Leukemia covers all aspects of the research and treatment of leukemia and related . has been previously considered for publication in another journal, please of the findings with concise objective comments that describe their relation to other . for submitting artwork can be found by downloading the guidelines PDF. In natural populations, examples in which adaptive mutations are Citation: Chang S-L, Leu J-Y () A Tradeoff Drives the Evolution of PLoS Genet 7(3): e catchsomeair.us NSCB ), and the Human Frontier Science Download PDF. Journal of Amino Acids is a peer-reviewed, Open Access journal that publishes original In addition to protein turn-over, in humans the pathways of Trp indole . and the indole alkaloid and natural hallucinogen dimethyltryptamine. . further explored in the field of peptides' structure-activity relationships.
Because leukemia prevents the immune system from working normally, some patients experience frequent infectionranging from infected tonsilssores in the mouthor diarrhea to life-threatening pneumonia or opportunistic infections. Finally, the red blood cell deficiency leads to anemiawhich may cause dyspnea and pallor. Some patients experience other symptoms, such as feeling sickhaving fevers, chills, night sweats, feeling fatigued and other flu-like symptoms. Some patients experience nausea or a feeling of fullness due to an enlarged liver and spleen ; this can result in unintentional weight loss.
Blasts affected by the disease may come together and become swollen in the liver or in the lymph nodes causing pain and leading to nausea.
Uncommon neurological symptoms like migrainesseizuresor coma can occur as a result of brain stem pressure. All symptoms associated with leukemia can be attributed to other diseases.
There was a problem providing the content you requested
Consequently, leukemia is always diagnosed through medical tests. The word leukemia, which means 'white blood', is derived from the characteristic high white blood cell count that presents in most afflicted patients before treatment. The high number of white blood cells is apparent when a blood sample is viewed under a microscopewith the extra white blood cells frequently being immature or dysfunctional.
The excessive number of cells can also interfere with the level of other cells, causing further harmful imbalance in the blood count. Some leukemia patients do not have high white blood cell counts visible during a regular blood count.
This less-common condition is called aleukemia. The bone marrow still contains cancerous white blood cells which disrupt the normal production of blood cells, but they remain in the marrow instead of entering the bloodstream, where they would be visible in a blood test. For an aleukemic patient, the white blood cell counts in the bloodstream can be normal or low. Aleukemia can occur in any of the four major types of leukemia, and is particularly common in hairy cell leukemia.
The few known causes, which are not generally factors within the control of the average person, account for relatively few cases. The different leukemias likely have different causes. Leukemia, like other cancers, results from mutations in the DNA. Certain mutations can trigger leukemia by activating oncogenes or deactivating tumor suppressor genesand thereby disrupting the regulation of cell death, differentiation or division.
These mutations may occur spontaneously or as a result of exposure to radiation or carcinogenic substances. Diet has very limited or no effect, although eating more vegetables may confer a small protective benefit. This predisposition is demonstrated by family histories and twin studies.
In some cases, families tend to develop the same kinds of leukemia as other members; in other families, affected people may develop different forms of leukemia or related blood cancers. The International Agency for Research on Cancer expert working group undertook a detailed review of all data on static and extremely low frequency electromagnetic energy, which occurs naturally and in association with the generation, transmission, and use of electrical power.
Diagnosis is usually based on repeated complete blood counts and a bone marrow examination following observations of the symptoms. Sometimes, blood tests may not show that a person has leukemia, especially in the early stages of the disease or during remission. A lymph node biopsy can be performed to diagnose certain types of leukemia in certain situations. Following diagnosis, blood chemistry tests can be used to determine the degree of liver and kidney damage or the effects of chemotherapy on the patient.
When concerns arise about other damage due to leukemia, doctors may use an X-rayMRIor ultrasound. These can potentially show leukemia's effects on such body parts as bones X-raythe brain MRIor the kidneys, spleen, and liver ultrasound. CT scans can be used to check lymph nodes in the chest, though this is uncommon. Despite the use of these methods to diagnose whether or not a patient has leukemia, many people have not been diagnosed because many of the symptoms are vague, non-specificand can refer to other diseases.
