key: cord-1026190-2jsyqka2
authors: Ardebili, Abdollah; Pouriayevali, Mohammad Hassan; Aleshikh, Sahar; Zahani, Marziyeh; Ajorloo, Mehdi; Izanloo, Ahdieh; Siyadatpanah, Abolghasem; Razavi Nikoo, Hadi; Wilairatana, Polrat; Coutinho, Henrique Douglas Melo
title: Antiviral Therapeutic Potential of Curcumin: An Update
date: 2021-11-19
journal: Molecules
DOI: 10.3390/molecules26226994
sha: cdceb483896dbf5b9b8442e9cc70797c3460c229
doc_id: 1026190
cord_uid: 2jsyqka2

The treatment of viral disease has become a medical challenge because of the increasing incidence and prevalence of human viral pathogens, as well as the lack of viable treatment alternatives, including plant-derived strategies. This review attempts to investigate the trends of research on in vitro antiviral effects of curcumin against different classes of human viral pathogens worldwide. Various electronic databases, including PubMed, Scopus, Web of Science, and Google Scholar were searched for published English articles evaluating the anti-viral activity of curcumin. Data were then extracted and analyzed. The forty-three studies (published from 1993 to 2020) that were identified contain data for 24 different viruses. The 50% cytotoxic concentration (CC50), 50% effective/inhibitory concentration (EC50/IC50), and stimulation index (SI) parameters showed that curcumin had antiviral activity against viruses causing diseases in humans. Data presented in this review highlight the potential antiviral applications of curcumin and open new avenues for further experiments on the clinical applications of curcumin and its derivatives.

According to the World Health Organization (WHO), infectious disease agents, such as bacteria, viruses, fungi, and parasites are estimated to be responsible for over 17 million deaths each year worldwide. Viruses are estimated to cause up to 390 million infections each year, with approximately 40% of the world's population at risk of infection [1] . They are a leading cause of life-threatening diseases, a feature that makes them one of the largest health challenges worldwide. There are about 90 commonly known viral diseases affecting

Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione), also called diferuloylmethane, is the best example of a plant derivative with an enormous number of therapeutic properties, such as anti-oxidant, anti-carcinogenic, anti-diabetic, anti-microbial, and antiviral activity [12] . In traditional Indian Ayurvedic medicine, curcumin was widely applied in many therapeutic remedies [13] . This compound is a natural polyphenolic substance and an active form of the traditional herb that is found in the rhizome of Curcuma longa (turmeric) and in other Curcuma spp, and that is commonly used as a spice and coloring agent in food [15] . Curcumin is the main molecule of the curcuminoids; the curcuminoids are comprised of curcumin (77%) as well as includes bisdemethoxycurcumin (BDMC) (17%) and demethoxycurcumin (DMC) (6%) [16] . For the purpose of this review, we will refer to the purified products by name, and curcuminoid will refer to two or more of these compounds together.

The first suggestion that curcumin had antiviral properties came in the 1990s, with the discovery that curcumin and curcumin boron complexes could inhibit the human immunodeficiency virus (HIV) viral protease in vitro, with an average inhibitory concentration (IC50) of 100 µM [17] . Since then, numerous studies have found that curcumin has antiviral activity against a diverse set of viruses, including both RNA and DNA viruses, both enveloped and non-enveloped, as is systematically updated in detail below [12, 14] .

