Review Article On:Brief Account of Metabolism: Oxidative Stress, Organ Malfunctioning & Syndromes.
-238126-2540Objectives: To understand what metabolism is, effect of oxidative stress on metabolism, Organ vitality & malfunctioning and metabolic syndromes.-95251616585Research Design And Methods: Searched for words, “metabolism”, “oxidative stress”, “oxidative stress related to metabolism”, “metabolic syndromes”, “organs involved in metabolism”, “malfunctioning of organs involved in metabolism”, on google.-19050269240Abstract:Metabolism is the set of chemical processes being carried out in an individual. It comprises of two types, catabolism and anabolism. If both of them are occurring simultaneously then that process is called amphibolism. Metabolism is the key behind many aspects. Oxidative stress is the disturbance in oxygen concentration in the body.
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And oxidative stress can cause various metabolic disorders, these disorders may lead to numerous diseases. Organs involved in metabolism are also affected by this imbalance. In metabolism following organs are involved: 1-Brain 2-Muscles 3-Adipose Tissues 4-Kidneys 5-LiverMetabolic stress causes disorders to get transformed into dangerous diseases. Imbalance in Insulin resistance can cause diabetes. Cancer is the fatal diseases which can be caused by metabolic stress or oxidative stress.
Cholesterol imbalance is also caused by oxidative stress. Renal diseases are also included in this list. Enzymatic disturbance is also a major problem which results when the fluid balance of body or metabolic activities are disturbed and this metabolic disorder is also caused when enzymatic environment gets disturbed. Hypertension is among the major issues, it results in many other problems, which can cause stroke, cardiac arrest or untimely death. To keep your body healthy you first need to keep your metabolic activities proper and that can cause all other aspects related to your body to be perfectly fine and make the individual fit.
This review article is based on all the information related to metabolism, metabolic disorders and metabolic stress. Oxidative stress and organs involved. Organ malfunctioning is also discussed here in the article. Introduction:-1225425Metabolism – suffused into every biological aspect.Metabolism is defined as the sum total of all biological processes taken place in a living body, which either produce or consume energy. Formidably above 8,700 processes (approx.) are being carried out simultaneously. Having 16,000 metabolites listed in the Kyoto Encyclopaedia of Genes and Genomes (http://www.
genome.jp/kegg/pathway.html). Major metabolism involves abundant nutrient molecules necessary for energy production in human body i.e. amino acids, carbohydrates, fatty acids, they are responsible for macromolecule production as well ( Figure 1).
Pathways of metabolism can be divided into three classes: synthesis of simple molecules or their polymerization into more complex macromolecules (anabolism), degradation of molecules for the release of energy (catabolism); and elimination of the toxic waste produced by the other classes (waste disposal).-9526403225Figure 1: showing a generalized view of metabolism, with regard to the use of micro nutrients (glucose, amino acids and fatty acids) to produce or store energy, and for growth.These pathways help us in resisting the urge of ending up into entropy. In the “golden age of biochemistry” (1920s-1960s) most of the metabolic network responsible for nutrient utilization and energy production in humans and other organisms has been defined. These include activities like glycolysis (Embden, Meyerhof and Parnas), respiration (Warburg), the tricarboxylic acid (TCA) and urea cycles (Krebs), glycogen catabolism (Cori and Cori), oxidative phosphorylation (Mitchell), and the supremacy of ATP in energy-transfer reactions (Lipmann). Research on metabolism has been instigated by the realization that metabolic anxiety is linked to common human diseases. Thus formal study of metabolism rooted from here. Relationship between precise metabolic activities and disease states emerged in the golden age and was much admired but soon with introduction of other biological branches it started diminishing leading to other fields’ researches.