For this reason, the American Cancer Society estimates that at least one-fifth of the people with leukemia have not yet been diagnosed. Some are also treated with radiation therapy. In some cases, a bone marrow transplant is effective. Additionally, treatment must prevent leukemic cells from spreading to other sites, particularly the central nervous system CNS e.
Leukemia - Wikipedia
In general, ALL treatment is divided into several phases: Induction chemotherapy to bring about bone marrow remission. For adults, standard induction plans include prednisonevincristineand an anthracycline drug; other drug plans may include L-asparaginase or cyclophosphamide. For children with low-risk ALL, standard therapy usually consists of three drugs prednisone, L-asparaginase, and vincristine for the first month of treatment.
Consolidation therapy or intensification therapy to eliminate any remaining leukemia cells. There are many different approaches to consolidation, but it is typically a high-dose, multi-drug treatment that is undertaken for a few months.
Patients with low- to average-risk ALL receive therapy with antimetabolite drugs such as methotrexate and 6-mercaptopurine 6-MP. All Trp residues in protein and peptide sequences are conventionally indicated with the alphabetic letter W. Hopkins inis also one of the 9 essential AAs for humans which cannot be endogenously synthesized and need to be supplied with aliments, as revealed through diet manipulation studies [ 1 ].
Hence, alterations of L-Trp-deriving compounds can be found associated with a variety of metabolic diseases and syndromes affecting those systems and organs responsible for maintaining the chemical, cellular, and behavioural homeostasis: In particular, an imbalanced metabolism of this AA can interfere with the ability of these systems to interact with as well as discriminate, during development, stressors and stimuli, exogenous and endogenous antigens, and nutrients and xenobiotics.
Amongst Trp-derived compounds produced in the human body, there is the ancient neurotransmitter serotonin 5-hydroxy-tryptamine, 5-HTa biogenic amine which is known to regulate, in the human CNS, the main adaptive reactions and responses to environmental changes, such as mood-anxiety, cognition, nociception, impulsivity, aggressiveness, libido, feeding behaviour, and body temperature [ 23 ]. Next to its role as a neurotransmitter, 5-HT also modulates the activity of peripheral districts, in particular the gut function, the immune and inflammatory responses, the differentiation process of blood stem cells, and the hemodynamic function [ 3 ].
Indeed, an altered 5-HT transmission has been found associated with mood-affective disorders [ 4 ], autism and cognitive deficit [ 56 ], anorexia or bulimia nervosa and obesity [ 6 ], and other syndromes presenting peripheral symptoms, such as fibromyalgia, chronic fatigue syndrome, and irritable bowel syndrome IBS [ 7 ]. Moreover, 5-HT is in turn the precursor of the circadian regulators N-acetylHT NAS and melatonin MLTprimarily produced in the pineal gland but also in periphery where the two indoleamines act as scavenger compounds [ 8 ].
We will then underpin those molecular players in Trp biochemistry which are considered or are possible vulnerability markers in the physiopathology of human complex diseases, trying to point out their regulation. At the same time, we will briefly introduce some Trp research targets actually under investigation for therapeutic strategies in human pathology as well as the utility of -Omics approaches.
The presence of the indole ring in the chemical structure of Trp gives high hydrophobic features to this molecule among all protein AAs. In fact, Trp is the AA at the highest number of C atoms C11 and the presence of other C atoms or substituent groups would be unnecessary. The advantage to keep indole in life chemistry derives either from the possibility to exploit its C11 skeleton in metabolism or to utilize it as —R residue in proteins and peptides to promote and stabilize their structure.
Also, Trp is metabolized to produce biologically active indole compounds which have great impact on life functions. In fact, beside being present in the chemical structure of the neurotransmitter 5-HT and, in turn, in the circadian molecules NAS and MLT in animals and humans Figure 1 cthe indole ring of Trp can be transformed into bioactive compounds also by plants: In particular, the plant hormone auxin has been found linked to a specific Trp metabolism pathway involved in plant photoperception and development [ 1112 ].
