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2.5.3 Malpighia glabra (Barbados cherry)
Antioxidants reduce the level of oxidative DNA damage caused by free radicals and
ionizing radiation. In this way, it is protected from cellular damage and disruption of cell
integrity. Malpighia glabra is also high in antioxidants [25]. Ref. [25] investigated the radiation
shielding effect of Barbados cherry fruit pulp in the treatment with mutagenic isotope
131
Iby
in vivo animal experiments. In the study,
131
I was given at the concentration used to treat hy-
perthyroidism, and chromosomal damage occurred in bone marrow cells of rats at this con-
centration. The rate of chromosomal aberrations caused by Barbados cherry and
131
I was
found to be much lower. The researchers believe that vitamin C is responsible for the protec-
tive effect. Before and during ionizing radiation therapy, this protective effect was observed.
After therapy, no protective effect was detected. In addition, Barbados cherry did not show
cytotoxic effects [25].
2.5.4 Podophyllum hexandrum (Himalayan may apple)
Podophyllum hexandrum is a Himalayan plant that has been shown to have anticancer and
radiation shielding effects. It is used in diseases such as constipation, colds, inflammation,
mental disorders, monocytoid leukemia, Hodgkin and non-Hodgkin lymphoma [26]. Ref.
[26] investigated the mechanism of action of the radiation shielding fraction REC-2001, ob-
tained from the rhizome of P. hexandrum, using murine peritoneal macrophages and plasmid
TABLE 13.1 Studies on the interaction of herbal medicines with radiopharmaceuticals.dcont’d
Plant name
Part of the
plant used The aim of the study
Type of
operation
Route of
application
Results of the
study
Publication
Tag
Rosmarinus
officinalis
Leaves 99mTc-sulfur colloid
uptake in blood
components and its
effects on 99mTc-
sulfur colloid
biodistribution
In vitro Enteral Increased hepatic
uptake and changes
in radiolabeling
[19]
Sechium edule Skin Effect of 99mTc on
labeling blood
components
In vivo
and
in vitro
Incubating blood
samples
Increased
radiolabeling of
blood components
[20]
Thuya
occidentalis
- Effects of 99mTc on
labeling of red blood
cells and plasma
proteins
In vitro Incubating blood
samples
Decreased labeling
of red blood cells
[21]
Uncaria
tomentosa
Lyophilized
leaves
Effect on the
biodistribution of
sodium pertechnetate
In vitro Enteral Sodium
pertechnetate
uptake is decreased
in the heart,
pancreas, and
muscles
[22]
13. Interactions between radiopharmaceutical products and herbal medicines318
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DNA. Cell death, intracellular reactive oxygen species (ROS), and apoptosis were studied us-
ing trypan blue exclusion assay, dichlorofluorescein diacetate, and DNA fragment ation
assay, respectively. In comparison to the radiation control group, preirradiation administra-
tion of REC-2001 to peritoneal macrophages dramatically reduced radiation-induced ROS
production, DNA damage, apoptosis, and cell death. However, REC-2001 shows cytotoxic
nature by causing cell death, ROS and DNA fragmentation in a dose-dependent manner.
In the presence of copper sulfate, REC-2001 formed hydroxyl radicals and superoxide anions,
demonstrating its ability to behave as a prooxidant. These results indicate that REC-2001’s
ability to act as a prooxidant in the presence of metal ions and as an antioxidant in the pres-
ence of free radicals responsible for its cytotoxic and radioactive properties, and that it may
provide radiation shielding by scavenging radiation-induced free radicals [26].
3. Discussion and conclusion
Drugs labeled with a radioactive moiety that can be utilized for diagnostic and/or thera-
peutic purposes in medicine are known as radiopharmaceuticals. Radioactive signs, on the
other hand, are radionuclide components with an atomic number and radiation-emitting ca-
pabilities that enable radiopharmaceuticals to become radioactive. In nuclear medicine, radio-
labeling is used for diagnostic imaging and targeted radionuclide therapy. Nuclear medicine
makes extensive use of radiopharmaceuticals. Many studies have shown that synthetic or
natural drugs impact the radiolabeling and bioavailability of these widely used products.
This is also true for herbal medicines, and research on herbal medicine-
radiopharmaceutical interactions is sparse. The extensive usage of herbal medicines among
the general public necessitates more research.
