key: cord-0727163-juitltpi
authors: Babaei, Fatemeh; Nassiri‐Asl, Marjan; Hosseinzadeh, Hossein
title: Curcumin (a constituent of turmeric): New treatment option against COVID‐19
date: 2020-09-06
journal: Food Sci Nutr
DOI: 10.1002/fsn3.1858
sha: b40ce43e34b2b48886031fc84c0dde570647fc38
doc_id: 727163
cord_uid: juitltpi

In late December 2019, the outbreak of respiratory illness emerged in Wuhan, China, and spreads worldwide. World Health Organization (WHO) named this disease severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) caused by a new member of beta coronaviruses. Several medications are prescribed to patients, and some clinical trials are underway. Scientists are trying to find a specific drug against this virus. In this review, we summarize the pathogenesis, clinical features, and current treatments of coronavirus disease 2019 (COVID‐19). Then, we describe the possible therapeutic effects of curcumin and its molecular mechanism against coronavirus‐19. Curcumin, as an active constituent of Curcuma longa (turmeric), has been studied in several experimental and clinical trial studies. Curcumin has some useful clinical effects such as antiviral, antinociceptive, anti‐inflammatory, antipyretic, and antifatigue effects that could be effective to manage the symptoms of the infected patient with COVID‐19. It has several molecular mechanisms including antioxidant, antiapoptotic, and antifibrotic properties with inhibitory effects on Toll‐like receptors, NF‐κB, inflammatory cytokines and chemokines, and bradykinin. Scientific evidence suggests that curcumin could have a potential role to treat COVID‐19. Thus, the use of curcumin in the clinical trial, as a new treatment option, should be considered.

transmitted among humans by respiratory droplets and close contact (Chan et al., 2020) . A recent research project revealed that sequence homology between SARS-CoV-2 and SARS-CoV was 79.5% and SARS-CoV-2 belongs to the same beta coronavirus (β CoV) clade as MERS-CoV and SARS-CoV (Yu, Du, Ojcius, Pan, & Jiang, 2020) . Moreover, it has been identified that SARS-CoV-2 had high homology with bat coronaviruses and likely derived from bats , but the intermediate hosts of SARS-CoV-2 have not been determined yet. The recent finding reveals that COVID-19 has similar pathogenesis with SARS-CoV or MERS-CoV and uses the same receptor as SARS-CoV for entrance to human host cells Wan, Shang, Graham, Baric, & Li, 2020) .

The most important articles about COVID-19 (from starting disease up to now) and curcumin were selected. We considered all articles of curcumin-human and animal studies-that could be effective to treat or rescue COVID-19-infected patients. PubMed and Web of Science were used as databases. As the importance of the subject, some selected papers were in the press. The keywords used for the search were as follows: coronavirus-19, COVID-19, SARS-CoV-2, curcumin, Curcuma longa, turmeric, curcumin and antiviral, curcumin and anti-inflammatory, curcumin and antipyretic, curcumin and lung, curcumin and acute lung injury, curcumin and fatigue, curcumin and antioxidant, curcumin and ARDS, curcumin and bradykinin, curcumin and fibrosis, curcumin and Interleukin-6 (IL-6), curcumin and tumor necrosis factor-alpha (TNF-α), curcumin and NF-κB, curcumin and Toll-like receptors (TLRs), curcumin and antiapoptotic.

The SARS-CoV-2 is an enveloped nonsegmented positive-sense RNA virus. Two-thirds of viral RNA is located in the first open reading frames that encode 16 nonstructural proteins, whereas the remaining part of the genome encodes four essential structural proteins including spike (S) glycoprotein, envelope (E) protein, matrix (M) protein, and nucleocapsid (N) protein (Cui, Li, & Shi, 2019) .

S protein contributes to virus pathogenesis through binding to cell surface receptor, angiotensin-converting enzyme 2 (ACE2), and the entrance of the virus into the host cell . The possible mechanism and molecules involved in membrane invagination during virus endocytosis are still unknown. S protein is divided into the S1 domain that is responsible for receptor binding, and S2 domain that mediates cell membrane fusion (He et al., 2004) .

Recent data showed that the S protein of SARS-CoV-2 binds to ACE2 with a higher affinity than SARS-CoV. For this reason, it spreads rapidly in human populations (Wrapp et al., 2020) . The ACE2 expressed on the surface of cells in the lung, arteries, heart, kidney, and intestine (Hamming et al., 2004) . Its concentration in the alveolar cells of men was higher than women, which may correlate with a high incidence rate of COVID-19 among men. Moreover, the expression level of ACE2 in the alveolar cells of Asians was higher than other races, which may lead to high susceptibility to disease and severe outcomes (Sun, Lu, Xu, Sun, & Pan, 2020) . The ACE2 is an enzyme that catalyzes vasoactive angiotensin II to vasodilator angiotensin[1-7] (Richards & Raizada, 2018) .

