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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 -
Brain and Nerve = Shinkei Kenkyu No... Nov 2008Aspirin inhibits platelet activation through the permanent inactivation of the cyclooxygenase (COX) activity of prostaglandin H synthase-1 (referred to as COX-1), and... (Review)
Review
Aspirin inhibits platelet activation through the permanent inactivation of the cyclooxygenase (COX) activity of prostaglandin H synthase-1 (referred to as COX-1), and consequently inhibits the biosynthesis of thromboxane A2 (TXA2), a platelet agonist. Recent meta-analysis has revealed that long-term aspirin administration has clear benefits for the secondary prevention of cardiovascular diseases with an odds reduction of 23% and an absolute risk reduction of 3.1% over 2 years. However, this indicates that not all individuals respond equally to aspirin therapy and cardiovascular events may occur during aspirin therapy, this is often denoted as "clinical aspirin resistance". Several reports have, indeed, suggested that the effect of aspirin administration varies considerably among the patients at high risk for cardiovascular events. Approximately one forth of the patients showed persistent platelet reactivity in vitro despite the use of aspirin (denoted "laboratory aspirin resistance"), this was determined by laboratory tests including the test for arachidonic acid-induced platelet aggregation and the assays using point-of-care devices. Recent clinical studies have proposed that resistance to aspirin (laboratory aspirin resistance) can relate to the cardiovascular outcomes in patients treated with aspirin (clinical aspirin resistance). A systematic review and meta-analysis on aspirin resistance have indicated that patients who are resistant to aspirin are at a greater risk (odds ratio: 3.85) of clinically important cardiovascular morbidity than patients who are sensitive to aspirin. However, many issues are yet to be resolved in order to apply the concept of "aspirin resistance" to actual clinical practice. The relevance of the various ex vivo functional indexes of platelet capacity to in vivo platelet activation and the precise mechanisms underlying aspirin resistance are still largely unknown. To assess what kind of laboratory assays is the best predictor for cardiovascular events and the risk factors of aspirin resistance, including non-compliance, concurrent intake of other drugs such as nonsteroid anti-inflammatory drugs, and polymorphism of COX-1, we have conducted a multicenter, prospective cohort study (ProGEAR study). We hope that these results will contribute to an individualized antiplatelet therapy through the identification of aspirin nonresponders as a high-risk group for cardiovascular events.
Topics: Aspirin; Cardiovascular Diseases; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Drug Resistance; Humans; Pharmacogenetics; Platelet Activation; Platelet Aggregation Inhibitors
PubMed: 19069170
DOI: No ID Found -
Molecular Biology Reports Dec 2012Evidence is accumulating that cyclooxygenase-2 (COX-2) may play an important role in prostate cancer (PCa). Recently, gene polymorphisms in COX-2 have been implicated to... (Meta-Analysis)
Meta-Analysis Review
Evidence is accumulating that cyclooxygenase-2 (COX-2) may play an important role in prostate cancer (PCa). Recently, gene polymorphisms in COX-2 have been implicated to alter the risk of PCa and overexpression of COX-2 may be associated with clinical and prognostic significance in PCa. However, the results of these studies are inconclusive or controversial. To derive a more precise estimation of the relationships, we performed an updated meta-analysis. A comprehensive search was conducted to examine all the eligible studies of COX-2 polymorphism and expression in PCa. We used odds ratios (ORs) to assess the strength of the association and the 95 % confidence intervals (CIs) give a sense of the precision of the estimate. Overall, no significant associations between COX-2 polymorphism and PCa risk were found. However, high expression of COX-2 was significantly higher in T3-T4 stages of PCa than in T1-T2 stages of PCa (OR = 2.33, 95 %CI: 1.54-3.53, P < 0.0001). COX-2 might play an important role in the progress of PCa, overexpression of COX-2 correlates with T3-T4 stages of PCa. COX-2 might be a potential therapy target for PCa and work as a prognostic factor for PCa patients.
Topics: Cyclooxygenase 2; Genetic Heterogeneity; Genetic Predisposition to Disease; Humans; Male; Neoplasm Staging; Polymorphism, Single Nucleotide; Prostatic Neoplasms; Publication Bias; Risk Factors
PubMed: 23053989
DOI: 10.1007/s11033-012-2001-5 -
Annals of Internal Medicine Sep 2015Placebo controls are essential in evaluating the effectiveness of medical treatments. Although it is unclear whether different placebo interventions for osteoarthritis... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Placebo controls are essential in evaluating the effectiveness of medical treatments. Although it is unclear whether different placebo interventions for osteoarthritis vary in efficacy, systematic differences would substantially affect interpretation of the results of placebo-controlled trials.
OBJECTIVE
To evaluate the effects of alternative placebo types on pain outcomes in knee osteoarthritis.
DATA SOURCES
MEDLINE, EMBASE, Web of Science, Google Scholar, and Cochrane Database from inception through 1 June 2015 and unpublished data.
STUDY SELECTION
149 randomized trials of adults with knee osteoarthritis that reported pain outcomes and compared widely used pharmaceuticals against oral, intra-articular, topical, and oral plus topical placebos.
