In an AP scenario several inflammatory

In an AP scenario, several inflammatory mediators are produced locally to orchestrate an immune response. Eicosanoids are among those molecules and represent a class of lipid mediators synthesized from arachidonic LOXO-101 through the action of cyclooxygenases or lipoxygenases to generate prostaglandins and thromboxanes or leukotrienes and lipoxins, respectively . Lipoxygenase metabolites have been found in rat inflamed dental pulp and human AP , , , , but only leukotriene B4 (LTB) is positively correlated to polymorphonuclear cell recruitment and pain , . LTB binds G-coupled receptors (leukotriene B4 receptor 1 [BLT1] and leukotriene B4 receptor 2 [BLT2]), resulting in an increase in intracellular calcium and a reduction of cyclic adenosine monophosphate (cAMP) to mediate kinase activation, genic transcription, and, ultimately, cell recruitment , . Despite the fact that lipid mediators are produced in response to an infection in AP, the role of the 5-lipoxygenase pathway in disease severity and associated bone loss is not known.
Inflammation and natural products Acute inflammation is an essential physiological response to confront injury and infection. However when inflammation becomes excessive and persists it may contribute to a wide range of diseases including rheumatoid arthritis, dermatitis, asthma, allergy, diabetes and cancer. Damage- or pathogen-associated molecular patterns (such as tissue injury or bacterial infection) induce acute inflammation to counter the threat. At a later stage, inflammation is actively resolved or, if not successful, turned into chronic inflammation. These processes require the interplay of specialized and non-specialized immune cells (e.g., macrophages and lymphocytes but also endothelial cells and fibroblasts) and a broad spectrum of counter-regulating pro-inflammatory, immunomodulatory and pro-resolving signaling pathways, which determine the cellular and organismal response (e.g., immune cell differentiation, recruitment and activation as well as swelling, fever and pain) depending on their kinetics, dynamics and locale of production. The eicosanoid and docosanoid network plays an important role in the initiation, progression and resolution of inflammation (Fig. 1) and is strongly interwoven with multiple other signaling pathways (e.g., cytokine storms), thereby regulating key aspects of immunity such as immune cell expansion, differentiation, adhesion, migration and chemotaxis (Dennis and Norris, 2015; Funk, 2001; Shimizu, 2009). Current anti-inflammatory therapy is based on three pillars: 1) non-steroidal anti-inflammatory drugs (NSAIDs) which suppress eicosanoid biosynthesis and are the most widely used drugs to treat inflammation, fever and pain, 2) glucocorticoids that agonize the glucocorticoid receptor, and 3) biopharmaceuticals such as therapeutic antibodies and protein ligands (Koeberle and Werz, 2014). Increasing evidence from network science suggests that complex diseases like inflammation are favorably tamed by smart polypharmacological approaches which readjust the dysregulated network during inflammation to homeostasis by synergistically targeting counter-supportive pathways while preventing adverse compensatory mechanisms (Csermely et al., 2013). Some of the most commonly used anti-inflammatory drugs were bioinspired. For example, the NSAID acetylsalicylic acid (aspirin) is the advancement of salicylic acid, which was already used in ancient times to treat inflammatory disorders and pain as active component of willow bark (Amann and Peskar, 2002). Meanwhile, it is well established that (acetyl)salicylic acid acts via multiple mechanisms (among others by targeting cyclooxygenases, kinases, transcription factors and pro-resolving eicosanoid formation) and that these multiple activities underlie the efficacy and safety of acetylsalicylic acid as one of the commercially most successful drugs (Amann and Peskar, 2002; Roth et al., 1975; Vane, 1971).
Eicosanoids: biosynthesis, key enzymes and functions