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Bioorganic & Medicinal Chemistry Dec 2021Desmosine and isodesmosine are crosslinking amino acids of elastin, which is an essential component of the dermal extracellular matrix protein. Quantitative analysis of...
Desmosine and isodesmosine are crosslinking amino acids of elastin, which is an essential component of the dermal extracellular matrix protein. Quantitative analysis of crosslinker desmosines in human skin dermis has not been fully achieved due to the insoluble nature of elastin protein. In the present study, chemical synthesis of isotopically labeled desmosine, desmosine-C,N, was carried out via isoChichibabin pyridinium synthesis starting from corresponding isotopically labeled amino acids. Isotope-dilution LC-MS/MS analysis of desmosine and isodesmosine utilizing synthetic desmosine-C,N enabled the quantitative analysis of desmosines in human skin for the first time. Thus, ca. 1.43 μg of desmosines was detected from analysis of 1 mg of dry human skin.
Topics: Carbon Isotopes; Chromatography, Liquid; Desmosine; Humans; Isodesmosine; Molecular Structure; Nitrogen Isotopes; Skin; Tandem Mass Spectrometry
PubMed: 34839160
DOI: 10.1016/j.bmc.2021.116519 -
Macromolecular Bioscience Nov 2023Elastin is an essential extracellular matrix protein that enables tissues and organs such as arteries, lungs, and skin, which undergo continuous deformation, to stretch...
Elastin is an essential extracellular matrix protein that enables tissues and organs such as arteries, lungs, and skin, which undergo continuous deformation, to stretch and recoil. Here, an approach to fabricating artificial elastin with close-to-native molecular and mechanical characteristics is described. Recombinantly produced tropoelastin are polymerized through coacervation and allysine-mediated cross-linking induced by pyrroloquinoline quinone (PQQ). A technique that allows the recovery and repeated use of PQQ for protein cross-linking by covalent attachment to magnetic Sepharose beads is developed. The produced material closely resembles natural elastin in its molecular, biochemical, and mechanical properties, enabled by the occurrence of the cross-linking amino acids desmosine, isodesmosine, and merodesmosine. It possesses elevated resistance against tryptic proteolysis, and its Young's modulus ranging between 1 and 2 MPa is similar to that of natural elastin. The approach described herein enables the engineering of mechanically resilient, elastin-like materials for biomedical applications.
Topics: Elastin; Tropoelastin; Amino Acids; Proteolysis
PubMed: 37441796
DOI: 10.1002/mabi.202300203 -
IUBMB Life May 2020Elastic fibers are essential assemblies of vertebrates and confer elasticity and resilience to various organs including blood vessels, lungs, skin, and ligaments. Mature... (Review)
Review
Elastic fibers are essential assemblies of vertebrates and confer elasticity and resilience to various organs including blood vessels, lungs, skin, and ligaments. Mature fibers, which comprise a dense and insoluble elastin core and a microfibrillar mantle, are extremely resistant toward intrinsic and extrinsic influences and maintain elastic function over the human lifespan in healthy conditions. The oxidative deamination of peptidyl lysine to peptidyl allysine in elastin's precursor tropoelastin is a crucial posttranslational step in their formation. The modification is catalyzed by members of the family of lysyl oxidases and the starting point for subsequent manifold condensation reactions that eventually lead to the highly cross-linked elastomer. This review summarizes the current understanding of the formation of cross-links within and between the monomer molecules, the molecular sites, and cross-link types involved and the pathological consequences of abnormalities in the cross-linking process.
Topics: 2-Aminoadipic Acid; Aging; Animals; Blood Vessels; Connective Tissue Diseases; Elastic Tissue; Elastin; Humans; Ligaments; Lung; Lysine; Microfibrils; Oxidation-Reduction; Protein Processing, Post-Translational; Protein-Lysine 6-Oxidase; Skin
PubMed: 31834666
DOI: 10.1002/iub.2213 -
Frontiers in Medicine 2023Developing an effective treatment for pulmonary emphysema will require a better understanding of the molecular changes responsible for distention and rupture of alveolar...
