The main iron status indicators: reference values for non-athletes and reported values in elite athletes
\r\n\tThe fifth topic is “complications and drug side effects in the treatment of pigmentation disorders”. These include drug allergies, hyper- and hypopigmentation, persistent skin depigmentation, scars, skin burns, and the potential for skin cancer and skin lymphoma. The last topic is called “coping and support along with skin pigmentation diseases”. Increase the quality of life, psychotherapy, team therapy, and asking for understanding and support from family members.
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In the human body it is mainly found in the oxygen transport and storage proteins haemoglobin (Hb) (60 - 70%) and myoglobin (10%), in various iron-containing enzymes (2%), as well as in the liver, bone marrow and muscle in the form of the storage proteins ferritin (Ferr) and hemosiderin (20 - 30%) [1]. Only a minor quantity (0.1 - 0.2%) of total iron, mostly bound to the iron-transport protein transferrin, circulates in the plasma and other extracellular fluids [1, 2]. Besides its essential character, excessive free iron could adversely affect the human body, by augmenting oxidative stress, mainly via the Fenton and Haber-Weiss reactions. Ferritin, hemosiderin and transferrin, assist the system to maintain iron balance under tight control by keeping free iron levels low and hence restrain the conversion of hydrogen peroxide to the highly reactive hydroxyl radical [3] that disturbs cellular homeostasis when it is increased at toxic levels.
Iron absorption is the main mechanism through which iron balance is maintained. Nevertheless, iron losses may occur at multiple organs, such as the gastrointestinal tract [4-6], the skin [7, 8], the urinary tract [4], and additionally due to several physiological conditions such as the menstrual cycle in women [9, 10]. To compensate for these losses, as well as for satisfying the body’s demands during growth and pregnancy, iron is absorbed from the diet. The percentage of food-iron that is absorbed from the intestine is approximately 10%, with heme-iron being absorbed in greater amounts compared with non-heme-iron [11-13]. Thus, from a typical daily diet of 2000 kcal that contains adequate quantities of meat, 1.8 mg of iron per day are absorbed [13]. In general, daily iron turnover (absorption and excretion) is approximately 1-2 mg per day [1, 2, 7].
There is a strong body of evidence suggesting that exercise affects iron status [14-17], although other studies do not support this association [18-20]. Iron plays a critical role in oxygen transport as it is necessary for the formation of Hb, the oxygen transport protein that is critical for aerobic capacity. Iron is also needed for the optimal function of many oxidative enzymes affecting the intracellular metabolism (i.e., the electron transport chain and oxidative phosphorylation pathway in mitochondria) [21]. Not only prolonged aerobic exercise but, to some extent, short duration activities (i.e. sprints), may influence the above mechanisms [22]. Consequently, a compromised iron status would negatively affect physical performance. On the other hand, iron deficiency is frequently attributed to exercise [14-16]. Therefore, iron supplementation is commonly used to avoid exercise-induced perturbations of iron homeostasis and maintain the required iron stores that are necessary to address exercise needs or enhance physical performance.
Numerous studies have attempted to clarify the effectiveness of enhanced iron intake, either through diet or through supplement consumption, to restore iron status or to enhance physical performance. Yet, no valid conclusions have been drawn. The results of these studies are contradictory as some of them produced positive effects [23, 24]) whereas others dispute such effects [25]. An important factor in iron absorption seems to be the previous iron status of the individual. This means that, several iron parameters are seen to be ameliorated following iron supplementation in situations of iron deficiency, whereas this is not always the case for individuals with normal iron status.
In this chapter, an attempt will be made, to clarify the effect of exercise on iron status in athletes. Furthermore, an effort will be made to address the role of dietary or supplemented iron on several indices of physical performance. Finally, the mechanisms through which exercise may alter iron homeostasis will also be discussed.
Exercise and/or physical activity is characterized by a substantial increase in oxygen needs. Iron is an indispensable factor for the formation of Hb, the protein responsible for oxygen transport from the respiratory organs to the peripheral tissues. Lack of adequate amounts of iron for the formation of Hb due to iron deficiency, can strongly affect physical work capacity, by reducing oxygen conveyance to the exercising muscles [21]. Iron is also a vital component for the formation of myoglobin, the iron-storage protein within the muscle that regulates the diffusion of oxygen from the erythrocytes to the cytoplasm and on to the mitochondria where it is used as the final acceptor of electrons processed by the respiratory chains producing water and forming energy in the process [26, 27]. The concentration of myoglobin in skeletal muscle is drastically reduced (40 - 60%) following iron deficiency, thus limiting the rate of oxygen diffusion from erythrocytes to mitochondria [28] which ultimately compromises the muscle’s oxidative capacity.
Apart from oxygen transport and storage, iron is also needed for the optimal function of many oxidative enzymes and proteins regulating the intracellular metabolism [21, 27, 29]. The mitochondrial content of oxidative enzymes and proteins is an important factor regarding the muscle’s capacity for work, as there is a strong association between the ability to maintain prolonged submaximal exercise and the activity of iron-dependent oxidative enzymes [29]. Iron deficiency negatively affects mitochondrial respiration mainly through the decline in heme iron-containing respiratory chain proteins cytochrome c and cytochrome c oxidase, as well as non-heme iron-containing enzymes succinate dehydrogenase and NADH dehydrogenase, but also the non-heme iron-sulfur protein content [27]. Therefore, iron deficiency may have detrimental effects, especially on endurance performance which is susceptible to, and negatively affected by disturbances in skeletal muscle’s iron concentrations [27].
Besides athletes’ training at sea level, iron deficiency could also affect athletes training at altitude. Staying at high altitude causes an increase in erythropoiesis in the bone marrow, stimulated by hypoxia. This increase in erythropoiesis is followed by an elevation in red blood cells volume and Hb concentration [30, 31]. Iron deficiency could negatively affect the above mechanism by limiting the rate of erythropoiesis and consequently aerobic performance. It has been demonstrated that athletes with low ferritin levels do not increase total red blood cell volume after 4 weeks at altitude, despite an acute increase in erythropoietin [32]. In contrast, a significant increase in erythropoietin but also in reticulocytes occurred in non-iron-deficient athletes during training at moderate altitude [30]. Such data suggests that iron sufficiency is critical for the favorable response of the athletes training to altitude, in an attempt to enhance their performance.
The need for iron supplementation in cases of iron deficiency anemia in athletes is indisputable. Nevertheless, the need for iron supplementation in situations of iron deficiency without anemia for enhanced performance is still under debate, despite the systematic use of iron supplements. The majority of studies do not report significant changes in physical capacity following iron supplementation [25, 33, 34]. Nevertheless, there are studies indicating an improvement of physical performance in iron depleted non anemic athletes following iron supplementation [23, 24].
Athletes at risk of iron deficiency include female and male middle and long distance runners, as well as all female athletes in other disciplines in which running is an important part of training or competition [17]. Iron demands during consecutive periods of intense training or competition are high, and may compromise iron status. In [15] is reported that a brief recovery following the in-season period may be insufficient to restore the reduced iron stores prior to the start of the subsequent high-intensity pre-season training. Additionally, even when the recommended dietary intake of iron is established through a controlled diet, iron status perturbations may be inevitable. In reference [35] the mean dietary intake of 16.3 mg per day was inadequate to prevent iron deficiency in female collegiate swimmers. Such disturbances however, if not treated, could be a threat, not only for athletic performance deterioration, but also for the athletes’ health. In a recent study [36], female collegiate rowers, categorized as iron-depleted non-anemic (Hb ≥ 12 gIdL, Ferr < 20 μg/L), rowed about 4% slower than normal controls with a serum Ferr ≥ 20 μg/L in a self-reported best 2-km simulated race on an row ergometer. These findings point out that non-anemic iron depletion may impair performance.
On the other hand, unjustified and uncontrolled iron supplementation could lead to iron overload that could be toxic and hazardous for the athletes’ health. Athletes with the homozygous form of hemochromatosis gene may be at risk of excessive iron storage due to excessive iron absorption [17]. According to the Department of Health and Human Services, Centers for Disease Control and Prevention (CDC) [37], hemochromatosis symptoms are non-specific, but the most commonly associated early hemochromatosis symptoms may include fatigue, weakness, weight loss, abdominal pain, and arthralgia. The simplest tests that indirectly indicate iron overloading are transferrin saturation (TS) and serum Ferr [37, 38]. TS levels >45% and Ferr >200 μg/L for premenopausal female or >300 μg/L for postmenopausal female and >300 μg/L for male, are indicative of iron overload. Nevertheless, the confirmation of hemochromatosis can be achieved indirectly by quantitative phlebotomy and hereditary hemochromatosis genotyping, or indirectly by liver biopsy [37, 38].
Taking the above under consideration, iron supplementation should be decided only after a thorough examination of athletes’ hematological and iron status at the beginning, in the middle, as well as at the end of training or the competitive season. Controlled iron supplementation for all athletes with serum Ferr below 35µg/L is recommended for the replenishment of iron stores.
Due to the significant role of iron in optimal physical performance and health, the evaluation of iron status in athletes is of great importance in order to prevent iron deficiency. According to the World Health Organisation [39], iron deficiency progresses in three stages: in the first stage iron stores in bone marrow, liver, and spleen are depleted (serum Ferr concentrations <12μg/L); in the second stage, erythropoiesis decreases as iron supply to erythroid marrow is reduced (TS <16%); in the final stage Hb production falls drastically (Hb concentration <12g/L) resulting in anemia.
Iron status evaluation is not a single-parameter estimation. Day-to-day or acute phase response variations occur in several indices of iron status. Therefore, in order to make a valuable and more accurate assessment, the estimation of iron status indices and several hematological parameters is needed. These will be described in the following sections. Additionally, the reference range for the main indicators of iron status, as well as reported values in elite athletes is presented in Table 1.
The most commonly used hematological index is haemoglobin which reflects the effects of mechanisms that control the red cell mass (RCM) and plasma volume (PV). It is used as an indicator of anemia, that is when an individual’s Hb concentration falls below the normal threshold of the person’s corresponding age and sex category, (then the third stage of iron deficiency anemia has been developed [40]). Normal values lie between 11.7 - 155 g/dL and 12.8 - 17.3 g/dL for women and men, respectively [41, 42]. According to WHO the recommended Hb values (in g/100 ml of venous blood) below which anemia develops, are <13 g/dL for adult men, <12 g/dL and <11 g/dL for non-pregnant and pregnant adult females, respectively, while in children aged 6 months - 14 years the corresponding values are between 11 g/dL and 12 g/dL [40]. Haemoglobin concentrations are normally stable demonstrating a relatively low day-to-day variation of 2 - 4% [39]. Alongside Hb, hematocrit (Hct), the mean corpuscular haemoglobin concentration (MCHC), as well as the size and volume of red blood cells (RBC) are also useful markers for anemia [16,29].The classic Hb and Hct changes as a result of acute or chronic exercise should be kept in mind before a diagnosis is to be made. Namely, acute strenuous and prolonged exercise typically leads to an increase of Hb and Hematocrit due to hemoconcentration [43]. On the other hand, a decrease in the concentration of these indices may be seen within the first days of a regular cardiovascular training program due to hemodilution. This decrease is temporary and most athletes demonstrate normal Hb levels at the completion of training or the end of a competitive phase [43, 44]. Hence, when determining hematological changes in athletes the above changes should be also taken into account in order to avoid a misleading interpretation of ‘‘sports anemia’’ or ‘‘pseudoanemia’’.
Serum Ferr concentration is one of the most frequently used indices in iron status examination. Serum concentration of Ferr and, in conditions of iron overload hemosiderin [2], serve as an indicator for body iron stores, available for protein and heme synthesis. Serum Ferr concentrations normally range within 10 - 300 μg/L [40, 42], whereas values lower than 12 μg/L reflect the absence of measurable iron stores in bone marrow, liver and spleen. Such values indicate the onset of a first stage iron deficiency [40]. Ferritin seems to be age- and sex-dependent, since lower values are reported for children and pre-menopause women as compared to adults and men, respectively.
Nevertheless, the expression and appearance of Ferr in serum are influenced by other factors as well. Ferritin is an acute-phase reactant and its serum concentration may be increased by liver disease, infections and other inflammatory conditions, malignant diseases, renal failure, cardiovascular diseases, high alcohol consumption, and aging [44-46]. Some types of physical activity are accompanied by inflammation-like reactions that can induce an acute phase response and increased Ferr levels for several days. In case of exercise-induced inflammation, normal Ferr levels could be deceptive, reflecting rather an acute phase response than the true efficiency of the athletes’ iron stores. Day-to-day variability in Ferr has been estimated in the range of 13% - 75% in endurance athletes [19] and therefore, its serum concentrations cannot independently be equated to iron stores [47]. In summary, although serum Ferr concentration is commonly reported to be affected by training [4, 16, 35], there should be some caution before iron adequacy or inadequacy is diagnosed in athletes when ferritin is the only available evaluating index.
Iron concentration, together with Total Iron Binding Capacity (TIBC) and TS provide information about iron status in plasma or serum.
Iron concentration expresses the total iron content per unit of serum volume, and its normal values typically range within 50 - 175 μg/dL [42, 48]. Iron concentration demonstrates a day-to-day variation of 15% - 26%, and a 10 - 20% variation during the day [49], and as a consequence, the measurement of serum iron concentration alone, cannot be rendered a valuable index of iron status.
Total Iron Binding Capacity (TIBC) reflects the total number of binding sites for iron atoms on transferrin per unit volume of plasma or serum [48]. The reference range for TIBC lies between 250-425 μg/dL (Tietz, 1995) and is a more stable indicator of iron status than iron concentration, with its day-to-day variation ranging within 8% - 12% while its diurnal variation is less than 5%. TIBC does not change before iron stores are depleted [48]. In depleted iron stores a rise in TIBC levels occurs as more free binding sites on transferrin are available for iron.