The main characteristics of the 46 selected studies are presented in Table 1 . Articles were published from July 1993 to November 2021. Multiple selected studies were on different types of human viruses, including human immunodeficiency virus (nine studies), hepatitis C virus (five studies), human cytomegalovirus (three studies), hepatitis B virus (four studies), herpes simplex viruses (four studies), dengue virus (four studies), enterovirus 71 (two studies), human T lymphocyte virus (two studies), vesicular stomatitis virus (two studies), and respiratory syncytial virus (two studies). There was one study for viruses including zika and chikungunya, coronavirus, Rift Valley fever virus, human norovirus, coxsackievirus B3, Japanese encephalitis virus, and viral hemorrhagic septicemia virus. To determine the cytotoxicity effect of curcumin, MTT (3-(4,5 dimethyl thiazoleyl -2)-2,5-diphenyl tetrazolium bromide) and trypan blue exclusion assays were used in eighteen and four studies, respectively; whereas the water-soluble tetrazolium salt (WST) and cell counting kit-8 (CCK8) method was used in two studies. These assays are dependent on the number of viable cells and the value is referred to as the median cellular cytotoxicity concentration (CC50). In all included studies, different dilutions of curcumin were evaluated to determine cytotoxicity concentration. The number of viable cells was directly determined by colorimetric methods and the 50% cytotoxicity concentration (CC50) was calculated by nonlinear regression analysis. Cell culture methods used for the evaluation of the cytotoxicity concentration were performed according to cell culture guidelines. Accordingly, CC50 values were determined in 36 studies. Others selected various concentrations of curcumin based on the observed low toxicity and cell viability decrease in a dose-dependent manner. Twelve, seven, thirteen, and one studies used plaque reduction assay, TCID50, MTT, hemagglutination inhibition assay (HI), and Immunofluorescence (IFA) methods, respectively, for in vitro antiviral activity of curcumin. The value of the minimum concentration of curcumin is referred to as the median effective or inhibitory concentration (EC50/IC50) to reduce a 50% cytopathic effect (CPE) and was calculated by linear regression analysis. Therapeutic index (TI) or selectivity index (SI) was expressed as the ratio of CC50/EC50. Virological methods used for the evaluation of viral titration were performed according to standard guidelines. Of the 43 studies reviewed, sixteen studies reported data on the EC50 or IC50 values of curcumin to the different viruses. Furthermore, 27 remaining studies showed that curcumin reduced the production of infectious particles in various infected cells in a dose-dependent manner. 22 and apoptosis in EV71-infected cells.

[17] Inhibition of viral entry into both hepatoma cell lines and cell-to-cell spread between neighboring cells.

Curcumin also did not affect viral assembly/release of both genotypes. Anti-inflammatory properties. Decreases HIV-1 and HSV-2 replication in chronically infected T-cells and primary GECs 28 , respectively.

[40] Inhibition of APE1, resulting in reduce of the transcription activity of AP-1 and NF-κB.

[54] 

Data from recent research into the antiviral properties of curcumin toward various RNA viruses, including influenza A virus (IAV), parainfluenza virus 3 (PIV-3), Zika (ZIKA), Chikungunya virus (CHIKV), Japanese encephalitis virus (JEV), enterovirus 71 (EV71), hepatitis C virus (HCV), vesicular stomatitis virus (VSV), Ebola virus (EV), respiratory syncytial virus (RSV), human immunodeficiency virus (HIV), human T-lymphocyte virus (HTLV-1), Rift Valley fever virus (RVFV), human norovirus (HuNoV), and coxsackievirus B3 (CVB3) were collected (Table 1, Figure 1 ). 

Curcumin components with αβ-unsaturated ketone groups reduce membrane fluidity of HCV, leading to inhibition of virus attachment and fusion to cells. Accordingly, curcumin inhibits the entrance of all HCV genotypes to cells tested in a dose-dependent manner with a half-maximal inhibitory concentration (IC50) of about 8.46 ± 1.27 µM [17, 18, 39, 61] . Other studies also demonstrated that curcumin can inhibit RNA replication and NS5A and NS5B expression of HCV in infected cell lines via suppression of the PI3K-AKT and Akt-SREBP-1 pathways and induction of heme oxygenase [29, 32, 46] .

Curcumin can be suppressive when added to cells before and after Zika or chikungunya infection, although curcumin acts against Zika exclusively during cell-attachment or 

Curcumin components with αβ-unsaturated ketone groups reduce membrane fluidity of HCV, leading to inhibition of virus attachment and fusion to cells. Accordingly, curcumin inhibits the entrance of all HCV genotypes to cells tested in a dose-dependent manner with a half-maximal inhibitory concentration (IC50) of about 8.46 ± 1.27 µM [17, 18, 39, 61] . Other studies also demonstrated that curcumin can inhibit RNA replication and NS5A and NS5B expression of HCV in infected cell lines via suppression of the PI3K-AKT and Akt-SREBP-1 pathways and induction of heme oxygenase [29, 32, 46] .