On the other hand, the binding of the SARS-CoV spike protein to ACE2 leads to ACE2 downregulation (Kuba et al., 2005) . It is not clear that SARS-CoV-2 could downregulate the expression of ACE2 or not as the homology of SARS-CoV-2 with SARS-CoV.

ACE2 downregulation resulted in excessive production of angiotensin by the ACE, suggesting lead to pulmonary hypertension, acute lung injury (ALI), and lung fibrosis (Tan, Liao, Zhou, Mei, & Wong, 2018) .

Previous studies have shown the protective role of ACE2 against various types of pulmonary illnesses such as acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), pulmonary hypertension, ALI, and asthma (Jia, 2016) . It has been suggested that increasing ACE2 levels such as using angiotensin II receptor blocker medications could be effective to treat COVID-19 (Gurwitz, 2020) . However, another study showed that decreasing ACE2 activity might be protective (Zhang, Penninger, Li, Zhong, & Slutsky, 2020) . Thus, these hypotheses might be the basis for more research to clarify new therapeutic options.

The patients mainly were 30-79 years old (Wu & McGoogan, 2020) .

A few cases were children below 15 years old such as 15 days old in Iran (Kamali Aghdam, Jafari, & Eftekhari, 2020). There were one or more coexisting medical conditions, including hypertension, diabetes, and cardiovascular disease in about half the patients . These coexisting medical conditions lead to a high mortality rate in COVID-19 patients (Wu & McGoogan, 2020) . There was a spectrum of clinical features ranging from asymptomatic infection to severe respiratory failure. The most prevalent manifestations include fever, fatigue, dry cough, myalgia, dyspnea, and anorexia (Qin et al., 2020; Rodriguez-Morales et al., 2020) . The uncommon symptoms were sputum production, headache, hemoptysis, diarrhea, nausea, and vomiting Qian et al., 2020; Rodriguez-Morales et al., 2020) .

According to laboratory examination, lymphopenia, hypoalbuminemia, and high levels of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and lactate dehydrogenase (LDH) were the most prevalent results in the patients (Mo et al., 2020; Qin et al., 2020; Rodriguez-Morales et al., 2020; Talebpour, Hadadi, Oraii, & Ashraf, 2020; Wang, Yang, Li, Wen, & Zhang, 2020).

Patients with severe symptoms had raised levels of coagulation indexes (prothrombin time, activated partial thromboplastin time, and D-dimer), procalcitonin, IL-6, and serum ferritin, and multiple organ involvement, such as liver (increased lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase levels), kidney (increased blood urea nitrogen and creatinine levels), and heart and muscle (increased creatinine kinase levels) compared with patients with mild symptoms. Also, there was higher neutrophil-to-lymphocyte ratio (NLR) and lower percentages of monocytes, eosinophils, and basophils in complete blood count (Qian et al., 2020; Qin et al., 2020; Talebpour et al., 2020; Wan, Xiang, et al., 2020) .

The elevated levels of IL-1B, interleukin-1 receptor antagonist (IL1RA), IL-7, IL-8, IL-9, IL-10, basic fibroblast growth factors (FGF), granulocyte colony-stimulating factor (GCSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-gamma (IFNγ), interferon γ-induced protein 10 kDa (IP-10), monocyte chemoattractant protein-1 (MCP1), macrophage inflammatory protein-1 alpha (MIP1-α), macrophage inflammatory protein-1β (MIP-1β), platelet-derived growth factor (PDGF), tumor necrosis factor-alpha (TNF-α), and vascular endothelial growth factor (VEGF) were observed in serum sample of patients. Plasma levels of IL-5, IL-12p70, IL-15, eotaxin, and RANTES (chemokine (C-C motif) ligand 5, CCL5) were similar between healthy adults and patients infected with SARS-COV-19. Moreover, plasma concentrations of IL2, IL7, IL10, GCSF, IP10, MCP1, MIP1A, and TNF-α were higher in the intensive care unit (ICU) patients compared with non-ICU patients. These data suggest that the initial response of the immune system may lead to the production of cytokines and chemokines, which damage normal host organs such as lung and heart. Also, hypersensitive troponin I (hs-cTnI) was increased in patients with virus-related cardiac injury .

The pathological features of COVID-19 were similar to SARS-CoV and MERS-CoV infection (van den Brand, Smits, & Haagmans, 2015; Hui & Zumla, 2019; Nassar, Bakhrebah, Meo, Alsuabeyl, & Zaher, 2018) .

