Lower COVID-19 mortality in Italian forested areas suggests immunoprotection by Mediterranean plants

Abstract

The COVID-19 pandemic has induced dramatic effects on the population of the industrialized north of Italy, whereas it has not heavily affected inhabitants of the southern regions. This might be explained in part by human exposure to high levels of fine particulate matter (PM) in the air of northern Italy, thus exacerbating the mortality. Since trees mitigate air pollution by intercepting PM onto plant surfaces and bolster the human immune system by emitting bioactive volatile organic compounds (VOCs), we hypothesize a protective role of evergreen forested areas in southern Italy. We compared the mortality rate due to COVID-19, the death number, the positivity rate and the forest coverage per capita in various Italian regions. Hectares of forest per capita and prevalence of deciduous versus evergreen forestal species were also estimated. In silico docking studies of potentially protective compounds found in Laurus nobilis L., a typical Mediterranean plant, were performed to search for potential antivirals. We found that the pandemic’s severity was generally lower in southern regions, especially those with more than 0.3 hectares of forest per capita. The lowest mortality rates were found in southern Italy, mainly in regions like Molise (0.007%) and Basilicata (0.005%) where the forest per capita ratio is higher than 0.5 Ha/person. Our findings suggest that evergreen Mediterranean forests and shrubland plants could have protected the southern population by emission of immuno-modulating VOCs and provision of dietary sources of bioactive compounds. Moreover, in silico studies revealed a potential anti-COVID-19 activity in laurusides, which are unexplored glycosides from bay laurel. Overall, our results highlight the importance of nature conservation and applications to the search for natural antivirals.

Full text

Vol.:(0123456789)
1 3
Environmental Chemistry Letters
https://doi.org/10.1007/s10311-020-01063-0
ORIGINAL PAPER
Lower COVID‑19 mortality inItalian forested areas suggests
immunoprotection byMediterranean plants
ValentinaRoviello1 · GiovanniN.Roviello2
Received: 19 June 2020 / Accepted: 28 July 2020
© Springer Nature Switzerland AG 2020
Abstract
The COVID-19 pandemic hasinduced dramatic effects on the population of the industrialized north of Italy, whereas it has
not heavily affected inhabitants of the southern regions. This might be explained in part by human exposure to high levels of
fine particulate matter (PM) in the airof northern Italy, thus exacerbating the mortality. Since trees mitigate air pollution by
intercepting PM onto plant surfaces and bolster the human immune system by emitting bioactive volatile organic compounds
(VOCs), we hypothesize a protective role of evergreenforested areas in southern Italy. We compared the mortality rate due
to COVID-19, the death number, the positivity rate and the forest coverage per capita in variousItalian regions. Hectares of
forest per capita and prevalence of deciduous versus evergreen forestal species werealso estimated. In silico docking studies
of potentially protective compounds found in Laurus nobilis L., a typical Mediterranean plant, were performed to search for
potential antivirals. We found that the pandemic’s severity was generally lower in southern regions, especially those with more
than 0.3 hectares of forest per capita. The lowest mortality rates were found in southern Italy, mainly in regions likeMolise
(0.007%) and Basilicata (0.005%) where the forest per capita ratio is higher than 0.5 Ha/person. Our findings suggest that
evergreenMediterranean forests and shrubland plants could have protected the southern population by emission of immuno-
modulating VOCs and provision of dietary sources of bioactive compounds. Moreover, in silico studies revealed a potential
anti-COVID-19 activity in laurusides, which are unexplored glycosides from bay laurel. Overall, our results highlight the
importance of nature conservation and applications to the search for natural antivirals.
Keywords SARS-CoV-2· COVID-19· Air pollution· Particulate matter· Forest bathing· Mediterranean vegetation·
Laurus nobilis· Plant therapeutics· Plant toxicity· Mpro inhibitors
Introduction
COVID-19 (COronaVIrus Disease 19) is a novel disease
characterized in several cases by severe pneumonia, caused
by severe acute respiratory syndrome coronavirus 2 (SARS-
CoV-2) previously indicated as 2019-new coronavirus
(2019-nCoV). COVID-19 emerged in Wuhan, central China,
in December 2019 (Lai etal. 2020; Wu etal. 2020). How-
ever, COVID-19 hasspread rapidly worldwide, becoming a
global issue with several countries all over the world report-
ing numerous cases of infection (Hunter 2020). This led the
world health organization (WHO) to declare it a pandemic
on 11 March 2020 (Sinonquel etal. 2020).
SARS-CoV-2 is a betacoronavirus closely related to other
bat-derived severe acute respiratory syndrome (SARS)-
like coronaviruses (Lu etal. 2020; Park etal. 2020), and
it is a subject of several research studies in environmental
chemistry in the attempt to understand its behaviour in the
environment (Sharma etal. 2020). This virus is also related
to the SARS-CoV-1, sharing about 79% genomic identity,
which caused SARS in 2002–2003 (Anderson etal. 2004),
a coronaviral epidemic which led to deaths mainly in Asia
(Anderson etal. 2004).
Recently, the ESA (European Space Agency) and NASA
(U.S. National Aeronautics and Space Administration)
Electronic supplementary material The online version of this
article (https ://doi.org/10.1007/s1031 1-020-01063 -0) contains
supplementary material, which is available to authorized users.
* Giovanni N. Roviello
giroviel@unina.it; giovanni.roviello@cnr.it
1 Department ofChemical, Materials andIndustrial
Production Engineering (DICMaPI), University ofNaples
Federico II, Piazzale V. Tecchio 80, 80125Naples, Italy
2 Istituto Di Biostrutture E Bioimmagini IBB - CNR, Via
Mezzocannone 16, 80134Naples, Italy

