Browsing Pathways

large non coding RNA, in repair DNA mechanims

Amiloride is a K+ (potassium-sparing diuretics) that works by directly blocking the epithelial sodium channel mainly in the distal convoluted tubule in the nephrons of the kidney in Homo Sapiens. This pathway focuses on the action of the diuretic Amiloride on the ENaC of the distal convoluted tubule which works by inhibiting sodium reabsorption. This promotes the loss of sodium in the sodium-potassium pump as well as water from the body, but without depleting potassium. Amiloride exerts its potassium-sparing effect through the inhibition of sodium reabsorption at the distal convoluted tubule, cortical collecting tubule, and collecting duct; this decreases the net negative potential of the tubular lumen and reduces both potassium and hydrogen secretion and their subsequent excretion. Amiloride is not an aldosterone antagonist and its effects are seen even in the absence of aldosterone. Usage of this drug alleviates symptoms of edema (swelling), oliguria (decreased urine output), high blood pressure, hypokalemia in patients taking diuretics.

Furosemide is a loop diuretic drug, administered orally or intravenously to treat conditions such as hypertension or edema associated with to congestive heart failure, cirrhosis, liver disease and renal failure. It targets the nephrons of the kidney, mainly the ascending limb of the loop of henle. The basolateral membrane of the ascending loop of henle, the Na+/K+ ATPase, Cl- channel and K+/Cl- co-transporter which are essential for the function for ion and water reabsorption. The Na+/K+ ATPase pumps Na+ from the cell into the peritubular fluid and K+ from the peritubular fluid into the cell. The K+/Cl- co-transporter moves K+ and Cl- from the cell into the peritubular fluid and the Cl- channel transports Cl- from the cell into the peritubular fluid. The apical membrane contains the Na+/K+/2Cl- co-transporter (NKCC2) and the K+ channel. The NCKCC2 is responsible for reabsorption Na+, K+ and Cl- from the lumen into the cells of the loop of henle. The K+ channel transports K+ from the cells back into the lumen. Furosemide is transported from the capillaries into the cells of the loop of henle via the OAT1 transporter (Solute carrier family 22 member 6). It is then transported from the cell into the lumen via multidrug resistant associated protein 4. Furosemide competes with Cl- for the NKCC2 transporter. It binds to this transporter, inhibiting it and preventing Na+, K+ and Cl- reabsorption from the lumen. The concentration of these ions builds up in the lumen, decreasing the slope of the concentration gradient between the cells and the lumen. Since water reabsorption is linked to ion reabsorption, water reabsorption is also decreased, resulting in a greater volume of water being excreted in urine. This is relieves symptoms such as swelling/ edema and hypertension in patients. Furosemide may also inhibit sodium and chloride reabsorption in the proximal and distal tubules. Side effects such as blurred vision, headache, diarrhea, constipation, fever, tinnitus, rash, jaundice, increased urination, dehydration, dizziness, nausea and vomiting, gout, hyperuricemia, muscle cramps may occur from taking furosemide.

Vinorelbine is a semi-synthetic third generation vinca alkaloid used in chemotherapy treatment for cervical, lung, breast, and esophageal cancers. It is differentiated from natural alkaloids by its eight-catharanine ring. Administered intravenously, vinorelbine acts on tumorous cells in the body to suppress their growth. Its main mechanism of action works by binding microtubules that are formed during the M phase of mitosis. This ceases the polymerization of microtubules, effectively pausing the cell at its G2/M phase. The disarray of microtubules induces two proteins; cellular tumor antigen p53 and cyclin-dependent kinase inhibitor p21. The latter protein works to inhibit cyclin-dependent kinases in the cell, which disrupt the phosphorylation of the apoptosis inhibitor Bcl-2. Bcl-2 suppresses apoptosis by regulating the permeability of the mitochondrial membrane but is unable to do so due to interrupted phosphorylation. The former protein, p53, acts on BAK and BAX to enact conformational changes, creating pores in the mitochondrial membrane that allow the exit of cytochrome c. Cytochrome c further activates caspases in the cell, which cleave essential cellular proteins. In this way, p53 and p21 work alongside each other to promote apoptosis and terminate unhealthy cells. Vinorelbine is especially valuable as a drug because it binds specifically to mitotic microtubules, likely decreasing its neurotoxicity.