The research on the genetic and molecular aspects of cancer, diabetes, obesity and neurodegeneration diverged focus from understanding the changed metabolic states in these diseases. Many of them are now considered in terms of inherited or somatic mutations that influence gene expression, signal transduction, cellular differentiation and other processes that are not traditionally studied in bioenergetics or metabolic terms. The last decade has highlighted a way of functioning for metabolites and metabolic pathways which could not be predicted from typical understanding of biochemistry. As a result, it is now not possible to view metabolism solely as a self-regulating network occurring independently of other biological systems. But, metabolism influences, or is influenced by, every other cellular process; now there is no space in biological research which is completely free from the influence of metabolism. This is not surprising if one considers that fundamental aspects of energy metabolism remain conserved throughout evolution, and higher regulation levels and the complexity in organization of multi-cellular organisms sprung much later (https://www.ncbi.nlm.
nih.gov/pmc/articles/PMC3337773/).28575227965Metabolic Profile of Each Organ:Brain- Except during prolonged starvation Glucose is considered the sole fuel for the human brain. The brain has no fuel stores and requires a continuous supply of glucose. It needs about 120 g daily, which equalizes to an energy input of approx. 420 kcal (1760 kJ), distribution of that amount is like; some 60% of the use of glucose by the whole body at resting state. Energy estimates suggest that from 60% to 70%, is used to power transport mechanisms that maintain the Na+-K+ membrane potential required for the transmission of the nerve impulses.
The brain has to synthesize neurotransmitters and their receptors for propagating nerve impulses. On the whole, glucose metabolism is not changed during mental activity, yet local increases are detected when a subject performs some specific tasks. GLUT3 transports glucose to the brain cells. GLUT3 has low value of KM for glucose (1.
6 mM), which shows that it is saturated often. Thus, the brain is usually supplied with a constant amount of glucose. Non-invasive Cytosine nuclear magnetic resonance measurements shows that the glucose concentration in the brain is around 1 mM provided the plasma level is 4.7 mM (84.7 mg/dl), that is normal value. When the glucose level approaches the KM value of hexokinase (~50 ?M) (the enzyme that traps glucose in the cell) Glycolysis slows down. This alarming point is reached when the plasma-glucose level drops at about below 2.2 mM (39.
6 mg/dl) and reaches the KM value of GLUT3. Fatty acids cannot serve as fuel for the brain, as they are bound to albumin in plasma and cannot traverse the blood-brain barrier. When in starvation, ketone bodies made by the liver partially replace glucose as fuel for the brain.Muscle- The important fuels for muscle are glucose, ketone bodies, and fatty acids. Muscle varied from the brain in having large reserves of glycogen (1200 kcal, or 5000 kJ). About three-fourths of total glycogen in the body is found as reserves in muscles. Which is readily transformed into glucose 6-phosphate for intra-muscular use. Muscles, for instance, the brain, do not have glucose 6-phosphatase, thus does not export glucose.
Rather, muscle possess glucose, its preferred fuel for bursts of activity. In skeletal muscles which actively contract, the rate of glycolysis succeeds that of the citric acid cycle, and most of the pyruvate formed gets reduced to lactate, some of which flows to the liver, and gets converted into glucose. This interchange, called as the Cori cycle transfers the metabolic burden of muscle to the liver. Additionally, a huge amount of alanine is formed in active muscle by the transamination of pyruvate. Alanine, can be converted into glucose by the liver. Muscle can absorb and transaminase branched-chain amino acids; but, it cannot form urea. As a result, the nitrogen is released into the blood as alanine. The liver absorbs the alanine, replenishes the nitrogen for removal as urea, and processes the pyruvate to glucose or fatty acids.
The metabolic pattern at resting state of a muscle is quite different. In resting state of muscle, fatty acids are regarded as major fuel, fulfilling 85% of energy needs. Heart muscle on the other hand functions exclusively aerobically, as proven by the density of mitochondria in heart muscle. In addition, the heart apparently has no glycogen reserves.
Heart’s main source of fuel are fatty acids, yet ketone bodies as well as lactate can serve as fuel for heart muscle. Heart muscle prefer intake of acetoacetate on glucose.Adipose tissue- In adipose tissue the triacylglycerol stored is a big reservoir of metabolic fuel. In human beings, the liver is the considered as the major site of fatty acid synthesis. Triacylglycerols are not taken up directly by adipocytes; rather, an extracellular lipoprotein lipase first hydrolyse it for uptake. Insulin stimulates this lipase. Once the fatty acids enter the cell, the adipose tissue has to activate these fatty acids and transport the resulting CoA derivatives to glycerol as glycerol 3-phosphate an essential intermediate of lipid biosynthesis that comes when glycolytic intermediate dihydroxyacetone phosphate gets reduced.
