It sounds like a great hypothesis, but how can we prove it, and how can we measure accumulated damage? You see, even if we were able to reduce exposure to environmental toxins, we’d still get older.
To test the idea that accumulating metabolic byproducts can lead to aging, the authors of this study used a new method called “metabolite profiling” to measure the amount of metabolites in flies as they aged.
Finally, the authors also used a calorie-restricted diet to extend the lifespan of a group of flies (although it’s not yet understood why, a severely restrictive diet can increase lifespan in many model animals, including mice and rats. Asthma is a lung condition characterized by inflammation and hypersensitivity of the airways of the lung [the bronchi]. In  many people a virus such as a cold, may trigger off asthma which may often present not as a wheeze but as a cough that lingers on for perhaps weeks after the cold started. Asthma may also be triggered off by allergies, smoke in the air or cigarette smoke, exercise induced asthma or pollutants in the environment. Airway narrowing occurs due to a large amount of mucus that is produced by inflammation triggered off by inflammatory cells in the airway wall releasing chemicals called cytokines. Airway narrowing also occurs due to contraction of the smooth muscle surrounding the airways [bronchoconstriction] due to various triggers such as allergens, smoke, air pollution, house dust mites etc.
Inhaled LTC4 and LTD4 are some of the most potent inhaled bronchoconstrictors known45 [the muscle around the airway goes into severe spasm with these leukotrienes].
LTC4, LTD4, LTE4 all seem to attach to a common receptor and so the race is on to find a pharmaceutical agent to block the action of these leukotrienes on these receptors45.
The pharmaceutical approach is to block the leukotrienes after they are formed at the receptor site. Use can also be made of curcumin to block the action of the LOX enzyme that leads to the production of these dangerous leukotrienes to asthmatics. There is evidence to show that asthmatics may suffer lower levels of magnesium in their airways and that supplementing with magnesium may be of benefit46. If inflammation is allowed to proceed unchecked, free radicals [charged electrons] and reactive oxygen species [ROS] are constantly produced in large quantities on a daily basis and this is termed oxidative stress leading to ongoing damage of the airways ultimately leading to scarring and permanent reduction in airway size. Oxidative stress is slowly progressive leading to progressively worsening asthma that is poorly responsive to any treatment.
Many asthmatics suffer from sulfite sensitivities and sulfite sensitivity has been linked to molybdenum deficiency. SF88-Plus has this important essential trace element in the formulation to ensure molybdenum levels are maintained. Please check to see if you have a wheat or gluten sensitivity and your general practitioner can order tests to see if this is a possible factor. You may have gluten intolerance instead of coeliac disease and HLA-DQ2 + HLADQ8 genetic testing will be able to distinguish between the two when blood antigliadin antibodies are raised. Compared to several other metal ions with similar chemical properties, zinc is relatively harmless. Trachea Position In children, trachea is shorter and the angle of the right bronchus at the bifurcation is more acute than in the adult. The diameter of an infant’s airway is approximately 4 mm, in contrast to an adult’s airway diameter of 20 mm. Question: Of the three anatomical differences in the eustachian tube between adults and small children (shorter, wider, more horizontal), which do you think could cause more problems for the child and why? Common Causes ? Usually preceded by a viral upper respiratory infection ? Fluid and pathogens travel upward from the nasopharyngeal area, invading the middle ear. Myringotomy Pressure-equalizing tubes ? A myringotomy – a pin hole opening is made in the ear drum to allow fluid removal.
Prevention ? Parents need to be taught ways to prevent OM: –sitting or holding an infant upright during bottle- feeding and breastfeeding. Post-operative Care ? Providing comfort and minimizing activities or interventions that precipitate bleeding –Maintain airway - Place in prone or side-lying position to avoid aspiration until fully awake –Monitor bleeding, esp. Discharge Teaching ? Avoid citrus juices, milk, carbonated drinks, and extremely hot or cold liquids ? Do not use straws or put tongue blade in mouth, no smoking (in teenagers). Medications ? Beta-agonist – racemic epinephrine, Albuterol ? Corticosteroids ? Which of these medications would the nurse give first? If condition worsens ? Take to emergency room ? Humidified oxygen ? IV fluids ? Sedatives are contraindicated – mask symptoms ? Monitor vital signs and pulse oximetry ? Have intubation equipment available should the childs condition change rapidly.