Curcumin can be suppressive when added to cells before and after Zika or chikungunya infection, although curcumin acts against Zika exclusively during cell-attachment or entry and not at later stages of infection. Mounce et al. showed that 5 µM curcumin was more effective when added before infection and decreased the viral titer by more than 0.5 log10 without any cytotoxicity effects. Curcumin had also an IC50 of 1.9 µM and 3.89 µM for Zika and chikungunya, respectively [48] . Furthermore, they found that curcumin prevented the entry or attachment of chikungunya virus (CHIKV) to host cells, but that it has no impact on the viral replication machinery [48, 62] . In general, data reported from this study indicates that curcumin likely inhibits these viruses directly through its effect on viral surface glycoproteins and by altering the conformation of viral surface proteins [48, 62] .

Regarding the activities of curcumin against arboviruses, it has been shown that curcumin inhibits dengue virus propagation in a dose-dependent manner that might be due to an increase of Lys48 ubiquitin-conjugated proteins and accumulation of viral proteins. The anti-dengue effect of curcumin was also evaluated on BHK-21 cells infected with dengue 2 virus. The CC50 and IC50 of treated BHK-21 cells with curcumin were 29.5 µM and 11.51 µM, respectively [62] . The anti-dengue activity of curcumin has been evaluated by four studies [34, 53, 56, 59] . A recent study in this review evaluated the inhibitory effect of the same selection of compounds against dengue virus (DENV) [62] . Gao et al. also found that curcumin significantly reduced plaque formation of all four strains (DENV-1-4, IC50 of 9.37, 3.07, 2.09, and 4.83 µM, respectively), with limited cytotoxicity effects (CC50 of 59.42 µM). Though the mechanism of action was not addressed [48] , another study demonstrated that curcumin likely inhibits DENV-2 indirectly through its impact on cellular systems, rather than directly on the virus [56] . In an in vitro study conducted by Balasubramanian et al., curcumin, bisdemethoxycurcumin, and three other synthesized analogues potentially inhibited viral protease activity (IC50 of~36-66 µM). Their compounds only modestly inhibited replication of a DENV2 reporter replicon construct, with the acyclic and cyclohexanone analogues of curcumin performing slightly better than the natural curcuminoids (50% effective concentration (EC50) of 8.61 and 8.07 µM versus 13.91 µM) [53] . They demonstrated that curcumin and other synthesized analogues likely inhibit DENV-2 indirectly through their impact on cellular lipid metabolism, such as acetyl-CoA carboxylase, fatty acid synthase, and lowered lipid droplet (LD) formation [53] .

Curcumin at a concentration of 5 µM significantly increased viability in JEV-infected cells, so that the results of the terminal deoxynucleotide transferase-mediated dUTP nickend labeling (TUNEL) assay showed that the apoptotic pattern of JEV-infected cells treated with curcumin reduced compared to the control group. Pre-treatment and co-treatment of infected cells with curcumin (10 µM) inhibited JEV plaque formation, while no change was observed when curcumin was added after 2 hours of infection, indicating the blocking function of curcumin on envelope proteins. The inhibitory effects of curcumin was found to be its suppression of the proteasome system, downregulating the reactive oxygen level, modulating the membrane integrity and cellular stress proteins level, and inhibiting proapoptotic signaling molecules [25, 34] .

Curcumin at concentrations ranging from 5 to 15 µM has been found to reduce the expression of the RSV N protein by 50 to 90%, respectively. Without any direct effect on the expression of cellular receptors and RSV binding process, curcumin inhibited viral infection during the entry and fusion phase [63] . Obeta et al. showed that both replication and expression of structural proteins in RSV were suppressed with 10 µg/mL of curcumin by increasing the protein kinase R expression and the phosphorylation of NF-kB and eIF-2a. Curcumin also prevented the epithelial inflammatory responses in human nasal epithelial cells by downregulation of cyclooxygenase-2 (COX2) [35] .

Two studies in this review evaluated the inhibitory effect of curcumin on enterovirus 71 [17, 51] .It has been found that enterovirus 71 showed significant abrogated viral proteins and reduced viral titer by about 6 log10 (10 6 fold) in the presence of curcumin at a concentration of 40 µM at early infection. One study revealed that curcumin reduced the activity of enterovirus-induced ubiquitin-proteasome without any effect on antioxidant activity and the interference of ERK. In addition, curcumin downregulates GBF1 and PI4KB, both of which are required for the formation of the viral replication complex. Anti-apoptotic properties of curcumin are related to decreases of PARP-1 and cleaved caspase-3 [17] . In the second study, curcumin induced PKCδ phosphorylation in intestinal epithelial cells, a process which is important for the replication of EV71 and protein expression [51] .