Environmental Chemistry Letters
1 3
released data showing that pollution in the main epicentres
of COVID-19 such as China, a country heavily affected by
air pollution (Feng and Zheng 2019), Italy, Spain and the
USA, has reduced significantly, up to 30% (Muhammad
etal. 2020), even though an unexpected rise of ozone air
pollution (Yu 2018) was observed in both urban and rural
areas (Wang etal. 2020). On the other hand, several studies
showed that air pollution is a risk factor for acute respira-
tory infection by affecting the body’s immune system and by
carrying microorganisms (Cai etal. 2007; Susanne Becker
1999; Sun etal. 2016; Xie etal. 2019). It was also shown
that environmental pollutants are in correlation with the
severity of COVID-19 (Bashir etal. 2020; Zhu etal. 2020)
and, in particular, particulate matter (PM) (Mukherjee and
Agrawal 2017, 2018; Dang and Shan 2017) in combination
with humidity significantly increases the risk of COVID-19
incidence (Jiang etal. 2020).
This would suggest that air pollution control can
reduce the harmful effects of the global pandemic (Bashir
etal. 2020). The air quality effect on the confirmed cases
of COVID-19 was stronger in the temperature range of
10–20°C, while the relative risk of COVID-19 transmission
associated with air quality was higher in the 10–20% relative
humidity range, suggesting a higher impact of air quality
on the COVID-19 spread under low relative humidity (Xu
etal. 2020). Northerly latitude was generally associated with
increased mortality and hospitalization rates for COVID-19
worldwide due to several factors such as the deficiency of
vitamin D, a vitamin with immuno-modulatory properties,
caused by low ultraviolet exposure, as well as low tempera-
ture and relative humidity conditions allowing the virus to
survive longer outside the human body (Panarese and Sha-
hini 2020).
Interestingly, several Mediterranean countries have expe-
rienced a milder impact of the virus, with low morbidity
and mortality linked to COVID-19 (Panarese and Shahini
2020). This can be explained by the rigorous control meas-
ures taken by the local governments who did not ignore the
lessons from northern Italy (Frogoudaki 2020; Saglietto
etal. 2020). Nevertheless, in concurrence with the measures
put in place, the above-cited effects of latitude, climate, the
availability of vitamin D as well as other environmental fac-
tors together with the Mediterranean diet could have resulted
in the more favourable outcome recorded in the Mediterra-
nean area (Cena and Chieppa 2020).
Italy showed significant regional differences in the impact
of COVID-19, with it being more dramatic in the north when
compared to the significantly milder situation observed in
the south (Signorelli etal. 2020).
Owing to the importance of trees in air pollution mitiga-
tion, as emitters of bioactive volatile organic compounds
(VOC) and as having beneficial effects in bolstering the
body’s immune system, we decided to explore the impact of
COVID-19 in the Italian regions in relationship to the abun-
dance of forest cover. Moreover, as an example, we inves-
tigated a typical Mediterranean plant, i.e. bay laurel (Lau-
rus nobilis L.) (Alessi etal. 2018), as a source of potential
anti-COVID-19 natural products, studied in silico for their
abilities to bind Mpro, the main protease of SARS-CoV-2 (Jin
etal. 2020). They were also studied for their toxicity with a
particular attention paid to laurusides, a scarcely explored
class of compounds from laurel that could disclose interest-
ing biological activities (Duc Dat etal. 2019).
Experimental
Estimation offorest area/inhabitant andother
parameters mentioned inthis work
The 2015 forest area data for the Italian regions, released
by Italian National Forest Service (INFC), are available in
the table reported on page 4 (CREA INFC 2015) of the fol-
lowing link: https ://www.polit ichea grico le.it/flex/cm/pages
/Serve Attac hment .php/L/IT/D/7%252Fe %252Fd %252FD
.fad37 6b863 247ad 7355a /P/BLOB%3AID%3D146 52/E/pdf.
To calculate the forest area per capita values of TableS1
(see Results and Discussion) for each region, we divided
the number of hectares of forest reported at the link above
by the number of inhabitants (reported at the link https ://
dati.istat .it/Index .aspx?Query Id=18460 &lang=en). We esti-
mated prevalence of deciduous vs. evergreen forestal species
in Aosta Valley, Trentino and South Tyrol regions (Results
and Discussion) by using the data furnished by INFC, avail-
able at the link: https ://www.sian.it/inven tario fores tale/caric
aDocu mento ?idAll e=421 COVID-19 data for Italian regions
were reported at the link https ://en.wikip edia.org/wiki/
COVID -19_pande mic_in_Italy (data as of 20 May 2020).
Molecular docking
The three-dimensional structure of the protein target from
SARS-Cov–2, i.e. the main protease Mpro (PDB ID: 6YB4),
was obtained from Protein Data Bank (Berman etal. 2002).
The 2D structures for the ligands were retrieved from
PubChem database (https ://pubch em.ncbi.nlm.nih.gov/),
while those not available in PubChem were drawn using the
molecular editor provided in 1-Click Mcule (Mcule Inc.,
Palo Alto, CA, USA) (Potemkin etal. 2019; Fik-Jaskółka
etal. 2020a,b, a; Kiss etal. 2012), a web-based platform
powered by AutoDock Vina docking algorithm (Trott and
Olson 2009) by which we realized our docking experi-
ments. The atomic coordinates of the binding site were
those reported in the recent literature (Umesh etal. 2020) (X:
9.204, Y: − 4.557 and Z: 19.602), and the size of the binding
site was 22 Angstrom. We selected the docking poses with

Environmental Chemistry Letters
1 3
the most negative docking scores (kcal/mol) corresponding
to the highest binding affinities. We validated the method
applying it to other literature dockings targeting Mpro, find-
ing our binding energy scores in line with those previously
reported for carnosol (Umesh etal. 2020), apixaban and
other ligands docked to the same protein target (Chakraborti
etal. 2020). The molecular graphics program incorporated
in 1-Clik Mcule was used for structural visualization of
protein–ligand interactions and to obtain the snapshot of
Fig.4,while the protein–ligand interaction diagram shown
in the same figure was obtained by ProteinsPlus (https ://
prote ins.plus/) (Rarey etal. 2020).
Potential oral lethal dose toxicity class
determination andother toxicity parameters.
The potential oral lethal dose toxicity class forlauruside 5
and reference compounds was evaluated on the ProTox web-
based server (tox.charite.de). The toxicities are classified
into six classes (I-VI) (Drwal etal. 2014) and the predicted
toxic doses (in rodents) were reported as LD50 values in mg/
kg body weight. ProTox also suggested the potential toxicity
targets for lauruside 5.
Results anddiscussion
COVID‑19 impact inItalian regions withdierent
forest cover areas
Comparing the number of deaths due to COVID-19 with
rates of forest area per inhabitants in the different Italian
regions (Fig.1, TableS1), we found there to be generally
less deaths in the regions having ≥ 0.34 hectares of forest/
number of inhabitants.
If one considers the Italian regions which have to date (as
of 26th May 2020) less than 300 fatalities related to SARS-
CoV-2 infection (TableS1), all but Sicily are endowed with
almost an acre of forest per capita (TableS1). Normalizing
the number of victims by total population, we observed that
5 out of 7 regions with less than 0.01% COVID-19 deaths/
total population still had at least 0.34 hectares of forest/
number of inhabitants. Peculiar features including proximity
Fig. 1 Bar graphs showing the abundance of forest areas (a) as well
as some parameters useful to describe the COVID-19 impact on
local populations within eight representative regions of Italy. These
include the percentage of COVID-19 fatalities/number of inhabitants
(b), positivity rates (c) and the number of deaths (d). Note the higher
coronavirus impact on regions like Emilia Romagna, Lombardia and
Veneto which have less than 0.2 hectares of forest per capita when
compared to the significantly more favourable situation within the
regions where the above ratio was higher than 0.34 hectares/inhabit-
ant
▸

