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The FEBS Journal Feb 2023p62/Sequestosome-1 (SQSTM1) is a selective autophagy receptor that recruits and delivers intracellular substrates for bulk clearance through the autophagy lysosomal... (Review)
Review
p62/Sequestosome-1 (SQSTM1) is a selective autophagy receptor that recruits and delivers intracellular substrates for bulk clearance through the autophagy lysosomal pathway. Interestingly, p62 also serves as a signaling scaffold to participate in the regulation of multiple physiological processes, including oxidative stress response, metabolism, inflammation, and programmed cell death. Perturbation of p62 activity has been frequently found to be associated with the pathogenesis of many liver diseases. p62 has been identified as a critical component of protein aggregates in the forms of Mallory-Denk bodies (MDBs) or intracellular hyaline bodies (IHBs), which are known to be frequently detected in biopsy samples from alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma (HCC) patients. Importantly, abundance of these p62 inclusion bodies is increasingly recognized as a biomarker for NASH and HCC. Although the level of p62 bodies seems to predict the progression and prognosis of these liver diseases, understanding of the underlying mechanisms by which p62 regulates and contributes to the development and progression of these diseases remains incomplete. In this review, we will focus on the function and regulation of p62, and its pathophysiological roles in the liver, by critically reviewing the findings from preclinical models that recapitulate the pathogenesis and manifestation of these liver diseases in humans. In addition, we will also explore the suitability of p62 as a predictive biomarker and a potential therapeutic target for the treatment of liver diseases, including NASH and HCC, as well as recent development of small-molecule compounds for targeting the p62 signaling axis.
Topics: Humans; Carcinoma, Hepatocellular; Sequestosome-1 Protein; Liver Neoplasms; Non-alcoholic Fatty Liver Disease; Liver; Biomarkers; Autophagy
PubMed: 34882306
DOI: 10.1111/febs.16317 -
American Journal of Physiology.... Jun 2017Intermediate filament proteins (IFs), such as cytoplasmic keratins in epithelial cells and vimentin in mesenchymal cells and the nuclear lamins, make up one of the three... (Review)
Review
Intermediate filament proteins (IFs), such as cytoplasmic keratins in epithelial cells and vimentin in mesenchymal cells and the nuclear lamins, make up one of the three major cytoskeletal protein families. Whether in digestive organs or other tissues, IFs share several unique features including stress-inducible overexpression, abundance, cell-selective and differentiation state expression, and association with >80 human diseases when mutated. Whereas most IF mutations cause disease, mutations in simple epithelial keratins 8, 18, or 19 or in lamin A/C predispose to liver disease with or without other tissue manifestations. Keratins serve major functions including protection from apoptosis, providing cellular and subcellular mechanical integrity, protein targeting to subcellular compartments, and scaffolding and regulation of cell-signaling processes. Keratins are essential for Mallory-Denk body aggregate formation that occurs in association with several liver diseases, whereas an alternate type of keratin and lamin aggregation occurs upon liver involvement in porphyria. IF-associated diseases have no known directed therapy, but high-throughput drug screening to identify potential therapies is an appealing ongoing approach. Despite the extensive current knowledge base, much remains to be discovered regarding IF physiology and pathophysiology in digestive and nondigestive organs.
Topics: Animals; Digestive System; Digestive System Diseases; Gene Expression Regulation; Genetic Predisposition to Disease; Humans; Intermediate Filament Proteins; Intermediate Filaments; Mallory Bodies; Mutation; Phenotype; Polymorphism, Genetic
PubMed: 28360031
DOI: 10.1152/ajpgi.00455.2016 -
FEBS Letters Aug 2016p62/SQSTM1 is a multifunctional signaling hub and autophagy adaptor with many binding partners, which allow it to activate mTORC1-dependent nutrient sensing,... (Review)
Review
p62/SQSTM1 is a multifunctional signaling hub and autophagy adaptor with many binding partners, which allow it to activate mTORC1-dependent nutrient sensing, NF-κB-mediated inflammatory responses, and the NRF2-activated antioxidant defense. p62 recognizes polyubiquitin chains via its C-terminal domain and binds to LC3 via its LIR motif, thereby promoting the autophagic degradation of ubiquitinated cargos. p62 accumulates in many human liver diseases, including nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC), where it is a component of Mallory-Denk bodies and intracellular hyaline bodies. Chronic p62 elevation contributes to HCC development by preventing oncogene-induced senescence and death of cancer-initiating cells and enhancing their proliferation. In this review, we discuss p62-mediated signaling pathways and their roles in liver pathophysiology, especially NASH and HCC.