Moreover, moderate microvascular steatosis, mild lobular, and portal activity were observed in the liver biopsy samples. The heart tissue also showed interstitial mononuclear inflammatory infiltrates. The CD4 and CD8 T cells were decreased in flow cytometric analysis of peripheral blood. Also, X-ray images showed a rapid progression of pneumonia in lung tissues .

Countries use various strategies to treat COVID-19 patients. Some protocols for the treatment are summarized in Table 1 . Some clinical trials try to find an effective drug (Li & De Clercq, 2020) . Organ dysfunction, including shock, ARDS, acute cardiac injury, acute kidney injury, liver dysfunction, and secondary inflammation are causes of death among COVID-19 patients Huang et al., 2020; Wan, Xiang, et al., 2020; Wang, Hu, et al., 2020) . Current medical therapies are symptomatic treatment or supportive care. There is no definitive treatment yet for this TA B L E 1 Some protocols used for the treatment of COVID-19 disease. Therefore, finding effective strategies to treat infected patients and protect organs is necessary to decrease the mortality rate.

Curcumin, as a potential agent, could be considered to treat COVID-19.

Curcumin, as an active constituent of rhizomes of C. longa (turmeric), is a hydrophobic polyphenol ( Figure 1 ) (Akbar et al., 2018; Soleimani, Sahebkar, & Hosseinzadeh, 2018) . Curcumin is used as a spice in foods and for different purposes such as cosmetic and pharmaceutical industries in world (Hosseini & Hosseinzadeh, 2018) . Curcumin has several pharmacological effects such as antioxidant, anticancer, antibacterial, antiviral, and antidiabetic effects (Fan et al., 2015; Moghadamtousi et al., 2014; Zhu et al., 2017) , as well as anti-inflammatory activity (Cheng, Yang, Hu, Zhu, & Liu, 2018) . As the potential role of curcumin to treat many inflammatory disorders, at the first step we will describe all effects of curcumin that may be useful to treat COVID-19, and then, we explain the possible molecular mechanisms of it.

Curcumin prevented the replication of SARS-CoV and inhibited 3Cl protease in Vero E6 cells. Also, it significantly has an inhibitory activity against the cytopathogenic effect of SARS-CoV in Vero E6 cells (Wen et al., 2007) . 

C. longa L, as herbal medicine, is used to treat vomiting from ancient times in Asian countries . Curcumin (20 mg/ kg, intragastric, 3 days) improved appetite of rats in chemotherapy induced by fluorouracil (5-FU) (Yao et al., 2013) . It may be effective against vomiting due to COVID-19.

In an animal study, oral administration of curcumin has an antifatigue function and improved physical function in mice (Huang et al., 2015) .

Administration of curcumin (1,000 mg/d, 30 days) reduced stress and fatigue in the subjects that experiencing occupational stress-related anxiety and fatigue in a randomized double-blinded placebo-controlled study (Pandaran Sudheeran et al., 2016) . Curcumin (2.5 g, two times a day) reduced delayed-onset muscle soreness of healthy men who have a heavy eccentric exercise (Nicol, Rowlands, Fazakerly, & Kellett, 2015) . The use of curcumin in myalgic encephalomyelitis/ chronic fatigue syndrome as a novel therapeutic option was mentioned . Curcumin inhibited sepsis-induced muscle wasting by inhibiting catabolic response in skeletal muscle via blocking NF-κB (Alamdari, O'Neal, & Hasselgren, 2009 ). Curcumin (Meriva®, 1 g, 3 months) prevented muscle loss and improved physical performance in healthy elder subjects and delayed the onset of sarcopenia in them (Franceschi et al., 2016) . These results suggest that curcumin may be effective to manage myalgia and fatigue symptoms induced by COVID-19.

The antinociceptive and anti-inflammatory effects of curcumin in animal and human studies were reviewed by Eke-Okoro, Raffa, Pergolizzi, Breve, & Taylor, 2018 (Eke-Okoro et al., 2018 . About the important molecular mechanism of these effects, it will discuss later that curcumin could be effective as a novel treatment against COVID-19. Also, in an animal study, curcumin (100 mg/kg, i.p.) has an antipyretic effect in rats (Haider et al., 2013) . It seems that curcumin overcomes the fever of COVID-19-infected patients.

Two meta-analyses of randomized controlled trials have shown that curcumin reduced circulating IL-6 and TNF-α levels that both are the key inflammatory mediators and increase in inflammatory diseases and RANTES (Ferreira, Nazli, Dizzell, Mueller, & Kaushic, 2015) . The summary of the clinical effects of curcumin that may be useful to treat COVID-19 is illustrated in Figure 2 .

In this section, we summarize the important molecular mechanisms of curcumin that show potential ability against COVID-19. 

