Hindawi
Evidence-Based Complementary and Alternative Medicine
Volume 2022, Article ID 4024331, 30 pages
https://doi.org/10.1155/2022/4024331
Review Article
Urtica dioica-Derived Phytochemicals for Pharmacological and
Therapeutic Applications
Yasaman Taheri ,1 Cristina Quispe,2 Jesús Herrera-Bravo ,3,4 Javad Sharifi-Rad ,1,5
Shahira M. Ezzat ,6,7 Rana M. Merghany,8 Shabnum Shaheen,9 Lubna Azmi,10
Abhay Prakash Mishra ,11 Bilge Sener,12 Mehtap Kılıç,13 Surjit Sen,14,15
Krishnendu Acharya,14 Azadeh Nasiri,16 Natália Cruz-Martins ,17,18,19,20
Patrick Valere Tsouh Fokou ,21 Alibek Ydyrys,22 Zhandos Bassygarayev,23
Sevgi Durna Daştan,24,25 Mohammed M. Alshehri ,26 Daniela Calina ,27
and William C. Cho 28
1
Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Facultad de Ciencias de la Salud, Universidad Arturo Prat, Avda. Arturo Prat 2120, Iquique 1110939, Chile
3
Departamento de Ciencias Básicas, Facultad de Ciencias, Universidad Santo Tomas, Chile
4
Center of Molecular Biology and Pharmacogenetics, Scientific and Technological Bioresource Nucleus,
Universidad de La Frontera, Temuco, 4811230, Chile
5
Facultad de Medicina, Universidad del Azuay, Cuenca, Ecuador
6
Department of Pharmacognosy, Faculty of Pharmacy, Cairo University, Kasr El Ainy Street, Cairo 11562, Egypt
7
Department of Pharmacognosy, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA),
6th of October 12451, Egypt
8
Department of Pharmacognosy, National Research Centre, Giza, Egypt
9
Department of Plant Sciences, LCWU, Lahore 54000, Pakistan
10
Hygia Institute of Pharmaceutical Education & Research, Lucknow, U. P. 226001, India
11
Department of Pharmacology, University of Free State, Bloemfontein 9300, Free State, South Africa
12
Gazi University, Faculty of Pharmacy, Department of Pharmacognosy, Ankara 06330, Turkey
13
Department of Pharmacognosy, Lokman Hekim University Faculty of Pharmacy, Ankara 06510, Turkey
14
Molecular and Applied Mycology and Plant Pathology Laboratory, Department of Botany, University of Calcutta,
Kolkata 700019, India
15
Department of Botany, Fakir Chand College, Diamond Harbour, West Bengal 743331, India
16
Department of Pharmacology and Toxicology, School of Pharmacy, Shahid Beheshti University
of Medical Sciences, Tehran, Iran
17
Faculty of Medicine, University of Porto, Porto, Portugal
18
Institute for Research and Innovation in Health (i3S), University of Porto, Porto, Portugal
19
Institute of Research and Advanced Training in Health Sciences and Technologies (CESPU), Rua Central de Gandra, 1317,
Gandra PRD 4585-116, Portugal
20
TOXRUN-oxicology Research Unit, University Institute of Health Sciences, CESPU, CRL, Gandra 4585-116, Portugal
21
Department of Biochemistry, Faculty of Science, University of Bamenda, Bambili, P.O. Box. 39, Cameroon
22
Biomedical Research Centre, Al-Farabi Kazakh National University, Al-Farabi av. 71, Almaty 050040, Kazakhstan
23
Department of Biophysics, Biomedicine and Neuroscience, Al-Farabi Kazakh National University, Al-Farabi av. 71,
Almaty 050040, Kazakhstan
24
Department of Biology, Faculty of Science, Sivas Cumhuriyet University, Sivas 58140, Turkey
25
Beekeeping Development Application and Research Center, Sivas Cumhuriyet University, Sivas 58140, Turkey
26
Pharmaceutical Care Department, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
27
Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, Craiova 200349, Romania
28
Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong
2
Correspondence should be addressed to Javad Sharifi-Rad; javad.sharifirad@gmail.com, Shahira M. Ezzat; shahira.ezzat@
pharma.cu.edu.eg, and Patrick Valere Tsouh Fokou; ptsouh@gmail.com
2
Evidence-Based Complementary and Alternative Medicine
Received 12 October 2021; Accepted 7 January 2022; Published 24 February 2022
Academic Editor: Lu sa Mota da Silva
Copyright © 2022 Yasaman Taheri et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
Urtica dioica belongs to the Urticaceae family and is found in many countries around the world. This plant contains a broad range of
phytochemicals, such as phenolic compounds, sterols, fatty acids, alkaloids, terpenoids, flavonoids, and lignans, that have been widely
reported for their excellent pharmacological activities, including antiviral, antimicrobial, antihelmintic, anticancer, nephroprotective,
hepatoprotective, cardioprotective, antiarthritis, antidiabetic, antiendometriosis, antioxidant, anti-inflammatory, and antiaging
effects. In this regard, this review highlights fresh insight into the medicinal use, chemical composition, pharmacological properties,
and safety profile of U. dioica to guide future works to thoroughly estimate their clinical value.
1. Introduction
Genus Urtica, commonly known as “nettle,” is a medicinal
plant belonging to the family Urticaceae with multiple health
benefits that have been used medicinally since at least the
times of Ancient Greece [1]. Several Urtica species have been
widely used to treat rheumatism and sciatica, asthma, coughs,
dandruff, diabetes, diarrhea, eczema, fever, gout, hemorrhoids, nose bleeds, scurvy, snake bites, and tuberculosis [2].
Moreover, Urtica species have been used most commonly as a
diuretic and for treating gout, anemia, and prostate hypertrophy, with several studies progressively reporting their
traditional medicinal use by local people [2–11].
These studies originated mostly from African, European,
Asian, and Oceanian countries, such as Algeria, Argentina,
Australia, Bolivia, Bhutan, Brazil, Bolivia, Belarus, Bolivia,
Canada, Chile, China, Colombia, Cyprus, Costa Rica, Cuba,
Ecuador, Egypt, France, Guatemala, India, Italy, Israel, Japan, Korea, Mexico, Nepal, New Zealand, Netherlands,
North America, Palestine, Paraguay, Peru, Russia, Sikkim,
Sweden, Spain, Taiwan, Turkey, Tunisia, United States,
Uruguay, Ukraine, and Vietnam [2–11].
Data obtained from these studies mostly underlined that
Urtica species exert excellent antirheumatoid arthritis,
antigout, anti-inflammatory, immunomodulatory, and antioxidant activities, all of which contribute to the protection of
joints. In addition, it has been revealed to be extremely useful
for the treatment of microbial and parasitic infections, cancer,
jaundice, stomach diseases, snakebites, diabetes, liver and
kidney problems, wounds, diuretic, libido, pulmonary diseases, hypotensive, blood purification, urticaria, allergic rhinitis, prostate disorders, hemorrhoids, and galactagogue and
as a depurative. Apart from this, these species have also been
reported to be used for exorcism, postcalving care, sprains,
bones fracture, hematuria, neck sore, and yolk sore [2, 12–26].
Despite the scientific advances that have allowed us to
understand the crucial contribution of the active molecules
present in this plant for their biological and therapeutic
potentialities, the relevance of this knowledge goes beyond
chemical features, as it is necessary to understand that due to
the increased daily living standards of rural populations,
decisions regarding the sustainable use of plant resources have
been even more underlined [27, 28]. In this sense, this review
aims to provide an overview of the botanical features,
chemical composition, and biological effects of Urtica species
towards well-being promotion and disease prevention.
2. Botanical Features and
Geographical Location
Urtica species is a nitrophilous plant that can grow up to 12 m in height depending on edaphic conditions. Despite
growing well in areas with high water availability [29–31], the
plant can spread widely with its stoloniferous rhizomes [32].
Leaves are simple, dark green, stipulate, opposite, serrated, oblong, or ovate with cordate base [33, 34]. Both leaves
surfaces are coated with stinging hairs; except in the European variety (Urtica galeopsifolia), the stinging hairs are
absent [35]. Stem is green, erect, hollow to solid, fibrous and
tough, indumentum of many stinging hairs and trichomes.
