Monday, April 10, 2017

Oxidative Stress and aging

Oxidative stress is the major pillar of the theory of aging. As a joke, I often say in my classes that we get old because we have the bad habit of spending our whole life breathing oxygen. Basically it is the oxygen that makes us live, but it is also the one that kills us little by little, that is, that makes us grow old...
And what is the relationship between oxygen and aging? The answer boils down to two words: oxidative stress! Sporadically, there are O2 molecules that transform into reactive oxygen species, most of which are neutralized by our antioxidant defenses (more information on this subject here). However, there are always some reactive oxygen species that can bypass our defenses and consequently can cause minor damage to some of our biomolecules. Although these damages do not have much biological significance, when evaluated isolated, as we grow older, they accumulate, and these cumulative damages begin to translate to the loss of some functionalities. Examples are loss of skin malleability, joint stiffness, loss of sensory ability, etc.

Therefore, everything that can accelerate our metabolic rate has the potential to make us age faster because it increases the production of reactive oxygen species. In this context, the effect of emotional stress is particularly evident! For example, people who have jobs and activities of high stress, age at a much higher rate than those who have a much more relaxed life.
Finally, I would like to make it clear that oxidative stress is not the only factor responsible for aging, but it is certainly one of the main ones, so if we want to age more slowly, we have to ensure an adequate balance between the pro-oxidants and the anti-oxidants!
.

Friday, March 17, 2017

Myoglobin

Myoglobin is a cytoplasmic hemoprotein composed by a single polypeptide chain of 154 amino acids. It is expressed solely in cardiac myocytes and oxidative skeletal muscle fibers. Myoglobin was so named because of its functional and structural similarity to hemoglobin. Like hemoglobin, myoglobin binds reversibly to O2 and thus may facilitate the transport of O2 from red blood cells to the mitochondria during periods of increased metabolic activity or serve as an O 2 reservoir during hypoxia or anoxia.The structure of myoglobin was first delineated by John Kendrew more than 40 years ago and subsequent work has shown that it is a polypeptide chain consisting of eight α-helices. It binds oxygen to its heme residue, a porphyrin ring with an iron ion. The polypeptide chain is folded and packs the heme prosthetic group, positioning it between two histidine, His64 and His93 residues. The iron ion interacts with six ligands, four of which are supplied by the nitrogen atoms of the four pyrrhols and share a common plane. The side chain imidazole of His93, provides the fifth ligand, stabilizing the heme group and slightly displacing the iron ion out of the heme plane. The position of the sixth ligand, in deoximoglobin, serves as the binding site for O2, as well as for other potential ligands, such as CO or NO. When O2 binds, the iron ion, it is partially drawn back toward the porphyrin plane. Although this shift is of little importance in the function of monomeric myoglobin, it provides the basis for the conformational changes that underlie the allosteric properties of tetrameric hemoglobin. In addition, studies using X-ray diffraction and xenon binding techniques have identified four highly conserved internal cavities within the myoglobin molecule that can help target molecules to bind to the heme residue.Related to its role as an O2 reservoir, myoglobin also functions as an intracellular pO2 buffer (partial pressure of O2). Similarly to the role of creatine phosphokinase, which works to buffer ATP concentrations when muscle activity increases, myoglobin works to buffer O2 concentrations. As a result, the intracellular concentration of O2 remains relatively constant and homogeneous, despite increases in O2 flow from the capillaries to the mitochondria, induced by physical activity.

Text written by:
Ana Rita Cardoso
João Faria
Joel Mateus
Pedro Desport
.

Friday, March 10, 2017

Oxidative stress and cellular respiration



During cellular respiration, electrons are transferred from NADH or FADH2, along 4 protein complexes in the inner mitochondrial membrane, to an O2 molecule (read more about this subject here). In the last stage of the process, the electrons are transported one by one, that is, they will reach the oxygen one at a time. 
This situation, which may seem only a detail to many, has, in fact, very important implications for our biochemistry, because it means that all O2 molecules are, even temporarily, transformed into a free radical, the superoxide anion. This means that, literally, at every instant we are producing large quantities of reactive oxygen species. However, this situation, which is potentially very dangerous, does not have, under normal conditions, dramatic consequences for cells, mainly for 2 reasons:
1. There are mechanisms that prevent the superoxide anion from diffusing from complex 4 before it is completely reduced to water. That is, the free radical is formed, but remains in place and quickly receives another electron, ceasing to be free radical.
2. As there are always some superoxide anions that can escape the first mechanism, we have other defense mechanisms, and in this context, the most important is the presence of a mitochondrial enzyme called superoxide dismutase. This enzyme, which also has a cytosolic isoform, will cause dismutation of the superoxide anion, converting two of these molecules into hydrogen peroxide.
Of course there will also be superoxide anions that will be able to escape from superoxide dismutase, but under normal conditions these are very few. In addition, we still have several other antioxidant defenses waiting for them...
.

