Biomedicine & Pharmacotherapy 143 (2021) 112191

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Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

Review

Current advances of functional phytochemicals in Nicotiana plant and

related potential value of tobacco processing waste: A review
Xinda Zou a, Amrit BK a, Tareq Abu-Izneid b, Ahsan Aziz a, Popy Devnath c, Abdur Rauf d, *,
Saikat Mitra e, Talha Bin Emran f, Adil A.H. Mujawah g, Jose M. Lorenzo h, i, **,
Mohammad S. Mubarak j, Polrat Wilairatana k, *, Hafiz A.R. Suleria a, *
a
School of Agriculture and Food, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, VIC 3010, Australia
b
Pharmaceutical Sciences, College of Pharmacy, Al Ain University Al Ain Campus, Unites Arab Emirates
c
Department of Microbiology, Faculty of Sciences, Noakhali Science and Technology University, Noakhali 3814, Bangladesh
d
Department of Chemistry, University of Swabi, Swabi, Anbar, KPK, Pakistan
e
Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka 1000, Bangladesh
f
Department of Pharmacy, BGC Trust University Bangladesh, Chittagong 4381, Bangladesh
g
Department of Chemistry, College of Science and Arts, Qassim University, Ar Rass 51921, Saudi Arabia
h
Centro Tecnológico de la Carne de Galicia, Avd. Galicia No. 4, Parque Tecnológico de Galicia, San Cibrao das Viñas, 32900 Ourense, Spain
i
Área de Tecnología de los Alimentos, Facultad de Ciencias de Ourense, Universidad de Vigo, 32004 Ourense, Spain
j
Department of Chemistry, The University of Jordan, Amman 11942, Jordan
k
Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand

A R T I C L E I N F O A B S T R A C T

Keywords: Tobacco is grown in large quantities worldwide as a widely distributed commercial crop. From the harvest of the
Tobacco field to the process into the final product, a series of procedures generate enormous amount of waste materials
Processing waste that are rarely recycled. In recent years, numerous potential bioactive compounds have been isolated from to­
Phytochemicals
bacco, and the molecular regulatory mechanisms related to the performance of some functionalities have been
Healthy functions
identified. This review describes the source of tobacco waste and expounds a large amount of biomass during the
Intestinal flora
Antioxidant activity tobacco processing, and the necessity of exploring the reuse of tobacco waste. In addition, the review summarizes
the bioactive compounds from tobacco that have been discovered so far, and links them to various functions from
tobacco extracts, including anti-inflammatory, antitumor, antibacterial, and antioxidant, thus proving the po­
tential value from tobacco waste reuse. In this regard, nornicotine in tobacco is the culprit of many health issues,
while the polyphenols and polysaccharides often contribute to the health benefits of tobacco extract. In addition,
it is hard to ignore that realization of these functions of tobacco extracts require the involvement of intestinal
flora metabolism, which should be considered in the development of new product dosage forms.

1. Introduction characterized acyclic hydroxygeranyllinalool, diterpene glycosides

Tobacco refers to a series of plants in the genus Nicotiana of the
Solanaceae family, which originated from Australia, Southwest Africa,
America, and the South Pacific region [1]. Nicotiana species are reservoir
of various phytochemical metabolites such as pyridine alkaloids,
including the eponymous nicotine, isoprenoids, aromatic compounds,
flavonoids, cembranoid compounds volatiles, and recently
[2–4]. And most importantly such metabolites have potential biological
activities. Studies reported that, from tobacco plants around thousands
of metabolites have been chemically and biologically charcterized and
researchces are continuing to explore more about its chemical com­
pounds [2,5].
Nicotiana species can grow naturally in different parts of the world
and used by humans for treatment and recreation purposes. Thus, it has

* Corresponding authors.
** Corresponding author at: Centro Tecnológico de la Carne de Galicia, Avd. Galicia No. 4, Parque Tecnológico de Galicia, San Cibrao das Viñas, 32900 Ourense,
Spain.
E-mail addresses: mashaljcs@yahoo.com (A. Rauf), jmlorenzo@ceteca.net (J.M. Lorenzo), polrat.wil@mahidol.ac.th (P. Wilairatana), hafiz.suleria@unimelb.edu.
au (H.A.R. Suleria).

