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Abstract

Background: Clinical studies demonstrated that continued exposure to copper oxide-embedded textiles, such as pillowcases, significantly reduces depth of facial wrinkles and skin sagging and enhances skin elasticity. Objective: Study the mechanisms by which the exposure to copper ions improve the well-being of the skin. Methods: Human skin explants, cultured ex-vivo, were exposed topically to saline alone or saline containing 0.02 or 1 µmol/L copper ions. The skin explants viability, histology and secretion of elastin, pro-collagen 1, and TGF-β1 to the culture medium were determined at various time intervals. Results: Exposure to saline containing 0.02 or 1 µmol/L copper ions did not affect the viability or morphological profile of the explants as compared to control explants treated with saline only. Notably, exposure of the skin grafts to 0.02 or to 1 µmol/L of copper ions resulted in ~100% and ~20% increases in elastin and pro-collagen 1 concentrations, respectively, in the culture supernatants already after 1 day of incubation, which remained statistically significantly elevated also after 6 days on incubation, as compared to the control explants. In addition, ~2- and ~4-fold increases in TGF-ß1 levels in the culture supernatants of explants exposed to the copper ions were detected after 4 and 6 days of culture, as compared to the explants exposed to saline alone. Conclusion: This study substantiated the anti-aging effect that copper ions have on the skin and gave insights into the mechanisms by which exposure of the skin to copper ions improves the skin well-being.

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... The absorbance at 570 nm was measured in an ELISA reader. Viability in the ex vivo skin was performed as described before [29]. Briefly, in order to detach the epidermis, the skin tissues were placed in PBS (56 • C) for 1 min. ...
... The efficacy and safety of SH-29 and SK-119 were investigated in the well-established HaCaT keratinocyte cell line and in the ex vivo human skin organ culture systems [29,[60][61][62][63]. Although the latter closely emulates the physical and biochemical properties of intact human tissue, it lacks the connection to the circulation, systemic inflammatory components, and the nervous system. ...
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Air pollution has been repeatedly linked to numerous health-related disorders, including skin sensitization, oxidative imbalance, premature extrinsic aging, skin inflammation, and increased cancer prevalence. Nrf2 is a key player in the endogenous protective mechanism of the skin. We hypothesized that pharmacological activation of Nrf2 might reduce the deleterious action of diesel particulate matter (DPM), evaluated in HaCaT cells. SK-119, a recently synthesized pharmacological agent as well as 2,2′-((1E,1′E)-(1,4-phenylenebis(azaneylylidene))bis(methaneylylidene))bis(benzene-1,3,5-triol) (SH-29) were first evaluated in silico, suggesting a potent Nrf2 activation capacity that was validated in vitro. In addition, both compounds were able to attenuate key pathways underlying DPM damage, including cytosolic and mitochondrial reactive oxygen species (ROS) generation, tested by DC-FDA and MitoSOX fluorescent dye, respectively. This effect was independent of the low direct scavenging ability of the compounds. In addition, both SK-119 and SH-29 were able to reduce DPM-induced IL-8 hypersecretion in pharmacologically relevant concentrations. Lastly, the safety of both compounds was evaluated and demonstrated in the ex vivo human skin organ culture model. Collectively, these results suggest that Nrf2 activation by SK-119 and SH-29 can revert the deleterious action of air pollution.
... Copper is an essential trace element involved in plenty of cellular, metabolic, and physiological pathways in the majority of body tissues [6]. In the skin, copper stimulates dermal fibroblast proliferation [7]; enhances production and secretion of various collagen and elastin types by fibroblasts in vitro [8] and ex vivo [9]; stabilizes the skin extracellular matrix (ECM) once formed [10,11]; serves as a cofactor of superoxide dismutase, an antioxidant enzyme present in the skin, important for protection against free radicals [12,13]; serves as a cofactor of lysyl oxidase, an enzyme that catalyzes lysine-derived crosslinks in ECM [14]; is vital for the catalytic activity of tyrosinase, essential for melanin synthesis in melanocytes [15]; and inhibits cellular oxidative effects, such as membrane damage and lipid peroxidation [8]. Recently, the capacity of copper oxide-impregnated wound dressings to enhance wound healing of chronic wounds was reported [16]. ...
... Furthermore, others and we have also suggested the dermocosmetic beneficial properties of copper treatment [38,39]. Ex vivo treatments with copper ions extracted from copper oxide-impregnated dressings on skin resulted in increased expression of collagen and elastin as well as an increase in the amount of their fibers in the dermal tissue [9]. Also, in the copper-treated burned samples, we found an increase in the amount of collagen fibers than in the saline-treated control group, as seen in the dermal layer in Figure 7b. ...
Article
Introduction: The zone of stasis is formed around the coagulation zone following skin burning and is characterized by its unique potential for salvation. The cells in this zone may die or survive depending on the severity of the burn and therefore are target for the local treatments of burns. Their low survival rate is consistent with decreased tissue perfusion, hypotension, infection, and/or edema, resulting in a significant increase in the wound size following burning. Copper is an essential trace mineral needed for the normal function of almost all body tissues, including the skin. Objective: The aim of the work was to study the effect copper ions have on skin burn pathophysiology. Methods: Skin obtained from healthy patients undergoing abdominoplasty surgery was cut into 8 × 8 mm squares, and round 0.8-mm diameter burn wounds were inflicted on the skin explants. The burned and control intact skin samples were cultured up to 27 days after wounding. Immediately following injury and then again every 48 h, saline only or containing 0.02 or 1 µM copper ions was added onto the skin explant burn wounds. Results: We found that exposing the wounded sites immediately after burn infliction to 0.02 or 1 µM copper ions reduced the deterioration of the zone of stasis and the increase in wound size. The presence of the copper ions prevented the dramatic increase of pro-inflammatory cytokines (interleukin (IL)-6 and IL-8) and transforming growth factor beta-1 that followed skin burning. We also detected re-epithelialization of the skin tissue and a greater amount of collagen fibers upon copper treatment. Conclusion: The deterioration of the zone of stasis and the increase in wound size following burning may be prevented or reduced by using copper ion-based therapeutic interventions.
... Previous studies have shown the effect and role of Cu 2+ supplementation on the synthesis of ECM proteins [16]. A recent report also suggested the effect of Cu 2+ on pro-collagen 1 and elastin expression in an ex vivo human skin model [12]. Furthermore, the effects of amino acid supplementation on ECM synthesis has been shown in the previous studies. ...