Topics: Carcinoma, Hepatocellular; Food; Gene Expression Regulation, Neoplastic; Humans; Inflammation; Liver Neoplasms; Mechanistic Target of Rapamycin Complex 1; Multiprotein Complexes; NF-kappa B; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Sequestosome-1 Protein; TOR Serine-Threonine Kinases
PubMed: 27404485
DOI: 10.1002/1873-3468.12301 -
PeerJ. Computer Science 2023Figures and captions in medical documentation contain important information. As a result, researchers are becoming more interested in obtaining published medical figures...
BACKGROUND
Figures and captions in medical documentation contain important information. As a result, researchers are becoming more interested in obtaining published medical figures from medical papers and utilizing the captions as a knowledge source.
METHODS
This work introduces a unique and successful six-fold methodology for extracting figure-caption pairs. The A-torus wavelet transform is used to retrieve the first edge from the scanned page. Then, using the maximally stable extremal regions connected component feature, text and graphical contents are isolated from the edge document, and multi-layer perceptron is used to successfully detect and retrieve figures and captions from medical records. The figure-caption pair is then extracted using the bounding box approach. The files that contain the figures and captions are saved separately and supplied to the end useras theoutput of any investigation. The proposed approach is evaluated using a self-created database based on the pages collected from five open access books: Sergey Makarov, Gregory Noetscher and Aapo Nummenmaa's book "Brain and Human Body Modelling 2021", "Healthcare and Disease Burden in Africa" by Ilha Niohuru, "All-Optical Methods to Study Neuronal Function" by Eirini Papagiakoumou, "RNA, the Epicenter of Genetic Information" by John Mattick and Paulo Amaral and "Illustrated Manual of Pediatric Dermatology" by Susan Bayliss Mallory, Alanna Bree and Peggy Chern.
RESULTS
Experiments and findings comparing the new method to earlier systems reveal a significant increase in efficiency, demonstrating the suggested technique's robustness and efficiency.
PubMed: 37547417
DOI: 10.7717/peerj-cs.1452 -
Redox Biology Jun 2022Autophagy is an evolutionarily conserved self-protecting mechanism implicated in cellular homeostasis. ATG4B plays a vital role in autophagy process via undertaking...
Autophagy is an evolutionarily conserved self-protecting mechanism implicated in cellular homeostasis. ATG4B plays a vital role in autophagy process via undertaking priming and delipidation of LC3. Chemical inhibitors and regulative modifications such as oxidation of ATG4B have been demonstrated to modulate autophagy function. Whether and how ATG4B could be regulated by metal ions is largely unknown. Copper is an essential trace metal served as static co-factors in redox reactions in physiology process. Excessive accumulation of copper in ATP7B mutant cells leads to pathology progression such as insoluble Mallory body (MB) in Wilson disease (WD). The clearance of MB via autophagy pathway was thought as a promising strategy for WD. Here, we discovered that copper ion instead of other ions could inhibit the activity of ATG4B followed by autophagy suppression. In addition, copper could induce ATG4B oligomers depending on cysteine oxidation which could be abolished in reduced condition. Copper also promotes the formation of insoluble ATG4B aggregates, as well as p62-and ubiquitin-positive aggregates, which is consistent with the components of MB caused by copper overload in WD cell model. Importantly, overexpression of ATG4B could partially reduce the formation of MB and rescue impaired autophagy. Taken together, our results uncovered for the first time a new damage mechanism mediated by copper and implied new insights of the crosstalk between the toxicity of copper and autophagy in the pathogenesis of WD.
