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Collagen metabolism as a regulator of proline dehydrogenase/proline oxidase-dependent apoptosis/autophagy.
Palka, J, Oscilowska, I, Szoka, L
Amino acids. 2021;(12):1917-1925
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Abstract
Recent studies on the regulatory role of amino acids in cell metabolism have focused on the functional significance of proline degradation. The process is catalysed by proline dehydrogenase/proline oxidase (PRODH/POX), a mitochondrial flavin-dependent enzyme converting proline into ∆1-pyrroline-5-carboxylate (P5C). During this process, electrons are transferred to electron transport chain producing ATP for survival or they directly reduce oxygen, producing reactive oxygen species (ROS) inducing apoptosis/autophagy. However, the mechanism for switching survival/apoptosis mode is unknown. Although PRODH/POX activity and energetic metabolism were suggested as an underlying mechanism for the survival/apoptosis switch, proline availability for this enzyme is also important. Proline availability is regulated by prolidase (proline supporting enzyme), collagen biosynthesis (proline utilizing process) and proline synthesis from glutamine, glutamate, α-ketoglutarate (α-KG) and ornithine. Proline availability is dependent on the rate of glycolysis, TCA and urea cycles, proline metabolism, collagen biosynthesis and its degradation. It is well established that proline synthesis enzymes, P5C synthetase and P5C reductase as well as collagen prolyl hydroxylases are up-regulated in most of cancer types and control rates of collagen biosynthesis. Up-regulation of collagen prolyl hydroxylase and its exhaustion of ascorbate and α-KG may compete with DNA and histone demethylases (that require the same cofactors) to influence metabolic epigenetics. This knowledge led us to hypothesize that up-regulation of prolidase and PRODH/POX with inhibition of collagen biosynthesis may represent potential pharmacotherapeutic approach to induce apoptosis or autophagic death in cancer cells. These aspects of proline metabolism are discussed in the review as an approach to understand complex regulatory mechanisms driving PRODH/POX-dependent apoptosis/survival.
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Diffuse Lamellar Keratitis in a Patient Undergoing Collagen Corneal Cross-Linking 18 Years After Laser In Situ Keratomileusis Surgery.
Grassmeyer, JJ, Goertz, JG, Baartman, BJ
Cornea. 2021;(7):917-920
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PURPOSE To report a case of diffuse lamellar keratitis (DLK) after corneal collagen cross-linking in an eye with a remote history of laser in situ keratomileusis (LASIK) surgery. METHODS This is a case report and literature review. RESULTS This report describes the development of unilateral stage IV DLK in a patient who underwent bilateral corneal cross-linking for corneal ectasia 18 years after LASIK surgery. The patient was treated with high-dose topical steroids that were tapered over 1 month and multiple flap lifts. The ultimate best-corrected visual outcome was 20/60. CONCLUSIONS DLK is a potential sight-threatening complication of refractive surgery that can occur at any time in the postoperative period, even years after the procedure. Undergoing a subsequent corneal procedure that may disrupt or promote inflammation within the surgical flap-stromal interface, such as corneal collagen cross-linking, is a recognized risk factor for the development of DLK. This case suggests that patients with any history of LASIK surgery undergoing corneal cross-linking or other lamellar corneal surgeries may benefit from closer follow-up (eg, daily) than patients with no history of LASIK.
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Recent advances in the anti-aging effects of phytoestrogens on collagen, water content, and oxidative stress.
Liu, T, Li, N, Yan, YQ, Liu, Y, Xiong, K, Liu, Y, Xia, QM, Zhang, H, Liu, ZD
Phytotherapy research : PTR. 2020;(3):435-447
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Abstract
Skin undergoes degenerative changes as it ages, which include the loss of elasticity, reductions in the epidermal thickness and collagen content, elastic fiber degeneration, and increased wrinkling and dryness. Skin aging can be significantly delayed by the administration of estrogen. Estrogen deficiency following menopause results in atrophic skin changes and the acceleration of skin aging. Estrogen administration has positive effects on human skin by delaying or preventing skin aging manifestations, but the use of estrogen replacement is a risk factor for breast and uterine cancer. Phytoestrogens are a large family of plant-derived molecules possessing various degrees of estrogen-like activity; they exhibit agonist or antagonist estrogenic properties depending on the tissue. These molecules could be ideal candidates to combat skin aging and other detrimental effects of hypoestrogenism. In this paper, we review the effects of phytoestrogens on human skin and the mechanisms by which phytoestrogens can alleviate the changes due to aging.