Hence, adipose cells need glucose for the synthesis of triacylglycerol. Triacylglycerol gets hydrolysed into fatty acids and glycerol by intracellular lipases. The rate-limiting step i.
e. release of the first fatty acid from a triacylglycerol, is catalysed by the help of hormone-sensitive lipase which is reversibly phosphorylated. Epinephrine triggers the formation of cyclic AMP that activates a protein kinase. Triacylglycerol in adipose cells are constantly being hydrolysed and resynthesized. Glycerol derived as a result of their hydrolysis is transported to the liver. Much of the fatty acids formed as a result of hydrolysis are esterified if glycerol 3-phosphate is in excess. On the contrary, they get released into the plasma if glycerol 3-phosphate is in small amount because of lack of glucose. Thence, the glucose level inside adipose cells helps in determination of the release of fatty acids in blood.
The kidney- The main function of the kidney is urine production, which works as a medium for excreting metabolic waste products and for maintenance of the osmolarity of the internal fluids. The blood plasma gets filtered around 60 times per day in the renal tubules. Most of the filtered material of the blood gets reabsorbed; and only 1 to 2 litres of urine is produced.
Water-soluble materials in the plasma (glucose, and water) are reabsorbed to prevent excessive loss. The kidneys need large amounts of energy to attain reabsorption. Although comprises only 0.5% of body mass, kidneys uptake 10% of the oxygen used in cellular respiration. Most of the glucose which is reabsorbed is taken to the kidney cells by the sodium-glucose cotransporter. At times of starvation, the kidney plays an important role in gluconeogenesis and can contribute as much as half of the blood glucose.Liver-The metabolic activities carried out by liver are essential for generating fuel to the brain, muscle, and other peripheral organs.
The liver, forms 2% to 4% of body weight, is a living organism’s metabolic hub. Majority of compounds absorbed by the intestine are first went through the liver, thus its able to regulate the level of many metabolites in the blood. The liver brushes off two-thirds of the glucose from the blood and all of the remaining monosaccharides. Limited amount of glucose is left in the blood for use of other tissues.
The absorbed glucose is transformed into glucose 6-phosphate by hexokinase and the liver-specific glucokinase. Most of the glucose 6-phosphate is converted into glycogen. Around 400 kcal (1700 kJ) can be stored in this form in the liver.
Excessive glucose 6-phosphate is converted to acetyl CoA which forms fatty acids, cholesterol, and bile salts. The pentose phosphate pathway, provides the NADPH for this reductive biosynthesis. The liver has ability to produce glucose for release into the blood by break down of glycogen and by performing gluconeogenesis. The vital precursors for gluconeogenesis are lactate and alanine from muscle, glycerol from adipose tissue, and glucogenic amino acids from the diet. The liver is important in the regulation of lipid metabolism. When fuels are in excess, fatty acids obtained from the diet or produced by the liver are esterified and secreted into the blood in the form of LDL. Whereas, in the fasting state, the liver transforms fatty acids to ketone bodies.
The choice is made according to whether the fatty acids enter the mitochondrial matrix. Carnitine acyltransferase I (carnitine palmitoyl transferase I), which speeds up the formation of acyl carnitine, is stopped by malonyl CoA an intermediate in the synthesis of fatty acids. When malonyl CoA is in excess, long-chain fatty acids are resisted from entering the mitochondrial matrix, the compartment of ?-oxidation and ketone-body formation. However, fatty acids are taken to adipose tissue for incorporating into triacylglycerols.On the contrary, the level of malonyl CoA is low when fuels are in limited quantity. Under such conditions, fatty acids are liberated from adipose tissues to enter the mitochondrial matrix for converting into ketone bodies.The liver also has an essential role in metabolism of amino acid. The liver absorbs the most of amino acids, leaving small amount in the blood for peripheral tissues.
