Introduction. Hydatid cyst, caused by Echinococcus granulosa, occurs rarely in the musculoskeletal region. Most of the time, clinically and radiologically it is diagnosed as a soft tissue tumor, benign or malignant. There are a few case reports of hydatid cyst presenting as an intramuscular thigh mass, which has been diagnosed at fine needle aspiration cytology (FNAC). Accurate preoperative diagnosis is essential in view of specific therapeutic options for this disease. Here we report a case of hydatid cyst occurring in an unusual location (thigh) and masquerading as a soft tissue tumour, diagnosed at FNAC. Case Report. 56-year-old male patient presented with gradually increasing swelling of the left thigh since 3 years. On examination, there was a firm non-tender 25 x 20 cm swelling on the posterior aspect of left thigh extending from the gluteal region to five cm above the knee joint. An ultrasound diagnosis of a soft tissue tumor was made. At FNAC, fluid was aspirated and smears showed granulomas along with multiple hyaline acellular membrane-like fragments, few showing vague laminations. A diagnosis of hydatid cyst was made at FNAC which was corroborated at histopathology. Conclusion. Intramuscular hydatid cyst of the thigh is a very rare manifestation. The possibility of hydatid cyst should be considered while aspirating any soft tissue mass lesion, especially when fluid is obtained and microscopy shows acellular hyaline membrane-like material, even when fewer laminations are noted.
Abstract Background: Some investigations show that obesity is associated with increase in bone mass due to excessive mechanical exertion. However, these data are contradictory as loss of mineral density of bone tissue and, respectively, the risk of fractures in this population group is higher. The aim of the research was to investigate impact of drug therapy with zoledronic acid on nanostructure of bones in rats with limited mobility and high-calorie diet. Methods: Rats (n = 56) were distributed into three groups: control (n = 18) – standard vivarium conditions, І experimental group (n = 18) – rats, which were on a high-calorie diet with limited mobility (HCD+LM), ІІ experimental group (n = 18) – HCD+LM+zoledronic acid. Zoledronic acid was injected at the dose 0.025 mg/kg intramuscularly every four weeks for six months. X-ray structure analysis, scanning electron microscopy and atomic absorption spectrometry were used for investigation of ultrastructure and quantitative assessment of mineral component loss in the femoral neck. Results: Obesity and limited mobility reduced the level of the mineral component in the femoral neck (−31.5%) compared with control. It is significant that zoledronic acid did not permit decrease in mineral component of the bone throughout the entire experiment compared with group I (+41.8%), and all parameters were higher than in control group (+15%). Conclusions: Obesity and limited mobility negatively affect mineral bone mass. Zoledronic acid induces increase in the mineral component as a result of remodeling inhibition under conditions of obesity and limited mobility modeling.
Abstract Objectives: Rhinoscleroma is a rare infectious disease of the upper respiratory tract caused by Klebsiella rhinoscleromatis. Apart from mandating an appropriate antibiotic therapy, it poses a unique challenge to the pathologists since it can clinically simulate a malignancy. The main objective was to study the cases of rhinoscleroma of the respiratory tract in a period of 3 years with an emphasis on the clinico-pathologic features. Methods: We report a retrospective analysis of 7 cases, histopathologically diagnosed at our centre as rhino-scleroma. The topography ranged from nasal mucosa (3), pharynx (2) and larynx (2). Results: Histopathological examination in all cases showed diffuse aggregates of foamy macrophages (Mikulicz cells) containing intracytoplasmic basophilic organisms; admixed with plasma cells in a fibrotic stroma. The overlying epithelium appeared atrophic to focally hyperplastic. The age ranged from 36–67 years, involving both genders. The significant clinical history included a nasal block without anosmia, atrophic rhinitis with septal perforation to subglottic stenosis, requiring immediate surgical intervention. In 4 of the 7 cases, the working clinical diagnosis was stipulated as a malignancy. Conclusions: Rhinoscleroma can affect different regions in the upper aero digestive tract. A lack of awareness and a delay in the diagnosis of this disease can lead to complications including upper airway obstruction, physical deformity, and rarely, sepsis. In addition, it must be remembered that the treatment of rhinoscleroma is challenging and requires a prolonged course of antibiotics to achieve a definite cure and avoid relapses.