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Corneal Cross-Linking: The Science Beyond the Myths and Misconceptions.
Rubinfeld, RS, Caruso, C, Ostacolo, C
Cornea. 2019;(6):780-790
Abstract
PURPOSE There has been a recent explosion in the variety of techniques used to accomplish corneal cross-linking (CXL) for the treatment of ectatic corneal diseases. To understand the success or failure of various techniques, we review the physicochemical basis of corneal CXL and re-evaluate the current principles and long-standing conventional wisdom in the light of recent, compelling, and sometimes contradictory research. METHODS Two clinicians and a medicinal chemist developed a list of current key topics, controversies, and questions in the field of corneal CXL based on information from current literature, medical conferences, and discussions with international practitioners of CXL. RESULTS Standard corneal CXL with removal of the corneal epithelium is a safe and efficacious procedure for the treatment of corneal ectasias. However, the necessity of epithelium removal is painful for patients, involves risk and requires significant recovery time. Attempts to move to transepithelial corneal CXL have been hindered by the lack of a coherent understanding of the physicochemistry of corneal CXL. Misconceptions about the applicability of the Bunsen-Roscoe law of reciprocity and the Lambert-Beer law in CXL hamper the ability to predict the effect of ultraviolet A energy during CXL. Improved understanding of CXL may also expand the treatment group for corneal ectasia to those with thinner corneas. Finally, it is essential to understand the role of oxygen in successful CXL. CONCLUSIONS Improved understanding of the complex interactions of riboflavin, ultraviolet A energy and oxygen in corneal CXL may provide a successful route to transepithelial corneal CXL.
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Mechanisms of Collagen Crosslinking in Diabetes and Keratoconus.
McKay, TB, Priyadarsini, S, Karamichos, D
Cells. 2019;(10)
Abstract
Collagen crosslinking provides the mechanical strength required for physiological maintenance of the extracellular matrix in most tissues in the human body, including the cornea. Aging and diabetes mellitus (DM) are processes that are both associated with increased collagen crosslinking that leads to increased corneal rigidity. By contrast, keratoconus (KC) is a corneal thinning disease associated with decreased mechanical stiffness leading to ectasia of the central cornea. Studies have suggested that crosslinking mediated by reactive advanced glycation end products during DM may protect the cornea from KC development. Parallel to this hypothesis, riboflavin-mediated photoreactive corneal crosslinking has been proposed as a therapeutic option to halt the progression of corneal thinning by inducing intra- and intermolecular crosslink formation within the collagen fibrils of the stroma, leading to stabilization of the disease. Here, we review the pathobiology of DM and KC in the context of corneal structure, the epidemiology behind the inverse correlation of DM and KC development, and the chemical mechanisms of lysyl oxidase-mediated crosslinking, advanced glycation end product-mediated crosslinking, and photoreactive riboflavin-mediated corneal crosslinking. The goal of this review is to define the biological and chemical pathways important in physiological and pathological processes related to collagen crosslinking in DM and KC.
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Collagen-binding proteins: insights from the Collagen Toolkits.
Farndale, RW
Essays in biochemistry. 2019;(3):337-348
Abstract
The Collagen Toolkits are libraries of 56 and 57 triple-helical synthetic peptides spanning the length of the collagen II and collagen III helices. These have been used in solid-phase binding assays to locate sites where collagen receptors and extracellular matrix components bind to collagens. Truncation and substitution allowed exact binding sites to be identified, and corresponding minimal peptides to be synthesised for use in structural and functional studies. 170 sites where over 30 proteins bind to collagen II have been mapped, providing firm conclusions about the amino acid distribution within such binding sites. Protein binding to collagen II is not random, but displays a periodicity of approximately 28 nm, with several prominent nodes where multiple proteins bind. Notably, the vicinity of the collagenase-cleavage site in Toolkit peptide II-44 is highly promiscuous, binding over 20 different proteins. This may reflect either the diverse chemistry of that locus or its diverse function, together with the interplay between regulatory binding partners. Peptides derived from Toolkit studies have been used to determine atomic level resolution of interactions between collagen and several of its binding partners and are finding practical application in tissue engineering.
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Effect of collagen supplementation on osteoarthritis symptoms: a meta-analysis of randomized placebo-controlled trials.