The foremost use of amino acids is for protein synthesis as compared to catabolism. The KM value for the aminoacyl-tRNA, synthetases is less than that of the enzymes participating in amino acid catabolism. Therefore, amino acids are used to make aminoacyl-tRNAs before they are catabolized. When catabolism occurs, the first step is the removal of nitrogen, which is ultimately processed to urea. The liver excretes from 20 to 30 g of urea per day. The ?-ketoacids help in gluconeogenesis or fatty acid anabolism. The liver is unable to remove nitrogen from the branch-chain amino acids (leucine, isoleucine, and valine).
Transamination occurs place in the muscle. ?-Ketoacids attained from the catabolism of amino acids are the liver’s own fuel. The main function of glycolysis in the liver is to form building blocks for biosynthesis.
And the liver cannot use acetoacetate as a fuel, because it has less amount of the transferase needed for acetoacetate’s activation to acetyl CoA. Thus, the liver avoids using the fuels that it transports to muscle and the brain (https://www.ncbi.nlm.nih.gov/books/NBK22436/). 952523685500Metabolic Syndrome in relation to organ malfunctioning or hormonal imbalanceA disease is a pathophysiological response to internal or external factors.
A disorder is a disruption to regular bodily structure and function. A syndrome is a collection of signs and symptoms associated with a specific health-related cause. Metabolic Syndrome is a set of conditions hypertension, hyperglycaemia, obesity and hyperlipidaemia, hypercholesterolemia that occur together, increasing risk of cardiovascular diseases, stroke and diabetes. Many of the disorders associated with metabolic syndrome show no symptoms, yet a large waist circumference is a visible sign. In case of high blood sugar, you might have signs and symptoms of diabetes including increased thirst and urination, fatigue, and blurred vision. (https://www.
omicsonline.org/scholarly/metabolic-syndrome-journals-articles-ppts-list.php) Oxidative stressOxidative stress is an imbalance between free radicals and antioxidants in your body. Oxygen-containing molecules with an uneven number of electrons are called free radicals. Which can easily react with other molecules.
( https://www.healthline.com/health/oxidative-stress) Figure 2: showing organ wise conditions caused by oxidative stress.Role of Kidney in Hypertension with respect to oxidative stressFigure 3: showing factors involve in renal oxidative stress caused hypertensionRenal oxidative stress is a potentiating factor for hypertension. Raised level reactive oxygen species (ROS) in the kidney have seen in multiple models of hypertension and inter-relate to renal vasoconstriction and alterations of renal function. Nicotinamide adenine dinucleotide phosphate oxidase is the main source of ROS in the hypertensive kidney, yet a defective antioxidant system can also take part. Increased renal ROS are related with renal vasoconstriction, renin release, activation of renal afferent nerves, augmented contraction, and myogenic responses of afferent arterioles, enhanced tubuloglomerular feedback, dysfunction of glomerular cells, and proteinuria. Inhibiting ROS with antioxidants, superoxide dismutase mimetics, or blockers of the renin-angiotensin-aldosterone system or genetic deletion of one of the components of the signalling path often reduce or procrastinate the occurrence of hypertension and maintains the renal structure and function.
The kidney has a crucial role in the onset of hypertension. Recent treatments with the help of ACE inhibitors, ARBs, and renin inhibitors have proved to be effective in reducing BP, yet do not completely prevent the progressive loss of kidney function in CKD. The therapeutic role of effective antioxidant strategies in human hypertension and CKD has to be known. (https://www.ncbi.
nlm.nih.gov/pmc/articles/PMC3880923/)Hyperglycaemia Hyperglycaemia, or high blood sugar is a condition in which amount of glucose in the blood plasma is increased. This develops when the body has little insulin or cannot use insulin properly.
gov/pmc/articles/PMC4016871/). These medical conditions can cause hyperglycaemia, including diabetes mellitus (DM), obesity, pancreatitis, chronic stress, and cancer. The present epidemiological proofs indicated that all of them hyperglycaemia-related conditions are associated with tumorigenesis or tumour progression. DM is the widely known medical conditions responsible for hyperglycaemia. In these patients, blood glucose levels get raised either because there is an less amount of insulin in the body or the body cannot use insulin properly.
