Rame (ology) – Wikipedia

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The copper It is an element necessary for the health of any form of life (Eucharistic and Procariali) with the exception of the archea. In the human body it is essential for the correct functioning of the organs and metabolic processes; A complex system of homeostasis regulates the presence of this metal, eliminating any excess quantities. In any case, the assumption of too much or too little copper, as in the case of each nutrient and essential element, leads to a corresponding state of excess or deficiency of organism with the relative effects on health.

The daily requirement of copper has been established by several health institutions all over the world; This needs can be different for adults, pregnant women, children and babies. For example, the National Academy of Science has established a recommended daily requirement for the USA (RDA, Recommended Dietary Allawance) of copper 0.9 mg for adults, 1.0 mg for pregnant women and 1.3 mg For breastfeeding women [first] .

Copper is a micro-nutrient necessary for the health of plants and animals. It is also required for the vital functions of aerobic microorganisms.

Copper is part of proteins and metal-enzymes that perform various metabolic functions: it comes into play in the development and maintenance of bones, connective tissues, brain, heart and other organs. Copper is also involved in the formation of red blood cells, in the absorption and transport of iron, in the metabolism of cholesterol and glucose and in the synthesis and release of proteins and enzymes. Copper stimulates the immune system to fight infections and repair the tissues; It also fights free radicals that can create serious damage to the cells.

The essentiality of copper was discovered in 1928: it was shown that rats, if they were fed with a poor copper milk, were not able to produce enough red blood cells [2] ; This anemia was treated with the addition of dust containing copper of vegetable or animal source.

Copper for the fetus, babies and children [ change | Modifica Wikitesto ]

Copper is necessary for the growth and development of the fetus, newborn and child [3] . The fetus accumulates in the liver during the third trimester of pregnancy. At birth, a healthy child has four times the concentration of copper compared to an adult: breast milk is relatively poor in copper and the stocks in the liver’s liver drop quickly after birth to provide an adequate copper intake during the breastfeeding period . These contributions are necessary for metabolic functions such as cellular respiration, the synthesis of connective tissues and the pigment of melanin, the metabolism of iron, the defense from free radicals, the gene expression, and the normal functioning of the heart and the immune system of the babies. Babies have special biochemical mechanisms for the adjustment of copper in their body waiting for the definitive mechanisms, which will function in the rest of life, develop and mature.

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A serious deficiency of copper in pregnant women increases the risk of health problems of their fetuses and babies, including low birth weight, muscle weakness and neurological problems. However, this copper deficiency can be avoided through a balanced diet. Since the availability of copper in the body can be hindered by an excess of iron and zinc, it must be ensured that the prescription of food supplements containing iron and zinc in pregnancy is accompanied by a significant amount of copper. Breed Baby Babies have a sufficient amount of copper, the one contained in their liver and that present in milk, for the first 4-6 months of life [4] ; In weaning the diet must provide adequate copper sources.

Cow’s milk and some old type of artificial milk are poor in copper; For this reason, most of the artificial sides are now added with copper. Well -fed children receive an adequate amount of copper. Otherwise, when there is a suspected copper deficiency, the diagnosis is evident and reliable and a administration of supplements under medical supervision generally promotes a full re -establishment of health conditions.

Homeostasis [ change | Modifica Wikitesto ]

Copper is absorbed, transported, distributed, stored and excreted in the body according to complex homeostasis mechanisms that ensure a constant and sufficient copper intake, simultaneously avoiding excess concentrations.

If for a certain period the intake of copper is insufficient, the body resorts to the stocks in the liver. This situation should continue, the symptoms of copper deficiency develop. Excess copper can also lead to health damage. In any case, thanks to the homeostatic regulation, the human body is capable of balanced the copper intake necessary for health. Many aspects of copper homeostasis are known at a molecular level [5] [6] . Copper is essential for its ability to behave as a donor or electron acceptor depending on that his state of oxidation is CU +1 o cu +2 [7] The copper is involved in obsidorduction reactions that occur in metabolic processes, such as mitochondrial breathing, the synthesis of melanin and the reticulation (cross-linking) of collagen. Copper is part of antioxidant enzymes such as copper-zinco super oxide dismutases (Cu/zn-sod) and has a role in iron homeostasis as a cofactor in ceruloplasmine.