Environmental Chemistry Letters
1 3
to the coast of the largest cities, particularly mild weather,
presence of cultivated areas with Mediterranean orchards
and Mediterranean wild shrubland with oleanders (Nerium
Oleander L.), holm oaks (Quercus Ilex L.), wild olive trees
(Olea europaea L.) or other plants with promising effects on
air pollution mitigation (Blanusa etal. 2015; Abed-Esfahani
etal. 2013a,b; Kaur and Nagpal 2017), could all account for
the favourable outcome of Sicily. This latter, in fact, pre-
sents the third lowest percentage of positive COVID-19 tests
(3.0%, TableS1) after Calabria (2.7%) and Basilicata (2.4%).
Interestingly, the two italian regions with the lowest mortali-
ties due to COVID-19, i.e. Molise and Basilicata, are also
situated in southern Italy and have high ratios of hectares
of forest/number of inhabitants: 0.56 and 0.70, respectively
(Fig.1, TableS1). Examining the same aspects for northern
Italy, we still found higher forest areas per inhabitant in the
regions with lower numbers of deaths due to COVID-19.
Remarkably, Lombardy, having the lowest forest area per
capita within northern Italy, was not only the region with
the highest number of COVID-19 victims (> 15,000, Fig.1,
TableS1), but it also had the highest level of occupancy
of intensive care unit beds (Odone etal. 2020) as well as
the highest rate of positive tests (23.8%, Fig.1, TableS1).
Within the northern regions with less than 300 COVID-19
victims, this rate (4.7–17.1%) was lower than Lombardy, but
generally higher than the ‘greener’ regions of southern Italy
(2.4–3.8%, TableS1). As an example, South Tyrol (520,000
inhabitants, northern Italy) presents a similar forest area per
capita (~ 0.7 Ha/person) compared to Basilicata (560,000
inhabitants, southern Italy), but a ~ 5 times higher rate of
positive tests (TableS1). This could be associated to sev-
eral factors including differences in virus abundance, due
to obvious different geographic distances from the regions
where the pandemic started in Italy (Odone etal. 2020), but
which could also include the differences in latitude, climate,
proximity to coast and the local diet. Nevertheless, there
is the possibility that the Mediterranean vegetation present
in the southern regions of the country could be playing a
protective role.
When comparing the neighbouring South Tyrol and
Trentino, we notice that the former, with forests composed
mainly of evergreen trees (see Experimental section) has a
significantly lower rate of COVID-19 deaths/total population
(0.053%) than the latter (0.084%) which has a large pre-
dominance of winter-dormant deciduous trees (see Experi-
mental section). Interestingly, Aosta Valley, despite its very
high ratio of hectares of forest (butwith a significant rate of
deciduous trees, see Experimental section)/number of inhab-
itants (0.89 Ha/person) presents a COVID-19 death rate per
total population that is more than 10 times higher than that
of Molise (0.007%) and Basilicata (0.005%). Lockdown
measures were undertaken in Aosta Valley at the same time
as these two regions. This difference could be tentatively
explained on the basis of a combination of factors besides
the most obvious, i.e. distance from COVID-19 epicentre
and the intense winter tourism fluxes in Aosta Valley from
Lombardy: latitude, sunlight/climate and the abundance in
southern Italy of Mediterranean plants, both cultivated and
spontaneous trees. Remarkably, studying the pandemic in
Italy using the basic reproduction number R0, average num-
ber of people that can be infected by an already infected
person, the four lowest R0 values determined by Distante
etal. (Distante etal. 2020) were given to the four southern
regions with the highest forest cover area per inhabitant.
A hypothesis of association between severity of the cur-
rent pandemic of COVID-19 and high levels of fine par-
ticulate matter (PM) in urban areas, an issue in Lombardy
and other areas of northern Italy, was recently brought forth
(Conticini etal. 2020). In fact, the particulate matter could
play a role in spreading the SARS-CoV-2 virus in the air
(Setti etal. 2020) and is also linked to respiratory patholo-
gies in turn responsible for higher COVID-19 mortality rates
(Dutheil etal. 2020). Fine PM penetrating into the respira-
tory system can easily provoke inflammatory responses as
well as cardiovascular and pulmonary diseases, thus exac-
erbating respiratory distress. This seemed particularly evi-
dent in northern Italy where COVID-19 disease provoked
the highest number of victims in the country, as well as one
of the most worrying situations worldwide, and where PM
concentrations of ≥ 50µg/m3 as PM10 daily averages were
often recorded (Setti etal. 2020).
The beneficial role of trees in removing air pollution
is well known and described in the literature (Grzędzicka
2019). In fact, by intercepting the particulate matter on
leaves and other plant surfaces, and absorbing gaseous pol-
lutants through their leaf stomata, urban trees are notoriously
adept to air purification (Nowak etal. 2014, 2018). In this
context, several plants belonging to the class of Mediter-
ranean vegetation, such as the holm oak (Quercus ilex L.),
bay laurel (Laurus nobilis L.) and others, were found able
to cleanse the atmosphere, trapping among other pollutants
several polycyclic aromatic compounds (Sgrigna etal. 2015;
Gratani and Varone 2013; Fellet etal. 2016). Owing to the
role of urban forests in decreasing concentrations of particu-
lates and other pollutants, thus improving air quality, it was
recently argued that they can also contribute to reducing the
impact of COVID-19 (Fares etal. 2020).
Mediterranean trees assources ofbiogenic volatile
organic compounds withimmune‑modulatory
activities
We have analysed the literature data on the protective role
of Mediterranean plants, viewed as unique sources of use-
ful metabolites displaying positive effects against various
pathogens (Kahkha etal. 2013), within the context of the

Environmental Chemistry Letters
1 3
current pandemic episode. We payed particular attention to
the effect on the human immune system triggered by the
inhalation of volatile compounds emitted by trees. We found
that ‘forest bathing’, the practice of visiting a forest for its
health benefits, has positive effects, especially on the human
immune function (Li 2009), which last more than one week
post-exposure (Li etal. 2008). These include the increase
in natural killer (NK) activity, mediated by increased NK
cell numbers and intracellular granulysin, perforin and gran-
zymes A/B release, with reported effects against tumours
and virus-infected cells (Li 2009). We also found several
literature reports on the beneficial effects of some plant ter-
penes on the anti-inflammation response elicited by these
volatile organic compounds (VOC) on airway inflammation
in animal models (Kim etal. 2020), as well as reports on
essential oil components able to reduce pulmonary inflam-
mation induced by air pollution (Kfoury etal. 2016).
Borneol and terpineol have been shown to have anti-
asthmatic activity, inhibiting invitro bronchoconstriction in
guinea pigs (Kim etal. 2020), whereas a placebo-controlled,
double-blind trial revealed the clinical efficacy of 1,8-cineole
in inflammatory airway diseases, such as chronic obstruc-
tive pulmonary disease and asthma (Worth and Dethlefsen
2012; Juergens 2014). A positive therapeutic effect of bornyl
acetate, a volatile compound isolated from twigs, leaves and
fruits of several plants including the Mediterranean Laurus
nobilis L. (Fidan etal. 2019), has been reported for the treat-
ment of lung inflammation in an animal model of acute lung
injury (Chen etal. 2014). Moreover, α-pinene was effective
for treatment of allergic rhinitis (Nam etal. 2014), while
β-caryophyllene has demonstrated both anti-inflammatory
and antinociceptive activity (da Silva etal. 2020; Klauke
etal. 2014). Since COVID-19 emerged in Italy during the
cold season, we wondered whether the VOC emissions in
Mediterranean countries were completely inhibited dur-
ing fall and winter months. Through literature analysis, we
found that even though biogenic VOCs are emitted in larger
amounts by plants during spring and summer than during
fall and winter, significant amounts of bioactive terpenes
can still be detected in Mediterranean ecosystems during
winter. This phenomenon has also been observed with beta-
caryophyllene, whose winter emission from Cistus mon-
speliensis L. was similar to that found during spring and
six times higher than the amount detected during summer
(Rivoal etal. 2010).
Mediterranean trees are classified as isoprene, α-pinene,
linalool and limonene emitters, and the most representative
of these is the Mediterranean oak, i.e. Quercus ilex L., also
known as holm oak, which is able to release in the air up to
19 VOCs (Owen etal. 2001). More abundant VOCs in Lau-
rus nobilis L are β-pinene (19.44%), 1,8-cineole (19.38%),
β-caryophyllene (8.55%) and sabinene (7.91%); however,
numerous other volatile compounds are found in lesser
amounts in this Mediterranean plant (D’Auria and Racioppi
2015).
Antiviral activity ofnatural compounds
fromMediterranean plants
Besides the study of plant VOCs with beneficial effects on
the immune system, we also focused on several other com-
pounds with therapeutic potential which are contained in
vegetal sources. We analysed the literature reports finding
that several Mediterranean plants of culinary use, such as
Salvia officinalis L., Satureja thymbra L. and Laurus nobi-
lis L., are used as folk remedies in different countries to
treat numerous diseases including viral ones (Loizzo etal.
2008). Strikingly, one of the most promising anti-COVID-19
candidates emerged by our literature analysis is Laurus
nobilisL. oil, characterized by the presence of β-ocimene,
1,8-cineole, α -pinene and β-pinene as its main constituents,
which exerted an interesting activity against SARS-CoV-1
with anIC50value of 120μg/ml and a selectivity index (SI)
of 4.16 (Loizzo etal. 2008). Laurus nobilis L. is a typical
Mediterranean plant, constituent of Laurisilva forests (Pig-
natti etal. 2015), commonly used as a flavouring agent for
food preparation, but also endowed with many biological
activities. These antioxidant and antimicrobial properties are
due to the chemical composition of the essential oil found
within its leaf which varies depending on the latitude and
climate of its cultivation site (Riabov etal. 2020).
For its part, Pistacia vera L. kernels and seeds showed
significant activity against Herpes simplexandParainflu-
enzaviruses in cell experiments (Özçelik etal. 2005). The
chemical components of the methanolic extract of Onopor-
dum illyricum L. aerial parts showed significant inhibition
activities against human immunodeficiency virus 1 (HIV-1)
reverse transcriptase, but also against HIV-1 integrase and
blocked viral replication in cell-based assays (Sanna etal.
2018). The ethyl acetate and methanol extracts of Daucus
virgatusexhibited significant inhibitory effects againstCox-
sackievirus B, a small RNA virus of the Picornaviridae fam-
ily (Snene etal. 2017). Worthy of note is the fact that the
wood extract from one of the most abundant trees in the
Mediterranean forests, Quercus ilex L., showed antiviral
effects against (H9N2) influenza and bovine viral diarrhoea
(BVD) viruses, this latter being a pestivirus model of hepa-
titis C virus (HCV), on MDCK cells (Yousef etal. 2014a, b).
In addition, we also explored the published data on the
olive tree (Olea europaea L.), a symbol of the Mediterra-
nean world since ancient times, and found that it is used as
a folk remedy for the cure of numerous disorders including
those of viral origin (Hashmi etal. 2015). This practice has
found scientific justification through the demonstrated anti-
viral activity of olive leaf extracts, safe both for our health