In an elegantly presented and thought-provoking manuscript published by the journal Radiotherapy and Oncology, Valstar et al. characterize previously unreported structures comprising salivary gland tissue near the torus tubarius [1]. The authors present their findings in three stages. First, they identify these entities in patients with prostate or urethral gland cancer who underwent positron emission tomography / computed tomography with prostate-specific membrane antigen ligands (PSMA PET/ CT), which technique—despite its name—demonstrates avidity for salivary glands. The investigators then evaluate these glands using human cadavers, and finally assess the effect of radiation therapy involving this region in head & neck cancer (HNC) patients. Ultimately, the authors proffer two conclusions from their findings. First, they propose recognition of this region as newly identified paired organs, suggesting the designation of “tubarial glands.” Second, they underscore the importance of sparing this area from the toxic effects of radiation therapy, to whatever extent feasible. Whereas the second of these points seems more resonant and straightforward, the authors appear to emphasize the first, in terms of coverage and explication. The dichotomy between these claims, and the relative prominence of the purported anatomic contribution within the manuscript, potentially detract from study’s significant clinical impact. The anatomic issue—whether these glands more closely resemble major or minor salivary glands—is an interesting question. In terms of features shared in common with major glands, the authors discuss several analogies between the tubarial glands and sublingual glands. For instance, the tubarial glands lack a capsule, and the sublingual glands show only partial encapsulation. The authors also demonstrate the tubarial glands’ “multiple macroscopically visible draining duct openings in the dorsolateral pharyngeal wall” in Figure 4. The sublingual gland secretes its products through multiple ducts as well. However, these features (absence of a fibrous capsule, and presence of multiple ducts) pertain to minor salivary glands as well as the sublingual gland, and therefore may not distinguish the tubarial glands as major versus minor. Conversely, the tubarial glands exhibit several aspects analogous to the minor salivary glands of the palate, potentially suggesting a designation as minor rather than major glands for the region in question. The authors concede these resemblances, stating “the tubarial glands have many similarities with the palatal conglomerate of microscopic glands.” From the perspective of a pathologist, anyway (and based on the text), the relationship between the radiologic features of the tubarial and palatal glands is difficult to discern. The authors alternately describe the PET avidity of the tubarial glands as “consistently more than the uptake in the palate,” and/or as “comparable to the mucous aspect and PSMA-ligand uptake of minor salivary glands in the palate.” Whether these statements represent contradictory assessments is perhaps beyond my purview. Anatomically and histologically, however, commonalities between the tubarial glands and the palatal glands are evident. The photomicrograph in Figure 3, for instance, appears to show arrangement of acini more reminiscent of minor salivary glands. The authors also invoke distribution of minor rather than major glands when discussing the historical omission of / inability to previously recognize these glands. Their explanation that “the newly detected tubarial glands involve flat submucosal glandular structures” seems to describe the configuration of minor salivary units, not major glandular structures. In some ways (and, perhaps, correctly), the authors undermine the significance of labeling these glands as major versus minor. By writing “we think these qualification systems may not be suited and relevant to interpret and appreciate this finding,” they contradict their emphasis on appropriate designation of the tubarial glands throughout much of the manuscript. Alternatively, they propose “all salivary glands together could be interpreted *Corresponding author: Andrew T. Turk, Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, USA, e-mail: att2101@cumc.columbia.edu