Flowers are small, reddish-brown to greenish-white in
colour, mostly dioecious occurring as racemes in the axial of
the upper leaves; staminate flowers with 4-5 long tepals,
stamens 4, exserted, filaments flat; pistillate flowers with 4
short tepals, sparsely pubescent, esetulose, ovary superior,
ovoid, 1-celled [1, 32, 34].
Urtica species present a subcosmopolitan distribution,
being found around the globe, except in Antarctica and some
tropical regions [36, 37]. The plant is commonly found as a
weed, mainly in moist and shady places and often in anthropogenic habitats. The genus comprises 46 species, being
the most important Urtica dioica (stinging nettle) and Urtica
urens (small nettle), which are native to Europe, Africa, Asia,
North America, and naturalized in other temperate parts of
the world (Table 1) [2, 5].
The widely distributed weedy species, U. dioica, is considered an ecological keystone species and, thus, it is significantly important for the biodiversity in the ecosystem
[38–42]. Island endemics are very common within this genus
and the species include U. dioica subsp. cypria on Cyprus
island, Urtica atrovirens on Corsica and Sardinia, Urtica
rupestris on Sicily, Urtica stachyoides on the Canary Islands,
Urtica portosanctana on Madeira, Urtica bianorii on Mallorca, Urtica domingensis on Hispaniola, Urtica glomerulaeflora on Juan Fernández Islands, Urtica grandidentata on
Indonesia, Urtica taiwaniana on Taiwan, Urtica papuana on
Evidence-Based Complementary and Alternative Medicine
3
Table 1: Geographical distribution, traditional uses, and pharmacology of Urtica species.
No.
1
2
Species
Urtica andicola Wedd.
Urtica angustifolia
Fisch. ex Hornem.
Geographical
distribution
Turkey
China, Japan, Korea,
Mongolia, Siberia
3
Urtica ardens Link
Bhutan, India, Nepal,
Sikkim
4
Urtica aspera Petrie
New Zealand
5
6
7
8
Urtica atrichocaulis
(Hand.-Mazz.) C.J.
Chen
Urtica atrovirens Req.
ex Loisel
Urtica australis
Hook.f.
Urtica ballotifolia
Wedd.
China, Japan, Korea,
Himalayas, Pakistan
France, Italy, Spain
New Zealand
Colombia, Ecuador
Chile, Bolivia,
Argentina, Colombia
Chile, Argentina
Russia, Sweden,
Netherlands, China,
Western Asia from
Siberia to Iran
Traditional uses
Pharmacological activities
Skin rashes, arthritis, fungal infections
—
None known
Antifatigue
Exorcism, jaundice, postcalving care,
sprains, bones fracture, hematuria, neck
sore, yolk sore
Stomach diseases, snakebites,
inflammation, rheumatoid arthritis,
hyperplasia, fungal infections
Rheumatoid arthritis, inflammatory,
antioxidant, immune-modulatory
Antihyperglycemic, antioxidant, hepatic
protective, antiviral, arthritis
Skin diseases, diabetes, eczema, fungal
infections, arthritis
—
—
—
—
—
—
—
—
—
—
—
—
Anti-inflammatory
9
Urtica berteroana Phil
10
Urtica buchtienii Ross
11
Urtica cannabina L.
12
Urtica chamaedryoides
Pursh
United States, Mexico
—
—
13
Urtica circularis Sorarú
Brazil, Argentina,
Paraguay, Uruguay
—
Antioxidant, anti-inflammatory
14
Urtica deltoidea Sw.
New Zealand
15
Urtica dentate Hand.Mazz
North America
16
Urtica dioica L.
United States, New
Zealand, Turkey,
Europe, Asia, North
America
17
Urtica echinata Benth
Bolivia, Peru,
Argentina, Ecuador
—
—
18
Urtica ferox Blanco
New Zealand, Australia
Skin problems, hyperglycemic, antiviral,
diuretic, hypotensive, antiaggregate
—
19
20
21
22
23
24
25
26
Arthritis, inflammation, antiulcer,
—
anticancer, antimicrobial activities
Kidney problems, rheumatoid arthritis,
Antiarthritis, antiurolithiatic
kidney calculi
Injuries to reduce swelling, diuretic, flu, Antiviral, antimicrobial, antioxidant,
diabetes disease, losing weight, cold, anti-inflammatory antiaging, cytotoxic/
anticancer Effect on benign prostatic
cancers, anemic conditions, libido,
hyperplasia, antidiabetic,
induce menstruation, stomach- ache,
antiendometriosis, nephroprotective
renal and pulmonary diseases
China, Taiwan, Egypt,
Rheumatoid arthritis
Vietnam
Bolivia, Peru, Ecuador,
Urtica flabellata Kunth
Chile, Colombia,
Skin rashes, arthritis, fungal infections
Turkey
Renal ailments, asthma, anemia, blood
Urtica galeopsifolia
Russia, Ukraine, Belarus
purification
J. Jacq. ex Blume
Urtica gracilenta
Kidney diseases, diabetes, fungal
Greene
infections
Urtica glomeruliflora
Chile
Steud.
Urtica haussknechtii
Turkey
Boiss.
Urtica hyperborea Jacq.
Nepal, India, China
Skin rashes, arthritis, fungal infections
exWedd.
Urtica incana Blume
Peru
Skin rashes, arthritis, fungal infections
Urtica fissa E. Pritz
—
—
—
—
—
—
Antioxidant
—
4
Evidence-Based Complementary and Alternative Medicine
Table 1: Continued.
No.
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
Species
Geographical
distribution
Traditional uses
Urtica kioviensis
Europe, Israel, Russia
Arthritis, hepatic protective, antiviral
Rogow.
Urtica lalibertadensis
Peru
Skin rashes, arthritis, fungal infections
Weigend
Urtica laetevirens
China, Japan, Korea
Maxim.
Urtica leptophylla
Costa Rica, Colombia,
Skin rashes, arthritis, fungal infections
Kunth
Peru, Bolivia, Ecuador
Urtica lilloi (Hauman)
Argentina
Geltman
Ecuador, Peru,
Cough, eczema, gout, urticaria, allergic
Urtica longispica Killip
Colombia
rhinitis, rheumatoid arthritis
Urtica macbridei Killip
Ecuador, Peru
Urtica magellanica
Chile, Peru, Bolivia,
Allergy, arthritis
Juss. ex Poir.
Argentina, Ecuador
Kidney pain. Its extract and paste kidney
China, India, Bhutan,
diseases, diabetes, fungal infections,
Urtica mairei H. Lév.
Himalaya, Myanmar
inflammation, arthritis
Urtica masafuerae
Chile
Phil.
Skin rashes, malaria, eczema, skin
Urtica massaica
Africa
rashes, dermatitis, diuretic
Mildbr.
Urtica membranacea
Israeli, Europe, Algeria
—
Poir. ex Savigny
Urtica mexicana Liebm
Mexico, Guatemala
—
Urtica mollis Steud.
Peru, Chile, Argentina
—
Urtica morifolia Poir.
Europe
—
Mexico, United States,
—
Urtica orizabae Liebm.
Cuba
Nepal, India, United
Arthritis, tumor, astringent, diuretic,
Urtica parviflora Roxb. States, Western China,
inflammatory
Bhutan, Himalaya
Skin and prostate disorders, rheumatoid
arthritis, diabetes, skin treatment,
inflammation, arthritis, internal
bleeding, anemia, excessive
menstruation, hemorrhoids,
Tunisia, Israel, Cyprus,
rheumatism, hay fever, kidney
Urtica pilulifera L.
Costa Rica, Turkey,
problems, pain, skin problems,
Palestine
abdominal pain, internal diseases,
antiasthmatic, antitumor, astringent,
diuretic, galactagogue, depurative,
antihyperglycemic, antidandruff
Urtica platyphylla
Japan, Russia
—
Wedd.
Urtica praetermissa
Mexico
—
V.W. Steinm.
Urtica pubescens
Mexico
—
Ledeb.
Urtica rupestris Guss.
Italy
—
Urtica sondenii
(Simmons) Avrorin ex
Canada
—
Geltman
Urtica spiralis Blume
Mexico
—
Urtica
stachyoidesWebb &
Spain, Mexico
—
Benth.
Urtica taiwaniana S.S.