There are two studies reporting data on the antiviral activity of curcumin against the influenza A virus. Curcumin at a 30 µM concentration showed a 90% decrease in influenza viral load in the infected Madin-Darby canine kidney (MDCK) cell line, while the EC50 and CC50 in MDCK were 0.47 µM and 43 µM, respectively. A timely assessment of drug-addition revealed a direct effect of curcumin on H1N1 and H6N1 infectivity through blocking of hemagglutination [27] . Another study revealed a significant decrease in the infectivity rate of enveloped viruses such as the influenza virus, Japanese encephalitis virus, and dengue virus with 30 µM of curcumin (EC50: 0.47 µM), which was not effective on non-enveloped viruses such as enterovirus. Taken together, these studies demonstrate curcumin's potential against enveloped viruses [34] . IAV needs NF-KB signaling to replicate, and curcumin inhibits this signaling [64] . Curcumin interrupts virus-cell attachment, which leads to the inhibition of influenza virus propagation [64] . Curcumin and its analogues can inhibit IAV by preventing entry and exit of viruses, and oral therapy with curcumin improved the survival of IAV-infected mice [65] .

Three studies in this review evaluated the antiviral activity of curcumin on HIV. In one study, curcumin degraded the Tat protein via the proteasome pathway and reduced Tat-dependent transactivation and replication in HIV-1 infected cells [20] . Curcumin significantly prevented the disruption of tight junction proteins and protected the epithelial barrier. On the other hand, pretreatment and co-treatment with curcumin significantly inhibited the induction of proinflammatory cytokines (Il-6, TNF) or chemokines (IL-8, IP-10, RANTES, MCP-1, MIP-1α, and eotaxin) [50] . Another study showed that curcumin can reduce inflammation in the female genital area, which allows easier infection by HIV [40] .

One study assessing the antiviral effect of curcumin showed that it reduces the expression and replication of coxsackievirus in infected HeLa cells. This study demonstrated that such antiviral effects were achieved by dysregulation of the ubiquitin-proteasome system (UPS) and inhibition of UPS activity by about 30% [22, 66] .

One study assessing the antiviral effect of curcumin showed that it reduces the replication of VSV in infected Vero cells. This study demonstrated that such antiviral effects were achieved by over-expression of Dicer-1 in VSV-EGFP infected cells, in comparison with the control (DMSO) [47] . They found that 10 µM of curcumin provided robust inhibition of recombinant VSV-EGFP infection of Vero cells, as measured via plaque assay and fluorescence, with approximately 33% reduced infection at MOI 0.0002 and a nearly 90% reduction at MOI 0.00002 after 24 h [45, 67] .

Curcumin can inhibit SARS-CoV replication with EC50 >10 µM (40) . Furthermore, several studies suggest that curcumin can inhibit SARS-CoV-2 replication [68, 69] . Curcumin can block the interaction between the spike glycoprotein and angiotensin-converting enzyme 2 (ACE2) and inhibit the Nsp15 protein, therefore blocking replication of the virus or inhibiting viral protease [70] [71] [72] . These observations were supported by a study by Han et al. who demonstrated that curcumin strongly inhibited TGEV proliferation and viral protein expression in a dose and time-dependent manner, and treatment with curcumin caused a reduction in both viral particles (IC50 of 8.6 µM) and protein levels in porcine kidney cells. This study suggested that curcumin may inhibit the adsorption of TGEV or that it possesses excellent virucidal activity [57] .

For enveloped viruses, direct incubation with curcumin frequently disrupts the membrane integrity and ability of the virus to bind to cells by blocking the action of surface glycoproteins on the virus [14, 34] . One study showed that curcumin reduces the infectivity of human norovirus by 91% in human norovirus (HuNoV) replicon-bearing HG23 cells. This study suggested that curcumin may involve viral entry or affects virus particle integrity and does not alter other aspects of the virus lifecycle [73] .

The anti-HPIV3 activity of curcumin was evaluated by one study. This study showed that curcumin disrupts F-actin, resulting in reduced viral inclusion body (IB) formation and inhibiting virus replication [58] .