Interestingly, indoleamines as 5-HT and MLT have been detected also in plants where their function is under investigation [ 13 ]. Tryptophan and other indole-containing compounds. If Trp is essential for animals, bacteria or other eukaryotes as fungi and plants are instead able to synthesize it from chorismic also the precursor of Tyr and Phe and anthranilic Trp path only acids.
In bacteria, fungi, and plants, the biosyntheses of Trp, Tyr, and Phe are linked together by the shikimate pathway: Prephenate derives from chorismate through the activity of the enzyme chorismate mutase; in turn, prephenate enters into a 3-branch path producing Tyr and Phe.
The biosynthesis of Trp in bacteria shares common genes and chemical reactions with plants or fungi: Bacteria and plants or fungi follow, however, different regulatory mechanisms of this metabolic path. In bacteria, chorismate produces Trp under the control of one of the most studied models of gene expression regulation in prokaryote organisms, the Trp operon, activated or repressed depending upon the intracellular concentrations of this AA: The regulation of Trp formation then diverges from the bacterial one because of the different gene organization in eukaryotes.
Additionally, Trp formation in plants has been found tightly regulated by several transcriptional factors acting on gene expression of the enzymes of the shikimate pathway and AAA metabolism, as evidenced in the Brassicaceae Arabidopsis.
Many of these transcriptional factors have been identified, each differentially stimulated by diverse stressors, as infections by pathogens, trauma, or light.
In the common ancestor of animal and vegetable cells, the shikimate path was localized in the cytosol whereas in higher plants this metabolic shunt occurs inside plastids [ 15 ]. Thus, genes of Trp biosynthesis would have been lost in plastid-lacking animal eukaryote cells. These considerations lead to reasonably think that AAAs metabolism and production of their bioactive derivatives occupy a central position in the early stages of the evolution of living organisms and trophism lineages.
It is not therefore surprising that AAAs represent foremost compounds for human nutrition and health. The importance of maintaining intact the indole ring in Trp derivatives is mirrored by natural therapeutic agents: Also, indole derivatives have been used in pharmacological research as the starting point for the synthesis of therapeutically relevant compounds. Tryptophan Residues in Proteins and Peptides The presence of Trp residues in polypeptides, as previously introduced, deserves a specific mention: The Trp indole ring is able to stabilize structures, domains, and interactions through Van der Waals forces while the indole-N shows propensity as a hydrogen bond donor evidencing a role of this AA also in protein binding and recognition.
Hydrophobic interactions between proteins and peptides or between these and other biologically active molecules have great importance in cell physiology. Some reviews in the current literature show interesting investigations focusing on these structural aspects of Trp residues: Tryptophan Requirement and Content in Food A main consideration deriving from previous paragraphs is that Trp is precious for life: This probably explains why L-Trp is an AA scarcely represented in the alimentary chain [ 2124 — 26 ] and its presence in animal cells and tissues must be tightly regulated.
Together with cysteine CysTrp is the essential AA required in lesser amount in human diet [ 2729 ]. The AA Trp is introduced along with all other AAs in the body with protein-rich foods, mainly of vegetal or animal origin. Aliments at higher Trp content include animal origin: Lower Trp amounts can be found in some varieties of cereals and maize. Thus, a normal, varied, and balanced diet, as in developed countries, can largely ensure the daily Trp requirement.
A main nutritional impact of Trp for human diet is represented by chronic exposure to a diet low in niacin vitamin B3 and Trp, which produces pellagra, a metabolic dysfunction defined by severe alterations of the skin, gut, and brain activity [ 30 ].
In fact, niacin is classified as a vitamin, but this compound can be produced through the metabolic transformations of L-Trp into its precursor quinolinic acid; this explains why L-Trp exerts a protective action against the onset of pellagra symptoms in low-niacin diets.
Thus, in economically disadvantaged countries, Trp content in foods, together with other essential AAs, can be of great importance. The analysis of the composition of nutrients, vitamins, essential elements, and AAs represents the basis for good health and children development in these countries. Besides, the amount of Trp in diet represents a challenge for human health and nutritional status worldwide, especially as concerns the regulation of its concentration in plasma as well as its uptake to tissues and brain.
