key: cord-0909989-8k48qiex
authors: Marmitt, Diorge Jônatas
title: Potential plants for inflammatory dysfunction in the SARS-CoV-2 infection
date: 2022-04-07
journal: Inflammopharmacology
DOI: 10.1007/s10787-022-00981-5
sha: 27a70ffd890604380a2e77513476658335d49d99
doc_id: 909989
cord_uid: 8k48qiex

The inflammatory process is a biological response of the organism to remove injurious stimuli and initiate homeostasis. It has been recognized as a key player in the most severe forms of SARS-CoV-2, characterized by significantly increased pro-inflammatory cytokine levels, the so-called "cytokine storm" that appears to play a pivotal role in this disease. Therefore, the aim of this systematic review was to select clinical trials with anti-inflammatory plants and relate the activity of these plants to inflammatory markers of SARS-CoV-2 infection. PRISMA guidelines are followed, and studies of interest are indexed in PubMed and ClinicalTrials.gov databases. As a result, 32 clinical trials encompassing 22 plants were selected. The main anti-inflammatory mechanisms described in the studies are the inhibition of inflammatory cytokines, such as IL-6, TNF-a, IFN-γ, and IL-1; decreased CRP and oxidative marker levels; increased endogenous antioxidant levels; modulation of cardiovascular risk markers. The data found are not directly related to SARS-CoV-2 infection. However, they provide possibilities for new studies as plants have a wide array of phytochemicals, and detecting which ones are responsible for anti-inflammatory effects can provide invaluable contribution to studies aiming to evaluate efficacy in scenarios of SARS-CoV-2 infection.

When the immune system responds to harmful stimuli, such as damaged cells, pathogens, irradiation, and toxic compounds, it triggers the inflammatory process, which acts to restore cell homeostasis. It is an essential defence mechanism for the health (Chen et al. 2018) . In general, cellular and molecular interactions effectively minimize any impending injury or infection during acute inflammatory responses. Nevertheless, acute inflammation might become chronic when it is uncontrolled, and it is involved in the pathogenesis of a variety of chronic diseases, such as cardiovascular diseases (CVDs) and cancer (Medzhitov 2010) .

Studies indicate that pulmonary inflammatory dysfunction is likely a leading cause of lethality in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which induces acute lung injury, mostly from the aggressive inflammation initiated by viral replication. Hence, SARS-CoV-2 infection induces increased secretion of interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), Interferon-gamma (IFN-γ), interleukin-8 (IL-8), interferon-γ-inducible protein 10 (IP-10), Monocyte chemoattractant protein-1 (MCP-1), interleukin-4 (IL-4), and interleukin-10 (IL-10), resulting in a potential cytokine storm associated with disease severity, manifested clinically by severe acute respiratory distress syndrome (SARDS) and systemic consequences, such as disseminated intravascular coagulation (Fu et al. 2020) .

Therefore, exacerbated inflammation causes multi-organ damage, particularly in the hepatic, cardiac, and renal systems. Aside from direct damages resulting from the virus, uncontrolled inflammatory cell infiltration ultimately leads to damage to the lung via the excessive secretion of reactive oxygen species (ROS) and proteases (Tay et al. 2020) . Together, they result in diffuse alveolar damage, including hyaline membrane formation, desquamation of alveolar cells, and pulmonary oedema. This scenario decreases the effective gas exchange in the lung, causing difficulty in breathing and low blood oxygen levels. Moreover, the lung becomes more vulnerable to other infections (Xu et al. 2020a ).

Considering how aggressive this disease is, new therapeutic options are required along with the vaccines that have already been developed, mainly to prevent or mitigate the damage induced by inflammatory dysfunction. During the early pandemic, the previous use of non-steroidal antiinflammatory drugs (NSAIDs) was suggested as a factor that could lead to disease severity in SARS-CoV-2 infection (Little 2020) . However, new studies have shown that the use of NSAID is not associated with higher mortality or increased severity (Drake et al. 2021) . A great number of NSAIDs are produced from plants, such as acetylsalicylic acid (Aspirin®) (Reis Nunes et al. 2020) . Thus, medicinal plants arise as an important source of studies in the search for new therapeutic options (Marmitt et al. 2021a) . South America has one of the most abundant flora, and the therapeutic potential contained here is immeasurable (Barlow et al. 2018) . A survey published in 2017 on the diversity of vascular plants in the Americas shows that there are 124,993 species, 6227 genera, and 355 families, which correspond to 33% of the 383,671 vascular plant species already identified worldwide. Differences in relief, climate, and altitude help to explain this diversity, and most of these species have several therapeutic applications, some already analysed and characterized. Nevertheless, there still is scope for further research (Ulloa Ulloa et al. 2017) .