... Copper stimulates dermal fibroblast proliferation in the skin and upregulates the protein expression of collagen (types I, II, and V) and elastin produced by fibroblasts [7,15,16]. More recently, in an ex vivo human skin model, the effect of copper on pro-collagen1 and elastin expression was examined [12]. These studies suggested that some of these effects are indirectly affected by other proteins, including HSp-37, and TGF-β expression. ...
Article
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The stimulation of extracellular matrix (ECM) protein production is an interesting target to maintain normal skin structure and delay skin aging. Copper has been shown to stimulate ECM protein synthesis by activating lysyl oxidase. Although copper increases elastin and collagen synthesis, the effect of copper and amino acid mixtures on gene expression and protein synthesis changes relating to the ECM have not been fully investigated. In this study, we showed that copper ions (Cu2+) and amino acid mixtures significantly increased the expression of genes and proteins related to the ECM in human dermal fibroblasts. The expression of genes involved in ECM production was evaluated through quantitative polymerase chain reaction in the presence of amino acid mixtures containing different Cu2+ concentrations. Cu2+ dose-dependently increased the gene expression of elastin and collagen I. In addition, a mixture of amino acids and Cu2+ increased the protein expression of elastin and collagen I. We further evaluated the effect of Cu2+ with or without amino acids. Although Cu2+ treatment increased the expression of genes encoding ECM proteins, the Cu2+ treatment without amino acids did not increase protein expression in the ECM. Our results demonstrated the synergistic effects of amino acids and a Cu2+ mixture on ECM protein synthesis in dermal fibroblasts.
... Together with Zn, Cu is a useful element in terms of wound healing [67] and its presence is allowed in cosmetics by EC 1223/2009. This element has been demonstrated to increase the expression of TGF-β1 in ex vivo skin models, thus leading to higher pro-collagen 1 and elastin production by fibroblasts [67]. ...
... Together with Zn, Cu is a useful element in terms of wound healing [67] and its presence is allowed in cosmetics by EC 1223/2009. This element has been demonstrated to increase the expression of TGF-β1 in ex vivo skin models, thus leading to higher pro-collagen 1 and elastin production by fibroblasts [67]. Moreover, Cu has been demonstrated to enhance skin cell migration (keratinocytes and fibroblasts), which is crucial for wound healing [68,69]. ...
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Inorganic hydrogels formulated with spring waters and clay minerals are used to treat musculoskeletal disorders and skin affections. Their underlying mechanism of action for skin disorders is not clear, although it is usually ascribed to the chemical composition of the formulation. The aim of this study was to assess the composition and in vitro release of elements with potential wound healing effects from hydrogels prepared with two nanoclays and natural spring water. In vitro Franz cell studies were used and the element concentration was measured by inductively coupled plasma techniques. Biocompatibility studies were used to evaluate the potential toxicity of the formulation against fibroblasts. The studied hydrogels released elements with known therapeutic interest in wound healing. The released ratios of some elements, such as Mg:Ca or Zn:Ca, played a significant role in the final therapeutic activity of the formulation. In particular, the proliferative activity of fibroblasts was ascribed to the release of Mn and the Zn:Ca ratio. Moreover, the importance of formulative studies is highlighted, since it is the optimal combination of the correct ingredients that makes a formulation effective.
... Type I collagen, the most abundant dermal collagen, is composed of two types of pro-collagen: pro-collagen I α I and α 2 chains. Thus, by measuring the protein levels of pro-collagen I α I it is possible to estimate alterations in the levels of collagen type I [47,48], which may be a critical step toward the development of any possible cosmetic ingredient. ...
Article
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Carboxymethyl cellulose is the most used water-soluble cellulose with applications in industries such as food, cosmetics, and tissue engineering. However, due to a perceived lack of biological activity, carboxymethyl cellulose is mostly used as a structural element. As such, this work sought to investigate whether CMC possesses relevant biological properties that could grant it added value as a cosmeceutical ingredient in future skincare formulations. To that end, CMC samples (Mw between 471 and 322 kDa) skin cell cytotoxicity, impact upon pro-collagen I α I production, and inflammatory response were evaluated. Results showed that samples were not cytotoxic towards HaCat and HDFa up to 10 mg/mL while simultaneously promoting intracellular production of pro-collagen I α I up by 228% relative to the basal metabolism, which appeared to be related to the highest DS and Mw. Additionally, CMC samples modulated HaCat immune response as they decreased by ca. 1.4-fold IL-8 production and increased IL-6 levels by ca. five fold. Despite this increase, only two samples presented IL-6 levels similar to those of the inflammation control. Considering these results, CMC showed potential to be a more natural alternative to traditional bioactive cosmetic ingredients and, as it is capable of being a bioactive and structural ingredient, it may play a key role in future skincare formulations.
... * Jiahai Wu jhwu333@163.com 1 is often manifested as inconspicuous estrus, infertility, or abortion [4,5]. Cu is one of the essential trace elements in the organism, participating in hematopoiesis and metabolism, increasing growth, improving reproduction, and enhancing resistance [6,7]. As an effective growth promoter, Cu can improve the growth performance and utilization rate of feed in livestock, and is widely used as an efficient, cheap, and convenient growth promoter in the livestock industry [8]. ...
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This research is to study the effects of nano-Cu2O on blood parameters, growth performance, and wool yield in the Cu-stripped ranches, and provide reference for further study on prevention and treatment in Cu-deficient Chinese Merino sheep. We selected twenty Chinese Merino sheep from Cu-deficient and normal ranch, respectively. The results have shown that the Cu content in the soils, forages, blood, and wool from Cu-deficient ranches was significantly lower than those from normal ranches (P < 0.01). There were no significant differences in the contents of other elements. Treatment experiments of nano-Cu2O were carried out for 50 days. We found that the Cu content in the blood was increased continuously in the sheep after adding nano-Cu2O, and reached the highest level at 40 days. The levels of Hb, RBC, PCV, MCV, and MCH in the nano-Cu2O-fed animals were remarkably higher than those in the control animals (P < 0.01). The daily gain and wool yield in the nano-Cu2O-fed animals were also significantly higher than those in the control sheep (P < 0.01). Therefore, adding nano-Cu2O not only remarkably increases the Cu content in the blood, but also greatly improves the daily gain and wool yield in Cu-deficient animals.
