Exploring the cross talk between ER stress and inflammation in age-related macular degeneration

Kheitan, Samira; Minuchehr, Zarrin; Soheili, Zahra‐Soheila

doi:10.1371/journal.pone.0181667

Cited by 20 publications

(12 citation statements)

References 79 publications

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“…In acute injuries, inflammation restores tissue homeostasis but prolonged inflammatory conditions stimulate the immunosuppressive network in an attempt to prevent excessive inflammatory damage in tissues (see below). There is clear evidence that ER stress can elicit inflammatory responses in many age-related diseases, e.g., atherosclerosis [72], hepatic steatosis [73], and age-related macular degeneration [74]. It seems that the activation of inflammasomes is involved in the crosstalk between ER stress and inflammatory responses in some diseases [72,73].…”

Section: Er Stress Is a Potent Inducer Of Inflammationmentioning

confidence: 99%

ER stress activates immunosuppressive network: implications for aging and Alzheimer’s disease

2020

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The endoplasmic reticulum (ER) contains stress sensors which recognize the accumulation of unfolded proteins within the lumen of ER, and subsequently these transducers stimulate the unfolded protein response (UPR). The ER sensors include the IRE1, PERK, and ATF6 transducers which activate the UPR in an attempt to restore the quality of protein folding and thus maintain cellular homeostasis. If there is excessive stress, UPR signaling generates alarmins, e.g., chemokines and cytokines, which activate not only tissue-resident immune cells but also recruit myeloid and lymphoid cells into the affected tissues. ER stress is a crucial inducer of inflammation in many pathological conditions. A chronic low-grade inflammation and cellular senescence have been associated with the aging process and many age-related diseases, such as Alzheimer's disease. Currently, it is known that immune cells can exhibit great plasticity, i.e., they are able to display both pro-inflammatory and anti-inflammatory phenotypes in a context-dependent manner. The microenvironment encountered in chronic inflammatory conditions triggers a compensatory immunosuppression which defends tissues from excessive inflammation. Recent studies have revealed that chronic ER stress augments the suppressive phenotypes of immune cells, e.g., in tumors and other inflammatory disorders. The activation of immunosuppressive network, including myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg), has been involved in the aging process and Alzheimer's disease. We will examine in detail whether the ER stress-related changes found in aging tissues and Alzheimer's disease are associated with the activation of immunosuppressive network, as has been observed in tumors and many chronic inflammatory diseases.

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Section: Er Stress Is a Potent Inducer Of Inflammationmentioning

confidence: 99%

ER stress activates immunosuppressive network: implications for aging and Alzheimer’s disease

2020

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“…In the process of protein folding, resident protein disulfide isomerases (PDI), endoplasmic reticulum oxidoreduction 1 (ERO1) and glutathione (GSH) cooperate as a chaperone-like assisted mechanism to prevent and correct aberrant disulfide bonds [ 15 ]. Previous studies have shown that excessive intracellular ROS may lead to depletion of the GSH pool and compromise the function of PDI, which disrupts the folding process of proteins in the ER and produces a massive amount of misfolded proteins [ 16 , 17 ]. However, the excessive accumulation of misfolded proteins in the ER may trigger an unfolded-protein response (UPR), which may enhance protein folding ability, as well as the homeostasis of protein translation and accelerate protein degradation to recover ER function [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Suppressing endoplasmic reticulum stress-related autophagy attenuates retinal light injury

Song

Fan

Che

et al. 2020

Aging

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Excessive light exposure is a principal environmental factor, which can cause damage to photoreceptors and retinal pigment epithelium (RPE) cells and may accelerate the progression of age-related macular degeneration (AMD). In this study, oxidative stress, endoplasmic reticulum (ER) stress and autophagy caused by light exposure were evaluated in vitro and in vivo . Light exposure caused severe photo-oxidative stress and ER stress in photoreceptors (661W cells) and RPE cells (ARPE-19 cells). Suppressing either oxidative stress or ER stress was protective against light damage in 661W and ARPE-19 cells and N-acetyl-L-cysteine treatment markedly inhibited the activation of ER stress caused by light exposure. Moreover, suppressing autophagy with 3-methyladenine significantly attenuated light-induced cell death. Additionally, inhibiting ER stress either by knocking down PERK signals or with GSK2606414 treatment remarkably suppressed prolonged autophagy and protected the cells against light injury. In vivo experiments verified neuroprotection via inhibiting ER stress-related autophagy in light-damaged retinas of mice. In conclusion, the above results suggest that light-induced photo-oxidative stress may trigger subsequent activation of ER stress and prolonged autophagy in photoreceptors and RPE cells. Suppressing ER stress may abrogate over-activated autophagy and protect the retina against light injury.