CB1 receptors can be found throughout the central and peripheral nervous system and have a range of effects on neurotransmitter release. They are part of the G-protein coupled receptor (GCPR) superfamily of heptihelical receptors and are one of the most abundant GPCR in the brain. This pathway illustrates a generic agonist binding to and activating a CB1 receptor. The resulting signaling pathway highlights cAMP signaling, which acts primarily through the inhibition of adenylyl cyclase to reduce protein kinase activity. This reduction influences current flow at voltage-dependent potassium channels, promoting the influx of ions into the presynaptic neuron. It also induces tyrosine phosphorylation of both FAK and FRNK (a distinct isoform of FAK). Activation of the receptor also inhibits calcium channels, reducing the flow of ions into the neuron. The combination of increased calcium and potassium within the synaptic cleft inhibits the proper polarization of the postsynaptic neuron, interrupting synaptic signalling. This leads to an analgesic effect, effectively preventing the propagation of pain signals. The activation of the CB1 receptor also activates MAPK, a serine kinase that is an essential part of the MAP signal transduction pathway. The MAPK signalling cascade is responsible for mediating a number of different cellular functions including adhesion and cell growth, which it achieves through regulating transcription and transcription. The effects of CB1 activation are broad, and the illustrated pathway serves as a general picture of its immediate cellular effects.

Etoposide is an antineoplastic drug given orally or IV to treat cancers such as leukemias, lymphomas, lung, testicular, ovarian, and prostate cancers. It acts in rapidly dividing cells since this is a major property of cancer cells. This means that in addition to targeting cancers cells, it would also target other rapidly dividing cells like hair follicles. Etoposide enters the cell via the canalicular multispecific organic anion transporter 2 and goes into the nucleus where it forms a complex with DNA and topoisomerase II. DNA topoisomerase II is responsible for cutting and religating double stranded DNA. Etoposide binds to and inhibits topoisomerase II. This prevents the repair of single and double stranded breaks in the DNA, leading to errors in DNA synthesis. Etoposide is cell cycle phase specific. In the cell cycle, G1 involves cell growth, S includes DNA synthesis, G2 includes more growth, preparation for mitosis (produce new proteins) and DNA checkpoint replicated DNA is repaired and M is mitosis/cell division. Etioposide inhibits the S and G2 phases of the cell cycle. The errors during DNA synthesis eventually triggers the cell death pathway, leading to apoptosis of the cell. This prevents growth and progression of the cancer as the cancer cells are dying. Common side effects of etoposide are nausea, vomiting, myelosuppression, alopecia, abdominal pain, hypotension, stomatitis, diarrhea, fatigue, allergic reactions and constipation.

Sotalol is a potassium channel beta blocker used to treat ventricular arrhythmias and to help maintain normal sinus rhythm in atrial fibrillation and flutter. After being taken orally, it is absorbed into the blood through the GI tract and inhibits the beta 1 adrenergic receptor and the potassium voltage gated channel subfamily H member 2 protein on the cell membranes of cardiomyocytes. The beta 1 adrenergic receptor is responsible for Gs signalling and the production of cyclic adenosine monophosphate (cAMP) which activates the L-type calcium channel. The L-type calcium channel is responsible for the influx of calcium from extracellular environment into the cytosol of cardiomyocytes which activates ryanodine receptors to release calcium from the sarcoplasmic reticulum. Calcium is important for the contraction of heart muscle for myosin to and actin to power-stroke so the slower influx of calcium slows down the contractions of the heart lowering the heart rate. The inhibition of potassium voltage gated channel subfamily H member 2 protein inhibits the efflux of potassium out of the cell during the repolarization phase of an action potential. This lengthens the QT interval of the heartbeat as well as prolonging the repolarization phase of action potentials. This regulates the heart rate and slows down any rapid heartrates.