Transferrin is the iron binding protein that delivers iron to cells [48]. Transferrin levels are not affected by inflammatory reactions or other diseases and can therefore be used for diagnosing iron deficiency even under such conditions [44]. Transferrin saturation is the percentage of serum iron to TIBC, and values < 15% are indicative of a second stage iron deficiency. This stage is characterized by iron deficient erythropoiesis, with a restricted iron supply in the absence of anemia [40]. Its normal values range within 20% - 50% and 15% - 50% for men and women respectively [42]. Since TIBC is rather stable, any alteration in plasma TS will be the result of changes in iron concentration. Consequently, anything that alters iron concentration will alter TS as well [48]. Transferrin saturation in conjunction with serum Ferr concentration and Hb are the three critical parameters for the determination of the severity of iron deficiency.
Erythrocyte Protoporphyrin (EP) or Zinc Protoporphyrin (ZPP), and the soluble Transferrin Receptor (sTfR) reflect the adequacy or inadequacy of iron for erythropoiesis into the bone marrow and tissues.
Protoporphyrin is a carrier molecule and together with ferrous iron forms the heme group of Hb, myoglobin and other heme-containing enzymes. In cases of iron absence, instead of iron, zinc is incorporated to protoporphyrin and ZPP is formed. A rise in ZPP concentration is one of the first indicators of insufficient iron levels in bone marrow [50, 51]. Additionally, the ratio of EP to Hb is an excellent indicator of iron failure to meet the normal demands of bone marrow [50]. In healthy individuals, EP concentration is < 40 - 50 µg EP/dl of red blood cells. When TS falls below 15%, EP concentration increases rapidly to more than 70 - 100 µg/dl, whereas concentrations as high as 200 µg/dl may be reached in cases of prolonged or severe iron deficiency. Day-to-day variation of EP concentration is reported to fall around 6.5% [52].
The concentration of sTfR has also been used as an indicator of iron deficiency erythropoiesis [19, 41]. Plasma sTfR is a truncated form of the cellular receptor (TfR), which is responsible for binding and transferring iron into the cell. Transferrin receptor is upregulated when the cell needs more iron, and sTfR is proportional to the cellular TfR content. Normal concentration of sTfR ranges within 1.15 - 2.75 mg/L [41]. When iron stores become depleted and the functional pool of iron diminishes, the levels of sTfR increase [41, 53]. In contrast to Ferr, sTfR is not an acute phase protein, and its concentration is not affected by infections or other inflammatory conditions [16, 54]. Additionally, the much lower day-to-day recorded variability of 4% - 16% for the sTfR compared with the corresponding value of Ferr (13% - 75%) [19] may render sTfR a more accurate index for the estimation of athletes’ iron status and the exercise-induced changes in iron metabolism [55]. The sTfR/log Ferr index with normal values ranging within 0.63 - 1.8 [41], is believed to be a more reliable index, as it is less variable and takes into account both the iron stores and the iron pool. Hence, it may reflect more accurately athletes’ iron status.
Haptoglobin (Hp) is used as an index of hemolysis. The destruction of the red blood cells membrane due to hemolysis allows Hb and its associated iron held within the cell to be released into the surrounding plasma. Haptoglobin binds free Hb released from erythrocytes, inhibiting its pro-oxidative activity [44]. The binding of Hb to Hp causes a decline in Hp levels, and the formed haemoglobin-haptoglobin complex is taken up exclusively by hepatocytes, thus preventing the excretion of free Hb in the urine [20]. Hence, the decline in Hp levels below normal values, which range between 15 - 200 mg/dL[42], reveals the occurrence of hemolysis. As a result, the regular return of catabolized red blood cells to the reticuloendothelial system (RES) is diminished. Therefore, the observed lower Hb concentration often seen in long distance runners may not always reflect iron deficiency. The shift of iron turnover from hepatocytes rather than the RES may represent an alternative explanation of the observed compromised iron status [20]. The estimation of Hp levels could be of great importance in the verification of true iron deficiency even when other parameters such as Hb, serum Ferr, or bone marrow hemosiderin appear to be lower than normal values.
Taking the above into consideration, an integral evaluation of an athlete’s iron status should not be based on the estimation of one parameter alone. Additionally, day-to-day variations of the estimated indices, as well as exercise-induced changes in blood volume, acute phase reactions, infections, or other inflammatory conditions, should also be considered. This way, the assessment would be more integrated, and false conclusions about the effect of exercise on the athlete’s iron status would be avoided.
\n\t\t\t | \n\t\t\t | |||||||
Reference values for non-athletes adults* | \n\t\t\tMales Females | \n\t\t\t13.2-17.3 11.7-15.5 | \n\t\t\t39-49 35-45 | \n\t\t\t4.3-5.7 3.8-5.1 | \n\t\t\t80-99 81-100 | \n\t\t\t27-34 27-34 | \n\t\t\t32-37 32-36 | \n\t\t\t0.5-1.5 0.1-1.5 | \n\t\t
Reported iron status indicators in elite Athletes (M±SD) | \n\t\t||||||||
Koehler et al. (2012)√\n\t\t\t\t (several sports) | \n\t\t\tMales Females | \n\t\t\t14.7±1.1 13.2±0.9 | \n\t\t\t42.3±2.6 38.6±2.4 | \n\t\t\t\n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t |
Della Valle & Haas, (2012)√\n\t\t\t | \n\t\t\tFemales (N) (D) | \n\t\t\t13.1±0.7 13.0±0.7 | \n\t\t\t40.1±2.1 40.2±2.1 | \n\t\t\t\n\t\t\t | 88.8±3.6 87.9±4.6 | \n\t\t\t\n\t\t\t | \n\t\t | |
Reinke et al. (2012) ↑\n\t\t\t | \n\t\t\tMales (CS) (R) (P) | \n\t\t\t12.2-17.1 11.6-17.2 12.4-16.5 | \n\t\t\t\n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t |
Schumacher et al. (2002)√\n\t\t\t | \n\t\t\tMales (EA) (PA) | \n\t\t\t15.7±1.0 16.4±1.0 | \n\t\t\t46.6±3.3 47.4±3.1 | \n\t\t\t5.24±0.52 5.47±0.36 | \n\t\t\t\n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t |
Malczewska et al. (2001)√\n\t\t\t | \n\t\t\tMales (N) (D) | \n\t\t\t16.38±1.1 15.92±1.1 | \n\t\t\t0.49±0.0¥\n\t\t\t\t 0.47±0.0¥\n\t\t\t | \n\t\t\t5.26±0.36 5.12±0.32 | \n\t\t\t90.9±3.9 91.7±3.3 | \n\t\t\t31.2±2.4 31.2±1.7 | \n\t\t\t34.3±4.5 33.7±1.5 | \n\t\t\t\n\t\t |
Females (N) (D) | \n\t\t\t14.5±0.9 13.8±0.8 | \n\t\t\t0.42±0.0¥ 0.42±0.0¥ | \n\t\t\t4.5±0.37 4.6±0.33 | \n\t\t\t91.8±4.9 88.9±3.3 | \n\t\t\t32.3±3.0 29.9±1.8 | \n\t\t\t35.0±2.9 33.2±1.6 | \n\t\t\t\n\t\t | |
Rowland et al. (1987) | \n\t\t\tMales Females | \n\t\t\t14.7±1.0 13.3±0.4 | \n\t\t\t\n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t |
Magnuson et al. (1984) | \n\t\t\tMales | \n\t\t\t14.6±0.9 | \n\t\t\t\n\t\t\t | \n\t\t\t | 87.9±7.2 | \n\t\t\t31.3±2.1 | \n\t\t\t35.8±1.8 | \n\t\t\t\n\t\t |
\n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t |
\n\t\t\t | \n\t\t\t | \n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t|||||
Reference values for non-athletes adults* | \n\t\t\tMales Females | \n\t\t\t20-300 10-120 | \n\t\t\t65-175 50-170 | \n\t\t\t250-425 250-425 | \n\t\t\t20-50 15-50 | \n\t\t\t1.15-2.75 1.15-2.75 | \n\t\t\t15-200 15-200 | \n\t\t\t< 40-50 < 40-50 | \n\t\t
Reported iron status indicators in elite Athletes (M±SD) | \n\t\t||||||||
Koehler et al. (2012)√\n\t\t\t\t (several sports) | \n\t\t\tMales Females | \n\t\t\t55.4±36.7 35.4±22.0 | \n\t\t\t\n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t |
Della Valle & Haas, (2012)√\n\t\t\t | \n\t\t\tFemales (N) (D) | \n\t\t\t43.0±20.3 13.9±5.1 | \n\t\t\t\n\t\t\t | \n\t\t\t | \n\t\t\t | 6.4±2.5 6.4±2.1 | \n\t\t\t\n\t\t\t | \n\t\t |
Reinke et al. (2012) ↑\n\t\t\t | \n\t\t\tMales (CS) (R) (P) | \n\t\t\t6-127 20-133 15-148 | \n\t\t\t\n\t\t\t | \n\t\t\t | 10.7-85.4 9.0-54.2 13.9-43.2 | \n\t\t\t\n\t\t\t | \n\t\t\t | \n\t\t |
Schumacher et al. (2002)√\n\t\t\t | \n\t\t\tMales (EA) (PA) | \n\t\t\t125.6±91.5 82.3±61 | \n\t\t\t125.0±50.2 105.5±38.6 | \n\t\t\t\n\t\t\t | \n\t\t\t | \n\t\t\t | 73.0±38.9 55.2±30.7 | \n\t\t\t\n\t\t |
Malczewska et al. (2001)√\n\t\t\t | \n\t\t\tMales (N) (D) | \n\t\t\t65.9±1.83 19.5±2.14 | \n\t\t\t104.3±28.2 72.8±20.5 | \n\t\t\t310±36.7 348±41.2 | \n\t\t\t\n\t\t\t | 1.78±1.3 3.15±1.2 | \n\t\t\t1.29±0.58 1.16±0.54 | \n\t\t\t\n\t\t |
Females (N) (D) | \n\t\t\t40.6±1.76 20.1±1.54 | \n\t\t\t105.3±32.9 81.7±20.4 | \n\t\t\t315±42.6 344±49.2 | \n\t\t\t\n\t\t\t | 1.72±1.2 4.36±2.5 | \n\t\t\t1.29±0.89 1.43±0.60 | \n\t\t||
Rowland et al. (1987) | \n\t\t\tMales Females | \n\t\t\t29.4±17.8 26.6±11.4 | \n\t\t\t\n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t |
\n\t\t\t\tMagnuson et al. (1984)\n\t\t\t | \n\t\t\t\n\t\t\t\tMales\n\t\t\t | \n\t\t\t\n\t\t\t\t64.3±47.8\n\t\t\t | \n\t\t\t\n\t\t\t\t19.1±7.3\n\t\t\t\t®\n\t\t\t | \n\t\t\t\n\t\t\t | \n\t\t\t\t31.8±11.6\n\t\t\t | \n\t\t\t\n\t\t\t | \n\t\t\t\t52.0±32\n\t\t\t | \n\t\t\t\n\t\t\t\t27±I8\n\t\t\t | \n\t\t
The main iron status indicators: reference values for non-athletes and reported values in elite athletes
Hb: Haemoglobin, Hct: Hematocrit, RBC: Red blood cells, MCV: Mean corpuscular volume, MCH: Mean corpuscular Hemoglobin concentration; RTC: Reticulocytes count, Ferr: Ferritin, TIBC: Total iron binding capacity, TS: Transferrin saturation, sTfR: soluble transferrin receptor, Hp: Haptoglobin, EP: Erythrocyte protoporphyrin
√Values reported in Mean±SD, ↑ the observed ranges, ¥Values reported in L/L, ® Values reported in μmol/L
N: normal iron status, D: iron deficiency, CS: Competitive season, R: Recovery, P: Preparation, EA: Endurance trained athletes, PA: Power trained athletes
* WHO, Assessing the Iron Status of populations (2004); Suominen et al., 1998; Tietz, 1995; Lynch, 2004; Beard, 2004; Labbe et al., 1999;
There is a great body of evidence indicating that several hematological and iron status parameters often appear altered as a result of chronic exercise (Table 2) giving the impression that athletes may be iron-deficient [14-17, 22, 43].
Several hematological variables in strength-trained athletes have been reported to be similarly low or even lower than that of endurance athletes [14, 56]. Nevertheless, it is mostly the endurance type of training that has been linked to lower values of several hematological indices [35, 43]. Actually, although within normal values, lower levels of RBC have been reported in endurance and/or power athletes as compared to sedentary individuals, while Hb and Hct were significantly lower in endurance athletes only when compared with power athletes [43]. These lower levels in endurance athletes have been attributed to reticulocytosis and expansion of plasma volume associated with chronic aerobic training [35, 43, 56]. However, abnormal Hb concentration (< 13 g/dL) was not only reported in endurance athletes, but in male athletes of combat sports as well [14]. What is more, even Hb levels below 12 g/dL, defining iron deficiency anemia, has been reported for female rowers, indicating that abnormal decrements in Hb concentration can be found in athletes other than runners [36].
While in the general population a serum Ferr concentration below 12μg/L is used for the identification of first stage iron deficiency, wider serum Ferr cut-offs values (ranging from 12 to 40 μg/L) have been adopted for the identification of diminished iron stores and iron deficiency in athletes [14, 15, 24, 33, 34\n\t\t\t\t\t36]. Additionally, iron deficiency has also been distinguished to absolute, when serum Ferr is below 30μg/L, or functional, when serum Ferr is within 30 - 90μg/L or serum Ferr is within 100 - 299μg/L and TS is below 20% [15].
