key: cord-0718394-yvc5x5ai authors: Fakhri, Sajad; Nouri, Zeinab; Moradi, Seyed Zachariah; Farzaei, Mohammad Hosein title: Astaxanthin, COVID‐19 and immune response: Focus on oxidative stress, apoptosis and autophagy date: 2020-08-04 journal: Phytother Res DOI: 10.1002/ptr.6797 sha: e1c7516e90bcfbeb8c47abf43aa031839af21f8b doc_id: 718394 cord_uid: yvc5x5ai nan Besides, several reports have indicated the crucial role of oxidative stress, inflammation, apoptosis, autophagy, in triggering the pathogenesis and complications of COVID-19. So, providing novel treatments with potential anti-inflammatory, antioxidative, antiapoptotic effects, as well as ameliorative candidates on autophagy, would be grateful in preventing the progression of COVID-19. Additionally, during the past viral infections such as SARS-CoV and influenza, natural origin based medicinal plants have been widely used for counteracting viral infections (Ang, Lee, Choi, Zhang, & Lee, 2020) . Astaxanthin (3,3 0dihydroxy-β,β-carotene-4,4 0 -dione) is a keto-carotenoid with a wide variety of health-promoting properties through its effects on a plethora of molecular targets (Fakhri, Astaxanthin is a lipid-soluble carotenoid with a polar-nonpolarpolar structure that could easily pass through and fix into the double layers of cell membrane. While the polar zones of astaxanthin's structure scavenge free radicals inside and outside the cell membrane, its polyene chain captures radicals in the cell membrane (Augusti et al., 2012) . This effect has been found to be several folds more than other antioxidants, like vitamin E (Heidari Khoei et al., 2019; Østerlie, Bjerkeng, & Liaaen-Jensen, 2000; Shimidzu, Goto, & Miki, 1996) . In terms of pharmacological mechanisms, astaxanthin decreased the membrane fluidity and increased the activation of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway (Wu et al., 2014) . The pathway, in turn, elevates the antioxidant enzymes, including catalase (CAT), superoxide dismutase (SOD), peroxidase, thiobarbituric acid reactive substances (TBARS), NAD(P)H quinine oxidoreductase-1 (NQO-1) glutathione-S-transferase-α1 (GST-α1) . Astaxanthin also showed potential inhibitory effects on superoxide radicals, nitrogen dioxide radicals, cytosolic calcium (Otton et al., 2010) , reactive oxygen species (ROS), myeloperoxidase (MPO), and other oxidative mediators, as well as lipid peroxidation (Campoio, Oliveira, & Otton, 2011; Kamath, Srikanta, Dharmesh, Sarada, & Ravishankar, 2008) . All the reports, are in the way to introduce astaxanthin as a super antioxidant, which could be a promising candidate in combating COVID-19. Astaxanthin is a multi-target agent which employs several mechanisms to apply potential anti-inflammatory effects. For instance, astaxanthin reduced the expression of N-methyl-D-aspartate receptor subtype 2B (NR2B), tumor necrosis factor-α (TNF-α), p-p38 mitogenactivated protein kinase (MAPK) , p-extracellular signal-regulated kinases (p-ERK)/ERK, and increased p-Akt/Akt to modulate inflammation (Fakhri, Dargahi, et al., 2019) . Astaxanthin also suppressed nuclear factor-κB (NF-κB) and down-stream mediators, including interleukin (IL)-6, IL-1β, matrix metalloproteinase (MMP-9) (Bhuvaneswari, Yogalakshmi, Sreeja, & Anuradha, 2014; Speranza et al., 2012) , nitric oxide (NO), and cyclooxygenase-2 (COX-2) (Choi, Park, Choi, & Chang, 2008) . The modulatory effects of astaxanthin on the phosphoinositide 3-kinases (PI3K)/Akt, ERK/MAPK, and the up-stream macrophage migration inhibitory factor (MIF) has also been shown regarding its antiinflammatory effects . Considering the role of Janus kinase/signal transducer and activator of transcription (JAK/STAT) in the initiation of interferonstimulated response elements (ISRE), attenuating the pathway would play a pivotal role in preventing the inflammation occurs in COVID-19. In this regard, the inhibitory effects of astaxanthin on JAK2/ STAT3 has been revealed (Kowshik et al., 2014) . All the pharmacological and mechanistic evidence are confirming a bright future for astaxanthin to be used against the destructive inflammatory pathways then related complications in COVID-19. Growing evidence is also making a precise association between the therapeutic effects of astaxanthin and its antiapoptotic properties (Fakhri, Yosifova Aneva, et al., 2019) . Astaxanthin exerted antiapoptotic effects by inhibiting Bax/Bcl-2, and caspases-3/9 (Masoudi et al., 2017) . 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