Developing an effective treatment for pulmonary emphysema will require a better understanding of the molecular changes responsible for distention and rupture of alveolar walls. A potentially useful approach to studying this process involves the concept of emergence in which interactions at different levels of scale induce a phase transition comprising a spontaneous reorganization of chemical and physical systems. Recent studies in our laboratory provide evidence of this phenomenon in pulmonary emphysema by relating the emergence of airspace enlargement to the release of elastin-specific desmosine and isodesmosine (DID) crosslinks from damaged elastic fibers. When the mean alveolar diameter exceeded 400 μm, the level of peptide-free DID in human lungs was greatly increased, reflecting rapid acceleration of elastin breakdown, alveolar wall rupture, and a phase transition to an active disease state that is less responsive to treatment. Based on this finding, it is hypothesized that free DID in urine and other body fluids may serve as a biomarker for early detection of airspace enlargement, thereby facilitating timely therapeutic intervention and reducing the risk of respiratory failure.
PubMed: 38164218
DOI: 10.3389/fmed.2023.1322283 -
Journal of the American Heart... Oct 2019Background It is recognized that factors beyond aortic size are important in predicting outcome in abdominal aortic aneurysm (AAA) disease. AAA is characterized by the... (Observational Study)
Observational Study
Background It is recognized that factors beyond aortic size are important in predicting outcome in abdominal aortic aneurysm (AAA) disease. AAA is characterized by the breakdown of elastin within the aortic tunica media, leading to aortic dilatation and rupture. The aim of this study was to investigate the association of plasma desmosine (pDES), an elastin-specific degradation product, with disease severity and clinical outcome in patients with AAA. Methods and Results We measured pDES and serum biomarker concentrations in 507 patients with AAAs (94% men; mean age, 72.4±6.1 years; mean AAA diameter, 48±8 mm) and 162 control subjects (100% men; mean age, 71.5±4.4 years) from 2 observational cohort studies. In the longitudinal cohort study (n=239), we explored the incremental prognostic value of pDES on AAA events. pDES was higher in patients with AAA compared with control subjects (mean±SD: 0.46±0.22 versus 0.33±0.16 ng/mL; <0.001) and had the strongest correlation with AAA diameter (=0.39; <0.0001) of any serum biomarker. After adjustment for baseline AAA diameter, pDES was associated with an AAA event (hazard ratio, 2.03 per SD increase [95% CI, 1.02-4.02]; =0.044). In addition to AAA diameter, pDES provided incremental improvement in risk stratification (continuous net reclassification improvement, 34.4% [95% CI, -10.8% to 57.5%; =0.09]; integrated discrimination improvement, 0.04 [95% CI, 0.00-0.15; =0.050]). Conclusions pDES concentrations predict disease severity and clinical outcomes in patients with AAA. Clinical Trial Registration http://www.isrctn.com. Unique identifier: ISRCTN76413758.
Topics: Aged; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Biomarkers; Cardiac Catheterization; Desmosine; Female; Follow-Up Studies; Humans; Incidence; Male; Prognosis; Prospective Studies; Survival Rate; Ultrasonography; United Kingdom
PubMed: 31595818
DOI: 10.1161/JAHA.119.013743 -
High value applications and current commercial market for eggshell membranes and derived bioactives.Food Chemistry Jul 2022Chicken eggshell membrane (ESM) is a highly insoluble structure that is greatly stabilized by extensive desmosine, isodesmosine, and disulfide cross-linkages. The ESM... (Review)
Review
Chicken eggshell membrane (ESM) is a highly insoluble structure that is greatly stabilized by extensive desmosine, isodesmosine, and disulfide cross-linkages. The ESM possesses numerous biological functions including anti-microbial, anti-inflammatory, anti-wrinkle, and antioxidant activities. The ESM is mainly proteinaceous; proteomics and bioinformatics analysis of ESM has identified > 500 proteins, such as collagens, glycoproteins, avian beta-defensins, and lysozyme. ESM also contains significant amounts of carbohydrate, including hyaluronic acid (HA). In general, HA plays an important role in tissue hydration and cellular mechanisms such as growth, differentiation, and transport, and has diverse health and medical applications. Despite ESM being rich in important bioactive compounds, it is often considered as a waste product of the egg-breaking industry and is under-utilized. A major challenge for the successful commercial exploitation of ESM and bioactive constituents is its limited solubility and bioavailability due to cross-linkages of ESM fibers. Various processing and extraction methods are employed to overcome these limitations and improve the production of HA and collagen-based ESM formats. Moreover, we believe that there is a wide scope to exploit ESM for novel applications, leading to new intellectual property (IP) and patenting opportunities. This review presents an overview of scientific background, IP landscape and current commercial market for ESM and derived bioactives including collagens and HA. A detailed literature survey is provided for each area of interest. We analyze regulatory guidelines for ESM, contrasting quality control / microbial safety assessment in cosmetics and personal care products (hazard based) with that of the food industry (risk-based). New perspectives for upcycling of ESM waste to commercially viable high-value biomaterials as nutraceutical supplements and as cosmetics ingredients are discussed. This overview of ESM separation techniques and applications could form the basis for directed research and product development in order to exploit the unique bioactivities of ESM.