Although within normal range, athletes demonstrated lower values of serum Ferr but similar transferrin and Hp values compared with sedentary controls [43]. Similarly, in [56] significantly lower Ferr concentration in endurance athletes is reported compared with strength-trained athletes and controls, and Ferr levels below 50μg/L in 18% of endurance athletes as compared to 12% in controls.
Decreased serum Ferr values (< 35 μg/L) were recorded to one third of elite athletes [14]. These results are in agreement with those in reference [4] where decreased serum Ferr values (< 35 μg/L) and low, instead of normal, hepatic iron stores were also reported in male distance runners, indicating a true prelatent iron deficiency. The lower cut-off point of < 20 μg/L for Ferr adopted by the authors in reference [36], identified 30% of the rowers as being non-anemic iron-depleted at the beginning of a pre-training period, while another 10% were identified as anemic according to Hb values of less than 12.0 g/dl.
A very intense training or competitive period may lead to absolute (Ferr < 30μg/L) and functional (Ferr within 30 - 90μg/L or Ferr within 100 - 299 μg/L + TS <20%) iron deficiency in professional male soccer players [15, 57], elite rowers [15] and female swimmers [35]. In some cases, the allowed recovery period before the next training phase may not be sufficient for the replenishment of the depleted iron stores [15], and this point definitely needs closer attention.
Based on data of several investigations, iron status disturbances are more frequent in female than in male athletes. In reference [14], female athletes were about twice as likely to exhibit reduced Ferr levels. In that study, 58.8% of females had Ferr below 35 μg/L, whereas the corresponding percentage of their male counterparts was 31.2%. In another study [58], 45% of the female cross country runners became iron-deficient at the end of the competitive season, while in males only 17% of them were characterized as iron-deficient. Similarly, the prevalence of iron deficiency was greater in female athletes of several events, as compared to male athletes. Determination of the transferrin receptor-ferritin index (sTfR/logFerr) revealed values of 2.62±0.94 and 3.33±1.71 for iron-deficient male and female athletes, respectively [16]. Additionally, critically low Ferr levels below 15μg/L or even below 12μg/L have also been reported for female runners [58- 60].
The cause of reduced levels in Ferr or serum iron in athletes is not fully understood. Exercise-induced hemolysis, as documented by the reduced Hp values, may offer a plausible explanation. In reference [20], although no differences were observed in Hb concentration, the levels of iron concentration, Hct, Ferr, TS, and bone marrow hemosiderin were lower in athletes compared to controls. However, no true iron deficiency was established based on the normal mean cell volume (MCV) and EP values, as well as on the normal sideroblast count in bone marrow smears of all athletes, confirming an adequate supply of iron to normoblasts. The lower Hct and Ferr values in athletes could be explained by the simultaneous marked decline of Hp levels, indicating a shift of iron to the hepatocytes as a result of increased intravascular hemolysis. Thus, diagnosing iron deficiency solely based on reduced Ferr or hemosiderin levels, could lead to an underestimation of iron reserves and a possible false-positive diagnosis of ‘‘sports anemia’’.
Not only chronic exercise, but also acute strenuous physical activity may alter several indices of iron status. A significant reduction in serum iron levels of 12.2 μmol/L was reported after a triathlon completion [61]. The authors proposed that heavy sweating or a prelatent iron deficiency may explain the observed severe reduction of serum iron. However, sweat iron concentration does not correlate with the increased whole body sweat rates [8].
A slight increase in sTfr, although within the normal range, has also been recorded after incremental running to exhaustion, but not after 45 min of submaximal exercise or after 3 consecutive days of aerobic training in highly trained endurance cyclists [55]. After the incremental running, an increase in Ferr, as well as in Hb and Packed Cell Volume (PCV) was also observed. This increase was mainly attributed to the concurrent hemoconcentration, as evidenced by the pronounced fall in plasma volume.
Regardless the acute or chronic character of exercise where most studies report variable responses in iron status, there are also studies that do not support significant differences in iron status between trained and untrained individuals. Indeed, similar incidence of iron deficiency between male endurance young athletes and non-athletes involved in several sport disciplines has been reported [18]. High physical activity of athletes did not affect iron stores, as it was found to be higher than in control subjects. It has to be mentioned though, that athletes had higher iron intake from the diet than controls, and that 18% of those that were iron-sufficient reported consumption of iron supplements. In a more recent study of the same institute [19] that involved female endurance athletes, lower incidence of iron deficiency was reported in athletes as compared to controls. These studies may lead to the assumption that the increased iron dietary intake and dietary factors involved in iron metabolism compensated for the augmented, exercise-induced losses of iron in young athletes. Regarding iron deficiency in athletes whose iron intake was sufficient, the authors attributed its prevalence in its diminished absorption for the male, and its leak to the blood due to menstrual cycle for the female athletes.
Taken together, these studies that attempted to evaluate the effects of exercise on iron status of athletes suggest that high volume training during a competitive season may compromise iron homeostasis. One determining factor that could help explain the reported discrepancies in iron status due to acute or chronic exercise is diet. Unfortunately, not many studies report athletes’ daily dietary intake of iron, and since iron intake or absorption are determining factors for iron balance future studies need to address this issue.
\n\t\t\t\t | \n\t\t||||
\n\t\t\t\t | \n\t\t||||
Kohler et al (2012) | \n\t\t\tRetrospective estimation of iron status in athletes from 25 different events | \n\t\t\t96 males 16.1±2.3yo and 97 females 16.3±3yo elite athletes | \n\t\t\tNutrition, Ferr, Fe, hematological parameters, CK, VO2peak\n\t\t\t | \n\t\t\t\n\t\t\t\t \n\t\t\t | \n\t\t
Della Valle & Haas (2012) | \n\t\t\tDetermination of the impact of iron depletion on performance at the beginning of a training season | \n\t\t\t165 female rowers (19.7±1.2yo) | \n\t\t\tHb, Ferr, sTfR, 2-km TT | \n\t\t\t30% 10% of the athletes had iron deficiency anemia ( | \n\t\t
Reinke et al (2012) | \n\t\t\tAssessment of iron status after 3 seasons: championship, recovery, preseason training | \n\t\t\t10 professional male soccer players 20-36yo, 20 elite rowers 21-35yo | \n\t\t\tHematological indices, Ferr, TS | \n\t\t\t27% of the athletes had iron deficiency after championship season which persisted in all time points in 14% of the athletes; | \n\t\t
Schumacher et al (2002) | \n\t\t\tEpidimiological study, estimation of hematological and iron status in endurance, mixed or power athletes | \n\t\t\t747 male athletes (24.2±8yo), 104 controls (29.9±6.9yo) | \n\t\t\tRBC,Hb, Hct, Fe, Ferr, Tf, Hp, VO2peak\n\t\t\t | \n\t\t\t\n\t\t\t\t \n\t\t\t\t \n\t\t\t\t | \n\t\t
Malczewska et al (2001) | \n\t\t\tAssessment of frequency of iron deficiency in athletes | \n\t\t\t131 males, 121 females of several events 16-36 years old | \n\t\t\tsTfR, Fe, TIBC, Ferr, Hp , TfR/log Ferr index | \n\t\t\tLatent iron deficiency in 29% of female and 11% of male athletes; higher sTfR and TIBC, lower Ferr levels in iron deficient compared with normal only in females | \n\t\t
Nachtigall et al (1996) | \n\t\t\tEstimation of iron status and iron metabolism throughout a training period | \n\t\t\t45 male distance runners | \n\t\t\tFerr, 59Fe absorption | \n\t\t\tFerr values <35μg in 51% of the athletes; up-regulated 59Fe absorption, decreased liver iron concentration | \n\t\t
Spodaryk et al (1993) | \n\t\t\tEstimation of hematological and iron status in endurance (E), strength-trained (S) athletes and controls (C) | \n\t\t\t39 male athletes from the 1988 Polish Olympic team (20.4 ± 2.2yo) | \n\t\t\tHb, PCV, RBC, Ret, Fe, Ferr, Tf, Hp, TS | \n\t\t\t\n\t\t\t\t | \n\t\t
Brigham et al (1993) | \n\t\t\tEstimation of iron status during a competitive season | \n\t\t\t25 female varsity collegiate swimmers | \n\t\t\tHb, Ferr | \n\t\t\tAt baseline 17 athletes were iron depleted and 5 athletes were anemic. After 5 wk Hb decreased (≥6 g/L) in 44%, and Ferr (≥5 μg/L) in 24% of the athletes \n\t\t\t | \n\t\t
Nickerson et al (1989) | \n\t\t\tEstimation of stage II iron deficiency (Ferr<12ng/ml and TS<16%) during the running session; iron supplementation or iron-rich diet or controls | \n\t\t\t41 female and 25 male cross-country runners and controls (15-18yo) | \n\t\t\tFerr, TS, blood losses | \n\t\t\t\n\t\t\t\t \n\t\t\t\t | \n\t\t
Rowland et al (1987) | \n\t\t\tEstimation of iron status during a competitive season; supplementation of iron in the iron | \n\t\t\t30 male and 20 female cross country runners (14.3-18.6yo) | \n\t\t\tFerr, Hb, RBC parameters | \n\t\t\t45% | \n\t\t
Magnusson et al (1984) | \n\t\t\tHematological and iron status comparison between distance runners | \n\t\t\t43 runners (19-46yo) and 119 controls (19-37yo) | \n\t\t\tHb,Hct, MCV, MCHC, EP, Fe, TS, Ferr, BMHem, Sideroblasts, Hp | \n\t\t\t\n\t\t\t\t \n\t\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t |
Rogers et al (1986) | \n\t\t\tEvaluation pre, post, and 30 min, 24h, and 48h after a 160-km triathlon (canoeing, cycling, and running) \n\t\t\t | \n\t\t\t18 triathlon athletes | \n\t\t\tFe, TIBC, lactoferrin, Ferr, Hp, cortisol, WCC, CRP, various enzymes | \n\t\t\tPost: ↑ in cortisol, WCC, lactoferrin and ↓ in Fe and TS; 24h: ↑by 300% in CRP, ↓ in Hp | \n\t\t
Schumacher et al (2002) | \n\t\t\tEstimation of exercise on sTfR and other variables after an incremental running test till exhaustion (IRTTE), 45min submaximal running, 3d aerobic cycling | \n\t\t\t39 athletes (33 men, 6 women) (19.6 – 32.5yo) | \n\t\t\tHb, Hct, BV, PV, RCV, sTfR, Ferr, Fe | \n\t\t\t\n\t\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t||||
Malczewska et al (1997) | \n\t\t\tEstimation of iron status in endurance athletes | \n\t\t\t178 male athletes, 52 male controls 18-20 years old | \n\t\t\tHb, PCV, RBC, WBC, MCHC, MCV, MCH, Fe, TS, TIBC, Ferr, Hp | \n\t\t\tSimilar iron depletion in athletes (19%) and controls (20%); ↓ Ferr, Fe and ↑TIBC in the iron depleted subgroups | \n\t\t
Malczewska et al (2000) | \n\t\t\tEstimation of iron status in endurance athletes | \n\t\t\t126 female athletes, 52 female controls 16-20 years old | \n\t\t\tHb, Hct, RBC, WBC, MCHC, MCV, MCH, Fe, TIBC, TS, Ferr, Hp | \n\t\t\tLower iron deficiency (26%) in athletes than controls (50%); ↓ Ferr, Fe and ↑TIBC in the iron deficient subgroups | \n\t\t
Iron status in competitive athletes
VO2max: Maximum Oxygen Consumption, TT: Time Trial, CK: Creatine Kinase, Ferr: Ferritin, Fe: Iron, Tf: Transferrin, TS: Transferrin Saturation, sTfR: Soluble Transferrin Receptor, TIBC: Total Iron Binding Capacity, Hb: Haemoglobin, Hct: Hematocrit, PCV: Packed Cell Volume, Ret: Reticulocytes, WCC: White Cells Count, RBC: Red Blood Cells, RCV: Red Cells Volume, WBC: White Blood Cells, MCH: Mean corpuscular Haemoglobin, MCHC: Mean Corpuscular Haemoglobin Concentration, MCV: Mean Corpuscular Volume, BMHem: Bone Marrow Hemosiderin, EP: Erythrocyte Protoporphyrin, Hp: Haptoglobin, PV: Plasma Volume, BV: Blood Volume, GOT: Glutamic Oxaloacetic Transaminase, CRP: C Reactive Protein
Iron absorption mainly, and to a lesser extent iron nutrition, are the two critical mechanisms by which iron balance is maintained since there is no other physiological process for iron excretion. The repletion of iron due to increased losses as well as the body’s need during growth and pregnancy are covered by dietary iron intake. Consequently, a low dietary iron intake, could lead to compromised iron status [9]. According to values reported by the Institute of Medicine, Food & Nutrition Board [62], the recommended dietary intake (RDI) for total iron is 8 mg/day for adult men and 18 mg/day for menstruating women. Usually, male, but not female athletes achieve the RDI for iron [14, 17, 63]. The mechanism of iron absorption by the intestine is regulated by iron bioavailability in diet and by individual’s iron status. Iron bioavailability has been found to be affected by the type of the diet and by the type of dietary iron [11]. Hence, mixed diet and heme iron provide greater bioavailability and absorption as compared to a vegetarian diet and nonheme iron, [11-13]. Furthermore, iron deficiency augments iron absorption.