https://doi.org/10.1016/j.biopha.2021.112191
Received 11 August 2021; Received in revised form 7 September 2021; Accepted 10 September 2021
Available online 22 September 2021
0753-3322/© 2021 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
X. Zou et al.
high economic value and its cultivation is distributed in over 120
countries [6]. Although over 75 tobacco species have been recognized,
only species Nicotiana rustical L. and Nicotiana tabacum L. were currently
commercially cultivated to satisfy human consumption [7,8]. Moreover,
several additional species are cultivated for ornamental or industrial
purposes [7]. N. tabacum is among the most notable species of the plant
kingdom with chemical and biological significance, which contains
around 2500 characterized metabolites so far, and also extensively
cultivated worldwide [2,9]. N. rustica, also known as Aztec or Indian
tobacco, is suspected to be the original tobacco species originated in
America, even though, N. tabacum is broadly used Aztec tobacco is still
cultivated in South America, Turkey, Russia, and Vietnam [9]. Apart
from these two species, other species such as N. benthamiana, N. atten­
uate, N. glutinosa, N. alata are used in various purposes mainly for their
phytochemicals [5].
Tobacco plants are not only vital crops in traditional agriculture
systems but also could be applied as ideal model plants on biological
mechanism studies [10]. This is because tobacco has the characteristics
of easy genetic transformation, short generation time, and high disease
susceptibility [11]. As stated earlier, Nicotiana species contains several
biologically active compounds, which have been exploited for
economical and biological purposes and one such species is
N. benthamiana, which has been extensively used as a model-plant to
study plant-pathogen interactions [12]. N. attenuata, known as wild
coyote tobacco, has also been used as a model organism to investigate
specific metabolites mediated ecological interactions [2].
Approximately 6 trillion cigarettes are consumed worldwide each
year, and according to a report published in 2019, the total tobacco
production was approximately 6.68 million metric tons, and China was
the biggest tobacco producer worldwide in that year [13]. Accordingly,
such big production led to trillions of tobacco manufacturing chemical
wastes, including nicotine, each year and exerting negative effects on
the environment. Though it is regulated that the tobacco industry should
own landfill particularly for the disposal of tobacco wastes, however, in
numerous developed countries, environmental laws are rarely observed
[14]. However, reports of tobacco phytochemicals application in other
purpose opens several research options. Studies related to tobacco plants
and their metabolites revealed that leaves and flowers of tobacco plants
can be used for novel causes other than production of cigarettes [5].
Within this context, waste generated from the tobacco production
plants could be further used to evaluate and extract plant-based me­
tabolites for future novel perspectives. Based on the preceding discus­
sion, the present review focuses on the current progress of functional
phytochemicals found in the Nicotiana plant and the potential applica­
tion of tobacco processing waste to reduce its role as a biological risk.
2. Tobacco processing and processing waste
2.1. Processing
Published research indicated that the types and concentrations of
phytochemicals in tobacco leaves change during ripening, drying,
fermentation, and storage period, and are influenced by a variety of
factors such as cultivation methods, climate and others [15]. The drying
process is able to decrease the starch content and increase the reducing
sugar content. Additionally, the proportion of polyphenols and carbo­
hydrates decreases in the process of fermentation [16].
2.2. Tobacco processing waste
In industrial sectors, tobacco processing produces an enormous
amount of tobacco by-products, which belong to agricultural industrial
waste [17]. According to a published report, 1.25 million metric tons of
tobacco wastes were generated in 2005 [17]. Due to the high concen­
tration of nicotine and total organic compounds in tobacco by-products,
it is difficult to be disposed of in landfills. In this regard, tobacco
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Biomedicine & Pharmacotherapy 143 (2021) 112191
processing waste is commonly defined as the solid waste, which consists
of tobacco powder waste and low-quality tobacco [18]. Other studies
indicated that tobacco waste refers to roots, leaf vein, stem [19], tobacco
leaves lower than standard quality [20], and the mixture of tobacco
residue and tobacco powder [21]. Along this line, tobacco waste is
accumulated in the tobacco processing period, and the main solid
by-products are tobacco particles; therefore, the type and content of
bioactive chemicals are similar to the original tobacco [22]. Moreover,
during pre-handling on the field, it is important to separate tobacco
scrap from broken leaves, to avoid taking them into the manufacturing
process. In the manufacturing stage, those small stems that extend from
the stalk would be removed, and small pieces of tobacco waste are
formed by offal and dust, which are difficult to apply for any objective,
and treated as useless waste [15].
As one of the most important non-food crops in the world, tobacco
plays a vital role in agricultural production. In this regard, China has
become the largest producer of tobacco, and this plant has become an
economic source for some low-income areas in central and western
China. Furthermore, the tobacco processing industry produces large
amounts of tobacco waste as a by-product, which is usually thrown away
because of its nicotine content, with only a small amount being recycled.
More than 1 million hectares of tobacco are cultivated every year, and
statistics show that the waste produced by tobacco processing has
reached 3–5 million tons per year by 2017, and this number was still
growing [23]. Different from the stalks of Gramineae crops such as rice,
wheat, or corn, tobacco stems are hard to decompose in a short time
under landfill conditions. Thus, tobacco residue is often directly burned
after harvesting the leaves, causing a serious air pollution and wasting
much potentially useful biomass [24].
Recycling and utilization of tobacco processing waste is an increas­
ingly serious challenge for sustainable development of tobacco pro­
duction. One of the promising strategies for the sustainable management
of crop stalks is to convert waste biomass to biochar through pyrolysis
[25], and this method has been lucubrated in recent years [26]. The
pyrolysis technique could significantly reduce the volume of waste
biomass and produce a stable carbonaceous solid material. This kind of
biochar is considered a strong adsorbent that reduces the mobility and
toxic potential of inorganic pollutants in soil and sediments, and thus
could be applied as a soil conditioner [27] and environment remediation
[28]. Although recycled tobacco fiber is able to produce recycle tobacco
paper which is named reconstituted tobacco, it would lead to wasting
many phytochemicals with valuable functions, such as
anti-inflammatory ability, antioxidant activity, and anti-fungal property
[15].
3. Phytochemicals in tobacco
In the past, bioactive substances were mainly referred to as second­
ary metabolites of plants. However, recent research started to consider
some primary metabolites as bioactive substances. Some of these phy­
tochemicals have been used to prevent disease occurrence and treat
various ailments, such as colchicine, which can relieve the symptoms of
ventilation. In plants, they have a protective effect against biotic and
abiotic stresses. Due to the presence of bioactive compounds varies in
quantity, it is meaningful to develop their products to obtain the best
concentrations and find suitable alternative sources for cost reduction
[29]. In this respect, different groups of components in tobacco extracts
such as alkaloids [30], polysaccharide [31], polyphenols, aroma com­
pounds [32], fatty alcohols, terpenoids, indole, pyridine [33], essential
oils [34], and phytosterols [35] have been determined. Below, there is a
description of these groups of compounds:
3.1. Alkaloids
Nicotine, 3-(1-methyl-2-pyrrolidinyl) pyridine (Fig. 1), is a major
and typical alkaloid content in tobacco extracts. The nicotine in tobacco
X. Zou et al. Biomedicine & Pharmacotherapy 143 (2021) 112191

Fig. 1. Chemical structure of different nicotine.