This leads to the ubiquitylation (Ub) of IκB and its subsequent degradation by the proteasome.
It’s more than just a philosophical question; it’s a puzzle that has frustrated scientists for decades.
Multiple external and internal factors can lead to the formation of free radicals and cell damage, which accelerates aging. Damage can be caused by a number of factors, and the types of damage that can occur varies wildly between species and even between individuals of the same species. This paper supports the hypothesis that accumulation of damage leads to aging by showing that metabolites accumulate at a rate that corresponds with relative age in fruit flies. This is a molybdoenzyme meaning it uses molybdenum as a cofactor enabling it to do its job.
The type of blood tests ordered to check for gluten sensitivity are outlined in the link provided above.
Just click on the following link: Join NutriDesk then you can access the references through the link below.
Only exposure to high doses has toxic effects, making acute zinc intoxication a rare event.
IntroductionIn the periodic table of the elements, zinc can be found in group IIb, together with the two toxic metals cadmium and mercury. An inflammatory process in the airway causes swelling that narrows the airway, and airway resistance increases.
Fluid behind the eardrum has difficulty draining back out toward the nasopharyngeal area because of the horizontal positioning of the Eustachian tube.
Propping bottles is discouraged to avoid the supine position and to encourage human contact during feeding.
Currently, the most accepted hypothesis is that aging is the result of accumulated damage to our cells during our lifetime.
To make matters worse, exposure to certain environmental influences or toxins can accelerate aging.
Most interestingly, when the authors compared metabolite accumulation in normal flies versus the lifespan-extended flies, they showed that the metabolite accumulation was slower in the longer-lived flies, corresponding with the slower progression of aging. Because most species share the same cellular metabolic processes, these results are relevant to mammals. In addition to acute intoxication, long-term, high-dose zinc supplementation interferes with the uptake of copper. Note that swelling of 1 mm reduces the infant’s airway diameter to 2 mm, but the adult’s airway diameter is only narrowed to 18 mm. Small children who are bottle fed in a supine position have a greater probability of developing otitis media because the eustachian tube opens when the child sucks and the horizontal angle provides easy access to the middle ear. Occasionally drainage is so profuse that the auricle and the skin surrounding the ear become excoriated from the exudate. ROS production can also trigger oxidative glutathionylation of NF-κB at its redox sensitive cysteine, which reduces its DNA binding affinity133. For example, overexposure to UV light from the sun can increase signs of aging in skin cells, and studies have shown that smoking can also accelerate aging. Unfortunately, these processes also create toxic byproducts such as reactive oxygen species (also known as free radicals).
This suggests that mistakes were being made during the metabolic reactions, causing new types of byproducts to appear that can damage cells. The next step will be to identify particular types of metabolites and determine how they contribute to aging in flies and mammalian models.
Air must move more quickly in the infant’s narrowed airway to get the same amount of air to the lungs. In older children the greater angle helps keep foreign substances and germs away from the middle ear. With the tubes in place, hearing should be normal and ear infections should be greatly reduced.
This is usually prevented by frequent cleansing and application of various moisture barriers or Vaseline.
Over time, the damage interferes with the body’s ability to maintain itself the way it used to, and the process we call “aging” occurs.
These byproducts cause damage and have often been associated with many age-related diseases such as cancer, heart disease, and Alzheimer’s disease.
Additionally, a subset of metabolites accumulated with age, which may indicate that these byproducts are not being sufficiently cleaned up by maintenance processes in the cells.
While systemic homeostasis and efficient regulatory mechanisms on the cellular level generally prevent the uptake of cytotoxic doses of exogenous zinc, endogenous zinc plays a significant role in cytotoxic events in single cells.


The friction of the quickly moving air against the side of the airway increases airway resistance.
A recent fruit fly paper published in eLife by the Gladyshev lab describes a new way to study damage accumulation. The authors found that many of these had previously been identified as damaging, directly confirming that accumulating toxic byproducts is correlated with aging. They found that many of the metabolites that differed between the lifespan-extended group and the normal group of flies were associated with processes for using and storing energy from fats and proteins (not surprising considering the flies were on a strict diet). Here, zinc influences apoptosis by acting on several molecular regulators of programmed cell death, including caspases and proteins from the Bcl and Bax families.
Instead of measuring the damage itself, they measure the byproducts of cellular metabolism as a proxy. The authors suggest that changing these metabolic processes through diet may have compensated somehow for the accumulation of toxic byproducts.