Environmental Chemistry Letters
1 3
and the environment, and the effectiveness of its main con-
stituent oleuropein (Micol etal. 2005).
Laurus nobilis againstSARS‑CoV‑2: insilico studies
onpotential laurel‑derived inhibitors ofSARS‑CoV‑2
main protease (Mpro) andtoxicity prediction
We decided to investigate laurel components as potential
anti-COVID-19 drugs starting from the evaluation in silico
of their binding affinity for one of the main viral protein tar-
gets. In fact, as reported in the previous section, an invitro
investigation on the biomedical properties of the essential
oil taken from Laurus nobilis L. revealed its potential anti-
viral activity against SARS-CoV-1 (Loizzo etal. 2008). This
called our attention to its possible therapeutic use against the
genetically close SARS-CoV-2, a hypothesis which has also
been brought forth in recent literature (Hensel etal. 2020).
The essential oil from the aerial parts of the plant, which
contains the monoterpenes 1,8-cineol and β-ocimene, and
the sesquiterpene dehydrocostus lactone in larger amounts
than other essential oils, inhibited the replication of SARS-
CoV-1 invitro (Loizzo etal. 2008).
Furthermore, we found published reports showing that,
besides the terpenic compounds, several other phytochemi-
cal constituents were isolated from Laurus nobilis L. includ-
ing alkaloids, phenolics and megastigmanes (De Marino
etal. 2004). Within this latter group, we noticed that the
recently identified laurusides 1–7 (Duc Dat etal. 2019) are
an almost unexplored class of laurel-derived compounds
(Fig.2).
Among the coronaviral protein targets evaluated in
computational studies, Mpro (also called 3CLpro) protease
represents a first choice potential target for the inhibition
of SARS-CoV–2 replication. This is a well-characterized
protein of SARS-CoV–2 which shares 96% identity with
SARS-CoV-1 Mpro (Zhang etal. 2020) and has a key role in
Fig. 2 Laurus nobilis L. plant foliage and molecular structure repre-
sentation of some of the compounds extracted from laurel with the
highest predicted affinity for SARS-CoV-2 main protease (Mpro). Of
these, Laurusides 1,2,5,6 and 7 belong to the class of laurel glyco-
sides, while 3α-acetoxyeudesma-1 4(15) 11(13)-trien-12 6α-olide and
Kaempferol are classified as sesquiterpene and flavonoidcompounds,
respectively. Photograph taken by Dr. V. Roviello in Aversa, South
Italy on 21 May 2020

Environmental Chemistry Letters
1 3
the coronaviral life cycle. All these aspects, together with
the absence of any similar protein homologues in humans,
rendered it an attractive target for our anti-COVID-19 drug
discovery. One should note that some of the repurposed
treatments for COVID-19 (Costanzo etal. 2020) are protease
inhibitors such as the lopinavir–ritonavir combination (Man-
gum and Graham 2001). Based on the importance of Mpro as
a drug target in the fight against SARS-CoV–2, we focused
on several phytochemicals derived from the bay laurel for
their potential antiviral activity towards the novel coronavi-
rus studied by docking to the main protease Mpro of SARS-
CoV-2. By using 1-Click Mcule docking server (Potemkin
etal. 2019; Kiss etal. 2012), which makes use of AutoDock
Vina software (Trott and Olson 2009), we have analysed
44 laurel-derived compounds. Nine molecules, belong-
ing to three molecular families: laurusides, sesquiterpene
lactones and tetrahydroxyflavones, showed high affinity
scores towards SARS-CoV-2 Mpro, with ≤ − 7.0 kcal/mol
binding energy values for the top ranked poses, as shown in
Fig.3 and TableS2.
Six out of nine of these ligands belong to the family of
laurusides described by Duc Dat etal. (Duc Dat etal. 2019),
natural products extracted by Laurus nobilis L. able to
inhibit, in cell, the lipopolysaccharide (LPS)-induced nitric
oxide release.
In particular, lauruside 5 showed in silico the lowest
binding energy (− 8.2kcal/mol, BE for the top scoring
pose, and − 7.5kcal/mol, average score; Fig.3, TableS2)
and, thus, the highest affinity for Mpro. Other good affinity
scores were found for laurusides 1, 2, 6 and 7, as well as for
kaempferol (− 7.4kcal/mol, score of the top ranked pose).
We examined the pose corresponding to the lowest energy
Fig. 3 Bar graph showing the predicted binding energy (BE) scores
in kcal/mol (as obtained by 1-Click Mcule web-based docking pro-
gram) for different classes of compounds, such as volatile compounds
and glycosides, found in the Laurus nobilis L. plant. Bars indicat-
ing the binding energy for the compounds with the highest affinities
for the protein target, SARS-CoV-2 main protease (Mpro; PDB ID:
6YB4), are evidenced in red

Environmental Chemistry Letters
1 3
for lauruside 5 and observed that this glucoside derivative
was involved in multiple H-bonding with residues Ser46,
Asn142, His163, Glu166 and Gln189 (Fig.4). These latter
interactions were previously reported for the interaction of
carnosol to the same protease target (Umesh etal. 2020).
We evaluated in silico the toxicity of the most promising
candidates belonging to the lauruside group by using the
program ProTox (tox.charite.de) and found, with a predic-
tion accuracy of ~ 70%, that all of them are assigned to the
predicted toxicity class IV (see as an example Fig. S1 for
lauruside 5, TableS3), that is the same corresponding to the
commonly-used anti-COVID-19 drug hydroxychloroquine
(Peytavin etal. 2020) (Fig. S3), with apredicted median
oral lethal dose (LD50) in rodents for the most promising
lauruside 5 of 2500mg/kg (Fig. S1). Possible toxicity targets
were predicted as Amine Oxidase A and Prostaglandin G/H
Synthase 1 (Fig. S2). On the other hand, the predicted toxic-
ity class (class V) of kaempferol (Fig. S3, TableS3) suggests
a higher biosafety potential for this tetrahydroxyflavone iso-
lated from Mediterranean plants, even though its affinity for
Mpro is lower than lauruside 5 (TableS2).
Since AutoDock Vina software tends to underestimate the
binding affinity of the ligands for the target (Lambert etal.
2019), our complexes could be endowed with an even lower
binding energy and thus, with a higher affinity than that the-
oretically computed. In other terms, our study could serve
as a starting point for future experimental investigations
directed to characterize the above ligand–protease interac-
tions and the invitro/in vivo anti-SARS-CoV-2 effects of
the compounds extracted from bay laurel and from other
Mediterranean plants. Nevertheless, before proposing lau-
rusides as antiviral drugs or the inhalative applications of
Laurus nobilis L. oil for ameliorating the health conditions
of COVID-19 patients, the toxicity of the compounds and
the allergenic potential of bay laurel essential oil should be
carefully evaluated (Hensel etal. 2020). In this context, we
suggest that chemical modifications of lauruside 5 could lead
to structures endowed with high affinity for Mpro and, hope-
fully, with even better toxicity profiles, which could be effec-
tively and safely employed in the anti-COVID-19 treatments.
Conclusion
We analysed the impact of COVID-19 in different Italian
regions and found clues on the relationship between the
severity of the disease and certain environmental factors,
including scarcity of non-deciduous vegetation. The low-
est impact of the pandemic was observed in the southern
regions which have the highest rates of forest area per capita
(≥ 0.34 hectares/inhabitant) such as Basilicata, Calabria and
Molise. This is interesting when compared to certain regions
of northern Italy like Lombardy, Emilia Romagna and
Veneto, which have less than 0.20 forest hectares/inhabitant
and where the effects of COVID-19 were much more severe.
We have, thus, suggested that a possible protective factor
could be the presence of Mediterranean evergreen vegetation
formed by both spontaneous and cultivated trees and shrubs.
Fig. 4 Putative best docking pose (a) and 2D protein–ligand interac-
tion diagram (b) at the active site of main protease Mpro for lauruside
5. Proximity of functional groups of the laurel glycoside to Ser46,
Asn142, Glu166 protein residues is observed in the pose view (a),
while main interactions, including H-bonds with amino acids Ser46,
Gln189, His163, Asn142, Glu166, are evidenced in the diagram (b).
Note the highly stabilized nature of the predicted lauruside-protease
complex due to the multiple H-bonding possibilities given by the
interactions of the compound hydroxyl moieties with the protein
amino acids

