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Theranostics 2021Macroautophagy (hereafter called autophagy) is a highly conserved physiological process that degrades over-abundant or damaged organelles, large protein aggregates and...
Macroautophagy (hereafter called autophagy) is a highly conserved physiological process that degrades over-abundant or damaged organelles, large protein aggregates and invading pathogens via the lysosomal system (the vacuole in plants and yeast). Autophagy is generally induced by stress, such as oxygen-, energy- or amino acid-deprivation, irradiation, drugs, . In addition to non-selective bulk degradation, autophagy also occurs in a selective manner, recycling specific organelles, such as mitochondria, peroxisomes, ribosomes, endoplasmic reticulum (ER), lysosomes, nuclei, proteasomes and lipid droplets (LDs). This capability makes selective autophagy a major process in maintaining cellular homeostasis. The dysfunction of selective autophagy is implicated in neurodegenerative diseases (NDDs), tumorigenesis, metabolic disorders, heart failure, . Considering the importance of selective autophagy in cell biology, we systemically review the recent advances in our understanding of this process and its regulatory mechanisms. We emphasize the 'cargo-ligand-receptor' model in selective autophagy for specific organelles or cellular components in yeast and mammals, with a focus on mitophagy and ER-phagy, which are finely described as types of selective autophagy. Additionally, we highlight unanswered questions in the field, helping readers focus on the research blind spots that need to be broken.
Topics: Autophagy; Humans; Macroautophagy; Mitophagy; Organelles
PubMed: 33391472
DOI: 10.7150/thno.49860 -
Science China. Life Sciences Feb 2024The endoplasmic reticulum (ER), which is composed of a continuous network of tubules and sheets, forms the most widely distributed membrane system in eukaryotic cells.... (Review)
Review
The endoplasmic reticulum (ER), which is composed of a continuous network of tubules and sheets, forms the most widely distributed membrane system in eukaryotic cells. As a result, it engages a variety of organelles by establishing membrane contact sites (MCSs). These contacts regulate organelle positioning and remodeling, including fusion and fission, facilitate precise lipid exchange, and couple vital signaling events. Here, we systematically review recent advances and converging themes on ER-involved organellar contact. The molecular basis, cellular influence, and potential physiological functions for ER/nuclear envelope contacts with mitochondria, Golgi, endosomes, lysosomes, lipid droplets, autophagosomes, and plasma membrane are summarized.
Topics: Endoplasmic Reticulum; Golgi Apparatus; Cell Membrane; Mitochondria; Lysosomes; Endosomes
PubMed: 38212460
DOI: 10.1007/s11427-023-2443-9 -
Emerging protein degradation strategies: expanding the scope to extracellular and membrane proteins.Theranostics 2021Classic small molecule inhibitors that directly target pathogenic proteins typically rely on the accessible binding sites to achieve prolonged occupancy and influence... (Review)
Review
Classic small molecule inhibitors that directly target pathogenic proteins typically rely on the accessible binding sites to achieve prolonged occupancy and influence protein functions. The emerging targeted protein degradation (TPD) strategies exemplified by PROteolysis TArgeting Chimeras (PROTACs) are revolutionizing conventional drug discovery modality to target proteins of interest (POIs) that were categorized as "undruggable" before, however, these strategies are limited within intracellular POIs. The novel new degrader technologies such as LYsosome-TArgeting Chimaeras (LYTACs) and Antibody-based PROTACs (AbTACs) have been successfully developed to expand the scope of TPD to extracellular and membrane proteins, fulfilling huge unmet medical needs. Here, we systematically review the currently viable protein degradation strategies, emphasize that LYTACs and AbTACs turn a new avenue for the development of TPD, and highlight the potential challenges and directions in this vibrant field.
Topics: Animals; Cellular Microenvironment; Drug Delivery Systems; Drug Discovery; Humans; Lysosomes; Membrane Proteins; Proteasome Endopeptidase Complex; Proteins; Proteolysis
PubMed: 34373745
DOI: 10.7150/thno.62686 -
European Journal of Medicinal Chemistry Dec 2023Targeted protein degradation (TPD) has emerged as a promising therapeutic approach with potential advantages over traditional occupancy-based inhibitors in terms of... (Review)
Review
Targeted protein degradation (TPD) has emerged as a promising therapeutic approach with potential advantages over traditional occupancy-based inhibitors in terms of dosing, side effects and targeting "undruggable" proteins. Targeted degraders can theoretically bind any nook or cranny of targeted proteins to drive degradation. This offers convenience versus the small-molecule inhibitors that must function in a well-defined pocket. The degradation process depends mainly on two cell self-destruction mechanisms, namely the ubiquitin-proteasome system and the lysosomal degradation pathway. Various TPD strategies (e.g., proteolytic-targeting chimeras, molecular glues, lysosome-targeting chimeras, and autophagy-targeting chimeras) have been developed. These approaches hold great potential for targeting dysregulated proteins, potentially offering therapeutic benefits. In this article, we systematically review the mechanisms of various TPD strategies, potential applications to drug discovery, and recent advances. We also discuss the benefits and challenges associated with these TPD strategies, aiming to provide insight into the targeting of dysregulated proteins and facilitate their clinical applications.
