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International Journal of Molecular... Mar 2021The revolutionary evolution in science and technology over the last few decades has made it possible to face more adequately three main challenges of modern medicine:... (Review)
Review
The revolutionary evolution in science and technology over the last few decades has made it possible to face more adequately three main challenges of modern medicine: changes in old diseases, the appearance of new diseases, and diseases that are unknown (mostly genetic), despite research efforts. In this paper we review the road travelled by pathologists in search of a method based upon the use of routine instruments and techniques which once were available for research only. The application to tissue studies of techniques from immunology, molecular biology, and genetics has allowed dynamic interpretations of biological phenomena with special regard to gene regulation and expression. That implies stepwise investigations, including light microscopy, immunohistochemistry, in situ hybridization, electron microscopy, molecular histopathology, protein crystallography, and gene sequencing, in order to progress from suggestive features detectable in routinely stained preparations to more characteristic, specific, and finally, pathognomonic features. Hematoxylin and Eosin (H&E)-stained preparations and appropriate immunohistochemical stains have enabled the recognition of phenotypic changes which may reflect genotypic alterations. That has been the case with hepatocytic inclusions detected in H&E-stained preparations, which appeared to correspond to secretory proteins that, due to genetic mutations, were retained within the rough endoplasmic reticulum (RER) and were deficient in plasma. The identification of this phenomenon affecting the molecules alpha-1-antitrypsin and fibrinogen has led to the discovery of a new field of cell organelle pathology, endoplasmic reticulum storage disease(s) (ERSD). Over fifty years, pathologists have wandered through a dark forest of complicated molecules with strange conformations, and by detailed observations in simple histopathological sections, accompanied by a growing background of molecular techniques and revelations, have been able to recognize and identify arrays of grotesque polypeptide arrangements.
Topics: Endoplasmic Reticulum; Gene Expression Regulation; Genotype; Humans; Immunohistochemistry; Metabolic Diseases; Mutation; alpha 1-Antitrypsin
PubMed: 33809321
DOI: 10.3390/ijms22062899 -
Journal of Microscopy Nov 2020The endoplasmic reticulum is a fascinating organelle at the core of the secretory pathway. It is responsible for the synthesis of one third of the cellular proteome and,... (Review)
Review
The endoplasmic reticulum is a fascinating organelle at the core of the secretory pathway. It is responsible for the synthesis of one third of the cellular proteome and, in plant cells, it produces receptors and transporters of hormones as well as the proteins responsible for the biosynthesis of critical components of a cellulosic cell wall. The endoplasmic reticulum structure resembles a spider-web network of interconnected tubules and cisternae that pervades the cell. The study of the dynamics and interaction of this organelles with other cellular structures such as the plasma membrane, the Golgi apparatus and the cytoskeleton, have been permitted by the implementation of fluorescent protein and advanced confocal imaging. In this review, we report on the findings that contributed towards the understanding of the endoplasmic reticulum morphology and function with the aid of fluorescent proteins, focusing on the contributions provided by pioneering work from the lab of the late Professor Chris Hawes.
Topics: Endoplasmic Reticulum; GTP Phosphohydrolases; Membrane Proteins; Organelles; Plant Cells; Plant Proteins
PubMed: 32426862
DOI: 10.1111/jmi.12909 -
Life Sciences Oct 2017Understanding the mechanism of nanoparticle (NP) induced toxicity is important for nanotoxicological and nanomedicinal studies. Endoplasmic reticulum (ER) is a crucial... (Review)
Review
Understanding the mechanism of nanoparticle (NP) induced toxicity is important for nanotoxicological and nanomedicinal studies. Endoplasmic reticulum (ER) is a crucial organelle involved in proper protein folding. High levels of misfolded proteins in the ER could lead to a condition termed as ER stress, which may ultimately influence the fate of cells and development of human diseases. In this review, we summarized studies about effects of NP exposure on ER stress. A variety of NPs, especially metal-based NPs, could induce morphological changes of ER and activate ER stress pathway both in vivo and in vitro. In addition, modulation of ER stress by chemicals has been shown to alter the toxicity of NPs. These studies in combination suggested that ER stress could be the mechanism responsible for NP induced toxicity. Meanwhile, nanomedicinal studies also used ER stress inducing NPs or NPs loaded with ER stress inducer to selectively induce ER stress mediated apoptosis in cancer cells for cancer therapy. In contrast, alleviation of ER stress by NPs has also been shown as a strategy to cure metabolic diseases. In conclusion, exposure to NPs may modulate ER stress, which could be a target for future nanotoxicological and nanomedicinal studies.
