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Journal of Cosmetic Dermatology Dec 2022The ubiquitin-proteasome system (UPS) is a highly conserved way of regulating intracellular protein balance. UPS mediates proteolysis and disruption of variation or... (Review)
Review
BACKGROUND
The ubiquitin-proteasome system (UPS) is a highly conserved way of regulating intracellular protein balance. UPS mediates proteolysis and disruption of variation or misfolding, while finely regulating proteins involved in differentiation and other biological processes.
AIMS
The aim of this review is to systematically introduce UPS as a key regulator of melanin metabolism.
METHODS
Systematic search and retrospective review were performed on the published data.
RESULTS
Melanocyte-inducing transcription factor (MITF) is a substrate of the ubiquitin ligase VCHL1 and acts as a transcription factor to regulate the expression of key enzymes in melanin synthesis such as tyrosinase (TYR). The rate-limiting enzyme TYR is modified by the ubiquitin ligase Hrd1 during melanosynthesis. Melanin itself is also regulated by multiple ubiquitin ligases including Fbp1 and Vhl. By regulating the ubiquitination modification to target each link of melanin synthesis, it plays an important role in correcting the disorder of melanin metabolism. A number of chemical agents have been proven to inhibit the activity of ubiquitin ligase.
CONCLUSIONS
Drugs targeting E3 ligase and deubiquitinating enzymes have great potential in the treatment of melanin metabolism disorders.
Topics: Humans; Melanins; Proteasome Endopeptidase Complex; Transcription Factors; Ubiquitin; Ubiquitin-Protein Ligases
PubMed: 36207998
DOI: 10.1111/jocd.15433 -
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 -
Inflammation Research : Official... Mar 2022Ischemia-reperfusion injury (IRI) is the inexplicable aggravation of cellular dysfunction that results in blood flow restoration to previously ischemic tissues. COX... (Review)
Review
INTRODUCTION
Ischemia-reperfusion injury (IRI) is the inexplicable aggravation of cellular dysfunction that results in blood flow restoration to previously ischemic tissues. COX mediates the oxidative conversion of AA to various prostaglandins and thromboxanes, which are involved in various physiological and pathological processes. In the pathophysiology of I/R injuries, COX has been found to play an important role. I/R injuries affect most vital organs and are characterized by inflammation, oxidative stress, cell death, and apoptosis, leading to morbidity and mortality.
MATERIALS AND METHODS
A systematic literature review of Bentham, Scopus, PubMed, Medline, and EMBASE (Elsevier) databases was carried out to understand the Nature and mechanistic interventions of the Cyclooxygenase modulations in ischemic injury. Here, we have discussed the COX Physiology and downstream signalling pathways modulated by COX, e.g., Camp Pathway, Peroxisome Proliferator-Activated Receptor Activity, NF-kB Signalling, PI3K/Akt Signalling in ischemic injury.
CONCLUSION
This review will discuss the various COX types, specifically COX-1 and COX-2, which are involved in developing I/R injury in organs such as the brain, spinal cord, heart, kidney, liver, and intestine.
Topics: Cyclooxygenase 2; Cyclooxygenase Inhibitors; Humans; Phosphatidylinositol 3-Kinases; Prostaglandins; Reperfusion Injury
PubMed: 35175358
DOI: 10.1007/s00011-022-01546-6 -
International Journal of Molecular... Aug 2020Despite a number of reports in the literature on the role of epigenetic mechanisms in periodontal disease, a thorough assessment of the published studies is warranted to... (Review)
Review
Despite a number of reports in the literature on the role of epigenetic mechanisms in periodontal disease, a thorough assessment of the published studies is warranted to better comprehend the evidence on the relationship between epigenetic changes and periodontal disease and its treatment. Therefore, the aim of this systematic review is to identify and synthesize the evidence for an association between DNA methylation/histone modification and periodontal disease and its treatment in human adults. A systematic search was independently conducted to identify articles meeting the inclusion criteria. DNA methylation and histone modifications associated with periodontal diseases, gene expression, epigenetic changes after periodontal therapy, and the association between epigenetics and clinical parameters were evaluated. Sixteen studies were identified. All included studies examined DNA modifications in relation to periodontitis, and none of the studies examined histone modifications. Substantial variation regarding the reporting of sample sizes and patient characteristics, statistical analyses, and methodology, was found. There was some evidence, albeit inconsistent, for an association between DNA methylation and periodontal disease. , , , , , and were identified as candidate genes that have been assessed for DNA methylation in periodontitis. While several included studies found associations between methylation levels and periodontal disease risk, there is insufficient evidence to support or refute an association between DNA methylation and periodontal disease/therapy in human adults. Further research must be conducted to identify reproducible epigenetic markers and determine the extent to which DNA methylation can be applied as a clinical biomarker.