plants is produced by the ornithine metabolism [36], and it would be levels of tobacco alkaloids [41]. In this regard, the main ingredients of
accumulated in leaves. The other proof of this is that there is no nicotine total nicotine in tobacco increase as the latitude decreases.
found in tobacco seeds [37]. Thus, the level of nicotine contained in
tobacco leaves is entirely dependent on the accumulation of nicotine 3.2. Solanesol
during plant growth. Nicotine is obtained from not only tobacco plants
and tobacco-related substances, but could be found in the extracts of Solanesol refers to a kind of polyisoprenoid alcohol that is normally
other Solanaceae plants. There have been numerous studies pertaining to found in many species of the Solanaceae family plant (Fig. 2). It is a
the nicotine content in plant samples and in vivo experiments. Most of critical source of isoprene units and a precursor of polycyclic aromatic
the reported data on the nicotine content in the leaves of tobacco sam­ hydrocarbons in tobacco [42], which are used for the chemical synthesis
ples ranged from 0.3% to 3% [38]. However, some higher concentra­ of vitamin K and quinones [43].
tions have been reported, indicating the greater potential for extracting Research findings have shown that solanitol exists in both free and
nicotine from tobacco by-products. The effect of nicotine on the body is bound forms in tobacco leaves, which means some solanitol is bonded in
based on its ability to interact with a range of receptors that target the esters of natural phytic acids such as linolenic acid, myristic acid,
neurotransmitter acetylcholine (nAChRs). These receptors, which are
normally present in nervous systems and neuromuscular junction, play a
role of ion channel across the membrane, and are also able to adjust the
release of other neurotransmitters [39]. When activated by acetylcho­
line or nicotine, selected ions would flow through the cell membrane
and might block the normal conduction of the central nervous system.
This is the reason nicotinoid pesticides can paralyze and kill pests.
Although production of pyridine alkaloids is one of the characteris­
tics of the plants in the genus Nicotiana [40], some significant differences
of alkaloids and abundance still exist across the varieties of the same
genus [41]. In general, the characteristics of alkaloids in tobacco were
not significantly related to geographic origin or morphology. However,
nicotine is dominant in almost all tobacco species, although there are
significant differences in alkaloid composition between different
subspecies.
In addition to genetic factors, growing environment and chromo­
some number also slightly affect the composition and concentration Fig. 2. Structure of solanesol.

3
X. Zou et al.
linoleic acid, palmitic acid, and oleic acid [15]. On the other hand,
solanesol showed value as a food additive and as a pharmaceutical
content. Tobacco is a major source of solanesol [44], and solanesol has
also been reported in some other solanaceous vegetables such as pep­
pers, tomatoes, eggplant, and potatoes [20]. Published research showed
that solanesol exhibits anti-proliferation and antibacterial activity, and
was proposed to be used in the production of drugs and the treatment of
a variety of diseases [45]. In addition, solanesol exhibits
cardio-excitatory [46] and antioxidant (Huang, Li, Niu, Wang and Qin
[44] activities.
3.3. Polysaccharide
Carbohydrates are vital components in tobacco, which would change
during fermentation and curing then contribute to the taste quality of
raw tobacco leaves and aroma attributes of final products. The specific
reaction mechanism is through the Maillard reaction, where these
polysaccharides condense with amino acids in tobacco leaves to make
tobacco leaves brown. In addition, they react with phenols, alcohols,
and sterols to form glycosides that have an effect on tobacco aroma [47].
Within this context, Troje, Fröbe and Perović [48] showed that 30.25%
of tobacco polysaccharides come from leaves mass, 22.58% of which are
reducing sugars. Qualitative and quantitative analysis of polysaccharide
species and content in tobacco has become a research hotspot in the past
few years. In addition, raffinose [49], glucose, sucrose, maltose, xylose,
and fructose [48] have been also found in tobacco leaves.
As has been previously mentioned, the product of Maillard reaction
between sugars and amino acids is able to improve tobacco quality,
while starch and protein contents have a negative effect on tobacco
quality. Therefore, bio-catalytic synthesis of reducing sugars and amino
acids from the above compounds has been used to improve tobacco
quality, although research on the biological activity of tobacco poly­
saccharides has not been in-depth. The current research trend is to link
polysaccharides with intestinal health and use molecular biology to
reveal the regulatory mechanism of tobacco polysaccharides on other
diseases [50]. The antioxidant activity of tobacco polysaccharides has
been previously reported [31]. In addition, the aldehyde, carboxyl, and
carbon-oxygen single bonds in reducing sugars could provide electrons
that provide polysaccharide the ability to stop the radical chain reaction
via reacting with free radicals and converting them to more stable forms.
This indicates that polysaccharides would contribute to the antioxidant