Topics: Animals; Apoptosis; Cell Line, Tumor; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Nanomedicine; Nanoparticles; Particle Size; Protein Folding
PubMed: 28782531
DOI: 10.1016/j.lfs.2017.08.003 -
Expert Review of Gastroenterology &... Sep 2016The accumulation of unfolded protein in the endoplasmic reticulum (ER) initiates an unfolded protein response (UPR) via three signal transduction cascades, which involve... (Review)
Review
INTRODUCTION
The accumulation of unfolded protein in the endoplasmic reticulum (ER) initiates an unfolded protein response (UPR) via three signal transduction cascades, which involve protein kinase RNA-like ER kinase (PERK), inositol requiring enzyme-1α (IRE1α) and activating transcription factor-6α (ATF6α). An ER stress response is observed in nearly all physiologies related to acute and chronic liver disease and therapeutic targeting of the mechanisms implicated in UPR signaling have attracted considerable attention.
AREAS COVERED
This review focuses on the correlation between ER stress and liver disease and the possible targets which may drive the potential for novel therapeutic intervention. Expert Commentary: We describe pathways which are involved in UPR signaling and their potential correlation with various liver diseases and underlying mechanisms which may present opportunities for novel therapeutic strategies are discussed.
Topics: Animals; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Liver Diseases; Molecular Targeted Therapy; Signal Transduction; Unfolded Protein Response
PubMed: 27093595
DOI: 10.1080/17474124.2016.1179575 -
Progress in Molecular and Subcellular... 2021Intracellular Ca signaling regulates a plethora of cellular functions. A central role in these processes is reserved for the inositol 1,4,5-trisphosphate receptor (IPR),... (Review)
Review
Intracellular Ca signaling regulates a plethora of cellular functions. A central role in these processes is reserved for the inositol 1,4,5-trisphosphate receptor (IPR), a ubiquitously expressed Ca-release channel, mainly located in the endoplasmic reticulum (ER). Three IPR isoforms (IPR1, IPR2 and IPR3) exist, encoded respectively by ITPR1, ITPR2 and ITPR3. The proteins encoded by these genes are each about 2700 amino acids long and assemble into large tetrameric channels, which form the target of many regulatory proteins, including several tumor suppressors and oncogenes. Due to the important role of the IPRs in cell function, their dysregulation is linked to multiple pathologies. In this review, we highlight the complex role of the IPR in cancer, as it participates in most of the so-called "hallmarks of cancer". In particular, the IPR directly controls cell death and cell survival decisions via regulation of autophagy and apoptosis. Moreover, the IPR impacts cellular proliferation, migration and invasion. Typical examples of the role of the IPRs in these various processes are discussed. The relative levels of the IPR isoforms expressed and their subcellular localization, e.g. at the ER-mitochondrial interface, is hereby important. Finally, evidence is provided about how the knowledge of the regulation of the IPR by tumor suppressors and oncogenes can be exploited to develop novel therapeutic approaches to fight cancer.
Topics: Biology; Calcium; Endoplasmic Reticulum; Humans; Inositol 1,4,5-Trisphosphate Receptors; Neoplasms
PubMed: 34050869
DOI: 10.1007/978-3-030-67696-4_11 -
The Protein Journal Jun 2019
Topics: Animals; Endoplasmic Reticulum; Humans; Protein Sorting Signals; Protein Translocation Systems; Protein Transport
PubMed: 31203483
DOI: 10.1007/s10930-019-09843-6 -
Wiener Medizinische Wochenschrift (1946) Sep 2018Cholesterol is an essential lipid for mammalian cells and its homeostasis is tightly regulated. Disturbance of cellular cholesterol homeostasis is linked to... (Review)
Review
Cholesterol is an essential lipid for mammalian cells and its homeostasis is tightly regulated. Disturbance of cellular cholesterol homeostasis is linked to atherosclerosis and cardiovascular diseases. A central role in the sensing and regulation of cholesterol homeostasis is attributed to the endoplasmic reticulum (ER). This organelle harbours inactive transcription factors, which sense ER cholesterol levels and initiate transcriptional responses after activation and translocation into the nucleus. Thereupon, these responses enable adaption to high or low cellular cholesterol levels. Besides the abovementioned canonical functions, ER stress-induced by metabolic burden-and the resulting unfolded protein response influence cholesterol metabolism relevant to metabolic disorders. This review summarizes basic as well as recent knowledge on the role of the ER in terms of regulation of cholesterol metabolism.
