Browsing Pathways

Blue diaper syndrome is a recessive metabolic disorder that has not yet been determined to be X-linked or autosomal. This syndrome is caused by a mutation in the large neutral amino acids transporter small subunit 1 protein, which allows tryptophan, among other amino acids, to be reabsorbed in the kidneys. The excess tryptophan found in the intestine is digested by bacteria which excrete indole, which can undergo oxidation to produce indigo blue. This is seen in the diapers of infants affected by blue diaper syndrome, due to the increased levels of indole in their urine or feces. Other symptoms can include bacterial infections, damage to various parts of the eye, hypercalcemia, and impaired kidney function due to this. Treatment can include a calcium restricted diet in order to prevent hypercalcemia, and a tryptophan restricted diet to prevent all systems. If bacterial infections are common, antibiotics may be prescribed.

Lysinuric protein intolerance (LPI), also called hyperdibasic aminoaciduria, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder of the kidney function pathway. It is caused by a mutation in the SLC7A7 gene which encodes the Y+L amino acid transporter 1 protein, which is involved in the uptake of amino acids, both with sodium for neutral amino acids, and without for dibasic amino acids. In this disorder, the amino acids lysin, arginine and ornithine, found in protein, cannot be broken down, which can cause problems in the systems that use these amino acids, such as the urea cycle. LPI is characterized by a shortage of lysine, arginine and ornithine within the body, causing elevated ammonia levels in the blood. Symptoms of the disorder include failure to thrive after weaning, nausea and vomiting following a meal containing large amounts of protein, as well as osteoporosis, and lung and kidney problems. Treatment with a protein restricted diet is effective, as well as prescription of medication to lower the levels of ammonia in the blood. It is estimated that the LPI affects 1 in 60,000 individuals in certain populations such as in Finland and Japan, and less frequently outside these populations.

Blood coagulation can be initiated by either an extrinsic or an intrinsic pathway, resulting in a cascade of serine protease activation that ultimately leads to the formation of thrombin, which converts soluble fibrinogen to an insoluble fibrin clot. The extrinsic, or tissue factor, pathway is initiated upon vascular injury, when the membrane-bound protein tissue factor (TF) comes into contact with factor VII or VIIa in plasma. The TF-VIIa complex is the strongest known activator of the coagulation cascade, and converts factors IX and X to IXa and Xa, respectively. Factors VII, IX, and X are vitamin-K-dependent proteins produced in the liver. In the intrinsic, or contact, pathway, injury exposes collagen to the bloodstream where is binds to factor XII and activates it to XIIa. Factor XIIa converts prekallikrein to kallikrein and factor XI to XIa. Both the extrinsic and intrinsic pathways result in the activation of factor IX to IXa, which forms the 'tenase' complex with factor VIIIa, calcium and phospholipids. This complex converts factor X to Xa and is important in haemostasis. Factor Xa complexes with factor Va (which functions as a non-enzymatic cofactor), calcium and a phospholipid membrane surface to form what is called the prothrombinase complex, which converts prothrombin to thrombin. Thrombin converts soluble fibrinogen to insoluble fibrin polymer, which is stabilized by cross-linking by coagulation factor XIIIa.

