scholarly journals The Role of Unfolded Protein Response in Human Intervertebral Disc Degeneration: Perk and IRE1-α as Two Potential Therapeutic Targets

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Tianyong Wen ◽  
Peng Xue ◽  
Jinwei Ying ◽  
Shi Cheng ◽  
Yue Liu ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Underlying Mechanism ◽  
Nucleus Pulposus Cells ◽  
Unfolded Protein ◽  
Underlying Mechanisms ◽  
Protein Response

Inflammation plays a key role in intervertebral disc degeneration (IDD). The association between inflammation and endoplasmic reticulum (ER) stress has been observed in many diseases. However, whether ER stress plays an important role in IDD remains unclear. Therefore, this study is aimed at investigating the expression of ER stress in IDD and at exploring the underlying mechanisms of IDD, ER stress, and inflammation. The expression of ER stress was activated in nucleus pulposus cells from patients who had IDD (D-NPCs) compared with patients without IDD (N-NPCs); and both the proliferation and synthesis capacity were decreased by inducer tunicamycin (Tm) and proinflammatory cytokines. Pretreatment of NPCs with 4-phenyl butyric acid (4-PBA) prevented the inflammatory cytokine-induced upregulation of unfolded protein response- (UPR-) related proteins and recovered cell synthetic ability. Furthermore, proinflammatory cytokine treatment significantly upregulated the expression of inositol-requiring protein 1 (IRE1-α) and protein kinase RNA-like ER kinase (PERK), but not activating transcription factor 6 (ATF6). Finally, knockdown of IRE1-α and PERK also restored the biological activity of NPCs. Our findings identified that IRE1-α and PERK might be the potential targets for IDD treatment, which may help illustrate the underlying mechanism of ER stress in IDD.

scholarly journals Nrf2 mediated ER-phagy protects against oxidative damage in intervertebral disc degeneration

2021 ◽  
Author(s):  
zhen lin ◽  
libin ni ◽  
cheng teng ◽  
zhao zhang ◽  
xinlei lu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Intervertebral Disc ◽  
Oxidative Damage ◽  
Er Stress ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Cellular Damage ◽  
Nucleus Pulposus Cells

Intervertebral disc degeneration (IDD) increases the risk of low back pain (LBP). Oxidative stress may induce cellular damage and contribute to various diseases including IDD. Endoplasmic reticulum autophagy (ER-phagy) is a specific type of autophagy, its role in oxidative stress induced damage as well as in IDD is unknown. This study explores the role of ER-phagy in oxidative damage in intervertebral disc nucleus pulposus cells (NPCs), as well as the Nrf2/FAM134B axis in ER-phagy regulation and IDD therapy. We found ER-phagy was decreased in NPCs during oxidative stress; while FAM134B may promote ER-phagy and alleviate oxidative stress induced ER-stress and apoptosis. In addition, the nuclear transcription factor Nrf2 may promote the expression of FAM134B as well as ER-phagy, and suppress ER-stress and apoptosis in NPCs. Furthermore, overexpression of FAM134B and Nrf2 could effectively attenuate the progression of IDD in rats in vivo. These results suggest Nrf2/FAM134B mediated ER-phagy may combat oxidative damage in cells; meanwhile, ER-phagy as well as Nrf2 could be potential therapeutic targets for IDD.

scholarly journals Silencing NDC80, RAD21 and BUB1B ameliorates intervertebral disc degeneration by promoting proliferation and inhibiting apoptosis of nucleus pulposus cells

2020 ◽  
Author(s):  
Bin Zhang ◽  
Yueyan Guan ◽  
Weixiao Liu ◽  
Wei Guo ◽  
Peng Peng ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Nucleus Pulposus ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Expression Profiles ◽  
Nucleus Pulposus Cells ◽  
Pathogenic Genes ◽  
Genes Expression ◽  
Underlying Mechanisms ◽  
Microarray Datasets