Environmental Chemistry Letters
1 3
In our hypothesis, we speculate that during the mild winter
of the Mediterranean regions, non-deciduous plants main-
tain, even though at a lower level, activities of air depuration
and biogenic VOC emission able in some cases to bolster the
human body’s immunity and, thus could have contributed to
the protection of southern populations from SARS-CoV-2.
Nevertheless, mild climate, higher average sunlight exposure
and the Mediterranean diet, which includes the consump-
tion of foods containing polyphenols and natural compounds
with potential antiviral activities, could have all contributed
in the defence against the pandemic. As an example, we
examined more than forty compounds discovered in bay
laurel, a typical Mediterranean evergreen tree of common
culinary use, and found that nine of them had a significantly
high affinity for SARS-CoV-2 main protease Mpro, one of
the most important targets in the anti-COVID-19 therapeutic
strategies. Among these laurel-derived ligands, lauruside 5
emerged from our study as the most promising candidate
as a potential Mpro inhibitor. Moreover, despite its lower
binding affinity for the protease when compared to lauru-
side 5, kaempferol, a natural compound isolated not only
from Laurus nobilis L. but also from other Mediterranean
plants like Quercus Ilex L. (Sebai etal. 2019), especially
in glucosidated form (Karioti etal. 2010), could act as a
potentially effective Mpro inhibitor. Remarkably, still show-
ing an interesting predicted binding energy (− 7.4kcal/mol
for the top scoring pose), it is also endowed with an even
more favourable predicted toxicity profile (Class V) than
laurusides.
Acknowledgements We are grateful to Mr. Gergely Prikler and Mr.
Gergely Takács (Mcule team, Hungary) for their kind support in molec-
ular docking studies, and to Mrs. Melinda Gilhen-Baker (Ottawa, Can-
ada) for useful discussion and editing the manuscript for English style
and logical flow.This study was performedby the authors in smart-
working mode (activated by Consiglio Nazionale delle Ricerche-CNR
and University of Naples Federico II-UNINAduring the COVID-19
crisis).We dedicate this study to all the health-care workers, and to all
the people who suffered and still suffer around the world as a result of
theCOVID-19 pandemic.
References
Abed-Esfahani A, Amini H, Samadi N, Kar S, Hoodaji M, Shirvani M,
Porsakhi K (2013a) The Evaluation of anticipated performance
index of some plants species in east green belt of Isfahan. Tech J
Eng Appl Sci 3(5):432–436
Abed-Esfahani A, Amini H, Samadi N, Kar S, Hoodaji M, Shirvani M,
Porsakhi K (2013b) Assessment of air pollution tolerance index
of higher plants suitable for green belt development in east of
Esfahan city. Iran J Ornam Hortic 3(2):87–94
Alessi N, Wellstein C, Spada F, Zerbe S (2018) Phytocoenological
approach to the ecology of Laurus nobilis L. Italy Rend Lin-
cei Sci Fis Nat 29(2):343–354. https ://doi.org/10.1007/s1221
0-018-0677-8
Anderson RM, May RM, McLean AR, Pattison J, Weiss RA, Fraser C,
Ghani AC, Donnelly CA, Riley S, Ferguson NM, Leung GM, Lam
TH, Hedley AJ (2004) Epidemiology, transmission dynamics and
control of SARS: the 2002–2003 epidemic. Philos Trans R Soc
Lond B Biol Sci 359(1447):1091–1105. https ://doi.org/10.1098/
rstb.2004.1490
Bashir MF, Ma BJ, Bilal KB, Bashir MA, Farooq TH, Iqbal N, Bashir
M (2020) Correlation between environmental pollution indica-
tors and COVID-19 pandemic: a brief study in Californian con-
text. Environ Res 187:109652. https ://doi.org/10.1016/j.envre
s.2020.10965 2
Becker S, Soukup JM (1999) Exposure to urban air particulates alters
the macrophage-mediated inflammatory response to respiratory
viral infection. J Toxicol Environ Health, Part A 57(7):445–457.
https ://doi.org/10.1080/00984 10991 57539
Berman HM, Battistuz T, Bhat TN, Bluhm WF, Bourne PE, Bur-
khardt K, Feng Z, Gilliland GL, Iype L, Jain S, Fagan P, Marvin
J, Padilla D, Ravichandran V, Schneider B, Thanki N, Weissig H,
Westbrook JD, Zardecki C (2002) The Protein Data Bank. Acta
Crystallogr Sect D Biol Crystallogr 58(6):899–907. https ://doi.
org/10.1107/s0907 44490 20034 51
Blanusa T, Fantozzi F, Monaci F, Bargagli R (2015) Leaf trapping and
retention of particles by holm oak and other common tree species
in Mediterranean urban environments. Urban For Urban Green
14(4):1095–1101. https ://doi.org/10.1016/j.ufug.2015.10.004
Cai Q-C, Lu J, Xu Q-F, Guo Q, Xu D-Z, Sun Q-W, Yang H, Zhao
G-M, Jiang Q-W (2007) Influence of meteorological factors and
air pollution on the outbreak of severe acute respiratory syn-
drome. Public Health 121(4):258–265. https ://doi.org/10.1016/j.
puhe.2006.09.023
Cena H, Chieppa M (2020) Coronavirus disease (COVID-19–SARS-
CoV-2) and nutrition: is infection in Italy suggesting a connec-
tion? Front Immunol. https ://doi.org/10.3389/fimmu .2020.00944
Chakraborti S, Bheemireddy S, Srinivasan N (2020) Repurposing
drugs against main protease of SARS-CoV-2: mechanism-based
insights supported by available laboratory and clinical data. Mol
Omics. https ://doi.org/10.1039/d0mo0 0057d
Chen N, Sun G, Yuan X, Hou J, Wu Q, Soromou LW, Feng H (2014)
Inhibition of lung inflammatory responses by bornyl acetate is
correlated with regulation of myeloperoxidase activity. J Surg Res
186(1):436–445. https ://doi.org/10.1016/j.jss.2013.09.003
Conticini E, Frediani B, Caro D (2020) Can atmospheric pollution be
considered a co-factor in extremely high level of SARS-CoV-2
lethality in Northern Italy? Environ Pollut 261:114465. https ://
doi.org/10.1016/j.envpo l.2020.11446 5
Costanzo M, De Giglio MAR, Roviello GN (2020) SARS CoV-2:
recent reports on antiviral therapies based on lopinavir/ritonavir,
darunavir/umifenovir, hydroxychloroquine, remdesivir, favipiravir
and other drugs for the treatment of the new coronavirus. Curr
Med Chem. https ://doi.org/10.2174/09298 67327 66620 04161
31117
da Silva JKR, Figueiredo PLB, Byler KG, Setzer WN (2020) Essen-
tial oils as antiviral agents, potential of essential oils to treat
SARS-CoV-2 infection: an in-silico investigation. Int J Mol Sci
21(10):3426. https ://doi.org/10.3390/ijms2 11034 26
Dang X, Shan Z (2017) Dust pollution and control with leather waste.
Environ Chem Lett 16(2):427–437. https ://doi.org/10.1007/s1031
1-017-0683-6
D’Auria M, Racioppi R (2015) The effect of drying of the composition
of volatile organic compounds in rosmarinus officinalis, laurus
nobilis, salvia officinalis and thymus serpyllum. a HS-SPME-GC-
MS study. J Essent Oil-Bear Plants 18(5):1209–1223. https ://doi.
org/10.1080/09720 60x.2014.89521 3
De Marino S, Borbone N, Zollo F, Ianaro A, Di Meglio P, Iorizzi
M (2004) Megastigmane and phenolic components from Lau-
rus nobilis L. leaves and their inhibitory effects on nitric oxide

