# Phytochemicals and Their Possible Mechanisms in Managing COVID-19 and Diabetes
## 4 Alternative Treatments with Phytochemicals (Curcumin, Silymarin, and Sulphorafane)
### Silymarin  
Silymarin, an extract from the seeds of the milk thistle (_Silbyum marianum_), of Mediterranean origin, contains a gamma of flavolignans such as sillybin, isosilbin, silvychristin, and silydianin [52]. Silymarin has been credited with having effects on liver disorders, in addition to anticancer, antihepatoprotector, antihyperlipidemic, antidiabetic, antiamnesic, anti-inflammatory, and antislerotic activities, and it modulates T cells [53; 54; 55]. It has been considered effective for the symptoms of respiratory diseases, fever, and influenza [56]. [PERSON], [PERSON] and [PERSON] [57] referred to silymarin as effective in alleviating lung injury, due to the fact that it inhibits inflammation in the tissue, even blocking ARDS development. Accordingly, the characteristics of silymarin have had beneficial effects on several pathologies. However, some studies have suggested that its potential is limited due to poor intestinal absorption and low bioavailability, with 23-47% in systemic circulation followed by oral administration [58; 59; 60; 61]. For this reason, there has been a suggestion for formulations research to increase the bioavailability, such as: soft capsules, nanoparticle, liposomes [61; 62; 63]. Silymarin and Its Effect on COVID-19 and Diabetes  
[PERSON] et al. [64] have considered silymarin as a potent ACE-2-peptide domain (PD)-ACE-2) inhibitor, due to the fact that silymarin maintains coupling with the active site. [PERSON] et al. [65] found that silymarin maintained binding with the principal protease of SARS-CoV-2; thus, it could be utilized as an antiviral agent. Another study demonstrated the binding of diverse phytochemicals, among these the silymarin of the viral protein, nanostructured protein 15 (Nsp15), which inhibited the replication of SARS-CoV-2 [66]. The silybin component of silymarin has a possible direct effect on the STAT3 regulator of the inflammatory cytokine pathway and on the immune response. It could be phenotypically related to the mechanisms of action of the monoclonal antibodies of IL-6 and pan-JAK1/2 inhibitors, with the purpose of inhibiting the production of cytokines and lymphopenia in T cells, both of which are recurrent in severe cases of COVID-19. In addition, it could be the most propitious inhibitor against SARS-CoV-2, due to its coupling with the target genes of the virus, inhibiting RNA-dependent RNA polymerase-mediated RNA (RdRp), which is indispensable in the replication/transcription of SARS-CoV-2 and above the peak of the ACE2 glycoprotein [67; 68] (Figure 3). In addition to exerting a possible effect against SARS-CoV-2, silymarin has been reported to exert an effect on diabetes, increasing serum insulin and the neogenesis of cells, normalizing serum glucose, and avoiding the development of diabetic complications. The effect is attributable to the antioxidant action that silymarin maintains, such as the following: inhibiting the formation of free radicals, reducing the inflammatory responses as a consequence of the inhibition of NF-kB-dependent pathways, and maintaining optical redox equilibrium due to the activation of antioxidant enzymes and nonenzymatic antioxidants by means of the activation of Nrf2 [69]. [PERSON] et al. [70] showed that silymarin maintains effective glucose control in diabetic patients with hepatic lesions, suggesting that the effect is associated with the antioxidant activity that exerts an impact, diminishing insulin resistance. [PERSON] et al. [69] noted that silymarin and/or its components, in confronting diabetes, have the capacity to attenuate the usual diabetic complications in diverse organs. Glucose levels diminished in rats after the administration of silymarin, improving insulin levels, due to a restoration of the pancreatic \(\beta\)-cells [71].