... contraceptive devices, osteoporosis, anti-aging nano-medicine, and animal feed additives. It has brought a technological revolution to medicine, industry, and animal husbandry [7][8][9][10][11]. Nano-Cu 2 O has the advantages of small particle size and large specific surface area. ...
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Kazakh sheep are vital to the production system of the Barkol prairie. The purpose of this study was to determine the effect of nano-copper oxide (Nano-Cu2O) on the antioxidant system of Cu-deficient Kazakh sheep in the Barkol prairie in Xinjiang, China. We analyzed mineral contents in soil, forage, and animal tissues. Blood parameters were also measured at the same time. The results showed that compared with healthy grassland, the Cu content in the soil and forage in Cu-deficient pastures was significantly lower than that in healthy grassland (P < 0.01). The Cu content in the blood, wool, and liver of Cu-deficient Kazakh sheep was significantly lower than that of healthy animals (P < 0.01). After Kazakh sheep were supplemented with Nano-Cu2O or CuSO4, the blood Cu concentration increased significantly (P < 0.01). From the 5th day, the Cu content of the Nano-Cu2O group was significantly higher than that of the CuSO4 group. The levels of hemoglobin (Hb), erythrocyte count (RBC), and packed cell volume (PCV) in the two experimental groups were significantly higher than those in Cu-deficient Kazakh sheep (P < 0.01). Compared with Cu-deficient Kazakh sheep, the serum ceruloplasmin (Cp) level of the two experimental groups increased significantly (P < 0.01), while the serum lactate dehydrogenase (LDH), alkaline phosphatase (AKP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) decreased significantly (P < 0.01). Compared with Cu-deficient Kazakh sheep, the activities of serum superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and total antioxidant capacity (T-AOC) in Nano-Cu2O and CuSO4 groups increased significantly (P < 0.01), while the level of serum malondialdehyde (MDA) decreased significantly (P < 0.01). Therefore, Nano-Cu2O could not only significantly increase the Cu content in the blood of Cu-deficient Kazakh sheep, but also greatly improve the antioxidant capacity.
... Many of the finely balanced wound healing repair mechanisms are dependent on their interaction with copper (thoroughly reviewed in [6]). This includes, Plateletderived growth factor (PDGF), involved in the hemostasis phase of wound healing, [15,16]; VEGF and angiogenin, key growth factors that stimulate angiogenesis, an essential process during the Proliferation Phase [17][18][19][20][21][22][23]; secretion of collagens (types I, II, and V), HSP-47 and elastin fiber components (elastin, fibrillins) by dermal fibroblasts during the Proliferation and Remodeling Phases [16,24,25]; activity of Lysyl oxidase (LOX) needed for efficient extracellular matrix (ECM) protein cross-linking between elastin and collagen [26]; stabilization of the skin ECM once formed [27,28]; modulation of integrins by differentiated keratinocytes during the Remodeling phase [29], and Matrix metalloproteinases (MMPs, mainly MMP-1, MMP-2, MMP-8, MMP-9) and the serine proteases (human neutrophil elastase, HNE) are the major groups of proteases involved in the wound healing process. It is thus not surprising that copper chelation delays wound closure [30]. ...
Chapter
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Copper has two key properties that endow it as an excellent active ingredient to be used in the “wound healing battle”. First, copper plays a key role in angiogenesis, dermal fibroblasts proliferation, upregulation of collagen and elastin fibers production by dermal fibroblasts, and it serves as a cofactor of Lysyl oxidase needed for efficient dermal extracellular matrix (ECM) protein cross-linking. Secondly, copper has potent wide-spectrum biocidal properties. Both gram-positive and gram-negative bacteria, including antibiotic resistant bacteria and hard to kill bacterial spores, fungi and viruses, when exposed to high copper concentrations, are killed. Copper has been used as a biocide for centuries by many different civilizations. Impregnation of copper oxide microparticles in wound dressings allows continuous release of copper ions. This results not only in the protection of the wounds and wound dressings from pathogens, but more importantly, enhances wound healing. The article discusses the molecular mechanisms of enhanced wound healing by the copper oxide impregnated dressings, which include in situ upregulation of pro-angiogenic factors and increased blood vessel formation. It also includes clinical cases showing clearance of infection, induction of granulation and epithelialization of necrotic wounds, reduction of post-operative swelling inflammation and reduction of scar formation, in wounds when they were treated with copper oxide impregnated dressings. We show the positive outcome at all wound healing stages of using the copper impregnated wound dressings, indicating the neglected critical role copper plays in wound healing.
... burn injuries have been described 31 , but due to anatomical and physiological differences, it is difficult to directly translate findings from animal models to the clinical situation 32 . Ex vivo skin organ culture models based on the cultivation of small skin biopsies allow for the analysis of skin pathologies including burn injuries in a fully human situation [32][33][34][35][36][37][38][39][40][41] , but they are dependent on rather artificial culture conditions. The aim of this study was to develop and evaluate a human ex vivo model, which is independent of culture conditions and in which the overall tissue structure is fully maintained. ...
Article
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Burn injuries initiate numerous processes such as heat shock response, inflammation and tissue regeneration. Reliable burn models are needed to elucidate the exact sequence of local events to be able to better predict when local inflammation triggers systemic inflammatory processes. In contrast to other ex vivo skin culture approaches, we used fresh abdominal skin explants to introduce contact burn injuries. Histological and ultrastructural analyses confirmed a partial-thickness burn pathology. Gene expression patterns and cytokine production profiles of key mediators of the local inflammation, heat shock response, and tissue regeneration were analyzed for 24 h after burn injury. We found significantly increased expression of factors involved in tissue regeneration and inflammation soon after burn injury. To investigate purely inflammation-mediated reactions we injected lipopolysaccharide into the dermis. In comparison to burn injury, lipopolysaccharide injection initiated an inflammatory response while expression patterns of heat shock and tissue regeneration genes were unaffected for the duration of the experiment. This novel ex vivo human skin model is suitable to study the local, early responses to skin injuries such as burns while maintaining an intact overall tissue structure and it gives valuable insights into local mechanisms at the very beginning of the wound healing process after burn injuries.
... Biofunctional textiles with UPF, anti-oxidant and anti-ageing benefits may incentivise mask-wearing. Copper oxide polyesters are associated with reduced facial wrinkles 4 , elevation of elastin, pro collagen 1 and TGF ß1 levels5 . Silver, zinc oxide and copper oxide nanoparticle incorporated textiles have broad-spectrum biocidal properties that are therapeutic for dermatological conditions, besides reducing antibiotic resistance in acne treatment. ...