In severe COVID-19 infection, pneumonia may cause hypoxemia, which, in turn, disturbs cell metabolism and reduces the energy supply, and increases anaerobic fermentation. Then, acidosis happens and causes oxygen free radicals to destroy the phospholipid layer of the cell membrane . Therefore, treatment with a drug that has antioxidant properties will be good for these SARS-CoV-2: severe acute respiratory syndrome coronavirus 2 lung injury in rats . Similarly, curcumin (200 mg/kg) increased SOD activity and decreased MDA content in the lung in acute injury induced by sepsis (Xiao, Yang, Sun, & Sun, 2012) .

ARDS is a clinical syndrome and is associated with increased permeability pulmonary edema, severe arterial hypoxemia, and impaired carbon dioxide excretion, eventually resulting in respiratory failure.

It may occur due to a pulmonary or extrapulmonary infectious or noninfectious insult (Matthay, Ware, & Zimmerman, 2012) .

Major inflammatory mediators in ADRS include cytokines (TNF-α, IL-1β, IL-6, IL-8, IL-10), chemokines such as macrophage inhibitory factor (MIF), and macrophage chemoattractant protein, metabolites of arachidonic acid (prostanoids and leukotrienes), and oxyradicals. Until yet, mechanical ventilation is only a proven strategy for treatment to improve the survival of patients (Matuschak & Lechner, 2010) . Recently, rescue therapy with high-dose vitamin C has been suggested to use for these patients (Fowler et al., 2019) . Therefore, finding new treatments to overcome these mediators and preventing respiratory failure are necessary. On the other hand, the protective effects of curcumin were studied in several pulmonary diseases such as COPD, ARDS, pulmonary fibrosis, and asthma in animal studies (Lelli, Sahebkar, Johnston, & Pedone, 2017; Venkatesan, Punithavathi, & Babu, 2007) . In this part of the review, we explain molecular F I G U R E 3 Possible molecular mechanisms of curcumin against COVID-19 in the pulmonary system. AA: arachidonic acid, ALI: acute lung injury, AP-1: activator protein 1, BK: bradykinin, ACE2: angiotensin-converting enzyme 2, Ang II: angiotensin II, ARDS: acute respiratory distress syndrome, Cas-3: caspase 3, COX: cyclooxygenase, CXCL: chemokine (C-X-C motif) ligand, 12-HPETE: 12-hydroperoxyeicosatetraenoic acid, JNK: c-Jun N-terminal kinase, 12 LOX: 12-lipoxygenase, MMP: matrix metalloproteinase NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells, MAPK: mitogen-activated protein kinase, PAI-1: plasminogen activator inhibitor-1, PLA2: phospholipase A2, PG: prostaglandin, SMAD3: mothers against decapentaplegic homolog 3, TGF-β1: transforming growth factor-beta 1, TNF-α: tumor necrosis factor-α, TLR: Toll-like receptor, TRPA1: transient receptor potential channel subfamily vanilloid member 1, TRPV1: transient receptor potential channel subfamily A member 1 mechanisms that curcumin may be useful to prevent or treat the ARDS.

ALI is a model that is used for the ARDS animal study (Karunaweera, Raju, Gyengesi, & Münch, 2015; Olivera et al., 2012; Tian et al., 2006; Wang, Tang, Duan, & Yang, 2018) , and curcumin exhibits its effects by predominantly targeting proinflammatory NF-ĸB pathway (Ahn, Sethi, Jain, Jaiswal, & Aggarwal, 2006; Karunaweera et al., 2015; Olivera et al., 2012; Puar et al., 2018; Wang, Tang, et al., 2018) . that were stimulated with S. aureus. It has been suggested that some part of the anti-inflammatory effects of curcumin are due to regulating NF-κB activity (Xu et al., 2015) .

Curcumin downregulated the production of proinflammatory cytokine (TNF-α, IFN-α, and IL-6) in influenza A virus-infected human macrophages and BAL fluid of infected mice. Similar to other noted studies, curcumin downregulated the expression of NF-κB and increased the cytosolic IκBα and inhibited its phosphorylation in the cytoplasm in human macrophages (Xu & Liu, 2017) . In this way, curcumin reduced TNF-α, MIP-2, and IL-6 in lipopolysaccharide (LPS)induced ALI in mice. It has been suggested that curcumin inhibits the release of cytokines by activation of 5′ adenosine monophosphate (AMP)-activated protein kinase (AMPK) (Kim et al., 2016) .

Curcumin reduced the production of TNF-α, IL-1β, IL-6, and IL-8, MMP-2, and MMP-9 both in mice and in A549 cells infected with influenza A virus. These cytokines exacerbate the ALI (Dai et al., 2018) .

