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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 -
BMC Ophthalmology Dec 2023Age-related macular degeneration (AMD) is a significant cause of severe vision loss. The main purpose of this study was to identify mass spectrometry proteomics-based... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Age-related macular degeneration (AMD) is a significant cause of severe vision loss. The main purpose of this study was to identify mass spectrometry proteomics-based potential biomarkers of AMD that contribute to understanding the mechanisms of disease and aiding in early diagnosis.
METHODS
This study retrieved studies that aim to detect differences relate to proteomics in AMD patients and healthy control groups by mass spectrometry (MS) proteomics approaches. The search process was accord with PRISMA guidelines (PROSPERO database: CRD42023388093). Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes Pathway Analysis (KEGG) were performed on differentially expressed proteins (DEPs) in the included articles using the DAVID database. DEPs were included in a meta-analysis when their effect size could be computed in at least two research studies. The effect size of measured proteins was transformed to the log2-fold change. Protein‒protein interaction (PPI) analysis was conducted on proteins that were statistically significant in the meta-analysis using the String online database.
RESULTS
Eleven studies fulfilled the inclusion criteria, and 161 DEPs were identified. The GO analysis showed that AMD is significantly related to proteolysis, extracellular exosome and protein binding. In KEGG, the most significant pathway was the complement and coagulation cascades. Meta-analysis results suggested that eight proteins were statistically significant, and according to PPI results, the most significant four proteins were serotransferrin (TF), apolipoprotein A1 (APOA1), complement C3 (C3) and lipocalin-1 (LCN1).
CONCLUSIONS
Four possible biomarkers, TF, APOA1, C3 and LCN1, were found to be significant in the pathogenesis of AMD and need to be further validated. Further studies should be performed to evaluate diagnostic and therapeutic value of these proteins.
Topics: Humans; Proteomics; Macular Degeneration; Biomarkers; Proteins; Mass Spectrometry
PubMed: 38087257
DOI: 10.1186/s12886-023-03237-0 -
Annals of Clinical and Laboratory... May 2017Aging of the population contributes to the increasing prevalence of heart failure. Autophagy is an evolutionarily conserved process aiming to degrade both long-lived... (Review)
Review
Aging of the population contributes to the increasing prevalence of heart failure. Autophagy is an evolutionarily conserved process aiming to degrade both long-lived proteins and damaged or excessive cyto-organelles via the lysosomal-mediated pathway. Although autophagy is involved in the normal homeostasis of cardiovascular cells, upregulation of autophagy and its abnormal modulation by inflammation may lead to cardiovascular functional decline and heart failure. Despite major improvements in the prevention, diagnosis, and treatment of cardiovascular diseases, heart failure remains one of the major diagnostic and therapeutic challenges. Here, we review the cardiovascular autophagy and its interplay with inflammation which may lead to heart failure exploring some potential treatment options.
Topics: Animals; Autophagy; Heart Failure; Humans; Inflammasomes; Metabolic Networks and Pathways; Mitophagy; Proteolysis
PubMed: 28667023
DOI: No ID Found -
Journal of Animal Physiology and Animal... May 2021The objective was to conduct a systematic review to evaluate the effects of dietary supplementation with beta-adrenergic agonists on calpains and calpastatin activity in...
The objective was to conduct a systematic review to evaluate the effects of dietary supplementation with beta-adrenergic agonists on calpains and calpastatin activity in bovine muscle and changes in meat tenderness. A survey was conducted in June 2019 on Science Direct, Web of Science, Scopus, PubMed and Capes Periodicals, using four keyword combinations: agonist and calpain and cattle; agonist and calpain and bovine; agonist and calpain and heifers; agonist and calpain and steers. Thirteen studies were selected, 54% concluded that supplementation with beta-adrenergic agonists increases calpastatin activity, 23% observed increase in their gene expression and 23% reported no effect on activity or expression of this enzyme. Nine studies evaluated the influence of beta-adrenergic agonists supplementation on meat texture and all found an increase in shear force values. There is strong evidence that beta-adrenergic agonists may increase calpastatin activity in the muscle, causing damage to meat tenderness.
