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Journal of Translational Medicine Sep 2019Post-transcriptional modifications have been recently expanded with the addition of RNA editing, which is predominantly mediated by adenosine and cytidine deaminases... (Review)
Review
Post-transcriptional modifications have been recently expanded with the addition of RNA editing, which is predominantly mediated by adenosine and cytidine deaminases acting on DNA and RNA. Here, we review the full spectrum of physiological processes in which these modifiers are implicated, among different organisms. Adenosine to inosine (A-to-I) editors, members of the ADAR and ADAT protein families are important regulators of alternative splicing and transcriptional control. On the other hand, cytidine to uridine (C-to-U) editors, members of the AID/APOBEC family, are heavily implicated in innate and adaptive immunity with important roles in antibody diversification and antiviral response. Physiologically, these enzymes are present in the nucleus and/or the cytoplasm, where they modify various RNA molecules, including miRNAs, tRNAs apart from mRNAs, whereas DNA editing is also possible by some of them. The expansion of next generation sequencing technologies provided a wealth of data regarding such modifications. RNA editing has been implicated in various disorders including cancer, and neurological diseases of the brain or the central nervous system. It is also related to cancer heterogeneity and the onset of carcinogenesis. Response to treatment can also be affected by the RNA editing status where drug efficacy is significantly compromised. Studying RNA editing events can pave the way to the identification of new disease biomarkers, and provide a more personalised therapy to various diseases.
Topics: Animals; Cytidine Deaminase; Disease; Health; High-Throughput Nucleotide Sequencing; Humans; RNA Editing; Transcriptome
PubMed: 31547885
DOI: 10.1186/s12967-019-2071-4 -
International Journal of Molecular... Apr 2021The conserved nuclease-helicase DNA2 has been linked to mitochondrial myopathy, Seckel syndrome, and cancer. Across species, the protein is indispensable for cell... (Review)
Review
The conserved nuclease-helicase DNA2 has been linked to mitochondrial myopathy, Seckel syndrome, and cancer. Across species, the protein is indispensable for cell proliferation. On the molecular level, DNA2 has been implicated in DNA double-strand break (DSB) repair, checkpoint activation, Okazaki fragment processing (OFP), and telomere homeostasis. More recently, a critical contribution of DNA2 to the replication stress response and recovery of stalled DNA replication forks (RFs) has emerged. Here, we review the available functional and phenotypic data and propose that the major cellular defects associated with DNA2 dysfunction, and the links that exist with human disease, can be rationalized through the fundamental importance of DNA2-dependent RF recovery to genome duplication. Being a crucial player at stalled RFs, DNA2 is a promising target for anti-cancer therapy aimed at eliminating cancer cells by replication-stress overload.
Topics: Animals; Cell Survival; Chromosomal Instability; DNA Helicases; DNA Replication; DNA, Mitochondrial; Disease; Humans
PubMed: 33924313
DOI: 10.3390/ijms22083984 -
Cells Jul 2020Cathepsins are the most abundant lysosomal proteases that are mainly found in acidic endo/lysosomal compartments where they play a vital role in intracellular protein... (Review)
Review
Cathepsins are the most abundant lysosomal proteases that are mainly found in acidic endo/lysosomal compartments where they play a vital role in intracellular protein degradation, energy metabolism, and immune responses among a host of other functions. The discovery that cathepsins are secreted and remain functionally active outside of the lysosome has caused a paradigm shift. Contemporary research has unraveled many versatile functions of cathepsins in extralysosomal locations including cytosol and extracellular space. Nevertheless, extracellular cathepsins are majorly upregulated in pathological states and are implicated in a wide range of diseases including cancer and cardiovascular diseases. Taking advantage of the differential expression of the cathepsins during pathological conditions, much research is focused on using cathepsins as diagnostic markers and therapeutic targets. A tailored therapeutic approach using selective cathepsin inhibitors is constantly emerging to be safe and efficient. Moreover, recent development of proteomic-based approaches for the identification of novel physiological substrates offers a major opportunity to understand the mechanism of cathepsin action. In this review, we summarize the available evidence regarding the role of cathepsins in health and disease, discuss their potential as biomarkers of disease progression, and shed light on the potential of extracellular cathepsin inhibitors as safe therapeutic tools.