Data from the recent research about the antiviral properties of curcumin toward various DNA viruses, including the hepatitis B virus (HBV), herpes simplex viruses (HSV-1 and 2), human cytomegalovirus (HCMV), Epstein-Barr virus (EBV), and human papillomavirus (HPV) were collected.

The anti-HBV activity of curcumin was evaluated by several studies. Aqueous extract of Curcuma longa Linn (CLL) in 200 mg/L and 500 mg/L caused a reduction of about 80% in HBsAg and HBV particle production compared with non-treated controls. This effect might be due to the specific inhibitory effect of CLL in HBV replication followed by repression of RNA transcription. Interestingly, CLL extract in a dose-dependent manner inhibited HBV enhancer I and X transcription by more than 80% through increasing expression and prolonged stability of p53 [24] . Wei et al. showed that 20 µmol/L of curcumin effects led to about 57% and 75.5% repression of HBs Ag and HBV cccDNA levels, respectively, without any cytotoxicity, compared with the control, which might be via reduction of cccDNA-bound histone acetylation [49] .

Further studies showed that the phenolic compound of curcumin suppresses HBV replication via reduction and degradation of the PGC-1a protein, a key factor of gluconeogenesis, which induces HBV expression. Furthermore, the combination of curcumin and anti-HBV reverse-transcriptase lamivudine reduces HBV expression by approximately 75% [26] . Additionally, one study suggested that curcumin may interrupt viral entry and suppress HBV re-infection [59] .

In two studies, the effect of curcumin on human adenoviruses was investigated. The A549 human lung adenocarcinoma cells were infected with human adenovirus types 4, 5, and 7 and the effect of curcumin showed that curcumin reduced the expression of viral early protein 1 (E1A) in several types of this virus. Curcumin also reduced the genome copy number of virus that were determined with plaque assay [74, 75] .

Curcumin inhibited HSV immediate early (IE) gene expression and infection. Curcumin, without interfering in HSV genome entry to the nucleus and VP16 binding to IE gene promoters, leads to reduced linkage of RNA polymerase II to promoters, although this effect was observed in the low concentration required to inhibit global H3 acetylation [23] . There are two studies reporting data on the antiviral activity of curcumin against herpes viruses. In a study by Flores et al., different concentrations of curcumin were investigated and the results showed that the minimum inhibitory concentration was 30 µM in the HSV1&2 infected Vero cell line. At this concentration, curcumin blocked viral adsorption and inhibited plaque formation about 92% and 88%, respectively. Curcumin and its derivatives, such as gallium-curcumin and Cu-curcumin showed also similar antiviral effects in vero cell line [43] . Anti HSV-2 activity of curcumin was evaluated in primary human GECs. Curcumin at a 5 µM concentration reduced viral replication 1000-fold in comparison to the control group and 50 µM of curcumin had a inhibitory property of 100% [76] .

An in vivo study of HCMV showed that curcumin can reduce anti-CMV antibody levels and viral load, and inhibit CMV pathological changes of the liver, kidneys, and lungs in an infected animal model. High (25 µg/mL) and middling (10 µg/mL) doses of curcumin can significantly inhibit CMV-induced apoptosis in an in vitro study [31] .

Given the increasing global incidence of viral infections, as well as the lack of preventive and therapeutic options, there is an urgent need for new anti-viral drug approaches to be elucidated. Curcumin is known today as a "highly effective natural compound" against several viruses [3] . Here, we investigated published studies about the in vitro antiviral activity of curcumin to better understand its properties on different types of viruses. This can help the scientific community to design effective infection control programs for the eradication of viral infections. According to studies in this review, curcumin showed potent activity against a wide range of viruses tested, such that all studies found that their included viruses were susceptible to this compound. There are several steps in the virus replicative cycle, including attachment/penetration, uncoating, genome replication, gene expression, assembly, and release, and each process may serve as an attractive target for chemotherapeutic intervention. In the present review, we showed different mechanisms-of-action (MOA) of curcumin and also discussed the target indications, as shown in Figure 2 .