The inhibitory role of curcumin on the expression of proinflammatory cytokines such as TNF-α, IL-1, and IL-6 was reviewed in ALI and fibrosis by Gouda and Bhandary (2019) . It seems that the most important molecular mechanism of curcumin on IL-6 activities may be related to the downregulation or inhibition of IL-6 signaling in different inflammatory diseases (Ghandadi & Sahebkar, 2017) .

Furthermore, curcumin has an inhibitory effect on IL-17 A that plays a pivotal role in the inflammation of the alveolar epithelial cells in ALI studies. In other words, IL-17 by activating P53 causes the stabilization of the PAI-1, which in turn mediates the accumulation of extracellular matrix (ECM) and subsequent development of pulmonary fibrosis in alveolar type II (ATII) cells, and curcumin inhibits IL-17A-mediated changes in the p53-fibrinolytic system (Figure 3 ) . Curcumin also reduced the gene expression of chemokines such as chemokine (C-X-C motif) ligand 1 (CXCL1), CXCL5, and CXCL12 that is increased during inflammation in the airway epithelial cells in bleomycin-induced ALI in mice (refer to Figure 3 for more details) .

The inhibitory effects of curcumin on the different subtypes of TLRs including extracellular TLR2 and TLR4 and TLR8 and intracellular TLR9 have been reported, which result in the therapeutic effects of curcumin in inflammation, infection, autoimmune, and ischemic disease (Boozari, Butler, & Sahebkar, 2019) . Curcumin at low concentrations (10, 20 µM) prevented apoptosis and cytokine production (TNF-α, IL-6) induced by 19-kDa Mycobacterium tuberculosis protein (P19) in human macrophages. Curcumin also reduced the expression of TLR2/JNK that may be involved in the apoptosis of macrophages . ALI/ARDS could be the consequence of severe influenza A virus infection with substantial morbidity and mortality.

On the other hand, curcumin decreased TLR2/4 gene expression and inhibited phosphorylation of p38, JNK, and NF-κB in infected A549 cells with influenza A virus. It seems that curcumin regulates the TLR-MAPK/NF-κB signaling pathways involved in the replication and influenza pneumonia (Figure 3) . However, other mechanisms have been suggested for the antiviral effects of curcumin.

Furthermore, curcumin increased the survival rate in infected mice with this virus (Dai et al., 2018) .

Pulmonary pathology of COVID-19 pneumonia in two patients with lung cancer showed the edema and prominent proteinaceous exudates, vascular congestion, and inflammatory clusters with fibrinoid material. Also, reactive alveolar epithelial hyperplasia and fibroblastic proliferation were reported in them .

On the other hand, PAI-1 plays a key mediator role in pulmonary fibrosis. Furthermore, PAI-1 and apoptosis have an important role in the progression and pathogenesis of pulmonary fibrosis (Johnson, Shaikh, Muneesa, Rashmi, & Bhandary, 2020) . Therefore, this issue led us to point out the antiapoptotic and the antifibrotic effects of curcumin here. The antiapoptotic effects of curcumin were found in different organ injuries including diabetes, nephrotoxicity, intestinal inflammation, neurotoxicity with several mechanisms (Loganes et al., 2017; Qihui, Shuntian, Xin, Xiaoxia, & Zhongpei, 2020; Soetikno et al., 2019; Sun et al., 2014) . Both antiapoptotic and antifibrotic effects of curcumin were shown on the ALI model in mice.

Curcumin reduced the expression of p53, PAI-1, and chemokines in bleomycin-induced ALI. Also, curcumin inhibited apoptosis mediated by IL-17 and downregulated cleaved caspase-3 in alveolar epithelial cells. The results suggest that the cross talk between the inflammatory, fibrinolytic, and apoptotic pathways is interrupted by curcumin . Similar results of curcumin were found with the bleomycin model in human alveolar basal epithelial cells (A549) (Gouda, Prabhu, & Bhandary, 2018) . Also, curcumin decreased PAI-1 with cytokines and chemokines in ALI induced by staphylococcus aureus (Xu et al., 2015) . On the other hand, curcumin inhibited the expression of TGF-β1 and SMAD3 pathway in ALI induced by sepsis in rats that may involve in the pathogenesis of ALI (Xu et al., 2013) . Curcumin reduced expression fibrosis markers including smooth muscle actin (α-SMA), and Tenascin-C in reovirus 1/L-induced ALI/ARDS in mice (Avasarala et al., 2013) . Intranasal curcumin reduced matrix metalloproteinases-9 (MMP-9)/tissue inhibitors of metalloproteinase (TIMP-1) expression and increased α-SMA, as a myofibroblast marker, which involves in muscle thickening in paraquat lung injury model in mice. It seems that pretreatment of curcumin prevented the early phase of pulmonary fibrosis by inhibiting inflammatory cells and producing fibrotic factors (Tyagi, Dash, & Singh, 2016) (Figure 3 ).