Topics: Animals; Cathepsins; Cytosol; Disease; Endosomes; Extracellular Space; Humans; Lysosomes
PubMed: 32668602
DOI: 10.3390/cells9071679 -
Frontiers in Immunology 2024Significant advancements have been achieved in understanding the roles of different immune cells, as well as cytokines and chemokines, in the pathogenesis of... (Review)
Review
Significant advancements have been achieved in understanding the roles of different immune cells, as well as cytokines and chemokines, in the pathogenesis of eosinophilic airway conditions. This review examines the pathogenesis of Chronic Rhinosinusitis with Nasal Polyps (CRSwNP), marked by complex immune dysregulation, with major contributions from type 2 inflammation and dysfunctional airway epithelium. The presence of eosinophils and the role of T-cell subsets, particularly an imbalance between Treg and Th17 cells, are crucial to the disease's pathogenesis. The review also investigates the pathogenesis of eosinophilic asthma, a unique asthma subtype. It is characterized by inflammation and high eosinophil levels, with eosinophils playing a pivotal role in triggering type 2 inflammation. The immune response involves Th2 cells, eosinophils, and IgE, among others, all activated by genetic and environmental factors. The intricate interplay among these elements, chemokines, and innate lymphoid cells results in airway inflammation and hyper-responsiveness, contributing to the pathogenesis of eosinophilic asthma. Another scope of this review is the pathogenesis of Eosinophilic Granulomatosis with Polyangiitis (EGPA); a complex inflammatory disease that commonly affects the respiratory tract and small to medium-sized blood vessels. It is characterized by elevated eosinophil levels in blood and tissues. The pathogenesis involves the activation of adaptive immune responses by antigens leading to T and B cell activation and eosinophil stimulation, which causes tissue and vessel damage. On the other hand, Allergic Bronchopulmonary Aspergillosis (ABPA) is a hypersensitive response that occurs when the airways become colonized by aspergillus fungus, with the pathogenesis involving activation of Th2 immune responses, production of IgE antibodies, and eosinophilic action leading to bronchial inflammation and subsequent lung damage. This analysis scrutinizes how an imbalanced immune system contributes to these eosinophilic diseases. The understanding derived from this assessment can steer researchers toward designing new potential therapeutic targets for efficient control of these disorders.
Topics: Animals; Humans; Asthma; Chronic Disease; Cytokines; Eosinophils; Inflammation; Nasal Polyps; Rhinitis; Sinusitis; Th2 Cells
PubMed: 38680486
DOI: 10.3389/fimmu.2024.1285598 -
Cells Jan 2022The Golgi apparatus is a membrane organelle located in the center of the protein processing and trafficking pathway. It consists of sub-compartments with distinct... (Review)
Review
The Golgi apparatus is a membrane organelle located in the center of the protein processing and trafficking pathway. It consists of sub-compartments with distinct biochemical compositions and functions. Main functions of the Golgi, including membrane trafficking, protein glycosylation, and sorting, require a well-maintained stable microenvironment in the sub-compartments of the Golgi, along with metal ion homeostasis. Metal ions, such as Ca, Mn, Zn, and Cu, are important cofactors of many Golgi resident glycosylation enzymes. The homeostasis of metal ions in the secretory pathway, which is required for proper function and stress response of the Golgi, is tightly regulated and maintained by transporters. Mutations in the transporters cause human diseases. Here we provide a review specifically focusing on the transporters that maintain Golgi metal ion homeostasis under physiological conditions and their alterations in diseases.