Topics: Animals; Biocompatible Materials; Chickens; Collagen; Egg Shell; Proteomics
PubMed: 35149473
DOI: 10.1016/j.foodchem.2022.132270 -
PloS One 2023Acute lung injury (ALI) is a life-threatening disease that has received considerable critical attention in the field of intensive care. This study aimed to explore the...
Acute lung injury (ALI) is a life-threatening disease that has received considerable critical attention in the field of intensive care. This study aimed to explore the role and mechanism of vitamin K2 (VK2) in ALI. Intraperitoneal injection of 7 mg/kg LPS was used to induce ALI in mice, and VK2 injection was intragastrically administered with the dose of 0.2 and 15 mg/kg. We found that VK2 improved the pulmonary pathology, reduced myeloperoxidase (MPO) activity and levels of TNF-α and IL-6, and boosted the level of IL-10 of mice with ALI. Moreover, VK2 played a significant part in apoptosis by downregulating and upregulating Caspase-3 and Bcl-2 expressions, respectively. As for further mechanism exploration, we found that VK2 inhibited P38 MAPK signaling. Our results also showed that VK2 inhibited ferroptosis, which manifested by reducing malondialdehyde (MDA) and iron levels, increasing glutathione (GSH) level, and upregulated and downregulated glutathione peroxidase 4 (GPX4) and heme oxygenase-1 (HO-1) expressions, respectively. In addition, VK2 also inhibited elastin degradation by reducing levels of uncarboxylated matrix Gla protein (uc-MGP) and desmosine (DES). Overall, VK2 robustly alleviated ALI by inhibiting LPS-induced inflammation, apoptosis, ferroptosis, and elastin degradation, making it a potential novel therapeutic candidate for ALI.
Topics: Mice; Animals; Ferroptosis; Lipopolysaccharides; Vitamin K 2; Elastin; Acute Lung Injury; Inflammation; Apoptosis; Lung
PubMed: 38011192
DOI: 10.1371/journal.pone.0294763 -
Experimental Eye Research Feb 2022Pseudoexfoliation syndrome (PXF) is an idiopathic disease with a high prevalence rate. The elastosis disorder is contributed by genetic and non-genetic factors. Elastin...
Pseudoexfoliation syndrome (PXF) is an idiopathic disease with a high prevalence rate. The elastosis disorder is contributed by genetic and non-genetic factors. Elastin dysregulation associated with the disease mechanism is incompletely understood. This study evaluated the molecules of the elastogenesis machinery in PXF. Lens capsule and aqueous humor (aqH) samples (age/sex-matched) were collected from the eyes with PXF alone and PXF with glaucoma (PXF-G) undergoing Extra Capsular Cataract Extraction (ECCE) surgery. The Elastin turnover was assessed by estimating Desmosine levels in the lens capsules by HPLC analysis. Expression of elastogenesis genes [EMILIN1, CLU, FBN1, FN1, FBLN5, FBLN4 and LOXL1] were evaluated in the lens capsule by qPCR while the proteins were assessed in aqH by western blot analysis. The Desmosine content in the lens capsules were 3-fold and 6-fold elevated in PXF (P = 0.02) and PXF-G (P = 0.01) respectively compared to the cataract-alone, indicating increased elastin degradation. A significant increase in the transcript levels of the CLU, FBLN4, EMILIN1, FBLN5, FN1, FBN1, LOXL1 along with significant changes in protein expression of CLU, FBLN5, FBN1 and LOXL1 signified up-regulation of the elastogenesis machinery. The study provides direct evidence of augmented elastin degradation and turnover in the lens capsule of PXF marked by increased Desmosine content and the expression of proteins involved in mature elastin formation.
