scholarly journals Role of Mitochondria-Associated Endoplasmic Reticulum Membrane in Inflammation-Mediated Metabolic Diseases

2016 ◽  
Vol 2016 ◽  
pp. 1-18 ◽  
Author(s):  
Themis Thoudam ◽  
Jae-Han Jeon ◽  
Chae-Myeong Ha ◽  
In-Kyu Lee
Keyword(s):  
Endoplasmic Reticulum ◽  
Signaling Pathways ◽  
Metabolic Diseases ◽  
Critical Role ◽  
Reactive Oxygen Species Generation ◽  
Inflammatory Factors ◽  
Endoplasmic Reticulum Membrane ◽  
Cellular Defense ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Inflammation is considered to be one of the most critical factors involved in the development of complex metabolic diseases such as type 2 diabetes, cancer, and cardiovascular disease. A few decades ago, the discovery of mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) was followed by the identification of its roles in regulating cellular homeostatic processes, ranging from cellular bioenergetics to apoptosis. MAM provides an excellent platform for numerous signaling pathways; among them, inflammatory signaling pathways associated with MAM play a critical role in cellular defense during pathogenic infections and metabolic disorders. However, induction of MAM causes deleterious effects by amplifying mitochondrial reactive oxygen species generation through increased calcium transfer from the ER to mitochondria, thereby causing mitochondrial damage and release of mitochondrial components into the cytosol as damage-associated molecular patterns (DAMPs). These mitochondrial DAMPs rapidly activate MAM-resident inflammasome components and other inflammatory factors, which promote inflammasome complex formation and release of proinflammatory cytokines in pathological conditions. Long-term stimulation of the inflammasome instigates chronic inflammation, leading to the pathogenesis of metabolic diseases. In this review, we summarize the current understanding of MAM and its association with inflammation-mediated metabolic diseases.

Migrating Progenitor Cells Derived From Injured Cartilage Surface Respond to Damage-Associated Molecular Patterns

Cartilage ◽  
2021 ◽  
pp. 194760352110495
Author(s):  
Lei Ding ◽  
Cheng Zhou ◽  
Hongjun Zheng ◽  
Quanming Wang ◽  
Haiyan Song ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Progenitor Cells ◽  
Quantitative Polymerase Chain Reaction ◽  
Critical Role ◽  
Cartilage Degeneration ◽  
Expression Levels ◽  
Chondrogenic Progenitor Cells ◽  
The Difference ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Objective: To delineate the response of migrating chondrogenic progenitor cells (CPCs) that arose from the surface of mechanically injured articular cartilage to proinflammatory damage-associated-molecular-patterns (DAMPs). Design: Bovine CPCs and non-CPC chondrocytes isolated from either impacted or scratched articular cartilage were studied. Those 2 types of cells were treated with mitochondrial DAMPs (MTDs; 10 nM fMLF and 10 µg/mL CpG DNA), or 10 nM HMGB1, or 10 ng/mL IL-1b for 24 hours. At the end of experiments, conditioned media and cell lysates were collected for analysis of expression levels of matrix metalloproteinases (MMPs), chemokines, and cytokines that are associated with cartilage degeneration with Western blotting and quantitative polymerase chain reaction. The difference of expression levels was compared by Welch’s t-test. Results: Our data indicated that HMGB1 and MTDs remarkably upregulated pro-MMP-13 expression in CPCs. Compared with non-CPCs, CPCs expressed significantly more baseline mRNAs of MMP-13, CXCL12, and IL-6. MTDs greatly increased the expression of MMP-13 and IL-6 in CPCs by over 100-fold ( P < 0.001). MTDs also significantly increased IL-8 expression in CPCs to a similar extent ( P < 0.001). However, when IL-1b was present, CPCs expressed less MMP-3 and active MMP-13 proteins as well as less CCL2 and IL-6 than did non-CPCs. Conclusions: We concluded that CPCs were more sensitive than non-CPCs in response to DAMPs, especially MTDs. The proinflammatory nature of CPCs implied their critical role in the early phase of posttraumatic osteoarthritis development.