Now researchers exclusively focus on the impacts of hyperglycaemia on eyes, kidneys, nerves, and heart and little attention is being paid to the roles of hyperglycaemia in cancer. (https://www.ncbi.
nlm.nih.gov/pmc/articles/PMC4016871/) Figure 4: conditions that contributes in hyperglycaemia. Hyperglycaemic (or associated) metabolic and vascular malfunctioning are known to effect the central nervous system (CNS), increasing risks of stroke, seizures, diabetic brain disorders and sensory compromise. Hyperglycaemia triggers osmotic gradients across cell membrane, triggering changes in cell volume regulation that transports water from the intracellular fluid space to the extracellular fluid space and consequently results in contraction of the cell volume. The hyperglycaemia in association with diabetes led to significant, rapid changes in the levels of osmolytes from the start to the acute stage followed by increased oxidative stress and neuronal dysfunction at the chronic stage.
HyperlipidaemiaHyperlipidaemia a medical condition identified by an increase in one or more of plasma lipids, including triglycerides, cholesterol, cholesterol esters, phospholipids and or plasma lipoproteins incorporating very low-density lipoprotein and low-density lipoprotein in addition with reduced high-density lipoprotein levels. This increase of plasma lipids is among the leading risk factors associated with cardiovascular diseases. In between this, statins and fibrates remain the major anti-hyperlipidaemia agents for treating increased plasma cholesterol and triglycerides respectively, of severe siaving side-effect on the muscles and the liver. (https://www.researchgate.net/publication/272213038_A_Review_Article_on_Hyperlipidemia_Types_Treatments_and_New_Drug_Targets/download).
left9080500Primary hyperlipidaemia usually takes place in result of genetic problems i.e., mutation within receptor protein, but secondary hyperlipidaemia occurs as a result of other simultaneously occurring diseases like diabetes. Changes and/ or abnormality in the metabolism of lipid and lipoproteins is a very common condition that taken place within masses, and it is regarded as one of the major risk factor in the happening of cardiovascular disease due to their influence on atherosclerosis.ObesityObesity is a major risk factor for an individual having metabolic disturbances, specifically in lipid and glucose metabolism. There is enough epidemiologic evidence that adiposity is interrelated with adverse lipid levels and biomarkers of glucose metabolism. In fact, disarrangements of these variables can be termed together as obesity, dyslipidaemia, insulin resistance, and hypertension. Hypertension, hyperlipidaemia, malfunctioned glucose tolerance, and obesity are agreeably traditional cardiovascular disease (CVD) risk factors.
When these risk factors are accumulated in one individual, CVD risk increases drastically. This accumulation of risk factors is, not a rare event but a common cause of CVD in modern society. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502543/)right1206500Its believed that information from various methods including gene expression, copy number variation, micro RNA regulation, methylation, special treatment of rare variants and study of other regulatory processes, in addition to information from proteomics, and from comprehensive databases on modules, pathways and networks of genes and proteins will make up to further understanding of the actual functioning of genes that increases chances of obesity and the metabolic syndrome.
nih.gov/pmc/articles/PMC5502543/)Breast Cancer Breast cancer, being the most common cancer in women globally. Where traditional risk factors for breast cancer include age, family history of cancer, and reproductive and menstrual history, the National Cancer Institute also enlists overweight, lack of physical activity, and consumption of alcohol as risk factors. Many of these risk factors are associated with metabolic syndrome.
(https://www.hindawi.com/journals/ijbc/2014/189384/)left3810000MS is a risk factor for various cancers, to name some breast, pancreatic, colorectal, and prostate cancers. The emerging prevalence of MS and its relation with breast cancer, among other coeval, point toward the desperate need to develop public health strategies to manage them. Providing the increasingly large global burden of metabolic risk factors, even a small association with breast cancer can have a great public health impact. Risk detection tools can be developed which include MS as a risk factor for breast cancer. Healthcare facilitators will then be better assessed to identify high-risk women for primary and secondary prevention.
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