Topics: Cyclooxygenase 2; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation; Genetic Markers; Histone Code; Histones; Humans; Interferon-gamma; Interleukin-6; Periodontal Diseases; Receptors, Interleukin-6; Suppressor of Cytokine Signaling 1 Protein; Tumor Necrosis Factor-alpha
PubMed: 32867386
DOI: 10.3390/ijms21176217 -
Journal of Cancer Research and Clinical... Jun 2022Purpose colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide. Some evidence has shown that aspirin can reduce the morbidity and mortality of... (Meta-Analysis)
Meta-Analysis
UNLABELLED
Purpose colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide. Some evidence has shown that aspirin can reduce the morbidity and mortality of CRC. The aim of this meta-analysis was to compare standard care of patients with CRC and standard care with the addition of aspirin in terms of the survival benefit.
METHODS
The systematic search was conducted by two independent reviewers in the databases PubMed and Web of Science. Survival data were extracted from studies published before July 2019. We searched for randomised controlled trials, cohort studies and case-control studies.
RESULTS
We included 27 studies in our meta-analysis. There was a sample size of 237,245 patients overall. Aspirin use after diagnosis was associated with an improvement in CRC-specific survival with a hazard ratio (HR) for cancer-related death of 0.74 (95% CI: 0.62-0.89). Our analysis of overall survival data revealed reduced mortality with an HR of 0.82 (95% CI: 0.74-0.90). Patients with the phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation profited from postdiagnosis aspirin use (HR = 0.74, 95% CI: 0.56-0.97). For a high expression of prostaglandin-endoperoxide synthase 2 (PTGS2) = COX-2, we found an HR of 0.65 (95% CI: 0.52-0.82).
CONCLUSION
Aspirin can improve the outcome of patients with CRC. PIK3CA mutation status and high expression of PTGS2 are associated with longer survival. However, randomised controlled trials are needed to investigate postdiagnosis aspirin use in CRC patients taking into account cancer stage and gene expression.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Case-Control Studies; Colorectal Neoplasms; Cyclooxygenase 2; Humans; Proportional Hazards Models; Randomized Controlled Trials as Topic
PubMed: 35171329
DOI: 10.1007/s00432-022-03942-1 -
Biomedicine & Pharmacotherapy =... Sep 2022Development and identification of molecular compounds capable of killing or inhibiting transformed cells promoting carcinogenesis without inducing toxic effects to the... (Review)
Review
Development and identification of molecular compounds capable of killing or inhibiting transformed cells promoting carcinogenesis without inducing toxic effects to the normal cells are of utmost significance. A systematic review was conducted in screening for important literature was extensively performed by searching the Web of Science, Ovid, BMC Springer, Elsevier, Embase, and MEDLINE databases for optimum selectivity. Google Scholar was also used to supplement information. Pharmacotherapeutic biomolecules active against colon cancer carcinogenesis in Musa acuminata and Musa balbisiana (bananas), Punica granatum L (pomegranate), Glycine max (Soybean), Brassica oleracea L var. italica Plenck (Broccoli), and Hibiscus rosa-sinesis and Hibiscus sabdariffa (hibiscus) were evaluated. Signaling pathways like phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinase (MAPK), protein kinase B (AKT), and nuclear factor-kappa B (NFκB) correlate the mediation of COX-2 expression. Increased levels of COX-2 are correlated with the occurrence and progression of colon cancer. Natural antioxidants in herbal plants including polyphenols and carotenoids inhibit the oxidation of lipids, proteins, and nucleic acids and thereby preventing the initiation of oxidizing chain reactions. These bioactive compounds should be considered an important dietary supplement.
