Pathways

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.

Antazoline is an antihistamine agent used for the symptomatic treatment of nasal congestion and allergic conjunctivitis. H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. H1-antihistamines act on H1 receptors in T-cells to inhibit the immune response, in blood vessels to constrict dilated blood vessels, and in smooth muscles of lungs and intestines to relax those muscles. H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. Reducing the activity of the NF-κB immune response transcription factor through the phospholipase C and the phosphatidylinositol (PIP2) signalling pathways also decreases antigen presentation and the expression of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors. Furthermore, lowering calcium ion concentration leads to increased mast cell stability which reduces further histamine release. First-generation antihistamines readily cross the blood-brain barrier and cause sedation and other adverse central nervous system (CNS) effects (e.g. nervousness and insomnia). Second-generation antihistamines are more selective for H1-receptors of the peripheral nervous system (PNS) and do not cross the blood-brain barrier. Consequently, these newer drugs elicit fewer adverse drug reactions.

Antazoline is an antihistamine agent used for the symptomatic treatment of nasal congestion and allergic conjunctivitis. H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. H1-antihistamines act on H1 receptors in T-cells to inhibit the immune response, in blood vessels to constrict dilated blood vessels, and in smooth muscles of lungs and intestines to relax those muscles. Allergies causes blood vessel dilation which causes swelling (edema) and fluid leakage. Antazoline inhibits the H1 histamine receptor on blood vessel endothelial cells. This normally activates the Gq signalling cascade which activates phospholipase C which catalyzes the production of Inositol 1,4,5-trisphosphate (IP3) and Diacylglycerol (DAG). Because of the inhibition, IP3 doesn't activate the release of calcium from the sarcoplasmic reticulum, and DAG doesn't activate the release of calcium into the cytosol of the endothelial cell. This causes a low concentration of calcium in the cytosol, and it, therefore, cannot bind to calmodulin. Calcium bound calmodulin is required for the activation of the calmodulin-binding domain of nitric oxide synthase. The inhibition of nitric oxide synthesis prevents the activation of myosin light chain phosphatase. This causes an accumulation of myosin light chain-phosphate which causes the muscle to contract and the blood vessel to constrict, decreasing the swelling and fluid leakage from the blood vessels caused by allergens.

Antazoline is a first-generation ethylenediamine H1-antihistamine. H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. Reducing the activity of the NF-κB immune response transcription factor through the phospholipase C and the phosphatidylinositol (PIP2) signalling pathways also decreases antigen presentation and the expression of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors. Furthermore, lowering calcium ion concentration leads to increased mast cell stability which reduces further histamine release. First-generation antihistamines readily cross the blood-brain barrier and cause sedation and other adverse central nervous system (CNS) effects (e.g. nervousness and insomnia). Second-generation antihistamines are more selective for H1-receptors of the peripheral nervous system (PNS) and do not cross the blood-brain barrier. Consequently, these newer drugs elicit fewer adverse drug reactions.

Antazoline is an antihistamine agent used for the symptomatic treatment of nasal congestion and allergic conjunctivitis. H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. H1-antihistamines act on H1 receptors in T-cells to inhibit the immune response, in blood vessels to constrict dilated blood vessels, and in smooth muscles of lungs and intestines to relax those muscles. H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. H1-antihistamines act on H1 receptors in T-cells to inhibit the immune response, in blood vessels to constrict dilated blood vessels, and in smooth muscles of lungs and intestines to relax those muscles. Allergies causes blood vessel dilation which causes swelling (edema) and fluid leakage. Antazoline also inhibits the H1 histamine receptor on bronchiole smooth muscle myocytes. This normally activates the Gq signalling cascade which activates phospholipase C which catalyzes the production of Inositol 1,4,5-trisphosphate (IP3) and Diacylglycerol (DAG). Because of the inhibition, IP3 doesn't activate the release of calcium from the sarcoplasmic reticulum, and DAG doesn't activate the release of calcium into the cytosol of the endothelial cell. This causes a low concentration of calcium in the cytosol, and it, therefore, cannot bind to calmodulin.Calcium bound calmodulin is required for the activation of myosin light chain kinase. This prevents the phosphorylation of myosin light chain 3, causing an accumulation of myosin light chain 3. This causes muscle relaxation, opening up the bronchioles in the lungs, making breathing easier.