One organ where zinc is prominently involved in cell death is the brain, and cytotoxicity in consequence of ischemia or trauma involves the accumulation of free zinc. An important factor seems to be zinc homeostasis, allowing the efficient handling of an excess of orally ingested zinc, because after intraperitoneal injection into mice, the LD50 for zinc was only approximately four-fold higher than for cadmium and mercury [3].
Future research may be able to expand upon these findings, and perhaps even figure out a way to interfere with these processes to slow or alter aging.  I just hope I live long enough to see it! In contrast to the other two metals, for which no role in human physiology is known, zinc is an essential trace element not only for humans, but for all organisms.
ROS production by NADPH oxidases (NOXs) following receptor activation by specific ligands, for example, epidermal growth factor receptor (EGFR), inhibits protein tyrosine phosphatases (PTPs), which promotes the phosphorylation of tyrosine kinases (TKs) and the subsequent signal transduction.
Whereas intoxication by excessive exposure is rare, zinc deficiency is widespread and has a detrimental impact on growth, neuronal development, and immunity, and in severe cases its consequences are lethal.
It is a component of more than 300 enzymes and an even greater number of other proteins, which emphasizes its indispensable role for human health. By contrast, ataxia-telangiectasia mutated (ATM) kinase is activated directly by ROS, through disulphide bond-mediated homodimerization, which leads to the phosphorylation of heat shock protein 27 (HSP27) and the subsequent activation of glucose-6-phosphate-dehydrogenase (G6PD). Zinc deficiency caused by malnutrition and foods with low bioavailability, aging, certain diseases, or deregulated homeostasis is a far more common risk to human health than intoxication.
Optimal nucleic acid and protein metabolism, as well as cell growth, division, and function, require sufficient availability of zinc [4].In this review, we will give a brief summary of zinc homeostasis, followed by a description of the effects of acute zinc intoxication and the consequences of long-term exposure to elevated amounts of zinc. The resulting increase in NADPH levels contributes to the maintenance of cellular redox homeostasis. In the end, we will also briefly discuss the detrimental effects of zinc deficiency, because, unless they are exposed to zinc in the workplace or by accident, healthy individuals are at far greater risk of suffering from the adverse effects associated with zinc deficiency than from those associated with intoxication.
Zinc HomeostasisThe human body contains 2–3 g zinc, and nearly 90% is found in muscle and bone [5].
Other organs containing estimable concentrations of zinc include prostate, liver, the gastrointestinal tract, kidney, skin, lung, brain, heart, and pancreas [6–8]. Oral uptake of zinc leads to absorption throughout the small intestine and distribution subsequently occurs via the serum, where it predominately exists bound to several proteins such as albumin, ?-microglobulin, and transferrin [9].On the cellular level, 30–40% of zinc is localized in the nucleus, 50% in the cytosol and the remaining part is associated with membranes [4].
Cellular zinc underlies an efficient homeostatic control that avoids accumulation of zinc in excess (see also Figure 1a). In addition, many mammalian cell types also contain membrane-bound vesicular structures, so-called zincosomes.
MTs are ubiquitous proteins, characterized by a low-molecular weight of 6–7 kDa, high cysteine content, and their ability to complex metal ions. Through different affinities of the metal ion binding sites, it can act as a cellular zinc buffer over several orders of magnitude [15]. Dynamic regulation of cellular zinc by MT results from the synthesis of the apo-form thionein (T) in response to elevated intracellular zinc levels by triggering the metal response element-binding transcription factor (MTF)-1 [16]. In addition, oxidation of cysteine residues can alter the number of metal binding thiols, connecting redox and zinc metabolism. Exposure to ZincThere are three major routes of entry for zinc into the human body; by inhalation, through the skin, or by ingestion [18]. Each exposure type affects specific parts of the body (Figure 2) and allows the uptake of different amounts of zinc. Exposure by InhalationInhalation of zinc-containing smoke generally originates from industrial processes like galvanization, primarily affecting manufacture workers. In addition, military smoke bombs contain zinc oxide or zinc chloride, making soldiers a group in which several cases of inhalation of zinc-containing fumes were described. For example, Homma and colleagues reported a case of two soldiers who developed adult respiratory distress syndrome (ARDS) upon exposure to a zinc chloride-containing smoke bomb [19]. Another soldier was exposed to concentrated zinc chloride for several minutes during military training [20]. After tracheal intubation and mechanical ventilation for eight days, he left the hospital, and four months after the incident he returned to work without any respiratory disorder [20]. There are a few additional reports of related incidents with smoke bombs having similar effects on the respiratory tract [21,22].However, in none of the incidents there was unequivocal evidence that zinc was the main cause for the respiratory symptoms. Not only was no information about the concentrations available, but also the inhaled smoke contained several other ingredients besides zinc chloride. In addition, zinc chloride is generally caustic, so the effects could have risen from the specific properties of the compound, rather than being a direct effect of zinc intoxication.The most widely known effect of inhaling zinc-containing smoke is the so-called metal fume fever (MFF), which is mainly caused by inhalation of zinc oxide.