Topics: Capsules; Cataract; Desmosine; Elastin; Exfoliation Syndrome; Glaucoma; Humans; Lens Capsule, Crystalline
PubMed: 34929161
DOI: 10.1016/j.exer.2021.108898 -
Biomarkers : Biochemical Indicators of... Jun 2022Desmosine and isodesmosine (DID) are biomarkers for elastic fibre damage in pulmonary emphysema. However, current methods for measuring lung DID involve tissue...
INTRODUCTION
Desmosine and isodesmosine (DID) are biomarkers for elastic fibre damage in pulmonary emphysema. However, current methods for measuring lung DID involve tissue hydrolysis and lack specificity for those fibres undergoing breakdown. To address this limitation, free (nonpeptide-bound) DID content in unhydrolyzed tissues was evaluated as a more accurate biomarker in an animal model of pulmonary emphysema.
METHODS
Hamsters were treated with either cigarette smoke and lipopolysaccharide (LPS), room air and LPS, or room air alone (controls). Free DID levels in fresh and formalin-fixed lungs were measured by LC-MS/MS and correlated with the mean linear intercept (MLI) measure of airspace size.
RESULTS
There was no significant difference in free DID between fresh and formalin-fixed lungs. Animals treated with smoke and LPS had significantly higher levels of free DID than the LPS only group (359 vs. 93.1 ng/g wet lung, respectively; = 0.0012) and room air controls (undetectable levels; = 0.0002). There was a significant positive correlation between free DID and MLI ( < 0.0001).
CONCLUSIONS
The results support the hypothesis that free lung DID is a sensitive indicator of alveolar wall injury that may be used to study the development of pulmonary emphysema in both animal models and post-mortem human lung tissue.
Topics: Animals; Biomarkers; Bronchoalveolar Lavage Fluid; Chromatography, Liquid; Cricetinae; Desmosine; Elastic Tissue; Formaldehyde; Humans; Isodesmosine; Lipopolysaccharides; Lung; Pulmonary Emphysema; Tandem Mass Spectrometry
PubMed: 35170389
DOI: 10.1080/1354750X.2022.2043443 -
Frontiers in Cardiovascular Medicine 2022Elastin degradation is implicated in the pathology of vulnerable plaque. Recent studies show promising results for plasma desmosine (pDES), an elastin-specific...
BACKGROUND
Elastin degradation is implicated in the pathology of vulnerable plaque. Recent studies show promising results for plasma desmosine (pDES), an elastin-specific degradation product, as a marker of cardiovascular disease (CVD) outcomes. The aim of this study was to investigate the potential role of pDES as a marker of clinical outcome in patients with acute myocardial infarction (AMI).
MATERIALS AND METHODS
In this case-control study, we studied 236 AMI patients: 79 patients who had death and/or myocardial infarction (MI) at 2 years, and 157 patients who did not have an event at 2 years. pDES was measured using a validated liquid chromatography-tandem mass spectrometry method. Association of pDES with adverse outcomes, and the incremental value of pDES to global registry of acute coronary events (GRACE) score for risk stratification was assessed.
RESULTS
pDES levels were elevated in patients with the composite outcome of death/MI at 2 years ( = 0.002). Logistic regression analyses showed pDES to be associated with death/MI at 2 years [Odds ratio (OR) 5.99 (95% CI 1.81-19.86) = 0.003]. pDES remained a significant predictor of death/MI at 2 years even after adjustment for age, sex, history of CVD, revascularisation, blood pressure, medications on discharge, Troponin I, and NT-proBNP levels.[OR 5.60 (95% CI 1.04-30.04) = 0.044]. In another multivariable model including adjustment for eGFR, pDES was significantly associated with the composite outcome at 6 months, but not at 2 years follow up. DES was also able to reclassify risk stratification for death/MI at 6 months, when added to the GRACE risk model [Net Reclassification Index (NRI) 41.2 (95% CI 12.0-70.4) = 0.006].
CONCLUSION
pDES concentrations predict clinical outcomes in patients with AMI, demonstrating its potential role as a prognostic marker in AMI.
PubMed: 36479574
DOI: 10.3389/fcvm.2022.992388