Pathology is one of the oldest medical disciplines, one that can be arguably rooted early in Egyptian medicine and Traditional Chinese Medicine 5,000 years ago [1,2]. In ancient times, documentation of diseases relied on the understandings of anatomy and observations of abnormalities that deviated from normal physiology. For many centuries ensued, vast knowledge was accumulated from observations of pathological conditions and autopsies, it is this wealth of information that laid the foundation for the modern medicine we see today. In the early beginning, pathology focused on morphological abnormalities. Random documentation of broken bones, abnormal masses, skin discoloration evolved into systematic gross anatomy in modern pathology in the 19th century [2,3]. The invention of the microscope in the 19th century was undoubtedly another force that propelled pathology and medicine forward, moving us from organbased to cell-based pathology with this “new technology”. Along with the microscope, other technological advances such as tissue fixation, embedding, microtomes, and biological stains, all enabled the practice of histopathology possible. However, for a century, despite the improvement of microscopes and a plethora of ancillary diagnostic tests (i.e. electron microscopy, fluorescent microscopy, immunohistochemistry, cytogenetics), the importance of detecting morphological abnormalities remained constant and central to scientific discoveries, journal publications, and patient care as research focuses moved from organs to cells, from organelles to chromosomes. In recent decades, we have seen an explosion of technologies in science, which enabled comparisons of normal vs. diseased states at molecular levels. Soon, analyses of DNA (single nucleotide polymorphism profiling, whole exome sequencing, cell-free DNA screening, etc.), RNA (RNA-Seq, single cell RNA-Seq, miRNA-Seq, ribosome profiling, etc.), protein (protein microarray, mass spectrometry, quantitative proteomics, etc.), epigenome (ChIPSeq, whole-genome bisulphite sequencing), and metabolome (MS-based metabolites or lipid profiles) at various depths and throughputs became a common practice in experimental approaches and journal publications [4,5]. These molecular analyses not only can identify dysfunctional genes and/or pathways that are responsible or have contributed to the diseased state and structural abnormalities that can be visualized grossly or under a microscope, but may also offer insights for personalized medicine. For instance, in the era of precision medicine for cancer treatment, we have come to recognize that not only there are differential sensitivities to a given therapy among patients, there exists cellular heterogeneity in a patient’s tumor. Therefore, a histological diagnosis of cancer in a patient can be complemented by molecular analyses to devise a personalized therapy that matches the tumor’s molecular profile. It is also the hope that advances in liquid biopsies and artificial intelligence will someday replace the need for tissue biopsy in disease diagnosis, although many obstacles remained [6]. Cell pathology can be defined at cellular, organelle, and molecular levels, and can be detected by histological analysis, functional assays, or molecular analyses. Genetic mutations, epigenetic changes, or metabolic dysfunction can all contribute to the pathogenesis of a disease. Presently, diagnosis of a disease often encompasses a combination of physical, gross, histological, and molecular examinations. Take the current COVID-19 as an example, the emergent of the disease was first noted for the abnormal pathology of the lungs in SARS-CoV-2 infected patients [7], which eventually led to the development of PCR-based diagnostic tests. To understand and combat COVID-19 take concerted efforts of comprehensive cellular and molecular investigations, in vitro and in vivo experiments, human and animal studies. We recognize that abnormal state of cells can be presented in a multifaceted manner, therefore it is only fitting that our journal, Cell Pathology, embraces anatomical, cellular, molecular, computation, mechanobiological, and organismal investigations of cell pathology, because only through inclu*Corresponding author: Gloria H. Su, Department of Pathology and Cell Biology, Department of Otolaryngology and Head and Neck Surgery, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, USA, e-mail: gs2157@cumc.columbia.edu
Cystic fibrosis (CF) is a life-shortening, genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). The primary cause of CF is reduced CFTR-mediated chloride and bicarbonate transport, due to mutations in CFTR. However, inflammation and persistent infections influence clinical outcome. Cellular stress response pathways, such as the unfolded protein response (UPR) and the integrated stress response (ISR), referred to here as cellular stress response pathways (SRPs), contribute to the pathology of human disorders. Multiple studies have indicated activation of SRPs in CF tissues. We review our present understanding of how SRPs are activated in CF and their contribution to pathology. We conclude that reduced CFTR function in CF organs establishes a tissue environment in which internal or external insults activate SRPs. SRPs contribute to CF pathogenesis by reducing CFTR expression, enhancing inflammation with consequent tissue remodeling. Understanding the contribution of SRPs to CF pathogenesis is crucial even in the era of CFTR "modulators" that are designed to potentiate, correct or amplify CFTR function, since there is an urgent need for supportive treatments. Importantly, CF patients with established pathology could benefit from the targeted use of drugs that modulate SRPs to reduce the symptoms.