Topics: Animals; Cholesterol; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Lipid Metabolism; Unfolded Protein Response
PubMed: 29488036
DOI: 10.1007/s10354-018-0626-2 -
Progress in Molecular and Subcellular... 2021The unfolded protein response (UPR) is an evolutionarily conserved adaptive regulatory pathway that alleviates protein-folding defects in the endoplasmic reticulum (ER)....
The unfolded protein response (UPR) is an evolutionarily conserved adaptive regulatory pathway that alleviates protein-folding defects in the endoplasmic reticulum (ER). Physiological demands, environmental perturbations and pathological conditions can cause accumulation of unfolded proteins in the ER and the stress signal is transmitted to the nucleus to turn on a series of genes to respond the challenge. In metazoan, the UPR pathways consisted of IRE1/XBP1, PEK-1 and ATF6, which function in parallel and downstream transcriptional activation triggers the proteostasis networks consisting of molecular chaperones, protein degradation machinery and other stress response pathways ((Labbadia J, Morimoto RI, F1000Prime Rep 6:7, 2014); (Shen X, Ellis RE, Lee K, Annu Rev Biochem 28:893-903, 2014)). The integrated responses act on to resolve the ER stress by increasing protein folding capacity, attenuating ER-loading translation, activating ER-associated proteasomal degradation (ERAD), and regulating IRE1-dependent decay of mRNA (RIDD). Therefore, the effective UPR to internal and external causes is linked to the multiple pathophysiological conditions such as aging, immunity, and neurodegenerative diseases. Recent development in the research of the UPR includes cell-nonautonomous features of the UPR, interplay between the UPR and other stress response pathways, unconventional UPR inducers, and noncanonical UPR independent of the three major branches, originated from multiple cellular and molecular machineries in addition to ER. Caenorhabditis elegans model system has critically contributed to these unprecedented aspects of the ER UPR and broadens the possible therapeutic targets to treat the ER-stress associated human disorders and time-dependent physiological deterioration of aging.
Topics: Animals; Caenorhabditis elegans; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Homeostasis; Humans; Unfolded Protein Response
PubMed: 34050871
DOI: 10.1007/978-3-030-67696-4_13 -
Current Opinion in Cell Biology Aug 2018In eukaryotic cells, various cellular functions are compartmentalized and performed by sophisticated and specialized organelles. However, the membrane-bounded organelles... (Review)
Review
In eukaryotic cells, various cellular functions are compartmentalized and performed by sophisticated and specialized organelles. However, the membrane-bounded organelles need to communicate with each other and with the cytoplasm, and sense the outside through the plasma membrane to coordinate various functions and to maintain cellular homeostasis. To maintain homeostasis, the information on the cellular state must be collected and appropriate responses initiated. The endoplasmic reticulum fulfils these functions. In this review, I will discuss various aspects of how the ER senses and relays information and acts to protect the cell, in what sometimes could be interpreted as an altruistic behavior.
Topics: Animals; Cell Membrane; Endoplasmic Reticulum; Eukaryotic Cells; Homeostasis; Humans
PubMed: 30006039
DOI: 10.1016/j.ceb.2018.06.004 -
Biological & Pharmaceutical Bulletin 2020Endoplasmic reticulum aminopeptidase 1 (ERAP1) is well known as a processing enzyme of antigenic peptides, which are presented to major histocompatibility complex (MHC)... (Review)
Review
Endoplasmic reticulum aminopeptidase 1 (ERAP1) is well known as a processing enzyme of antigenic peptides, which are presented to major histocompatibility complex (MHC) class I molecules in the lumen of endoplasmic reticulum. Besides antigen processing, ERAP1 performs multiple functions in various cells depending on its intracellular and extracellular localization. Of note is the secretion of ERAP1 into the extracellular milieu in response to inflammatory stimuli, which further activates immune cells including macrophages and natural killer cells. Furthermore, secreted ERAP1 enhances the expression of pro-inflammatory cytokines like tumor necrosis factor-α, interleukin-1β, and interleukin-6. Such findings indicate that ERAP1 plays a significant role in the field of innate and acquired immunity. This review summarizes the functional analyses of ERAP1 that support our current understanding of its role as more than an antigenic peptide-processing enzyme, specifically emphasizing on its secretory form.
Topics: Aminopeptidases; Animals; Endoplasmic Reticulum; Humans
PubMed: 32009107
DOI: 10.1248/bpb.b19-00857