A list of key enzymes containing copper is exposed below together with their function [8] :

The transport and metabolism of copper in living organisms are currently subject to numerous research. On cellular level, copper is brought through the cell wall and inside the cell from selective transporters [6] . In the blood flow, most of the copper is transported by ceruloplasmine; The percentage of copper linked to ceruloplasmina can vary from 70 to 95%, while the remainder is linked to the albumin and other proteins. The intracellular copper is directed to the places where the enzymes containing copper and organules are synthesized thanks to specialized proteins called metallochaperons. Another group of these transporters brings copper to cell compartments. There are other mechanisms to release copper from the cell; Specialized transporters return excess copper to the liver, for a further storage or for excretion through bile. Thanks to these mechanisms, the existence of copper ions not linked in the majority of the population is improbable, or by those who are not affected by defects of the metabolism of genetic origin.

Copper is brought to the cell through the cell wall by a protein known as Copper Transporter 1, or CTR1; This is quickly linked to an intracellular chaperone protein. The ATOX1 protein delivers the copper to the secretory routes and interacts either with the ATP7B (an atpase protein that transports copper) to the liver or with the ATP7A in the other cells. The ATP7B directs the copper to the Ceruloplasmina contained in the plasma or bile in concert with a slightly discovered chaperon, the Murr1.The Atp7A directs the copper in the Golgi system to the dopamine-Beta-brown proteins, peptidilglicine-alfa- AMIANTO MONOOXIGENASE, LISIL-Ossidase and Tyrosinase, depending on the type of cell. CCS is the copper chaperon for the super oxide Cu/zn dismutase that protects cells against the reactive oxygen species; Bring the copper to the cytoplasm and intermitocondrial space. The COX17 protein brings copper to mitochondria to cytochrome-c-oxidase through the chaplators Cox11, Sco1 and Sco2. Other copper chapons may exist and may include metallotionine and proteins precursors of beta-amyloid (app).

The absorption of copper [ change | Modifica Wikitesto ]

In mammals the absorption of copper takes place in the stomach and in the small intestine, although differences between the species regarding the stretch of maximum absorption appear; For humans it is believed that they are the stomach and the duodenum. The copper absorption rate varies from 15 to 97%, depending on the amount of copper, the shape under which it is located and the content of the diet [9] [ten] [11] [twelfth] [13] . Among the various factors that influence absorption there is, for example, the ingestion of animal, citrate and phosphate proteins that increase their absorption. Copper salts including gluconate, acetate and sulphate, are better absorbed than oxides.

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High levels of zinc and cadmium contained in the diet can inhibit the absorption of copper, as well as large quantities of phytic acid, and simple sugars (fructose, sucrose). Some forms of copper are not soluble in gastric juices and cannot be absorbed in the small stomach or intestine and some foods contain non -digestible fibers that bind to copper. High supply of vitamin C or iron influence the absorption of copper, proof that micronutrients must be consumed in a balanced way. Individuals with chronic digestive problems may not absorb sufficient quantities of copper even in the presence of a diet rich in this metal.

The excess of copper, as well as that of other metal ions, such as zinc and cadmium, is removed from the metallotionine of the entities, the predominant cells in the mucous membrane of the small intestine.

Copper distribution [ change | Modifica Wikitesto ]

The copper released by the intestinal cells moves towards the capillaries on the serous membrane, where it is linked to the albumin, glutathione and amino acids in the venous portal circle [14] [15] . There is evidence that a small protein, the trans Cupreine, has a specific role for the transport of copper in the plasma. Many or all of these proteins that bind copper can participate in the transport of copper in the bloodstream.

The copper from the portal circulation is mainly collected by the liver, where it is incorporated into the proteins that require this metal. Copper is transported to non-ephetical tissues through the albumin and by amino acids, or excreted in the bile. Through the release of copper, the liver exerts its homeostatic control.

The excretion of copper [ change | Modifica Wikitesto ]

Bile is the privileged path for the excretion of copper and is vital in the control of copper levels in the liver [16] [17] [18] . Most of the copper contained in the feces derive from biliary excretion, the rest comes from copper non -absorbed or coming from the desquamation of mucosa cells.