Topics: Adrenergic beta-Agonists; Animals; Calpain; Cattle; Female; Meat; Muscle, Skeletal; Muscles; Proteolysis
PubMed: 33452737
DOI: 10.1111/jpn.13479 -
Brazilian Journal of Microbiology :... 2017Specific proteases capable of degrading native triple helical or denatured collagen have been required for many years and have a large spectrum of applications. There... (Meta-Analysis)
Meta-Analysis Review
Specific proteases capable of degrading native triple helical or denatured collagen have been required for many years and have a large spectrum of applications. There are few complete reports that fully uncover production, characterization and purification of fungi collagenases. In this review, authors searched through four scientific on line data bases using the following keywords (collagenolytic OR collagenase) AND (fungi OR fungus OR fungal) AND (production OR synthesis OR synthesize) AND (characterization). Scientific criteria were adopted in this review to classify found articles by score (from 0 to 10). After exclusion criteria, 21 articles were selected. None obtained the maximum of 10 points defined by the methodology, which indicates a deficiency in studies dealing simultaneously with production, characterization and purification of collagenase by fungi. Among microorganisms studied the non-pathogenic fungi Penicillium aurantiogriseum and Rhizoctonia solani stood out in volumetric and specific collagenase activity. The only article found that made sequencing of a true collagenase showed 100% homology with several metalloproteinases fungi. A clear gap in literature about collagenase production by fungi was verified, which prevents further development in the area and increases the need for further studies, particularly full characterization of fungal collagenases with high specificity to collagen.
Topics: Collagen; Collagenases; Culture Media; Enzyme Activation; Fungi; Proteolysis; Substrate Specificity
PubMed: 27756540
DOI: 10.1016/j.bjm.2016.08.001 -
Molecular Biotechnology Jul 2023The methylotrophic yeast Pichia pastoris is garnering interest as a chassis cell factory for the manufacture of recombinant proteins because it effectively satisfies the... (Review)
Review
The methylotrophic yeast Pichia pastoris is garnering interest as a chassis cell factory for the manufacture of recombinant proteins because it effectively satisfies the requirements of both laboratory and industrial set up. The optimisation of P. pastoris cultivation is still necessary due to strain- and product-specific problems such as promoter strength, methanol utilisation type, and culturing conditions to realize the high yields of heterologous protein(s) of interest. Techniques integrating genetic and process engineering have been used to overcome these problems. Insight into the Pichia as an expression system utilizing MUT pathway and the development of methanol free systems are highlighted in this systematic review. Recent developments in the improved production of proteins in P. pastoris by (i) diverse genetic engineering such as codon optimization and gene dosage; (ii) cultivating tactics including co-expression of chaperones; (iii) advances in the use of the 2A peptide system, and (iv) CRISPR/Cas technologies are widely discussed. We believe that by combining these strategies, P. pastoris will become a formidable platform for the production of high value therapeutic proteins.
PubMed: 37400712
DOI: 10.1007/s12033-023-00803-1 -
Plant Science : An International... Mar 2020Protease inhibitors (PIs) are regulatory proteins found in numerous animal tissues and fluids, plants, and microorganisms that reduce and inhibit the exacerbated and...
Protease inhibitors (PIs) are regulatory proteins found in numerous animal tissues and fluids, plants, and microorganisms that reduce and inhibit the exacerbated and uncontrolled activity of the target proteases. Specific PIs are also effective tools for inactivating proteases involved in human diseases like arthritis, pancreatitis, hepatitis, cancer, AIDS, thrombosis, emphysema, hypertension, and muscular dystrophy among others. Plant PIs-small peptides with a high content of cystine residues in disulfide bridges-possess a remarkable resistance to heat treatment and a high stability against shifts in pH, denaturing agents, ionic strength, and proteolysis. In recent years, novel biologic activities have been reported for plant PIs, including antimicrobial, anticoagulant, antioxidant action plus inhibition of tumor-cell growth; thus pointing to possible applications in medicine, agriculture, and biotechnology. In this review, we provide a comparative overview of plant-PIs classifying them in four groups according of their thermal and pH stability (high stability and hyperstable -to temperature and to pHs-, respectively), then emphasizing the relevance of the physicochemical characteristics of these proteins for potential biotechnological and industrial applications. Finally, we analyze the biologic activities of the stable protease inhibitors previously characterized that are the most relevant to potential applications in biomedicine, the food industry, and agriculture.