Topics: Autophagy; Autophagy-Related Proteins; Copper; Cysteine Endopeptidases; Microtubule-Associated Proteins
PubMed: 35349929
DOI: 10.1016/j.redox.2022.102284 -
Experimental and Molecular Pathology Jun 2016There is a possibility that the aggresomes that form in the brain in neurodegenerative diseases like Alzheimer's disease (AD) and in the liver where aggresomes like... (Review)
Review
There is a possibility that the aggresomes that form in the brain in neurodegenerative diseases like Alzheimer's disease (AD) and in the liver where aggresomes like Mallory-Denk Bodies (MDB) form, share mechanisms. MDBs can be prevented by feeding mice sadenosylmethionine (SAMe) or betaine. Possibly these proteins could prevent AD. We compared the literature on MDBs and AD pathogenesis, which include roles played by p62, ubiquitin UBB +1, HSPs70, 90, 104, FAT10, NEDD8, VCP/97, and the protein quality control mechanisms including the 26s proteasome, the IPOD and JUNQ and autophagosome pathways.
Topics: Alzheimer Disease; Animals; Autophagosomes; Humans; Mallory Bodies; Models, Biological; Neurodegenerative Diseases; Proteasome Endopeptidase Complex; Protein Aggregates; Protein Aggregation, Pathological
PubMed: 27068270
DOI: 10.1016/j.yexmp.2016.03.010 -
The Journal of Adolescent Health :... Jun 2021To synthesize the diverse body of literature on sexual and gender minority youth (SGMY) and sexual health education. (Review)
Review
PURPOSE
To synthesize the diverse body of literature on sexual and gender minority youth (SGMY) and sexual health education.
METHODS
We conducted a systematic search of the literature on SGMY and sexual health education, including SGMY perspectives on sexual health education, the acceptability or effectiveness of programs designed for SGMY, and SGMY-specific results of sexual health education programs delivered to general youth populations.
RESULTS
A total of 32 articles were included. Sixteen qualitative studies with SGMY highlight key perspectives underscoring how youth gained inadequate knowledge from sexual health education experiences and received content that excluded their identities and behaviors. Thirteen studies examined the acceptability or effectiveness of sexual health interventions designed for SGMY from which key characteristics of inclusive sexual health education relating to development, content, and delivery emerged. One study found a sexual health education program delivered to a general population of youth was also acceptable for a subsample of sexual minority girls.
CONCLUSIONS
Future research on SGMY experiences should incorporate populations understudied, including younger adolescents, sexual minority girls, and transgender persons. Further, the effectiveness of inclusive sexual health education in general population settings requires further study.
Topics: Adolescent; Female; Humans; Sex Education; Sexual Behavior; Sexual Health; Sexual and Gender Minorities; Transgender Persons
PubMed: 33162290
DOI: 10.1016/j.jadohealth.2020.09.032 -
Trends in Molecular Medicine Jul 2016A key aspect of cellular function is the proper assembly and utilization of ribonucleoproteins (RNPs). Recent studies have shown that hyper- or hypo-assembly of various... (Review)
Review
A key aspect of cellular function is the proper assembly and utilization of ribonucleoproteins (RNPs). Recent studies have shown that hyper- or hypo-assembly of various RNPs can lead to human diseases. Defects in the formation of RNPs lead to 'RNP hypo-assembly diseases', which can be caused by RNA degradation outcompeting RNP assembly. By contrast, excess RNP assembly, either in higher order RNP granules, or due to the expression of repeat-containing RNAs, can lead to 'RNP hyper-assembly diseases'. Here, we discuss the most recent advances in understanding the cause of disease onset, as well as potential therapies from the aspect of modulating RNP assembly in the cell, which presents a novel route to the treatment of these diseases.