Abstract Background Intervertebral disc degeneration (IVDD) is a commonly occurring musculoskeletal disorder, which is closely associated with low back pain. Accumulating evidence has demonstrated that dysregulated genes expression profiles play important roles in pathogenesis of IVDD. Hence, the current study was aimed to identify key genes to understand underlying mechanisms and therapeutic targets of IVDD. Methods Microarray datasets of GSE34095, GSE63492 and GSE45856 were downloaded to identify the hub genes that participate in the IVDD pathogenesis. After establishment of rat IVDD models, the expressions of NDC80, BUB1B and RAD21 in rat IVDD samples were evaluated by reverse transcription quantitative PCR (RT-qPCR) and immunochemistry. Subsequently, we assessed the proliferation, cycle and apoptosis of nucleus pulposus (NP) cells that transfected with siRNA-NDC80, siRNA-BUB1B and siRNA-RAD21. Results Our results showed indicated that NDC80, BUB1B and RAD21 were the key pathogenic genes with higher expression in IVDD rats, and silencing of NDC80, BUB1B and RAD21 gene could promote the aggrecan and collagen II synthesis, cell cycle and proliferation of NP cells, and inhibit NP cells apoptosis. Conclusion Our study suggests that silencing NDC80, RAD21 and BUB1B genes ameliorates intervertebral disc degeneration by promoting proliferation and inhibiting apoptosis of nucleus pulposus cells.

scholarly journals Analysis of key genes and pathways associated with the pathogenesis of intervertebral disc degeneration

2020 ◽  
Author(s):  
Shiyu Hu ◽  
Yucheng Fu ◽  
Bin Yan ◽  
Zhe Shen ◽  
Tao Lan
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Target Genes ◽  
Underlying Mechanism ◽  
Hub Genes ◽  
Protein Protein Interaction ◽  
Matrix Organization ◽  
Underlying Mechanisms ◽  
Upregulated Genes

Abstract Background: Intervertebral disc degeneration (IDD) is widely known as a main contributor to low back pain which has a negative socioeconomic impact worldwide. However, the underlying mechanism remains unclear. This study aims to analyze the dataset GSE23130 using bioinformatics methods to identify the pivotal genes and pathways associated with IDD.Material/Methods: The gene expression data of GSE23130 was downloaded and differentially expressed genes (DEGs) were extracted from 8 samples and 15 controls. GO and KEGG pathway enrichment analyses were performed. Also, Protein–protein interaction (PPI) network was constructed and visualized, followed by identification of hub genes and key module.Results: A total of 30 downregulated and 79 upregulated genes were identified. The DEGs mainly enriched in regulation of protein catabolic process, extracellular matrix organization, collagen fibril organization, and extracellular structure organization. Meanwhile, we found that most of DEGs were primarily enriched in PI3K-Akt signaling pathway. The top 10 hub genes were FN1, COL1A2, SPARC, COL3A1, CTGF, LUM, TIMP1, THBS2, COL5A2, and TGFB1.Conclusions: In summary, key candidate genes and pathway were identified by using integrated bioinformatics analysis, which may provide insights into underlying mechanisms and offer potential target genes for the treatment of IDD.

scholarly journals Analysis of key genes and pathways associated with pathogenesis of intervertebral disc degeneration

2020 ◽  
Author(s):  
Shiyu Hu ◽  
Yucheng Fu ◽  
Bin Yan ◽  
Zhe Shen ◽  
Tao Lan
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Target Genes ◽  
Underlying Mechanism ◽  
Hub Genes ◽  
Protein Protein Interaction ◽  
Matrix Organization ◽  
Underlying Mechanisms ◽  
Upregulated Genes