Abstract Ire1 and its family protein PERK are endoplasmic reticulum (ER)-stress sensors that initiate cellular responses against ER accumulation of unfolded proteins. As reviewed in this article, many publications describe molecular mechanisms by which yeast Ire1 senses ER conditions and gets regulated. We also cover recent studies which reveal that mammalian Ire1 (IRE1α) and PERK are controlled in a similar but not exactly the same manner. ER-located molecular chaperone BiP captures these ER-stress sensors and suppresses their activity. Intriguingly, Ire1 is associated with BiP not as a chaperone substrate, but as a unique ligand. Unfolded proteins accumulated in the ER promote dissociation of the Ire1-BiP complex. Moreover, Ire1 is directly bound with unfolded proteins, leading to its cluster formation and potent activation. PERK also captures unfolded proteins and then forms self-oligomers. Meanwhile, membrane-lipid aberrancy is likely to activate these ER-stress sensors independently of ER accumulation of unfolded proteins. In addition, there exist a number of reports that touch on other factors that control activity of these ER-stress sensors. Such a multiplicity of regulatory mechanisms for these ER-stress sensors is likely to contribute to fine tuning of their activity.
Background: Transmissible spongiform encephalopathies are a collection of rare neurodegenerative disorders characterized by loss of neuronal cells, astrocytosis, and plaque formation. The causative agent of these diseases is thought to be abnormally folded prions and is characterized by a conformational change from normal, cellular prion protein (PrPc) to the abnormal form (PrPTSE). Although, there is evidence that normal prion protein can contribute to these disorders. The unfolded protein response, a conserved series of pathways involved in resolving stress associated with unfolded protein accumulation in the Endoplasmic Reticulum (ER), has been shown to play a role in regulating the development of prion diseases. Methods: This review chose papers based on their relevance to current studies involved in prion protein synthesis and transformation, identifies various links between prion diseases and ER stress, and reports on current and potential treatments as they relate to ER stress and prion diseases. Conclusion: For the advancement of prion disease treatment, it is important to understand the mechanisms involved in prion formation, and ER stress is implicated in prion disease progression. Therefore, targeting the ER or pathways involved in response to stress in the ER may help us treat prion diseases.
Abstract Increasing evidence suggests that endoplasmic reticulum (ER) stress and autophagy play an important role in regulating brain function. ER stress activates three major branches of the unfolded protein response (UPR) pathways, namely inositol-requiring enzyme-1 (IRE1), double stranded RNA-activated protein kinase (PKR)-like ER kinase (PERK) and activating transcription factor 6 (ATF6)-mediated pathways. Recent studies have suggested that these UPR signals may be linked to autophagy. In this review article, we summarize recent evidence and discuss a possible link between ER stress and autophagy with regard to neurodegenerative diseases. Furthermore, possible pharmacological strategies targeting UPR and autophagy are discussed.
The conception that protein aggregates composed by misfolded proteins underlies the occurrence of several neurodegenerative diseases suggests that this phenomenon may have a common origin, ultimately driven by disruption of proteostasis control. The unfolded protein response (UPR) embodies a major element of the proteostasis network, which is engaged by endoplasmic reticulum (ER) stress. Chronic ER stress may operate as a possible mechanism of neurodegeneration, contributing to synaptic alterations, neuroinflammation and neuronal loss. In this review we discuss most recent findings relating ER stress and the development of distinct neurodegenerative diseases, and the possible strategies for disease intervention.