Besides iron absorption and intake, several other mechanisms have been proposed to account for iron loss and iron balance disturbances, and ultimately the prevalence of iron deficiency in athletes. These mechanisms include increased gastrointestinal blood loss, hematuria, hemolysis [5, 6, 17, 64-67], increased iron loss in sweat [7, 8], as well as menstruation in women [9, 10, 68].
In athletes, gastrointestinal bleeding usually accompanied by occult blood, is a well-established phenomenon, mostly seen in distance runners [6, 60]. Gastrointestinal blood loss has shown to be the main contributor to the negative iron balance, as the excretion of 59Fe in sweat and urine appears to be negligible compared to fecal excretion of 3 - 5 mg/day [4]. Running a marathon was associated with a gastrointestinal blood loss [67], and positive occult heme stools were found in runners after intensive training or competitive running [4, 5, 60, 67]. The origin of running-related intestinal bleeding has still to be clarified, but endoscopic examination has revealed bleeding lesions in the stomach and colon [65, 66]. Gastrointestinal bleeding is partly attributed to ischemic injury, and running has been shown to reduce visceral blood flow by up to 43% of pre-exercise levels [69] due to the diversion of blood flow from the splanchnic viscera to the working muscles. Exercise intensity, seems to play a significant role in the development of gastric ischemia [70], which increases mucosa permeability and enhances occult blood loss [6].
Increased iron loss through sweat has also been proposed as a mechanism related to the compromise of iron status as a result of increased sweat rates during exercise in athletes, or increased temperature in individuals living and exercising in hot climates. The daily loss of iron from the skin has been reported to be 0.24 mg/d [71] or 0.33 mg/d [72]. The reported 0.183 mg of iron loss during prolonged exercise at 50% of VO2max, represented the 55% - 76% of the estimated daily iron loss from the skin, and the 23% for men and 10% for women of the estimated total daily iron loss [8]. It has to be mentioned that although the sweat rate increases during the 1st hour of exercise and remains constant thereafter, and males have higher sweat rates than females, the iron loss in males and females remains comparable. Additionally, the sweat iron loss declines in both genders during the 2nd hour of exercise [8], or after the first 30 min in a hot environment [7]. This reduction could be attributed to the initial sweat containing iron present in cellular debris [7], to the increased sweat rates while the total iron loss remains constant, or to a conservation mechanism that may prevent excessive iron loss during exercise [8]. Still, iron loss in sweat remains insignificant compared to that of the gastrointestinal tract.
Another explanation for compromised iron status in athletes is the shift of iron return to hepatocytes, rather than the RES, as a consequence of the increased intravascular hemolysis occurring mostly in weight-bearing activities, such as running. In these activities, hemolysis is due to the impact forces generated by the foot strike [73, 74]. Increased intravascular hemolysis has been reported in runners [20] and female artistic gymnasts [73]. However, foot strike cannot totally explain the exercise-induced hemolysis since hypohaptoglobinemia, a situation that reveals the presence of hemolysis, has also been observed in swimmers [75]. In non-weight-bearing activities hemolysis may result from the compression of the blood vessels caused by the vigorous contraction of the involved muscles [75].
Female athletes seem to be more prone to the development of iron deficiency [14, 16] and blood loss during menstruation may further explain this greater prevalence. Although menstrual blood loss in a single woman is very constant during menarche and throughout the fertile life, there is a large variation in blood loss among women [68]. Thus, in a mean cycle length of 28 days, menstrual blood loss may vary by as much as 26 - 44 ml, with a corresponding daily iron loss of about 0.5 - 0.7 mg [9, 76]. This great variation in blood and iron loss reported by these two studies could be associated with an extensive use of oral contraceptives which are known to reduce the amount of blood loss during menstruation [77]. Finally, menstrual iron loss in women has been shown to negatively correlate with serum Ferr, and iron status to significantly correlate with the duration and intensity of the menses in endurance athletes [19]. Taking into consideration the iron loss during menstruation along with the relative failure to achieve the daily RDI for iron the greater frequency of iron deficiency in female athletes can be justified.
Whether the increased uptake of iron through diet or supplements improves iron status in athletes is still under debate. This is mainly due to the great divergence of iron doses, intervention period, population, and exercise regimens used between studies. In situations of iron deficiency a proposed minimum therapeutic requirement corresponds to 100 mg/day of elemental iron, for a period of 12 weeks [17]. However, in several studies, much lower quantities of 20 - 50 mg/day of elemental iron for 12 weeks [10, 35] or smaller duration (of even two weeks) of iron supplementation have also been used and reported to be adequate to restore iron status to normal [78]. Table 3 summarizes the effects of iron supplementation on several indices of iron status.
A treatment with 100 mg/day of ferrous iron for 3 months, significantly increased the values of serum Ferr (from 34±11 to 54±18 μg/L) and liver iron (from 105±42 to 227±67 μg/g liver) [4]. In this study, 23 out of 45 athletes showed decreased baseline serum values (<35μg/L), and the typical iron deficiency in runners was confirmed in a subgroup of eight athletes in which iron metabolism was studied in detail using radio-iron labelling and liver iron quantification. These eight athletes showed up-regulated 59Fe absorption and a decreased liver iron concentration as compared to a control group. The results of the eight athletes confirm that in cases of true iron deficiency, iron absorption is greater.
A moderate dose of 39 mg/day of elemental iron for 5 weeks effectively prevented the negative changes of iron status over the course of a competitive season in female collegiate swimmers [35]. Absence of iron supplementation resulted in decreased Hb levels despite mean dietary iron intakes of 16.3 mg/day.
The ingestion of 105 mg/day of elemental iron combined with 500 mg of Vitamin C for 60 days resulted in the amelioration of iron status of previously iron-depleted, non-anemic elite female athletes [79]. The improved iron stores were reflected by the increase of Ferr in conjunction with the decrease of transferrin, sTfR and sTfR/log ferritin index.
Taken together the aforementioned results suggest that the initial stage of either iron sufficiency or iron deficiency, combined with the amount of iron ingested, plays a critical role in the absorption of iron from diet or supplementation.
Supplementation of iron is commonly used, not only in iron-deficient athletes, but also in athletes with normal iron status. The rationale behind this practice dictates that supplementation will preserve or enhance their performance. This concept is probably based on the catalytic role of iron on the oxygen transport and optimal function of oxidative enzymes and proteins during exercise. The hypothesis could be that with increased consumption of iron, the above mechanisms would be reinforced and exercise performance would be improved. Nevertheless, unlike the numerous studies addressing iron-deficient individuals, only few [25, 57, 63] have focused in iron-sufficient athletes.
The response of iron stores during a sports season was assessed in professional football players with normal iron stores at the beginning of the season [57]. The players consumed 50 mg/day of elemental iron over two periods during the training season. Supplementation took part for 15 days prior to the beginning of the season and 15 days during the middle season. Blood was collected three times during the season, one following the first supplementation period, another following the second supplementation period and a third time at the end of the season, where no iron supplementation had occurred. Ferritin, as well as calculated iron stores, showed a significant reduction at the end of the season which coincided with the absence of iron supplementation. In contrast, Ferr and iron store levels remained stable following supplementation regardless of the intensive training.
In another study, non-anemic, non-iron-deficient adolescent male and female swimmers aged 12-17 years old were either supplemented with 47 mg of elemental iron daily or consumed a diet rich in iron [25]. Both approaches failed to affect the athletes’ iron status. In that study, despite the significant fluctuations during the six months of training, iron levels, TS and Ferr levels were similar at the end of the study as compared to baseline values. The authors attributed the failure of high iron intake to affect iron status to homeostatic mechanisms such as iron absorption. It could also be suggested that the quantity of elemental iron was not enough to improve iron status and that higher doses of iron are needed to achieve a favorable change in iron status. The younger age and the possible higher demands in reference [25] compared with that of reference [57], may have influenced the absorption of iron that resulted in different responses in these two studies.
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
\n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t | |
Nachtigal et al. (1996) | \n\t\t\t100mg/d of elemental iron for 3 months, radio-iron labeling (59Fe) in 8 iron deficient athletes | \n\t\t\t45 runners (23 out of 45 were iron deficient, Ferr<35 μg /L), and controls | \n\t\t\tFerr, liver iron, iron absorption | \n\t\t\tFerr: ↑ from 34±11 to 54±18 μg/L; liver Fe: ↑from 105 ±42 to 227±67 μg/g liver | \n\t\t
Brigham et al. (1993) | \n\t\t\t39mg/d of elemental iron (IG) or placebo (PG) for 5 wks | \n\t\t\t25 female, iron depleted, varsity collegiate swimmers | \n\t\t\tHb, Ferr | \n\t\t\tHb:↑ in 24% of the subjects in the IG and in 12% in PG Ferr: ↑ in 68% of the subjects in the IG and in 4% in PG | \n\t\t
Pitsis et al. (2004) | \n\t\t\t105mg/d elemental iron + 500mg/d Vit C for 60 days | \n\t\t\t36 elite iron-depleted, non-anemic female athletes of several disciplines (13-26yo) | \n\t\t\tRed cell and reticulocyte parameters, Fe, Ferr, Tf, TS, sTfR | \n\t\t\tFerr: ↑; Tf: ↓; sTfR: ↓; sTfR/ log Ferr: ↓ Red cell and reticulocyte parameters: no changes | \n\t\t
Rowland et al. (1987) | \n\t\t\tEstimation of iron status during a competitive season; supplementation of iron in the iron deficient athletes (IG) in the midpoint of the season (the dose is not reported) | \n\t\t\t30 male and 20 female cross country runners (14.3-18.6yo) | \n\t\t\tFerr, Hb, RBC, MCV, RBCDW, | \n\t\t\tFerr: ↑in IG and ↓in untreated athletes at the end of the season; Hb, RBC, MCV, RBCDW: no changes | \n\t\t
Escanero et al. (1997) | \n\t\t\tVariation of iron metabolism through a season; 50mg of iron/day for the last 15 days at the beginning (A) and the middle of (B), but not at the end (C) the season | \n\t\t\t9 soccer players at the 1st division (24±2.1yo) | \n\t\t\tRBC, MCV, MCH, MCHC, Fe, Tf, Ferr, TIBC, TS | \n\t\t\tFerr, Iron stores: ↓at the end of the season (no iron supplement); remained stable at the beginning and the middle of the season (iron supplementation) | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t |
Friedmann et al. (2001) | \n\t\t\t2 x 100mg/d elemental iron (IG) or placebo (PG) for 12 wks; the usual training | \n\t\t\t40 iron depleted endurance athletes (13.6-21.1yo, Ferr < 20 ng/mL) IG: 20 males and females (PG: 20 females and 8 males 14.5 -17.5yo) | \n\t\t\tHematological indices, Fe, Ferr, Trf, TS, BV, PV, VO2, VCO2, VE, MAOD, LA | \n\t\t\tIG: VO2max, VO2, TTE: ↑; Ferr: ↑ 20.1μg/ L, Tf: ↓ PG: no changes | \n\t\t
Rowland et al. (1988) | \n\t\t\t975mg/day ferrous sulfate (IG) or placebo (PG) for 4 wks (time C), after a 4wk control period (time B) | \n\t\t\t14 iron-deficient (Ferr < 20ng/mL) female cross-country runners (high-school age) | \n\t\t\tTTE, HR, VO2max, VE, Hb, MCV, RBCDW, Ferr | \n\t\t\tTTE: ↑in both groups at time B, ↑ in IG and ↓in PG at time C; Ferr: ↓at time B in both groups, ↑at time C in IG; Hb, MCV, RBCDW: No changes in both groups | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t |
Peeling et al. (2007) | \n\t\t\tIntramuscular iron injections (5 x 2mL Ferrum H/day) (IG) or placebo for 20 days | \n\t\t\t16 iron depleted, female distance runners and controls | \n\t\t\tVO2max, HR, LA, run-TTE, 10min submaximal economy test, Ferr | \n\t\t\tFerr: ↑in IG; HR, LA, TTE: no differences between IG and PG | \n\t\t
Tsalis et al. (2004) | \n\t\t\t47mg/d (IG) or dietary plan rich in iron (DIG) or regular diet for 6 months (endurance training: 3m; power training: 2m; tapering: 1m) | \n\t\t\t21 males and 21 females, 12-17yo, non-anemic, non-iron-deficient | \n\t\t\tHematological indices; Fe, TIBC, TS, Ferr; swimming tests: 2000m, 800m, 200m and 25m sprint | \n\t\t\tFe, TIBC, TS, Ferr: fluctuations within the phases; At m6: no differences from baseline; RBC, Hb and PVC: ↑at m6; performance tests: similar ↑in all groups | \n\t\t
Klingshirn et al. (1992) | \n\t\t\t8wks of iron supplementation (IG), or placebo (PG) | \n\t\t\t18 iron depleted, female distance runners and controls, 22-39yo | \n\t\t\tVO2max, endurance run-TTE, LA, iron status | \n\t\t\tFerr, TIBC: ↑ in IG compared with PG at wk 8 Endurance performance, LA: similar ↑ both groups | \n\t\t
Powell & Tucker (1991) | \n\t\t\t130mg of elemental iron /day (IG) or placebo (PG), for 2wks; single blind design | \n\t\t\t10 female cross-country runners (20.2±1.3yo) with normal iron status | \n\t\t\tVO2max, CO2, RER, VE, Fe, TIBC, Ferr, Hp, Hb, Hct, MCHC, MCV, WCC, LA | \n\t\t\tHematological & iron status parameters: no significant changes; Metabolic parameters: no changes | \n\t\t
The effect of dietary or supplemented iron on exercise-induced changes of iron status and physical performance
VO2max: Maximal Oxygen Consumption, VCO2: Exhaled Carbon Dioxide, VE: Ventilation, MAOD: Maximal Accumulated Oxygen Deficit, TTE: Time to Exhaustion, HR: Heart Rate, CK: Creatine Kinase, LA: Lactate, Ferr: Ferritin, Fe: Iron, Tf: Transferrin, TS: Transferrin Saturation, sTfR: Soluble Transferrin Receptor, TIBC: Total Iron Binding Capacity, Hb: Haemoglobin, Hct: Hematocrit, PCV: Packed Cell Volume, MCHC: Mean Corpuscular Haemoglobin Concentration, BV: Blood volume, PV: Plasma Volume, MCV: Mean Corpuscular Volumes, RBC: Red Blood Cells Count, RBCDW: Red Blood Cell Distribution Width, WCC: White Cells Count, MAOD: Maximal Accumulated Oxygen Deficit
There is no doubt that iron-deficiency anemia, which amongst other indicators (e.g. Ferr<12μg/L, TS<16%), is characterized by a decline in blood Hb concentration, clearly impairs physical performance by limiting oxygen transport to exercising muscles [22]. However, the need for iron supplementation in cases of depleted iron stores without observed anemia for optimal physical performance is still under debate (Table 3). Some studies have shown that iron supplementation improved physical performance [23, 24], whereas others report no alterations following iron supplementation [25, 34, 63].