Topics: Proteolysis; Proteasome Endopeptidase Complex; Autophagy; Drug Discovery; Lysosomes
PubMed: 37778240
DOI: 10.1016/j.ejmech.2023.115839 -
Frontiers in Cellular and Infection... 2023Identifying novel biomarkers that are both specific and sensitive to periprosthetic joint infection (PJI) has the potential to improve diagnostic accuracy and ultimately... (Review)
Review
BACKGROUND
Identifying novel biomarkers that are both specific and sensitive to periprosthetic joint infection (PJI) has the potential to improve diagnostic accuracy and ultimately enhance patient outcomes. Therefore, the aim of this systematic review is to identify and evaluate the effectiveness of novel biomarkers for the diagnosis of PJI.
METHODS
We searched the MEDLINE, EMBASE, PubMed, and Cochrane Library databases from January 1, 2018, to September 30, 2022, using the search terms "periprosthetic joint infection," "prosthetic joint infection," or "periprosthetic infection" as the diagnosis of interest and the target index, combined with the term "marker." We excluded articles that mentioned established biomarkers such as CRP, ESR, Interleukin 6, Alpha defensin, PCT (procalcitonin), and LC (leucocyte cell count). We used the MSIS, ICM, or EBJS criteria for PJI as the reference standard during quality assessment.
RESULTS
We collected 19 studies that analyzed fourteen different novel biomarkers. Proteins were the most commonly analyzed biomarkers (nine studies), followed by molecules (three studies), exosomes (two studies), DNA (two studies), interleukins (one study), and lysosomes (one study). Calprotectin was a frequently analyzed and promising marker. In the scenario where the threshold was set at ≥50-mg/mL, the calprotectin point-of-care (POC) performance showed a high sensitivity of 98.1% and a specificity of 95.7%.
CONCLUSION
None of the analyzed biomarkers demonstrated outstanding performance compared to the established parameters used for standardized treatment based on established PJI definitions. Further studies are needed to determine the benefit and usefulness of implementing new biomarkers in diagnostic PJI settings.
Topics: Humans; Prosthesis-Related Infections; Arthritis, Infectious; Biomarkers; Procalcitonin; Leukocyte Count; alpha-Defensins; Sensitivity and Specificity
PubMed: 37529352
DOI: 10.3389/fcimb.2023.1210345 -
Journal of Alzheimer's Disease : JAD 2022The endosomal-lysosomal and autophagy (ELA) pathway may be implicated in the progression of Alzheimer's disease (AD); however, findings thus far have been inconsistent. (Meta-Analysis)
Meta-Analysis
BACKGROUND
The endosomal-lysosomal and autophagy (ELA) pathway may be implicated in the progression of Alzheimer's disease (AD); however, findings thus far have been inconsistent.
OBJECTIVE
To systematically summarize differences in endosomal-lysosomal and autophagy proteins in the cerebrospinal fluid (CSF) of people with AD and healthy controls (HC).
METHODS
Studies measuring CSF concentrations of relevant proteins in the ELA pathway in AD and healthy controls were included. Standardized mean differences (SMD) with 95% confidence intervals (CI) between AD and healthy controls in CSF concentrations of relevant proteins were meta-analyzed using random-effects models.
RESULTS
Of 2,471 unique studies, 43 studies were included in the systematic review and meta-analysis. Differences in ELA protein levels in the CSF between AD and healthy controls were observed, particularly in lysosomal membrane (LAMP-1: NAD/NHC = 348/381, SMD [95% CI] = 0.599 [0.268, 0.930], I2 = 72.8%; LAMP-2: NAD/NHC = 401/510, SMD [95% CI] = 0.480 [0.134, 0.826], I2 = 78.7%) and intra-lysosomal proteins (GM2A: NAD/NHC = 390/420, SMD [95% CI] = 0.496 [0.039, 0.954], I2 = 87.7%; CTSB: NAD/NHC = 485/443, SMD [95% CI] = 0.201 [0.029, 0.374], I2 = 28.5%; CTSZ: NAD/NHC = 535/820, SMD [95% CI] = -0.160 [-0.305, -0.015], I2 = 24.0%) and in proteins involved in endocytosis (AP2B1:NAD/NHC = 171/205, SMD [95% CI] = 0.513 [0.259, 0.768], I2 = 27.4%; FLOT1: NAD/NHC = 41/45, SMD [95% CI] = -0.489 [-0.919, -0.058], I2 <0.01). LC3B, an autophagy marker, also showed a difference (NAD/NHC = 70/59, SMD [95% CI] = 0.648 [0.180, 1.116], I2 = 38.3%)), but overall there was limited evidence suggesting differences in proteins involved in endosomal function and autophagy.