This acute syndrome is an industrial disease which mostly occurs by inhalation of fresh metal fumes with a particle size <1 ?m in occupational situations such as zinc smelting or welding [23]. Symptoms of this reversible syndrome begin generally a few hours after acute exposure and include fever, muscle soreness, nausea, fatigue, and respiratory effects like chest pain, cough, and dyspnea [24]. The respiratory symptoms have been shown to be accompanied by an increase in bronchiolar leukocytes [23].
In general, MFF is not life-threatening and the respiratory effects disappear within one to four days [25].Development of MFF is connected to the exposure level, but very little data is available concerning the zinc concentrations that trigger this syndrome [26]. Dermal ExposureDermal absorption of zinc occurs, but the number of studies is limited and the mechanism is still not clearly defined.
In another study comparing the dermal effect of different zinc compounds in mice, rabbits, and guinea pigs, zinc chloride was clearly the strongest irritant, followed by zinc acetate, causing moderate, and zinc sulfate, causing low irritations.
Consistent with the study by Agren, zinc oxide did not show any irritant effect on skin [35].As mentioned above, zinc chloride is caustic, and the irritation does not necessarily indicate a toxic effect of zinc. In contrast to a potentially harmful effect of zinc on skin, it should be noted that zinc is a well-known supplement for topical treatment of wounds and several dermatological conditions [34,36–38].
Based on the existing data, it can be concluded that dermal exposure to zinc does not constitute a noteworthy toxicological risk.
Oral ExposureDue to its nature as an essential trace element, oral uptake of small amounts of zinc is essential for survival.
In general, uptake of such an amount is unlikely, because approximately 225–400 mg zinc have been determined to be an emetic dose [40].
However, there is one published report of a woman who died after oral intake of 28 g zinc sulfate. She died five days later of hemorrhagic pancreatitis and renal failure [41].Immediate symptoms after uptake of toxic amounts of zinc include abdominal pain, nausea, and vomiting.
This correlation seems to be caused by the competitive absorption relationship of zinc and copper within enterocytes, mediated by MT. The expression of MT is upregulated by high dietary zinc content, and MT binds copper with a higher affinity than zinc. Consequently, available copper ions are bound by MT and the resulting complex is subsequently excreted [51,52]. Zinc-induced copper deficiency was confirmed by elevated serum zinc and low copper and ceruloplasmin serum levels. Another case report described a 31-year-old schizophrenic man who had been ingesting coins for 10 years [60].
Furthermore, profound anemia, neutropenia, and virtually absent serum copper and ceruloplasmin levels together with elevated zinc levels were diagnosed.
Upon X-ray examination a large number of coins (totaling $22.50) were identified and surgically removed. His copper deficiency was attributed to the ingestion of pennies, which since 1982 are composed of 98% zinc and 2% copper [60]. Several additional reports of zinc-induced copper deficiency leading to anemia and several other cytopenias were reviewed by Fiske and colleagues [55].The mechanism by which copper deficiency induces anemia is based on the requirement of copper for several enzymes involved in iron transport and utilization and, therefore, in heme synthesis. For example, ceruloplasmin is a ferroxidase that binds copper and converts ferrous to ferric iron, allowing it to bind to transferrin and be transported. Cytochrome-c oxidase is also dependent on copper, and is required for the reduction of ferric iron to be incorporated into the heme molecule [61–63]. In addition to interference with heme synthesis, copper deficiency causes approximately 85% reduction of ESOD in the red blood cell (RBC) membrane, decreasing RBC survival time [64].Whereas a recent meta-analysis found no general effect of zinc supplementation on serum lipoproteins [65], it may occur as a consequence of disturbed copper homeostasis.