Environmental Chemistry Letters
1 3
production. J Agric Food Chem 52(25):7525–7531. https ://doi.
org/10.1021/jf048 782t
Distante C, Piscitelli P, Miani A (2020) Covid-19 outbreak pro-
gression in Italian regions: approaching the peak by the end
of march in Northern Italy and first week of April in South-
ern Italy. Int J Environ Res Pub He 17(9):3025. https ://doi.
org/10.3390/ijerp h1709 3025
Drwal MN, Banerjee P, Dunkel M, Wettig MR, Preissner R (2014)
ProTox: a web server for the in silico prediction of rodent oral
toxicity. Nucleic Acids Res 42(W1):W53–W58. https ://doi.
org/10.1093/nar/gku40 1
Duc Dat L, Viet Duc N, Thuy Luyen BT, Van Oanh H, Jang HJ,
Huong TT, Ho Kim Y, Thao NP (2019) Megastigmane and
abscisic acid glycosides from the leaves of Laurus nobilis
L. Phytochem Lett 33:1–5. https ://doi.org/10.1016/j.phyto
l.2019.06.011
Dutheil F, Navel V, Clinchamps M (2020) The indirect benefit on res-
piratory health from the world’s effort to reduce transmission of
SARS - CoV-2. Chest. https ://doi.org/10.1016/j.chest .2020.03.062
Fares S, Sanesi G, Vacchiano G, Salbitano F, Marchetti M (2020)
Urban forests at the time of COVID-19 protect us from fine dust.
Forest@ - Rivista di Selvicoltura ed Ecologia Forestale 17(3):48-
51. https ://doi.org/10.3832/efor3 494-017
Fellet G, Pošćić F, Licen S, Marchiol L, Musetti R, Tolloi A, Barbieri
P, Zerbi G (2016) PAHs accumulation on leaves of six evergreen
urban shrubs: a field experiment. Atmos Pollut Res 7(5):915–924.
https ://doi.org/10.1016/j.apr.2016.05.007
Feng R, Zheng H-j (2019) Evidence for regional heterogeneous atmos-
pheric particulate matter distribution in China: implications for
air pollution control. Environ Chem Lett 17(4):1839–1847. https
://doi.org/10.1007/s1031 1-019-00890 -0
Fidan H, Stefanova G, Kostova I, Stankov S, Damyanova S, Stoyanova
A, Zheljazkov VD (2019) Chemical composition and antimicro-
bial Activity of Laurus nobilis L. Essent Oils Bulg Mol 24(4):804.
https ://doi.org/10.3390/molec ules2 40408 04
Fik-Jaskółka MA, Mkrtchyan AF, Saghyan AS, Palumbo R, Belter
A, Hayriyan LA, Simonyan H, Roviello V, Roviello GN (2020a)
Biological macromolecule binding and anticancer activity of syn-
thetic alkyne-containing l-phenylalanine derivatives. Amino Acids
52(5):755–769. https ://doi.org/10.1007/s0072 6-020-02849 -w
Fik-Jaskółka MA, Mkrtchyan AF, Saghyan AS, Palumbo R, Belter
A, Hayriyan LA, Simonyan H, Roviello V, Roviello GN (2020b)
Spectroscopic and SEM evidences for G4-DNA binding by a
synthetic alkyne-containing amino acid with anticancer activity.
Spectrochim Acta A Mol Biomol Spectrosc 229:117884. https ://
doi.org/10.1016/j.saa.2019.11788 4
Frogoudaki AA (2020) Preparing for the tsunami or the way towards
flattening the curve, the Greek perspective. Eur J Heart Fail. https
://doi.org/10.1002/ejhf.1872
Gratani L, Varone L (2013) Carbon sequestration and noise attenuation
provided by hedges in Rome: the contribution of hedge traits in
decreasing pollution levels. Atmos Pollut Res 4(3):315–322. https
://doi.org/10.5094/apr.2013.035
Grzędzicka E (2019) Is the existing urban greenery enough to cope
with current concentrations of PM2.5, PM10 and CO2? Atmos
Poll Res 10(1):219–233. https ://doi.org/10.1016/j.apr .2018.08.002
Hashmi MA, Khan A, Hanif M, Farooq U, Perveen S (2015) Tradi-
tional uses, phytochemistry, and pharmacology of olea europaea
(Olive). Evid-Based Complement Altern Med 2015:1–29. https
://doi.org/10.1155/2015/54159 1
Hensel A, Bauer R, Heinrich M, Spiegler V, Kayser O, Hempel G,
Kraft K (2020) Challenges at the time of COVID-19: opportuni-
ties and innovations in antivirals from nature. Planta Med. https
://doi.org/10.1055/a-1177-4396
Hunter P (2020) The spread of the COVID-19 coronavirus. EMBO
Rep. https ://doi.org/10.15252 /embr.20205 0334
Jiang Y, Wu X-J, Guan Y-J (2020) Effect of ambient air pollutants and
meteorological variables on COVID-19 incidence. Inf Control
Hosp Epidem 11:1–5. https ://doi.org/10.1017/ice.2020.222
Jin Z, Du X, Xu Y, Deng Y, Liu M, Zhao Y, Zhang B, Li X, Zhang L,
Peng C, Duan Y, Yu J, Wang L, Yang K, Liu F, Jiang R, Yang X,
You T, Liu X, Yang X, Bai F, Liu H, Liu X, Guddat LW, Xu W,
Xiao G, Qin C, Shi Z, Jiang H, Rao Z, Yang H (2020) Structure of
M pro from SARS-CoV-2 and discovery of its inhibitors. Nature.
https ://doi.org/10.1038/s4158 6-020-2223-y
Juergens U (2014) Anti-inflammatory properties of the monoterpene
1.8-cineole: current evidence for co-medication in inflamma-
tory airway diseases. Drug Res 64(12):638–646. https ://doi.
org/10.1055/s-0034-37260 9
Kahkha MRR, Amanloo S, Kaykhaii M (2013) Antiaflatoxigenic
activity of Carum copticum essential oil. Environ Chem Lett
12(1):231–234. https ://doi.org/10.1007/s1031 1-013-0439-x
Karioti A, Bilia AR, Skaltsa H (2010) Quercus ilex L.: A rich source of
polyacylated flavonoid glucosides. Food Chem 123(1):131–142.
https ://doi.org/10.1016/j.foodc hem.2010.04.020
Kaur M, Nagpal AK (2017) Evaluation of air pollution tolerance index
and anticipated performance index of plants and their application
in development of green space along the urban areas. Environ
Science Poll Res 24(23):18881–18895. https ://doi.org/10.1007/
s1135 6-017-9500-9
Kfoury M, Borgie M, Verdin A, Ledoux F, Courcot D, Auezova L,
Fourmentin S (2016) Essential oil components decrease pulmo-
nary and hepatic cells inflammation induced by air pollution par-
ticulate matter. Environ Chem Lett 14(3):345–351. https ://doi.
org/10.1007/s1031 1-016-0572-4
Kim T, Song B, Cho KS, Lee I-S (2020) therapeutic potential of
volatile terpenes and terpenoids from forests for inflammatory
diseases. Int J Mol Sci 21(6):2187. https ://doi.org/10.3390/ijms2
10621 87
Kiss R, Sandor M, Szalai FA (2012)http://Mcule .com: a public
web service for drug discovery. J Cheminform. https ://doi.
org/10.1186/1758-2946-4-s1-p17
Klauke AL, Racz I, Pradier B, Markert A, Zimmer AM, Gertsch J,
Zimmer A (2014) The cannabinoid CB2 receptor-selective phyto-
cannabinoid beta-caryophyllene exerts analgesic effects in mouse
models of inflammatory and neuropathic pain. Eur Neuropsy-
chopharmacol 24(4):608–620. https ://doi.org/10.1016/j.euron
euro.2013.10.008
Lai C-C, Shih T-P, Ko W-C, Tang H-J, Hsueh P-R (2020) Severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavi-
rus disease-2019 (COVID-19): The epidemic and the challenges.
Int J Antimicrob Agents 55(3):105924. https ://doi.org/10.1016/j.
ijant imica g.2020.10592 4
Lambert H, Mohan N, Lee T-C (2019) Ultrahigh binding affinity of a
hydrocarbon guest inside cucurbit[7]uril enhanced by strong host–
guest charge matching. Phys Chem Chem Phys 21(27):14521–
14529. https ://doi.org/10.1039/c9cp0 1762c
Li Q (2009) Effect of forest bathing trips on human immune function.
Environ Health Prevent Med 15(1):9–17. https ://doi.or g/10.1007/
s1219 9-008-0068-3
Li Q, Morimoto K, Kobayashi M, Inagaki H, Katsumata M, Hirata
Y, Hirata K, Suzuki H, Li YJ, Wakayama Y, Kawada T, Park BJ,
Ohira T, Matsui N, Kagawa T, Miyazaki Y, Krensky AM (2008)
Visiting a forest, but not a city, increases human natural killer
activity and expression of anti-cancer proteins. Int J Immuno-
pathol Pharmacol 21(1):117–127. https ://doi.org/10.1177/03946
32008 02100 113
Loizzo MR, Saab AM, Tundis R, Statti GA, Menichini F, Lampronti
I, Gambari R, Cinatl J, Doerr HW (2008) Phytochemical analy-
sis and invitro antiviral activities of the essential oils of seven
lebanon species. Chem Biodivers 5(3):461–470. https ://doi.
org/10.1002/cbdv.20089 0045