CONCLUSION
Dysregulation of proteins in the ELA pathway may play an important role in AD pathogenesis. Some proteins within this pathway may be potential biomarkers for AD.
Topics: Alzheimer Disease; Autophagy; Biomarkers; Endosomes; Humans; Lysosomes; NAD
PubMed: 35754279
DOI: 10.3233/JAD-220360 -
World Journal of Clinical Cases Apr 2021The proton pump inhibitors (PPIs), used to reduce gastric acid secretion, represent one of the most widely used pharmaceutical classes in the world. Their consumption as...
BACKGROUND
The proton pump inhibitors (PPIs), used to reduce gastric acid secretion, represent one of the most widely used pharmaceutical classes in the world. Their consumption as a risk factor for the evolution of severe forms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been investigated as well as the mortality of these patients. These risks also appear to be linked to the duration and the dosage. On the other hand, several studies have emerged with regard to the protective or therapeutic effects of these drugs. More and more evidence underlines the immunomodulatory and anti-fibrotic role of PPIs. In addition, their ability to alkalize the contents of endosomes and lysosomes serves as an obstacle to the entry of the virus into the host cells.
AIM
To identify studies on the relationship between the intake of PPIs and coronavirus disease 2019 (COVID-19) in patients affected by SARS-CoV-2 infection, with the main objective of evaluating the outcomes related to severity and mortality.
METHODS
A literature review was performed in November 2020. The MEDLINE/PubMed, Cochrane Library, EMBASE and Google Scholar databases were searched for all relevant articles published in English on this topic. The search terms were identified by means of controlled vocabularies, such as the National Library of Medicine's MESH (Medical Subject Headings) and keywords. The MESH terms and keywords used were as follows: "COVID-19", "proton pump inhibitors", "PPIs", "SARS-CoV-2", "outcomes", "severity" and "mortality". The inclusion criteria regarding the studies considered in our analysis were: meta-analysis, case-control, hospital-based case-control, population-based case-control, retrospective studies, online survey, as well as cohort-studies, while articles not published as full reports, such as conference abstracts, case reports and editorials were excluded. We tried to summarize and pool all the data if available.
RESULTS
A total of 9 studies were found that described the use of PPIs, of which only 5 clearly reported the severity and mortality data in SARS-CoV-2 patients. Our pooled incidence analysis of severe events did not differ between patients with and without PPIs (odds ratio 1.65, 95% confidence interval: 0.62-4.35) ( = 0.314), or for mortality (odds ratio 1.77, 95% confidence interval: 0.62-5.03) ( = 0.286).
CONCLUSION
Detailed and larger case studies are needed to accurately understand the role of PPIs in this viral infection.
PubMed: 33969059
DOI: 10.12998/wjcc.v9.i12.2763 -
International Journal of Molecular... Jun 2017Eukaryotes use autophagy as a mechanism for maintaining cellular homeostasis by degrading and recycling organelles and proteins. This process assists in the... (Review)
Review
Eukaryotes use autophagy as a mechanism for maintaining cellular homeostasis by degrading and recycling organelles and proteins. This process assists in the proliferation and survival of advanced cancers. There is mounting preclinical evidence that targeting autophagy can enhance the efficacy of many cancer therapies. Hydroxychloroquine (HCQ) is the only clinically-approved autophagy inhibitor, and this systematic review focuses on HCQ use in cancer clinical trials. Preclinical trials have shown that HCQ alone and in combination therapy leads to enhancement of tumor shrinkage. This has provided the base for multiple ongoing clinical trials involving HCQ alone and in combination with other treatments. However, due to its potency, there is still a need for more potent and specific autophagy inhibitors. There are multiple autophagy inhibitors in the pre-clinical stage at various stages of development. Additional studies on the mechanism of HCQ and other autophagy inhibitors are still required to answer questions surrounding how these agents will eventually be used in the clinic.