This study was stopped after 11 weeks because four participants experienced cardiac abnormalities. Klevay and colleagues fed one man an omnivorous diet providing a Zn to copper ratio ? 16 for 105 days.


Plasma copper and ceruloplasmin decreased, whereas total cholesterol and LDL cholesterol increased [70]. Taking into account several additional studies, Sandstead suggested that cardiac abnormalities were associated with Zn to copper ratios ?16 [57]. For instance, zinc influences the lymphocyte response to mitogens and cytokines, serves as a co-factor for the thymic hormone thymulin, and is involved in leukocyte signal transduction [81–83]. In cell culture, very high zinc concentrations (above 100 ?M) in a serum-free culture medium stimulate monocytes to secrete pro-inflammatory cytokines [84], but actually inhibit T cell functions.
In general, T cells have a lower intracellular zinc concentration and are more susceptible to increasing zinc levels than monocytes [85,86]. Also, in vitro alloreactivity was inhibited in the mixed lymphocyte reaction (MLC) after treatment with more than 50 ?M zinc [87]. A similar inhibition was observed when the MLC was done ex vivo with cells from individuals that had been supplemented with 80 mg zinc per day for one week, indicating that zinc supplementation has the potential to suppress the allogeneic immune response at relatively low doses [88].An in vivo study supported the finding that zinc excess can affect lymphocyte function. The treatment had a small but significant influence on the lymphocyte response to the mitogens phytohemagglutinin (PHA) and Concanavalin A (Con A). The Role of Zinc in Cell DeathIn addition to the systemic toxic effects of zinc, this metal is also involved in the regulation of live and death decisions on the cellular level.
Second, we will focus on an organ where zinc toxicity has been investigated in great detail, the brain. Impact of Zinc on ApoptosisThe exact role of zinc in the regulation of apoptosis is ambiguous. A variety of studies indicate that, depending on its concentration, zinc can either be pro- or anti-apoptotic, and both, zinc deprivation and excess, can induce apoptosis in the same cell line [90–93].The induction of apoptosis by high levels of intracellular zinc has been shown in different tissues and cell types [93–95].
Reports indicate that accumulation of intracellular zinc, either as a consequence of exogenous administration or release from intracellular stores by reactive oxygen species or nitrosation, activates pro-apoptotic molecules like p38 and potassium channels, leading to cell death [93,96–98].
Increased intracellular zinc levels may also induce cell death by inhibition of the energy metabolism [99,100].Sensitive targets of zinc toxicity are the anti-apoptotic Bcl-2-like and pro-apoptotic Bax-like mitochondrial membrane proteins. As a consequence, dissipation of the mitochondrial membrane potential leads to the release of cytochrome-c from mitochondria into the cytosol [96,102–105].The anti-apoptotic properties of zinc likely comprise two main mechanisms.
First, zinc limits the extent of damage induced during oxidative stress, thereby suppressing signaling pathways resulting in apoptosis. Second, zinc directly affects several proteins and pathways that regulate apoptosis.Consistent with the first issue, zinc deficiency has been shown to induce oxidative stress [106–108].
Mechanisms by which the redox-inert zinc protects cells against oxidative damage seem to include its property to protect sulfhydryl groups in proteins from oxidation [109].
Furthermore, by stabilizing lipids and proteins, zinc can preserve cellular membranes and macromolecules from oxidative damage. On the other hand, it has to be noted that elevated availability of zinc may also induce oxidative stress, and its impact on redox homeostasis may either be protective or promoting, depending on its availability [17].With regard to the second mechanism, interaction of zinc with several apoptosis-regulating molecules has been reported. Furthermore, inhibition of caspases-6, -7, and -8 at low zinc concentrations was also shown, with caspase-6 being the most sensitive of the three [112].Zinc deficiency can also induce apoptosis by disrupting growth factor signaling molecules such as ERK and Akt [113].
Other molecular targets for zinc are the anti-apoptotic Bcl-2-like and pro-apoptotic Bax-like mitochondrial membrane proteins. Consistent with this, in a study by Zalewski and colleagues apoptosis was induced in premonocytic cells by treatment with hydrogen peroxide. Supplementation with 1 mM zinc increased the ratio of Bcl-2 to Bax resulting in the inhibition of active caspase-3 and reduction of apoptosis [115].