Bradykinin has an important role in the inflammatory events during acute and chronic inflammatory diseases such as respiratory tract infection and asthma (Broadley, Blair, Kidd, Bugert, & Ford, 2010; Hewitt et al., 2016) . Furthermore, it seems that bradykinin could trigger cough in these inflammatory diseases or other conditions such as in patients with cough associated with captopril and enalapril as ACE inhibitors (Hewitt et al., 2016; Katsumata, Sekizawa, Ujiie, Sasaki, & Takishima, 1991) Curcumin is an inhibitor of activated protein-1 (AP-1) (Singh & Aggarwal, 1995) . Curcumin prevented the expression of IL-6 induced by bradykinin in human airway smooth muscle cells via this inhibition (Huang, Tliba, Panettieri, & Amrani, 2003) .

On the other hand, it has shown that curcumin has a greater affinity to bradykinin B 1 receptor (BK1) with strong inhibition activity (Ki value = 2.173 µg/ml) compared with BK2 receptor (Ki value = 58 µg/ml) (Yimam et al., 2016) . The possible molecular mechanism of bradykinin for sensitizing cough reflex is through activation B 2 receptors, which in turn stimulate the release of COX and COX-2 (Rao, 2007) . Furthermore, curcumin has shown these inhibitory effects in the airway studies (Kumari, Singh, Dash, & Singh, 2019; Yuan, Liu, Ma, Zhang, & Xie, 2018) . Thus, curcumin is likely to inhibit the activity of bradykinin by inhibiting the COX enzyme ( Figure 3 ).

Curcumin (20 mg/kg, p.o.) significantly inhibits ovalbumin (OVA)induced airway constriction and airway hyperreactivity to histamine in sensitized guinea pigs (Ram, Das, & Ghosh, 2003) . Also, curcumin (2.5 and 5 mg/kg, intranasal) significantly reduced bronchoconstriction in the mouse model of asthma (Subhashini et al., 2013) .

Moreover, C. longa extract (1.5, 3 mg/ml) reduced tracheal contractile response to OVA and maximum response to methacholine in rats. It also decreased interstitial fibrosis (Shakeri, Roshan, & Boskabady, 2020) . Standard therapy with capsule curcumin 500 mg BD daily for 30 days in patients of bronchial asthma significantly improved forced expiratory volume one second (FEV1) compared with standard therapy. However, the mean scores for cough, dyspnea, wheezing, chest tightness, and nocturnal symptoms were insignificant. Curcumin is recommended to use as an add-on therapy for bronchial asthma (Abidi, Gupta, Agarwal, Bhalla, & Saluja, 2014) .

Dietary administration of curcumin (150 mg kg -1 day -1 , gavage during Ang II infusion) decreased the protein level of the AT1 receptor and enhanced the expression of the AT2 receptor/ACE2 and results in the attenuation of myocardial fibrosis in a rat model of angiotensin II infusion (Pang et al., 2015) . These data suggest that similar events happen in the lung tissues to prevent fibrosis. However, this hypoth- cells, human capillary, and kidney organoids through preventing entry into host cells. However, they did not study lung organoids that are the major target organ for COVID-19 (Monteil et al., 2020) .

Advantage of curcumin over other important natural agents with reported anti-inflammatory activities such as zerumbone (Prasannan et al., 2012) , thymoquinone (Siveen, Mustafa, et al., 2014) , honokiol (Rajendran et al., 2012) , escin (Tan et al., 2010) , pinitol (Sethi, Ahn, Sung, & Aggarwal, 2008) , and tocotrienols is that it has additional antiviral, antiemetic, antinociceptive, antifatigue, and bronchodilator effects that previously has been discussed in this review. Also, it has significant protective effects in the ARDS model in animal studies. These mentioned effects help us to conclude that curcumin has the potential to be effective against COVID-19 infection.

To date, over 100 clinical trials have been completed with curcumin and safety, tolerability, and outcome have been reported in all of them (Kunnumakkara et al., 2017) . An oral dose of 500 mg (two times a day, 30 days) was reported safe for curcumin (Soleimani et al., 2018) .

Curcumin up to 8,000 mg/day was safe, tolerable, and effective in humans, and higher doses were with toxicity (Kunnumakkara et al., 2019; Shanmugam et al., 2015) . Curcumin has low bioavailability, but a lot of data from clinical trials showed the high efficacy of curcumin or turmeric against several diseases (Kunnumakkara et al., 2019) . However, various strategies are used including analogs of curcumin and formulations such as adjuvants, nanoparticles, liposomes, micelles, and phospholipid complexes to improve its bioavailability (Kunnumakkara et al., 2017) . Recently, it has been shown that the encapsulation of curcumin into specific nanocarrier could enhance its therapeutic efficacy (Moballegh Nasery et al., 2020).

