Pathways

Tumour necrosis factor alpha (TNF-a) is a cytokine that activates TNF rector 1 (TNFR1) signalling complex. TNFR1 mediates cell death signalling and inflammation in response to cytokines, bacteria and cellular stress. The classical NFkB pathway involves activation of TNF receptor associated factor 2, receptor interacting serine/threonine protein kinase and death domains which activate the IKK complex, phosphorylating the IKB proteins triggering their degradation resulting in NF-kB dimers dissociation and release. Caspase 2 interacts with TNF-receptor associated factor 2 and receptor interacting serine/threonine protein kinase to activate NFkB. Mitogen activated protein kinases of the MAP3K family are also involved in TNFR1-mediated IKK activation. Mitogen activated kinases can phosphorylate IKK to activate it as well. Activation of Mitogen-activated protein kinase 8 and 14 are involved in the cross-talk of other inflammatory pathways.

Tumour necrosis factor alpha (TNF-a) is a cytokine that activates TNF rector 1 (TNFR1) signalling complex. TNFR1 mediates cell death signalling and inflammation in response to cytokines, bacteria and cellular stress. The classical NFkB pathway involves activation of TNF receptor associated factor 2, receptor interacting serine/threonine protein kinase and death domains which activate the IKK complex, phosphorylating the IKB proteins triggering their degradation resulting in NF-kB dimers dissociation and release. Caspase 2 interacts with TNF-receptor associated factor 2 and receptor interacting serine/threonine protein kinase to activate NFkB. Mitogen activated protein kinases of the MAP3K family are also involved in TNFR1-mediated IKK activation. Mitogen activated kinases can phosphorylate IKK to activate it as well. Activation of Mitogen-activated protein kinase 8 and 14 are involved in the cross-talk of other inflammatory pathways.

Tumour necrosis factor alpha (TNF-a) is a cytokine that activates TNF rector 1 (TNFR1) signalling complex. TNFR1 mediates cell death signalling and inflammation in response to cytokines, bacteria and cellular stress. The classical NFkB pathway involves activation of TNF receptor associated factor 2, receptor interacting serine/threonine protein kinase and death domains which activate the IKK complex, phosphorylating the IKB proteins triggering their degradation resulting in NF-kB dimers dissociation and release. Caspase 2 interacts with TNF-receptor associated factor 2 and receptor interacting serine/threonine protein kinase to activate NFkB. Mitogen activated protein kinases of the MAP3K family are also involved in TNFR1-mediated IKK activation. Mitogen activated kinases can phosphorylate IKK to activate it as well. Activation of Mitogen-activated protein kinase 8 and 14 are involved in the cross-talk of other inflammatory pathways.

Tumour necrosis factor alpha (TNF-a) is a cytokine that activates TNF rector 1 (TNFR1) signalling complex. TNFR1 mediates cell death signalling and inflammation in response to cytokines, bacteria and cellular stress. The classical NFkB pathway involves activation of TNF receptor associated factor 2, receptor interacting serine/threonine protein kinase and death domains which activate the IKK complex, phosphorylating the IKB proteins triggering their degradation resulting in NF-kB dimers dissociation and release. Caspase 2 interacts with TNF-receptor associated factor 2 and receptor interacting serine/threonine protein kinase to activate NFkB. Mitogen activated protein kinases of the MAP3K family are also involved in TNFR1-mediated IKK activation. Mitogen activated kinases can phosphorylate IKK to activate it as well. Activation of Mitogen-activated protein kinase 8 and 14 are involved in the cross-talk of other inflammatory pathways.

Tobramycin (also named aktob or tobi) is an aminoglycoside antibiotic that can be used to treat various gram-negative bacterial infections such as the species of Pseudomonas. Bacterial 30S ribosomal subunit protein and four nucleotides of 16S rRNA will be bound with tobramycin irreversibly to cause misreading of mRNA; so that formation of mRNA could be prevented because of incorrect insertion of amino acids to polypeptide will result nonfunctional or toxic peptides. Therefore, there is no protein synthesis for bacteria.