The increased use of medicinal plants has cultural, economic, and therapeutic reasons (Ekor 2013) . However, only a small portion of these plants has undergone thorough scientific analyses to prove their pharmacological effects. The actual number of plants native to South America that are used to treat inflammations is rather unknown. However, the knowledge that plants can be used to treat inflammations has led to an increase in experimental and clinical investigations designed to analyse anti-inflammatory properties (French et al. 2017) . This is important because pharmacological treatments have some disadvantages, including drug resistance (reduction in efficiency), side effects, and even toxicity (Bindu et al. 2020; Fendrick and Greenberg 2009) . Thus, new studies are required so that efficacy and safety are ensured, as they are in clinical trials. Therefore, the present study aimed to select South American plants in clinical trials with anti-inflammatory properties, and relate them to the hyper-inflammation of SARS-CoV-2, analysing the potential mechanism these plants have for inhibiting/decreasing inflammatory markers.

This systematic review focused on clinical trials analysing South American plants with anti-inflammatory properties.

All open access texts published up to May 2021 were considered, regardless of language. The studies of interest are indexed in two important electronic databases, PubMed and the ClinicalTrials.gov portal. Since there were numerous manuscripts on inflammation and plants, the search focused on clinical trials.

Data analysis and interpretation were based on the same key items that guided the method; these items are described in Tables 1 and 2. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed in the design of this systematic review. The flowchart in Fig. 1 shows the study stages.

In the first stage, the keywords used to search the PubMed database were the scientific names of native South American plants, following the National Relation of Medicinal Plants of Interest to the Unified Health System (RENISUS) of Brazil (Marmitt et al. 2021b; Marmitt and Shahrajabian 2021) and the books: Medicinal and Aromatic plants of South America Vol. 1 and 2 (Albuquerque et al. 2018; Máthé and Bandoni 2021) , Medicinal Plants of Latin America (Duke 2008) , and Pharmacological Properties of Native Plants from Argentina (Alvarez 2019) . Additionally, terms such as 'inflammation', 'inflammatory bowel diseases', 'inflammatory rheumatism', 'inflammatory arthritis', and 'inflammatory myopathy' were used, as well as 'clinical trials'. A wide array of studies were found through these terms but only the clinical trials (Clinical Trial Phase I, II, III, IV; Clinical Study; Clinical Trial Protocol; Randomized Controlled Trial; Controlled Clinical Trial) were selected. To refine the search for more specific results in the ClinicalTrials.gov portal, an advanced search was performed using the following filters: Condition or disease (oxidative stress; oxygen radical damage; free radical oxidation of tissue); other terms (scientific name of native South American plants); Study Results (Study with Results); Status: Recruitment (Active, not recruiting; Terminated; Completed). Plant names were checked using The Plant List (TPL). The second stage was to analyse the clinical trials through their abstracts. The third and last stage consisted of analysing the clinical trials by reading their full texts.

Inclusion criteria were as follows: clinical trials (stage one); anti-inflammatory effects of plants (stage two); and therapeutic evidence (positive results over placebo) in clinical trials with methods or formulations using plants (stage three). In vitro and in vivo studies, comments, reviews, semi-structured interviews, conferences, letters, guidance articles, and studies that only mentioned the empirical use of plants were Daily 70 ml of 100% camu-camu juice, corresponding to 1050 mg of vitamin C (camu-camu group; n = 10) for 7 days In 20 male smoking volunteers, considered to have an accelerated oxidative stress state, oxidative stress markers such as the levels of urinary 8-hydroxy-deoxyguanosine (8-OHdG) (9.0 to 7.0 ng/mg) and total reactive oxygen species (ROS) (128 to 123 Unit) and inflammatory markers such as serum levels of hs-CRP (0.05 to 0.02 mg/dL), interleukin IL-6 (6.0 lactis BB-12) In twenty-nine volunteers (over 65 years age), for 8 weeks: a prefeeding period (2 weeks), followed by a feeding period (4 weeks) and a postfeeding period (2 weeks Aspirin was tested (alone or associated with other drugs) in mild or moderate cases of ARDS, pneumonia, COVID-19 patients with severe pneumonia-associated respiratory failure who underwent treatment with continuous positive airway pressure (CPAP), and SARS-CoV-2 patients on chronic treatment with anticoagulants or antiplatelet agents. Clinical evolution (survival and thromboembolic complications) was evaluated, as well as the use of adjuvant therapies compared to the control group. Treatment was associated with a significantly lower cumulative incidence of in-hospital death.