Copper is an essential microelement that must be taken through food.

From food can virtually arrive all the copper consumed by humans [19] [20] [21] . The best sources are seafood, especially crustaceans and meat (liver), cereals, legumes (beans and lentils) and chocolate. Dry fruit is very rich in copper and the same can be said of wheat (wheat and rye) and some fruits including lemons and raisins. Other sources of copper are cereals, potatoes, peas, red meat, mushrooms, some leafy vegetables (cabbage), some fruits such as coconut walnuts, papaia and apples. Tea, rice and chicken are relatively poor in copper, but they can provide a sufficient dose if consumed in large quantities.

Another source of copper is water, which can provide 20-25% of the needs. Copper is an element that is naturally found in the earth’s crust and therefore exists in underground and surface waters, even if its concentration varies according to the geographical area. A balanced diet with a wide variety of different foods is the best way to avoid copper deficiency.

Food additions [ change | Modifica Wikitesto ]

Food supplements can avoid copper deficiency, but must only be taken under medical supervision. Food integration can be necessary in the case of premature babies or with low birth weight, or fed with artificial milk -poor milk or cow’s milk in the first year of life. Copper additions are sometimes also prescribed in the following cases:

  1. diseases that reduce digestion (diarrhea or other infections, alcoholism),
  2. insufficient food consumption,
  3. patients taking medicines that block the use of copper,
  4. anemic patients treated with iron supplements,
  5. zinc supplements,
  6. osteoporosis.

Deficiency and excess of copper: non -genetic conditions [ change | Modifica Wikitesto ]

If the copper intake is insufficient, the reserves present in the liver are depleted and the lack of this metal can lead to diseases or damage to tissues (in extreme cases, death). The toxicity due to copper deficiency can be treated with an appropriate diet or an integration under medical supervision. On the other hand, even an excess of copper (well beyond the limits set by the World Health Organization) as well as for any other substance, can rely toxicity. Acute toxicity is generally associated with accidental ingestion; The symptoms subside when wealthy copper foods are no longer eaten. In 1996, the International Program on Chemical Safety, an institution associated with WHO, declared that “there are greater risks for health derived from copper deficiency rather than for one of his excessive assumptions “. The health conditions associated with deficiency and excess (of non -genetic origin) of copper are described below.

Rame deficiency [ change | Modifica Wikitesto ]

In humans and animals, copper deficiency affects blood and the hematopoietic system, the cardiovascular system, connective tissues and bones, the nervous and immune system [3] [22] [23] .
The symptoms of copper deficiency include osteoporosis, osteoarthritis, rheumatoid arthritis, cardiovascular disorders, colon cancer chronic problems involving bones, connective tissues, heart and blood vessels [5] [22] [24] .
Furthermore, an acquired copper deficiency has recently been implicated in a progressive myelopathy that arose in adulthood [25] and in the development of serious blood disorders including myelodysplasic syndrome.

A slight deficiency of copper, which is considered more widespread than previously designed, can affect human health in a thinner way [26] : less resistance to infections, general fatigue, reduced neurological functions, high risk of coronary and osteoporosis diseases. The deficiency of copper alters the role of other cellular constituents involved in antioxidant activities, such as iron, selenium, glutathione and consequently plays an important role in diseases in which oxidative stress is high [27] [28] [29] .
Fortunately, copper deficiency can be confirmed by very low metal concentrations in the bloodstream and ceruloplasmin in the blood.

In the population, copper deficiency can affect individuals with Menkes syndrome, children with low birth weight, newborn baby milk instead of breastfeeding and breastfeeding women, patients receiving a total parenteral nutrition (i.e. With nutrients administered venously), diabetics, individuals with food and alcoholic disorders.
The elderly and athletes can be at risk due to special needs that increase the requested daily requirement. Vegetarians can have a decreased copper intake due to the consumption of vegetable foods with a low bioavailability of copper. Feti and babies from mothers with subject to severe copper deficiency have a greater risk of low birth weight, muscle weakness and neurological problems. Copper deficiencies for these categories of people can manifest themselves such as anemia, bone anomalies, growth problems, frequent infections (influence, cold, pneumonia), poor coordination in movements and little energy.