activity of tobacco extracts. Although, bioactive carbohydrates have
very complex chemical structures that slow the research development,
many of their potential anti-pathological functions and physiologically
related activities have been detected [51]. In addition to its antitumor
and anti-inflammatory properties, its widespread prebiotic effects also
help improve intestinal health.
3.4. Polyphenols
Phenolic is a general term for plant components with poly-hydroxyl
groups, which is widely distributed in plants tissue [52,53] and
commonly used as antioxidants in the human diet [53,54] due to high
reactive oxygen radical (ROS) scavenging capacity [55–57]. Polyphenol
compounds are grouped into a) simple phenols, b) flavonoids, and c)
non-flavonoids.
a) simple phenols sub-grouped into 1) coumarins and 2) phenolic acids.
Again, phenolic acids are sub-sub grouped into i) hydroxybenzoic
acids ii) hydroxycinnamic acids.
b) flavonoids are sub-grouped into1) flavonols, 2) flavones, 3) iso­
flavones, 4) flavanols, 5) flavanones, 6) anthocyanins, and 7)
chalcones.
c) nonflavonoids are sub-grouped into 1) tannins, 2) lignans, and 3)
stilbenes [58]. Plants are the key sources of natural antioxidants
polyphenols, such as different types of phenolic acids, including a
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Biomedicine & Pharmacotherapy 143 (2021) 112191
group of hydroxybenzoic acids [59] and hydroxycinnamic acids
[60], flavonoids, including flavonols [61], flavones [62], flavanols
[63], flavanones [64], isoflavones, anthocyanins, chalcones, and
nonflavonoids, including tannins, lignans, and stilbenes [58]. It is
conceivable that the mechanism of formation of polyphenols sug­
gests that plants would secret some specific secondary metabolites to
resist the abiotic stress [65]. Literature has shown that abiotic stress
such as drought [66] and salinity stress [67] enhanced the total
phenolic content [68], and flavonoid contents [69] and individual
phenolic acids and flavonoid compounds [60]. The intensity of their
antioxidant activities is based on their ability to combine with free
radicals, and they could lower the free radicals level in vivo by
regulating the phenolic and flavonoid compounds [70] and antiox­
idant enzymes activities [71,72] or chelating with metal ions
through the Fenton reaction [73] to terminate the chain reaction.
After polyphenols antioxidant properties were discovered, they
became the research hotspot of phytochemicals with biological ac­
tivity [72,74]. In general, there are many forms of polyphenols in
plant tissue, such as free form, derivatives (esters or glycosylated
compounds), polymers, or oligomers (combined with poly­
saccharides) [50] (Fig. 3).
The function of plant polyphenols is to protect plants from ultraviolet
radiation, fungal pathogens, and avoid cells damaged by oxidative stress
[75]. The mechanisms of polyphenol synthesis are determined as the
shikimic acid and malonic acid pathways [76]. In addition to protecting
plants from pathogens and predators, polyphenols also contribute to
plant color and aroma attributes [15].
Several studies have reported differences in the content and species
of phenolic compounds in tobacco [77]. Tobacco leaves contain many
kinds of polyphenols, among which phenolic acid and flavonoid glyco­
sides are in a dominant position [77]. Moreover, researchers found that
kaempferol-3-O-rutinoside and quercetin-3-O-rutinoside as well as
chlorogenic acid (3-O-caffeoylquinic acid) and its isomers 4-O-caf­
feoylquinic acid, and neochlorogenic acid (5-O-caffeoylquinic acid) are
the most abundant polyphenols in tobacco extraction [78]. For example,
research findings have shown that the polyphenol contents of Virginia
tobacco and Oriental tobacco varieties were higher than 3% [50].
3.5. Chlorogenic acid and rutin
Natural chlorogenic acid has been found in coffee beans, leafy
vegetable amaranth [62], and tea which is an ester of quinic acid and
caffeic acid [79] (Fig. 4). Its function is to resist insects, prevent enzy­
matic browning of fruits and vegetables, prevent fungal pathogens
infection, and act as the natural antioxidant [80]. In the human diet, the
intake of foods containing chlorogenic acid would against oxidative
stress, delay aging, anti-inflammation, anti-cancer and other health
functions [81]. Nevertheless, there is no strong evidence to prove the
antioxidant function of chlorogenic acid inside the plants.
It is reliable to isolate polyphenols from tobacco by RP-HPLC system.
The absorption peaks of rutin at 205.1 nm, 257.8 nm, and 356.8 nm and
chlorogenic acid at 218.9 nm, 244.1 nm, and 328.7 nm were deter­
mined by combining with UV-Vis scanning spectrum [82]. According to
using HPLC-MS technique, it was found that the molecular weight of
chlorogenic acid was [M-H] m/z 353.05 [83], and the value of [M-H]
m/z 191.10 represented the ion fraction of chlorogenic acid after the
loss of 3,4-dihydroxy cinnamyl group, and the molecular weight of rutin
was [M-H] m/z 609.00 [82]. These results provide more convincing
evidence for the identification of tobacco polyphenols; also prove that
the main components of tobacco polyphenols are chlorogenic acid and
rutin.
3.6. Summary of phenols in tobacco and tobacco smoke
Polyphenols in tobacco extract have a variety of health benefits with
X. Zou et al. Biomedicine & Pharmacotherapy 143 (2021) 112191