In adults with cardiovascular diseases, low-dose aspirin medication (100 mg/day) was associated with a lower mortality risk compared to the control group NCT04425863; NCT04757792; NCT04368377; NCT04518735; CTRI/2020/07/026791 Prospective Cohort (Carvallo, 2021) ; Retrospective multicenter study (Alkholy, 2021; Sant Pau, 2020; Meizlish et al. 2021) ; Clinical trial -Phase II (Flumignan et al. 2020 ); Open-label, randomized control trial (Ghati et al. 2020) ; Observational Study (Qiang et al. 2021 ) excluded. Duplicate studies and those that did not fall within the search scope have not been considered. Limitations of the study were risk of biases that may affect study evidence (e.g. publication bias, duplicated papers, and 'in vitro' and 'in vivo' studies, which were not considered); and limited results (restricted to two databases and limited by the presence or absence of the keywords used in the present study).

The results in Table 1 show South American plants studied in clinical trials concerning the inflammatory process. Thirty-two studies were found in the databases searched within the study scope, encompassing twenty-two native plants from different places in South America (Fig. 2) . Among the major anti-inflammatory mechanisms involved in clinical studies with selected plants, the following stand out: decrease in CRP levels (Rondanelli et al. 2020; Viecili et al. 2014; Somanah et al. 2012; Miranda-Vilela et al. 2009; Kim et al. 2018; Panza et al. 2019; Talsma et al. 2016; Inoue et al. 2008; Kitada et al. 2017; Kaspar et al. 2011; Solà et al. 2012; Stote et al. 2012; Monagas et al. 2009 ); cytokines and pro-inflammatory markers such as: IL-6 (Buchwald-Werner et al. 2018; Stockler-Pinto et al. 2014; Colpo et al. 2014; Santamarina et al. 2020; Panza et al. 2019; Kitada et al. 2017; Li et al. 2013; Alayón et al. 2019; Manzoni et al. 2017; Kaspar et al. 2011; Stote et al. 2012; Davis et al. 2020 Viecili et al. 2014; Somanah et al. 2012; Miranda-Vilela et al. 2009; Petrilli et al. 2016; Wang et al. 2020a; Solà et al. 2012) ; decreased cardiovascular risk markers such as FMD in the brachial artery (Kitada et al. 2017) , fibrinogen (Petrilli et al. 2016; Stote et al. 2012 2018). Decreased OA levels (Rondanelli et al. 2020; Gomes et al. 2021; Decha et al. 2019; Piscoya et al. 2001) , reduced uric acid levels (Somanah et al. 2012) , TLR4 (Santamarina et al. 2020 ), haptoglobin (McFarlin et al. 2015 , p47 phox protein (Panza et al. 2019) , as well as reduced pharyngitis score (Dirjomuljono et al. 2008 ) and plaque gingival index (Amaliya et al. 2018) (Table 1) . Table 2 , on the other hand, shows the major anti-inflammatory drugs that have already been tested against the SARS-CoV-2 infection in clinical trials. Results of fifteen medications were found in the databases used. These drugs act to inhibit the activity of interleukins (Anakinra (Vanassche et al. 2020; Maes et al. 2020; Bozzi et al. 2021; Kyriazopoulou et al. 2021; Franzetti et al. 2021; Pontali et al. 2021) , Canakinumab (Cremer 2021) , Siltuximab (Maes et al. 2020 ), Tocilizumab -Strohbehn et al. 2021 Price et al. 2020; Tian et al. 2021; Dastan et al. 2020; Chachar et al. 2021 Deftereos et al. 2020; Mehta et al. 2020; Tardif 2020) , immunoglobulin monoclonal antibody (Infliximab - Kennedy et al. 2021; Ixekizumab -Liu et al. 2020) , or as corticosteroids (Dexamethasone -Carvallo 2021; Syeda 2020; Kocks 2021; Tomazini et al. 2020; Villar et al. 2020; Pinzón 2020) . These studies have good results, such as decreased clinical and laboratory inflammation levels, and increased prolonged survival in SARS-CoV-2 patients. However, none of these drugs has yet shown unequivocal clinical use against SARS-CoV-2 infection. Treatment results are summarized, providing evidence for new studies.