... In the meantime, the increase of anti-inflammatory mediators such as IL-10 further supplemented the anti-inflammatory capacity [114]. In other studies, VEGF and TGF-β1 were related to angiogenesis and collagen deposition, respectively, and showed high expression under the influence of CS/ CuNPs [115,116]. Figure 4 shows the effects of copper on various cytokines associated with wound healing [113]. e accelerated wound healing benefits from CS/CuNPs for the regulation of cytokines and growth factors. ...
Article
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Chitosan (CS) has been extensively studied as a natural polymer, in the field of wound repair, due to its useful properties, which include a lack of toxicity and stimulation, excellent biological affinity, degradability, and promotion of collagen deposition. However, inferior mechanical strength and moderate antibacterial properties are the drawbacks restricting its further clinical application. Many researchers have adopted the use of nanotechnology, in particular metallic nanoparticles (MNPs), in order to improve the mechanical strength and specific antibacterial properties of chitosan composites, with promising results. Furthermore, chitosan naturally functions as a reducing agent for MNPs, which can also reduce cytotoxicity. Thus, CS, in combination with MNPs, exhibits antibacterial activity, excellent mechanical strength, and anti-inflammatory properties, and it has great potential to accelerate the process of wound healing. This review discusses the current use of CS and MNPs in wound healing and emphasises the synergy and the advantages for various applications in wound healing.
... Following LPS treatment, the epidermis was separated from dermis, and viability was determined, as described before [17]. Briefly, the skin was incubated for 1 min in phosphate-buffered saline (PBS) at 56 • C, after which the epidermis was physically detached from the dermis using forceps and scalpel. ...
Article
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Several in vitro models that mimic different aspects of local skin inflammation exist. The use of ex vivo human skin organ culture (HSOC) has been reported previously. However, comprehensive evaluation of the cytokine secretory capacity of the system and its kinetics has not been performed. Objective: the aim of the current study was to investigate the levels and secretion pattern of key cytokine from human skin tissue upon lipopolysaccharide (LPS) stimulation. HSOC maintained in an air–liquid interface was used. Epidermal and tissue viability was monitored by MTT and Lactate Dehydrogenase (LDH) activity assay, respectively. Cytokine levels were examined by ELISA and multiplex array. HSOCs were treated without or with three different LPS subtypes and the impact on IL-6 and IL-8 secretion was evaluated. The compounds enhanced the secreted levels of both cytokines. However, differences were observed in their efficacy and potency. Next, a kinetic multiplex analysis was performed on LPS-stimulated explants taken from three different donors to evaluate the cytokine secretion pattern during 0-72 h post-induction. The results revealed that the pro-inflammatory cytokines IL-6, IL-8, TNFα and IL-1β were up-regulated by LPS stimuli. IL-10, an anti-inflammatory cytokine, was also induced by LPS, but exhibited a different secretion pattern, peak time and maximal stimulation values. IL-1α and IL-15 showed donor-specific changes. Lastly, dexamethasone attenuated cytokine secretion in five independent repetitions, supporting the ability of the system to be used for drug screening. The collective results demonstrate that several cytokines can be used as valid inflammatory markers, regardless of changes in the secretion levels due to donor’s specific alterations.
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In this work, we present biocompatible nanocarriers based on modified polysaccharides capable of transporting insulin macromolecule through human skin without any auxiliary techniques. N-alkylamidated carboxymethyl cellulose (CMC) derivatives, CMC-6 and...
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The biochemical basis for the essentiality of copper, the adequacy of the dietary copper supply, factors that condition deficiency, and the special conditions of copper nutriture in early infancy are reviewed. New biochemical and crystallographic evidence define copper as being necessary for structural and catalytic properties of cuproenzymes. Mechanisms responsible for the control of cuproprotein gene expression are not known in mammals; however, studies using yeast as a eukaryote model support the existence of a copper-dependent gene regulatory element. Diets in Western countries provide copper below or in the low range of the estimated safe and adequate daily dietary intake. Copper deficiency is usually the consequence of decreased copper stores at birth, inadequate dietary copper intake, poor absorption, elevated requirements induced by rapid growth, or increased copper losses. The most frequent clinical manifestations of copper deficiency are anemia, neutropenia, and bone abnormalities. Recommendations for dietary copper intake and total copper exposure, including that from potable water, should consider that copper is an essential nutrient with potential toxicity if the load exceeds tolerance. A range of safe intakes should be defined for the general population, including a lower safe intake and an upper safe intake, to prevent deficiency as well as toxicity for most of the population.
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Background: The purpose of this study was to determine the effectiveness of copper-impregnated composite hard surfaces and linens in an acute care hospital to reduce health care-associated infections (HAIs). Methods: We performed a quasiexperimental study with a control group, assessing development of HAIs due to multidrug resistant organisms (MDROs) and Clostridium difficile in the acute care units of a community hospital following the replacement of a 1970s-era clinical wing with a new wing outfitted with copper-impregnated composite hard surfaces and linens. Results: The study was conducted over a 25.5-month time period that included a 3.5-month washout period. HAI rates obtained from the copper-containing new hospital wing (14,479 patient-days; 72 beds) and the unmodified hospital wing (19,177 patient-days) were compared with those from the baseline period (46,391 patient-days). The new wing had 78% (P = .023) fewer HAIs due to MDROs or C difficile, 83% (P = .048) fewer cases of C difficile infection, and 68% (P = .252) fewer infections due to MDROs relative to the baseline period. No changes in rates of HAI were observed in the unmodified hospital wing. Conclusions: Copper-impregnated composite hard surfaces and linens may be useful technologies to prevent HAIs in acute care hospital settings. Additional studies are needed to determine whether reduced HAIs can be attributed to the use of copper-containing antimicrobial hard and soft surfaces.