Fig. 3. Classification of phenol compounds.

Fig. 4. The structure of chlorogenic acid and rutin.

high commercial potential. However, phenolic compounds in tobacco
smoke may have negative effects on health, and the possible conse­
quences include tumor promotion, genetic toxicity, and cardiovascular
issues [84]. As a result, qualitative and quantitative analysis of poly­
phenols in tobacco smoke is critical.
Phenolic compounds that have been characterized in tobacco smoke
include c-cresol, catechol, m-cresol, resorcinol, p-cresol, and hydroqui­
none [85]. During combustion, the original polyphenols are destroyed
by heat into smaller phenols, and some of the typical changes are shown
in Fig. 5. These simple phenols not only give cigarettes their distinctive
flavor and aroma characteristics, but they also pose a potential cancer
risk.
3.7. Sterols
It has been known that steroid hormones are produced in

5
X. Zou et al.
Fig. 5. Phenols changing during tobacco burning.
mammalian female and male gonads, and adrenal glands only, however,
reports of steroid production by plants are also found in several studies
[86,87]. In addition, steroids are also present in tobacco plants and
several studies extracted different type of steroids having potential
bioactivities. Steroids present in the plant help its defense mechanism
against certain viruses and pathogens [2]. Tobacco (N. tabacum) plants
are found capable of synthesizing animal steroid hormone such as pro­
gesterone and androst-4-ene-3,17-dione, testosterone, and estradiol
[86–88]. From seeds of N. tabacum L., steroidal glycosides of the spi­
rostane and furostane series have also been isolated.
3.8. Terpenoids
Terpenoids represent the largest class of natural products and many
attractive products in industrial sectors use terpenoids such as in flavors,
perfumes, spices, perfumes, and cosmetics [89]. Many terpenoids have
biological functions and are also used for therapeutic purposes [90].
Ragsuso et al., reported 23 monoterpenoids (hydrocarbons and alcohols)
and 27 sesquiterpenoids with diverse hydrocarbon skeletons synthesized
from Nicotiana plants [91].
Such as five irregular terpenoids, E-4,8-dimethyl nona-1,3,7-triene,
1,3,3-trimethyl-7-oxa-bicyclo[4.1.0]heptan-2,5-dione, 2,6,6-trimethyl-
2-cyclohexene- 1,4-dione (4-oxoisophorone), 2,6,6-trimethyl-1,4-cyclo­
hexadione, and E-geranyl acetone, were found as major constituents of
N. bonariensis and in N. rustica [2,91]. Diterpene compounds with major
components such as manool, sclarene, and manoyl oxide, were also
found from N. glutinosa L. which is a relatively less studied Nicotiana
species (Solanaceae) [92].
4. Applications of tobacco metabolites
In recent years, the interest in reusing industrial by-products
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Biomedicine & Pharmacotherapy 143 (2021) 112191
processed by factories is growing. This is able to develop new function
products, reduce carbon emissions, and upgrade their original value. For
plant processing wastes, they are natural sources of bioactive com­
pounds. Application of proper techniques to extract phytochemicals
makes it possible to turn waste into treasure, and replace expensive raw
materials used in the past. At the same time, reducing biomass waste also
meets the needs of sustainable development in the future. Fig. 6 shows a
simple lay out of tobacco leaves extraction and its biological application.
4.1. Anti-bacterial activity
Many compounds in tobacco plants such as polyphenols, terpenes,
phytolexin, and polysaccharides, among others exhibit antimicrobial
activities, and many of those are naturally secreted by the Nicotiana
plants [2]. In this regard, several studies corroborated the fact that
Nicotiana plants could be used as a potent antimicrobial agent [86–88].
Akinpelu and Obuotor reported that 25 mg/mL of leaf extracts of
N. tabacum inhibits the growth of both gram positive and gram negative
bacteria, including Bacillus subtilis, Corynebacterium pyogenes, Pseudo­
monas aeruginosa, Serratia marcescens, Shigella dysenteriae, and Staphy­
lococcus aureus [89]. A few years later, Haiyan and coworkers evaluated
the antibacterial activity of tobacco leaf extract, and found positive re­
sults against E. coli, B. subtilis, and S. aureus [82]. Moreover, these re­
searchers found that the tobacco leaf extract was as potent as an
antibacterial agent as gentamicin, used as the positive control. Similarly,
two independent studies conducted in Pakistan indicated that extracts of
N. tabacum exert significant antibacterial activity against gram positive
S. aureus [88,90]. Sharma and colleagues demonstrated that the acetone
stem extract of tobacco exerts antagonistic effect against the growth of
E. coli, S. aureus, P. aeruginosa, and B. amyloliquefaciens, whereas the
methanol, aqueous, and ethanol extracts of the tissue of tobacco were
also effective against E. coli [91].
X. Zou et al.
Fig. 6. A simple layout of tobacco leaves extraction and its biological application.
Other studies indicated that the methanol leaf extract of N. tabacum
also exhibit antimicrobial activity against S. aureus and E. coli [92]. It
was also shown that all parts of tobacco have anti-bacterial potential,
which offers theoretical feasibility of developing antibacterial drugs
from the tobacco industry waste.
A study conducted in Ethiopia reported that 100 and 200 mg/mL
plant extract of N. tabacum exhibits antagonistic effect against S. aureus,
S. agalactiae, S. dysgalactiae, and Dermatophilus congolensis [93].
Recently, a group of researchers showed that the crude extracts of
N. tabacum exert antimicrobial activity against the biofilm forming
uropathogens, while the clinical isolates were the most resistant group
[94]. Similarly, a recent Saudi Arabian study reported that leaves and
flower extracts of N. glauca inhibited the growth of E. coli and S. aureus
[95], suggesting that leaves and flowers extracts of N. glauca could be
used for the treatment of bacterial infections, and the plant could be
used for the medicinal and economical purposes.
Researchers also evaluated the antimicrobial activities of poly­
phenols in tobacco leaves against E. coli, S. aureus, and B. subtilis. Results
showed that polyphenols from tobacco leaf possess great potential as
antimicrobial agents [87]. Nicotiana plants normally produce numerous
substances such as acyl sugars which protect them naturally from plant
pathogens [96]; however, such extracted compounds can also be used as
potential antibacterial substances [86]. Recently, the antibacterial
characteristics of organic extracts of the roots of the Nicotiana plants
were evaluated. Results revealed that the n-hexane and acetone
N. tabacum root extracts exhibit potent antagonistic activities against
S. aureus MRSA, E. faecium, E. coli, S. sonnei, P. aeruginosa, C. albicana,
and E. floccosum [97].
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Biomedicine & Pharmacotherapy 143 (2021) 112191
4.2. Antifungal activity
Nicotine-based pesticides have been gaining attention as research
findings showed that these compounds are highly active against fungal
pathogens and exert low toxicity for plants. Thus, such compounds are
often termed as “green pesticides” [98]. In this regard, the antifungal
effect of nicotine has been the subject of several studies, and extracts
from Nicotiana plants have been suggested as a source of biological
pesticides [99–101]. In 2000, published work indicated that
100–250 µg/mL of nicotine inhibits opportunistic fungal pathogens such
as Cryptococcus neoformans and Candida albicans [99]. Furthermore,
researchers reported that the presence of cembranoids in tobacco plants
could inhibit the growth of fungal species. These researchers concluded
that tobacco cembranoids at 80 μg/mL could completely inhibit the
growth of Valsa mali, with an EC50 value of 13.18 μg/mL. In addition,
results suggested that the inhibitory activity of tobacco flower extracts
against V. mali are higher than those of the leaf extracts [98].
In a similar fashion, it was reported that enzymes isolated from the
tobacco plant are able to inhibit fungal growth. In this context, different
isoforms of chitinases and β-1,3-glucanases of tobacco were tested for
their antifungal activities; results revealed that these isoforms are active
against Fusarium solani germlings, due to the lysis of the hyphal tips,
which inhibited the fungal growth [100]. Other research groups showed
that a stress inducible protein, named osmotin, which was first isolated
from tobacco cells exposed to saline conditions [102], exhibits anti­
fungal properties [103,104]. The over-expression of osmotin has been
reported to exhibit anti-fungal activity [105]. Similarly, Abad et al. re­
ported that osmotin from Nicotiana significantly inhibited the hyphal
growth of Bipolaris, Fusarium, Phytophthora species, and Trichoderma
longibrachiatum. However, it was less effective against Aspergillus flavus,
X. Zou et al.
A. parasitica, Rhizoctonia solani, and Macrophomina phaseolina. More­
over, these researchers showed that osmotin can either induce spore
lysis, inhibit spore germination, or reduce germling viability in seven
fungal species that exhibited some degree of sensitivity in hyphal growth
inhibition tests [106]. In addition, a novel plant defensin called NaD1
was extracted from the flowers of ornamental tobacco (Nicotiana alata);
this was a cationic antimicrobial peptide and showed remarkable anti­
fungal activity against plant-pathogenic fungi [12].
4.3. Anti-parasitic activity
Nicotine contents in N. tabacum L. are the main component of
nicotinic insecticides, and its insect repellent mechanism is based on the
pharmacological action of making insects over-excited to promote in­
testinal emptying [107]. Other alkaloids in tobacco may have similar
effects. Current toxicological findings have shown that each
nicotine-rich tobacco extraction can knock down any species of ticks at
any stage, which is positively correlated with the dosage, but could not
effectively knock down fleas and blowfly larvae [108]. On the other
hand, synthetic neonicotinoid pesticides have led to extensive environ­
mental pollution due to their unique photo-stability, low volatility, and
hydrophilicity, [109], especially for pollinating insects [110]. In this
regard, natural tobacco extracts provide an environmentally friendly
alternative to synthetic pesticides. There are more than 4000 phyto­
chemicals in tobacco leaves, while the crude methanol extract of tobacco
leaves is a highly complex mixture because many chemical components
have free and bound states [111].
Tobacco (Nicotiana spp.) plants are source of several alkaloids, which
has anti-parasitic activities [2] and were used for centuries in agricul­
tural sector for controlling pests or parasites of medical and veterinary
importance [108]. However, discovery of more specific and potent
synthetic pesticides limited the non-nicotine-based commercially
un-available products [108]. Within this context, studies are ongoing to
demonstrate the potentialities of Nicotiana plans in parasite control such
as the methanol extracts of N. glutinosa, N. glauca, N. debneyi, and
N. tabacum used in one study to control several parasites. Results showed
that only N. tabacum and N. glutinosa exhibited moderate anthelmintic
activity, and all extracts significantly repelled R. sanguineus ticks [108].
Similarly, published work by Nouri and colleagues indicated that ex­
tracts of tobacco (N. tabacum) exert considerable anthelminthic activity,
and more potent effects were observed with the highest concentrations
against Marshallagia marshalli, a typical abomasal nematodes in sheep,
goats, and wild ruminants [112]. Nicotine is obviously not the only
insecticide active component in Nicotiana family, N. glauca, which is rich
in anabasine, has been listed as a natural repellent against arthropods
[113].
Unlike nicotine and tick-nockdown dosage relation, the repellent
effect could not be merely related to only one of the major alkaloids in
tobacco. The mechanism of repellent activity is often related to the
biochemical interaction with enhancement or synergy between some or
all alkaloids compounds and other non-alkaloid tobacco phytochemi­
cals, which might be responsible for the avoidance effect of the extracts.
This requires researchers to evaluate very complex mixtures of extracts
rather than individual molecules, causing the problem extreme diffi­
culty. Nevertheless, the relatively low vapor pressure of active in­
gredients seems to be an important attribute of triggering repellent,
which is matched with the characteristics of tobacco alkaloids.
4.4. Antioxidant activity
Polyphenols extracted from plants exert potent antioxidant activity,
which offers beneficial health benefits by retarding aging and prevent­
ing cancer and cardiovascular diseases [87]. In this regard, published
reports indicated that polyphenols from tobacco plants exhibit antioxi­
dant activities.
Research findings showed that flavonoids, polyphenolic compounds,
8
Biomedicine & Pharmacotherapy 143 (2021) 112191
in tobacco scavenge free radicals like 2,2’-azino-bis(3-ethylbenzthiazo­
line-6-sulphonic acid (ABTS) and 1,1-diphenyl-2-picrylhydrazyl
(DPPH), and capture superoxide anion, and their activity is equivalent
to the ascorbic acid solution in a concentration of 600 µg/mL [114].
Wang et al. (2008), extracted crude polyphenols from tobacco leaf by
80% aqueous ethanol, and the antioxidant activities of polyphenols of
tobacco (PTL) leaves were investigated using free radical scavenging
assays. Results showed that the IC50 values of PTL for DPPH radical,
hydroxyl radical, and superoxide anion radical-scavenging activities, as
well as lipid peroxidation inhibition activity were 49.6, 44.0, 5.02, and
132 μg/mL, respectively, suggesting that PTL possess strong antioxidant
activity [87].
Similarly, a group of researchers evaluated the antioxidant proper­
ties of flavonoids and polysaccharides from tobacco (N. tabacum) leaves
in in vitro systems, using scavenging activities on hydroxyl, superoxide
anion, DPPH, and ABTS radicals, and reducing power. Results also
showed that flavonoids exhibit much better activity than poly­
saccharides in scavenging free radicals. Moreover, when compared to