scholarly journals SUN-559 Involvement of Sarco/Endoplasmic Reticulum Ca- ATPase (SERCA) in Membrane Progesterone Receptor Alpha (PAQR7)-Mediated Progesterone Induction of Vascular Smooth Muscle Relaxation

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Yefei Pang ◽  
Peter Thomas
Keyword(s):  
Endoplasmic Reticulum ◽  
Smooth Muscle ◽  
Progesterone Receptor ◽  
Protein Expression ◽  
Signaling Pathways ◽  
Muscle Relaxation ◽  
Critical Role ◽  
Akt Signaling ◽  
Membrane Progesterone Receptor ◽  
Membrane Progesterone Receptor Alpha

Abstract Progesterone (P4) exerts multiple beneficial effects on the human cardiovascular system through its actions on vascular endothelial cells and also by acting directly on vascular smooth muscle cells (VSMCs). Membrane progesterone receptor alpha (mPRα) has been shown to mediate the rapid P4-induction of human VSMC relaxation through activation of MAPK, Akt/Pi3k and RhoA/ROCK signaling pathways and the resulting reduction of calcium influx through calcium channels. In this study, we demonstrate that treatment of cultured human VSMCs with P4 for 1-2 hours increases both the mRNA and protein expression of sarco/endoplasmic reticulum Ca- ATPase (SERCA), the major transporter of calcium from the cytosol into the sarcoplasmic reticulum (SR) during muscle relaxation. Knockdown of mPRα with siRNA completely blocked this stimulatory effect of P4 as well as that of OD 02-0, a mPR selective agonist, on SERCA protein expression. In contrast, expression levels of phospholamban (PLB), a SR protein that reversibly inhibits SERCA were downregulated by this P4 treatment, and mRNA expression of a channel that releases calcium from the SR, inositol trisphosphate receptor (IP3R), was unaltered after treatment with P4. Moreover, treatments with P4 and OD 02-0, but not with R5020, a nuclear PR agonist, increased PLB phosphorylation, which would result in disinhibition of SERCA function. P4 and OD 02-0 significantly increased calcium levels in the SR detected with Fluo-5N, a specific SR calcium indicator, and caused VSMC relaxation. These effects were blocked by cyclopiazonic acid (CPA, a SERCA inhibitor), suggesting that SERCA plays a critical role in P4 induction of VSMC relaxation. Similarly, the effects of P4 and OD 02-0 on relaxation of umbilical artery rings measured with a myograph were significantly attenuated by CPA, which confirms the critical role of SERCA in the rapid action of P4 and 02-0 on vascular muscle relaxation. P4 has previously been shown to activate MAPK and Akt signaling pathways to induce VSMC relaxation. The P4- and OD 02-0-induced increases in calcium in the SR were blocked by MAPK and Akt/Pi3k signaling inhibitors, AZD6244 and wortmannin. Taken together, these results suggest that the direct, rapid effects of P4 on relaxation of VSMCs through mPRα involves regulation of the expression and function of the SR proteins SERCA and PLB through MAPK and Akt signaling pathways.

scholarly journals The Roles of Endoplasmic Reticulum in NLRP3 Inflammasome Activation

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1219 ◽  
Author(s):  
Yang Zhou ◽  
Zhizi Tong ◽  
Songhong Jiang ◽  
Wenyan Zheng ◽  
Jianjun Zhao ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Nlrp3 Inflammasome ◽  
Critical Role ◽  
Immune Defense ◽  
Inflammasome Activation ◽  
Nucleotide Binding Domain ◽  
Cholesterol Trafficking ◽  
Pyrin Domain ◽  
Nlrp3 Inflammasome Activation ◽  
Molecular Patterns