Studies have shown that many plants reduce radiolabeling. Plants such as G. biloba, H. per-
foratum, P. guajava, T. occidentalis are some examples of plants reducing radiolabeling. There
are fewer examples that increase the effect of radiopharmaceuticals. It has been concluded
that medicinal plants such as Peumus boldus, Rosmarinus officinalis, Sechium edule, Nectandra
membranacea increase the effect.
Many plants have been identified to alter radiopharmaceutical biodistribution. Plants like
broccoli, C, angustifolia, and R. officinalis, N. membranacea, and U. tomentosa inhibited it. Both
scenarios appear to have unfavorable outcomes. Herbal medications are hypothesized to alter
radiolabeling and biodistribution in a variety of ways, including binding to a protein in the
same location and interrupting the radiolabeling mechanism in the case of blood components.
Inhibition of tin and pertechnetate ions is another method. Because its chelator action is vital
in radiopharmaceutical biodistribution and labeli ng, it has a pharmacokinetic role. Further-
more, the presence of antioxidant and oxidant compounds in herbal medications may cause
the labeling to change. Polyphenols, which have antioxidant properties, are also found in me-
dicinal plants. The antioxidant property can limit the binding of radiopharmaceuticals to
plasma proteins by blocking the activity of tin ions. Another way is to change the transport
system with changes in plasma membrane structure and receptors. Although it is thought
that interaction occurs through such mechanisms, this issue has not been fully clarified.
3. Discussion and conclusion 319
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Some medicinal plants did not affect the radiolabeling and biodistribution because the
radiolabeling process depends on the presence of the reducing agent or chemical component.
There is no interference in the radiolabeling process because there are no pos sibly interfering
components.
Furthermore, while examining the interactions, it was discovered that some plants can be
used to defend against radiation. Broccoli, G. biloba, and P. hexandrum are believed to have
antiinflammatory properties. The antioxidant capabilities of the plants listed are assumed
to be responsible for this impact. They should, however, be used at the proper dose to allow
imaging. More studies are needed to clarify the issue of radiation shielding effects.
All of the research included here have involved animal studies. This makes it unclear
whether the studies can be generalized. As a result, it is also required to conduct these inves-
tigations on volunteers. Animal studies have proven enlightening, despite the fact that gen-
eralizations cannot be established. Radiolabeling and biodistribution changes can have major
effects for patients, particularly when there is an undiscovered relationship. It can result in
needless exposure to radiation, imaging errors, duplicated imaging, or, worst of all, incorrect
treatment.
In evaluating the interactions between radiopharmaceutical products with herbal medi-
cines, both the doctor and the pharmacist play a significant role. Th e potential for interaction
of radiopharmaceuticals with herbal medicines, as well as the potential for interaction of
other drugs used by the patient, should be considered by the nuclear medicine physician
and radiopharmacist. That ’ s why medicinal plants that the patient does not use with the
thought of medicine, considered extremely harmless, and perha ps bought from a place other
than a pharmacy, should also be questioned. For example, food supplements are not
approved by the Ministry of Health, which lead to a lot of inconvenient situations and a
lack of control.
In conclusion, the nuclear medicine doctor and radiopharmacists bear a significant amount
of responsibility for the patient’s proper diagnosis and treatment. The interaction of radio-
pharmaceuticals with herbal medications is a serious concern that may affect the correct diag-
nosis and treatment of the disease. Furthermore, it is critical to increase the number of studies
on herbal medication interactions and to start human trials.
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14
Use of microfluidic organ-on-a-chip
systems for the screening and
development of
phytopharmaceuticals and herbal
drugs
Fahimeh Shahabipour
1, 2
, Abdullah Aldhaher
3
,
Andrea I. Doseff
4
, Seyed Ehsan Alavian
5
,
Ahmed A.M. Elnour
6, 7
and Nureddin Ashammakhi
8
1
Skin Research Center, Shahid Beheshti University of Medical Science, Tehran, Iran;
2
Orthopedic Research Center, Mashhad University of Medical Sciences, Mashhad, Iran;
3
Department of Chemistry, Faculty of Chemistry, Sharif University of Technology, Tehran,
Iran;
4
Department of Physiology and Department of Pharmacology and Toxicology, Michigan
State University, East Lansing, MI, United States;
5
Middle East Liver Diseases (MELD)
Virology Laboratory, MELD Center, Tehran, Iran;
6
Faculty of Chemical and Process
Engineering Technology, University of Malaysia Pahang-UMP, Pekan, Pahang, Malaysia;
7
International Institute for Halal Research and Training, International Islamic University
Malaysia (IIUM), Gombak. Kuala Lumpur, Malaysia;
8
Department of Biomedical Engineering,
College of Engineering, College of Human Medicine and Institute for Quantitative Health
Science and Engineering, Michigan State University, East Lansing, MI, United States
1. Introduction
Natural products (NPs) and their derivatives are the most broadly found metabolites or
byproducts that originate from animals, plants, or microorganisms [1,2]. The large diversity
CHAPTER
323
Phytopharmaceuticals and Herbal Drugs
https://doi.org/10.1016/B978-0-323-99125-4.00013-5 © 2023 Elsevier Inc. All rights reserved.