Topics: Animals; Antimalarials; Antineoplastic Agents; Autophagy; Clinical Trials as Topic; Humans; Hydroxychloroquine; Neoplasms
PubMed: 28621712
DOI: 10.3390/ijms18061279 -
Journal of Inherited Metabolic Disease May 2022Lysosomal storage disorders are rare multiorgan, degenerative conditions requiring invasive treatment. Rare disorders pose unique challenges; therefore, exploring their... (Review)
Review
Lysosomal storage disorders are rare multiorgan, degenerative conditions requiring invasive treatment. Rare disorders pose unique challenges; therefore, exploring their impact is crucial for understanding family needs. This novel review aimed to understand the psychosocial outcomes for parents of children with lysosomal storage disorders. Five electronic databases were systematically searched. Thirty-eight (23 qualitative, 10 qualitative and 5 mixed methods) studies were included, analysed using a sequential explanatory narrative synthesis and appraised for their methodological quality. Quantitative data revealed the multifaceted impact on parents' psychological and social wellbeing. Qualitative data informed the challenges that these parents faced which were expressed within three main themes: (a) Uncertainty and the unknown, (b) All-encompassing impact and (c) Finding a way forward. The synthesis demonstrated that factors associated with the condition (symptoms, behaviour and severity) had a substantial negative impact on parental outcomes, upheld by concurrent loss (deterioration and poor prognosis) and uncertainty. This substantive integrated review revealed considerable unmet parental psychosocial needs.
Topics: Child; Humans; Lysosomes; Parenting; Parents; Qualitative Research
PubMed: 35124835
DOI: 10.1002/jimd.12482 -
JBI Evidence Synthesis Jun 2022The objective of this review was to investigate the experiences of patients with lysosomal storage disorders who are receiving enzyme-replacement therapy and the... (Review)
Review
Experiences of patients with lysosomal storage disorders who are receiving enzyme-replacement therapy and the experiences of their family members: a qualitative systematic review.
OBJECTIVE
The objective of this review was to investigate the experiences of patients with lysosomal storage disorders who are receiving enzyme-replacement therapy and the experiences of their family members.
INTRODUCTION
Lysosomal storage disorders are rare diseases caused by mutations in the genes that encode proteins required for lysosomal function. The age of onset of these disorders varies from infancy to adulthood, depending on the specific disease and type. Enzyme-replacement therapy is the standard treatment for some lysosomal storage disorders. However, patients' adherence to this treatment is affected not only by the resultant changes (or lack thereof) in their symptoms, but also by the scheduling of the frequent hospital visits necessary to receive this treatment. No previous qualitative systematic review has examined the experiences of these patients and their families.
INCLUSION CRITERIA
Qualitative studies on the experiences of patients with lysosomal storage disorders who were receiving enzyme-replacement therapy and/or the experiences of the family members of these patients were included. These experiences could include satisfaction/dissatisfaction with diagnosis, difficulties and expectations regarding continuing treatment, advantages/disadvantages concerning school and work life, the psychological burden on families, and the support provided by families. This review considered studies in all settings because relevant experiences may occur outside medical institutions.
METHODS
MEDLINE, CINAHL Plus, APA PsycINFO, Scopus, and Igaku Chuo Zasshi were searched for articles published between January 1991 and May 13, 2021. No language restrictions were applied. The study selection, critical appraisal, data extraction, and data synthesis were performed in accordance with the JBI methodology for systematic reviews of qualitative evidence.
RESULTS
Seven studies were included in this review, from which 37 findings with narrative illustrations were extracted; of these, 33 were assessed as unequivocal and four as credible. These findings were integrated into 10 categories and three synthesized findings. The first synthesized finding was encouraging awareness of the minor changes in physical symptoms caused by the treatment, which contains categories such as physical change caused by treatment. The second synthesized finding was supporting acceptance of the disease and coping with associated psychological challenges, which contains categories such as concerns regarding the future. The third synthesized finding was customization of treatment plans to minimize restrictions on the lives of patients and their families, which contains categories such as restrictions on patients' lives. According to the ConQual criteria, all three synthesized findings had low confidence levels.
CONCLUSION
Evidence obtained through the synthesized findings produced in this review identified the primary experiences of patients with lysosomal storage disorders who are receiving enzyme-replacement therapy and their family members. These experiences concerned challenges regarding physical, psychological, and social health. When supporting patients with lysosomal storage disorders and their families, it is necessary to consider not only the symptoms and treatments but also the mental and social aspects.
SYSTEMATIC REVIEW REGISTRATION NUMBER
PROSPERO CRD42019147751.
Topics: Adaptation, Psychological; Adult; Enzyme Replacement Therapy; Family; Humans; Lysosomes; Qualitative Research
PubMed: 34839313
DOI: 10.11124/JBIES-21-00074