The NLRP3 (nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3) inflammasome senses pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), and activates caspase-1, which provokes release of proinflammatory cytokines such as interleukin-1β (IL-1β) and IL-18 as well as pyroptosis to engage in innate immune defense. The endoplasmic reticulum (ER) is a large and dynamic endomembrane compartment, critical to cellular function of organelle networks. Recent studies have unveiled the pivotal roles of the ER in NLRP3 inflammasome activation. ER–mitochondria contact sites provide a location for NLRP3 activation, its association with ligands released from or residing in mitochondria, and rapid Ca2+ mobilization from ER stores to mitochondria. ER-stress signaling plays a critical role in NLRP3 inflammasome activation. Lipid perturbation and cholesterol trafficking to the ER activate the NLRP3 inflammasome. These findings emphasize the importance of the ER in initiation and regulation of the NLRP3 inflammasome.

scholarly journals The Chondroprotective Role of TMF in PGE2-Induced Apoptosis Associating with Endoplasmic Reticulum Stress

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Jianqiong Yang ◽  
Haiqing Liu ◽  
Linfu Li ◽  
Hai Liu ◽  
Weimei Shi ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Signaling Pathways ◽  
Inflammatory Cytokine ◽  
Critical Role ◽  
Osteoarthritic Chondrocytes ◽  
Induced Apoptosis

Endoplasmic reticulum stress (ERS) has been demonstrated to exhibit a critical role in osteoarthritic chondrocytes. Whether 5,7,3′,4′-tetramethoxyflavone (TMF) plays the chondroprotective role in inhibition of PGE2-induced chondrocytes apoptosis associating with ERS has not been reported. To investigate this, the activation of PERK, ATF6, and IRE1 signaling pathways in ERS in chondrocytes pretreated with PGE2was studied. By treatment with PGE2, the chondrocytes apoptosis was significantly increased, the proapoptotic CHOP and JNK were upregulated, the prosurvival GRP78 and XBP1 were downregulated, and GSK-3βwas also upregulated. However, TMF exhibited the effectively protective functions via counteracting these detrimental effects of PGE2. Finally, the inflammatory cytokine PGE2can activate ERS signaling and promote chondrocytes apoptosis, which might be associated with upregulation of GSK-3β. TMF exhibits a chondroprotective role in inhibiting PGE2-induced ERS and GSK-3β.

Progenitor Cells Derived From Injured Cartilage Surface Respond to Damage Associated Molecular Patterns

2020 ◽  
Author(s):  
Lei Ding ◽  
Cheng Zhou ◽  
Hongjun Zheng ◽  
Quanming Wang ◽  
Haiyan Song ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Critical Role ◽  
Cartilage Degeneration ◽  
Mrna Levels ◽  
Cartilage Surface ◽  
Cpg Dna ◽  
Expression Levels ◽  
Chondrogenic Progenitor Cells ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Abstract Objective: To elucidate how chondrogenic progenitor cells (CPCs) originated from mechanically injured cartilage surface respond to proinflammatory endogenous damage-associated-molecular-patterns (DAMPs). Design: Passage 1 bovine CPCs and non-CPCs isolated from injured articular cartilage either by blunt impaction or by scratches were treated with mitochondrial DAMPs (MTDs) composed of fMLF and CpG DNA, or HMGB1 (a nuclear DAMP), or IL-1b for 24 hrs. At the end of the experiments, the expression levels of matrix metalloproteinases (MMPs), chemokines, and cytokines that are associated with cartilage degeneration was examined with Western blotting and quantitative PCR. Results: Both HMGB1 and MTDs remarkably up-regulated expression level of pro-MMP-13 protein in CPCs while showed weak effect on non-CPCs. Compared to non-CPCs, CPCs expressed significantly higher baseline mRNA levels of MMP-13, CXCL12, and IL-6. MTDs further increased the expression levels of MMP-13 and IL-6 in CPCs while HMGB1 did not show such effect. When treated with MTDs, CPCs also expressed significantly higher levels of IL-8 mRNA than did non-CPCs. However, compared to non-CPCs, CPCs expressed much lower levels of MMP-3 and active MMP-13 proteins as well as lower mRNA levels of CCL2 and IL-6 in response to IL-1b. Conclusions: CPCs were more sensitive than non-CPCs in response to DAMPs, especially MTDs, to up-regulate expression of MMP-13, IL-6 and -8. When IL-1b was present, CPCs were less responsive than non-CPCs in terms of up-regulating MMP-3, CCL2, and IL-6 expression. The proinflammatory nature of CPCs implied their critical role in the early phase of PTOA development.