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“…Hard-to-cure human diseases such as diabetes, cancer or neurodegenerative disorders are often multifactorial in nature implying that a diverse range of underlying mechanisms behind disease genesis and progression need to be taken into consideration for improved management. An important manifestation of the biological networks is shown by gene regulatory networks that provide functional explanations for many biological phenomena and pathological conditions by identifying key molecules, their relevant pathways, and their causative relationships [28]. BC heterogeneity that drives tumorigenesis, metastasis, recurrence, and drug resistance necessitates drugs combinatory and multi-target strategies to be halted.…”

Section: Discussionmentioning

confidence: 99%

Investigating the Inhibitory Aspects of Metformin/Curcumin Co-Treatment through Convergence of In-Silico and In-Vitro Approaches

Afzali

Nayeri

Minuchehr

et al. 2019

Preprint

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Nearly 16% of people with breast cancer (BC) have Diabetes Mellitus type 2 (DM2) and are at a higher risk of death worldwide. Their common regulatory factors and functional mechanisms can be targeted applying multi-target drugs including Metformin (MTFN) and Curcumin (CURC). In this study, we used in-silico approaches to study the potential underlying mechanisms of this co-treatment strategy on BC and DM2 in order to introduce novel therapeutic targets.The total number of 48 shared differentially expressed genes (17 up-regulated and 31 down-regulated) were identified through establishing diseases' protein-protein network and BC RNA-sequencing expression data. The integration of functional clustering and pathway analyses revealed that the most involved cellular pathways and processes are regard to cells' proliferation, death, migration, and response to external stimulus. Afterwards, the MTFN/CURC correlation and co-treatment optimization was probed through response surface methodology (RSM) based on MCF7 cell line and confirmed by MDA-MB-231. Combination index calculation by MTT viability assay proved supportive effects on both cell lines. The superior apoptotic potential of co-treatment compared to single treatments was shown on inhibition of MCF7 proliferation and induction of cell death demonstrated by cell body co-staining and flow cytometry as well as gene expression analysis via RT-PCR. Furthermore, wound-healing scratch assay showed that this co-treatment has a slightly higher effect on migration inhibition compared to single treatments.In conclusion, our study used in-silico and in-vitro approaches and introduced a potential regulatory panel between BC and DM2. We also provided a linear model and equation that show the positive relation of drugs' co-treatment. The proposed co-treatment strategy successfully controlled the biological processes under investigation. METHODS Identification and validation of overlapped DEGs between BC and DM2The STRING disease network importer of Cytoscape 3.6 was used to establish the PPI networks of BC and DM2 with ultimate number of proteins (2000 nodes) and 0.7 as the minimum interaction score. The networks were merged together to find the overlapped factors and subsequently, filtered by BC differentially expressed genes (DEGs) of The Cancer Genome Atlas (TCGA) database. TCGA database contains the RNA-sequencing (RNA-seq) expression data of 33 different types of human cancers. In this study, BC RNA-seq raw data of 224 samples (112 cancerous tissues and 112 adjacent normal ones) was downloaded and normalized using TCGAbiolinks package of R v3.5.2 software. To identify the (DEGs) the criteria of FDR < 0.05 and |logFC| > 1 were applied. Functional Annotation Clustering and Pathway AnalysisTo understand the biological meaning behind the obtained DEGs in groups, Functional Annotation Clustering tool of David 6.7 database, based on Kappa statistics and fuzzy heuristic clustering algorithms, was used to make the ontology report easier to follow [23]. Each cluster contains Gene Ont...

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Exploring the cross talk between ER stress and inflammation in age-related macular degeneration

Cited by 20 publications

References 79 publications

ER stress activates immunosuppressive network: implications for aging and Alzheimer’s disease

ER stress activates immunosuppressive network: implications for aging and Alzheimer’s disease

Suppressing endoplasmic reticulum stress-related autophagy attenuates retinal light injury

Investigating the Inhibitory Aspects of Metformin/Curcumin Co-Treatment through Convergence of In-Silico and In-Vitro Approaches

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