The improvement of iron status due to iron supplementation has been accompanied by an improvement in endurance capacity [23, 24]. In young elite athletes with normal Hb concentrations, the return of low Ferr to normal values following supplementation of 200 mg/day of elemental iron for 12 weeks, even in the absence of increased erythropoiesis, has been shown to improve maximal aerobic capacity [23].
Iron supplementation also prevented the decline in performance that was associated with the progressive reduction of serum Ferr levels [24]. Iron deficient cross-country female runners were treated with 975 mg/d of ferrous sulfate or placebo for 4 weeks. Iron supplementation resulted in an increase in ferritin levels which was accompanied by an improvement of physical performance. Subjects not receiving iron therapy exhibited a decline in their performance [24].
Besides the aforementioned positive results in exercise performance there are studies reporting no beneficial effects due to iron supplementation [25, 34, 63]. In reference [63], no significant improvement of iron status or metabolic parameters related to running performance was found after 2 weeks of 130 mg elemental iron supplementation in non-anemic, iron-deficient female cross-country runners. Likewise, in [34], 8 weeks of iron supplementation in iron-depleted, non-anemic female distance runners, resulted in similar improvement of the endurance capacity in the supplemented and the placebo group, despite the improved iron status in the iron-supplemented group. In another study, the injection of 2 mL of Ferrum H (100mg of elemental iron) five times daily for 10 days did not result in any beneficial outcomes on submaximal economy, VO2max and time to fatigue in non-anemic, iron-deficient female runners [33]. This study, failed to demonstrate any beneficial effect of iron supplementation on aerobic capacity, despite a significant rise in serum Ferr levels (from 19 to 65μg/L).
In one of the very few studies that used healthy, non-iron-depleted and non-anemic adolescent swimmers, the enhanced iron intake either through supplement or diet ranging from one to five times the RDA, did not change iron status or result in favorable changes of physical performance [25]. The authors attributed the observed fluctuations over the training period of six months to the different demands of each training phase irrespective of iron treatment. These observations strengthen the notion that the initial levels of iron status are of critical importance in the improvement of physical performance as a result of iron supplementation.
In [35], the mean dietary intake of 16.3 mg/day was not adequate to prevent the disturbance of iron status in female collegiate swimmers. Haemoglobin levels decreased at about 6 g/L in 44% of the athletes given placebo treatment, whereas the corresponding decrement in plasma Ferr was 5μg/L in 24% of the swimmers given the iron supplement. Consequently, the reductions in Hb and Ferr levels were lower in the athletes that were under iron supplementation.
Although the favorable effects of iron supplementation on physical capacity in iron-deficient anemic athletes has been well established, relatively little research has been conducted addressing iron-deficient non-anemic athletes. Therefore, further research is needed to clarify the necessity of iron supplementation in athletes with depleted iron stores, yet, normal Hb concentrations for improvement of their performance.
Despite the great importance of iron balance in athletes, no normative data for athletes exist and hence it is essential such norms are established. Such data would be more critical if appropriate discriminations were made, e.g. regarding the type of training (endurance or power-training athletes), sex, age, or seasonal demands and so on.
The commonly used parameters for the estimation of iron status in the general population (Hb, Hct, Ferr, iron concentration, TIBC, TS), may not always be adequately representative for athletes. Therefore, it would be useful if future studies incorporated additional parameters such as erythrocyte protoporphyrin, soluble transferrin receptor or haptoglobin, in order to get more accurate and complete estimation of iron status.
Iron is one of the most important elements for health and exercise performance. It is unclear whether iron intake by an athlete through diet is adequate in order to prevent iron balance disturbances and further research is needed to clarify dietary methods to prevent iron deficiency. It seems that exercise, acute or chronic, results in significant disturbances in iron balance due to different reasons. Changes in iron absorption and iron intake due to exercise, iron losses through the gastrointestinal tract, intravascular hemolysis, and to a lesser extent iron losses through sweat, are probable mechanisms for iron balance disturbances during exercise.
Alterations in iron status balance are reported as a result of exercise, especially in endurance trained, and women athletes. Iron-deficiency without anemia is a very commonly reported phenomenon among athletes, and occasionally iron deficiency anemia is also reported.
Iron balance is of great importance for optimal work capacity, and a compromise of iron status would have detrimental effects on physical performance in iron-depleted anemic athletes. In these situations, iron supplementation is required for restoration of iron levels and optimization of the athlete’s performance and health. However, similar effects have not been well documented for athletes that are iron-deficient without the presence of anemia. Nevertheless, iron supplementation among athletes is a very common practice, despite the discrepancy regarding its beneficial effects in non-anemic, iron-depleted, or even normal iron status athletes. This discrepancy is attributed to the divergence in iron doses, athletic population, and the great variance in the intervention period, and exercise regimens that are used between studies.
Because of the different demands in iron through the several phases of training or competitive periods, evaluation of iron status of the athletes should be performed at the beginning, at the midpoint, and finally at the end of the season. Controlled iron supplementation for all athletes with serum Ferr below 35µg/L is recommended for the replenishment of iron stores.
A new virus called the 2019 novel coronavirus (an enveloped beta-coronavirus) is identified in December 2019 and associated with a de novo contagious respiratory disease. The coronavirus disease 2019 (COVID-19) has been declared as a “pandemic” by the World Health Organization (WHO). Previous reports have recognized various human coronaviruses, like in 2003 SARS-CoV, in 2004 HCoVNL63, in 2005 HKU1, in 2012 MERS-CoV, and now in 2019 pathogenic SARS-CoV-2. In humans, the effects of these viruses are correlated with severe respiratory tract infections. COVID-19 disease has signs that are similar to a common cold. However, this infection can lead to serious respiratory failure, as well as compromised and harmful immune responses. Increased monocyte-neutrophil ratios and exacerbated release of inflammatory mediators particularly IL-6, characterize this condition, which can contribute to organ dysfunction. Given the fact that other coronavirus outbreaks have occurred, there is no known treatment or vaccination for COVID-19.
Another major problem is the urgent need for easy and fast instruments to detect viruses in clinical and environmental samples. Early identification of SARS-CoV-2 in asymptomatic and/or presymptomatic individuals is crucial for stopping the transmission chain [1]. Plasmapheresis is also essential for extracorporeal removal of SARS-CoV-2 from blood in order to present alternative therapies. These dynamic pictures have imposed a fight against time through numerous fields of knowledge such as biomedical research, biotechnology, drug production, and molecular analysis in order to find as many resolutions as possible to these and other complications presented by the pandemic.
Viral members of the CoVs family restrain a positive-sense, single-strand RNA genome, which are 26 to 32- kilo bases in length [1]. The infectivity and immeasurable distribution capacity of CoVs have been established them as an important pathogen. In addition to numerous avian hosts, various members of CoVs have been recognized in a range of mammals, like masked palm civets, bats, dogs, mice, camels, and cats are responsible for disease related to gastrointestinal systems, hepatic, respiratory, and nervous system in humans. The outer surface membrane (M), envelope (E), and spike (S) structural proteins are coupled within the envelope of coronavirus which consists of a lipid bilayer. It is believed that glycosylated SARS-CoV-2 spike (S) protein, mediates host cell entry by binding to the angiotensin- converting enzyme 2 (ACE2) and establish the host tropism. Similar to many other viral fusion proteins, the SARS-CoV-2 spikes also utilize a highly dense coating of non-immunogenic or weakly immunogenic complex carbohydrates - glycan shield to thwart the host immune response [2]. Glycans are carbohydrate-based polymers made by all living organisms. The heavily glycosylated SARS-CoV spike protein suppresses almost 23 putative
The glycan shield plays a crucial role in concealing the surface S protein from molecular recognition. However, to effectively perform, the spike has to acknowledge and bind to ACE2 receptors as the primary infection route. For this reason, the RBM should become absolutely exposed and accessible. During this situation, the glycan shield works as one with an outsized conformational modification that permits the RBD to emerge higher than the N-glycan coverage. Each the S-glycoprotein and ACE2 receptor are proverbial to be extensively glycosylated, i.e. they contain covalently linked complex oligosaccharides referred to as glycans. Recently published studies have shown that the spike glycoprotein contains sixty-six glycosylation sites with forty-four of them being enclosed within the model. Another recent study analyzed site-specific N-linked glycosylation of MERS and respiratory illness SARS S glycoproteins, indicating that every of those glycosylation sites is occupied by up to 10 totally different glycans (called glycoforms), which greatly extends epitope diversity [4, 5].
The synthesis, folding, and glycosylation (as alternative PTMs) of infectious agent proteins depend upon host organelles (ribosome, endoplasmic reticulum, and Golgi apparatus) and enzymes (glycosyltransferases and glycosidases). The present experimental knowledge relating to the glycosylation of viral proteins depends on the carbohydrate processing enzymes present within the biological systems accustomed to propagate the viral strain. During this sense, our data regarding the natural pattern of viral protein glycosylation is incredibly restricted. It’s conjointly vital to think that viral proteins could follow totally different pathways than those discovered from host glycoproteins [5, 6]. Attribute to their chemical complexity and restricted sensitivity of existing analytical instruments, glycans are left neglected. This can be unfortunate as they verify a major part of the structure and performance of the many glycoproteins. This can be very true within the field of host/pathogen interactions, wherever glycan diversity is employed by each host to evade recognition by pathogens and therefore the pathogens to flee the system response. Moreover, glycans, and specifically their outmost components, have vital conformational flexibility. This contributes to the overall conformational dynamics of the molecule that may each generate novel potential drug binding sites or shield binding sites predicted mainly from polypeptide-only models [7].
Beyond a function in shielding the underlying proteins from recognition by antibodies, the glycans on infective proteins may additionally attenuate the flexibility of the host system to lift antibodies against any epitopes that embrace the glycan. In an exceedingly T-cell-dependent adaptative immune reaction, peptides from the infective agent are presented on antigen- presenting cells by major histocompatibility complex II molecules, conjointly referred to as human leukocyte antigen (HLA) complexes. HLA complexes have the most popular peptide antigen motifs, and supported data of those preferences it’s doable to predict that peptides in exceedingly infective proteins are probably to be HLA antigens [8]. However, once that peptide contains a glycosylation site, the probability of the peptide to be presented in an HLA complex could also be compromised, if as an example the peptide cannot bind to the HLA molecule owing to the steric presence of the glycan. However, glycopeptides could also be presented in HLA complexes if the glycan is compact enough or if it’s found on the end of the peptide antigen wherever it does not interfere with HLA binding. The glycan-mediated shielding of predicted HLA antigens derived from the S glycoprotein is conjointly containing a glycosite. Glycosylation systematically decreases the surface exposure of the residues proximal to the glycosites however conjointly junction rectifier to non-sequential changes in exposure, as a result of the 3D topology of the protein surface within the close proximity of every glycosite [8, 9].
The SARS-CoV-2 envelope glycoproteins are involved in the viral adhesion and entry processes. The presence of glycoproteins in the viral envelope opens up a world of possibilities for using carbohydrate-binding agents like lectins to fix some of the pandemic’s most pressing issues. Lectins can recognize glycans, allowing them to be used in a number of biotechnological applications. The presence of glycoproteins on the viral envelope unfolds a large vary of prospects for the application of lectins to deal with some urgent issues concerned during this pandemic. The growing popularity of glycans enables the use of lectins for many biotechnological applications. Significantly, these agglutinins block the viral adhesion to the host cells by targeting the sugar moieties in surface proteins, and are considered as broad-spectrum inhibitors of viral invasion. The interaction with glycoproteins conjointly allows the use of lectins within the development of devices for identification and characterization of glycoproteins in a viral envelope or alterations in host glycoproteins throughout virus infection. Lectins are natural proteins that focus on the sugar moieties of a large vary of glycoproteins [10]. They are prevailing among higher plants and are divided into seven families of structurally and evolutionarily connected proteins. Over a decade ago, studies revealed that through inhibition of virus-cell fusion, plant lectins were reportable to inhibit HIV replication in lymphocyte cell cultures [9].