COVID-19 is spreading worldwide, leading a pandemic. There is no

definitive treatment yet for this disease. In this review, we summarized clinical and molecular mechanisms that curcumin might be effective to treat COVID-19. Research evidence suggests that curcumin will be useful to treat patients especially in ARDS cases with high mortality risk. Curcumin has several therapeutic effects including antiviral, antinociceptive, anti-inflammatory, antipyretic, and antifatigue effects with several molecular mechanisms such as antioxidant, antiapoptotic, antifibrotic effects, and inhibitory effects on NF-κB, inflammatory cytokines and chemokines, Toll-like receptors, and bradykinin. The importance of this review is due to the fact that curcumin is a nutraceutical that could be a new treatment option to combat the COVID-19 pandemic. Designing the best formulation with high efficacy and good bioavailability is necessary. Further clinical studies should focus on curcumin against COVID-19 infection.

The authors have no conflict of interest to declare.

The study did not involve any human or animal testing.

Marjan Nassiri-Asl https://orcid.org/0000-0003-3701-0758

Hossein Hosseinzadeh https://orcid.org/0000-0002-3483-851X

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Bradykinin-induced cough reflex markedly increases in patients with cough associated with captopril and enalapril

Effect of curcumin (Curcuma longa extract) on LPS-induced acute lung injury is mediated by the activation of AMPK

A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury

Intranasal curcumin protects against LPS-induced airway remodeling by modulating toll-like receptor-4 (TLR-4) and matrixmetalloproteinase-9 (MMP-9) expression via affecting MAP kinases in mouse model

Curcumin, the golden nutraceutical: Multitargeting for multiple chronic diseases

Is curcumin bioavailability a problem in humans: Lessons from clinical trials

Curcumin use in pulmonary diseases: State of the art and future perspectives

Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China

Therapeutic options for the 2019 novel coronavirus (2019-nCoV)

The protective effect of curcumin against the 19-kDa Mycobacterium tuberculosis protein-induced inflammation and apoptosis in human macrophages

The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients

High amplification of the antiviral activity of curcumin through transformation into carbon quantum dots. Small (Weinheim an Der Bergstrasse

Preventive effect of curcumin against chemotherapy-induced side-effects

Functional carbon quantum dots as medical countermeasures to human coronavirus

Curcumin anti-apoptotic action in a model of intestinal epithelial inflammatory damage

Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding

Metal chelating ability and antioxidant properties of curcumin-metal complexes -A DFT approach

The acute respiratory distress syndrome

Acute lung injury and the acute respiratory distress syndrome: Pathophysiology and treatment

Clinical characteristics of refractory COVID-19 pneumonia in Wuhan, China

Curcumin delivery mediated by bio-based nanoparticles: A review

A review on antibacterial, antiviral, and antifungal activity of curcumin

Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2

Myalgic encephalomyelitis/chronic fatigue syndrome: From pathophysiological insights to novel therapeutic opportunities

Middle East respiratory syndrome coronavirus (MERS-CoV) infection: Epidemiology, pathogenesis and clinical characteristics

Curcumin supplementation likely attenuates delayed onset muscle soreness (DOMS)

Inhibition of the NF-κB signaling pathway by the curcumin analog, 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31): Anti-inflammatory and anti-cancer properties

Curcumin reduces the expression of interleukin 1β and the production of interleukin 6 and tumor necrosis factor alpha by M1 macrophages from patients with Behcet's disease

Safety, tolerance, and enhanced efficacy of a bioavailable formulation of curcumin with fenugreek dietary fiber on occupational stress: A randomized, double-blind, placebo-controlled pilot study

Attenuation of myocardial fibrosis with curcumin is mediated by modulating expression of angiotensin II AT1/AT2 receptors and ACE2 in rats. Drug Design

Anti-infective properties of the golden spice curcumin

Key cell signaling pathways modulated by zerumbone: Role in the prevention and treatment of cancer

Evidence for the involvement of the master transcription factor NF-κB in cancer initiation and progression

Epidemiologic and clinical characteristics of 91 hospitalized patients with COVID-19 in Zhejiang, China: A retrospective, multi-centre case series

Protection of curcumin against streptozocin-induced pancreatic cell destruction in T2D rats

Dysregulation of immune response in patients with COVID-19 in Wuhan. China

Curcumin inhibits the replication of enterovirus 71 in vitro

Honokiol inhibits signal transducer and activator of transcription-3 signaling, proliferation, and survival of hepatocellular carcinoma cells via the protein tyrosine phosphatase SHP-1

Curcumin attenuates allergen-induced airway hyperresponsiveness in sensitized guinea pigs

Regulation of COX and LOX by curcumin

ACE2 and pACE2: A pair of aces for pulmonary arterial hypertension treatment?