The role of the gut microbiome is also an interesting aspect that is emerging as a link between nutrition, gut absorption, Trp fates, and health. Tryptophan Absorption, Transport, and Uptake: AA uptake occurs in all tissues and cells according to the need for protein synthesis or degradation, with gut, liver, and muscle tissue primarily involved in its modulation.
- Navigation menu
- Tryptophan Biochemistry: Structural, Nutritional, Metabolic, and Medical Aspects in Humans
Once introduced with food, all AAs, including Trp, are absorbed by the gut, pass into the bloodstream, are transported to all main tissue districts, overall muscles, and liver, and are finally taken by cells to be part of the AA pool used for the synthesis and turn-over of proteins.
Proteolysis and protein catabolism inside cells regenerate, in part, the intracellular reserve of AAs and Trp for subsequent protein synthesis and, in part, provoke their release in the bloodstream.
Insulin, glucagon, and cortisol are the regulatory hormones of endogenous protein turn-over: Cortisol increases the AAs plasma levels efflux from muscleshifting the balance towards proteolysis [ 31 ]. At the same time, each AA can undergo its own regulation originating its own cell in- and out-flow, in relation to AA composition of both endogenous proteins and those derived from the diet; these last at more variable content [ 32 ].
Journal of Amino Acids
Also, multiple factors as age, gender, or physical activity concur to affect plasma concentrations of AAs [ 32 ]. Differently from nonessential AAs, for which, in addition to diet, the rate of de novo synthesis is able to control the homeostatic balance of endogenous contents, essential AAs and Trp plasma concentrations are more directly related to their amount in diet. A foremost and intriguing aspect of human Trp biology is in fact defined by the observation that diet and the type of meal can change its plasma levels as well as its uptake by different cell types.
After food digestion, for gut absorption this AAA shares its passage across enterocytes with other neutral AAs through two distinct carrier molecules: Tryptophan has also the lowest affinity for the apical carrier than other competitive NAAs, except lysine Lysconfirming that tissues require defined amounts of Trp and suggesting that gut absorption is a regulated step for the subsequent transport and biotransformation of this AAA.
A widely studied model of Trp uptake mechanism is that regulating its transport across the blood-brain barrier BBB. For that, insulin and other large neutral AAs, valine Valleucine Leuisoleucine IleuTyr, and Phe, have been found to play a chief role: This explains why a protein-rich meal increases Trp plasma levels but not its uptake to the brain. Trp uptake to CNS is thus rather favoured by carbohydrate-rich meals.
After a carbohydrate meal, 5-HT biosynthesis in raphe nuclei is increased. This mechanism has been extensively studied in mammals: Val, Ileu, and Leutransported from the bloodstream to muscles, thus increasing Trp availability for CNS uptake and, as described later, to 5-HT synthesis.
The 5-HT release at the hypothalamic level activates specific 5-HT receptor subtypes devolved to inhibit appetite brain nuclei [ 34 ]. Thus, meal composition, palatable food, and poor protein foods all contribute to Trp uptake across the BBB in favor of 5-HT synthesis. Protein-rich foods in fact contain Trp, but at lower levels than other LNAAs, which, on the whole, rather provoke inhibition of Trp brain uptake. Thus, conclusively, proteins can enhance 5-HT synthesis but in relation to their low or high content in Trp [ 3536 ].
Another important uptake regulatory aspect is represented by the fact that Trp is highly lipophilic and scarcely soluble in aqueous solutions at the physiological pH, so that its transport in blood requires plasma albumin binding: Trp is the only AA transported by albumin.
Therefore, a finely regulated equilibrium between free and bound Trp levels exists in plasma, an argument of actual scientific interest and debate. Next to nutritional considerations, for a deeper understanding of Trp uptake, the transport proteins across tissues and the BBB are currently under investigation. The ratio between free and albumin-bound Trp has been also found to modulate Trp passage into the brain: