*1.1. Inflammatory Pathways and Models*

Multiple inflammatory pathways play a role in innate immunity and activate adaptive immunity to combat the cause of inflammation. These pathways are initiated by several classes of receptors present on leukocytes known as pattern recognition receptors. Common examples of such receptors are (1) the toll-like receptor family (TLR), (2) C-type lectin receptors, (3) retinoic acid-inducible gene-I-like receptors, and (4) nucleotide-binding

and oligomerization domain (NOD)-like receptors (NLR) [8,9]. The activation of immune cells such as macrophages, neutrophils, and other immune cells leads to the secretion of cytokines, which sustain the inflammatory response. These cytokines bind to the immune cells and activate their function. The common cytokine receptor families are the: (1) immunoglobulin superfamily, (2) class I cytokine receptor family, (3) class II cytokine receptor family, (4) tissue necrosis factor (TNF) receptor superfamily, and (5) chemokine receptor family. Ligand binding on the pattern recognition receptors or cytokine receptors activates several signaling pathways, which ultimately induces the transcription of several inflammation regulatory genes. There are four broad categories of signaling pathways activated during the inflammation process: (1) the mitogen-activated protein kinase (MAPK) pathway, (2) phosphoinositide 3-kinase signaling pathway, (3) Janus kinase (JAK) signal transducer and activator of transcription (STAT), and (4) I kappa B kinase (IκB)/nuclear factor kappa B (NF-κB) signaling pathways [10,11].

The sustained activation of these signaling pathways underlies the cause of several inflammatory diseases. For instance, the NF-kB signaling pathway is a classic pathway in the regulation of inflammation. The activation of NF-kB via IκBα increases the expression of various downstream inflammatory mediators, such as proinflammatory cytokines (interleukin 1β (IL-1β), IL-6, and TNFα); key proinflammatory enzymes, including inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2); and their derivatives nitric oxide (NO) and prostaglandin E2 (PGE2) [12,13]. Multiple experimental models are available to study the activation of inflammatory signaling and transcription for various inflammatory diseases. These experimental models are also widely used to evaluate potential anti-inflammatory compounds and to understand the mechanism(s) of their therapeutic effects. Various experimental models have been designed and implemented to study the preliminary efficacy of anti-inflammatory compounds. For example, carrageenan-induced paw edema in mouse [14] and 12-O-tetradecanoylphorbol-13-acetate (TPA) mouse ear inflammation models [15]. Other specific experimental models are also available and have been used for the assessment of chronic inflammatory diseases, including the dextran sodium sulfate (DSS)-induced colitis model [16], which has been widely used to screen the anti-inflammatory effects of marine drugs. For example, this model was recently used to study the anti-inflammatory effects of polysaccharides isolated from the mussel *Mytilus couscous* [17]. Another well-known model to study cytokine-mediated inflammatory signaling pathways is TNFα-induced intestinal inflammation in colon cancer cell lines [18]. For example, krill oil was screened for its anti-inflammatory effects by using this model in HT-29 and Caco-2 cells [19]. The free fatty acid (FFA)-mediated activation of inflammatory signaling in hepatocytes is a well-known model for nonalcoholic steatohepatitis [20]. Jiena et al. [21] demonstrated that fucoxanthin, a popular marine-derived compound, attenuated FFA-induced inflammation via the AMP-activated protein kinase/nuclear factor erythroid 2–related factor 2/TLR4 signaling pathway in normal human Chang liver cells.