https://t.me/med1917
in chemical structure and biological activities of NPs has made them a promising source for
pharmaceutical agents used in the prevention and treatment of disease conditions, as anti-
viral [3], antimicrobial [4], antioxidant [5], anticancer [6,7], antiinflammatory, and immuno-
regulatory agents [8,9].
Plant-derived NPs or phytochemicals have historically been used in different cultures to
ameliorate pathological conditions [10], such as infections and pain. Additionally, phyto-
chemicals are used as dietary supplements, or as antiinflammatory and anticarcinogenic com-
pounds [11]. Plant extracts were used as concoctions, which were composed of a mixture of
different bioactive ingredients. The bioactivity of NPs stem from their receptor-binding activ-
ities, and finding these interactive receptors is considered an important issue; while some of
the components do not have therapeutic activity, their synergistic effects are important
[12,13].
Recently, the World Health Organization (WHO) reported that almost 60% of the world
population relies on traditional medicine, and the Chinese are pioneers in the use of NPs
to treat disease conditions in which the Shen Nung Pen ’Ts’ao predated the oldest Chinese
herbs, which mentioned 1898 herbal drugs and described about 8160 [14e17]. In the United
States, NP application has a long history, though not as long as the Chinese [18]. Although
the application of traditional remedies is very limited compared to modern medications,
they are considered as a source for the development of potential drugs [19].
Since 1980, w51% of new drugs that have been derived from NPs comprise 65% of anti-
bacterial and 73% of all anticancer compounds [20]. In fact, nearly 80% of all drugs with anti-
microbial, cardiovascular, immunosuppressive, and anticancer activities are derived from
NPs or derivatives [21]. The global market of these drugs accounted for US$ 65 billion in
2003 [22]. In spite of the success in the application of NPs in the past, many pharmaceutical
companies have reduced the use of NPs in drug discovery screening due to some defects in
NP application such as complexities of NP chemistry, difficulties in access and supply, and
slow process in working with NPs [23]. Hence, only a few herbal drugs have been docu-
mented in drug discovery programs due to the complexity of herbal plant extractions. This
is in part due to the com plex composition of herbal mixtures and the lack of enough under-
standing of the compounds present in NPs. Additionally, methodologies to simplify
screening for the active compounds responsible for the beneficial health effects remain labo-
rious and expensive [24].
Several technologies are currently used for monitoring NPs nutraceuticals, such as tar-
geted purification, drug discovery, molecular tracking, food science, and biomechanics
[25]. The gold standard in the last two decades for drug discovery has been relying on the
use of macroscopic systems. These systems incorporate automatic analysis and robotics to
provide high-throughput screening (HTS) methods. However, these methods suffer from
some limitations, including cost, processing time, and the need to use expensive equipment
[26]. Thus, the development of microfluidic devices will potentially contribute to overcome
these limitations in future.
Microfluidic devices provide unique systems to perform potentially high-throughput ex-
periments with minimal reagent consumption and attain fast reaction times [
27e30]. More-
over, microfluidic devices have small microchannels, thus facilitating the study of a small
14. Use of microfluidic organ-on-a-chip systems for the screening and development of phytopharmaceuticals and herbal drugs324
https://t.me/med1917
number of cells. Therefore, microfluidic devices enable rapid detection of early drug cytotox-
icity, e.g., on cancer cells before commencing treatment [31]. This chapter focuses on the
importance and applications of microfluidic devices such as organ-on-a-chip (OoC) [32]
and biochip for phytopharmaceuticals and herbal drug discovery.