García-Coronado, JM, Martínez-Olvera, L, Elizondo-Omaña, RE, Acosta-Olivo, CA, Vilchez-Cavazos, F, Simental-Mendía, LE, Simental-Mendía, M
International orthopaedics. 2019;(3):531-538
Abstract
PURPOSE Osteoarthritis (OA) is one of the most common causes of disability and a prevalent chronic disease. The use of collagen is growing due to the satisfactory results in the treatment of OA. However, the possible beneficial effects of collagen for the treatment of OA are currently controversial. The aim of the present meta-analysis was to evaluate the effect of collagen-based supplements on OA symptoms. METHODS PubMed-Medline, Scopus, and Google Scholar databases were searched for randomized placebo-controlled trials evaluating the effect of orally administered collagen on OA symptoms using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scale and/or the Visual Analog Scale (VAS). Meta-analysis was conducted using a random-effects model and a generic inverse variance method. Heterogeneity was tested using the I2 statistic index. RESULTS Collagen treatment showed a significant reduction in the score of total WOMAC index (WMD - 8.00; 95% CI - 13.04, - 2.95; p = 0.002). After subgroup analysis of the WOMAC subscores, the collagen supplementation revealed a significant decrease in the stiffness subscore (WMD - 0.41; 95% CI - 0.74, - 0.08; p = 0.01), whereas the pain (WMD - 0.22; 95% CI - 1.58, 1.13; p = 0.75) and functional limitation (WMD - 0.62; 95% CI - 5.77, 4.52; p = 0.81) subscores did not have significant differences. Finally, a significant reduction was found in the VAS score after collagen administration (WMD - 16.57; 95% CI - 26.24, - 6.89; p < 0.001). CONCLUSION The results of this meta-analysis showed that collagen is effective in improving OA symptoms by the decrease of both total WOMAC index and VAS score.
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Collagen Cross-Linking in the Management of Microbial Keratitis.
Bonzano, C, Di Zazzo, A, Barabino, S, Coco, G, Traverso, CE
Ocular immunology and inflammation. 2019;(3):507-512
Abstract
Increasing resistance to antimicrobial agents has contributed to an elevated risk of complications of infectious keratitis. Corneal collagen cross-linking (CXL) has been widely adopted for the management of keratoconus and post-refractive surgery corneal ectasia. It has recently been introduced as an option for treating keratitis due to multidrug resistant organisms. The purpose of this review is to discuss the rationale, safety, and evidence for CXL in infectious keratitis and its possible effect on ocular surface inflammation. Published data show that CXL is effective and safe as an adjunct to antibiotic treatment in selected cases of bacterial keratitis. The benefit of CXL probably varies according to the etiology of the infection.
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Combined application of prophylactic corneal cross-linking and laser in-situ keratomileusis - a review of literature.
Chan, TCY, Ng, ALK, Chan, KKW, Cheng, GPM, Wong, IYH, Jhanji, V
Acta ophthalmologica. 2017;(7):660-664
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Laser in-situ keratomileusis (LASIK) is safe and effective laser refractive procedures in treating refractive errors. However, regression of treatment and iatrogenic keratectasia remain to be a major concern, especially in treating thin cornea with high ametropia. Collagen cross-linking (CXL) is an effective method in stopping keratoconus progression through increasing the biomechanical strength of the cornea. Adjuvant cross-linking to refractive procedures can theoretically help prevent regression and reduce the risk of keratectasia development by increasing the mechanical stability of cornea. During the procedure, riboflavin is directly applied to the corneal stroma, thereby reducing the need of de-epithelialization as in the conventional protocol for keratoconus. Currently, there is still no consensus regarding the indication of CXL during refractive procedure, nor any standardized treatment protocol. This article aims to summarize the current evidence regarding the use of adjuvant CXL in LASIK.
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Riboflavin for corneal cross-linking.
O'Brart, DP
Drugs of today (Barcelona, Spain : 1998). 2016;(6):331-46
Abstract
Corneal collagen cross-linking (CXL) with riboflavin and ultraviolet A (UVA) radiation is the first therapeutic modality that appears to arrest the progression of keratoconus and other corneal ectasias. Riboflavin is central to the process, acting as a photosensitizer for the production of oxygen singlets and riboflavin triplets. These free radicals drive the CXL process within the proteins of the corneal stroma, altering its biomechanical properties. Riboflavin also absorbs the majority of the UVA radiation, which is potentially cytotoxic and mutagenic, within the anterior stroma, preventing damage to internal ocular structures, such as the corneal endothelium, lens and retina. Clinical studies report cessation of ectatic progression in over 90% of cases and the majority document significant improvements in visual, keratometric and topographic parameters. Clinical follow-up is limited to 5-10 years, but suggests sustained stability and enhancement in corneal shape. Sight-threatening complications are rare. The optimal stromal riboflavin dosage for CXL is as yet undetermined.