DATA EXTRACTION
Study data were independently double-extracted; study quality was assessed by using the Cochrane risk of bias tool.
DATA SYNTHESIS
Placebo effects that were evaluated by using a network meta-analysis with 4 separate placebo nodes (differential model) showed that intra-articular placebo (effect size, 0.29 [95% credible interval, 0.09 to 0.49]) and topical placebo (effect size, 0.20 [credible interval, 0.02 to 0.38]) had significantly greater effect sizes than did oral placebo. This differential model showed marked differences in the relative efficacies and hierarchy of the active treatments compared with a network model that considered all placebos equivalent. In the model accounting for differential effects, intra-articular and topical therapies were superior to oral treatments in reducing pain. When these differential effects were ignored, oral nonsteroidal anti-inflammatory drugs were superior.
LIMITATIONS
Few studies compared different placebos directly. The study could not decisively conclude whether disease severity and co-interventions systematically differed between trials evaluating different placebos.
CONCLUSION
All placebos are not equal, and some can trigger clinically relevant responses. Differential placebo effects can substantially alter estimates of the relative efficacies of active treatments, an important consideration for the design of clinical trials and interpretation of their results.
PRIMARY FUNDING SOURCE
Agency for Healthcare Research and Quality.
Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase 2; Humans; Hyaluronic Acid; Osteoarthritis, Knee; Pain; Placebo Effect; Randomized Controlled Trials as Topic
PubMed: 26215539
DOI: 10.7326/M15-0623 -
Climacteric : the Journal of the... 2015The genesis of the endometrial polyp is as yet unclear. There is evidence that the polyp is related to the inflammatory process and that it interacts with the... (Review)
Review
BACKGROUND
The genesis of the endometrial polyp is as yet unclear. There is evidence that the polyp is related to the inflammatory process and that it interacts with the cyclooxygenase-2 (COX-2) enzyme.
OBJECTIVE
To review the influence of COX-2 on the postmenopausal endometrial polyp.
METHODS
A systematic review was made of the Medline, Embase, and Cochrane databases, covering the years of 2001-2014. The inclusion criteria were: experimental studies with immunohistological analysis of COX-2 in endometrial polyps; women; hysteroscopic and surgical evaluation; and studies with comparisons between the endometrial polyp and other tissues (normal endometrium, adjacent endometrium, and other uterine diseases). The exclusion criteria were: polyps in other organs; genetic polymorphisms; endometrial cancer exclusively; abnormal uterine bleeding unrelated to polyps. The search key words (taken from the Medical Subject Headings - MeSH) were endometrial polyp and cyclooxygenase-2.
RESULTS
Seven of ten articles were selected. Results showed positive COX-2 expression in the glandular epithelium of the polyps, and expression was more intense when the polyp was malignant. However, there was a study which did not find any difference between polyps and the normal endometrium, and there was another which compared polyps in menacme with postmenopausal polyps.
CONCLUSION
There is no consensus in the literature as to the participation of COX-2 in the development of benign and/or malignant endometrial polyps. In all of the studies, COX-2 was present in the postmenopausal polyps and with greater intensity in the malignant ones.
Topics: Biomarkers; Cyclooxygenase 2; Endometrial Neoplasms; Endometrium; Female; Humans; Polyps; Postmenopause; Uterine Diseases
PubMed: 25242379
DOI: 10.3109/13697137.2014.966240 -
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 -
Advances in Clinical and Experimental... 2015Colorectal cancer (CRC) has become the third most common cancer in developed countries. Each year more and more people die from CRC. CRC is also one of the most... (Review)
Review
Colorectal cancer (CRC) has become the third most common cancer in developed countries. Each year more and more people die from CRC. CRC is also one of the most effectively studied topics in recent years. It has been found that the key phenomena in CRC development are genetic and inflammatory processes. Well-known genetic bases for the carcinogenesis of CRC include chromosomal changes characteristic of the chromosomal instability pathway which correlates with specific and well-defined genetic alterations (such as APC, K-RAS, DCC and p53) and genomic instability characteristics for the mutator pathway focused on KRAS and BRAF mutations. Recent studies have highlighted the impact of inflammation in CRC, especially elevated levels of pro-inflammatory cytokines. Among important risk factors of colon carcinogenesis are colorectal polyps, which are currently the subject of intense research. Recent studies have shown that different adenomas are characterized by different pathways of carcinogenesis as well as diverse COX-2 expression in various polyps. Understanding the mechanism of inflammatory processes in CRC parallel to basic genetic alterations might allow for effective and targeted treatment.
Topics: Animals; Anti-Inflammatory Agents; Anticarcinogenic Agents; Biomarkers, Tumor; Cell Transformation, Neoplastic; Colon; Colorectal Neoplasms; Cyclooxygenase 2; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Humans; Inflammation; Inflammation Mediators; Mutation; Phenotype; Prognosis; Risk Factors
PubMed: 26469098
DOI: 10.17219/acem/31239