Taiwan
—
Ying
Pharmacological activities
—
—
Anticancer
—
—
—
—
—
Antiprotatic hyperplasia
—
—
Antioxidant, anti-inflammatory
—
—
—
—
Nephroprotective, antidiabetic,
antioxidant
Antidiabetic
—
—
—
—
—
—
—
—
Evidence-Based Complementary and Alternative Medicine
5
Table 1: Continued.
No.
53
54
55
56
Species
Urtica thunbergiana
Siebold & Zucc.
Urtica triangularis
Hand.-Mazz.
Urtica trichantha
(Wedd.) Acevedo &
Navas
Urtica urens L.
Geographical
distribution
Traditional uses
Pharmacological activities
Japan, Korea, China
—
Antiaging
China
—
—
Chile, Bolivia, Peru,
Japan, China
—
—
Unite States, Mexico,
Europe, Israel, New
Zealand
Blood depurative, antihypoglycemic,
antioxidant, hepatic protective, antiviral,
diuretic, hypotensive, antiaggregate,
kidney problems
Antioxidant, anti-inflammatory
Papua New Guinea, and Urtica perconfusa on New Zealand.
This indicates that island colonization within the genus is a
unique feature amongst the flowering plants [3, 4].
3. Phytoconstituents
Phytochemicals are plant metabolites produced in response
to any infectious attack or as a byproduct of any metabolic
pathway, despite exerting beneficial effects in many ways
[43, 44]. The active chemical part of nettle includes nearly
fifty compounds of the lipophilic and hydrophilic fractions
and whose chemical structure is known. Globally, few Urtica
species have been screened for their phytochemical composition, with those available so far reporting the presence of
sterols, triterpenes, coumarins, phenols, lignans, ceramides,
and fatty acids, amongst other minor compounds, all with a
distribution varying in the various organs of the plant
(Tables 2–11).
Beta-sitosterol, transferulic acid, dotriacontane, erucic
acid, ursolic acid, scopoletin, rutin, quercetin, and phydroxylbenzalcohol are some of the constituents found in
Urtica species that may be applied for preventive or therapeutic purposes in communicable and noncommunicable
diseases [16, 45–59]. The liquid contained in the hairs of a
nettle causes it to sting, being composed of formic acid and
leukotrienes in modest amounts, 1% acetylcholine, 1 in 500
to 1 in 2000 histamine, and 5-hydroxy-tryptamine
(serotonin).
Essential ketones (38.5%), esters (14.7%), free alcohols
(2%), nitrogenous compounds, phenols, aldehydes, p-sitosterol, formic acid and acetic acid, chlorophyll and phytol,
vitamins, and carotenoids are also found in the aerial sections. Many organic acids were also identified in the aerial
parts, including caffeic, ferulic, caffeylmalic, chlorogenic,
and sinapic acids, according to chromatographic
examination.
Flavonoids: isorhamnetol 3-O-glucoside, quercetol 3-Oglucoside, kaempferol 3-O-glucoside, isorhamnetol 3-Orutinoside, and quercetol 3-O-rutinoside were extracted and
identified in flowers, in addition to p-sitosterol, p-sitosterol
glucoside, and scopoletol, which are found in all sections of
the plant. The roots contained many molecules belonging to
different chemical families, including polysaccharides: glycans, glucogalacturonans, arabinogalactan acid, fatty acid:
(10E, 12Z)-9-hydroxy-10, 12-octadecadienoic acid, lectins,
ceramides, terpenes diols, and terpenes diols glucosides [60].
Amongst Urtica species, Urtica pilulifera and U. dioica
essential oil compositions have been investigated and consist
mainly of hexahydrofarnesyl acetone, 1,8-cineole, α -ionone,
β-ionone, farnesylacetone, methylbenzene, (−)-limonene, 3carene, (+)-limonene, gamma-terpinene, vanillin, butyl
acetate, 1, 2-benzenedicarboxylic acid, and 7-acetyl-6-ethyl1, 1, 4, 4-tetramethyltetralin (Table 12) [61, 62]. Overall,
considerably less attention has been paid to the phytochemistry of bioactive compounds in these plants.
4. Pharmacological Activities of the
Genus Urtica
Except for U. dioica, which has extensively been studied for
various pharmacological properties, few Urtica species have
been investigated for their biological activity, including
U. angustifolia, U. laetivirens, U. parviflora, U. dentata,
U. pilulifera, U. mairei, U. membranacea, U. urens,
U. circularis, U. hyperborean, U. cannabina, and
U. thunbergiana that mostly displayed anti-inflammatory
and antioxidant activities (Tables 1–13), and for antiviral,
antimicrobial, antihelmintic, anticancer, nephroprotective,
hepatoprotective, cardioprotective, antiarthritis, antidiabetic, antiendometriosis, and antiaging purposes (Figure 1)
4.1. In Vitro Pharmacological Findings
4.1.1. Antiviral Activity. Antiviral treatment is limited to
severe cases of most viral infections, stressing the need for
more effective therapy. The aqueous extract of U. dioica fresh
bark showed an antiviral effect against Petaluma virus (FIVPet) that infected Crandell feline kidney cell line (CrFK) by
significantly inhibiting viral replication through reducing
syncytia formation at low doses (0.5–1 g/ml) in a dose-dependent manner [73].
U. dioica extract (0.5–1 g/ml) and derived N-acetyl
glucosamine-specific lectin (the 50% effective concentration
(EC50) for HIV ranged from 0.3 to 9 mg/ml) also revealed to
be able to inhibit syncytium synthesis between CD4+
MOLT/4 cells and HUT-78 cells when infected by HIV-1
and HIV-2 (Uncini Manganelli, Zaccaro & Tomei, 2005).
6
Table 2: Lignans extracted from Urtica.
Sr. no.
Compound name
Structural
OH
O
1.
Cycloolivil; 9′-O-b-d-Glucopyranoside
HO
OH
O
OHOH
OH
HO
OH
HO
O
2.
4-[Bis(3, 4-dihydroxyphenyl)
methyl]dihydro-3-(hydroxymethyl)-2(3H)-furanone;
(8R∗ , 8′R∗ )-form,3′,
4-Di-Me ether, 7-O-b-D-glucopyranoside
O
O
HO
O
O
OH
OH
O
HO
O
3.
4-[Bis(3, 4-dihydroxyphenyl)
methyl]dihydro-3-(hydroxymethyl)-2(3H)-furanone;
(8R∗ , 8′R∗ )-form,3′,
4-Di-Me ether,
4′-O-b-D-glucopyranoside
O
O
O
O
OH
HO
OH
HO
Evidence-Based Complementary and Alternative Medicine
O
Sr. no.
Compound name
Structural
OH
O
HO
4.
O
4-[Bis(3, 4-dihydroxyphenyl)
methyl]dihydro-3-(hydroxymethyl)-2(3H)-furanone;
(8R∗ , 8′R∗ )-form,3′, 4-Di-Me ether
O
O
OH
HO
O
O
5.
O
Neoolivil
OH
OH
OH
OH
HO
6.
3, 3′, 4, 4′, 8′, 9-Hexahydroxy-7,
9′-epoxylignan;
(7S,8R, 8′S)-form, 3,
3′-Di-Me ether,
9-O-β-D-glucopyranoside
Evidence-Based Complementary and Alternative Medicine
Table 2: Continued.
O
HO
O
HO
O
HO
OH
O
HO
O
O
HO
7.
3, 3′, 4, 4′, 8′, 9-Hexahydroxy-7, 9′-epoxylignan;
(7S,8R,8′S)-form, 3, 3′, 4-Tri-Me ether, 8′-Ac
O
O
OH
O
O
O
7
8
Table 2: Continued.
Sr. no.
Compound name
Structural
O
O
8.
3, 3′,
4, 4′, 8′,
9-Hexahydroxy-7, 9′-epoxylignan;
(7S,8R,8′S)-form,
3, 3′, 4-Tri-Me
ether, 8′-Ac,
4′-O-[aarabinopyranosyl-(1 ⟶ 6)-bd-glucopyranoside]
O
HO
O
OH
O
O
O
HO
OH
O
OH
O
HO
O
HO
HO
O
O
9.
O
O
Neoolivil; 9-Ac,
4-O-b-D-glucopyranoside
O
O
OH
HO
HO
O
O
10.