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Copper plays a key role in many of the physiological processes that occur in the skin. Previously it was found that sleeping on pillowcases impregnated with microscopic copper oxide particles results in reduction of wrinkles and fine lines. In the current study, it was examined if sleeping on copper oxide impregnated pillowcases results also in skin lifting and skin brightness. A four week, double blind, randomized study was performed, during which 45 women, aged 37–54, slept on copper oxide containing pillowcases (test group, n = 23) or on control pillowcases without copper oxide (control group, n = 22). Facial and eye skin surface was measured using an Fray 3D measurement system and surface analysis was conducted using Image-pro ® plus. Skin brightness was measured using a tristimulus colorimeter. Sleeping on the test pillowcases resulted in statistically significant skin lifting on the cheek area (p = 0.039) and eye area (p = 0.001) after four weeks of use as compared to baseline. The mean skin brightness in those sleeping on the test pillowcases increased after two (p = 0.024) and four weeks (p = 0.008). No statistically significant changes occurred during the study in the study participants using the control pillowcases. Statistically significant differences between both groups were recorded at two and four weeks for skin brightness and skin lifting, respectively. In conclusion, sleeping on copper oxide containing pillowcases results in facial skin lifting and brightness of the skin.
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Physiological tissue repair aims at restoring the mechano-protective properties of the extracellular matrix. Consequently, redundant regulatory mechanisms are in place ensuring that tissue remodelling terminates once matrix homeostasis is re-established. If these mechanisms fail, stromal cells become continuously activated, accumulate excessive amounts of stiff matrix, and fibrosis develops. In this mini-review, I develop the hypothesis that the mechanical state of the extracellular matrix and the pro-fibrotic transforming growth factor (TGF)-β1 cooperate to regulate the remodelling activities of stromal cells. TGF-β1 is stored in the matrix as part of a large latent complex and can be activated by cell contractile force that is transmitted by integrins. Matrix straining and stiffening lower the threshold for TGF-β1 activation by increasing the mechanical resistance to cell pulling. Different elements of this mechanism can be pharmacologically targeted to interrupt the mechanical positive feedback loop of fibrosis, including specific integrins and matrix protein interactions. Copyright © 2015. Published by Elsevier B.V.
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Copper has two key properties that are being exploited in consumer and medical device products in the last decade. On the one hand, copper has potent biocidal properties. On the other hand, copper is involved in numerous physiological and metabolic processes critical for the appropriate functioning of almost all tissues in the human body. In the skin, copper is involved in the synthesis and stabilization of extracellular matrix skin proteins and angiogenesis. This manuscript reviews clinical studies that show that the use of textile consumer and medical device products, embedded with microscopic copper oxide particles, improve the well-being of the skin. These include studies showing a) cure of athlete’s foot infections and improvement in skin elasticity, especially important for individuals suffering from diabetes; b) reduction of facial fine line and wrinkles; and c) enhancement of wound healing; by copper oxide embedded socks, pillowcases and wound dressings, respectively. The manuscript also reviews and discusses the mechanisms by which the presence of copper in these products improves skin well-being.
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Copper has two key properties that make it an active ingredient in the medical devices currently being developed. First, copper is an essential trace element needed by humans, which plays a key role in many physiological processes in different tissues. For example, copper has been shown to be involved in angiogenesis and in wound healing. Second, copper has very potent antibacterial, antifungal, antiviral, and acaricidal properties. Recently, a novel technology has been developed that introduces copper oxide particles into polymeric materials, where they serve as a slow release source of copper ions. For example, by using this technology, copper oxide containing wound dressings that enhance wound healing; copper oxide containing antiviral respiratory masks that reduce the risk of infection; socks that protect from athlete's foot, and acaricidal bedding products that kill dust mites, have been developed. While copper oxide is used as the source of copper in mineral and vitamin supplements and is considered safe, its use in medical devices, as well as in industrial and consumer products, is novel. The current manuscript reviews the safety aspects of the use of copper oxide in products that come in contact with open and closed skin. Copper oxide products have been tested in 9 clinical trials and in several non-clinical studies and have been found to be non-irritating, non-sensitizing, and safe to use, with not even one adverse reaction recorded, both when in contact with intact and broken skin. This is in accordance with the extremely low risk of adverse reactions attributed to dermal exposure to copper.
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Skin aging is associated with the loss of the structural collagens and the elastin fiber components that form the extracellular matrix (ECM). It is associated with reduced transforming growth factor-β (TGF-β), angiogenesis and increased oxidative stress. Copper has been incorporated into cosmetics for anti-skin aging. This research investigated the mechanism for the anti-skin aging effect copper ions, from cuprous oxide powders. Dermal fibroblasts were exposed to copper and examined for expression (protein and/or promoter levels) of types I, III, V collagen, heat shock protein-47 (HSP-47), elastin, fibrillin-1, and fibrillin-2, TGF-β1, vascular endothelial growth factor (VEGF), and in addition for membrane damage and lipid peroxidation. The direct antioxidant activity of copper was also determined. The research indicates that copper's anti-skin aging and skin regeneration potential is through its stimulation of ECM proteins, TGF-β1, VEGF, and inhibition of oxidative stress effects at physiological concentrations; and supports its use in cosmetics. Dr. Gadi Borkow is the chief medical scientist of Cupron Scientific.
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Correspondence: Dr Borkow, Hameyasdim 44, Gibton 76910, Israel (gadi@cupron.com).Financial Disclosure: Dr Borkow is employed by Cupron Inc. Cupron owns the patents for the technology used to impregnate polymeric materials with copper oxide. The socks were donated to the trapped miners by Cupron's agent in Chile.1 +Borkow G, Gabbay J.Copper as a biocidal tool. Curr Med Chem. 2005;12(18):2163-2175PubMed | Link to Article[[XSLOpenURL/10.2174/0929867054637617]]2 +Borkow G, Gabbay J.Putting copper into action: copper-impregnated products with potent biocidal activities. FASEB J. 2004;18(14):1728-1730PubMed3 +Zatcoff RC, Smith MS, Borkow G.Treatment of tinea pedis with socks containing copper-oxide impregnated fibers. Foot (Edinb). 2008;18(3):136-141PubMed4 +Havlickova B, Czaika VA, Friedrich M.Epidemiological trends in skin mycoses worldwide. Mycoses. 2008;51:(Suppl 4) 2-15PubMed | Link to Article[[XSLOpenURL/10.1111/myc.2008.51.issue-s4]]5 +Seebacher C, Bouchara JP, Mignon B.Updates on the epidemiology of dermatophyte infections. Mycopathologia. 2008;166(5-6):335-352PubMed | Link to Article[[XSLOpenURL/10.1007/s11046-008-9100-9]]
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Lysyl oxidase (LOX), an amine oxidase critical for the initiation of collagen and elastin cross-linking, has recently been shown to regulate cellular activities possibly by modulating the functions of growth factors. In this study, we investigated the interaction between LOX and transforming growth factor-beta1 (TGF-beta1), a potent growth factor abundant in bone, the effect of LOX on TGF-beta1 signaling, and its potential mechanism. The specific binding between mature LOX and mature TGF-beta1 was demonstrated by immunoprecipitation and glutathione S-transferase pulldown assay in vitro. Both proteins were colocalized in the extracellular matrix in an osteoblastic cell culture system, and the binding complex was identified in the mineral-associated fraction of bone matrix. Furthermore, LOX suppressed TGF-beta1-induced Smad3 phosphorylation likely through its amine oxidase activity. The data indicate that LOX binds to mature TGF-beta1 and enzymatically regulates its signaling in bone and thus may play an important role in bone maintenance and remodeling.