2. Phytochemica ls and herbal phytopharmaceuticals
The application of herbs as medicines, dietary products, and nutritional supplements has a
long tradition in different cultures. The action of herbal medicines, also referred to as “phy-
totherapeutic” has show n health beneficial effects, yet lack of understanding of their molec-
ular mechanisms has also triggered some skepticism [24,33]. Phytotherapeutics are originated
from plants and are also well known as secondary metabolites or phytochemicals. Secondary
metabolites, which are produced from biosynthetic intermediates of the basic cellular process,
including glycolysis, Krebs cycle, and photosynthesis, were exposed to different modifica-
tions, such as alkylation, aldol, decarboxylation, Claisen, and Schiff base formation to pro-
duce an unlimited number of secondary metabolites [34]. Unlike primary metabolites,
secondary products are not required for plant growth but play essential functions such as de-
fense against pathogens and ultraviolet (UV) light [33,35,36]. Phytochemicals have attracted
increasing attention for various therapeutic purposes due to their chemical diversity and
consequent biological activities [37]. Hence, herbal phytopharmaceuticals are extensively
used in the pharmaceutical market due to their less harmful side effects and lower cost as
compared to synthetic drug analogs [38]. They cover a range of therapeutic applications,
such as their use as anticancer, antidiabetic, antiinflammatory, antioxidant, and antimicrobial
agents [39]. Perhaps among the best known anticancer drugs is Taxol, which is derived from
Taxus brevifolia, vinblastine, which is derived from Catharanthus roseus, and antimalarial drugs
such as quinine, which are derived from Cinchona spp, and Artemisinin, which are derived
from Artemisia annua [10,40]. Tapping into the wide diversity provided by NPs is paramount
to obtain additional active compounds with health beneficial activities [41].
2.1 Bioactive nutraceuticals
Natural plant products have been used for thousands of years as drugs in folk medicine
without knowing the bioactive compounds they contain [42]. In addition, plant extracts
contain polar compounds such as fatty acids [43] and polar molecules such as polyphenols,
flavonoids [44,45], and chlorophyll [46]. Currently, tea polyphenols are considered an effec-
tive treatment of genital warts, and they are still under clinical trial for the prevention of
various cancers [47,48].
Phytochemicals are used either as a part of the diet rituals or as pharmaceutical products.
They are found in all parts of the plants, and their activities may change based on whether
they are cooked, soaked or eaten fresh, providing additional opportunities to increase the
chemical repertoire [47]. In most cases, herbal medicines were used as concentrated plants
extracts or concoctions without isolating their active components [10]. Great efforts have
2. Phytochemicals and herbal phytopharmaceuticals 325
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been invested in pinpointing the active ingredients responsible for the beneficial health effects
of traditional medicine, emphasizing that the activity of natural products can rely on a rela-
tively small number of compounds or with a single component [49].
Thus, knowledge about the therapeutic activity of natural products, which has been ob-
tained from the folkloristic application, provided the basis for the discovery of NP-based
drugs [47]. Since the active components of natural products are still not completely defined,
the accessibility of the starting substance and collection of the plants for the NP-based drug
discovery process remains challenging [50]. A key obstacle is that most NPs are often avail-
able in small amounts, which need to be used to determine a wide range of biological
activities [47,51].
The disadvantages of using traditional methods such as chromatographic techniques lie in
that large amounts of natural products are required to achieve efficient screening [41]. There-
fore, the use of new technologies such as the OoC, which requires only small amounts of sam-
ple volumes, is well suited for this purpose.
3. Organ-on-a-chip systems
NPs continue as a source of novel drugs that require analyzing their single components by
different analysis methods such as high-performance liquid chromatography (HPLC), HPLC-
mass spectrometry (HPLC-MS), HPLC-nuclear magnetic resonance (HPLC-NMR), chemical
methods, and fingerprints are limited due to the lack of appropriate detectors thus making
it difficult to determine all components and formulae. Therefore, the use of microfluidic de-
vices provides a potential alternative approach to identify the bioactive compounds present
in NP preparations, giving an unprecedented opportunity to decode the unknown treasures
of traditional herbal medicine [52].
OoC constitutes a new class of microfluidic devices that enable us to recapitulate the
in vivo physiological con ditions at a microscale level [53]. Additionally, OoC devices are
cost-effective, portable, and require only a minimal amount of reagents [54]. OoC consists
of microchannels, cells, and sensors [55]. Together, the properties of OoCs make them an
ideal platform for rapid screening and testing of unique or synergistic biological properties
of constituents of plant extracts [32,53].