Abstract Background: Intervertebral disc degeneration (IDD) is widely known as a main contributor to low back pain which has a negative socioeconomic impact worldwide. However, the underlying mechanism remains unclear. The aim of this study is to analyze the dataset GSE23130 using bioinformatics methods to identify the pivotal genes and pathways associated with IDD. Material/Methods: The gene expression data of GSE23130 was downloaded and differentially expressed genes (DEGs) were extracted from 8 samples and 15 controls. GO and KEGG pathway enrichment analyses were performed. In addition, Protein–protein interaction (PPI) network was constructed and visualized, followed by identification of hub genes and key module. Results: A total of 30 downregulated and 79 upregulated genes were identified. The DEGs mainly enriched in regulation of protein catabolic process, extracellular matrix organization, collagen fibril organization, and extracellular structure organization. Meanwhile, we found that most of DEGs were primarily enriched in PI3K-Akt signaling pathway. The top 10 hub genes were FN1, COL1A2, SPARC, COL3A1, CTGF, LUM, TIMP1, THBS2, COL5A2, and TGFB1. Conclusions: In summary, key candidate genes and pathway were identified by using integrated bioinformatics analysis, which may provide insights into underlying mechanisms and offer potential target genes for the treatment of IDD.

scholarly journals Effectors Targeting the Unfolded Protein Response during Intracellular Bacterial Infection

2021 ◽  
Vol 9 (4) ◽  
pp. 705
Author(s):  
Manal H. Alshareef ◽  
Elizabeth L. Hartland ◽  
Kathleen McCaffrey
Keyword(s):  
Bacterial Infection ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Host Defense ◽  
Effector Proteins ◽  
Dual Nature ◽  
Unfolded Protein ◽  
Bacterial Replication ◽  
The Unfolded Protein Response ◽  
Protein Response

The unfolded protein response (UPR) is a homeostatic response to endoplasmic reticulum (ER) stress within eukaryotic cells. The UPR initiates transcriptional and post-transcriptional programs to resolve ER stress; or, if ER stress is severe or prolonged, initiates apoptosis. ER stress is a common feature of bacterial infection although the role of the UPR in host defense is only beginning to be understood. While the UPR is important for host defense against pore-forming toxins produced by some bacteria, other bacterial effector proteins hijack the UPR through the activity of translocated effector proteins that facilitate intracellular survival and proliferation. UPR-mediated apoptosis can limit bacterial replication but also often contributes to tissue damage and disease. Here, we discuss the dual nature of the UPR during infection and the implications of UPR activation or inhibition for inflammation and immunity as illustrated by different bacterial pathogens.

scholarly journals Unfolded protein response triggers differential apoptotic mechanisms in ovaries and early embryos exposed to maternal type 1 diabetes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Aslı Okan ◽  
Necdet Demir ◽  
Berna Sozen
Keyword(s):  
Embryonic Development ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Molecular Mechanisms ◽  
Early Embryonic Development ◽  
Unfolded Protein ◽  
Caspase 12 ◽  
Early Embryos ◽  
Protein Response

AbstractDiabetes mellitus (DM) has profound effects on the female mammalian reproductive system, and early embryonic development, reducing female reproductive outcomes and inducing developmental programming in utero. However, the underlying cellular and molecular mechanisms remain poorly defined. Accumulating evidence implicates endoplasmic reticulum (ER)-stress with maternal DM associated pathophysiology. Yet the direct pathologies and causal events leading to ovarian dysfunction and altered early embryonic development have not been determined. Here, using an in vivo mouse model of Type 1 DM and in vitro hyperglycaemia-exposure, we demonstrate the activation of ER-stress within adult ovarian tissue and pre-implantation embryos. In diabetic ovaries, we show that the unfolded protein response (UPR) triggers an apoptotic cascade by the co-activation of Caspase 12 and Cleaved Caspase 3 transducers. Whereas DM-exposed early embryos display differential ER-associated responses; by activating Chop in within embryonic precursors and Caspase 12 within placental precursors. Our results offer new insights for understanding the pathological effects of DM on mammalian ovarian function and early embryo development, providing new evidence of its mechanistic link with ER-stress in mice.

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