O
O
Neoolivil;
4-O-b-D-glucopyranoside
O
OH
OH
HO
OH
HO
OH
HO
O
O
11.
O
O
Neoolivil; 9, 9′-Di-Ac,
4-O-b-D-glucopyranoside
OH
O
O
O
HO
O
O
HO
OH
Evidence-Based Complementary and Alternative Medicine
OH
OH
HO
O
Sr. no.
Compound name
Structural
HO
O
OH
O
O
O
12.
Pinoresinol; (+)-form,
4-O-[a-L-rhamnopyranosyl-(1
⟶ 2)-b-d-glucopyranoside]
OH
O
OH
HO
O
O
O
HO
OH
13.
Secoisolariciresinol
OH
O
Evidence-Based Complementary and Alternative Medicine
Table 2: Continued.
O
HO
HO
OH
O
14.
Isolariciresinol
HO
OH
OH
O
O
HO
O
O
15.
Urticene; (−)-form
O
OH
9
10
Table 2: Continued.
Sr. no.
Compound name
Structural
OH
O
O
HO
16.
O
OH
O
Neoolivil; 9-O-b-d-Glucopyranoside
HO
OH
O
OH
O
O
O
O
17.
Dehydrodiconiferyl alcohol
OH
HO
HO
18.
Olivil
O
HO
OH
HO
O
O
HO
O
19.
3,4-Divanillyltetrahydrofuran
OH
O
O
Evidence-Based Complementary and Alternative Medicine
OH
Evidence-Based Complementary and Alternative Medicine
11
Table 3: Sterols extracted from Urtica.
Sr.
no.
Compound name
Structural formula
OH
HO
1.
OH
O
Stigmastane-3, 6-diol; (3β, 24R)-form, O-[b-d-Glucopyranosyl-(1 ⟶ 4)-al- HO
arabinopyranoside]
O
O
O
HO
OH
2.
Stigmastane-3, 6-diol; (3b, 7a, 24R)-form, 3-O-b-d-Glucopyranoside
OH
OH
O
O
HO
OH
3.
OH
Stigmastane-3, 6-diol; (3b, a6a, 24R)-form
HO
OH
4.
Daucosterol
OH
HO
HO
OH
O
O
O
OH
5.
CH4
Ethyl iso-allocholate
HO
6.
O
OH
Cholesterol
HO
Also, the N-acetyl glucosamine-specific lectin from Urtica
dioica was inhibitory to cytomegalovirus (CMV), respiratory
syncytial virus (RSV), and influenza A virus-induced cytopathic at an EC50 ranging from 0.3 to 9 mg/ml [74].
Another study showed that U. dioica agglutinin (UDA)
suppressed the SARS-CoV virus replication by 90% at a
concentration of 1.1 ± 0.4 ug/ml in Vero 76 cells by likely
targeting the early stages of the replication phase through
12
Evidence-Based Complementary and Alternative Medicine
Table 4: Fatty acids isolated from genus Urtica.
Sr.
Name
Structural formula
1
Palmitic acid
2
Erucic acid
O
O
OH
O
3
Linolenic acid
OH
O
4
Pentadecanoic acid
OH
Table 5: Flavonoids isolated from genus Urtica.
Sr.
Name
OH
HO
OH
HO
1.
O
O
2′, 4′, 5, 7, 8-Pentahy-droxyflavone; 7, 8-Di-Me ether
O
HO
HO
OH
HO
OH OH
OH
OH
2.
O
OH
O
Luteolin 7-O-neohes-peridoside
OH
OH
O
HO
O
OH
O
OH
O
HO
OH
O
HO
3.
OH
Quercetin
OH
OH O
OH
O
HO
4.
Kaempferol
OH
OH O
OH
HO
OH
HO
5.
O
HO
Nicotiflorin
OH
O
O
O
OH
O
O
OH
HO
OH O
OH
6.
Gossypetin
HO
OH
O
OH
OH
OH
HO
7.
Luteolin 7-O-b-d-Glucopyranoside
HO
OH O
OH
O
O
OH
O
OH
OH
HO
8.
Afzelin
OO
HO
OH
O
O
HO
OH
Evidence-Based Complementary and Alternative Medicine
13
Table 5: Continued.
Sr.
Name
OH
OH
OH O
HO
9.
HO
Isovitexin
O
HO
O
OH
OH
OH
HO
OH O O
10.
OH
Astragalin
O
HO
O
OH
Table 6: Phenols extracted from Urtica spp.
Sr. no.
Compound name
Structural formula
O
1.
OH
p-Coumaric acid
HO
O
O
2.
OH
Vanillic acid
HO
O
3.
OH
4-Methoxybenzoic acid
O
O
OH
O
4.
Caffeoylmalic acid
HO
O
O
OH
HO
O
O
5.
OH
Ferulic Acid
HO
OH
HO
O
6.
Chlorogenic acid
HO
OH
O
OH
O
HO
O
7.
OH
Salicylic acid
OH
14
Evidence-Based Complementary and Alternative Medicine
Table 6: Continued.
Sr. no.
Compound name
Structural formula
HO
8.
Protocatechuic aldehyde
O
HO
O
HO
9.
OH
Caffeic acid
HO
Table 7: Alcohols isolated from genus Urtica.
Sr.
Name
Chemical structure
OH
OH
O
1.
N-Tetracosanoylphytosphingosine
N
OH
H
OH
2.
Erythritol
OH
HO
OH
OH
3.
4.
1, 2, 3-Butanetriol
OH
OH
OH
14-Octacosanol
Table 8: Alkaloids isolated from genus Urtica.
Name
Chemical structure
Benzylisoquinoline
N
N
N
Mg
N
N
Chlorophyll A
O
O
O
O
O
Evidence-Based Complementary and Alternative Medicine
15
Table 8: Continued.
Name
Chemical structure
O
NN Mg 2+N
N-
Chlorophyll B
O
O
O
O
O
Table 9: Benzopyranoids isolated from genus Urtica.
Sr.
Chemical
structure
Name
O
1.
6, 6′, 7, 7′-Tetrahy-droxy-[8, 8′-bi-2H-1-benzopyran]-2, 2′-dione; Tetra-Me ether
O
O
O
O
O
O
O
O
2.
O
O
7, 7′-dimethoxy-6, 6′-biscoumarin
O
O
OH
OH
HO
3.
O
Scopolin
OH
O
O
O
O
O
4.
6, 6′, 7, 7′-Tetrahydroxy-8,8′-bicoumarin; 6, 6′-Di-Me ether
HO
O
O
HO
O
O
O
O
O
O
O
O
5.
Scoparone
O
HO
6.
Scopoletin
O
binding to the glycoprotein associated with the pseudotyped
virus, thereby preventing the virus attachment to host cells [70].
4.1.2. Antimicrobial and Antifungal Activity. Despite the
growing number of antimicrobials available, the rate of
microorganisms with acquired drug resistance is alarming,
and thus more research is needed to discover alternative
therapies more effective and safer than the currently
available ones [75, 76].
U. dioica ethanol and aqueous extracts showed antibacterial activity against both Gram-positive and Gram-
16
Evidence-Based Complementary and Alternative Medicine
Table 10: Other compounds isolated from genus Urtica.
Sr.
Chemical
structure
Name
OH
1.
O
HO
Tartaric acid
OH
O
OH
O
O
2.
Bis(5-formylfurfu-ryl) ether
3.
Dotriacotane
4.
2, 3-Dihydrobenzo-furan
5.
Formic acid
6.
Oxime- methoxy-phenyl
O
O
O
O
O
HO
HO
N
O
O
7.
1-Methoxy-4, 4a, 5, 6, 7, 8-hexahydro-2 (3H)-naphthalenone
8.
Silane, triethyl (2-phenylethoxy)
9.
N, N-Dimethyldo-decylamine
10.
Naphthalene
O
O
Si
N
Table 11: Terpenoids isolated from genus Urtica.
Sr.
Structural
name
Name
O
1.
HO
3′-Hydroxyacetophenone
OH
OH
O
2.
4,7-Megastigma-diene-3, 9-diol; (3S,6R,7E,9R)-form, 3-Ketone, 9-O[b-D-glucopyranosyl-(1 ⟶ 2)-b-d-glucopyranoside]
OH
O
O
O
OH
HO
O
OH
OH
HO
3.