Amongst others, variables in this complex network are tissue and cell type, zinc concentration, expression of zinc transporters and zinc-binding proteins, other environmental circumstances like oxidative or nitrosative stress, and the involvement of multiple molecular targets with opposing functions. Role of Zinc in Neuronal DeathA prominent and well investigated example for the control that zinc exerts on survival on the cellular level is the brain.
This will now be discussed in more detail as an example of the mechanisms by which zinc can influence cellular survival.Normally, homeostatic mechanisms should prevent zinc from accumulating in the brain to reach toxic concentrations as a result of excessive oral ingestion. On the other hand, experimental evidence indicates that endogenous zinc might be a relatively potent, rapidly acting neurotoxin, and, to a lesser extent, also a gliotoxin [122–126].Zinc is stored in and released from vesicles in presynaptic terminals of a specific subset of neurons that also releases glutamate. Zinc can be released from presynaptic terminals during synaptic transmission, enabling it to enter postsynaptic somata and dendrites of cells via zinc-permeable ion channels [105]. The MT-III isoform is found only in the brain and it is abundant in the gluzinergic neurons [134,135].Exposure to 300–600 ?M zinc for 15 minutes results in extensive neuronal death in cortical cell culture [136]. Considering that neurons store high amounts of free zinc in their terminals [137] that are released upon depolarization [138,139], zinc may play an active role in neuronal injury. Furthermore, membrane depolarization, which is associated with acute brain injury [140], greatly increases the potency of zinc to act as a neurotoxin [141]. The first study providing evidence that zinc accumulation may play a role in the selective death of dentate hilar neurons after global ischemia in rats was done by Tonder and colleagues [144].
In the meantime, zinc accumulation in dying or dead neurons has not only been shown in the hippocampal hilar region, but also in all brain regions damaged in global ischemia such as hippocampal CA1, neocortex, thalamus, and striatum [145].
Consistent with the hypothesis that zinc-accumulation may lead to neuronal cell death, this event was prevented by the intraventricular injection of the zinc-chelating agent CaEDTA [145].Zinc release and accumulation of zinc ions was also observed in a rat model of traumatic brain injury, where Suh and colleagues showed that trauma is associated with loss of zinc from presynaptic boutons and appearance of zinc in injured neurons. Again, neuroprotection occurred by intraventricular administration of a zinc chelator [146].For some time, vesicular zinc was thought to be the only releasable pool of zinc in the brain [127]. This led to the assumption that the zinc ions accumulating in injured neurons must be entirely of presynaptic origin [127], but when ZnT-3 knock-out mice were investigated, which lack histochemically reactive zinc in synaptic vesicles, they still showed zinc accumulation in degenerating neurons, pointing toward sources other than synaptic vesicular zinc [147]. Alternative dynamic zinc sources might be MT-III as well as mitochondrial stores in the postsynaptic neurons [148,149].Although zinc is redox-inactive in biological systems and exists only as a bivalent cation, there is evidence that zinc toxicity in neurons is mediated mainly by oxidative stress [141]. Zinc-induced cell death is associated with increased levels of reactive oxygen species in neurons [150,151].
In addition, free-radical-generating enzymes like NADPH oxidase are induced and activated by exposure to zinc [152].
Finally, zinc-induced cell death has been shown to be attenuated by various antioxidant interventions [96,153].Besides oxidative stress, nitrosative stress can also affect zinc-induced neuronal injury.
Nitric monoxide plays a crucial role in zinc toxicity by releasing zinc ions from MT [154], and inhibition of nitric oxide synthase significantly reduces zinc release from brain slices during oxygen and glucose deprivation [155]. Consistent with this, Frederickson and colleagues observed that nitric oxide also rapidly releases zinc from presynaptic terminals [156].In addition to the impact of zinc on apoptosis discussed above, zinc-induced apoptosis in neurons might be based on two additional mechanisms.
First, zinc-exposed neurons show an induction of the neutrophin receptor p75NTR and p75NTR-associated death executor (NADE) [157], a combination that can trigger caspase activation and apoptosis [158]. Second, high intracellular zinc concentrations trigger dysfunction of neuronal mitochondria, resulting in the release of pro-apoptotic proteins such as cytochrome-c and apoptosis-inducing factor (AIF) [148].Although the release of intracellular zinc triggers neuronal apoptosis [96,159,160], indicators of necrosis such as cell body swelling and destruction of intracellular organelles have also been observed [96,150], indicating that zinc-induced neuronal cell death might encompass both apoptotic and necrotic mechanisms [143].