Environmental Chemistry Letters
1 3
Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, Wang W, Song H, Huang B,
Zhu N, Bi Y, Ma X, Zhan F, Wang L, Hu T, Zhou H, Hu Z, Zhou
W, Zhao L, Chen J, Meng Y, Wang J, Lin Y, Yuan J, Xie Z, Ma J,
Liu WJ, Wang D, Xu W, Holmes EC, Gao GF, Wu G, Chen W, Shi
W, Tan W (2020) Genomic characterisation and epidemiology of
2019 novel coronavirus: implications for virus origins and recep-
tor binding. Lancet 395(10224):565–574. https ://doi.org/10.1016/
s0140 -6736(20)30251 -8
Mangum EM, Graham KK (2001) Lopinavir-Ritonavir: a new pro-
tease inhibitor. Pharmacotherapy 21(11):1352–1363. https ://doi.
org/10.1592/phco.21.17.1352.34419
Micol V, Caturla N, Perezfons L, Mas V, Perez L, Estepa A (2005)
The olive leaf extract exhibits antiviral activity against viral
haemorrhagic septicaemia rhabdovirus (VHSV). Antivir Res
66(2–3):129–136. https ://doi.org/10.1016/j.antiv iral.2005.02.005
Muhammad S, Long X, Salman M (2020) COVID-19 pandemic and
environmental pollution: a blessing in disguise? Sci Total Environ
728:138820. https ://doi.org/10.1016/j.scito tenv.2020.13882 0
Mukherjee A, Agrawal M (2017) World air particulate matter: sources,
distribution and health effects. Environ Chem Lett 15(2):283–309.
https ://doi.org/10.1007/s1031 1-017-0611-9
Mukherjee A, Agrawal M (2018) Air pollutant levels are 12 times
higher than guidelines in Varanasi, India. Sources Transfer Envi-
ron Chem Lett 16(3):1009–1016. https ://doi.org/10.1007/s1031
1-018-0706-y
Nam S-Y, Chung C-k, Seo J-H, Rah S-Y, Kim H-M, Jeong H-J (2014)
The therapeutic efficacy of α-pinene in an experimental mouse
model of allergic rhinitis. Int Immunopharmacol 23(1):273–282.
https ://doi.org/10.1016/j.intim p.2014.09.010
Nowak DJ, Hirabayashi S, Bodine A, Greenfield E (2014) Tree and
forest effects on air quality and human health in the United States.
Environ Pollut 193:119–129. https ://doi.org/10.1016/j.envpo
l.2014.05.028
Nowak DJ, Hirabayashi S, Doyle M, McGovern M, Pasher J (2018) Air
pollution removal by urban forests in Canada and its effect on air
quality and human health. Urb For Urb Green 29:40–48. https ://
doi.org/10.1016/j.ufug.2017.10.019
Odone A, Delmonte D, Scognamiglio T, Signorelli C (2020) COVID-
19 deaths in Lombardy, Italy: data in context. Lancet Public
Health. https ://doi.org/10.1016/s2468 -2667(20)30099 -2
Owen SM, Boissard C, Hewitt CN (2001) Volatile organic com-
pounds (VOCs) emitted from 40 Mediterranean plant species.
Atmos Environ 35(32):5393–5409. https ://doi.org/10.1016/s1352
-2310(01)00302 -8
Özçelik B, Aslan M, Orhan I, Karaoglu T (2005) Antibacterial, anti-
fungal, and antiviral activities of the lipophylic extracts of Pistacia
vera. Microbiol Res 160(2):159–164. https ://doi.org/10.1016/j.
micre s.2004.11.002
Panarese A, Shahini E (2020) Letter: Covid-19, and vitamin D. Ali-
ment Pharmacol Ther 51(10):993–995. https ://doi.org/10.1111/
apt.15752
Park M, Thwaites RS, Openshaw PJM (2020) COVID-19: lessons
from SARS and MERS. Eur J Immunol 50(3):308–311. https ://
doi.org/10.1002/eji.20207 0035
Peytavin G, Yazdanpanah Y, Ader F, Mentré F, Néant N, Guedj J,
Peiffer-Smadja N, Lê MP, Ader F, Yazdanpanah Y, Mentre F,
Lescure F-X, Peiffer-Smadja N, Bouadma L, Poissy J, Timsit J-F,
Lina B, Morfin-Sherpa F, Peytavin G, Burdet C, Laouenan C, Bel-
hadi D, Dupont A, Basli B, Chair A, Laribi S, Level J, Schneider
M, Tellier M-C, Dechanet A, Couffin-Cadiergues S, Delmas C,
Esperou H, Fougerou C, Gelley A, Moinot L, Wittkop L, Cag-
not C, Diallo A, Le Mestre S, Lebrasseur-Longuet D, Mercier N,
Petrov-Sanchez V, Icard V, Leveau B, Guillon J, Taburet A-M,
Noret M, d’Ortenzio E, Puechal O, Saillard J, Semaille C (2020)
Rationale of a loading dose initiation for hydroxychloroquine
treatment in COVID-19 infection in the DisCoVeRy trial. J Anti-
microb Chemother. https ://doi.org/10.1093/jac/dkaa1 91
Pignatti E, Pignatti S, D’Angeli D, De Nicola C, Maffei L, Testi A,
Tinelli A (2015) The Laurisilva as a cultural heritage: proposal
for the protection of the relict of laurel forest near Ponte Renaro.
Rend Lincei 26(S3):643–649. https ://doi.org/10.1007/s1221
0-015-0389-2
Potemkin V, Potemkin A, Grishina M (2019) Internet resources for
drug discovery and design. Curr Top Med Chem 18(22):1955–
1975. https ://doi.org/10.2174/15680 26619 66618 11291 42127
Rarey M, Steinegger R, Nittinger E, Meyder A, Flachsenberg F, Fähr-
rolfes R, Diedrich K, Schöning-Stierand K (2020) Proteinsplus:
interactive analysis of protein–ligand binding interfaces. Nucleic
Acids Res. https ://doi.org/10.1093/nar/gkaa2 35
Riabov PA, Micić D, Božović RB, Jovanović DV, Tomić A, Šovljanski
O, Filip S, Tosti T, Ostojić S, Blagojević S, Đurović S (2020)
The chemical, biological and thermal characteristics and gastro-
nomical perspectives of Laurus nobilis essential oil from differ-
ent geographical origin. Ind Crop Prod 151:112498. https ://doi.
org/10.1016/j.indcr op.2020.11249 8
Rivoal A, Fernandez C, Lavoir AV, Olivier R, Lecareux C, Greff
S, Roche P, Vila B (2010) Environmental control of terpene
emissions from Cistus monspeliensis L. in natural Mediter-
ranean shrublands. Chemosphere 78(8):942–949. https ://doi.
org/10.1016/j.chemo spher e.2009.12.047
Saglietto A, D’Ascenzo F, Zoccai GB, De Ferrari GM (2020) COVID-
19 in Europe: the Italian lesson. Lancet 395(10230):1110–1111.
https ://doi.org/10.1016/S0140 -6736(20)30690 -5
Sanna C, Rigano D, Cortis P, Corona A, Ballero M, Parolin C, Del
Vecchio C, Chianese G, Saccon E, Formisano C, Tramontano
E, Esposito F (2018) Onopordum illyricum L., a Mediterra-
nean plant, as a source of anti HIV-1 compounds. Plant Biosyst
Int J Deal Aspects Plant Biol 152(6):1274–1281. https ://doi.
org/10.1080/11263 504.2018.14391 18
Sebai H, Rtibi K, Selmi S, Jridi M, Balti R, Marzouki L (2019) Modu-
lating and opposite actions of two aqueous extracts prepared from
Cinnamomum cassia L. bark and Quercus ilex L. on the gastro-
intestinal tract in rats. RSC Adv 9(38):21695–21706. https ://doi.
org/10.1039/c9ra0 2429h
Setti L, Passarini F, De Gennaro G, Barbieri P, Perrone MG, Borelli
M, Palmisani J, Di Gilio A, Torboli V, Fontana F, Clemente L,
Pallavicini A, Ruscio M, Piscitelli P, Miani A (2020) SARS-
Cov-2RNA found on particulate matter of Bergamo in Northern
Italy: first evidence. Environ Res. https ://doi.org/10.1016/j.envre
s.2020.10975 4
Sgrigna G, Sæbø A, Gawronski S, Popek R, Calfapietra C (2015) Par-
ticulate Matter deposition on Quercus ilex leaves in an industrial
city of central Italy. Environ Pollut 197:187–194. https ://doi.
org/10.1016/j.envpo l.2014.11.030
Sharma VK, Jinadatha C, Lichtfouse E (2020) Environmental chem-
istry is most relevant to study coronavirus pandemics. Environ
Chem Lett 18(4):993–996. https ://doi.org/10.1007/s1031 1-020-
01017 -6
Signorelli C, Scognamiglio T, Odone A (2020) COVID-19 in Italy:
impact of containment measures and prevalence estimates of
infection in the general population. Acta Biomed 91((3-S)):175–
179. https ://doi.org/10.23750 /abm.v91i3 -S.9511
Sinonquel P, Roelandt P, Demedts I, van Gerven L, Vandenbriele C,
Wilmer A, Van Wijngaerden E, Bisschops R (2020) COVID-
19 and gastrointestinal endoscopy: what should be taken into
account? Digest Endosc. https ://doi.org/10.1111/den.13706
Snene A, El Mokni R, Jmii H, Jlassi I, Jaïdane H, Falconieri D, Piras
A, Dhaouadi H, Porcedda S, Hammami S (2017) Invitro anti-
microbial, antioxidant and antiviral activities of the essential oil
and various extracts of wild (Daucus virgatus (Poir.) Maire) from