3.1 Screening and extraction of herbal drug nutraceutical components
Gramowski et al. designed multielectrode neurochips containing a central recording ma-
trix with indium tin oxide conductors and 64 electrodes. This electrode array neurochip is
a confined adhesive region and is activated by a short pulse from a butane flame through
a stainless-steel mask to ensure the attachment of cells. This neurochip was successfully
used to screen the physiological activities of antidepressant components of Neurapas. The
herbal antidepressant Neurapas is composed of three herbal extracts derived from Passiflora,
Valeriana, and Hypericum that function by blocking gamma-aminobutyric acid [32] and se-
rotonin (5-HT) receptors, which are well-known targets for antidepressant agents [32].
14. Use of microfluidic organ-on-a-chip systems for the screening and development of phytopharmaceuticals and herbal drugs326
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Besides the screening of natural components, the extraction of bioactive compounds from
plants is an essential procedure. Unlike the conventional Liquid-Liquid Extraction [56] tech-
niques that require large amounts of solvent and the usage of toxic extractants, a microfluidic
device using microchannels can be applied for the extraction of components by decreasing
the volume of solvent and the time process [32,57,58]. Heydarid et al. optimized the oleuro-
pein extraction into an aqueous phase using a microfluidic device. Compared to conventional
techniques such as batch process, microfluidic method showed higher yield. Moreover,
maximum yield of extraction was obtained by optimizing parameters such as flow rate ratio
to 0.16, resi dence time to 0.1010 min, and temperature to 40
C[59].
3.2 Screening of cytotoxicity of herbal phytopharmaceutical drugs
Identification of the exact toxin in highly toxic substances is a critical issue to ensure that
the correct dose of drugs for different pharmaceutical purposes is used. In essence, to eval-
uate toxicity, systematic screening of component effects in a concentration-dependent way
is required [58,60]. Although analytical methods for identifying and screening NPs have
been used, there are limitations in using these methods due in part to the intrinsic complexity
of NP components, scarcity of plant sources, and purification [50]. Therefore, microfluidic
single-cell analysis approaches can be an attractive option to study the cytotoxicity of drugs
[61]. The combination of microfluidics with nanosensors, for instance, enabled quick detec-
tion and quantification of the bacterial botulinum neurotoxin A (BoNT/A). In this context,
Weingart et al. developed a new microfluidics-based strategy that contained cell-mimicking
nanoreactors (NMN), which allowed rapid detection of BoNT/A by measu ring fluorescence
intensity related to the presence of active toxic molecules in the solution (Fig. 14.1). The de-
vice was fabricated by using microcontact printing to deposit biotinylated bovine serum al-
bumin onto the glass of the device in a stripe fashion [60]. In another study, Min Ju et al. [58]
developed a microfluidic high-throughput cytotoxicity testing device (mHTCD) to evaluate
acetaminophen cytotoxicity (APAP) using linear-gradient concentrations. The mHTCD was
composed of an array of eight separate microchambers for seeding liver HepG2 cells that
were subsequently exposed to eight different concentration gradients of APAP. The concen-
tration gradients were created by using a diffusive-mixing gradient generator [58](Fig. 14.1).
3.3 Single cellebased microfluidic biochip
There is an increasing demand for the rapid detection of drug candidate cytotoxicity
derived from various sources, including herbal compounds. A m uscle chip (Li et al.) with
a cell retention chamber was developed to compose a weir structure to study cardiomyocytes
[62]. A weir structure was built based on 1-photomask microfabrication and on-chip etching
step for the study of cardiomyocytes compared to a 2-mask photolithography process in the
conventional method and provide better cell retention for the cardiomyocyte study
(Fig. 14.2). By using this device, the dynamic intracellular calcium mobilization ([Ca
2þ
]i) of
individual cardiomyocytes during exposure to various drugs such as the anticancer drug
candidate, isoliquiritigenin [44], and the chemotherapeutic drug-daunorubicin, were quanti-
fied. Among various drug exposures, isoliquiritigenin (IQ) displayed a less undesirable effect
on the [Ca
2þ
]i of the cardiomyocytes, indicating that the IQ is safer for the cardiovascular
3. Organ-on-a-chip systems 327
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