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Protein-lysine 6-oxidase (lysyl oxidase) is a cuproenzyme that is essential for stabilization of extracellular matrixes, specifically the enzymatic cross-linking of collagen and elastin. A hypothesis is proposed that links dietary copper levels to dynamic and proportional changes in lysyl oxidase activity in connective tissue. Although nutritional copper status does not influence the accumulation of lysyl oxidase as protein or lysyl oxidase steady state messenger RNA concentrations, the direct influence of dietary copper on the functional activity of lysyl oxidase is clear. The hypothesis is based on the possibility that copper efflux and lysyl oxidase secretion from cells may share a common pathway. The change in functional activity is most likely the result of posttranslational processing of lysyl oxidase. Copper is essential for organic cofactor formation in amine oxidases such as lysyl oxidase. Copper-containing amine oxidases have peptidyl 2,4,5 tri(oxo)phenylalanine (TOPA) at their active centers. TOPA is formed by copper-catalyzed oxidation of tyrosine, which takes place as part of Golgi or trans-Golgi processing. For lysyl oxidase, recent evidence (Science 1996;273:1078-84) indicates that as an additional step, a lysyl group at the active center of lysyl oxidase reacts with TOPA or its precursor to form lysyl tyrosylquinone.
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Copper ions, either alone or in copper complexes, have been used for centuries to disinfect liquids, solids, and human tissue. Today copper is used as a water purifier, algaecide, fungicide, nematocide, molluscicide, and antibacterial and antifouling agent. Copper also displays potent antiviral activity. We hypothesized that introducing copper into clothing, bedding, and other articles would provide them with biocidal properties. A durable platform technology has been developed that introduces copper into cotton fibers, latex, and other polymeric materials. This study demonstrates the broad-spectrum antimicrobial (antibacterial, antiviral, antifungal) and antimite activities of copper-impregnated fibers and polyester products. This technology enabled the production of antiviral gloves and filters (which deactivate HIV-1 and other viruses), antibacterial self-sterilizing fabrics (which kill antibiotic-resistant bacteria, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci), antifungal socks (which alleviate symptoms of athlete's foot), and anti-dust mite mattress covers (which reduce mite-related allergies). These products did not have skin-sensitizing properties, as determined by guine pig maximization and rabbit skin irritation tests. Our study demonstrates the potential use of copper in new applications. These applications address medical issues of the greatest importance, such as viral transmissions; nosocomial, or healthcare-associated, infections; and the spread of antibiotic-resistant bacteria.
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Background: Hospital linens and patient gowns are frequently touched and contaminated, and may contribute to endogenous, indirect-contact, and aerosol transmission of nosocomial-related pathogens. Recently Sentara Healthcare adopted biocidal copper oxide-impregnated linens across its hospitals. Aim: To assess whether the replacement of the linens resulted in the reduction of healthcare-associated infection (HCAI). Methods: Rates of HCAI caused by Clostridium difficile and multidrug-resistant organisms (MDROs) were compared in six Sentara Healthcare hospitals with similar patient demographics (total of 1019 beds) in three parallel periods (90, 180 and 240 days) before and after (periods A1, A2 and A3, and periods B1, B2, and B3, respectively), replacing all the regular non-biocidal linens with the copper oxide-impregnated biocidal linens. Findings: During periods B1, B2, and B3, compared with periods A1, A2 and A3, there were 61.2% (P < 0.05), 41.1% (P < 0.05) and 42.9% (P < 0.01) reductions in HCAI per 10,000 patient-days in hospital caused by C. difficile, respectively; 48.3% (P > 0.05), 36.4% (P > 0.05), and 19.2% (P > 0.05) reductions in HCAI per 1000 patient-days caused by MDROs; and 64.3% (P < 0.01), 39.9% (P < 0.05), and 37.2% (P < 0.05) in the reduction of HCAI per 1000 patient-days caused by C. difficile and MDROs combined. Conclusion: The use of biocidal copper oxide-impregnated linens in the six analysed Sentara Healthcare hospitals resulted in significant reduction in both HCAI caused by C. difficile, and the combined metric of C. difficile or MDRO infection. Similar reductions in HCAI caused by MDROs were observed, although these reductions did not reach statistical significance, probably due to very low HCAI rates caused by these pathogens in the study facilities.
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Soldiers' fungal and bacterial infections,especially in their feet,cause significant reduction in their performance. Copper has potent antifungal and antibacterial properties. Copper is also an essential trace element vital for the normal function of skin and wound healing. Socks containing copper oxide particles,such as socks designed to protect the feet of diabetic individuals,are commercially available in many countries. This article describes the results of a trial conducted with 53 soldiers undergoing intensive basic training. The soldiers used the socks with copper oxide daily for a period of three weeks. At the end of the trial the vast majority of soldiers reported a notorious reduction in their feet skin irritation,itching,and dryness and reduction in foot and sock odour. Reduced foot infection and discomfort improves the soldiers' physical and mental health,increases productiveness and decreases medical treatment costs and days lost for treatment. For these reasons,and in view of the results of this trial,socks containing copper oxide particles may be an important part of every soldier's arsenal of personal equipment.
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The manuscript reviews the biocidal mechanisms of copper and its current uses in the fight against transmission of health-associated (nosocomial) pathogens, foodborne diseases, dust mites loads and fungal and wound infections. The manuscript also discusses possible future applications such as filtration devices capable of deactivating contaminated blood products and breastmilk.