Sugar-binding proteins that are neither antibodies nor enzymes are known as lectins. To be labeled as a lectin, a glycoprotein must meet three distinct criteria. To begin, lectin is a carbohydrate-binding protein or glycoprotein (s). Second, lectins aren’t the same as immunoglobulins (antibodies). Finally, lectins do not alter the biochemistry of the carbohydrates they bind. Plant lectins are a specific type of carbohydrate-binding proteins which are capable of specific recognition and reversible binding to carbohydrates. Since lectins can recognize specific carbohydrate structures such as proteoglycans, glycoproteins, and glycolipids, they can control various cells through glycoconjugates and their physiological and pathological phenomena via host-pathogen interactions and cell–cell communications.
Initially, it had been reported that plant lectins inhibit virus replication by forestalling virus adsorption however studies had been later shown that they prevent the fusion of HIV particles with their target cells. Additionally to the antiviral impact of mannose- and N-acetylglucosamine-specific agglutinins on HIV, the associate repressive impact of those plant lectins was reported on respiratory syncytial viral infection, CMV infection, and influenza A virus infection in vitro. Carbohydrate-binding agents are thought of as anti-CoV agents that focus on spike protein and restrain CoV entry [10]. They’re proficient to bind specifically with the oligosaccharides on virus surfaces like HIV and S glycoprotein. In mouse model and additionally, in vitro condition they inhibit a large variety of CoVs, as well as SARS-CoV, HCoV NL63, HCoV 229E, and HCoV OC43. Plant lectins, such as those present in leeks, have been shown to be effective coronavirus inhibitors by interacting with two targets in the viral replication cycle. The first target was discovered early in the replication cycle, most likely during viral attachment, while the second was discovered toward the end of the infectious virus cycle. Depending on the nature of their sugar specificity, the antiviral activity spectrum of plant lectins varies considerably. In general, the plant lectins which were mannose-specific found to be highly effective against coronaviruses. Mannose-binding glycoprotein (MBL; additionally called mannan-binding lectin) could be a pattern-recognition molecule that plays a critical role in spacing and orientation of the carbohydrate-recognition domains [2, 10].
In several expression systems, glycosylation act as a live to gauge antigen quality. For styling appropriate immunogens for vaccine development, it is important to have basic understanding concomitant with the RBD domain of the SARS-CoV-2 spike protein which is able to incorporate complicated sialylated N-glycans and sialylated glycoprotein O-glycans. The interaction with glycoproteins additionally permits the utilization of lectins within the development of devices for the identification and characterization of glycoproteins in infectious agent envelopes or alterations in host glycoproteins throughout virus infection. MBL could be a serum C-type glycoprotein, that is in a position to bind SARS-CoV intrinsically or infected cell and additionally capable to inhibit the infectivity of the virus. Hence, with this background knowledge, we could to anticipate that glycosylation of infectious agent peptides by “Lock and Key Technology” may be considerate as a novel therapeutic strategy against the current COVID-19 pandemic (Figure 1) [2, 10, 11].
Potential role of MBL in prevention of SARS-CoV2. 1. Attachment of MBL at the glycosylation site of spike protein by “Lock and Key” mode. 2. Prevent ACE2 mediated entry of viral pathogen. 3. Lectin pathway-mediated phagocytosis of intracellular pathogens (adapted from reference [
The “glycome biology” or “glycobiology” studies the thorough repertoire i.e. the structure, biosynthesis, and biology of glycoconjugates composed of carbohydrate chains, or glycans, which are covalently, linked to lipid or protein molecules. The formation of glycoconjugates, differences in their glycan sequences, their length, and the connection between them depends upon on a process called glycosylation. Synthesis of glycoconjugate is a dynamic process that relies on the sugar precursors, the local milieu of enzymes, structures of organelle as well as cellular signals, and the cell types. Studies of rare genetic disorders that have an effect on glycosylation 1st highlighted the biological importance of the glycome, and technological advances have improved our understanding of its heterogeneousness and quality. However the replication process of secreted and cell-surface glycomes, overall cellular standing in health and sickness requires a detail research and assessment. In fact, changes in glycosylation will modulate inflammatory responses, alter viral immune escape, promote neoplastic cell metastasis, or regulate apoptosis; the composition of the glycome conjointly affects urinary organ operate in health and sickness. Easy and extremely dynamic protein-bound glycans also are well endowed within the nucleus and living substance of cells, wherever they exert restrictive effects. In fact, additionally to forming vital structural options, the sugar elements of glycoconjugates modulate or mediate a good form of functions in physiological and pathophysiological states. Glycoproteins and polysaccharides have vital functions in viral cells, and even glycoproteins have central roles within the biology of most viruses [10, 12]. Glycoconjugates are measured by the addition of sugars to proteins and lipids. A huge range of naturally occurring sugars will be combined to make a variety of distinctive glycan structures on lipid and protein molecules that modulate their activity. Multiple enzymatic site preferences, similarly because the use of stereochemical α or β conjugations, produce diversity in wherever and the way these sugars are linked to every alternative. In fact, altogether, these options imply the potential existence of ~1012 completely different branched glycan structures.
Protein glycosylation includes the addition of N-linked glycans, O-linked glycans, phosphorylated glycans, glycosaminoglycans, and glycosylphosphatidylinositol (GPI) anchors to amide backbones similarly to C-mannosylation of essential amino acid residues. Glycolipids are glycoconjugate which include glycosphingolipids (GSLs) formed through the addition of sugars to lipids. Glycosylation of proteins and lipids happens within the endoplasmic reticulum (ER) and with most of the terminal processing occurring within the cis-, medial- and trans-Golgi compartments. In these organelles, glycosidases, and glycosyltransferases form carbohydrate structures in a series of steps that are dominance by the availability of the enzyme activity, substrate, levels of gene transcription, and enzyme location. In fact, the glycome of a specific cell reflects its distinctive gene-expression pattern that controls the level of the enzymes responsible for glycoconjugation. The glycome is created in a non-templated manner and is in an elaborate way controlled at multiple levels within the ER and cyst, unlike exome or proteome [12, 13].
The covalently N-linked glycans are superimposed co-translationally to native polypeptides within the endoplasmic reticulum (ER) as blocks of fourteen sugars (Glc3Man9GlcNAc2). These glycans are measure then subject to extensive modification throughout their transport through the ER and also the Golgi body before reaching their final destinations within or outside the cell. Within the ER and also the early secretory pathway, the sugar repertoire is still very little. Within the Golgi body, however, the glycans acquire complicated and extremely numerous structures by terminal glycosylation, which ends up in a very tremendous heterogeneity. Such diversity differs between cell sorts, tissues and species, and helps to additional increase microheterogeneity in the presence of the same genetic polypeptide background. This leads to the creation of new functionalities and specificities. The N-glycans may also have a very important role in correct macromolecule folding and degradation, and solubility, by avoiding the precipitation that’s caused by lipophylic aminoacid stretches within the emergent polypeptide. The presence of a glycan protect on the peptides additionally allows the protection of the glycoproteins against degradation by proteases [13, 14].
Glycosylation will occur on amino acids with functional hydroxyl group teams, that is most frequently Ser and Thr. In humans, the foremost common sugars joined to Ser or Thr are GlcNAc and N-acetylgalactosamine (GalNAc)7. GalNAc-linked glycans usually referred to as mucin-type O-glycans, are abundant on various living things and secreted glycoproteins together with mucins, which type an important interface between animal tissue cells and the external tissue layer surfaces of the body. Mucins are characterized by a variable range of tandem repeats with Ser and Thr that create many sites for O-glycosylation. O-glycosylation performs various functions, such as providing resistance to proteolysis of stem regions of membrane proteins, creating specific recognition phenomena, and selection of ligands for selectins. Masking of immunogenic epitopes on the protein is in need to special mention [13, 14].
GSLs comprise a sphingolipid to which a glycan is connected at the C1 group position of a ceramide; they are one in every of the foremost plentiful glycolipids in humans are generally found within the lipid bilayers of cellular membranes. GSL glycosylation starts with the addition of glucose or galactose to the lipid moiety at the protoplasm facet of the ER or the Golgi body; however, the structure is then flipped to the luminal side for the additional process. The enzymes that initiate GSL glycosylation are specific for lipids, but an additional process of the sugar chain is performed by additional general glycosyltransferase [13, 14].
Proteoglycans are glycoproteins within the extracellular matrix that, in addition to containing canonical N-glycans and O-glycans, are characterized by the presence of long sugar repeats connected via O-linked glycosylation motifs [13, 14]. These extended sugar chains are termed glycosaminoglycans and contribute to a considerable proportion of the proteoglycan’s molecular mass. Whereas N-glycans generally embrace 5–12 monosaccharides, a glycosaminoglycan motif will simply contain more than eighty sugars (for example, keratan salt is a poly-N-acetyl lactosamine chain that contains up to fifty oligosaccharide units). These long chains are constructed through oligosaccharide repeats fashioned by GlcNAc or GalNAc, combined with associate uronic acid (that is, glucuronic or iduronic acid) or brain sugar. Glycosaminoglycans are functionally various and include heparan salt, chondroitin salt, keratin sulfate, and hyaluronan. Glycosaminoglycans are crucial to the formation of the glycocalyx, an important structure for the upkeep of the cytomembrane that conjointly functions as a reservoir for sequestered growth factors [13, 14, 15].
Cells of the immune system, equally to any or all different cells, express cell surface-associated glycoproteins and glycolipids that, besides glycan-binding proteins and different molecules, sense environmental signals. Many immune receptors that are expressed on innate and adaptive immune cells acknowledge glycans found on the surface of microorganisms that are referred to as pathogen-associated molecular patterns. Examples of such glycan-containing molecules embrace bacterial lipopolysaccharides, peptidoglycans, teichoic acids, capsular polysaccharides, and fungal mannans. The recognition of those glycosylated microbial patterns by the immune system has been exploited for the vaccine’s development, example diplococcus vaccines, are developed employing a mixture of capsular polysaccharides. The recent progress in HIV-1 immunogen development has conjointly been driven by a far better understanding of the HIV-1 envelope (Env) conjugated protein and the effects of its glycan composition on immune responses and immune evasion [15, 16].
Pro-inflammatory cytokines may contribute to inflammatory vascular diseases by inducing changes in cell-surface N-glycosylation of epithelial tissue cells. In the adaptive immune system, glycans even have crucial and multifarious roles in B lymphocyte and lymphocyte differentiation. These functions involve multiple cell-surface and secreted proteins (such as CD43, CD45, selectins, galectins, and siglecs), differing kinds of cell–cell interactions, and also the recognition of glycan-containing antigens. The regulation of cellular glycosylation and its impact on the molecules that perform as ligands and receptors throughout associate inflammatory response is controlled through numerous mechanisms and is dependent on the inflammatory insult. These mechanisms, that embrace ERK, and p65 signaling are vital to understanding the failure to regulate chronic inflammation in multiple disease states. Immunoglobulins, for instance, are crucial parts of humoral immunity, and altered glycosylation patterns of some antibody isotypes are known in chronic inflammatory reaction, and infectious diseases, like arthritis (RA), systemic lupus erythematosus (SLE), and HIV infection [16, 17].
The glycoproteins CD43 and CD45 are profusely expressed on the surface of B cells and T cells and contain each O-glycans and N-glycans. Glycosylation of those proteins is modulated throughout cellular differentiation and activation and regulates multiple T cell functions, as well as cellular migration, T cell receptor signaling, cell survival, and apoptosis. CD45 has an active receptor-like protein tyrosine phosphatase domain that interacts with Src family kinases in B cells and T cells to control the signaling threshold for the activation of B lymphocyte receptors (BCRs) and T cell receptors. CD45 additionally has non-catalytic functions, for instance, in modulating the function of the repressive co-receptor CD22 on B cells [17, 18].
Siglecs are sialic acid-binding proteins expressed on several cells of the system that perform varied functions, as well as the regulation of antigen-specific immune responses and cell homing. CD22 is one in all sixteen siglec proteins characterized in humans and is expressed on B cells, wherever it specifically binds α-2, 6-linked sialic acid-containing ligands; this interaction is crucial for the formation of nanoclusters within the cell wall that manage BCR signaling following antigen binding [17, 18].
The selectin family of proteins consists of E-selectin, P-selectin, and L-selectin that are chiefly expressed on epithelium cells, platelets, and leukocytes, respectively. These cell adhesion molecules are vital for white cells rolling on the epithelial tissue before tissue extravasations. Another study demonstrates that targeting selectins could be helpful in some inflammatory diseases. Immunoglobulin isotypes disagree within the variety of N-glycans present on their serious chains. Some immunoglobulin, such as IgA1 and immune globulin, additionally contain O-glycans, which are sometimes clustered within the hinge-region segments of these antibodies. Immunoglobulin glycans impact the effect or functions of antibodies counting on the branching of N-glycans and/or the terminal sugars of N-glycans or O-glycans that embody brain sugar and sialic acid. In fact, immunoglobulin glycosylation can verify glycoform is pro-inflammatory, like Ig with galactose-deficient N-glycans, or anti-inflammatory drug, like Ig with sialylated N-glycans [17, 18, 19].
Coronavirus illness 2019 (Covid-19) has a broad clinical spectrum, not nevertheless absolutely delineate or understood, with a regarding the potential for severe respiratory illness, multiorgan involvement, and death. As a result of containment of the virus has verified to be very troublesome, mitigation efforts like mask-wearing, physical distancing, confinement, and quarantines are enforced worldwide leading to restricted exposures/contagious events with also a robust social, health, and economic burden [2]. Since ideal preventive ways like repurposing of known medication to treat Covid-19, and vaccines associated with inevitably long testing, development, and producing time emerges as an attractive approach to timely fulfill the continued need.
Glycoproteins of SARS-CoV-2 are concerned with cell adhesion and invasion, maturation, and modulation response processes. Though alternative SARS-CoV-2 proteins have foreseeable glycosylation sites (such as M-protein, E-protein), the bulk of experimental knowledge is presently accessible on the S-protein. This might be a trimeric protein that mediates viral adhesion through binding to the human angiotensin-converting accelerator two (hACE2) and conjointly interacts with the host immune defense [19, 20].