Tuesday, February 28, 2017

Insulin

Insulin is a polypeptide hormone produced, stored and secreted in Beta cells of the islets of Langerhans, in the pancreas (in a histological section it is seen that they occupy the central part). It is an anabolic hormone that acts at the level of the liver, adipose tissue and with influence in the brain.
This protein has two polypeptide chains, with 21 amino acids in the A chain and 30 in the B chain, joined by disulfide bonds, which gives a greater stability and a correct folding. It begins to be produced in the form of pre-pro-insulin which, by action of the peptidase is cleaved to form the proinsulin. The proteolytic cleavage of peptide C forms the two chain bioactive insulin, which is stored in secretory granules for subsequent insulin secretion.Its main function is to regulate blood glucose levels in a context of hyperglycemia. In this way, glucose acts as a biochemical signal that triggers its secretion. Thus, when carbohydrate-containing foods are absorbed, glucose is metabolized to ATP and this in turn triggers insulin secretion. Protein-protein interactions and phosphorylations are used to transmit the signal. In adipose tissue and muscle, the binding of insulin to membrane receptors triggers the displacement of GLUT4-rich vesicles that fuse with the membrane, increasing cell uptake, being an insulin-dependent transport.
On the other hand, in the liver, insulin activates the enzyme glycokinase, which is responsible for the conversion of glucose into glucose-6-phosphate; Guarantees an intracellular concentration of glucose lower than the extracellular concentration and, therefore, a gradient of glucose concentration favorable to its entry into these cells, through the GLUT-2 transporter, following metabolization by glycolysis, Krebs and the respiratory chain to produce ATP. Thus, after food intake, glucose is absorbed into the intestines and is released into the bloodstream, causing blood concentrations to rise, leading to transient hyperglycemia. The pancreas releases insulin to lower glucose concentration, allowing glucose to be consumed by the cells, as well as stimulating the storage of glucose in the liver in the form of glycogen; The liver also metabolize glucose into triacylglycerols, transported as VLDL to be stored in adipose tissue, which are useful reserves in fasting situations. Signal transmission ceases, at meal time, by dephosphorylation of the insulin receptor by protein tyrosine phosphatase.
In summary, insulin stimulates glycogenesis, fatty acid synthesis and glycolysis and inhibits antagonistic pathways: glycogenolysis, fatty acid degradation and hepatic gluconeogenesis. It also stimulates protein synthesis. It has action on inherent enzymes as well as effects on gene transcription. It also acts on specific receptors in the hypothalamus to inhibit the act of eating, thus regulating feeding and energy conservation.
Inborn errors of beta cell metabolism can produce excessive or defective production of insulin by gene mutations (GCK), Kir 6.2 alterations, or insulin synthesis transcription factors, respectively. Increased glucose leads to increased osmotic pressure, glycation of proteins and formation of reactive oxygen species (EROS).
Diabetes is the metabolic disease characterized by increased blood sugar: It may be Type I - in which the body stops producing insulin by destroying the B cells of the pancreas. It is important to check for symptoms of polydipsia, fruity aroma breathing, blood glucose and blood ketones levels. Essential therapies focus on insulin therapy, fluid replacement, replacement of electrolytes and nourishment. In turn, in Type II diabetes, the cells do not produce enough insulin to lower the concentration of gucose or there is a condition of insulin resistance. Adipocytes, myocytes and hepatocytes do not respond correctly. It presents symptoms similar to type I but more gradual. It is necessary to test for fasting blood glucose and for abnormal levels to continue the investigation for glycemic curve; glycated hemoglobin, control alcohol consumption, etc.
They can lead to complications such as diabetic retinopathy, atherosclerosis, diabetic nephropathy, neuropathy, myocardial infarction/stroke, infections - leucocytes less effective in hyperglycemia, hypertension and oxidation of blood vessels. There are currently several drugs on the market that address problems with insulin, as well as different types of injectable insulin depending on the cause of the disease and the purpose of action.


Text written by:
Denilson Araújo
Prescília Sampa
Solange da Costa
.