the positive control, ascorbic acid, both showed weaker antioxidant
potential. However, flavonoids possessed comparable superoxide anion,
DPPH, and ABTS radical scavenging abilities comparable to ascorbic
acid at high concentration (600 μg/mL) [115]. Results from another
study revealed that the methanol extract obtained from the flowers of
N. glauca contained the largest amount of phenolic compounds (111 µg
garlic acid equivalents/g of extract), and showed the best antioxidant
activity (94.80% inhibition of DPPH and 97.57% of ABTS) and
anti-inflammatory activity (81.93% inhibition of inflammation) [116].
Superoxide dismutase and glutathiones transferase were also found in
the stem of N. tabacum, which enhance the antioxidant activity of to­
bacco extracts [91]. Similarly, the antioxidant activity of N. tabacum’s
roots extract was assessed using the DPPH assay; results showed that the
n-hexane extract was the most potent with an IC50 of 2 μg/mL [97,117].
4.5. Antitumor activity
Cembranoid-type diterpenes (CBDs) were first identified in tobacco
and pines, which have been found to exhibit good antimicrobial, anti­
tumor, and neuroprotective activities [118]. Studies on the mechanisms
underlying the anticancer effects of CBDs against hepatocellular carci­
noma cells are ongoing [4]. Its anticancer properties were first reported
in 1985 by Saito et al. [119]. Recently, the use of tobacco α-2,7,
11-cyprotermine-4,6-diol (α-CBD) was evaluated via the MTT assay (in
vitro cell proliferation assay). Results revealed that α-CBD reduces the
formation of cell clones and inhibits the proliferation of hepatocellular
carcinoma cells. In addition, morphological observations showed that
α-CBD alters cell morphology and membrane permeability before
inducing apoptosis [118].
5. Medicinal function of Nicotiana tabacum
Tobacco, as a natural medicinal plant, has been recorded in many
places since it spread from America. Spanish sailors and Indian chroni­
clers first recorded the use of tobacco and its important role in the new
world, then it was widely used by European pharmacists to treat various
diseases [39]. However, the widespread use of nicotine also brought
about the problem of poisoning, so that tobacco was once suspected of
drugs. The direct consequence is that tobacco dependence has become
an intractable medical and public health-related challenge, which
caused an increase in the cost of public health [120]. A new study
showed that tobacco use, whether smoking or chewing, increases the
susceptibility of COVID-19 and reduces the ability to fight the New
Coronavirus [121]. However, tobacco waste extraction products can
avoid nicotine ingredients into the formula, thus avoiding a series of
negative health effects. Moreover, the contribution of bioactive com­
ponents in tobacco to anti-inflammatory and anti-tumor in modern
medicine is hard to ignore. This further indicates that the functional
X. Zou et al.
health products extracted from tobacco waste have great potential value
and are worthy of further study.
5.1. Uses of tobacco in traditional medicine
The genus Nicotiana has medical applications in a wide range of
geographical areas. According to records, the most common use of this
herb is fumigated into strips of cigars, which reduce fatigue and act as a
disinfectant by inhaling the aroma produced after ignition [39]. Leaves
of Nicotiana rusticas are applied for bronchitis, tonsillitis, wounds, sore
throat, and arthritis. Meanwhile, its extract could also be applied as a
toothache remedy, and effective to respiratory tract diseases [122].
Moreover, leaves of Nicotiana tabacum have similar functions and still
effective on digestive system disorders, skin illness, sinusitis, and to cure
stomach infections [123]. In Madagascar, extract of tobacco is able to
stop nosebleeds and cure bilharzia [124]. It is also used to treat ear
problems, narcotic, and gynecological disorders [122]. All these clues
indicate that bioactive substances in tobacco have multiple health
functions and complex mechanisms of action.
5.2. Application of tobacco phytochemicals in modern medicine
Dried tobacco stems and leaves could be employed as analgesics,
anti-inflammatory, and anti-rheumatic drugs [125]. In this respect,
chlorogenic acid has been detected in tobacco leaf extract which would
respond to its anti-inflammatory effects [83]. Moreover, research car­
ried out by Plant Biotechnology Inc. (Hayward, CA, USA) showed that
tobacco-derived proteins could be used against the Ebola virus, and have
contributed to control the outbreak in Africa. Researchers produced an
immune adhesin (DPP4-FC) in transgenic tobacco, and this high purity
compound can efficiently bind with MERS-CoV, thus preventing the
virus from infecting lung cells [126].
In addition, numerous studies have been conducted on the anti-
inflammatory effect of plant-derived compounds. Findings indicated
that many phenolic compounds could be considered as potential anti-
inflammatory drugs because they have significant negative regulation
on the nuclear factor- jB (NF-jB) pathway, which is an important
signaling pathway in the inflammatory response. Due to the various
chemical structures of polyphenols, they can significantly inhibit the NF-
jB cascade pathway at different stages [127]. In this regard, previous
studies have revealed that sirtuins 1 (SIRT1) also interacts with the
NF-jB signaling pathway. In a similar fashion, researchers showed that
rutin [128], caffeic acid phenethyl ester, hydroxycinnamic acids [129],
ferulic acid, and quercetin [130] could evoke the sirtuins 1 (SIRT1) in
rats or cultured cells to avoid the senescence-associated secretory
phenotype (SASP) development according to the NF-jB pathway
repression.
Excepting the function of curing disease, anti-aging is usually one of
the goals of modern medicine. The definition and criteria of aging
characteristics have been set out, including loss of protease inhibition,
mitochondrial dysfunction, cellular senescence, and changes in inter­
cellular communication [131]. Along this line, numerous plant poly­
phenols have been shown to have the ability to regulate some of the
aging characteristics listed above, and thus act as potential anti-aging
agents [132].
The anti-aging theory of polyphenols is based on reducing the
damage caused by oxidative stress to cell components including DNA
and protein, protecting the normal function of the cell membrane, pre­
venting senescence related secretory phenotype (SASP), and delaying
the aging process [132]. Based on these cellular anti-aging mechanisms,
scientists further studied how the anti-aging effect of polyphenols is
realized at the tissue or body level. One standpoint is that polyphenols
can change the aging symptoms of organ systems, such as the cardio­
vascular system, immune system, reproductive system, nervous system,
skin, and organs, by improving intercellular interaction [50]. Some
polyphenols have potential prebiotic effects, which are called dietary
9
Biomedicine & Pharmacotherapy 143 (2021) 112191
polyphenols and they are also natural antioxidants [55]. These exoge­
nous antioxidants reduce oxidative stress by electron donating,