OH
1-(3, 4-Dihydroxyphe-nyl)-1, 2-propanediol; 3′-Me ether
O
OH
OH
4.
(9Z,11E)-1, 3-hy-droxy-9, 11-octadeca-dienoic acid
O
OH
Evidence-Based Complementary and Alternative Medicine
17
Table 11: Continued.
Sr.
Name
5.
Hexahydrofarnesyl acetone
6.
Geranyl acetone
Structural
name
O
O
O
7.
(E)-Anethole
8.
p-Hydroxybenzalde-hyde
9.
b-Ionone
HO
O
O
Table 12: Chemical composition of essential oil extracted of Urtica pilulifera and Urtica diorca.
NO
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
Compound
1-(4-Isopropylphenyl)-2-methylpropyl acetate
1-(4′-pentenyl)-1, 2-epoxycyclopentane
1, 2-Benzenedicarboxylic acid
1, 4-Diazepine
1,8-Cineole
1-Penten-3-one
2-(1-Pentenyl)furan
2, 2, 6-Trimethylcyclohexanone
2, 4, 6-Trimethyl-5H-1, 3, 5-dithiazine
2-Methoxy-4-vinylphenol
2-Pentylfuran
2-Propenoic acid
3, 5-Dimethyl-1, 2, 4-trithiolane
3-Carene
3-Octanone
5, 6-Dihydro-4-pentyl-2, 6-dimethyl-4H-1, 3, 5-dithiazine
5, 6-Dihydro-4-pentyl-2, 6-dimethyl-4H-1, 3, 5-dithiazine
7-Acetyl-6-ethyl-1, 1, 4,4-tetramethyltetralin
.alpha-Cetone
Anozol
Apoatropine
Apoatropine
Benzaldehyde
Benzaldehyde
Benzofuranone
Benzoic acid
Bicyclo[10.1.0]trideca-4, 8-diene-13-carboxamide
Bisabolene
Bisomel
Borneol
Bornyl acetate
Butyl acetate
Cadinene
Cadinene
Camphor
Carvacrol
Carvone
Urtica pilulifera (RT)
30.5829
24.2355
32.0424
27.0528
13.686
27.5551
—
—
—
12.3214
—
5.302
—
15.8651
—
—
—
32.5855
26.6658
29.1437
—
—
11.371
—
27.9014
30.7118
25.2741
—
32.28
—
—
6.7208
—
—
—
—
20.9362
Urtica diorca (RI)
—
—
—
—
—
—
1056
1035
1199
—
991
—
1134
—
988
1588
1588
—
—
—
2093
2093
—
964
—
—
—
1506
—
1171
1283
—
1510
1516
1145
1299
—
%
2.062
0.1271
13.5056
0.3009
8.2085
0.3782
0.29
0.28
0.30
0.1087
0.84
2.2418
0.30
3.7624
0.28
0.57
0.57
19.618
0.9039
0.1346
0.82
0.82
0.1391
0.29
0.1183
0.873
0.1325
0.39
3.7872
0.31
2.14
3.2399
1.57
2.37
0.27
0.30
0.1721
18
Evidence-Based Complementary and Alternative Medicine
Table 12: Continued.
NO
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
Compound
Citronellyl
Copaene-8-ol
Decan-2-one
Decanal
Diethoxylated tridecyl alcohol
Ethylhexyl benzoate
Farnesol
Farnesol
Farnesylacetone
Farnesylacetone
Furan-3-aldehyde
Geranyl acetone
Geranyl acetone
Geranyl acetone
Hexahydrofarnesylacetone
Hexahydrofarnesylacetone
Hexatriacontane
Humulene
-Ionon β
Ionone
Ionone
Isopropyl dodecanoate
Isopropyl dodecanoate
Lilyal
Limonene (−)Limonene (+)Menthol
Methyl dihydrojasmonate
Methyl palmitate
Methyl palmitate
Methylbenzene
Neophytadiene
n-Nonanal
n-Octanal
Nonanal
Ocimene
Octanal
Octyl heptafluorobutyrate
p-Guaiacol
Phytol
Phytol
Safranal
β-Selinene
Terpinene
Thymol
Trans-2,3-dimethylbicyclo[2.2.2]octane
Vanillin
Vetivenene
Vinyl
Xylene
α-Copaene-8-ol
α-Humulene
α-Ionone
α-Longipinene
α-Selinene
β-2--Pinene
β-Bisabolene
β-Caryophyllene
β-Cyclocitral
Urtica pilulifera (RT)
19.7143
—
—
—
30.9494
31.187
—
—
—
—
7.325
25.953
—
—
—
—
6.7208
—
26.822
—
—
—
—
27.7113
13.5638
23.3733
—
30.3181
—
—
5.302
32.3751
15.9873
—
—
20.59
31.6555
17.9696
15.5392
—
—
—
—
14.5413
—
22.4161
21.812
—
31.0445
8.3229
—
—
—
—
—
11.853
—
—
—
Urtica diorca (RI)
—
1579
1192
1206
—
—
1715
1715
1908
1908
—
—
1448
1448
1844
1844
—
1453
—
1421
1479
1627
1627
—
—
—
1178
—
1925
1925
—
—
—
1004
1105
—
—
—
—
2110
2110
1196
1485
—
1292
—
—
1532
—
—
1579
1453
1421
1347
1493
—
1506
1416
1217
%
0.1388
3.28
0.28
0.29
0.1828
0.3837
1.88
1.88
1.26
1.26
0.1458
0.3483
2.22
2.22
31.20
31.20
11.5631
0.75
0.1714
4.04
11.86
5.27
5.27
1.8666
1.2463
6.7658
0.29
0.8451
0.28
0.28
1.6415
5.2683
0.3288
0.30
0.59
0.6869
2.0563
0.1347
0.1521
11.20
11.20
0.33
0.78
0.1705
0.60
0.3454
1.7906
0.49
0.3754
0.3848
3.28
0.75
4.04
0.30
0.70
0.3957
0.39
1.62
0.35
Evidence-Based Complementary and Alternative Medicine
19
Table 12: Continued.
NO
97
98
99
100
101
102
103
104
Compound
β-Homocyclocitral
β-Ionone
β-Selinene
β-Vetivenene
c-Cadinene
c-Terpinen
c-Terpinene
δ-Cadinene
Urtica pilulifera (RT)
—
—
—
—
—
18.2615
18.6552
—
Urtica diorca (RI)
1254
1479
1485
1532
1510
—
—
1516
%
0.28
11.86
0.78
0.49
1.57
0.3824
2.415
2.37
RI: retention time; RI: retention indices.
Table 13: In vivo studies of the genus Urtica.
Extract/compound
Total coumarins from Urtica
dentata Hand
Doses
20, 40, 60 mg/kg
Route of
administration
Antiarthritis effect
Orally every other
day for 4 weeks after
induction of arthritis
Model
Effect
Reference
Collagen-induced
arthritis BALB/c
mice model
Dose-dependent ↓ arthritis
score ↓paw swelling protect
tissues against bone
destruction ↓IFN-g, ↓IL-2
↑IL-10, ↑TGF-B
[63]
Antioxidant effect
Total 80% ethanolic extract
of Urtica dioica L. leaves
50, 100 mg/kg
Hexane, ethyl acetate and
chloroform extracts of Urtica
pilulifera
Two doses: 250
and 500 mg/kg
ZnO
nanoparticles + aqueous
extract of Urtica dioica leaves
ZnO + extract:
8 mg/dl
Hexane, ethyl acetate and
methanol extracts of Urtica
dioica L. aerial parts
100 mg/kg
↑cytochrome b5, ↑NADHcytochrome b5 reductase,
↑glutathione S-transferase,
↑DT-diaphorase,
↑glutathione peroxidase,
↑glutathione reductase,
↑superoxide dismutase,
Orally daily for 14 Normal Swiss albino
↑catalase ↓cytochrome
days
mouse model
P450, ↓lactate
dehydrogenase, ↓NADPHcytochrome P450 reductase,
↓total sulfhydryl groups,
↓nonprotein sulfhydryl
groups, ↓protein-bound
sulfhydryl groups
Antidiabetic effect
Hypoglycemic effect - ethyl
acetate and chloroform
extracts ↓glucose level,
Streptozotocin and
Orally daily for 4
↓HbA1C, ↓ insulin
high-fat diet-induced
weeks starting from
resistance antitype2 diabetes adult
day11 of diabetes
inflammatory: ↓CRP,
male albino rat
induction
↓TNF-α antioxidant:
model
↓MDA, ↑GSH, ↑SOD,
↑catalase
Both ZnO-extract and
insulin (reference) ↓fasting
blood glucose level in
serum, while increased
Intraperitoneally
Alloxan-induced
insulin level. ZnO-extract:
daily for 16 days
diabetic rat model
↑high-density lipoprotein
↓total cholesterol,
↓triglycerides
Antiendometriosis effect
Methanol extract: ↓implant
volumes, ↓adhesion scores
Surgery-induced
↓TNF-α, ↓VEGF, ↓IL-6;
Orally for 4 weeks
endometriosis rat
histopathological outcomes
model
supported the results
[64]
[65]
[66]
[67]
20
Evidence-Based Complementary and Alternative Medicine
Table 13: Continued.