The S-protein from SARS-CoV-2 has 2 practical subunits (S1 and S2) with 23 potential sites for N-glycosylation and O-glycosylation. Some variations within the glycosylation sites repertoire and famed epitopes are rumored for the SARS-CoV-2 spike protein, despite it’s similarity with the SARS-CoV spike (approximately 87.2%). The oligo mannose-type glycans were predominant in 2 sites (N234 and N709). Complex-type glycans were preponderantly exhibited in fourteen organic compound residues (N17, N74, N149, N165, N282, N331, N343, N616, N657, N1098, N1134, N1158, N1173, and N1194), whereas six sites showed a combination of oligomannose- and complex-type glycans (N1074, N801, N717, N603, N122, and N61). The foremost common configuration of oligomannose-type glycans was Man5GlcNAc2. Afucosylated and fucosylated hybrid-type glycans were detected in a minimum of 9 sites. Studies highlighted that the glycosylation profile of the SARS-CoV-2 S-protein was completely different from those discovered for host glycoproteins or for alternative engulfed viruses. Another experimental study revealed the configuration of the N-glycosylation and O-glycosylation of spike protein subunits, even in the HEK293-based expression system. The authors have solved the structures of N-linked glycans in seventeen foretold sites and rumored the presence of three categories of N-glycans. Significantly, this study discovered O-glycosylation modifications on 2 residues (Thr323 and Ser325) present within the receptor-binding domain (RBD) of the S1 monetary unit. Recently, the characterization of the glycosylation profile of the S-protein expressed in BTI-Tn-5B1–4 insect cells was rumored to show the presence of high-mannose N-glycans altogether twenty two foretold sites. Apparently, these glycans cowl most of the RBD space [17, 20].
The glycan shield plays a vital role in hiding the S protein surface from molecular recognition. However, to effectively operate, the spike has to recognize and bind to ACE2 receptors as the primary host cell infection route. For this reason, the RBM should become totally exposed and accessible. During this state of affairs, the glycan shield works in concert with an oversized conformational amendment that permits the RBD to emerge on top of the N-glycan coverage. The glycans protect the RBD region that does not directly act with ACE2 by “up” and “down” conformations. Ultimately, this analysis shows that the RBM is often accessible once RBD is “up”, whereas it’s terribly well camouflaged when “down”. This implies that the glycan shield of this vital domain is effectively paired with its “down-to-up” conformational amendment, allowing the RBM to transiently emerge from the glycan shield and bind to ACE2 receptors [16, 19, 20].
Protein glycosylation plays a crucial role in the infective agent pathological process, as incontestable by the characteristically thick N-glycan coating of the infective agent fusion proteins. Within the HIV-1 envelope spike (Env), as an example, the protein-accessible expanse is nearly entirely coated in N-glycans. These are thus densely packed that they account for quite half the protein’s mass. The N-glycans present on the surface of viral envelope glycoproteins show terribly diverse type of biological roles. Infective agent entry through membrane fusion is initiated by envelope glycoproteins through molecular recognition events involving cell surface receptors, which are usually mediated by specific N-glycan epitopes. Furthermore, an extremely dense coating of nonimmunogenic or frail immunogenic advanced carbohydrates on otherwise perilously exposed infective agent proteins constitutes a perfect camouflage (or shield) to evade the immune system. To the current study, the HIV-1 Env glycan defends, which is essentially structured by oligomannose (Man5–9) N-glycans, has been shown to be quite effective in allowing the virus to thwart the system [16, 17, 19].
Developments within the field of glycobiology have enabled the development of a range of glycan-based medical specialties. As an example, envelope conjugated protein gp120 is expressed on the surface of HIV-1, and its variable glycosylation facilitates viral escape from immune detection. Adding new glycan-dependent epitopes to the recombinant gp120 used for vaccination inflated the ability of broadly speaking neutralizing being antibodies to recognize HIV-1, suggesting that this approach is used to optimize vaccination protocols and antigens. Moreover, HIV-1 envelope glycoproteins not solely differentiate HIV-1 clad however can even be wont to estimate the efficacy of vaccine regimens on the premise of protein binding to a panel of gp120 glycan-dependent epitopes 240. As printed antecedently, glycosylation plays an important role in regulating purposeful immune responses through complex receptor–glycan motif interactions. This site is currently being exploited in Ig therapies [20].
Lectins, are glycan-binding proteins (GBPs) that are present in plants and lots of alternative species, are known to act with various glycan molecules either attached or released to a peptide backbone. This distinctive property has been explored within the development of analytics for glycan determination. Many relevant platforms are according to which lectin-based microarray has incontestable a utility in capturing glycan profiles of therapeutic compound glycoprotein [21].
As antecedently mentioned, the S-protein of SARS-CoV-2 encompasses a crucial role in infectious agent adhesion by binding to hACE2. Therefore, the disruption of this interaction is taken into account as a gorgeous target for antiviral medical care. Some non-mammalian-derived lectins (from plants and bacteria) are pointed as various antiviral agents against swallowed viruses thanks to their ability to acknowledge the glycans present within the structural proteins and to impair the initial steps of the infectious agent pathological process. Given the recent emergence of SARS-CoV-2, solely the glycoprotein isolated from Indian bean [Flt3 receptor-interacting glycoprotein (FRIL)] has been according up to now as an antiviral against this virus. FRIL may be a glucose/mannose glycoprotein conjointly called DLL-I. This protein molecule utterly inhibited the cytopathic result of SARS-CoV-2 (strain hCoV-19/Taiwan/NTU04/2020) toward Vero cells at higher concentrations [17, 21].
According to a study, evaluation of the in vitro antiviral activity of thirty three plant lectins toward coronaviruses (SARS-CoV and feline infectious redness virus). Mannose-binding agglutinins showed the best anti-SARS-CoV effects. Among the studied lectins, the upper selective indexes (SIs) were found for those isolated from alliaceous plant (APA; SI > 222.2), black mulberry (Morniga M II; SI > 62.5), and helleborine (EHA; SI > 55.5). Nettle (UDA) and common tobacco agglutinins (NICTABA), each specific for GlcNAc, conjointly showed promising activity. NICTABA and FTO have conjointly shown restrictive activity against different swallowed viruses as well as respiratory disease A/B, breakbone fever virus kind a pair of (DENV-2), herpes simplex virus varieties one and a pair of (HSV-1 and HSV-2) and human immunological disorder viruses (HIV-1/2). Other plant lectins are shown to exhibit restrictive action toward different coronaviruses. Some mannose-binding lectins: concanavalin A (Con A), amaryllis hybrid antibody (HHA),
Crystal structure of different mannose specific lectins (structures adapted from RCSB PDB).
Non-plant-derived agglutinins also are pointed as promising agents against coronaviruses, e.g. the mannose-binding-lectins cyanovirin-N (from
The mitogenicity and pro-inflammatory properties of lectins raise many queries relating to their worth to treat clinical conditions with severe inflammatory elements, as seen in COVID-19. The broad-spectrum activity of those agents and therefore the techniques utilized in their style ought to be thought of within the hunt for anti-infective compounds toward SARS-CoV-2. These compounds ought to enhance the response iatrogenic by the immunogen, whereas keeping the equilibrium between body substance and cellular immune responses. Noteworthy to say that even the right induction of Th1-biased response, which is very important for defense against infectious agents, still remains a limitation for a few adjuvants.
Lectins are well-known to push the proliferation of lymphocytes and modulate the discharge of effectors molecules (cytokines and gas oxide) by immune cells. For example, many lectins are potent inducers of IL-12 and IFN-γ production that are key cytokines in the establishment of the Th1 axis. Some lectins may also bind to toll-like receptors and/or increase their expression levels, which can conjointly modulate the discharge of pro-inflammatory cytokines and increase the receptor’s ability to acknowledge the pathogens. In fact, the improvement of Th1-based response is very important for protecting immunity against viruses and different intracellular pathogens thanks to the activation of cytotoxic cells (natural killer cells and TCD8 lymphocytes) and production of neutralizing antibodies concerned in immunologic memory. During this sense, the immunomodulatory properties of lectins build them attractive candidates for vaccine adjuvant. Some studies involving glycoprotein as an adjuvant for respiratory disease vaccines need special mention [21].
Innate immunity plays an essential role against numerous pathogens, in that, physical barriers complement components, coagulation cascade, antigen-presenting cells, and immunoglobulins synergistically regulate opsonisation, inflammation, and phagocytosis. Although the innate system might not determine each antigen getting into the host, it will acknowledge numerous microorganisms mainly based on pathogen-associated molecular patterns (PAMPs) present on the cell surface. The notable examples of PAMPs are bacterial peptidoglycan, lipopolysaccharides, mannans, lipoteichoic acids, bacterial DNA, double-stranded ribonucleic acid, glucans, and infective agent surface macromolecule. Duly, the complement system could be a wing of an innate immune response having varied biological effects against a good vary of bacteria, fungal, and infective agent infections [22].
The complement cascade consists of soluble factors and cell surface receptors which will sensitize and counteract against both invading and self-antigens. The complement system bridges the innate and accommodative reaction through humoral immunity, and by modulating T- and B-cell functions. Complement pathways, which, once activated, lead to consecutive protein reactions, breakdown of complement components C3 and C5, and end in by-products formation (C3a and C5a). These anaphylatoxins elicit an excessiveness of physiochemical responses that successively activate phagocytic cells, and release cytokines, chemokines, reactive element species (ROS), adhesion molecules, and inflammation at the site of infection. Immunoglobulin and cytokines are essential parts of antiviral immunity. In fact, there are 3 main phases of complement activation - (1) foreign molecule recognition, (2) convertase enzyme formation which will cleave C3 and C5, and (3) fabrication of MAC for cell lysis. The alternative, classical, and mannose-binding lectin (MBL) pathways are activation cascades of assorted host-pathogen interaction conditions, joining at the juncture C3, from wherever the central complement cascade proceeds. Among the 3 pathways of complement activation, the MBL pathway is primary in infective agent infections to induce a pro-inflammatory response. Detail Investigations involving the complement system activation by the lectin pathway in COVID-19 and diseases are in need of the hour [22, 23].
Glycosylation could be a common modification of proteins and lipids that involves non-template dynamic and complex processes. Glycans have multiple crucial roles in cellular responses to environmental stimuli likewise as cellular growth and differentiation; specific changes in glycan composition are directly joined to several diseases. Technological advances are commencing to overcome many of the challenges display by the complexities of glycoconjugates, improving our understanding of the physiological and pathological processes that are regulated by glycans.
The application of lectins to unravel differing types of issues involved in viral infections like COVID-19 depends upon the presence of glycoproteins within the viral envelope. Within the therapeutic space, the lectins can be thought-about leading molecules for the event of the latest antiviral approaches because of their ability to inhibit microorganism entry within the host cell. The advances in glycoprotein style methods are necessary to spice up the clinical application of those agents thought-about for the treatment of SARS-CoV-2 and alternative microorganism infections. The immunomodulatory action of some lectins may also be exploited to boost the effectiveness of immunization schemes for microorganism infections.
On the opposite hand, lectin–carbohydrates interactions will be accustomed style devices for diagnosing targeting microorganism glycoproteins or host glycoproteins alterations throughout microorganism infections. This kind of apparatuses hold the promise of producing sensitive, quick, and cost-effective identification of infected people and are of important would like throughout the pandemic things, as obligatory for COVID-19.
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',metaTitle:"Horizon 2020 Compliance",metaDescription:"General requirements for Open Access to Horizon 2020 research project outputs are found within Guidelines on Open Access to Scientific Publication and Research Data in Horizon 2020. The guidelines, in their simplest form, state that if you are a Horizon 2020 recipient, you must ensure open access to your scientific publications by enabling them to be downloaded, printed and read online. Additionally, said publications must be peer reviewed. ",metaKeywords:null,canonicalURL:null,contentRaw:'[{"type":"htmlEditorComponent","content":"Publishing with IntechOpen means that your scientific publications already meet these basic requirements. It also means that through our utilization of open licensing, our publications are also able to be copied, shared, searched, linked, crawled, and mined for text and data, optimizing our authors' compliance as suggested by the European Commission.
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\n\nMetadata for all publications is also automatically deposited in IntechOpen's OAI repository, making them available through the Open Access Infrastructure for Research in Europe's (OpenAIRE) search interface further establishing our compliance.
\n\nIn other words, publishing with IntechOpen guarantees compliance.
\n\nRead more about Open Access in Horizon 2020 here.