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The rate of skin aging, or that of tissue in general, is determined by a variable predominance of tissue degeneration over tissue regeneration. This review discusses the role of oxidative events of tissue degeneration and aging in general, and for the skin in particular. The mechanisms involved in intrinsic and extrinsic (photo-) aging are described. Since photoaging is recognized as an important extrinsic aging factor, we put special emphasize on the effects of UV exposure on aging, and its variable influence according to global location and skin type. We here summarise direct photochemical effects of UV on DNA, RNA, proteins and vitamin D, the factors contributing to UV-induced immunosuppression, which may delay aging, the nature and origin of reactive oxygen species (ROS) and reactive nitrogen species (RNS) as indirect contributors for aging, and the consequences of oxidative events for extracellular matrix (ECM) degradation, such as that of collagen. We conclude that conflicting data on studies investigating the validity of the free radical damage theory of aging may reflect variations in the level of ROS induction which is difficult to quantify in vivo, and the lack of targeting of experimental ROS to the relevant cellular compartment. Also mitohormesis, an adaptive response, may arise in vivo to moderate ROS levels, further complicating interpretation of in vivo results. We here describes how skin aging is mediated both directly and indirectly by oxidative degeneration.This review indicates that skin aging events are initiated and often propagated by oxidation events, despite recently recognized adaptive responses to oxidative stress.
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Background Copper is an essential mineral involved in the formation and stabilisation of extracellular skin proteins. As copper can be absorbed through intact skin, we reasoned that using socks containing copper-impregnated fibres may have an effect on skin elasticity.MethodsA double blind, placebo controlled study was conducted in which one group of healthy volunteers (n = 32) wore socks with fibres containing microscopic copper oxide particles and the other group wore identical socks without copper oxide (n = 28). The socks were worn for at least 10 h a day for 4 weeks. Skin elasticity measurements were taken from three separate test sites on the side of the ankle using a Cutometer at baseline and after 2 and 4 weeks of product use.ResultsThere was an increase in the mean net skin elasticity (R5) of 6.4% (P = 0.6) and 31.4% (P = 0.004) after 2 and 4 weeks respectively, in the group of individuals that used the copper oxide containing socks, but no increase in the group of individuals that used the control socks. Similarly, there was an increase in the mean biological elasticity (R7 values) of 3% (P = 0.55) and 20.7% (0.014) after 2 and 4 weeks, respectively, only in the group of individuals that used the copper oxide containing socks. The differences between treatments (i.e. socks used) were statistically significant at 4 weeks (P = 0.0058 and P = 0.0327 for R5 and R7, respectively).Conclusion Using copper oxide containing socks results in an increase in skin elasticity of the feet.
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Copper up-regulates the secretion of extracellular skin proteins and stabilizes the extracellular matrix once formed. As copper can be absorbed through intact skin, we reasoned that sleeping on pillowcases containing copper-impregnated fibers would reduce skin wrinkles. Demonstrate that sleeping on pillowcases containing copper-impregnated fibers reduce facial skin wrinkles. An 8-week, double blind, parallel, randomized study was carried out, in which healthy volunteers, aged 30-60, used either copper oxide-containing pillowcases (1% weight/weight) (test group, n = 30) or control pillowcases without copper (control group, n = 31). Skin conditions of the subjects were evaluated by visual grading by two expert graders and by 3D Image Analysis GFM PRIMOS(®) at baseline (before treatment) and following 4 and 8 weeks of sleeping on the pillowcases. The use of the copper oxide-containing pillowcase resulted in significant decrease of crow's feet after 4 (P = 0.01) and 8 (P = 0.002) weeks, but none was observed in the control group, as determined by the expert graders. On the basis of the 3D measurements, three roughness (R) parameters were improved after 4 and 8 weeks (P < 0.02) and the Rmax parameter at 8 weeks (P = 0.016) in the test group, but there were no changes in the R-parameters during the course of the study in the control group. The average reduction per month in the R-parameters was approximately 9%. No adverse reactions were observed or reported during the 8 weeks study. Sleeping on copper oxide-containing pillowcases results in reduction of wrinkles depth and overall improvement of skin appearance.
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Healing of a deeper burn wound is a complex process that often leads to scar formation. Skin wound model systems are important for the development of treatments preventing scarring. The aim of this study is to develop a standardized in vitro burn wound model that resembles the in vivo situation. A burn wound (10 x 2 mm) was made in ex vivo skin and the skin samples were cultured at the air-liquid interface for 7, 14, and 21 days. Cells in the skin biopsies maintained their viability during the 21-day culture period. During culture, reepithelialization of the wound took place from the surrounding tissue and fibroblasts migrated into the wound area. Cells of the epithelial tongue and fibroblasts near the wound margin were proliferating. During culture, skin-derived antileukoproteinase and keratin 17 were expressed only in the epithelial tongue. Both collagen type IV and laminin were present underneath the newly formed epidermis, indicating that the basement membrane was restored. These results show that the burn wound model has many similarities to in vivo wound healing. This burn wound model may be useful to study different aspects of wound healing and testing pharmaceuticals and cosmetics on, e.g., migration and reepithelialization.
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Copper is essential to wound healing as well as a widespread environmental pollutant, with skin aging potential. Wound healing and skin aging are facilitated by matrixmetalloproteinases (MMP), which remodel the extracellular matrix, and interleukin-8 (IL-8), linked with copper. This research investigated the mechanism to copper's role in wound healing or skin aging by regulation of MMP-1 and IL-8 genes. It examined the dose-responsive effects of copper on MMP-1, -2, and -9 activities; MMP-1 and IL-8 gene regulation at protein, mRNA, and promoter levels; tissue inhibitor of matrixmetalloproteinases-1 (TIMP-1) expression; and cell proliferation. Copper stimulated cell proliferation and the expression of MMP-1 and IL-8 genes at the protein, mRNA, and promoter levels, indicating transcriptional regulation, without significantly altering TIMP-1. The research suggests that copper facilitates wound healing as well as skin aging via the induction of MMP-1 expression, with limiting MMP effect at the higher concentrations through enhanced IL-8 expression, which favors extracellular matrix deposition.