Extract/compound
Polysaccharide fraction of
Urtica fissa
Doses
62.5, 125, 250 mg/
kg
Total 95% ethanol extract of
Urtica dioica
Dose: 100 mg/kg
Urtica dioica agglutinin
(UDA)
Three doses: 20,
10, 5 mg/kg
Two doses: 0.1%
Total extract (50% ethanol)
and 1% g/kg of the
of Urtica thunbergiana leaves
animals’ dry diet
Dichloromethane extract of
Urtica dioica
Two doses: 10 and
20 mg/kg
Route of
Model
administration
Effect on prostate hyperplasia
Effect
↓prostate hyperplasia the
lowest dose (62.5 mg/kg)-↓
indexes of wet weight,↓ dry
weight , ↓volume by 17%,
23% and 32% highest dose
Testosterone
propionate-induced (250 mg/kg)-↓indexes of wet
Orally daily for 3
prostate hyperplasia weight, dry weight, ↓volume
weeks
were further reduced by
castrated rat model
25%, 33% and 37%;
histopathological
examination supported the
results
Effect on nephrotoxicity
↓ serum creatinine, ↓blood
Gentamicin-induced
Orally daily for 10
urea, ↓ nitrogen
nephrotoxicity in
days
antioxidant-↑glutathione,
male rabbit model
↓malondialdehyde
Antiviral effect
Treatment with UDA at
dose 5 mg/kg significantly
sheltered the mice against
lethal infection with the
SARS-CoV- infected
Intraperitoneally
virus but did not decrease
BALB/c mouse
daily for 4 days
virus titers in the lung;
model
prevented weight loss and
lung pathology scores of
infected mice
Antiaging effect
↓thinner and superficial
wrinkles ↓erythema index
UVB-induced skin
↑skin hydration;
Orally for 10 weeks aging hairless mouse
histopathological
model
investigations supported the
results
Anticancer effect
↓tumor size and weight.
↑apoptosis, ↓proliferation.
4T1 (breast cancer
↓Bcl2, ↑caspase 3;
cell line) allograft
Intraperitoneally
histopathology
tumor BALB/c
daily for 28 days
examinations supported the
mouse model
results
Reference
[68]
[69]
[70]
[71]
[72]
Symbols: ↑ increase, ↓decrease.
negative bacteria and yeasts, including Proteus mirabilis,
Pseudomonas aeruginosa, Enterobacter aerogenes, Escherichia coli, Citrobacter koseri, S. pneumonia, S. aureus,
M. luteus, S. epidermidis, and Candida albicans. They were
also active against M. tuberculosis in case of multiple drug
resistance [77–79]. Of note, the aqueous (microwaveassisted, ultrasound-assisted, and subcritical water extraction) and ethanol extracts of U. dioica leaves also
confirmed antibacterial activity with minimal inhibitory
concentration (MIC) of 9.76 ug/mL and 0.0625–0.500 mg/
ml against methicillin-resistant (MRSA) and methicillin-
sensitive (MSSA) S. aureus strains [80]; these observed
effects were linked to their high content of hydroxycinnamic acids (chlorogenic, caffeic, and rosmarinic acids)
and flavonoids (quercetin) (Table 1) [81].
4.1.3. Anthelmintic Activity. The ethanolic extract of
U. dioica displayed in vitro anthelmintic activity against
protoscoleces of Echinococcus granulosus, increasing the
concentration and duration of exposure, reaching 96.2%
inhibition at a concentration of 4 μg/ml for 30 min (Table 1)
Evidence-Based Complementary and Alternative Medicine
Anticancer
21
Anti-inflammatory
Pharmacological properties
↓NO
↓tumor size
Antioxidant
tumor cells
free radicals
scavenging
↓proliferation
↓migration
↓miR-21
↓MMPs
↑E-cadherin
stop cell cycle
G0 phase
↑apoptosis
Urtica spp.
bioactive
compounds
Anti-aging of skin
young skin
aging skin
Antiviral
Antibacterial
↓viral
replication
↓bacterial
growth
↓collagenase
↓elastase
Antihelmintic
Echinococcus
granulosus
Figure 1: The most important pharmacological properties and potential mechanisms of bioactive compounds of Urtica spp. ↑: increase; ↓:
decrease; NO: nitric oxide; MMPs: matrix metalloproteinases; miR-21: microRNA-21.
[82]. Anthelmintic activity of the methanol extract was also
investigated using adult Indian earthworms (Pheretima
posthuma) and revealed a dose-dependent increase in anthelmintic activity at 25, 50, and 100 mg/mL [83].
4.1.4. Anticancer Activity. Cancer is the largest cause of
death in the world due to poor timely access to high-quality
diagnosis and treatment [84, 85]. U. dioica significantly
suppressed the human breast cancer cell line (MCF-7) and
fibroblasts secluded from foreskin tissue, with IC50 values of
MCF-7 (31.37 mg/ml), MDA-MB-23 (38.14 mg/ml), 4T1
(44.07 μg/mL to 35.21 mg/ml), and HFFF2 (69.42 mg/ml).
QRT-PCR showed that U. dioica extracts inhibited cell
migration by downregulating the expression of miR-21,
matrix metalloproteinase (MMP) 1, MMP9, and MMP13,
and C-X-C motif chemokine receptor 4 (CXCR4) and
upregulating the expression of E-cadherin [86]. U. dioica
leaves also increased cell apoptosis in 4T1 cells [72].
The aqueous extract of U. dioica leaves significantly
decreased the cell proliferation of AML U937 cell line
(acute myeloid leukemia), with IC50 of 24 ug/ml for the first
48 h and then 16 ug/ml after 72 h [87]. Moreover, flow
cytometry showed that the extract was able to stop the cell
cycle into the G0 phase and increase cell apoptosis at the
early and late stages by increasing proapoptotic protein Bax
expression and decreasing antiapoptotic protein Bcl-2
expression [87].
Zekovic et al. reported the antiproliferative effect of the
subcritical water extract of U. dioica against Hep2c, RD, and
L2OB cells (13.42 ug/ml, 9.69 ug/ml, and 7.52 ug/ml, respectively) (Table 1) [80]. Moreover, the bioactive compound, 5a,
6b-dihydroxy-daucosterol, from U. laetevirens showed anticancer activity against MH7A cells by inhibiting proliferation
and inducing apoptosis (Table 1) [88, 89].
4.1.5. Antioxidant Activity. Antioxidants are synthetic or
natural compounds that can help to prevent or delay cell
damage [90, 91]. The aqueous extract of U. dioica leaves
presented antioxidant activity, assessed through the DPPH
radical scavenging (IC50 � 16.93 ug/mL), reducing power
(EC50 � 30.07 ug/mL) and polarographic (HPMC � 243.2%/
mL) assays [80].