Clinical, laboratory and imaging features of COVID-19: A systematic review and meta-analysis

Curcumin downregulates human tumor necrosis factor-α levels: A systematic review and meta-analysis of randomized controlled trials

Pinitol targets nuclear factor-kappaB activation pathway leading to inhibition of gene products associated with proliferation, apoptosis, invasion, and angiogenesis

Hydro-ethanolic extract of Curcuma longa affects tracheal responsiveness and lung pathology in ovalbumin-sensitized rats

The multifaceted role of curcumin in cancer prevention and treatment

Activation of transcription factor NFkappa B is suppressed by curcumin (diferuloylmethane)

Y-tocotrienol inhibits angiogenesis-dependent growth of human hepatocellular carcinoma through abrogation of AKT/mTOR pathway in an orthotopic mouse model

Thymoquinone overcomes chemoresistance and enhances the anticancer effects of bortezomib through abrogation of NF-κB regulated gene products in multiple myeloma xenograft mouse model

Pre-treatment with curcumin ameliorates cisplatin-induced kidney damage by suppressing kidney inflammation and apoptosis in rats

Turmeric (Curcuma longa) and its major constituent (curcumin) as nontoxic and safe substances: Review

From SARS to MERS, thrusting coronaviruses into the spotlight

Intranasal curcumin and its evaluation in murine model of asthma

Understanding of COVID-19 based on current evidence

Activation of SIRT1 by curcumin blocks the neurotoxicity of amyloid-β25-35 in rat cortical neurons

Sina Hospital Covid-19 registry (SHCo-19R)

Identification of beta-escin as a novel inhibitor of signal transducer and activator of transcription 3/Janus-activated kinase 2 signaling pathway that suppresses proliferation and induces apoptosis in human hepatocellular carcinoma cells

Targeting the renin-angiotensin system as novel therapeutic strategy for pulmonary diseases

Pulmonary pathology of early-Phase 2019 novel coronavirus (COVID-19) pneumonia in two patients with lung cancer

Effect of nuclear factor kappa B on intercellular adhesion molecule-1 expression and neutrophil infiltration in lung injury induced by intestinal ischemia/reperfusion in rats

Renoprotective effect of the antioxidant curcumin: Recent findings

Curcumin inhibits paraquat induced lung inflammation and fibrosis by extracellular matrix modifications in mouse model

Protection from acute and chronic lung diseases by curcumin

Clinical features and treatment of COVID-19 patients in northeast Chongqing

Receptor recognition by the novel coronavirus from Wuhan: An analysis based on decade-long structural studies of SARS coronavirus

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan

Curcumin ameliorated ventilator-induced lung injury in rats

Curcumin as a therapeutic agent for blocking NF-κB activation in ulcerative colitis

Clinical features of 69 cases with coronavirus disease 2019 in Wuhan. China

Specific plant terpenoids and lignoids possess potent antiviral activities against severe acute respiratory syndrome coronavirus

Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation

A new coronavirus associated with human respiratory disease in China

Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72 314 cases from the Chinese center for disease control and prevention

Curcumin protects against sepsis-induced acute lung injury in rats

Curcumin attenuates staphylococcus aureus-induced acute lung injury

The effect of curcumin on sepsis-induced acute lung injury in a rat model through the inhibition of the TGF-β1/SMAD3 pathway

Curcumin alleviates macrophage activation and lung inflammation induced by influenza virus infection through inhibiting the NF-κB signaling pathway. Influenza and Other Respiratory Viruses

Pathological findings of COVID-19 associated with acute respiratory distress syndrome

Protective effect of curcumin on chemotherapy-induced intestinal dysfunction

Analgesic and anti-inflammatory effects of UP1304, a botanical composite containing standardized extracts of Curcuma longa and Morus alba

Measures for diagnosing and treating infections by a novel coronavirus responsible for a pneumonia outbreak originating in Wuhan

Curcumin attenuates airway inflammation and airway remolding by inhibiting nf-κb signaling and COX-2 in cigarette smoke-induced COPD mice

Angiotensinconverting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: Molecular mechanisms and potential therapeutic target

A pneumonia outbreak associated with a new coronavirus of probable bat origin

Curcumin suppresses lung cancer stem cells via inhibiting Wnt/β-catenin and sonic hedgehog pathways

A novel coronavirus from patients with pneumonia in China

Coronaviruses -drug discovery and therapeutic options

Curcumin (a constituent of turmeric): New treatment option against COVID-19