Pathways

Antipyrine is an NSAID used for the symptomatic treatment of acute otitis media, most commonly in combination with benzocaine. Antipyrine possesses anti-inflammatory, analgesic and antipyretic activity. It targets the prostaglandin G/H synthase-1 (COX-1) and prostaglandin G/H synthase-2 (COX-2) in the cyclooxygenase pathway. The cyclooxygenase pathway begins in the cytosol with phospholipids being converted into arachidonic acid by the action of phospholipase A2. The rest of the pathway occurs on the endoplasmic reticulum membrane, where prostaglandin G/H synthase 1 & 2 converts arachidonic acid into prostaglandin H2. Prostaglandin H2 can either be converted into thromboxane A2 via thromboxane A synthase, prostacyclin/prostaglandin I2 via prostacyclin synthase or prostaglandin E2 via prostaglandin E synthase. COX-2 is an inducible enzyme, and during inflammation, it is responsible for prostaglandin synthesis. It leads to the formation of prostaglandin E2 which is responsible for contributing to the inflammatory response by activating immune cells and for increasing pain sensation by acting on pain fibers. Antipyrine inhibits the action of COX-1 and COX-2 on the endoplasmic reticulum membrane. This reduces the formation of prostaglandin H2 and therefore, prostaglandin E2 (PGE2). The low concentration of prostaglandin E2 attenuates the effect it has on stimulating immune cells and pain fibers, consequently reducing inflammation and pain. Fever is triggered by inflammatory and infectious diseases. Cytokines are produced in the central nervous system (CNS) during an inflammatory response. These cytokines induce COX-2 production that increases the synthesis of prostaglandin, specifically prostaglandin E2 which adjusts hypothalamic temperature control by increasing heat production. Because antipyrine decreases PGE2 in the CNS, it has an antipyretic effect. Antipyretic effects results in an increased peripheral blood flow, vasodilation, and subsequent heat dissipation.

Antipyrine (also named Fenazone or Phenazone) is often used for testing the effect of other drugs on drug-metabolizing enzymes in the liver. Antipyrine can block prostaglandin synthesis by the action of inhibition of prostaglandin G/H synthase 1 and 2. Prostaglandin G/H synthase 1 and 2 catalyze the arachidonic acid to prostaglandin G2, and also catalyze prostaglandin G2 to prostaglandin H2 in the metabolism pathway. Decreased prostaglandin synthesis in many animal model's cell is caused by presence of antipyrine.

Antihemophilic factor, human recombinant of the coagulation Factor VIII, also known as Advate, Adynovate, Helixate, Kogenate, Kovaltry, Novoeight, Recombinate, to treat hemophilia A, von Willebrand disease and Factor XIII deficiency. Antihemophilic factor, human recombinant is administered intravenously and acts to correct coagulation defects, by activating coagulation factor X and IX.

Antihemophilic factor human, also known as Hemofil, Koate, and Wilate is used as factor VIII replacement therapy to treat hemophilia A. It is a non-recombinant concentrate of the endogenous coagulation factor VIII, produced by reducing von Willebrand Factor antigen and purified by affinity chromatography. Hemophilia A is caused by mutations in the coagulation factor VIII gene that leads to functional deficiency and or complete loss of the coagulation factor. These mutations lead to bleeding and being able to bruise easily, exogenous replacement of coagulation factor VIII in order to counteract the deficiencies. Administered intravenously the antihemophilic factor human replaces the abnormal coagulation factor VIII, acting as a cofactor to activate coagulation factor IX and X.