The unfolded protein response (UPR) is activated in response to impairments of the folding environment in the endoplasmic reticulum (ER). The most conserved arm of the UPR, inositol-requiring ER-to-nucleus signaling protein (IRE1α), has been linked to the regulation of a diverse array of cellular processes including ER-associated degradation, inflammatory signaling, cell proliferation and membrane biogenesis. Recent studies have utilized the selective, small molecule inhibitor, 4μ8c, to examine the role of IRE1α endoribonuclease (RNase) activity in various cell types including multiple myeloma, mouse embryonic fibroblasts and pancreatic beta cells [1-5]. In the present study we utilized this inhibitor to examine the role of IRE1α RNase activity in hepatoma cells (H4IIE), specifically concentrating on cell proliferation and the identification of potential off target effects under both unstressed and stressed conditions. Experiments were performed in H4IIE hepatoma cells in the absence (control conditions (LG)) or presence (LG + Thapsigargin (Thap)) of ER stress. The presence of 4μ8c decreased IRE1α RNase activity, based on reduced splicing of X-box binding protein-1 (XBP1s) and regulated IRE1α-dependent decay of mRNA in both treatments and at concentrations ranging from 10-90 μM. Cell proliferation was significantly reduced at higher concentrations (> 60 μM 4μ8c) in unstressed cells and displayed a dose-response relationship with 4μ8c in both treatments. The presence of 4μ8c did not promote cytoxicity in either of the treatment conditions but higher concentrations of the inhibitor (60 μM) were associated with apparent off-target or compensatory responses that were not observed at 10 μM. Overall, the small-molecule inhibitor, 4μ8c is an effective inhibitor of IRE1α RNase activity in H4IIE cells. Potential off-target effects associated with this inhibitor require the use of multiple inhibitor concentrations in all experiments.
Abstract In the classical form of α1-antitrypsin deficiency (ATD) a point mutation leads to accumulation of a misfolded secretory glycoprotein in the endoplasmic reticulum (ER) of liver cells and so ATD has come to be considered a prototypical ER storage disease . It is associated with two major types of clinical disorders, chronic obstructive pulmonary disease (COPD) by lossof- function mechanisms and hepatic cirrhosis and carcinogenesis by gain-of-function mechanisms. The lung disease predominantly results from proteolytic damage to the pulmonary connective tissue matrix because of reduced levels of protease inhibitor activity of α1-anitrypsin (AT) in the circulating blood and body fluids. Cigarette smoking is a powerful disease-promoting modifier but other modifiers are known to exist because variation in the lung disease phenotype is still found in smoking and non-smoking homozygotes. The liver disease is highly likely to be caused by the proteotoxic effects of intracellular misfolded protein accumulation and a high degree of variation in the hepatic phenotype among affected homozygotes has been hypothetically attributed to genetic and environmental modifiers that alter proteostasis responses. Liver biopsies of homozygotes show intrahepatocytic inclusions with dilation and expansion of the ER and recent studies of iPS-derived hepatocyte-like cells from individuals with ATD indicate that the changes in the ER directly vary with the hepatic phenotype i.e there is much lesser alteration in the ER in cells derived from homozygotes that do not have clinically significant liver disease. From a signaling perspective, studies in mammalian cell line and animal models expressing the classical α1-antitrypsin Z variant (ATZ) have found that ER signaling is perturbed in a relatively unique way with powerful activation of autophagy and the NFκB pathway but relatively limited, if any, UPR signaling. It is still not known how much these unique structural and functional changes and the variation among affected homozygotes relate to the tendency of this variant to polymerize and aggregate and/ or to the repertoire of proteostasis mechanisms that are activated.
AbstractInhibition of IRE1 (inositol requiring enzyme-1), the major signaling pathway of endoplasmic reticulum stress, significantly decreases tumor growth and proliferation of glioma cells. To elucidate the role of IRE1- mediated glioma growth, we studied the expression of a subset genes encoding for TNF (tumor necrosis factor)- related factors and receptors and their hypoxic regulation in U87 glioma cells overexpressing dominant-negative IRE1 (dnIRE1). We demonstrated that the expression of TNFAIP1, TNFRSF10D, TNFRSF21, TNFRSF11B, TNFSF7, and LITAF genes is increased in glioma cells with modified IRE1; however, TNFRSF10B, TRADD, and TNFAIP3 is down-regulated in these cells as compared to their control counterparts. We did not find TNFRSF1A gene expression to change significantly under this experimental condition. In control glioma cells, hypoxia leads to the up-regulated expression of TNFAIP1, TNFAIP3, TRADD, and TNFRSF10D genes and the concomitant down-regulation of TNFRSF21, TNFRSF11B, and LITAF genes; while, TNFRSF10B and TNFRSF1A genes are resistant to hypoxic treatment. However, inhibition of IRE1 modifies the hypoxic regulation of LITAF, TNFRSF21, TNFRSF11B, and TRADD genes and introduces hypoxia-induced sensitivity to TNFRSF10B, TNFRSF1A, and TNFSF7 gene expressions. Furthermore, knockdown by siRNA of TNFRSF21 mRNA modifies the hypoxic effect on the IRE1-dependent rate of proliferation and cell death in U87 glioma cells. The present study demonstrates that fine-tuned manipulation of the expression of TNF-related factors and receptors directly relating to cell death and proliferation, is mediated by an effector of endoplasmic reticulum stress, IRE1, as well as by hypoxia in a gene-specific manner. Thus, inhibition of the kinase and endoribonuclease activities of IRE1 correlates with deregulation of TNF-related factors and receptors in a manner that is gene specific and thus slows tumor growth.