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Diabetic individuals frequently suffer from skin pathologies, especially in their feet. Co-existing peripheral vascular disease and neuropathy exacerbate the capacity of these individuals to cope with infections, minor cuts and wounds, often leading to hard to treat and chronic ulcers. Copper has potent anti-fungal and antibacterial properties. Copper is also an essential trace element vital for the normal function of many tissues and indispensable for the generation of new capillaries and skin. Human skin is not sensitive to copper and the risk of adverse reactions due to dermal exposure to copper is extremely low. We hypothesize that part of the increased risk of developing foot skin pathologies in diabetic patients with compromised blood circulation to the foot is due to low local copper levels. We further hypothesize that copper ions released from copper impregnated socks and absorbed through the skin would improve the well-being of the skin of diabetic patients by inducing angiogenesis and expression and stabilization of extracellular skin proteins, in addition to their biocidal effect of reducing the risk of fungal and bacterial infection of the diabetic foot. Thus, the use of copper impregnated socks may be used as a preventive modality. Furthermore, we hypothesize that the copper released from the socks may even be beneficial in the healing of cuts, wounds and even hard to treat skin pathologies.
Article
Copper plays a key role in several processes of skin formation and regeneration. Copper has been shown to be absorbed through intact skin. We hypothesized that sleeping on fabrics containing copper-impregnated fibres would have a positive cosmetic effect on the skin. The aim of this study was to confirm our hypothesis. A 4-week, double blind, parallel, randomized study was carried out in which 57 volunteers aged 40-60 years used either copper oxide containing pillowcases (0.4% weight/weight) or control pillowcases not containing copper. Photographs were taken by a professional photographer of each participant at the beginning of the study and at 2 and 4 weeks after the commencement of the study. Two expert graders (a dermatologist and a cosmetologist) evaluated the pictures for the effect on several cosmetic facial skin characteristics. The copper-containing pillowcases had a positive effect for the following facial characteristics: reduction of wrinkles (P < 0.001) and crow's feet/fine lines (P < 0.001) and improvement of general appearance (P < 0.001) at both 2 and 4 weeks. The differences were statistically significant (Wilcoxon scores and chi-squared tests). Consistent sleeping for 4 weeks on copper oxide containing pillowcases caused a significant reduction in the appearance of facial wrinkles and crow's feet/fine lines and significant improvement in the appearance of facial skin. In most trial participants, this effect was already noticeable within 2 weeks of using the copper oxide containing pillowcases.
Article
The present investigation was carried out to understand the effect of metal catalyzed oxidation on glycation and crosslinking of collagen. Tail tendons obtained from rats weighing 200-225 g were incubated with glucose (250 mM) and increasing concentrations of copper ions (5, 25, 50 and 100 microM) under physiological conditions of temperature and pH. Early glycation, crosslinking and late glycation (fluorescence) of collagen samples were analyzed periodically. Early glycation was estimated by phenol sulfuric acid method, and the crosslinking was assessed by pepsin and cyanogen bromide digestion. A concentration-dependent effect of metal ions on the rate of glycation and crosslinking of collagen was observed. Tendon collagen incubated with glucose and 100 microM copper ions showed 80% reduction in pepsin digestion within seven days, indicating extensive crosslinking, whereas collagen incubated with glucose alone for the same period showed only 7% reduction. The presence of metal ions in the incubation medium accelerated the development of Maillard reaction fluorescence on collagen, and the increase was dependent on the concentration of metal ions used. The metal chelator diethylene triamine penta-acetate significantly prevented the increase in collagen crosslinking by glucose and copper ions. Free radical scavengers benzoate and mannitol effectively prevented the increased crosslinking and browning of collagen by glucose. The results indicate that the metal catalyzed oxidation reactions play a major role in the crosslinking of collagen by glucose. It is also suggested that the prevention of increased oxidative stress in diabetes may prevent the accelerated advanced glycation and crosslinking of collagen.
Article
Transforming growth factor beta (TGF-beta) stimulates collagen and matrix metalloproteinase-2 expression and inhibits MMP-1 expression in dermal fibroblasts. Anti-TGF-beta antibodies have been proposed in the prevention of wound scars. The goal of this research was to investigate the regulation of matrix metalloproteinases-1 and -2 expression at the protein, mRNA, and transcriptional levels using an anti-TGF-beta antibody to TGF-beta 1, 2, 3, and 5 (all isoforms), and specifically by an anti-TGF-beta 1 antibody. Both antibodies, though at doses lower than the recommended neutralization dose, stimulated the expression of TGF-beta, and exhibited TGF-beta-like regulation of the matrix metalloproteinases. The antibodies inhibited matrix metalloproteinase-1 protein, mRNA, and promoter activity. The protein levels of matrix metalloproteinase-2 were up-regulated to a greater extent than the matrix metalloproteinase-2 mRNA level by both antibodies. These effects of anti-TGF-beta and anti-TGF-beta 1 antibodies on matrix metalloproteinase regulation were mimicked by exogenous TGF-beta 1 but not rabbit or chicken IgG. We infer that the anti-TGF-beta1 isoform that forms part of the composition of the anti-TGF-beta antibody to all isoforms may be responsible for the feedback stimulation of TGF-beta and the resultant alterations in the expression of the matrix metalloproteinases by the anti-TGF-beta antibodies.
Article
Aim of the study was to shed light on the long-standing controversy whether wearing copper bangles benefits patients suffering from inflammatory conditions such as arthritis. Sequential tape stripping was implemented on healthy volunteers to examine the diffusion of copper through human stratum corneum in vivo following application of the metal as powder on the volar forearm for periods of up to 72 h. Exposure sites were stripped 20 times and the strips analyzed for metal content by inductively coupled plasma-mass spectroscopy with a detection limit for copper of 0.5 ppb. Untreated skin was stripped in the same fashion, to determine baseline copper levels for comparison with exposure values resulting from exposure in respective volunteers. Under occlusion with exclusion of air, up to 72 h copper values decreased from the superficial to the deeper layers of the stratum corneum with gradients increasing commensurately with occlusion time, characteristic of passive diffusion processes. From the tenth strip on, however, levels reverted to background values. Under semi-occlusion allowing access of air by covering the skin with "breathable" tape, initial copper values lay significantly above baseline values and concentration gradients increased proportionally with occlusion time. At 72 h, from the tenth to the twentieth strip reaching the glistening epidermal layer, copper values continued at constant levels, significantly above baseline values. The results indicate that, in contact with skin, copper will oxidize and may penetrate the stratum corneum after forming an ion pair with skin exudates. The rate of reaction seems to depend on contact time and availability of oxygen. A marked inter-individual difference was observed in baseline values and amounts copper absorbed.
Cosmetotextiles -sometimes the simple things work
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