Medical Uses of Copper in Antiquity - Copper Applications in Health & Environment
The first recorded medical use of copper is found in the Smith Papyrus, an Egyptian medical text, written between 2600 and 2200 B.C., which records the use of copper to sterilize chest wounds prevent infection and sterilize drinking water.
Copper and immunity
The immune system requires copper to perform several functions, of which little is known about the direct mechanism of action. Animal models and cells in culture have been used to assess copper's role in the immune response.
Neutrophil-like HL-60 cells accumulate copper as they differentiate into a more mature cell population and this accumulation is not reflected by increases in Cu/Zn superoxide dismutase or cytochrome-c oxidase activities.
Copper and Inflammation
Copper belongs to the biochemically active and essential transition metals. At present more than twenty different copper proteins are known. Their molecular properties and functional side is well characterized. In each of these proteins, the copper is coordinated to the respective polypeptide side chains and is, in fact, the active center. Copper exerts several distinct properties including the positive redox potential, the pronounced chelating activity, and the extraordinary kinetic properties. Attributable to these properties this transition metal is preferentially active in electron transport reactions. Oxygen belongs to the preferred substrates. Very little is known on the biochemical reactivity of copper in inflammation. One of the major causes of inflammation is assigned to the action of excited oxygen species. Quite frequently, a rise of the copper concentration in serum up to a factor of four is observed in the course of inflammatory diseases. Extraneously administered copper has an anti-inflammatory effect. We do not know whether or not the reactivity of copper must be exclusively seen in the biochemistry of oxygen. It is attempted to summarize the present thoughts and facts on the general biochemistry of both copper and inflammation. It will be attempted to correlate the biochemical properties of this most prominent transition metal with the biological aspects of inflammation.
Human copper homeostasis a network of interconnected pathways
Copper plays an essential role in normal human physiology. Copper imbalance affects heart development, CNS and liver function, influences lipid metabolism, inflammation, and resistance to chemotherapeutic drugs. Recent studies yielded new information on the structure, function, and regulation of human copper transporters, uncovered unanticipated functions for copper chaperones, and established connections between copper homeostasis and other metabolic pathways. It has become apparent that the copper trafficking machinery is regulated at several levels and that the cross-talk between cell compartments contributes to the intracellular copper balance.
Influence of copper (II) complex on the activity of selected oxidative enzymes
Antioxidative capacity tests confirmed that complex compounds with Cu (II) ions have a significant influence on the antioxidative status.
Increase of glutathione peroxidase and catalase activity by about 50% in all patients, who were administered the dichlorobis copper (II).
Endothelial Antioxidant-1: a Key Mediator of Copper-dependent Wound Healing in vivo
Copper (Cu) chaperone Antioxidant-1 (Atox1) in the cytosol supplies Cu to the secretory enzymes such as lysyl oxidase (LOX), while Atox1 in the nucleus functions as a Cu-dependent transcription factor. In addition, Atox1 delivers Cu through ATP7A to the secretory Cu-dependent enzymes such as extracellular superoxide dismutase (ecSOD) or lysyl oxidase (LOX) which plays an important role in tissue remodeling and wound healing by regulating the cross-linking of collagen.
Biological activities of selected peptides: skin penetration ability of copper complexes with peptides
The results obtained demonstrated that copper complexes permeate through the membranes modeling the horny lipid layer and showed the influence of peptides on the dynamics of copper ion diffusion.
A Cooperative Copper Metal-Organic Framework-Hydrogel System Improves Wound Healing in Diabetes.
Cytotoxicity and apoptosis due to copper ion release were significantly reduced while dermal cell migration in vitro and wound closure rates in vivo were significantly enhanced.
A cooperatively stabilized, copper ion-releasing H-HKUST-1 hydrogel is a promising innovative dressing for the treatment of chronic wounds.
Antimicrobial properties of copper
The 3-dimensional structure of proteins can be altered by copper, so that the proteins can no longer perform their normal functions. The result is the inactivation of bacteria or viruses.
Copper facilitates deleterious activity in superoxide radicals. Repeated redox reactions on site-specific macromolecules generate OH- radicals, thereby causing "multiple hit damage" at target sites. Scientists are also actively demonstrating the intrinsic efficacies of copper alloy "touch surfaces" to destroy a wide range of microorganisms that threaten public health.
Copper deficiency alters cell bioenergetics and induces mitochondrial fusion through up-regulation of MFN2 and OPA1 in erythropoietic cells.
In mitochondria, copper is a cofactor for respiratory complex IV, the cytochrome c oxidase. Low copper content is associated with anemia and the appearance of enlarged mitochondria in erythropoietic cells. These findings suggest a connection between copper metabolism and bioenergetics, mitochondrial dynamics and erythropoiesis, which has not been explored so far.
Bathocuproine disulfonate-induced copper deficiency does not alter erythropoietic cell proliferation nor induce apoptosis. However, it does impair erythroid differentiation, which is associated with a metabolic switch between the two main energy-generating pathways.
Copper as a key regulator of cell signaling pathways
Places copper in a unique role as a key modulator of cell signal transduction pathways. These pathways are the complex sequence of molecular interactions that drive all cellular mechanisms and are often associated with the interplay of key enzymes including kinases and phosphatases but also including intracellular changes in pools of smaller molecules.
Mechanism of copper-activated transcription - activation of AP-1 and the JNK/SAPK and p38 signal transduction pathways
Copper is an essential metal that is able to produce reactive oxygen species and to induce intracellular oxidative stress. Several studies have examined the effects of excessive copper and oxidative stress on various organisms and tissues, but few have addressed the molecular mechanisms by which copper affects transcription. Our results demonstrated that, in COS-7 cells, copper treatment caused an increase in the binding of nuclear proteins to activating protein-1 and antioxidant response elements. The level of copper-inducible nuclear protein binding was modulated by increasing or decreasing the level of intracellular oxidative stress. Copper exposure also led to an increase in the steady-state levels of c-fos, c-jun, and c-myc mRNAs. Exposure to copper resulted in an increase in the levels of phosphorylation and activation of the c-Jun N-terminal kinase/stress-activated protein kinase and p38 pathways.
Copper complexes of bis(thiosemicarbazones) from chemotherapeutics to diagnostic and therapeutic radiopharmaceuticals
The molecules known as bis(thiosemicarbazones) derived from 1,2-diones can act as tetradentate ligands for Cu(II), forming stable, neutral complexes. As a family, these complexes possess fascinating biological activity. This critical review presents a historical perspective of their progression from potential chemotherapeutics to more recent applications in nuclear medicine. Methods of synthesis are presented followed by studies focusing on their potential application as anti-cancer agents and more recent investigations into their potential as therapeutics for Alzheimer's disease. The Cu(II) complexes are of sufficient stability to be used to coordinate copper radioisotopes for application in diagnostic and therapeutic radiopharmaceuticals. Detailed understanding of the coordination chemistry has allowed careful manipulation of the metal-based properties to engineer specific biological activities. Perhaps the most promising complex radiolabelled with copper radioisotopes to date is Cu(II)(atsm), which has progressed to clinical trials in humans (162 references).
Serum copper levels in elderly patients with femoral-neck fractures
The serum copper levels of 46 elderly patients with fractures of the femoral neck were assayed and found to be significantly lower than those of a group of controls matched for age and sex. These findings are consistent with a nutritional copper deficiency which may contribute to the development of fractures by reducing bone strength.