Except for the study (NCT04810728) in both databases, no results were found relating the scientific names of native South American plants to SARS-CoV-2, COVID-19, Middle East respiratory syndrome coronavirus (MERS-CoV), or SARS-CoV, up to May 2021. This randomized clinical trial (phase III -NCT04810728) hypothesized the anti-viral efficacy of P. guajava extract (two capsules of the extract, three times daily) in increasing neutrophil, lymphocyte, and monocyte counts, and decreasing hs-CRP, thus causing a Fig. 1 Flow diagram of the literature search and study selection process following PRISMA guidelines shorter SARS-CoV-2 seroconversion into mild and symptomless cases (Heppy 2020 ).

There are thousands of published studies involving the inflammatory process. This is because chronic inflammation is involved in the pathogenesis of several diseases, including SARS-CoV-2 (Medzhitov 2010) . The selected clinical trials (Table 1) show that plant effects are induced via different anti-inflammatory mechanisms. In SARS-CoV-2 patients, the severe inflammatory responses induced by a cytokine storm (Fig. 3 ) start locally and spread systemically, causing collateral damage in tissues (Gupta et al. 2020 ). There are increased serum levels of pro-inflammatory cytokines that are also observed in SARS-CoV and MERS-CoV infections, which lead to several adverse reactions in the human body (Prompetchara et al. 2020) .

CRP levels are correlated with inflammation intensity. It is an important marker for the diagnosis and assessment of severe pulmonary infectious diseases. Its levels can be used in the early diagnosis of pneumonia, and patients presenting with severe pneumonia have high CRP levels (Chalmers et al. 2019 ). This suggests that CRP levels can cause lung lesions and increase disease severity in the early stage of SARS-CoV-2, and can be used as a key indicator for infection monitoring (Wang 2020) . In the present review, many native South American plants analysed in clinical trials showed potential to decrease CRP levels; namely, A. oleracea (Rondanelli et al. 2020) , C. xanthocarpa (Viecili et al. 2014) , C. papaya (Somanah et al. 2012) , C. brasiliense (Miranda-Vilela et al. 2009 ), E. oleracea (Kim et al. 2018) , I. paraguariensis (Panza et al. 2019) , M. esculenta (Talsma et al. 2016) , M. dubia (Inoue et al. 2008) , P. edulis (Kitada et al. 2017) , S. tuberosum (Kaspar et al. 2011) , and T. cacao (Solà et al. 2012; Stote et al. 2012; Monagas et al. 2009 ).

Inhibition of the NF-κB pathway plays a therapeutic role in alleviating the severe form of SARS-CoV-2 infection, as the activation of NF-κB in some cells (e.g. the macrophages in the lung, liver, kidney, gastrointestinal system, central nervous system, and cardiovascular system) leads to the production of several cytokines, such as IL-1, IL-6, IL-8, TNF-α, and several chemokines. Thus, immunomodulation at the level of NF-κB activation and inhibitors of NF-κB (IκB) degradation together with TNF-α inhibition can result in reduced cytokine storm levels and mitigate the severity of SARS-CoV-2 infection (Hariharan et al. 2021) . P. americana induces inhibition of the NF-κB signalling pathway (Li et al. 2013) .

Severe SARS-CoV-2 patients show high levels of IL-6, which play a major role in coagulation; this provides a Fig. 2 South American antiinflammatory plants. Source: VectorStock major contribution to tissue damage and inflammation, and to atherogenesis (Smail et al. 2021) . Studies show that even moderate IL-6 levels (higher than 80 pg/mL) are sufficient to identify SARS-CoV-2-infected patients with a high risk of respiratory failure (Herold et al. 2020) . It was also suggested that a serial measurement of circulating IL-6, IL-8, and TNF-α might be important in identifying disease progression, and it might predict the next respiratory failure (Del Valle et al. 2020) . In this review, A. citriodora (Buchwald-Werner et al. 2018 ), B. excelsa (Stockler-Pinto et al. 2014 Colpo et al. 2014 ), E. edulis (Santamarina et al. 2020) , I. paraguariensis (Panza et al. 2019) , P. edulis (Kitada et al. 2017) , P. americana (Li et al. 2013) , P. volubilis (Alayón et al. 2019) , S. sonchifolius (Manzoni et al. 2017) , S. tuberosum (Kaspar et al. 2011) , and T. cacao (Stote et al. 2012; Davis et al. 2020) , decreased IL-6 levels in clinical trials.