Excess of copper [ change | Modifica Wikitesto ]

The excess of copper, still the subject of many research in progress, can cause stomach, nausea and diarrhea and can cause damage and diseases to the tissues. High quantities of copper have been indirectly associated with some neurological disorders [30] , although the data is not unique: it seems that copper has a positive role in neurological diseases, such as Alzheimer’s disease. [thirty first] The oxidative skills of copper, following its ingestion in excessive quantities, can be responsible for the peroxidation of lipids or other macromolecules [32] .

In humans, the liver is the main organ that undergoes the consequences of excess copper [23] . Other target organs are the bones, the central nervous system and the immune system. An excessive intake of copper affects the body also indirectly interacting with other nutrients: for example, it causes anemia, as it interferes with the transport and/or the metabolism of iron [3] .

Acute exposure [ change | Modifica Wikitesto ]

In the cases reported in the ingestion of high concentrations of copper salts in generally unknown doses, but reported to be 20-70 grams of copper, a progression of symptoms has been observed that include abdominal pain, headache, nausea, head turning , vomiting and diarrhea, tachycardia, breathing difficulties, hemolytic anemia, blood, massive gastrointestinal bleeding, liver and renal failure, and death. Episodes of acute gastrointestinal disorders following single or repeated ingestion of drinking water with very high concentrations of copper (above 3–6 mg/l) are characterized by vomiting and irritation in the stomach. Symptoms disappear when copper in the water is reduced.

Three studies were conducted that show that the threshold for acute gastrointestinal disorders is about 4–5 mg/l for healthy adults, although it is not clear if the symptoms are due to copper and/or metal, bitter and salty flavor of the water [33] [34] [35] [36] .

Chronic exposure [ change | Modifica Wikitesto ]

Long -term toxicity has not been well studied on humans, but is rare in the normal population that does not present hereditary defects in copper homeostasis [37] . There are some indications that chronic exposure may occur in fact systemic as well as damage to the liver. [38] . No effects on liver serum enzymes, bioindicators (bio -mars) of oxidative stress, and other biochemical indicators on young and healthy volunteers, to which doses of 6–10 mg/copper day up to 12 weeks [39] [40] [41] [42] . Babies of 3-12 months, which consumed water containing 2 mg/l for 9 months did not differ compared to a control group in symptoms in the gastrointestinal tract, growth rate, predisposition to diseases, liver serum enzymes, bilirubin levels e Other biochemical indicators [43] . Ceruloplasmine in the serum was temporarily high in infants of 9 months and similar to controls at 12 months, suggesting the adaptation of homeostasis and/or maturation of the homeostatic response [6] .

Copper bioindicators [ change | Modifica Wikitesto ]

Although a number of indicators are useful for diagnosing copper deficiency, there is no reliable bio-marker for excess copper diet, if not its concentration in the liver; However, it is an intrusive measure, which is generally carried out only in cases of suspected copper poisoning. Aging levels of copper in the serum or ceruloplasmine do not give certainty, since they can also derive from inflammation, diseases, pregnancies and other biological stressors. Levels of enzymes containing copper, such as cytochrome-c-oxidase, super oxidodismutase, and diaminase oxidase, vary not only in relation to the level of copper, but also to a variety of other psychological and biochemical factors and therefore are not unequivocal indicators of the excess of copper [44] .

A new “candidate” to detect both the deficiency and excess copper is a chaperone protein, which delivers the copper to the antioxidant sod1 (Cu-zn SuperOxidodismutase). It is called CCS (Copper Chaperone for Sod1) and the data on animals support its use as a marker in accessible cells, such as heterocytes, while studies on humans are underway.

Rare genetic diseases (Wilson disease, Menkes disease, Indian infantile cirrhosis and copper idiopathic toxicosis) are due to the mutation of genes responsible for the production of proteins involved in the absorption and in the distribution of copper [45] . Thus there is either the accumulation of copper in the liver or its lack of absorption by the body.
These diseases are hereditary and cannot be acquired; The adjustment of copper levels in diet or drinking water do not treat the causes, although therapies can act on symptoms.