The activation of Endoplasmic Reticulum (ER) stress and Unfolded Protein Response (UPR) was first observed in patients with familial interstitial pneumonia (FIP) carrying mutations in the C-terminal BRICHOS domain of surfactant protein C (SFTPC). Here, aggresome formation and severe ER stress was demonstrated in type-II alveolar epithelial cells (AECII), which specifically express this very hydrophobic surfactant protein. In subsequent studies, FIP-patients with mutations in the gene encoding surfactant protein A2 (SFTPA2) were discovered, whose overexpression in epithelial cells in vitro also resulted in significant induction of ER stress. Moreover, prominent ER stress in AECII was also observed in FIP-patients not carrying the SFTPC/SFTPA2 mutations, as well as in patients with the more common sporadic forms of IP. Additionally, cases of adult-onset FIP with mutations in Telomerase genes and other telomere-associated components were reported. These mutations were associated with telomere shortening, which is a potential cause for triggering a persistent DNA damage response and replicative senescence in affected cells. Moreover, shortened telomeres were observed directly in the AECII of FIP-patients, and even sporadic IP cases, in the absence of any gene mutations. Here, we try to figure out the possible origins of ER stress in sporadic IP cases and non-SFTPC/SFTPA2-associated FIP.
IRE-1 alpha (inositol requiring enzyme-1 alpha), the most evolutionarily conserved of the endoplasmic reticulum stress signaling pathways, is highly implicated in sustaining the proliferation of glioma cells and subsequent tumor growth, which is decreased by the inhibition of IRE-1 alpha. To explore the IRE-1 alpha mediated regulation of ubiquitin system in glioma cells, the expression of a subset of ubiquitin specific peptidases (USP) and of ubiquitin activating enzyme E1-like protein/autophagy related 7 (GSA7/ATG7) genes was studied, during hypoxic stress in wild type and U87 glioma cells with inhibited IRE-1 alpha. Hypoxic treatment of wild type glioma cells leads to the up-regulation of USP25 and the concomitant down-regulation of USP1, USP10, USP14, and GSA7 genes. USP4 and USP22 genes expression did not significantly change with hypoxic treatment. Inhibition of IRE-1 alpha activity led to up-regulation of USP1, USP4, USP10, USP22, and USP25, while USP14 and GSA7 genes were down-regulated. Therefore, IRE-1 alpha activity modifies substrate-targeting specificity to proteasome during hypoxic stress, which in turn can affect cell survival. Inhibition of IRE-1 alpha correlates directly with deregulation of ubiquitin specific peptidases and GSA7 in a fashion that ultimately slows tumor growth.
Over the past decade, a handful of evidence has been provided that nonsteroidal anti-inflammatory drugs (NSAIDs) display effects on the homeostasis of the endoplasmic reticulum (ER). Their uptake into cells will eventually lead to activation or inhibition of key molecules that mediate ER stress responses, raising not only a growing interest for a pharmacological target in ER stress responses but also important questions how the ER-stress mediated effects induced by NSAIDs could be therapeutically advantageous or not. We review here the toxicity effects and therapeutic applications of NSAIDs involving the three majors ER stress arms namely PERK, IRE1, and ATF6. First, we provide brief introduction on the well-established and characterized downstream events mediated by these ER stress players, followed by presentation of the NSAIDs compounds and mode of action, and finally their effects on ER stress response. NSAIDs present promising drug agents targeting the components of ER stress in different aspects of cancer and other diseases, but a better comprehension of the mechanisms underlying their benefits and harms will certainly pave the road for several diseases’ therapy.