A major component in deteriorating lung function in SARS-CoV-2 patients is capillary leak resulting from inflammation caused by key inflammatory cytokines (TNFα, IL-1, IL-6, IL-8, and VEGF) that up-regulate adhesion molecules and disrupt endothelial barrier in blood vessels. TNF-α is a cell signalling inflammatory cytokine and acts as an inflammation amplifier (Robinson et al. 2020) . In blood and tissue samples of SARS-CoV-2 patients, the presence of TNF-α molecules was observed (Wang et al. 2020b) . B. excelsa (Stockler-Pinto et al. 2014; Colpo et al. 2014 ), E. edulis (Santamarina et al. 2020 ), E. oleracea (Kim et al. 2018 guianensis (Piscoya et al. 2001 ) are plants with inhibitory activity against TNF-α. B. excelsa (Colpo et al. 2014 ) and T. cacao (Davis et al. 2020 ) decreased IL-1β levels, which are released from cells undergoing pyroptosis (an inflammatory form of programmed cell death observed in infections with cytopathic viruses, such as CoVs) and are high in serum and bronchoalveolar fluid (BALF) of patients with severe SARS-CoV-2 infection. Cytokine also increases tissue inflammation, fibrosis, and fever (Liao et al. 2020) . IL-8 is another biomarker to predict different disease severities and prognoses of COVID-19 patients. Serum IL-8 is easily detectable in COVID-19 patients with mild syndromes (Li et al. 2020) . The Amazonian plant M. dubia showed potential to inhibit IL-8 in clinical trials (Inoue et al. 2008 ). On the other hand, after viral infection, IL-18 release induces ferritin synthesis, which explains the hyperferritinemia observed in viral infections. Aside from the cytokine storm, the pathogenesis of SARS-CoV-2 is also characterized by hyperferritinemia. Moreover, serum concentrations of IL-18 correlate with other inflammatory markers and can predict disease outcomes (Satış et al. 2021) . T. cacao (Davis et al. 2020 ) decreased serum IL-18 concentrations. It is important to understand the role played by IFN-γ in SARS-CoV-2 pathogenesis since it is still ambiguous. This cytokine is essential for antiviral defence, it downregulates virus replication and activates cytokine production by T cells, increasing the killing activity of cytotoxic T lymphocytes. Nevertheless, persistently high levels of IFN-γ worsen systemic inflammation, increasing tissue injury and organ failure Fig. 3 The potential mechanisms of 'cytokine storm' induced by Th1, CD4 + T, and Th17 cells, culminating in multiple organ damage. Source: VectorStock (Gadotti et al. 2020) . B. excelsa (Colpo et al. 2014 ), E. oleracea (Kim et al. 2018) , P. amarus (George et al. 2019) are plants that induce decrease in IFN-γ levels in humans. In contrast, there are elevated amounts of anti-inflammatory cytokine, IL-10, in the serum of COVID-19 patients, which is generally regarded as an immune-inhibitory mechanism, stimulated by the rapid accumulation of pro-inflammatory cytokines as a negative feedback loop (Zhao 2020) . However, some lines of clinical evidence suggest that the early and dramatic IL-10 rise during SARS-CoV-2 infection might play a detrimental pathological role in COVID-19 severity (Lu et al. 2021) . B. excelsa (Colpo et al. 2014 ), E. edulis (Kim et al. 2018 ) and S. sonchifolius (Manzoni et al. 2017) increased IL-10 levels.