Diseases derive from defects in two “pumps” of similar copper: Menkes’ Cuatpasi and Wilson’s Cuatpasi [forty six] . Menkes’ Cuatpasi is expressed in the tissues such as the fibroblasts that give rise to the skin, the kidneys, the placenta, the brain the bowels and the vascular system; While Wilson’s Cuatpasi is mainly expressed in the liver, but also in the mammary glands and in other specialized tissues.

Malattia in the Minister of Health [ change | Modifica Wikitesto ]

Menkes’ disease is a genetic condition that leads to copper deficiency: it was first described by dr. John Menkes in 1962. It is a rare defect (1 out of about 200,000 births) that mainly affects males.
With Menkes’ disease, the liver is unable to absorb the copper necessary for survival. Death takes place before 10 years of age, although many patients have reached adolescence and 20 years.

The protein produced by the Menkes gene is responsible for transporting copper through the mucosa of the gastrointestinal tract and the blood-deceptive barrier [6] [47] . Defects in the gene that codes the copper atpasi make the copper remain trapped on the walls of the small intestine. Therefore the copper cannot be pumped out of the intestinal cells towards the blood that will bring it to the liver and after the rest of the body [47] [48] . The disease therefore causes a serious copper deficiency despite its adequate intake.
The symptoms of the disease include hair and permanent hair, rough and fragile, neonatal problems, such as the inability to control body temperature, mental retardation, skeleton defects and abnormal growth of connective tissues.
Patients with Menkes disease show neurological anomalies, apparently due to the lack of enzymes dependent on the copper required for the development of the brain [49] [50] , like the reduced activity of cytochrome-c-oxidase. The appearance of the hair (depicted, rough and fragile) is due to the lack of an unidentified cuproidal. The reduced activity of lisil-oxidase creates a defective polymerization of collagen and elastine, with the corresponding anomalies of the connective tissues, including the aneurism to the aorta, skin lax and bone fragility.

There is also a variant of Menkes disease called the occipital horn disease [51] , this variant causes milder symptoms and generally a greater life expectancy.

Wilson’s disease [ change | Modifica Wikitesto ]

Wilson’s disease is a rare genetic disorder (chromosome 13) transmitted in an autosomal recessive way that causes a accumulation of copper in the liver [52] [53] [54] . The disease is now negotiable.
Wilson’s disease is due to a mutation of a protein that transports copper from the liver to bile for excretion [53] : Therefore a poor incorporation of copper in Ceruloplasmina and its defective bile excretion takes place. The mutation damages the functions of Wilson’s Cuatpasi and produces a metal accumulation not only in the liver, but also in the brain and to a lesser extent, in the kidneys, eyes and other organs. The disease affects about 1 newborn in 30,000 and can present an evident clinical picture at any time from childhood to adulthood: the manifestation of the disease varies from 3 to 50 years of age.

The first symptoms include liver, neurological or psychiatric disorders and, more rarely, kidney, skeletal or endocrine problems. The disease progresses with growing jaundice and the development of brund -olds, serious anomalies in blood coagulation, occasionally intravascular, and renal failure. A peculiar type of tremor at the higher ends, slowness in behavioral movements and changes become posters; Kayser-Fleitscher rings (a brown ring at the outer edge of the iris noted in 90% of patients), become evident as soon as the copper begins to accumulate in the liver and influence the nervous system.
Death almost always comes if the disease is not treated; Fortunately, the identification of the mutation in Wilson’s Atpasi gene (at the basis of most cases of Wilson’s disease) made a diagnosis possible through a DNA test. If diagnosed and treated in time, patients with Wilson’s disease can live for a long time.

Other hereditary syndromes [ change | Modifica Wikitesto ]

Other diseases that seem to be linked to alterations of copper metabolism include Indian infantile cirrhosis (Indian, Childhood Cyrrhosis, ICC), Endemic Tyrolean Copper Toxicosis (ETIC) and copper idiopathic toxicosis (ICT, IDIopathic Copper cirrhosis), also note like non-Indian infantile cirrhosis. The ICT is a genetic disorder recognized in the early twentieth century in the regions of Tyrol (Austria) and in the Punto region (India) ICC, ITC, ETIC are childhood diseases that are similar in etiology and appearance. They seem to have a genetic component and a contribution from a high recreation of copper. The prevailing hypothesis is that the ICT is due to a genetic defect (which causes a defective copper metabolism) associated with a high copper intake, due to the heating and conservation of milk in brass containers or from high concentrations of copper in the ‘waterfall. This hypothesis is supported by the frequency of consanguinity in most cases, absent in areas with high quantities of copper in drinking water and where these syndromes do not happen.