Topics: Animals; Disease; Golgi Apparatus; Health; Homeostasis; Humans; Ions; Metals
PubMed: 35053405
DOI: 10.3390/cells11020289 -
International Journal of Molecular... Feb 2022Dementia is a global medical and societal challenge; it has devastating personal, social and economic costs, which will increase rapidly as the world's population ages.... (Review)
Review
Dementia is a global medical and societal challenge; it has devastating personal, social and economic costs, which will increase rapidly as the world's population ages. Despite this, there are no disease-modifying treatments for dementia; current therapy modestly improves symptoms but does not change the outcome. Therefore, new treatments are urgently needed-particularly any that can slow down the disease's progression. Many of the neurodegenerative diseases that lead to dementia are characterised by common pathological responses to abnormal protein production and misfolding in brain cells, raising the possibility of the broad application of therapeutics that target these common processes. The unfolded protein response (UPR) is one such mechanism. The UPR is a highly conserved cellular stress response to abnormal protein folding and is widely dysregulated in neurodegenerative diseases. In this review, we describe the basic machinery of the UPR, as well as the evidence for its overactivation and pathogenicity in dementia, and for the marked neuroprotective effects of its therapeutic manipulation in murine models of these disorders. We discuss drugs identified as potential UPR-modifying therapeutic agents-in particular the licensed antidepressant trazodone-and we review epidemiological and trial data from their use in human populations. Finally, we explore future directions for investigating the potential benefit of using trazodone or similar UPR-modulating compounds for disease modification in patients with dementia.
Topics: Animals; Brain; Dementia; Humans; Trazodone; Unfolded Protein Response
PubMed: 35216136
DOI: 10.3390/ijms23042021 -
JAMA Network Open Jan 2022Progress in understanding and preventing diagnostic errors has been modest. New approaches are needed to help clinicians anticipate and prevent such errors. Delineating...
IMPORTANCE
Progress in understanding and preventing diagnostic errors has been modest. New approaches are needed to help clinicians anticipate and prevent such errors. Delineating recurring diagnostic pitfalls holds potential for conceptual and practical ways for improvement.
OBJECTIVES
To develop the construct and collect examples of "diagnostic pitfalls," defined as clinical situations and scenarios vulnerable to errors that may lead to missed, delayed, or wrong diagnoses.
DESIGN, SETTING, AND PARTICIPANTS
This qualitative study used data from January 1, 2004, to December 31, 2016, from retrospective analysis of diagnosis-related patient safety incident reports, closed malpractice claims, and ambulatory morbidity and mortality conferences, as well as specialty focus groups. Data analyses were conducted between January 1, 2017, and December 31, 2019.
MAIN OUTCOMES AND MEASURES
From each data source, potential diagnostic error cases were identified, and the following information was extracted: erroneous and correct diagnoses, presenting signs and symptoms, and areas of breakdowns in the diagnostic process (using Diagnosis Error Evaluation and Research and Reliable Diagnosis Challenges taxonomies). From this compilation, examples were collected of disease-specific pitfalls; this list was used to conduct a qualitative analysis of emerging themes to derive a generic taxonomy of diagnostic pitfalls.
RESULTS
A total of 836 relevant cases were identified among 4325 patient safety incident reports, 403 closed malpractice claims, 24 ambulatory morbidity and mortality conferences, and 355 focus groups responses. From these, 661 disease-specific diagnostic pitfalls were identified. A qualitative review of these disease-specific pitfalls identified 21 generic diagnostic pitfalls categories, which included mistaking one disease for another disease (eg, aortic dissection is misdiagnosed as acute myocardial infarction), failure to appreciate test result limitations, and atypical disease presentations.
CONCLUSIONS AND RELEVANCE
Recurring types of pitfalls were identified and collected from diagnostic error cases. Clinicians could benefit from knowledge of both disease-specific and generic cross-cutting pitfalls. Study findings can potentially inform educational and quality improvement efforts to anticipate and prevent future errors.
Topics: Adult; Ambulatory Care; Diagnostic Errors; Disease; Female; Humans; Male; Malpractice; Medical Errors; Middle Aged; Outcome Assessment, Health Care; Qualitative Research; Quality of Health Care; Retrospective Studies
PubMed: 35061037
DOI: 10.1001/jamanetworkopen.2021.44531 -
Neurobiology of Disease Aug 2023Neurological conditions such as Alzheimer's disease (AD) and related dementias (ADRD) present with many challenges due to the heterogeneity of the related disease(s),... (Review)
Review
Neurological conditions such as Alzheimer's disease (AD) and related dementias (ADRD) present with many challenges due to the heterogeneity of the related disease(s), making it difficult to develop effective treatments. Additionally, the progression of ADRD-related pathologies presents differently between men and women. With two-thirds of the population affected with ADRD being women, ADRD has presented itself with a bias toward the female population. However, studies of ADRD generally do not incorporate sex-based differences in investigating the development and progression of the disease, which is detrimental to understanding and treating dementia. Additionally, recent implications for the adaptive immune system in the development of ADRD bring in new factors to be considered as part of the disease, including sex-based differences in immune response(s) during ADRD development. Here, we review the sex-based differences of pathological hallmarks of ADRD presentation and progression, sex-based differences in the adaptive immune system and how it changes with ADRD, and the importance of precision medicine in the development of a more targeted and personalized treatment for this devastating and prevalent neurodegenerative condition.