Angiotensin is a peptide hormone that is part of the renin-angiotensin system responsible for regulating fluid homeostasis and blood pressure. It is involved in various means to increase the body's blood pressure, hence why it is a target for many pharmceutical drugs that treat hypertension and cardiac conditions. Angiotensin II, the primary agent to inducing an increased blood pressure, is formed in the general circulation when it is cleaved from a string of precursor molecules. Angiotensinogen is converted into angiotensin I with the action of renin, an enzyme secreted from the kidneys. From there, angiotensin I is converted to the central agent, angiotensin II, with the aid of angiotensin-converting enzyme (ACE) so that it is available in the circulation to act on numerous areas in the body when an increase in blood pressure is needed. Angiotensin II can act directly on receptors on the smooth muscle cells of the tunica media layer in the blood vessel to induce vasoconstriction and a subsequent increase in blood pressure. However, it can also influence the blood pressure by aiding in an increase of the circulating blood volume. Angiotensin II can cause vasopressin to be released, which is a hormone involved in regulating water reabsorption. Vasopressin is created in the supraoptic nuclei and they travel down the neurosecretory neuron axon to be stored in the neuronal terminals within the posterior pituitary. Angiotensin II in the cerebral circulation triggers the release of vasopressin from the posterior pituitary gland. From there, vasopressin enters into the systemic blood circulation where it eventually binds to receptors on epithelial cells in the collecting ducts of the nephron. The binding of vasopressin causes vesicles of epithelial cells to fuse with the plasma membrane. These vesicles contain aquaporin II, which are proteins that act as water channels once they have bound to the plasma membrane. As a result, the permeability of the collecting duct changes to allow for water reabsorption back into the blood circulation. Angiotensin II also has an effect on the hypothalmus, where it helps trigger a thirst sensation. Correspondingly, there will be an increase in oral water uptake into the body, which would then also increase the circulating blood volume. Another way that angiotensin II helps increase the blood volume is by acting on the adrenal cortex to stimulate aldosterone release, which is responsible for increasing sodium reuptake in the distal convoluted tubules and the collecting duct. It is formed when angiotensin II binds to receptors on the zona glomerulosa cells in the adrenal cortex, which triggers a signaling cascade that eventually activates the steroidogenic acute regulatory (StAR) protein to allow for cholesterol uptake into the mitochondria. Cholesterol then undergoes a series of reactions during steroidogenesis, which is a process that ultimately leads to the synthesis of aldosterone from cholesterol. Aldosterone then goes to act on the distal convoluted tubule and the collecting duct to make them more permeable to sodium to allow for its reuptake. Water subsequently follows sodium back into the system, which would therefore increase the circulating blood volume. In addition, potassium and hydrogen are also being excreted into the urine simultaneously to maintain the electrolyte balance.

Tubular striated muscle cells (i.e. skeletal and cardiac myocytes) are composed of bundles of rod-like myofibrils. Each individual myofibril consists of many repeating units called sarcomeres. These functional units, in turn, are composed of many alternating actin and mysoin protein filaments that produce muscle contraction. The muscle contraction process is initiated when the muscle cell is depolarized enough for an action potential to occur. When acetylcholine is released from the motor neuron axon terminals that are adjacent to the muscle cells, it binds to receptors on the sarcolemma (muscle cell membrane), causing nicotinic acetylcholine receptors to be activated and the sodium/potassium channels to be opened. The fast influx of sodium and slow efflux of potassium through the channel causes depolarization. The resulting action potential that is generated travels along the sarcolemma and down the T-tubule, activating the L-type voltage-dependent calcium channels on the sarcolemma and ryanodine receptors on the sarcoplasmic reticulum. When these are activated, it triggers the release of calcium ions from the sarcoplasmic reticulum into the cytosol. From there, the calcium ions bind to the protein troponin which displaces the tropomysoin filaments from the binding sites on the actin filaments. This allows for myosin filaments to be able to bind to the actin. According to the Sliding Filament Theory, the myosin heads that have an ADP and phosphate attached binds to the actin, forming a cross-bridge. Once attached, the myosin performs a powerstroke which slides the actin filaments together. The ATP and phosphate are dislodged during this process. However, ATP now binds to the myosin head, which causes the myosin to detach from the actin. The cycle repeats once the attached ATP dissociates into ADP and phosphate, and the myosin performs another powerstroke, bringing the actin filaments even closer together. Numerous actin filaments being pulled together simultaneously across many muscles cells triggers muscle contraction.