Topics: Carcinogenesis; Colonic Neoplasms; Cyclooxygenase 2; Hibiscus; Humans; Phosphatidylinositol 3-Kinases; Plants, Medicinal
PubMed: 35820316
DOI: 10.1016/j.biopha.2022.113383 -
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 -
Molecular Biology Reports Apr 2023FF adenosine triphosphate (ATP) synthase, also known as the complex V, is the central ATP-producing unit in the cells arranged in the mitochondrial and plasma membranes.... (Review)
Review
FF adenosine triphosphate (ATP) synthase, also known as the complex V, is the central ATP-producing unit in the cells arranged in the mitochondrial and plasma membranes. FF ATP synthase also regulates the central metabolic processes in the human body driven by proton motive force (Δp). Numerous studies have immensely contributed toward highlighting its regulation in improving energy homeostasis and maintaining mitochondrial integrity, which otherwise gets compromised in illnesses. Yet, its role in the implication of non-communicable diseases remains unknown. FF ATP synthase dysregulation at gene level leads to reduced activity and delocalization in the cristae and plasma membranes, which is directly associated with non-communicable diseases: cardiovascular diseases, diabetes, neurodegenerative disorders, cancer, and renal diseases. Individual subunits of the FF ATP synthase target ligand-based competitive or non-competitive inhibition. After performing a systematic literature review to understand its specific functions and its novel drug targets, the present article focuses on the central role of FF ATP synthase in primary non-communicable diseases. Next, it discusses its involvement through various pathways and the effects of multiple inhibitors, activators, and modulators specific to non-communicable diseases with a futuristic outlook.
Topics: Humans; Adenosine Triphosphate; Glycogen Synthase; Noncommunicable Diseases; Mitochondria; Mitochondrial Membranes; Mitochondrial Proton-Translocating ATPases
PubMed: 36715790
DOI: 10.1007/s11033-023-08299-3 -
Journal of Assisted Reproduction and... Feb 2024Although significant improvements in assisted reproductive technology (ART) outcomes have been accomplished, a critical question remains: which embryo is most likely to... (Review)
Review
PURPOSE
Although significant improvements in assisted reproductive technology (ART) outcomes have been accomplished, a critical question remains: which embryo is most likely to result in a pregnancy? Embryo selection is currently based on morphological and genetic criteria; however, these criteria do not fully predict good-quality embryos and additional objective criteria are needed. The cumulus cells are critical for oocyte and embryo development. This systematic review assessed biomarkers in cumulus-oocyte complexes and their association with successful IVF outcomes.
METHODS
A comprehensive search was conducted using PubMed, Embase, Scopus, and Web of Science from inception until November 2022. Only English-language publications were included. Inclusion criteria consisted of papers that evaluated genetic biomarkers associated with the cumulus cells (CCs) in humans and the following three outcomes of interest: oocyte quality, embryo quality, and clinical outcomes, including fertilization, implantation, pregnancy, and live birth rates.
RESULTS
The search revealed 446 studies of which 42 met eligibility criteria. Nineteen studies correlated genetic and biochemical biomarkers in CCs with oocyte quality. A positive correlation was reported between oocyte quality and increased mRNA expression in CCs of genes encoding for calcium homeostasis (CAMK1D), glucose metabolism (PFKP), extracellular matrix (HAS2, VCAN), TGF-β family (GDF9, BMP15), and prostaglandin synthesis (PTGS2). Nineteen studies correlated genetic and biochemical biomarkers in CCs with embryo quality. A positive correlation was reported between embryo quality and increased mRNA expression in CCs of genes encoding for extracellular matrix (HAS2), prostaglandin synthesis (PTGS2), steroidogenesis (GREM1), and decreased expression of gene encoding for hormone receptor (AMHR2). Twenty-two studies assessed genetic and biochemical biomarkers in CCs with clinical outcomes. Increased expression of genes encoding for extracellular matrix (VCAN), and TGF-β family (GDF9, BMP15) were positively correlated with pregnancy rate.
CONCLUSION
Genetic biomarkers from cumulus cells were associated with oocyte quality (CAMK1D, PFKP, HAS2, VCAN, GDF-9, BMP-15, PTGS2), embryo quality (GREM1, PTGS2, HAS2), and pregnancy rate (GDF9, BMP15, VCAN). These results might help guide future studies directed at tests of cumulus cells to devise objective criteria to predict IVF outcomes.
Topics: Pregnancy; Female; Humans; Cumulus Cells; Cyclooxygenase 2; Oocytes; Fertilization in Vitro; Reproductive Techniques, Assisted; Genetic Markers; RNA, Messenger; Transforming Growth Factor beta; Prostaglandins
PubMed: 37947940
DOI: 10.1007/s10815-023-02984-9