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I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. 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After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:{name:"Semenov Institute of Chemical Physics",country:{name:"Russia"}}},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). He is the member of many Pharmaceutical Associations and acts as a reviewer of scientific journals and European projects under different research areas such as: drug delivery systems, nanotechnology and pharmaceutical biotechnology. Dr. Sezer is the author of many scientific publications in peer-reviewed journals and poster communications. Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"61051",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100762",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"St David's Medical Center",country:{name:"United States of America"}}},{id:"107416",title:"Dr.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Texas Cardiac Arrhythmia",country:{name:"United States of America"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. 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I am a Reviewer for several refereed journals and international conferences, such as IEEE Transactions on Biomedical Engineering, IEEE Transactions on Industrial Electronics, Optic Letters, Measurement Science Review, and also a member of the International Advisory Committee for 2012 IEEE Business Engineering and Industrial Applications and 2012 IEEE Symposium on Business, Engineering and Industrial Applications.",institutionString:null,institution:{name:"Joseph Fourier University",country:{name:"France"}}},{id:"55578",title:"Dr.",name:"Antonio",middleName:null,surname:"Jurado-Navas",slug:"antonio-jurado-navas",fullName:"Antonio Jurado-Navas",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",biography:"Antonio Jurado-Navas received the M.S. degree (2002) and the Ph.D. degree (2009) in Telecommunication Engineering, both from the University of Málaga (Spain). 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As a result, an attempt has been made in this work to investigate hydrogen synthesis and utilization in fuel cell vehicles. Low-temperature combustion technology has recently been applied in engine technology to reduce smoke and NOx emissions at the same time. The advantages and limitations of homogeneous charge compression ignition, partially premixed charge compression ignition, premixed charge compression ignition, and reactivity regulated compression ignition are described separately in low-temperature combustion strategy.",book:{id:"11164",title:"Diesel Engines and Biodiesel Engines Technologies",coverURL:"https://cdn.intechopen.com/books/images_new/11164.jpg"},signatures:"Babu Dharmalingam, Ramakrishna Reddy Ramireddy, Santhoshkumar Annamalai, Malinee Sriariyanun, Deepakkumar Rajagopal and Venkata Ramana Katla"},{id:"82176",title:"Replacement of Diesel Fuel by DME in Compression Ignition Engines: Case for India",slug:"replacement-of-diesel-fuel-by-dme-in-compression-ignition-engines-case-for-india",totalDownloads:14,totalDimensionsCites:0,doi:"10.5772/intechopen.104969",abstract:"Decarbonising of transport, industrial and all sectors of economy is a necessity to stop or reverse global warming. Use of batteries, fuel-cells, hybrid topographies with smaller IC engines and use of alternative fuels like methanol, ethanol, DME in the IC engines are some of the ways through which emission of green-house gases can reduced/eliminated. Diesel engines are highly efficient due to higher compression ratios and are used in the heavy-duty transportation vehicles. DME is a single molecule fuel having high cetane number and which can be used as a drop-in fuel on the diesel engines albeit with retro-fitment of these engines with a new pressurized fuel system. DME with a chemical formula CH3-O-CH3 can be produced by different feedstocks such as coal, natural gas, biomass and bio-waste and municipal solid waste. India has a large reserve of high ash coal and generates high quantities of biomass and MSW, all of which can be converted to DME by use of clean production technologies. India’s transport and industrial sectors consume about 100 billion liters of diesel fuel per year produced entirely from imported petroleum. This amount of diesel can be replaced by indigenously produced DME from locally available coal, biomass and MSW.",book:{id:"11164",title:"Diesel Engines and Biodiesel Engines Technologies",coverURL:"https://cdn.intechopen.com/books/images_new/11164.jpg"},signatures:"Anirudh Gautam and Ankita Singh"},{id:"81979",title:"The Influence of Exhaust Gas Recirculation on Performance and Emission Characteristics of a Diesel Engine Using Waste Plastic Pyrolysis Oil Blends and Conventional Diesel",slug:"the-influence-of-exhaust-gas-recirculation-on-performance-and-emission-characteristics-of-a-diesel-e",totalDownloads:7,totalDimensionsCites:0,doi:"10.5772/intechopen.105011",abstract:"Through an experimental study, this work focused on finding the influence of exhaust gas recirculation (EGR) on waste plastic pyrolysis oils (WPPOs) with diesel as a base comparison fuel. The results show the amount of carbon monoxide emissions seemed to decrease at low engine loads up to intermediate loads of (50%), thereafter continued to increase significantly but marginally. Among fuels tested, blend WPPOB100 reported the highest BSFC, at 0% EGR flow rate. The value was 0.4751g/kW.hr. compared with 0.7235 g/kW.hr. at 30% EGR flow rate. Increased blend ratio had a direct decrease in brake power linearly. At 30% engine load, CD, WPPOB10, WPPOB20, WPPOB30 and WPPOB40 recorded values of 2.125 kW, 2.15 kW, 2.05 kW, 1.98 kW, 1.86 kW and 1.75 kW, respectively. Exhaust gas temperature (EGT) at 30% EGR flow rate, blend WPPOB10 had the highest reduction in temperature compared with the any other WPPO blends at 320°C. Increased blend ratio and EGR percentage flow rate increased smoke emissions within the test fuels blends. At 15% EGR flow rate, the following data were recorded: 7.53%, 7.1%, 6.72%, 6.25%, 6.0% and 5.4% for CD, WWPO10, WPPO20, WPPO30, WPPO40 and WPPO100, respectively.",book:{id:"11164",title:"Diesel Engines and Biodiesel Engines Technologies",coverURL:"https://cdn.intechopen.com/books/images_new/11164.jpg"},signatures:"Semakula Maroa and Freddie L. Inambao"},{id:"81895",title:"Performance and Emission Characteristics of Hydrogenation Derived Renewable Diesel as Diesel Engine Fuel",slug:"performance-and-emission-characteristics-of-hydrogenation-derived-renewable-diesel-as-diesel-engine-",totalDownloads:12,totalDimensionsCites:0,doi:"10.5772/intechopen.104820",abstract:"Growing anxieties about the continued depletion of fossil fuel reserves, improving the performance of diesel engines, and mandates to reduce greenhouse gas emissions have made the search for alternative fuels for diesel engines more imperative. Hydrogenation Derived Renewable Diesel (HDRD) is recognized as a sustainable, reliable, and cost-effective alternative to petroleum-based diesel (PBD) fuel for compression ignition (CI) engines. This may be because the physicochemical properties of HDRD are similar to that of PBD fuel. The current effort examines the performance and emission characteristics of HDRD in unmodified CI engines. Performance emissions characteristics such as power, torque, brake specific fuel consumption, thermal efficiency, nitrogen oxides, carbon monoxide, carbon dioxide, particulate matter, and exhaust gas temperature were interrogated and compared with that of PBD fuel in a CI engine. The outcome of the study shows that HDRD is better than biodiesel and a sustainable replacement for PDB fuel to achieve improved performance and reduced emissions of CI engines. Going forward, more investigations are needed to further simplify the preparation and democratize the utilization of HDRD as CI fuels for various applications.",book:{id:"11164",title:"Diesel Engines and Biodiesel Engines Technologies",coverURL:"https://cdn.intechopen.com/books/images_new/11164.jpg"},signatures:"Omojola Awogbemi, Daramy Vandi Von Kallon and Josiah Pelemo"},{id:"81114",title:"Research and Innovation to Improve the Efficiency of Modern Diesel Engines",slug:"research-and-innovation-to-improve-the-efficiency-of-modern-diesel-engines",totalDownloads:10,totalDimensionsCites:0,doi:"10.5772/intechopen.102759",abstract:"Modern diesel engines are one of the main mobile energy sources and are characterized by a high degree of workflow completeness, design, and manufacturing technology. The chapter summarizes the authors’ experience in improving diesel engines, increasing specific volume power, and reliability, ensuring a low level of environmental pollution emissions. The results of research using industry 4.0 technologies for systematization, choice of directions, and the search for rational ways to improve the efficiency of diesel engines are presented. The application of anergo-exergy method for analyzing the efficiency of the working process of the engine and its systems is considered. Taking into consideration the operating conditions, technical solutions are proposed to improve the reliability of the most heat-stressed parts of high-powered engines. The possibilities for a comprehensive assessment of the fuel efficiency and environmental qualities of diesel engines have been expanded taking into account CO2 emissions when using traditional, alternative, and hybrid diesel fuel.",book:{id:"11164",title:"Diesel Engines and Biodiesel Engines Technologies",coverURL:"https://cdn.intechopen.com/books/images_new/11164.jpg"},signatures:"Andriy Marchenko, Igor Parsadanov, Volodymyr Pylyov, Oleksandr Osetrov, Linkov Oleh, Serhii Kravchenko, Oleksandr Trynov, Denys Meshkov, Serhii Bilyk, Anatolii Savchenko, Inna Rykova and Rasoul Aryan"},{id:"81849",title:"A Comparative Evaluation of Biodiesel and Used Cooking Oil as Feedstock for HDRD Application: A Review",slug:"a-comparative-evaluation-of-biodiesel-and-used-cooking-oil-as-feedstock-for-hdrd-application-a-revie",totalDownloads:24,totalDimensionsCites:0,doi:"10.5772/intechopen.104393",abstract:"The search for clean energy for transportation fuel across the globe has grown in intensity. The use of biodiesel as a fuel for compression ignition (CI) engines has shown some deficiencies, e.g., poor storage, and poor pour point. The carbon chain of biodiesel is one of the factors to be considered; the longer carbon chain length leads to decreased ignition delay, which leads to the formation of OH during the premixed combustion phase. The major challenges that render biodiesel inefficient are discussed, like higher viscosity, lower energy content, higher nitrogen oxide (NOX) emissions, lower engine speed and power, injector coking, engine compatibility, high cost, and higher engine wear. The novelty of this work is that it shows that biodiesel conversion to green diesel is possible using a biowaste heterogeneous catalyst to obtain quality and high yield of HDRD with lower cost. This renewable energy (HDRD) possesses properties that are directly compatible with CI engines and transportation engines. This research reviewed biodiesel and UCO as feedstocks for the production of HDRD, including the cost–benefit of these feedstocks. Hydrogenation of biodiesel has the potential to overcome the drawbacks of conventional chemically catalyzed processes.",book:{id:"11164",title:"Diesel Engines and Biodiesel Engines Technologies",coverURL:"https://cdn.intechopen.com/books/images_new/11164.jpg"},signatures:"Josiah Pelemo, Kayode Timothy Akindeji, Freddie L. 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",coverUrl:"https://cdn.intechopen.com/series/covers/23.jpg",latestPublicationDate:"August 12th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:0,editor:{id:"280770",title:"Dr.",name:"Katherine K.M.",middleName:null,surname:"Stavropoulos",slug:"katherine-k.m.-stavropoulos",fullName:"Katherine K.M. Stavropoulos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRdFuQAK/Profile_Picture_2022-05-24T09:03:48.jpg",biography:"Katherine Stavropoulos received her BA in Psychology from Trinity College, in Connecticut, USA and her Ph.D. in Experimental Psychology from the University of California, San Diego. She completed her postdoctoral work at the Yale Child Study Center with Dr. James McPartland. Dr. Stavropoulos’ doctoral dissertation explored neural correlates of reward anticipation to social versus nonsocial stimuli in children with and without autism spectrum disorders (ASD). She has been a faculty member at the University of California, Riverside in the School of Education since 2016. Her research focuses on translational studies to explore the reward system in ASD, as well as how anxiety contributes to social challenges in ASD. She also investigates how behavioral interventions affect neural activity, behavior, and school performance in children with ASD. She is also involved in the diagnosis of children with ASD and is a licensed clinical psychologist in California. She is the Assistant Director of the SEARCH Center at UCR and is a faculty member in the Graduate Program in Neuroscience.",institutionString:null,institution:{name:"University of California, Riverside",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:2,paginationItems:[{id:"89",title:"Education",coverUrl:"https://cdn.intechopen.com/series_topics/covers/89.jpg",isOpenForSubmission:!1,editor:{id:"260066",title:"Associate Prof.",name:"Michail",middleName:null,surname:"Kalogiannakis",slug:"michail-kalogiannakis",fullName:"Michail Kalogiannakis",profilePictureURL:"https://mts.intechopen.com/storage/users/260066/images/system/260066.jpg",biography:"Michail Kalogiannakis is an Associate Professor of the Department of Preschool Education, University of Crete, and an Associate Tutor at School of Humanities at the Hellenic Open University. He graduated from the Physics Department of the University of Crete and continued his post-graduate studies at the University Paris 7-Denis Diderot (D.E.A. in Didactic of Physics), University Paris 5-René Descartes-Sorbonne (D.E.A. in Science Education) and received his Ph.D. degree at the University Paris 5-René Descartes-Sorbonne (PhD in Science Education). His research interests include science education in early childhood, science teaching and learning, e-learning, the use of ICT in science education, games simulations, and mobile learning. He has published over 120 articles in international conferences and journals and has served on the program committees of numerous international conferences.",institutionString:"University of Crete",institution:{name:"University of Crete",institutionURL:null,country:{name:"Greece"}}},editorTwo:{id:"422488",title:"Dr.",name:"Maria",middleName:null,surname:"Ampartzaki",slug:"maria-ampartzaki",fullName:"Maria Ampartzaki",profilePictureURL:"https://mts.intechopen.com/storage/users/422488/images/system/422488.jpg",biography:"Dr Maria Ampartzaki is an Assistant Professor in Early Childhood Education in the Department of Preschool Education at the University of Crete. Her research interests include ICT in education, science education in the early years, inquiry-based and art-based learning, teachers’ professional development, action research, and the Pedagogy of Multiliteracies, among others. She has run and participated in several funded and non-funded projects on the teaching of Science, Social Sciences, and ICT in education. She also has the experience of participating in five Erasmus+ projects.",institutionString:"University of Crete",institution:{name:"University of Crete",institutionURL:null,country:{name:"Greece"}}},editorThree:null},{id:"90",title:"Human Development",coverUrl:"https://cdn.intechopen.com/series_topics/covers/90.jpg",isOpenForSubmission:!0,editor:{id:"191040",title:"Dr.",name:"Tal",middleName:null,surname:"Dotan Ben-Soussan",slug:"tal-dotan-ben-soussan",fullName:"Tal Dotan Ben-Soussan",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBf1QAG/Profile_Picture_2022-03-18T07:56:11.jpg",biography:"Tal Dotan Ben-Soussan, Ph.D., is the director of the Research Institute for Neuroscience, Education and Didactics (RINED) – Paoletti Foundation. 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