Wu
The previous study reported that APP/PS1 transgenic mice developed beta-amyloid deposits in their brains by 6 to 7 months of age [13]. To ensure that the 12-month-old transgenic mice developed Aβ deposits in the brains, an ELISA analysis of Aβ1–42 level in APP/PS1 mice cortex was performed. The results showed that the Aβ1–42 level was two folds higher in the APP/PS1 mice than in the wild-type control mice (Figure 1(a)). The importance of ATF6 in maintaining tissue homeostasis is relevant to brain disorders. To assess whether the expression of ATF6 changed in APP/PS1 mice, we assessed ATF6 protein level in brain samples of APP/PS1 and wild-type mice aged 12 months. The results showed that the level of ATF6 was substantially reduced by 50% in APP/PS1 mice compared with that in the wild-type controls (Figure 1(b)). In addition, to explore whether ATF6 had an influence on Aβ deposits, LN229 cells were transfected with ATF6-expressing plasmids. qPCR analysis demonstrated that ATF6 was efficiently overexpressed (Figure 1(c)). We also detected the expression of GRP78 (another name for HSPA5), which is a downstream target gene of ATF6, and the results also suggested that the overexpression of ATF6 was successful (Figure 1(d)). Then, an ELISA for Aβ was performed to assess the level of Aβ1–42 in LN229 cell supernatants. We found that ATF6 overexpression reduced the level of the Aβ1–42 (Figure 1(e)). Next, we used shRNA to knockdown the ATF6 gene and verify the effect of ATF6 on Aβ level (Figure 1(f)–(h)). These results suggested ATF6 could reduce Aβ1–42 and suppress Aβ level in cells.