neutralizing the free radicals, and chelating metal ions [71], so as to
protect mitochondrial function and avoid cell apoptosis. In addition,
polyphenols can activate the nuclear factor erythroid 2-related factor 2
(Nrf2) then arouse the endogenous antioxidant enzymes [50].
5.3. The toxin effects of nicotine
Nicotine causes numerous adverse health effects. It is the main pre­
cursor of N’-nitroguanine (NNN), a tobacco specific nitrosamine
(TSNA), and has been proven to have the risk of inducing cancer in
animal in vivo experiments [133]. Other than that, nornicotine can
cause abnormal protein glycosylation and catalyze covalent modifica­
tion of some prescription drugs such as steroids and prednisone [134].
Moreover, nornicotine-catalyzed retinal isomerization, which could
promote age-related macular degeneration, aggravate smoking related
congenital defects, and other smoking related diseases caused by reti­
noic acid metabolic disorders are also negative effect on human health
caused by nicotine [135]. In addition, long term smoking also increases
the risk of periodontal disease, and there is evidence that it is also
associated with nornicotine [136]. Therefore, elimination of nornicotine
in tobacco and related products will be the focus of developing new
products.
5.4. Relationship of tobacco phytochemical function and intestinal flora
Participation of intestinal microflora is an important part of plant
compounds to realize the health function of the human body. During
digestion, and after the ingestion of polyphenols, the first target these
compounds encounter and interact with is the intestinal microorganisms
living in the human digestive system. In this regard, the intestinal
microbiota decomposes polyphenols into metabolites, and polyphenols
also regulate the balance of intestinal microbiota and inhibit the pro­
duction of adverse microbial toxins [137]. Some polyphenols are con­
jugated such as quercetin, which is conjugated with rutinose and the
corresponding metabolites are glycoside quercetin and rutin. In general,
the sugar part cannot be hydrolyzed by the intestinal β-glucosidase, so
the metabolism of intestinal microbiota, including Bacteroides, Blautia,
and Enterococcus, is needed to produce quercetin aglycone by glycosyl­
ation [50].
On the other hand, phenolic acids are the products of the ring
splitting reaction of flavonoids, and may be released from the food
matrix. Chlorogenic acid is the general term of coffee, which is rich in
quinic acid and caffeic acid esters, and also exists in tobacco. Most of
chlorogenic acid and aglycone reach the colon together, and release a
large number of bioactive substances such as protocatechuic acid (PA),
quinic acid, dehydroquinic acid (dhqa), dihydroferuloylquinic acid
(dhfqa), dihydroxycyclohexane carboxylic acid (dhcca), trihydrox­
ycyclohexane carboxylic acid (thcca), cyclohexanecarboxylic acid
(CCA), hydroxycyclohexanecarboxylic acid (HCA), caffeic acid, and
dehydroquinic acid (DHCQA) [138]. These catabolic reactions require
the participation of a variety of bacteria, some of which need to be
further strengthened [50].
The prebiotic function of polyphenols has been widely recognized as
a health-related issue, where some specific dietary polyphenols not only
enhance the growth of probiotics such as Lactobacillus and Bifidobacte­
rium but also inhibit the reproduction of pathogenic bacteria. For
example, several polyphenols identified in mango [139] and lemon
[140] and non-extractable polyphenols [141] can promote the growth of
some bacteria that are beneficial to human health, such as Ackermann,
Christensenellaceae, Verrucomicrobia Bifidobacterium, and Lactobacillus
(Fig. 7).
Research findings have shown that polyphenols exhibit a variety of
in vitro and in vivo biological activities including the ability to scavenge
free radicals; however, their bioavailability is low from the perspective
X. Zou et al.
Fig. 7. The prebiotic effect of polyphenols.
of human absorption [114]. After extensive metabolism with intestinal
microbiota, the bound polyphenols release many small molecular de­
rivatives, which can effectively improve the absorption rate and
bioavailability. These microbial metabolites always show similar bio­
logical activities to their precursors, such as antitumor and antilipid
oxidation functions of resveratrol and resveratrol glucoside [142] and
vasodilation properties of chlorogenic acid and 3HPPA [143]. Similarly,
research by Xichun and coworkers revealed that 3,4-dihydroxyphenyl­
acetic acid (3,4-DHPAA) and derivatives exert higher antioxidant abil­
ity than quercetin and daidzein [144]. Therefore, microbial metabolism
could promote the bioactivity of polyphenols and improve health
function. Meanwhile, this also proves that the health potential of plant
compounds depends on the contribution of intestinal microflora. The
metabolites of polyphenols from microorganisms can reveal a longer
biological effect than their parent polyphenols, to show a longer effect in
human circulation [50].
6. Conclusions
Large-scale cultivation of tobacco and the amount of waste from the
tobacco processing industry is huge, and improper treatment may lead
to nicotine poisoning, environmental pollution, and biomass waste.
With the discovery of many bioactive substances in tobacco, tobacco
10
Biomedicine & Pharmacotherapy 143 (2021) 112191
waste can become a very useful new raw material. Compounds present
in tobacco exhibit important biological activities including resistance to
numerous diseases, regulation of human health, sterilization, and pest
control. Such a wide range of application scenarios gives a high potential
value to the by-products of the tobacco processing industry. During the
development of new tobacco related products, the first consideration is
the harm, which nornicotine can cause to the human body, in order to
avoid toxic and side effects. Secondly, the influence of intestinal flora on
tobacco bioactive substances should be considered for health products
from tobacco waste, and tobacco fermentation products will be a po­
tential research direction. Finally, the influence of the extraction
method on the results is critical in the industry. Each technique has its
own extraction selectivity and limitations, and this will determine the
extraction efficiency of tobacco bioactive substances. Thus, developing
new technology, and improving and promoting the existing method will
be key to enhancing the value of tobacco processing by-products.
CRediT authorship contribution statement
Authors have written their respective part in the review therefore, all
the authors have equally contributed to this review under the supervi­
sion of Prof. Dr. Abdur Rauf.
X. Zou et al.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgments
The authors thanks for funding provided by “McKenzie Fellowship
Scheme” (Grant No. UoM-18/21), the “Faculty Research Initiative
Funds” and “Richard WS Nicholas Agricultural Science Scholarship”
funded by the Faculty of Veterinary and Agricultural Sciences, the
University of Melbourne, Australia.
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