AbstractThe endoplasmic reticulum (ER) is an organelle that plays a crucial role in protein quality control such as protein folding. Evidence to indicate the involvement of ER in maintaining cellular homeostasis is increasing. However, when cells are exposed to stressful conditions, which perturb ER function, unfolded proteins accumulate leading to ER stress. Cells then activate the unfolded protein response (UPR) to cope with this stressful condition. In the present review, we will discuss and summarize recent advances in research on the basic mechanisms of the UPR. We also discuss the possible involvement of ER stress in the pathogenesis of Alzheimer’s disease (AD). Potential therapeutic opportunities for diseases targeting ER stress is also described.
Non-communicable diseases (NCDs) such as cardiovascular disease, cancers, diabetes and obesity are responsible for about two thirds of mortality worldwide, and all of these ailments share a common low-intensity systemic chronic inflammation, endoplasmic reticulum stress (ER stress), and the ensuing Unfolded Protein Response (UPR). These adaptive mechanisms are also responsible for significant metabolic changes that feedback with the central clock of the suprachiasmatic nucleus (SCN) of the hypothalamus, as well as with oscillators of peripheral tissues. In this review we attempt to use a systems biology approach to explore such interactions as a whole; to answer two fundamental questions: (1) how dependent are these adaptive responses and subsequent events leading to NCD with their state of synchrony with the SCN and peripheral oscillators? And, (2) How could modifiers of the activity of SCN for instance, food intake, exercise, and drugs, be potentially used to modulate systemic inflammation and ER stress to ameliorate or even prevent NCDs?
Introduction: Diabetes is a major contributor to cardiovascular disease. There is a growing body of evidence pointing towards intra-myocellular lipid accumulation as an integral etiological factor. Here we aimed to determine the effect of two common fatty acids on lipid accumulation and cellular stress in primary cardiomyocytes.Methods: We evaluated lipid accumulation biochemically (by triacylglyceride assay and radiolabeled fatty acid uptake assay) as well as histologically (by BODIPY 493/503 staining) in mouse and rat neonatal cardiomyocytes treated with saturated (palmitate) or mono-unsaturated (oleate) fatty acids. Endoplasmic reticulum (ER) stress was evaluated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting. Cell viability was assessed by propidium iodide staining.Results: We found that both oleate and palmitate led to significant increases in intracellular lipid in cardiomyocytes; however there were distinct differences in the qualitative nature of BODIPY staining between oleate and palmitate treated cardiomyocytes. We also show that palmitate caused significant apoptotic cell death and this was associated with ER stress. Interestingly, co-administration of oleate with palmitate abolished cell death, and ER stress. Finally, palmitate treatment caused a significant increase in ubiquitination of Grp78, a key compensatory ER chaperone.Conclusion: Palmitate causes ER stress and apoptotic cell death in primary cardiomyocytes and this is associated with apparent differences in BODIPY staining compared to oleate treated cardiomyocytes. Importantly, the lipotoxic effects of palmitate are abolished with the co-administration of oleate.
Over the past decade, a handful of evidence has been provided that nonsteroidal anti-inflammatory drugs (NSAIDs) display effects on the homeostasis of the endoplasmic reticulum (ER). Their uptake into cells will eventually lead to activation or inhibition of key molecules that mediate ER stress responses, raising not only a growing interest for a pharmacological target in ER stress responses but also important questions how the ER-stress mediated effects induced by NSAIDs could be therapeutically advantageous or not. We review here the toxicity effects and therapeutic applications of NSAIDs involving the three majors ER stress arms namely PERK, IRE1, and ATF6. First, we provide brief introduction on the well-established and characterized downstream events mediated by these ER stress players, followed by presentation of the NSAIDs compounds and mode of action, and finally their effects on ER stress response. NSAIDs present promising drug agents targeting the components of ER stress in different aspects of cancer and other diseases, but a better comprehension of the mechanisms underlying their benefits and harms will certainly pave the road for several diseases' therapy.
