**2.2 Terpenoids**

Terpenoids, also known as isoprenoids, comprise five carbon isoprene units (C5H8). It is a broad and diversified family of naturally occurring chemical compounds from the 5-carbon molecule isoprene. The term terpenes are used as another name for the polymers of isoprene. For terpenes, oxygen is the primary functional group. Quite a few pharmacological effects are present [47]. Found in several conventional herbal remedies, including eucalyptus leaves, the flavours of cinnamon, cloves, and sunflowers, as well as foods like ginger and tomatoes. The bioactive components of terpenoids include citral, menthol, camphor, salvinorin A, cannabinoids, ginkgolide, bilobalide, and curcuminoids [48, 49]. In addition, the bioactive immunomodulating drugs andrographolide and oleanolic acid are active. Andrographolide is a bicyclic diterpenoid lactone compound. It is an official Chinese herbal medicine component and has strong anti-inflammatory properties. Additionally, it can be found in the leaves of Andrographis paniculata and is used to treat

rheumatoid arthritis, laryngitis, and diarrhoea. Nitric oxide (NO) generation is known to be reduced, and iNOS expression is inhibited by andrographolide in RAW 264.7 cells [50]. According to in-vitro research, andrographolide regulates the activity of immune cells like macrophages and microglia, which produces immunomodulatory effects by reducing the levels of TNF-α, COX-2, IL-12, iNOS, and PGE2 proteins [51]. Additionally, it actively modifies the virality of the influenza virus by downregulating the genes for the JAK/STAT signalling and NF-kB signal pathways [52].

Oleanic acid (3β-hydroxy-olea-12-en-28-oic acid) is another name for oleanolic acid. It is naturally related to betulinic acid and contains a pentacyclic triterpenoid moiety. Olea europaea, Rosa woodsii, Prosopis glandulosa, Phoradendron juniperinum, Syzygium claviflorum, Hyptis capitata, Mirabilis jalapa, and Ternstroemia gymnanthera are a few examples of foods and plants that contain it. It is composed of an aglycone component for triterpenoid saponins and a free acid group chemically and has historically been used for its cardiotonic, analgesic, antiinflammatory, and hepatoprotective effects [53]. Oleanolic acid is known to have immune-modulatory effects by causing eukaryotic cells to release high mobility group box-1 protein (HMGB1) and macrophages to release C-reactive protein, endotoxins, and TNF-α. Through the secretion of pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α produced by macrophages, this extracellular HMGB1 acts as a potent immune stimulator [54]. Numerous immune-inflammatory diseases, including disseminated intravascular coagulation, atherosclerosis, sepsis, rheumatoid arthritis, xenotransplantation, and periodontitis, are known to have these immunological reactions. Oleanolic acid also prevents the LPS-induced activation of macrophage-like RAW264.7 cells by reducing the levels of HMGB1 proteins [55]. It is discovered to interact with a cyclooxygenase-2(COX2)-dependent mechanism to stimulate prostaglandin I2 (PGI2) release by human coronary smooth muscle cells [56]. Since it manages immunological problems, it is regarded as an immunomodulator.

Carotenoids are pigmented tetraterpenes, since they have strong light absorption and brilliant colour. They typically have a 40-carbon polyene chain and are made up of eight isoprene units. This nonradiative energy transfer mechanism enables them to absorb extra energy from other molecules [57]. Carotenoids are naturally occurring, lipid-soluble pigments that give host plants and animals their vibrant colour. Plant carotenoids may be crucial to maintaining human health [58]. They can act as potent antioxidants and are thought to treat several chronic illnesses, including cancer, osteoporosis, and cardiovascular disease. Some carotenoids, including lutein, β-carotene, and lycopene, may be able to reduce some inflammatory responses by modulating redox-sensitive signalling pathways like NF-kB and ROS [59–61]. The most prevalent cyclic tetraterpene and most potent pro-vitamin A in nature are β-carotene. It can be turned into vitamin A and is stored in the liver [57]. Lutein, a dihydroxy derivative of β-carotene and a standard component of many fruits and vegetables as well as egg yolks, is one of the lipophilic xanthophylls. It can prevent age-related macular degeneration, guard against oxidative stress, and have a neuroprotective impact on retinal inflammation [62, 63]. Lycopene, an additional acyclic tetraterpene, is the most prevalent carotenoid in the human body [58]. It is primarily found in fruits and vegetables that are red in colour. Since lycopene is a more potent antioxidant than vitamin E, it helps shield cells from free radical damage when there is oxidative stress. It has also been asserted that it lowers the chance of several chronic illnesses, including cardiovascular problems, RA, and atherosclerosis [57, 58]. These carotenoids with antioxidant properties may be developed into immunomodulators in the future.