Topics: Male; Female; Humans; Alzheimer Disease; Dementia; Immune System
PubMed: 37330146
DOI: 10.1016/j.nbd.2023.106202 -
Journal of the American Heart... Feb 2024Multisystemic inflammatory syndrome in adults is a hyperinflammatory condition following (within 4-12 weeks) SARS-CoV-2 infection. Here, the dysregulation of the... (Review)
Review
Multisystemic inflammatory syndrome in adults is a hyperinflammatory condition following (within 4-12 weeks) SARS-CoV-2 infection. Here, the dysregulation of the immune system leads to a multiorgan involvement often affecting the heart. Cardiac involvement in multisystemic inflammatory syndrome in adults has been described mainly in young men without other comorbidities and may present with different clinical scenarios, including acute heart failure, life-threatening arrhythmias, pericarditis, and myocarditis, with a nonnegligible risk of mortality (up to 7% of all cases). The heterogeneity of its clinical features and the absence of a clear case definition make the differential diagnosis with other postinfectious (eg, infective myocarditis) and hyperinflammatory diseases (eg, adult Still disease and macrophage activation syndrome) challenging. Moreover, the evidence on the efficacy of specific treatments targeting the hyperinflammatory response underlying this clinical condition (eg, glucocorticoids, immunoglobulins, and other immunomodulatory agents) is sparse and not supported by randomized clinical trials. In this review article, we aim to provide an overview of the clinical features and the diagnostic workup of multisystemic inflammatory syndrome in adults with cardiac involvement, highlighting the possible pathogenetic mechanisms and the therapeutic management, along with remaining knowledge gaps in this field.
Topics: Adult; Male; Humans; Myocarditis; Patients; Heart; COVID-19; Diagnosis, Differential; Syndrome
PubMed: 38348793
DOI: 10.1161/JAHA.123.032143 -
Transfusion and Apheresis Science :... Feb 2023The latest WHO report determined the increasing diversity within the CoV-2 omicron and its descendent lineages. Some heavily mutated offshoots of BA.5 and BA.2, such as... (Review)
Review
The latest WHO report determined the increasing diversity within the CoV-2 omicron and its descendent lineages. Some heavily mutated offshoots of BA.5 and BA.2, such as BA.4.6, BF.7, BQ.1.1, and BA.2.75, are responsible for about 20% of infections and are spreading rapidly in multiple countries. It is a sign that Omicron subvariants are now developing a capacity to be more immune escaping and may contribute to a new wave of COVID-19. Covid-19 infections often induce many alterations in human physiological defense and the natural control systems, with exacerbated activation of the inflammatory and homeostatic response, as for any infectious diseases. Severe activation of the early phase of hemostatic components, often occurs, leading to thrombotic complications and often contributing to a lethal outcome selectively in certain populations. Development of autoimmune complications increases the disease burden and lowers its prognosis. While the true mechanism still remains unclear, it is believed to mainly be related to the host autoimmune responses as demonstrated, only in some patients suffering from the presence of autoantibodies that worsens the disease evolution. In fact in some studies the development of autoantibodies to angiotensin converting enzyme 2 (ACE2) was identified, and in other studies autoantibodies, thought to be targeting interferon or binding to annexin A1, or autoantibodies to phospholipids were seen. Moreover, the occurrence of autoimmune heparin induced thrombocytopenia has also been described in infected patients treated with heparin for controlling thrombogenicity. This commentary focuses on the presence of various autoantibodies reported so far in Covid-19 diseases, exploring their association with the disease course and the durability of some related symptoms. Attempts are also made to further analyze the potential mechanism of actions and link the presence of antibodies with pathological complications.
Topics: Humans; COVID-19; Syndrome; Autoantibodies; Disease Progression; Hemostatics
PubMed: 36585276
DOI: 10.1016/j.transci.2022.103625