scholarly journals Roles of PRR-Mediated Signaling Pathways in the Regulation of Oxidative Stress and Inflammatory Diseases

2021 ◽  
Vol 22 (14) ◽  
pp. 7688
Author(s):  
Pengwei Li ◽  
Mingxian Chang
Keyword(s):  
Oxidative Stress ◽  
Signaling Pathways ◽  
Inflammatory Diseases ◽  
Therapeutic Strategies ◽  
Signaling Cascades ◽  
Oxygen Species ◽  
Inflammatory Signaling ◽  
Future Studies ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Oxidative stress is a major contributor to the pathogenesis of various inflammatory diseases. Accumulating evidence has shown that oxidative stress is characterized by the overproduction of reactive oxygen species (ROS). Previous reviews have highlighted inflammatory signaling pathways, biomarkers, molecular targets, and pathogenetic functions mediated by oxidative stress in various diseases. The inflammatory signaling cascades are initiated through the recognition of host cell-derived damage associated molecular patterns (DAMPs) and microorganism-derived pathogen associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs). In this review, the effects of PRRs from the Toll-like (TLRs), the retinoic acid-induced gene I (RIG-I)-like receptors (RLRs) and the NOD-like (NLRs) families, and the activation of these signaling pathways in regulating the production of ROS and/or oxidative stress are summarized. Furthermore, important directions for future studies, especially for pathogen-induced signaling pathways through oxidative stress are also reviewed. The present review will highlight potential therapeutic strategies relevant to inflammatory diseases based on the correlations between ROS regulation and PRRs-mediated signaling pathways.

scholarly journals Roles and Therapeutic Implications of Endoplasmic Reticulum Stress and Oxidative Stress in Cardiovascular Diseases

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1167
Author(s):  
Yan Zhou ◽  
Dharmani Devi Murugan ◽  
Haroon Khan ◽  
Yu Huang ◽  
Wai San Cheang
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Cardiovascular Diseases ◽  
Er Stress ◽  
Metabolic Diseases ◽  
Critical Role ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Therapeutic Implications ◽  
And Oxidative Stress

In different pathological states that cause endoplasmic reticulum (ER) calcium depletion, altered glycosylation, nutrient deprivation, oxidative stress, DNA damage or energy perturbation/fluctuations, the protein folding process is disrupted and the ER becomes stressed. Studies in the past decade have demonstrated that ER stress is closely associated with pathogenesis of obesity, insulin resistance and type 2 diabetes. Excess nutrients and inflammatory cytokines associated with metabolic diseases can trigger or worsen ER stress. ER stress plays a critical role in the induction of endothelial dysfunction and atherosclerosis. Signaling pathways including AMP-activated protein kinase and peroxisome proliferator-activated receptor have been identified to regulate ER stress, whilst ER stress contributes to the imbalanced production between nitric oxide (NO) and reactive oxygen species (ROS) causing oxidative stress. Several drugs or herbs have been proved to protect against cardiovascular diseases (CVD) through inhibition of ER stress and oxidative stress. The present article reviews the involvement of ER stress and oxidative stress in cardiovascular dysfunction and the potential therapeutic implications.

scholarly journals MCD4Encodes a Conserved Endoplasmic Reticulum Membrane Protein Essential for Glycosylphosphatidylinositol Anchor Synthesis in Yeast

1999 ◽  
Vol 10 (3) ◽  
pp. 627-648 ◽  
Author(s):  
Erin C. Gaynor ◽  
Guillaume Mondésert ◽  
Stephen J. Grimme ◽  
Steve I. Reed ◽  
Peter Orlean ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Wall ◽  
Essential Gene ◽  
Critical Role ◽  
Single Amino Acid ◽  
Endoplasmic Reticulum Membrane ◽  
Gpi Anchor ◽  
Bud Emergence ◽  
Single Amino Acid Change ◽  
Lumenal Domain