SARS-Cov-2 levels are high in the first week, and then, decrease sharply in the second week of infection (Petrilli et al. 2016) . Therefore, antiviral therapy can be initiated at an early stage of infection. In general, when patients seek medical help, the disease has already developed into the second or third stage, with respiratory difficulties and organ failures. Therefore, studies should look further, beyond the virus, focusing on the cytokine storm and on the action of free radicals as the actual pathogens (Wu 2020) . The pathogenic role of free radical damage is clear in inflammations and in respiratory virus infection. IL-6 and TNF-α have been reported to lead to production of superoxide in neutrophils, and hydrogen peroxide can stimulate IL-6 production (Kharazmi et al. 1989) . Inhibition of NO synthesis can decrease IL-6 production by more than 50%. In summary, it is essential to understand that free radicals are the downstream product of the cytokine storm, causing direct damage to cells and many organs (Willis et al. 1994) . Therefore, the present study found that South American plants showed inhibitory potential against some free radicals, such as TBARS (Miranda-Vilela et al. 2009 ) (C. brasiliense), ROS (Inoue et al. 2008) (M. dubia) , NO (Decha et al. 2019; Davis et al. 2020) (P. amarus and T. cacao), 8-OHdG (Inoue et al. 2008; Kaspar et al. 2011) (M. dubia and S. tuberosum) , as well as dROM (Kitada et al. 2017 ) (P. edulis). On the other hand, natural antioxidant substances play a preventive role in protecting against the production of free radicals and are, therefore, a therapeutic agent to reduce the conditions triggered by oxidative stress, e.g. inflammation (Marmitt et al. 2021c ). It has been suggested that there is an inverse relationship between consuming natural antioxidant plant sources and the prevalence of chronic illnesses (Arulselvan et al. 2016) . The selected clinical trials show good results with plants that stimulate increased levels of endogenous antioxidants; A. citriodora (Buchwald-Werner et al. 2018) and B. excelsa (Stockler-Pinto et al. 2014) increased GPx levels, I. paraguariensis increases GSH levels (Panza et al. 2019) , and P. amarus (Decha et al. 2019) up-regulated SOD levels.

The association between cardiovascular events and infectious diseases is well established (Collard et al. 2021) . In short, the presence of more than one CVD marker, such as fibrinogen, haptoglobin, and hyperCKemia (increased CK levels), in SARS-CoV-2 inpatients might indicate a mortality risk higher than 50%. The accumulation of CVD risk factors (presence of coronary artery disease, smoking, and obesity) is associated with mortality, regardless of age or sex. These results are consistent with previous SARS-CoV and MERS-CoV infections (Nishiga et al. 2020) . The present review relates decrease in CVD markers with some plants in clinical trials on inflammation; for instance, decreased CK by A. citriodora (Buchwald-Werner et al. 2018 , decreased NOX by C. papaya (Das et al. 2018 , decreased FMD by P. edulis (Kitada et al. 2017) , decreased fibrinogen by I. paraguariensis and T. cacao (Petrilli et al. 2016; Stote et al. 2012) , and decreased haptoglobin by T. cacao (McFarlin et al. 2015) . Similarly, studies have also reported that patients with comorbidities and risk factors such as obesity are more susceptible to a more serious SARS-CoV-2 infection. Cholesterol (LDL-high levels) is an important risk factor in CVDs. It has been suggested that it is involved in regulating the entry of the SARS-CoV-2 virus into the host cell. Higher membrane cholesterol coincides with a more effective SARS-CoV-2 entry (Kočar et al. 2021) . Conversely, SARS-CoV-2 patients show low levels of blood cholesterol, such as LDL. HDL already seems to play an array of roles, ranging from virus scavenger, immune modulator, to mediator of viral entry. Clinical studies with the following plants inducing a decrease in LDL levels were found; B. excelsa , and T. cacao (Solà et al. 2012) , which also decreased ApoB levels, which is the primary LDL apolipoprotein, responsible for transporting cholesterol to tissues. Some plants induce increase in HDL levels, e.g. B. excelsa (Stockler-Pinto et al. 2014) , C. papaya (Petrilli et al. 2016) , and I. paraguariensis (Petrilli et al. 2016) . Analysing these results, Fig. 4 shows a potential mechanism through which these plants can provide their anti-inflammatory effects.