In the attachment step, infectious particles enter host cells by attaching to receptors on the host cell membrane surface to promote uptake by receptor-mediated endocytosis [27, 34] . Reductions of infectious viral loads in several enveloped viruses treated with curcumin were found in numerous studies, indicating the inhibitory effect of curcumin on viral envelope proteins [34] . As was first described by Li et al., curcumin affects the membrane lipid bilayer as a modulating agent [77] . Additionally, numerous studies have shown that curcumin inhibits the entry of the different viruses into cell and particle production by its interaction with the viral surface proteins [39, 41, 46] . Regarding the effect of curcumin on virus entry, eight studies in the present review reported that curcumin can potentially inhibit the uptake of viruses and reduce viral particle production [34, 38, 73] . Chen et al., found a 90% decrease in influenza viral load in infected MDCK cell lines treated with 30 µM curcumin. In addition, they showed a direct effect of curcumin on H1N1 and H6N1 infectivity through the blocking of hemagglutination [27] . A recent study indicated that curcumin inhibits enveloped virus infectivity, such as the influenza A virus, dengue virus type II, and Japanese encephalitis virus (JEV), through disruption of the integrity of viral membranes [34] . Particularly, this study showed that the EC50 value of curcumin in terms of inhibition of plaque formation for larger viruses is greater than that for smaller viruses (1.15 µM and 4.61 µM for influenza and PRV, respectively) [34] . Another study revealed that curcumin blocks the entry of CHIKV (Tongaviridae) and Zika virus by inhibiting the binding of viruses to host cells. In particular, they found a significant decrease in viral titers in a dose-dependent manner, so that concentrations at or above 100 nM showed effective antiviral activity in infected cells compared to untreated controls [48] . With the exception of two studies, which reported a 91% decreased viral load of human norovirus (HuNoV) as a non-enveloped virus, others confirmed that curcumin blocks the entry of viruses, or disrupts the integrity of the membranes of viral envelopes [48, 78] . Additionally, curcumin influences viral replication machinery in two ways: (i) directly targeting the viral replication machinery, and (ii) interrupting viral replication machinery through modulating host cell signaling pathways, for instance, NF-κB, PI3K-AKT, Jab-1, and inflammation, as well as transcription/translation factors, which then cardinally hinder virus replication. In the attachment step, infectious particles enter host cells by attaching to receptors on the host cell membrane surface to promote uptake by receptor-mediated endocytosis [27, 34] . Reductions of infectious viral loads in several enveloped viruses treated with curcumin were found in numerous studies, indicating the inhibitory effect of curcumin on viral envelope proteins [34] . As was first described by Li et al., curcumin affects the mem- It has been shown that curcumin influences viral replication machinery in two ways: (i) direct targeting the viral replication machinery, and (ii) interruption of viral replication machinery through modulating cellular factors [24, 33, 71, 78] . In 5 studies included in this review, the inhibitory effects of curcumin on HIV-integrase, protease as well as transactivator factor Tat was evaluated [17] [18] [19] 30, 50] . Two studies revealed that curcumin interacts with the active sites of HIV protease and integrase. One of the five studies reported that curcumin treatment inhibited 55% of Tat-dependent transcription of HIV [18, 66] . In addition to the direct targeting of viral proteins, curcumin can reduce the production of the HIV-1 virion in transfected HEK-293T cell line that treated with 80 µM curcumin from 0-8 hrs. In general, data reported from their study indicate that the viral p24 level in infected TZM-bl cells also decreased by 30% at a curcumin concentration of 20 µM and reached up to 90% at an 80 µM concentration [18, 19] .

Several distinct modulating cellular pathways have been described as responsible for antiviral effects mediated by curcumin. Three studies showed antiviral effects of curcumin against hepatitis viruses [26, 28, 29, 32] . One study reported that the proteins level of HBV, such as HBsAg and core, were decreased by 73% and 45%, respectively, in stable transfected hepatoma cells [26] . They found that treatment of HBV with curcumin significantly suppressed HBV gene expression and replication through the downregulation of a coactivator of key gluconeogenesis pathway, PGC1α, resulting in suppressed HBV transcription [26] . In two different studies, curcumin reduced the replication of HCV by suppressing cellular factors, such as AKT-SREBP-1, ERK, and NF-κB [29, 32] . One study reported that curcumin at a 25 µM concentration inhibited replication by suppressing the AKT pathway, which, in turn, suppressed the transcriptional factors, such as ERK and NF-κB. The second study showed that curcumin decreases HCV gene expression by suppression of AKT-SREBP-1, not by NF-κB [29] . Another study revealed that curcumin inhibits the replication of Rift Valley fever virus (RVFV; Phenuiviridae) by interfering with IKK-2-mediated phosphorylation of the viral protein NSs, as well as by altering the cell cycle of the treated cells. Notably, this did not only hold true in vitro, but also in mice subcutaneously treated with curcumin, which showed increased survival (60% compared to untreated animals) and decreased hepatic viral load (90% compared to controls) [33] . A recent study has shown that curcumin inhibits the replication of recombinant VSV-EGFP by increasing the expression level of Dicer-1. They found that treatment of recombinant VSV-EGFP with 10 µM of curcumin significantly reduced infection at MOI 0.0002, with a nearly 90% reduction at MOI 0.00002 after 24 h [47] .