Topics: Agriculture; Biomedical Research; Biomedical Technology; Biotechnology; Plant Proteins; Plants; Protease Inhibitors
PubMed: 32005400
DOI: 10.1016/j.plantsci.2019.110398 -
International Journal of Molecular... Jul 2014Osteoarthritis (OA) is one of the most widespread degenerative joint diseases affecting the elderly. Research into the regulatory mechanisms underlying the pathogenesis... (Review)
Review
Osteoarthritis (OA) is one of the most widespread degenerative joint diseases affecting the elderly. Research into the regulatory mechanisms underlying the pathogenesis of OA is therefore warranted, and over the past decade, there has been an increased focus on the functional role of microRNAs (miRNAs or miRs). In this systematic review, we aimed to review the evidence implicating miRNAs in the pathogenesis of chondrogenesis and OA. Systematic reviews of PubMed and Embase were performed to search for studies using strings of miRNAs, non-coding RNAs, cartilage, chondrocytes, chondrogenesis, chondrocytogenesis and OA. The identified studies were retrieved, and the references provided were searched. The selected studies were required to focus on the role of miRNAs in chondrogenesis and OA. The results of this review indicated that more than 25 miRNAs have been implicated in chondrogenesis and OA. In particular, chondrocytogenesis, chondrogenic differentiation, chondrocyte proliferation, chondrocyte hypertrophy, endochondral ossification, and proteolytic enzyme regulation are targeted or facilitated by more than 1 miRNA. To date, limited efforts have been performed to evaluate translational applications for this knowledge. Novel therapeutic strategies have been developed and are under investigation to selectively modulate miRNAs, which could potentially enable personalized OA therapy. miRNAs appear to be important modulators of chondrogenesis and OA. Their expression is frequently altered in OA, and many are functionally implicated in the pathogenesis of the disease. The translational roles and therapeutic potential of miRNAs remains to be evaluated.
Topics: Aged; Cartilage; Cell Differentiation; Cell Proliferation; Chondrocytes; Chondrogenesis; Gene Expression Regulation; Humans; MicroRNAs; Molecular Targeted Therapy; Osteoarthritis; Osteogenesis; Precision Medicine; Proteolysis; SOX Transcription Factors
PubMed: 24736803
DOI: 10.3892/ijmm.2014.1743 -
Future Medicinal Chemistry Oct 2019Proteolysis-targeting chimeras (PROTACs) have received much attention for their promising therapeutic intervention in recent years. These molecules, with the mechanism...
Proteolysis-targeting chimeras (PROTACs) have received much attention for their promising therapeutic intervention in recent years. These molecules, with the mechanism of simultaneous recruitment of target protein and an E3 ligase, can trigger the cellular ubiquitin-proteasome system to degrade the target proteins. This article systematically introduces the mechanism of small-molecule PROTACs, and summarized the research progress of small-molecule PROTACs. The prospect for further application and the problems to be solved are also discussed.
Topics: Cell Line, Tumor; Humans; Proteasome Endopeptidase Complex; Proteolysis; Recombinant Fusion Proteins; Ubiquitin
PubMed: 31571504
DOI: 10.4155/fmc-2019-0161 -
Critical Care Medicine Oct 2009To review current knowledge about the impact of prolonged mechanical ventilation on diaphragmatic function and biology. (Review)
Review
OBJECTIVE
To review current knowledge about the impact of prolonged mechanical ventilation on diaphragmatic function and biology.
MEASUREMENTS
Systematic literature review.
CONCLUSIONS
Prolonged mechanical ventilation can promote diaphragmatic atrophy and contractile dysfunction. As few as 18 hrs of mechanical ventilation results in diaphragmatic atrophy in both laboratory animals and humans. Prolonged mechanical ventilation is also associated with diaphragmatic contractile dysfunction. Studies using animal models revealed that mechanical ventilation-induced diaphragmatic atrophy is due to increased diaphragmatic protein breakdown and decreased protein synthesis. Recent investigations have identified calpain, caspase-3, and the ubiquitin-proteasome system as key proteases that contribute to mechanical ventilation-induced diaphragmatic proteolysis. The scientific challenge for the future is to delineate the mechanical ventilation-induced signaling pathways that activate these proteases and depress protein synthesis in the diaphragm. Future investigations that define the signaling mechanisms responsible for mechanical ventilation-induced diaphragmatic weakness will provide the knowledge required for the development of new medicines that can maintain diaphragmatic mass and function during prolonged mechanical ventilation.
Topics: Animals; Antioxidants; Calpain; Caspase 3; Critical Illness; Diaphragm; Enzyme Inhibitors; Humans; Muscle Contraction; Muscular Atrophy; Proteasome Endopeptidase Complex; Respiration, Artificial; Risk Factors; Ubiquitin; Ventilator Weaning
PubMed: 20046120
DOI: 10.1097/CCM.0b013e3181b6e760