Gastric acid plays a key role in the digestion of proteins by activating digestive enzymes to break down long chains of amino acids. In addition, it aids in the absorption of certain vitamins and minerals and also acts as one of the body's first line of defence by killing ingested micro-organisms. This digestive fluid is formed in the stomach (specifically by the parietal cells) and is mainly composed of hydrochloric acid (HCl). However, it is also constituted of potassium chloride (KCl) and sodium chloride (NaCl). The main stimulants of acid secretion are histamine, gastrin, and acetylcholine which all, after binding to their respective receptors on the parietal cell membrane, trigger a G-protein signalling cascade that causes the activation of the H+/K+ ATPase proton pump. As a result, hydrogen ions are able to be pumped out of the parietal cell and into the lumen of the stomach. The hydrogen ions are available inside the parietal cell after water and carbon dioxide combine to form carbonic acid(the reaction is catalyzed by the carbonic anhydrase enzyme) which dissociates into a bicarbonate ion and a hydrogen ion. Moreover, the chloride and potassium ions are transported into the stomach lumen through their own channels so that hydrogen ions and/or potassium ions can form an ionic bond with chloride ions to form HCl and/or KCl, which are both constituents of stomach acid. In addition, the peptide hormone somatostatin is the main inhibitor to gastric acid secretion. Not only does it inhibit the G-protein signalling cascade that leads to proton pump activation, but it also directly acts on the enterochromaffin-like cells and G cells to inhibit histamine and gastrin release, respectively.

Ibuprofen is a very common NSAID drug used to treat pain and inflammation. This includes headaches, muscle pain and fever. It is sold under the brand name Advil or Motrin. Ibuprofen is typically ingested orally, although in the USA an intravenous version can be used. It inhibits cyclooxygenase (COX) non-selectively. This enzyme is responsible for the creation of prostaglandins, which allow pain to be felt. Inhibiting COX makes prostaglandin creation more sparse, thus resulting in less pain for the patient using ibuprofen. Arachdonic acid is converted into prostaglandin H2 by using cytosolic prostaglandin G/H synthase (COX). These enzymes are available as COX1 and COX2, and are encoded by PTGS1 (COX1) and PTGS2 (COX2). Ibuprofen may also inhibit fatty acid amide hydrolase (FAAH), which results in the activation of antinociceptive axis, which then metabolizes the endocannabinoid anandamide.

Benazepril (trade name: Lotensin) belongs to the class of drugs known as angiotensin-converting enzyme (ACE) inhibitors and is used primarily to lower high blood pressure (hypertension). This drug can also be used in the treatment of congestive heart failure and type II diabetes. Benazepril is a prodrug which, following oral administration, undergoes biotransformation in vivo into its active form benazeprilat via cleavage of its ester group by the liver. Angiotensin-converting enzyme (ACE) is a component of the body's renin–angiotensin–aldosterone system (RAAS) and cleaves inactive angiotensin I into the active vasoconstrictor angiotensin II. ACE (or kininase II) also degrades the potent vasodilator bradykinin. Consequently, ACE inhibitors decrease angiotensin II concentrations and increase bradykinin concentrations resulting in blood vessel dilation and thereby lowering blood pressure.

Cilazapril (trade name: Dynorm, Inhibace, Vascace) belongs to the class of drugs known as angiotensin-converting enzyme (ACE) inhibitors and is used primarily to lower high blood pressure (hypertension). This drug can also be used in the treatment of congestive heart failure and type II diabetes. Cilazapril is a prodrug which, following oral administration, undergoes biotransformation in vivo into its active form cilazaprilat via cleavage of its ester group by the liver. Angiotensin-converting enzyme (ACE) is a component of the body's renin–angiotensin–aldosterone system (RAAS) and cleaves inactive angiotensin I into the active vasoconstrictor angiotensin II. ACE (or kininase II) also degrades the potent vasodilator bradykinin. Consequently, ACE inhibitors decrease angiotensin II concentrations and increase bradykinin concentrations resulting in blood vessel dilation and thereby lowering blood pressure.

Enalapril (trade name: Vasotec) belongs to the class of drugs known as angiotensin-converting enzyme (ACE) inhibitors and is used primarily to lower high blood pressure (hypertension). This drug can also be used in the treatment of congestive heart failure and type II diabetes. Enalapril is a prodrug which, following oral administration, undergoes biotransformation in vivo into its active form enalaprilat via cleavage of its ester group by the liver. Angiotensin-converting enzyme (ACE) is a component of the body's renin–angiotensin–aldosterone system (RAAS) and cleaves inactive angiotensin I into the active vasoconstrictor angiotensin II. ACE (or kininase II) also degrades the potent vasodilator bradykinin. Consequently, ACE inhibitors decrease angiotensin II concentrations and increase bradykinin concentrations resulting in blood vessel dilation and thereby lowering blood pressure.