The NCT04810728 study (Heppy 2020) showed an antiviral effect based on in vitro studies, indicating that guava leaves contain a large amount of flavonoids, especially quercetin. The study on type 2 Dengue virus (DEN-2) found that quercetin significantly inhibited DEN-2 virus activity (IC 50 : 53 μg/mL). Quercetin also inhibited the enzyme reverse transcriptase, HIV-1(RT), with an inhibitory concentration of 0.6 µM. Another study found that quercetin in P. guavaja inhibits RNA polymerase, which is important in Dengue virus replication. In addition, quercetin can inhibit protease enzyme, helicase domain, and viral ATPase enzyme. Considering antiviral effects, these results may be important for future analyses of treatments against SARS-CoV-2 infection.

Even considering other scientific study levels (in vitro, in vivo), the only studies related to SARS-CoV-2 in the databases are with P. edulis, P. amarus, S. tuberosum, and T. cacao. The compounds in these four plants with inhibitory potential against SARS-Cov-2 were analysed in silico using molecular docking. P. edulis showed that lucenin, isoorientin, oleanolic acid, luteolin, isochaphoside, schaftoside, and saponarin are potential ligands with ACE2 protease, with binding energy higher than −8.0 kcal/mol (Yalçın et al. 2021) . Phytochemicals from P. amarus (astragalin, kaempferol, quercetin, quercetin-3-O-glucoside, quercetin, corilagin, furosin, and geraniin) had a binding docking score lower than − 6.0 kcal/mol (Hiremath et al. 2021) . The compounds curcumenol, N-desmethylselegiline, phentermine, and sphingolipid, which are derived from S. tuberosum, have been suggested as selective candidates for the effective modulation of ACE2 and TMPRSS2 receptors (Dave et al. 2020) . Isorhoifolin and rutin are T. cacao compounds that already stand out due to their more negative binding to the SARS-CoV-2 major viral protease (Yañez et al. 2021 ). The phytochemicals present in these plants might have a potential effect on multiple target sites of SARS-CoV-2, providing further possibilities for experiments aiming to validate these molecules as inhibitors of SARS-CoV-2 protease.

It is also worth noting that from 1981 to 2019, 53 of the 1,881 drugs produced were anti-inflammatory; of these, fifteen derived from natural products or their derivatives (Newman and Cragg, 2020) . Two of the fifteen anti-inflammatory drugs selected in Table 2 are natural, plant-produced drugs. Colchicine is a poisonous alkaloid, originally extracted from Colchicum autumnale L. -Colchicaceae. It has been used in the treatment of several diseases such as gout, pericarditis, and inflammatory arthritis. Additionally, it has had novel applications within oncology, immunology, cardiology, and dermatology, yet it has been used on a smaller scale due to its high toxicity (Dasgeb et al. 2018) . Acetylsalicylic acid (Aspirin) was originally synthesized from the bark of white willow (Salix alba L. -Salicaceae) (Montinari et al. 2019) and it is important to describe the benefits of salicylates, such as salicylic acid (SA), which is the major aspirin metabolite, and a compound that reduces inflammation. A genome-analysis identified potential SA-binding proteins (SABPs) using in vitro cells. Approximately 2000 proteins were identified. Pathway analysis with 95 proteins candidate SABPs (cSABPs) revealed a potential involvement of SA in multiple biological pathways, including glycolysis, cytoskeletal assembly and/or signalling, and NF-κB-mediated immune signalling (Choi et al. 2019) . SA is an endogenous signal for innate immunity in plants.

Researchers have identified pathways through which SA can be synthesized, numerous proteins that regulate SA synthesis and metabolism, as well as some of the signalling components that act downstream of SA, including a large number of SA targets or receptors. Thus, numerous SABPs might be required to mediate myriad effects of SA. Therefore, while the primary mode of action of aspirin in humans has been ascribed to the inhibition of cyclooxygenases COX1 and COX2, several lines of evidence argue that additional SA targets exist, as potential of salicylates in the anti-viral activity (Klessig et al. 2016) . In addition, a significant SA-mediated antiviral activity against DNA and RNA viruses, including different coronaviruses, has been documented. The use of SA in patients with different types of infections has been associated with lower rates of clinical complications and in-hospital mortality, as well as reduced thrombo-inflammation. However, safety issues related to the risk of adverse effects, such as the risk of bleeding and of developing rare liver and brain damage should be considered (Bianconi et al. 2020 ). Moreover clinical trials show the potential of SA (Goldfine et al. 2008 (Goldfine et al. , 2016 , since the randomized controlled studies (n = 35) showed that high doses of salicylate (up to 4 g/day) reduce inflammation, glucose and triacylglycerols, improve insulin sensitivity, and reduce adipose tissue NF-κB activity, suggesting a therapeutic potential in impaired fasting glucose and/or impaired glucose tolerance in the randomized controlled study (n = 35). These data support the targeting of inflammation and NF-kB as a therapeutic approach in type 2 diabetes.