In addition to being an essential nutrient for humans, copper is vital for the health of plants and animals and plays an important role in agriculture [55] [56] .

Plant [ change | Modifica Wikitesto ]

The concentration of copper in soils is not uniform. In many areas, soils have an insufficient concentration of copper and often require copper supplements before the crop, such as cereals, is growing.
Copper deficiency in the soil is a problem for the production of food, as it leads to a decrease in the yields and the quality of the harvest. Nitrogen fertilizers can worsen the deficiency of copper in the soils. Rice and wheat, the two most important harvest foods in the world, are very sensitive to the deficiency of copper: the same applies to other important foods including citrus fruits, oats, spinach and carrots. Other foods such as coconut walnuts, soybeans and asparagus are not particularly sensitive to copper deficiency.

The most effective strategy to counteract copper deficiency is to provide copper in the form of salts, often as a sulphate. Muds are often used in some area to enrich agricultural land with organic material and trace metals, including copper.

Animals [ change | Modifica Wikitesto ]

Cattle and sheep have signs of a copper deficiency in their body. Lordosis is a sheep disease associated with copper deficiency and causes enormous costs for breeders, especially in Europe, North America and tropical countries.
In pigs, copper has shown to be a remarkable promoter of growth.

Copper has always existed in nature, but over the past centuries “anthropogenic” emissions have been added, that is, due to the work of man: just think of the wear of the brakes of cars and the salts used in agriculture. It was necessary to evaluate whether these contributions can involve dangers for man and the environment: for this reason in 2000 the European copper industry has started a voluntary risk assessment procedure (Voluntary Risk Assessment, V.R.A. [57] [58] [59] ) linked to the production and use of metal copper, copper powders and four compounds.

The entire evaluation process was agreed with the Superior Institute of Health, since Italy being the country in charge of the revision on behalf of the European Commission and the Member States of the Union. In 2008 the Vra dossier was in fact approved by the Technical Committee for New and Existing Substances (TCNES) of the European Commission; The Scientific Committee on Health and Environmental Risk (Scheri) of the European Commission has carried out a final assessment and has further approved the conclusions on the characterization of risks for the environment and human health.
Vra covers the aspects of the production, use and end of life of copper and shows that the current legislative framework guarantees the environment, the health of industry and the European population.

The main conclusions achieved by the European Commission and by the experts of the Member States are the following [60] [sixty one] [62] :

  • The use of copper products is, in general, safe for the environment and for the health of Europe’s citizens.
  • The threshold value because acute effects occur is 4.0 mg/l of copper in drinking water, while the level to which the general public is generally exposed is 0.7 mg/l. This is consistent with the guidance level of the copper of 2.0 mg/l, established by the World Health Organization.
  • For adults, the minimum daily intake of copper through the diet is 1 mg, with a maximum threshold of 11 mg. The average real intake is between 0.6 and 2 mg, thus suggesting that a problematic aspect may be that of a deficiency.
  • In Europe, safety levels for the presence of copper in fresh and marine waters are 7.8 and 2.6 µg/l. The level of safety for the presence of copper in the ground is 79 mg/kg of dry weight. The safety levels in the sediments of fresh water, estuary and marine are 87, 144 and 338 mg of Cu respectively per kg of dry weight. The copper levels actually measured in Europe in the waters, sediments and soils are generally very below these safety thresholds.
  • Environmental risks are possible in 14% of industrial sites, where the on -site treatments of the waters are insufficient or where the effluents in the water have a low level of dilution.
  • Professional health risks are possible in some industrial sites, especially for workers employed in the production of chemical compounds and copper powders.
  • Copper is not a CMR (carcinogenic, mutageno, harmful for reproduction) or PBT material (persistent, bio-accumulating, toxic).
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