Batches of U. dioica analyzed for their antioxidant potency
revealed batch 14 as the most potent (2.71 TEAC) using the
CUPRAC assay and batch 27 (0.73 TEAC) using the FRAP
assay. The resulting response surface plots approved a positive
association between the antioxidant actions and the phenolic
acids content [92]. A comparative study performed by Carvalho et al. demonstrated the superior antioxidant properties of
U. dioica in all assays: DPPH (2.89 g/100 g lyophilized), ABTS
(2.60 TEAC), and FRAP (3.81 TEAC) when compared to
U. membranacea and U. urens aerial parts (Table 1) [89].
Methanol and direct-ethanol extracts of Urtica root
showed free radical scavenging activity of 46.71% and
45.03% at 500 μg/ml, respectively. Moreover, Urtica parviflora (methanol/aqueous extract) has been reported for free
radical scavenging and reducing activity, with biological
activity varying in a dose-dependent manner. The antioxidant potential has also been reported in the ethanolic extracts of Urtica circularis, Urtica hyperborean (methanol
extract), Urtica cannabina (polyphenols), and U. urens
(Table 1) [93–96].
22
4.1.6. Anti-Inflammatory Activity. Although nonsteroidal
medicines can be useful, herbs can be a safer and often
effective alternative for pain management, especially when
used for a long period [97]. U. dioica (leaves extract) and
isolated flavonoids were active against thrombin-induced
platelet aggregation (IC50 values of 0.25 ± 0.05 and
0.40 ± 0.04 mg/ml) [98]. A comparative study between 50%
ethanol extracts of U. dioica, U. membranacea, and U. urens
aerial parts showed that U. urens extract (350 ug/mL) could
act as a more potent anti-inflammatory agent by showing the
highest reduction in nitric oxide production (up to 41%)
(Table 1) [89].
4.1.7. Antiaging of Skin. Those who are prone to wrinkles
and fine lines and those who have loose, sagging skin usually
consider antiaging therapies [99]. Different extracts of
U. dioica demonstrated antiaging efficacy using elastase and
collagenase enzymes inhibition assay. The more potent
batches were batch 1 that inhibited collagenase enzyme by
16.23% and batch 26 that inhibited elastase enzyme by
24.51%. This potency was linked to the high content of
quercetin and ursolic acid, respectively (Table 1) [92].
4.2. In Vivo Pharmacological Findings
4.2.1. Antiviral Activity. U. diorca was also investigated for
its in vivo antiviral potency. U. dioica agglutinin (UDA) at a
dose of 5 mg/kg (b.w/day; i.p.) significantly sheltered the
mice against lethal infection with the virus but did not
decrease the virus titers in the lung of the SARS-CoV-infected BALB/c mouse model, also preventing the weight loss
and lung pathology scores of infected mice [70] (Table 13).
4.2.2. Anthelmintic Activity. The fight against helminth
infectious is still pending complete eradication either
through a vaccine or pharmacological therapies. In vivo
study showed that daily oral administration (175 mg/ml) of
the methanol extract obtained from leaves and seeds of
U. dioica showed anthelmintic activity in Swiss albino mice
naturally infected with Aspiculuris tetraptera (Table 13)
[100].
4.2.3. Anticancer Activity. The dichloromethane extract of
U. dioica further showed anticancer activity by significantly
reducing the tumor size and weight on 4T1 (breast cancer
cell line) allograft tumor in BALB/c mouse model at 10 and
20 mg/kg b.w/day (i.p.). This efficacy was linked to increased
cell apoptosis and suppression of cell proliferation through
BCL2 downregulation and increased caspase-3 activity [72].
4.2.4. Nephroprotective. The kidney is a key organ of the
metabolism of any xenobiotic; thus, preventing its alteration
is crucial [101]. The 95% ethanol extract of U. dioica showed
therapeutic action against nephrotoxicity on gentamicininduced nephrotoxicity in the male rabbit model at a dose
(100 mg/kg b.wt./day P.O.). The extract has a potent antioxidant activity through enhancing glutathione level and
Evidence-Based Complementary and Alternative Medicine
decreasing malondialdehyde level and helps in controlling
serum creatinine and blood urea nitrogen levels [69]. Urtica
parviflora extract (aerial parts) showed neuroprotective
activity against nephrotoxicity induced by paracetamol and
gentamicin and renal disability in Wistar rats and rabbits
(Table 1) [77, 96].
4.2.5. Hepatoprotective. Because the liver is such an important part of any xenobiotic metabolism, preventing its
alteration is also of utmost importance [102]. U. urens and
U. dioica have been reported for their hepatoprotective
activity against CCl4-induced liver toxicity in rats. For example, U. dioica (methanol extract) promoted an antioxidant system against cisplatin-induced toxicity in Ehrlich
ascites tumor (mice model) and exerted hepatoprotective
activity (Table 13) [83, 89].
4.2.6. Cardioprotective. Cardioprotection refers to all systems and methods that help keep the heart healthy by decreasing or even preventing myocardial damage [103].
U. dioica water and petroleum ether extract at, respectively,
20 and 150 mg/kg/day improved blood lipid level in rats,
decreased blood cholesterol levels and LDL/HDL lipoprotein ratios after 30 days. On the other hand, U. dioica ethanol
extract decreased cholesterol and LDL levels at a dose of 100
and 300 mg/kg [104, 105]. Urtica parviflora (350 and
500 mg/kg p.o.) effectively decreased cardiac complications
and enhanced serum LDL level.
U. dioica aqueous extract (1 and 2 g/L) decreased heart
rate and improved pressure in the left ventricle in Langendorff-perfused rat heart. It also improved the tolerance
level of isolated rat heart against ischemia-reperfusion
(Table 13) [106–108].
4.2.7. Antiarthritis Effect. Urtica species has also been
shown to be effective for anti-inflammatory purposes,
particularly in the treatment of arthritis. For example, a total
coumarins extract from Urtica dentata demonstrated a dosedependent antiarthritis activity in collagen-induced arthritis
BALB /c mice model at three doses (20, 40, and 60 mg/kg
b.w. P.O. every other day). Total coumarins also protected
tissues against bone destruction by reducing IFN-g and IL-2
production and increasing IL-10 and TGF-B (Table 13) [63].
4.2.8. Antidiabetic Effect. Diabetes mellitus is a significant
metabolic illness that can affect the central nervous system
in a variety of ways, both functionally and morphologically
[109]. Ethyl acetate and chloroform extracts of U. pilulifera
showed antidiabetic activity at two doses (250 and 500 mg/
kg b.w./day P.O.) on streptozotocin and high-fat diet-induced type 2 diabetes adult male albino rat model. Briefly,
the extracts decreased glucose level, HbA1C percentage,
and insulin resistance, with this hypoglycemic effect being
associated with the anti-inflammatory effect through reducing C-reactive protein (CRP) levels in serum and TNF-a
level and exerting antioxidant activity through decreasing
MDA and increasing GSH levels, SOD, and catalase
Evidence-Based Complementary and Alternative Medicine
activities in pancreatic tissues (Table 13) [65]. Also, a
formulation containing U. dioica, Artemisia judaica, Morus
folium, Taraxacum officinale, and Canella winteriana has
been reported to treat insulin-dependent (type I) and
noninsulin-dependent (type II) diabetes. Furthermore, a
lectin isolated from seeds of U. pilulifera exerted an antidiabetic impact on diabetic rats (streptozotocin (STZ)
model) when administered for 30 days at a dose of 100 mg/
kg. U. parviflora leaves (aqueous extract) also exerted
hypoglycemic effect in normoglycemic rats, while
U. angustifolia (leaves, stems, and roots) exerted hypoglycemic effects in a dose-dependent way (Table 13)
[79, 110–112]. More recently, ZnO nanoparticles of
aqueous extract from U. dioica leaves confirmed the antidiabetic activity of the combination (8 mg/dl. b.w./day
I.P.) in an alloxan-induced diabetic rat model by significantly decreasing fasting blood glucose, total cholesterol,
and total triglycerides levels in serum, while increasing
high-density lipoprotein and insulin levels (Table 13) [66].
4.2.9. Antiendometriosis Effect. Endometriosis is a painful
disorder in which tissue from the womb’s lining (uterus) is
present both inside and outside the uterus. Some herbs may
raise the risk of endometriosis, while others may help to heal
it faster. The methanol extract of U. dioica aerial parts
showed an antiendometriosis effect on the surgery-induced
endometriosis rat model at a dose of 100 mg/kg b.wt./day
P.O. by decreasing implant volumes and adhesion scores and
peritoneal TNF-α, VEGF, and IL-6 levels as supported by
histopathological outcomes (Table 13) [67].