Glycosylphosphatidylinositol (GPI)-anchored proteins are cell surface-localized proteins that serve many important cellular functions. The pathway mediating synthesis and attachment of the GPI anchor to these proteins in eukaryotic cells is complex, highly conserved, and plays a critical role in the proper targeting, transport, and function of all GPI-anchored protein family members. In this article, we demonstrate that MCD4, an essential gene that was initially identified in a genetic screen to isolate Saccharomyces cerevisiae mutants defective for bud emergence, encodes a previously unidentified component of the GPI anchor synthesis pathway. Mcd4p is a multimembrane-spanning protein that localizes to the endoplasmic reticulum (ER) and contains a large NH2-terminal ER lumenal domain. We have also cloned the human MCD4 gene and found that Mcd4p is both highly conserved throughout eukaryotes and has two yeast homologues. Mcd4p’s lumenal domain contains three conserved motifs found in mammalian phosphodiesterases and nucleotide pyrophosphases; notably, the temperature-conditional MCD4 allele used for our studies (mcd4–174) harbors a single amino acid change in motif 2. The mcd4–174 mutant (1) is defective in ER-to-Golgi transport of GPI-anchored proteins (i.e., Gas1p) while other proteins (i.e., CPY) are unaffected; (2) secretes and releases (potentially up-regulated cell wall) proteins into the medium, suggesting a defect in cell wall integrity; and (3) exhibits marked morphological defects, most notably the accumulation of distorted, ER- and vesicle-like membranes. mcd4–174 cells synthesize all classes of inositolphosphoceramides, indicating that the GPI protein transport block is not due to deficient ceramide synthesis. However,mcd4–174 cells have a severe defect in incorporation of [3H]inositol into proteins and accumulate several previously uncharacterized [3H]inositol-labeled lipids whose properties are consistent with their being GPI precursors. Together, these studies demonstrate that MCD4 encodes a new, conserved component of the GPI anchor synthesis pathway and highlight the intimate connections between GPI anchoring, bud emergence, cell wall function, and feedback mechanisms likely to be involved in regulating each of these essential processes. A putative role for Mcd4p as participating in the modification of GPI anchors with side chain phosphoethanolamine is also discussed.

scholarly journals Chromomycin A5 induces bonafide immunogenic cell death in metastatic melanoma

2021 ◽  
Author(s):  
Katharine G. D. Florêncio ◽  
Evelline A. Edson ◽  
Francisco C. L. Pinto ◽  
Otília D. L. Pessoa ◽  
João Agostinho Machado-Neto ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Metastatic Melanoma ◽  
Melanoma Cell Line ◽  
Atp Release ◽  
Immunogenic Cell Death ◽  
First Line ◽  
Metastatic Melanoma Cell ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

AbstractSome first-line cytotoxic chemotherapics, e.g. doxorubicin, paclitaxel and oxaliplatin, induce activation of the immune system through immunogenic cell death (ICD). Tumor cells undergoing ICD function as a vaccine, releasing damage-associated molecular patterns (DAMPs), which act as adjuvants, and neoantigens of the tumor are recognized as antigens. ICD induction is rare, however it yields better and long-lasting antitumor responses to chemotherapy. Advanced metastatic melanoma (AMM) is incurable for more than half of patients. The discovery of ICD inducers against AMM is an interesting drug discovery strategy with high translational potential. Here we evaluated ICD induction of four highly cytotoxic chromomycins A (CA5-8). B16-F10, a metastatic melanoma cell line, treated with CA5-8 and doxorubicin exhibited ICD features such as autophagy and apoptosis, externalization of calreticulin, and releasing of HMGB1. However, CA5-treated cells had the best profile, also inducing ATP release, ERp57 externalization, phosphorylation of eIF2α and altering expression of transcription of genes related to autophagy, endoplasmic reticulum stress, and apoptosis. Bonafide ICD induction by CA5 was confirmed by a C57BL/6 mice vaccination assay with CA5-treated cells. These findings support a high potential of CA5 as an anticancer candidate against AMM.

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