As the bacteria are cleared, tryptophan levels continue to drop as the indole dioxygenase (IDO) enzyme becomes more active. IDO activation results in the generation (from tryptophan) of kynurenine (and its other metabolites) through a self-stimulating autocrine process. Kynurenine binds to the arylhydrocarbon receptor (AhR) found in most immune cells [5-7]. In addition to increased kynurenine production via IDO mediated synthesis, hyopalbuminemia can also lead to the release of bound kynurenine (and other immunosuppressive LysoPCs) into the bloodstream to fuel this kynurenine-mediated immunosuppression process. Regardless of the source of kynurenine, the kynurenine-bound AhR will migrate to the nucleus to bind to NF-kB which leads to more production of the IDO enzyme, which leads to more production of kynureneine and more loss of tryptophan. High kynurenine levels and low tryptophan levels leads to a shift in T-cell differentiation from a TH1 response (pro-inflammatory) to the production of Treg cells and an anti-inflammatory response [5-7]. This often marks the beginning of the body’s return to normal and the impending end of the bacterial infection. High kynurenine levels also lead to the production of more IL10R (the interluekin-10 receptor) via binding of kynurenine to the arylhydrocarbon receptor (AhR). Activated AhR effectively increases the anti-inflammatory response from interleukin 10 (an anti-inflammatory cytokine). Low tryptophan levels also lead to the activation of the general control non-depressible 2 kinase (GCN2K) pathway, which inhibits the mammalian target of rapamycin (mTOR), and protein kinase C signaling. This leads to T cell autophagy and anergy. High levels of kynurenine also lead to the inhibition of T cell proliferation through induction of T cell apoptosis [5-7]. After bacterial clearance, the anti-inflammatory pathway is further activated and the pro-inflammatory process further deactivated. With the bacteria cleared, the production of pro-inflammatory cytokines are reduced due to lack of activity from TLR4 and other TLR stimulation. Additionally, anti-inflammatory cytokines (IL-10 and IL-4) are induced leading to a shift in the T-cells from a pro-inflammatory TH1 response to an anti-inflammatory Treg response. Likewise, with this T-cell shift, levels of cortisol and epinephrine drop, as do levels of glucose and NO. Blood pressure begins to rise to normal. Kynurenine levels fall due to continued kynurenine metabolism and uptake by serum albumin. More tryptophan is released or produced to arrest the IDO synthesis (which reduces kynurenine levels) which further reduces activation of the arylhydrocarbon receptor (AhR) which leads to the de-activation of the NF-κB pathway, which leads to lower levels of pro-inflammatory cytokines. Itaconate, accumulated by pro-inflammatory B-cells and T-cells, promotes the post-transcriptional modification of KEAP1, which induces the expression of the antioxidant response and PPARγ. PPARγ inhibits the NF-κB pathway and induces the expression of anti-inflammatory genes while at the same time increasing fatty-acid β-oxidation and glutaminolysis. Glutamine and fatty acids fuel the TCA cycle to support oxidative-phosphorylation. Aerobic glycolysis stops. The accumulated lactate and α-Ketoglutarate promote cysteine modifications that induce the expression of anti-inflammatory genes. Lactate levels in the blood drop as do glucose levels. Macrophages and other T-cells and B-cells begin to die or apoptose, the number of white blood cells drops and the body returns to normal.

Anthocyanin biosynthesis

Anthocyanidin sambubioside biosynthesis is a pathway by which anthocyanins (plant pigments) become sambubiosides, diglucosides containing an attached xylose on the 2''-O-position of the 3-O-glucose moiety of anthocyanidins. First, anthocyanidin 3-O-glucoside 2'''-O-xylosyltransferase uses UDP to convert delphinidin 3-glucoside into delphinidin 3-sambubioside, cyanidin 3-glucoside into cyanidin 3-sambubioside, and pelargonidin 3-glucoside into pelargonidin-3-sambubioside. Second, the predicted enzyme anthocyanin 3-O-sambubioside 5-O-glucosyltransferase (coloured orange) is theorized to use UDP to convert cyanidin 3-sambubioside into cyanidin 3-sambubioside 5-glucoside and pelargonidin-3-sambubioside into pelargonidin 3-sambubioside-5-glucoside.