Dysregulation of UPS appears to be one of the general mechanisms by which curcumin restricts infection of viruses, including two flaviviruses, Japanese encephalitis virus (JEV), dengue virus type 2 (DNV-2), two enteroviruses, EV71, and coxsackievirus B3 (CVB3) [22, 25, 51, 53] .

Based on evidence obtained from this review, curcumin is known today as a "highly effective natural compound" that also has adequate in vitro activity against a wide range of viruses, as tested through various mechanisms. Although curcumin showed potent activity with no or minimal toxicity, it has low bioavailability and is rapidly metabolized. To overcome these drawbacks, several nanoparticle compounds with enhanced efficacy has been developed. Curcumin with enhanced efficacy has been developed through nanoparticle-based approaches (liposomes or micelles) and matrix-based formulations (hydrogels and nano-emulsions), resulting in increased absorption and/or bioavailability of curcumin than with unenhanced curcumin. Although extensive studies have been performed in a detailed manner to identify different molecular and cellular mechanisms of curcumin against viruses, some of these mechanisms are unclear, hampering the use of curcumin in clinics. Since the clinical efficacy of curcumin remains a matter of controversy, and only a few clinical trials have evaluated the safety, pharmacokinetics, and antiviral effectiveness of curcumin, more primary research articles and clinical trials are necessary.

Author Contributions: H.R.N. and P.W. conceived and designed the study, acquired the data, analyzed and interpreted the data, drafted the manuscript and revised it critically for important intellectual content, and approved the final version to be submitted; A.A. acquired the data, analyzed and interpretated the data, drafted the manuscript and revised it critically for important intellectual content, and approved the final version to be submitted; M.H.P. contributed to analyzing the results and reviewing the manuscript; S.A., M.Z., M.A., A.I. and A.S. acquired the data and drafted the manuscript; M.H.P. revised the manuscript critically for important intellectual content and approved the final version to be submitted. H.D.M.C. and P.W. coordinated the project. All authors have read and agreed to the published version of the manuscript.

Funding: This research received no external funding.

The authors declare no conflict of interest.

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3D-quantitative structure-activity relationship and antiviral effects of curcumin derivatives as potent inhibitors of influenza H1N1 neuraminidase

Curcumin protects mice from coxsackievirus B3-induced myocarditis by inhibiting the phosphatidylinositol 3 kinase/Akt/nuclear factor-κB pathway

Combination of virotherapy with VSV and tumor vaccination significantly enhances the efficacy of antitumor therapy

Potential effects of curcumin in the treatment of COVID-19 infection

Study on SARS-CoV-2 strains in Iran reveals potential contribution of co-infection with and recombination between different strains to the emergence of new strains

Structure-based drug designing for potential antiviral activity of selected natural products from Ayurveda against SARS-CoV-2 spike glycoprotein and its cellular receptor

Identification of phytochemicals as potential therapeutic agents that binds to Nsp15 protein target of coronavirus (SARS-CoV-2) that are capable of inhibiting virus replication

Activity of phytochemical constituents of Curcuma longa (turmeric) and Andrographis paniculata against coronavirus (COVID-19): An in silico approach

Curcumin shows antiviral properties against norovirus

Functions of adenovirus E1A

Antiviral Effects of Curcumin on Adenovirus Replication. Microorganisms 2020, 8, 1524

Curcumin can decrease tissue inflammation and the severity of HSV-2 infection in the female reproductive mucosa

Curcumin is a modulator of bilayer material properties

Virucidal efficacy of treatment with photodynamically activated curcumin on murine norovirus bio-accumulated in oysters