Environmental Chemistry Letters
1 3
Tunisia. Ind Crop Prod 109:109–115. https ://doi.org/10.1016/j.
indcr op.2017.08.015
Sun Q, Xu Q, Li X, Wang S, Wang C, Huang F, Gao Q, Wu L, Tao L,
Guo J, Wang W, Guo X (2016) Fine particulate air pollution and
hospital emergency room visits for respiratory disease in urban
areas in Beijing, China, in 2013. PLoS ONE 11(4):e0153099.
https ://doi.org/10.1371/journ al.pone.01530 99
Trott O, Olson AJ (2009) AutoDock Vina: improving the speed and
accuracy of docking with a new scoring function, efficient optimi-
zation, and multithreading. J Comput Chem 31(2):455–461. https
://doi.org/10.1002/jcc.21334
Umesh KD, Selvaraj C, Singh SK, Dubey VK (2020) Identification
of new anti-nCoV drug chemical compounds from Indian spices
exploiting SARS-CoV-2 main protease as target. J Biomol Struct
Dyn. https ://doi.org/10.1080/07391 102.2020.17632 02
Wang L, Li M, Yu S, Chen X, Li Z, Zhang Y, Jiang L, Xia Y, Li J, Liu
W, Li P, Lichtfouse E, Rosenfeld D, Seinfeld JH (2020) Unex-
pected rise of ozone in urban and rural areas, and sulfur dioxide
in rural areas during the coronavirus city lockdown in Hangzhou,
China: implications for air quality. Environ Chem Lett. https ://doi.
org/10.1007/s1031 1-020-01028 -3
Worth H, Dethlefsen U (2012) Patients with asthma benefit from con-
comitant therapy with cineole: a placebo-controlled. Double-Blind
Trial J Asthma 49(8):849–853. https ://doi.org/10.3109/02770
903.2012.71765 7
Wu D, Wu T, Liu Q, Yang Z (2020) The SARS-CoV-2 outbreak: what
we know. Int J Infect Dis 94:44–48. https ://doi.org/10.1016/j.
ijid.2020.03.004
Xie J, Teng J, Fan Y, Xie R, Shen A (2019) The short-term effects of
air pollutants on hospitalizations for respiratory disease in Hefei.
China Int J Biometeorol 63(3):315–326. https ://doi.org/10.1007/
s0048 4-018-01665 -y
Xu H, Yan C, Fu Q, Xiao K, Yu Y, Han D, Wang W, Cheng J (2020)
Possible environmental effects on the spread of COVID-19 in
China. Sci Total Environ 731:139211. https ://doi.org/10.1016/j.
scito tenv.2020.13921 1
Yousef OM, El Raaey M, El Shaaraw TH, El Sanousi AA, Shalaby
MA (2014a) Primary screening of antiviral potential of quercus
ilex (wood) extract against BVDV: a pestivirus model of hepati-
tis C virus. Int J Virol 10(2):112–120. https ://doi.org/10.3923/
ijv.2014.112.120
Yousef O, El-Raey M, El-Sanousi AA, Shalaby MA (2014b) Invitro
primary evaluation of antiviral activity of crude extract of quercus
ilex L. against amantadine resistant orthomyxo virus. Int J Virol
10(1):17–27. https ://doi.org/10.3923/ijv.2014.17.27
Yu S (2018) Fog geoengineering to abate local ozone pollution at
ground level by enhancing air moisture. Environ Chem Lett
17(1):565–580. https ://doi.org/10.1007/s1031 1-018-0809-5
Zhang L, Lin D, Sun X, Curth U, Drosten C, Sauerhering L, Becker
S, Rox K, Hilgenfeld R (2020) Crystal structure of SARS-
CoV-2 main protease provides a basis for design of improved
α-ketoamide inhibitors. Science. https ://doi.org/10.1126/scien
ce.abb34 05
Zhu Y, Xie J, Huang F, Cao L (2020) Association between short-term
exposure to air pollution and COVID-19 infection: evidence from
China. Sci Total Environ 727:138704. https ://doi.org/10.1016/j.
scito tenv.2020.13870 4
Publisher’s Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.