Here, the use of metal chelators such as clioquinol to restore normal neuronal zinc homeostasis has shown promising results in vivo [163]. On the other hand, due to its essentiality, a lack of this trace element leads to far more severe and widespread problems. Both, nutritional and inherited zinc deficiency generate similar symptoms [164], and clinical zinc deficiency causes a spectrum from mild and marginal effects up to symptoms of severe nature (Figure 2) [165].Human zinc deficiency was first reported in 1961, when Iranian males were diagnosed with symptoms including growth retardation, hypogonadism, skin abnormalities, and mental lethargy, attributed to nutritional zinc deficiency [166].
Later studies with some Egyptian patients showed remarkably similar clinical features [167]. Additional studies in the ongoing years manifested zinc deficiency as a potentially widespread problem in developing as well as in industrialized nations [168].Severe zinc deficiency can be either inherited or acquired. The most severe of the inherited forms is acrodermatitis enteropathica, a rare autosomal recessive metabolic disorder resulting from a mutation in the intestinal Zip4 transporter [169]. Symptoms of this condition include skin lesions, alopecia, diarrhea, neuropsychological disturbances, weight loss, reduced immune function, as well as hypogonadism in men, and can be lethal in the absence of treatment [170].Acquired severe zinc deficiency has been observed in patients receiving total parental nutrition without supplementation of zinc, following excessive alcohol ingestion, severe malabsorption, and iatrogenic causes such as treatment with histidine or penicillamine [165]. The symptoms are mostly similar to those arising during acrodermatitis enteropathica.Some reports indicate the existence of another group of inherited disorders of zinc metabolism. Even though this exceeds the amount normally found in serum after zinc intoxication, symptoms range from none to severe anemia, growth failure, and systemic inflammation, and resemble zinc deficiency rather than chronic or acute intoxication [172–175]. Hence, the large amounts of zinc in the serum of these patients are sequestered by proteins, potentially even depleting biologically available zinc [175].Clinical manifestations of moderate zinc deficiency are mainly found in patients with low dietary zinc intake, alcohol abuse, malabsorption, chronic renal disease, and chronic debilitation.
Symptoms include growth retardation (in growing children and adolescents), hypogonadism in men, skin changes, poor appetite, mental lethargy, delayed wound healing, taste abnormalities, abnormal dark adaptation, and anergy [165].Moderate zinc deficiency can also occur as a consequence of sickle cell disease [176]. Hyperzincuria and a high protein turnover due to increased hemolysis lead to moderate zinc deficiency in these patients, which causes clinical manifestations typical for zinc deficiency, such as growth retardation, hypogonadism in males, hyperammonemia, abnormal dark adaptation, and cell-mediated immune disorder [177] connected with thymic atrophy [178].In mild cases of zinc deficiency, slight weight loss, oligospermia and hyperammonemia were observed [165]. One population in which mild zinc deficiency occurs with high prevalence, even in industrialized countries, are the elderly. Here, a significant proportion has reduced serum zinc levels, and zinc supplementation studies indicate that this deficiency contributes significantly to increased susceptibility to infectious diseases [44].The overall frequency of zinc deficiency worldwide is expected to be higher than 20% [179].
Furthermore, it has been estimated that only 42.5% of the elderly (?71 years) in the Unites States have adequate zinc intake [183].
This widespread occurrence combined with the variety of clinical manifestations makes zinc deficiency a serious nutritional problem, which has a far greater impact on human health than the relatively infrequent intoxication with zinc.
ConclusionsZinc is an essential trace element, and the human body has efficient mechanisms, both on systemic and cellular levels, to maintain homeostasis over a broad exposure range.
Consequently, zinc has a rather low toxicity, and a severe impact on human health by intoxication with zinc is a relatively rare event.Nevertheless, on the cellular level zinc impacts survival and may be a crucial regulator of apoptosis as well as neuronal death following brain injury.



Normal glucose levels throughout the day graph
Random blood sugar 90


Comments

  1. 18.06.2015 at 12:13:40


    Much controls my life?�Im at my wits end and dont.

    Author: ANAR84
  2. 18.06.2015 at 21:18:55


    Monitored subsequently for the development of diabetes as outpatients pronounced for those with management.

    Author: 123321