Tobramycin is an antibiotic that is commonly used to treat bacterial infections such as cystic fibrosis-associated bacterial, lower respiratory tract, urinary tract, eye, skin, and bone infections. This drug is a part of the aminoglycoside antibiotics family. It can be administered via inhalation, injection (intravenously or intramuscular), or even via topical cream. Tobramycin acts by binding to bacterial membranes causing displacement of divalent cations and increasing membrane permeability allowing entry into the bacterial cell. Once inside the bacterial cell, tobramycin then targets the bacterial 30S ribosome and binds to it, halting protein synthesis. It binds to the site where the normal base pairing of codon and anti-codon takes place as well as adding amino acids to the growing polypeptide chain, with this blocked it leads to termination of the chain and production of non-functional proteins. The adverse effects of tobramycin are not well known therefore if a patient is experiencing overdose hemodialysis should be performed to clear the excess of tobramycin as they are at risk of nephrotoxicity, ototoxicity, neuromuscular blockade, respiratory paralysis, and/or respiratory failure.

This pathway illustrates the tocainide targets involved in antiarrhythmic therapy. Contractile activity of cardiac myocytes is elicited via action potentials mediated by a number of ion channel proteins. During rest, or diastole, cells maintain a negative membrane potential; i.e. the inside the cell is negatively charged relative to the cellsŠ—È extracellular environment. Membrane ion pumps, such as the sodium-potassium ATPase and sodium-calcium exchanger (NCX), maintain low intracellular sodium (5 mM) and calcium (100 nM) concentrations and high intracellular potassium (140 mM) concentrations. Conversely, extracellular concentrations of sodium (140 mM) and calcium (1.8 mM) are relatively high and extracellular potassium concentrations are low (5 mM). At rest, the cardiac cell membrane is impermeable to sodium and calcium ions, but is permeable to potassium ions via inward rectifier potassium channels (I-K1), which allow an outward flow of potassium ions down their concentration gradient. The positive outflow of potassium ions aids in maintaining the negative intracellular electric potential. When cells reach a critical threshold potential, voltage-gated sodium channels (I-Na) open and the rapid influx of positive sodium ions into the cell occurs as the ions travel down their electrochemical gradient. This is known as the rapid depolarization or upstroke phase of the cardiac action potential. Sodium channels then close and rapidly activated potassium channels such as the voltage-gated transient outward delayed rectifying potassium channel (I-Kto) and the voltage-gated ultra rapid delayed rectifying potassium channel (I-Kur) open. These events make up the early repolarization phase during which potassium ions flow out of the cell and sodium ions are continually pumped out. During the next phase, known as the plateau phase, calcium L-type channels (I-CaL) open and the resulting influx of calcium ions roughly balances the outward flow of potassium channels. During the final repolarization phase, the voltage-gated rapid (I-Kr) and slow (I-Ks) delayed rectifying potassium channels open increasing the outflow of potassium ions and repolarizing the cell. The extra sodium and calcium ions that entered the cell during the action potential are extruded via sodium-potassium ATPases and NCX and intra- and extracellular ion concentrations are restored. In specialized pacemaker cells, gradual depolarization to threshold occurs via funny channels (I-f). Tocainide, the alpha-methyl analogue of lidocaine, is a Class 1B antiarrhythmic drug. It has similar electrophysiological effects as lidocaine and may be used to treat ventricular arrhythmias. Unlike lidocaine, tocainide may be administered orally and has a long plasma half-life of 12 hours (plasma t1/2 of lidocaine = 15 Š—– 30 minutes). Like other Class 1B antiarrhythmic agents, tocainide preferentially blocks sodium channels in their inactivated state. Voltage-gated sodium channels (I-Na) are responsible for the rapid depolarization phase of cardiac myocyte action potentials. Inhibition of I-Na results in an increased threshold of excitability and decreased automaticity. The membrane stabilizing effects of tocainide also cause a slight decrease in action potential duration. Tocainide is administered as a racemic mixture. The R-isomer is four times more potent than the S-isomer and is cleared faster in anephric patients.