Clinical results of anti-inflammatory drugs tested against SARS-CoV-2 infection (Table 2 ) are important but not definitive, as most treatments have not shown significant improvement in the survival of the severe form of SARS-CoV-2 Fig. 4 The suggested mechanism through which plants could exert their inhibitory/inducing effects in SARS-CoV-2 infection. Source: VectorStock infection. It is worth considering that the prognosis of healing from hyperinflammation is generally unfavourable (Herold et al. 2020 ). NSAIDs such as aspirin work as inhibitors of the COX enzyme, which is responsible for the production of inflammatory prostaglandins. The World Health Organization (WHO) has contraindicated the use of NSAIDs in the early COVID-19 pandemic since NSAIDs down-regulate ACE2 in the respiratory system, which decreases pulmonary function. However, NSAIDs also up-regulate ACE2 especially in diabetic patients and patients that take ACE2 receptor inhibitors (Rinott et al. 2020) , and therefore, the over-expression of ACE2 receptors could facilitate the entry of SARS-CoV-2 and increase the chances of infection. However, the WHO soon became favourable to the use of NSAIDs, as findings showed that not only these drugs are not contraindicated but also their use could help in the treatment of SARS-CoV-2 infection (WHO 2020). In addition, the reasons for not using NSAIDs do not hold since the up-regulation of ACE2 occurs during the chronic use of drugs, which renders the person vulnerable to the disease. On the other hand, the evidence of ACE2 up-regulation by these drugs was obtained in in vivo studies, and may be not transferable to clinical trials (NICE 2020) .

Similarly, immunotherapeutic drugs mostly act as antiinflammatory agents; however, their side effects should be considered since decreased immunity delays virus clearance and increases the chances of the patient having a bacterial infection (Singanayagam et al. 2018 ). In addition, most immunotherapeutic drugs have a specific target, as they inhibit only one cytokine, such as JAK inhibitors or IL-6 blockers, which renders the inflammation difficult to control (Zídek et al. 2009 ). Targeting the IL-6 signalling pathway is a potential strategy for relieving inflammation symptoms in SARS-CoV-2 infection (Salomé and Magen 2020) . Six clinical trials with findings on Tocilizumab, an anti-IL-6 receptor antibody, were selected for SARS-CoV-2 mitigation (Strohbehn et al. 2021; Price et al. 2020; Tian et al. 2021; Dastan et al. 2020; Chachar et al. 2021) . Moreover, tocilizumab has been approved by China for the treatment of SARS-CoV-2 infection through the clinical trial (ChiCTR2000029765); its results showed rapidly controlled fever and improved respiratory function in patients with severe COVID-19, and all patients recovered (Xu et al. 2020b ). There was a Phase III Clinical trial with another IL-6 blocker, Siltuximab (Maes et al. 2020) . Inhibitors of the JAK signalling pathway are powerful anti-inflammatory agents that are effective against the effects of high cytokine levels. Baricitinib and ruxolitinib are selective JAK inhibitors that have been used in SARS-CoV-2 infection, and have been selected in the present review (Kalil et al. 2021; Novartis Pharmaceuticals 2021) . Baricitinib was administered to SARS-CoV-2 patients associated with direct-acting antivirals, and reduced viral replication and inflammatory response (Stebbing et al. 2020 ). However, the risks and benefits of cytokine inhibition must be carefully assessed in the administration of these treatments (Schett et al. 2020 ).

The clinical results found are not directly related to the context of the SARS-CoV-2 infection. However, they provide possibilities for further studies with native South American plants considering their anti-inflammatory activity by inhibiting levels of cytokines that play a role in hyperinflammation or even other inflammatory markers detected in SARS-CoV-2 patients. Plants have a variety of compounds, and identifying which ones are responsible for anti-inflammatory effects can help in studies conducted with the aim to evaluate their efficacy in scenarios of SARS-CoV-2 infection.

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Author contributions DM has elaborated, designed, and analysed the data; he has also written the paper.