**4.3 Anti-inflammatory effects of Morin**

Morin, a natural bioflavonoid belonging to the family Moraceae, is found in the structure of many plants commonly used in alternative medicine [119, 120]. Morin has antihyperglycemic and hepatoprotective effects. Morin's anti-inflammatory effects have been reported in many studies [121–124]. MAPK signaling pathway plays an important role in the transcription of some proinflammatory cytokines as eotaxin-1, MCP-1, and IL-8, which leads to a worsened airway inflammation [125]. Morin attenuates inflammation by regulating MAPK signaling pathway in ovalbumin-induced airway inflammation [126]. Eotaxin-1 provides the delivery of eosinophils to airways and could cause tissue injury and heavy inflammation. It is known that eotaxin-1 expression is regulated by TNF- via the p38 MAPK/NF-B signaling pathways [127]. MCP-1 stimulates histamine release from basophils and TNF- stimulates MCP-1 secretion from airway smooth muscle cells [128]. IL-8 has proinflammatory effects on immune cells and stimulates the infiltration of neutrophils into the airways in asthma [129]. In the study has been determined that Morin significantly reduced the increases in eotaxin-1, MCP1, and IL-8 in human and Morin inhibits lung inflammation with these effects [123]. NF-κB pathway activation is considered to respond to oxidative stress [130] and leads to an increase in the expression of inflammatory cytokines and consequently, inflammation develops. It has been reported that Morin administration caused NF-κB inhibition in the Parkinson model which was experimentally created in mice [124]. It has been determined that Morin prevents inflammatory damage by regulating the NF-κB pathway in indomethacin-induced gastric ulcer [131]. In another study was determined that Morin attenuates the expression of inflammatory cytokine with downregulation of MAPK and NF-κB signaling pathways in LPS-induced primary bovine mammary epithelial cells [132]. Tian et al. has been determined that Morin has hepatoprotective effects by inhibiting to NF-κB/TLR4 signaling pathway in LPS/Dgalactosamine-induced acute liver injury [127]. Also, Morin prevents inflammation

by inhibiting PI3K/AKT/NF-κB signaling pathway the cigarette smoke-induced lung inflammation in mice. Morin significantly inhibits the levels of proinflammatory cytokines as TNF-α, and IL-1β and reduces the inflammatory cells, including neutrophils and macrophages [133]. NF-κB-signaling pathway is a crucial regulator of proinflammatory cytokines such as TNF-α, IL-6, L-1β, and levels of proinflammatory cytokines increase inflammation. It was observed that Morin has protective effects by inhibiting proinflammatory cytokines in LPS-induced mastitis [134]. TNF-α, IL-6, and IL-1β promote the development of lung fibrosis and proinflammatory cytokines expression has increased in bleomycin-induced pulmonary fibrosis [135]. Morin inhibited the increase of inflammatory cells such as eosinophils, macrophages, and lymphocytes and reduces total IL-4, IL-13, and IgE levels in OVA-induced mice. Overexpression of Th2 and IgE cytokines causes eosinophilrich inflammation, mucus hypersecretion, and increased collagen deposition in the lungs. Therefore, Morin prevents mucus hypersecretion, inflammatory cell infiltration, and collagen deposition/fibrosis. In another study reported that TNF-α, IL-6, IL-18, and IL-1β levels importantly increased in bronchoalveolar lavage fluid after LPS-induced Acute Lung Injury, and Morin treatment markedly decreased to these raises due to its anti-inflammatory effects [136].

#### **4.4 Anti-inflammatory effects of Silymarin**

The main content of Silybin, which is a complex compound obtained from the seeds of *Silybum marianum* is composed of slybin, and it contains isosilybin, silychristin, silydianin and taxifolin, which is a flavonoid, in its structure [137]. Milk thistle extract is noted to be anti-carcinogenic in human prostate cancer. It is stated that silibinin can be anti-carcinogenic through insulin-like growth factor receptor type I (IGF-I), epidermal growth factor receptor, and NF-κB signaling [138]. Silymarin regulates inflammatory mediators such as interleukins, TNF-α, and inhibits NF-κB activation [139–142]. Silymarin inhibits the inflammatory cytokines (IFN-γ, IFN-α, and IL-1β) [27]. It is well known that silymarin generally has antioxidative and chemo-protective properties in the liver. It is thought that the hepatoprotective activity of silymarin is due to its antioxidant and membrane stabilizing properties. Silymarin shows hepatoprotective activity by inhibiting the function of Kupfer cells and the formation of leukotriene. Silymarin shows strong antioxidant, cytoprotective, anti-inflammatory, and anti-carcinogenic activities [143, 144]. In a rat sepsis model, Silymarin has been shown to suppress transcription of the transporter gene that binds NF-κB. It was also shown in the same study that silymarin showed anti-inflammatory activity by inhibiting prostaglandin-E2 and cyclooxygenase-2 in macrophages stimulated with LPS [145]. Silymarin reduces the increase in TNF-α, IL-1β, MCP-1, TGF-β1, and CRP levels with oxidative stress caused by sodium nitrite, and also, DNA fragmentation due to decrease in cytochrome C oxidase and increase in caspase-3 activity significantly. It has been reported to improve [146]. In the Methotrexate-induced nephrotoxicity model, it was noted that the increase in NF-KB, TNF-α, IL-6, and IL - 1β levels caused by Methotrexate decreased silymarin and prevented inflammatory responses by suppressing the activation of COX-2 and iNOS. Also, silymarin has been reported to play a protective role against apoptosis and autophagy by reducing caspase-3 and light chain 3D activities.

*Can Polyphenols be Used as Anti-Inflammatory Agents against Covid-19… DOI: http://dx.doi.org/10.5772/intechopen.98684*

#### **Figure 3.**

*Possible anti-inflammatory role of Apigenin, resveratrol, Morin, and Silymarin in the treatment of Covid-19. IFN: Interferon; IL: Interleukin; JAK/STAT; Janus kinase-signal transducer and activator of transcription; NK: Natural killer; RLR: Retinoic acid-inducible gene-1-like receptor; TCR: T cell receptor; TLR: Toll-like receptor; TNF-α: Tumor necrosis factor-alpha.*

## **5. Conclusion**

As a result, a more effective treatment method has not yet been found against the highly contagious and deadly coronavirus epidemic. This situation encourages scientists to look for alternatives to human coronavirus infections. Looking at various studies, it is known that Apigenin, Resveratrol, Morin, and Silymarin play an important role in relieving inflammation in various tissues. It is seen that coronavirus causes severe inflammation in various tissues and death after tissue damage. In this context, we believe that the flavonoids and phenolic compounds mentioned can be an alternative to the agents currently used in preventing/treating these adverse effects caused by coronavirus (**Figure 3**).

*Phenolic Compounds - Chemistry, Synthesis, Diversity, Non-Conventional Industrial...*