Topics: Animals; Dwarfism; Dyskeratosis Congenita; Fetal Growth Retardation; Hair; Hirschsprung Disease; Humans; Immunologic Deficiency Syndromes; Mallory Bodies; Microcephaly; Muscular Atrophy, Spinal; Muscular Dystrophies; Mutation; Osteochondrodysplasias; Parkinson Disease; Primary Immunodeficiency Diseases; RNA Stability; Ribonucleoproteins; Scoliosis; Walker-Warburg Syndrome
PubMed: 27263464
DOI: 10.1016/j.molmed.2016.05.005 -
Hepatology (Baltimore, Md.) Oct 2022The NASH Clinical Research Network histologic scoring system, the gold-standard NASH histology assessment for clinical trials, has demonstrated intrarater and interrater...
BACKGROUND AND AIMS
The NASH Clinical Research Network histologic scoring system, the gold-standard NASH histology assessment for clinical trials, has demonstrated intrarater and interrater variability. An expert panel in a previous systematic Research and Development/University of California Los Angeles (RAND/UCLA) study determined that existing histologic scoring systems do not fully capture NASH disease activity and fibrosis, and standardized definitions of histologic features are needed. We evaluated the reliability of existing and alternate histologic measures and their correlations with a disease activity visual analog scale to propose optimal components for an expanded NAFLD activity score (NAS).
APPROACH AND RESULTS
Four liver pathologists who were involved in the prior RAND/UCLA study underwent standardized training and multiple discussions with the goal of improving agreement. They were blinded to clinical information and scored histologic measures twice, ≥2 weeks apart, for 40 liver biopsies representing the full spectrum of NAFLD. Index intraclass correlation coefficient (ICC) estimates demonstrated intrarater (0.80-0.85) and interrater (0.60-0.72) reliability. Hepatocyte ballooning items had similar interrater ICCs (0.68-0.79), including those extending scores from 0-2 to 0-4. Steatosis measures (interrater ICCs, 0.72-0.80) correlated poorly with disease activity. Correlations with disease activity were largest for hepatocyte ballooning and Mallory-Denk bodies (MDBs), with both used to develop the expanded NAS (intrarater ICC, 0.90; interrater ICC, 0.80). Fibrosis measures had ICCs of 0.70-0.87.
CONCLUSIONS
After extensive preparation among a group of experienced pathologists, we demonstrated improved reliability of multiple existing histologic NAFLD indices and fibrosis staging systems. Hepatocyte ballooning and MDBs most strongly correlated with disease activity and were used for the expanded NAS. Further validation including evaluation of responsiveness is required.
Topics: Biopsy; Fibrosis; Humans; Liver; Non-alcoholic Fatty Liver Disease; Reproducibility of Results; Severity of Illness Index
PubMed: 35332569
DOI: 10.1002/hep.32475 -
Mayo Clinic Proceedings Feb 2015Spinal cord injury can be defined as a loss of communication between the brain and the body due to disrupted pathways within the spinal cord. Although many promising... (Review)
Review
Spinal cord injury can be defined as a loss of communication between the brain and the body due to disrupted pathways within the spinal cord. Although many promising molecular strategies have emerged to reduce secondary injury and promote axonal regrowth, there is still no effective cure, and recovery of function remains limited. Functional electrical stimulation (FES) represents a strategy developed to restore motor function without the need for regenerating severed spinal pathways. Despite its technological success, however, FES has not been widely integrated into the lives of spinal cord injury survivors. In this review, we briefly discuss the limitations of existing FES technologies. Additionally, we discuss how optogenetics, a rapidly evolving technique used primarily to investigate select neuronal populations within the brain, may eventually be used to replace FES as a form of therapy for functional restoration after spinal cord injury.
Topics: Electric Stimulation Therapy; Humans; Optogenetics; Spinal Cord; Spinal Cord Injuries
PubMed: 25659246
DOI: 10.1016/j.mayocp.2014.12.004