4.2.10. Effect on Prostate Hyperplasia. Prostate enlargement,
commonly known as benign prostatic hyperplasia (BPH), is
a noncancerous increase in the size of the prostate gland.
Prostatic hyperplasia was suppressed by a polysaccharide
fraction of Urtica on testosterone propionate-induced
prostate hyperplasia castrated rat model at three doses (62.5,
125, and 250 mg/kg b.wt. P.O.). Treatment with the lowest
dose (62.5 mg/kg) reduced the indexes of wet weight, dry
weight, and volume by 17%, 23%, and 32%, respectively.
With the highest dose (250 mg/kg), the indexes of wet
weight, dry weight, and volume were further reduced by
25%, 33%, and 37%, respectively (Table 13) [68].
Many herbal preparations from U. dioica extracts can
inhibit 5-α-reductase [113]. Indeed, U. dioica roots (methanol extracts) were able to inhibit aromatase (AR) and 5areductase (5aRE) in a dose-dependent manner (ED50 of 3.58
and 14.7 mg/mL, respectively). Urtica mairei (roots) reduced
BPH and inhibited the activity of 5a-reductase (Table 13)
[114, 115].
Hartmann et al. evaluated the effect of a combination
between methylene chloride extract of Pygeum africanum
bark and 30% methanol extract of U. dioica roots with a ratio
of 1 : 12 (Prostatonin ) on BPH. This combination also
significantly inhibited reductase and aromatase enzymes
with ED50 of 14.15 mg/ml and 0.24 mg/ml, respectively
(Table 13) [116].
®
23
4.2.11. Antioxidant Activity. Antioxidants are widespread in
the plant kingdom. For example, the 80% ethanol extract of
U. dioica leaves confirmed antioxidant activity in a normal
Swiss albino mouse model at two doses (50 and 100 mg/kg
b.w./day P.O.). Both doses of the extract led to a marked
increase in the activities of cytochrome b5, NADH-cytochrome b5 reductase, glutathione S-transferase, DT-diaphorase, glutathione peroxidase, glutathione reductase,
superoxide dismutase, and catalase in liver tissues. On the
other hand, they showed a reduction in cytochrome P450,
lactate dehydrogenase, NADPH-cytochrome P450 reductase, total sulfhydryl groups, nonprotein sulfhydryl groups,
and protein-bound sulfhydryl groups (Table 13) [64].
4.2.12. Anti-Inflammatory Activity. The discovery of new
anti-inflammatory agents has long been a source of concern.
The aqueous extract of U. dioica leaves showed analgesic
effect at 1200 mg/kg by reducing thermal situation in a hot
plate test (55°C), improving resistance to ache and hyperstimulation of the sensory nociceptors leading to TENS-like
effect [94, 117].
The aerial part of U. urens (ethanol extract) inhibited
62.8% of the licking time during the final stage of the formalin test at a dose of 500 mg/kg in chemically induced
mouse pain models [118, 119]. U. urens (methanol extract of
aerial parts) at 100 to 400 mg/kg significantly displayed
anxiolytic effect against mice model (Table 1) [120].
Furthermore, U. dioica aqueous extract (150 mg/kg dose)
showed antipyretic activity in albino mice, while Urtica
macrorrhiza aqueous extract (stem) decreased fever intensity
in rats at 200 and 400 mg/kg [79, 121]. Indeed, it has been
reported that U. dioica act by either blocking or interfering
with chemical processes in the body related to chemicals
found in the body, including dihydrotestosterone. In the
carrageenan-induced paw edema model of rats, U. urens
showed outstanding anti-inflammatory efficacy. Extract of
its aerial parts revealed a percentage inhibition of 41.5% at
300 mg/kg i.p. in case of hind paw edema in rats. Moreover,
petroleum ether extract of seeds of U. pilulifera and n-butanol and aqueous of U. macrorrhiza have also reported antiinflammatory activity against carrageenan-induced paw
edema in rats (Table 13) [111, 120, 122, 123]. In addition,
some compounds from Urtica circularis, namely vicenin-2,
caffeic acid, chlorogenic acid, and vitexin displayed a dosedependent antinociceptive activity in nociceptive mice, in
the following order of activity: vitexin (91%)> caffeic acid
(41%) � vicenin-2 (41%)> chlorogenic acid (72%) (Table 13)
[118, 119].
4.2.13. Antiaging of Skin. The use of natural plant extracts in
the cosmetic industry as antiaging agents has received rising
attention. Hwang et al. demonstrated the antiaging activity
of the 50% ethanol extract of Urtica thunbergiana leaves on
UVB-induced skin aging hairless mouse model at two doses
(0.1% and 1% g/kg b.w. of animals’ diet). The extract (100 ug/
mL) improved the aging disorders implied by UVB-irradiated NHDF, with ROS generation being reduced by 17%,
MMP-1 and MMP-3 by 61% and 29%, respectively, and IL-6
24
secretion by 60%. Moreover, procollagen type 1 generation
was upregulated by 255% and phosphorylation of ERK, JNK,
and p38K was suppressed by 14%, 32%, and 38%, respectively. Dephosphorylation of NFAT was also inverted possibly due to the high content of chlorogenic acid in
U. thunbergiana (Table 13) [71].
4.2.14. Diuretic and Antiurolithiatic Effects. U. dioica has
traditionally been used as a diuretic in indigenous medicine.
Experimentally, U. dioica (aqueous extract) possess natriuretic and diuretic activity in rabbits; the rate of K+ remains
unaffected. U. dioica also revealed effectiveness against
urinary infections. Indeed, its aerial part (methanol extract)
also exerts antiurolithiatic potential can suppress the increased levels of urinary calcium and creatinine while significantly reducing the renal deposition of calcium and
oxalate. U. dentata (n-butanol extract) also exert antiurolithiatic activity, prevent the deposition of calcium oxalate, and protect renal tissue from injury produced by
kidney calculi (rat model) (Table 13) [112, 124].
4.3. Miscellaneous. The hypotensive activity of the methanol
and water extract of U. dioica has also been shown in human
cells culture and in vitro models of prostatic antihyperplasic
activity [125]. U. dioica aqueous extract has been revealed to
exert good in vivo antiulcer efficacy against ethanol-induced
ulcers [113], while leaves and seed extract (400 µg/mL)
possess in vitro immunomodulatory potential (Table 13)
[47, 126]. Finally, U. angustifolia (polysaccharides) showed
antifatigue properties in mice [112].
5. Health-Promoting Effects: Clinical
Trial Findings
5.1. Anti-Inflammatory Effect. Earlier literature reported that
the administration of 1340 mg of powdered extract of U. dioica
(nettle leaves) reduced arthritis to half. A randomized control
trial in 50 patients suffering from a chronic joint disease in
Germany demonstrated the effectiveness of a combination of
stewed nettle along with 50 mg of diclofenac treatment (group
D50+U) compared to a standard dose of diclofenac (200 mg)
[127, 128]. Results of this study indicated that both treatments
were equally effective in mitigating clinical symptoms occurring due to acute arthritis. These results are of great importance
for patients who suffer from nonsteroidal anti-inflammatory
drugs (NSAIDs) intolerance because of ulceration or other
gastric problems. However, further studies are required to find
out whether nettle could be effective in the absence of NSAIDs
[127, 129].
5.2. Diuretic Effect. In a study aiming to assess the impact of
15 mL nettle herb juice for treating myocardial or chronic
insufficiency, 32 patients received 3 times daily such preparation in an open 2-week study. Later, the frequency of
dosing was reduced to once a day in the morning. The daily
volume of urine was increased significantly throughout the
treatment. The patients with myocardial insufficiency in the
Evidence-Based Complementary and Alternative Medicine
2nd day of treatment was 9.2% higher (p ≤ 0.0005) than the
baseline and patients of chronic venous insufficiency reported 23.9% higher (p ≤ 0.05) urine volume. Patients’
weight (about 1%) and systolic blood pressure showed slight
decreases. Apart from slight side effects, like diarrhea, serum
parameters remained stable and treatments were smoothly
tolerated. Additionally, diuretic and natriuretic effects were
detected, implying a renal function effect [127, 130]. Some
objective indicators in this clinical investigation indicated
statistically significant improvement, despite the small
number of patients and the short duration of the study
limiting the establishment of solid conclusions.
5.3. Antiallergic Effect. The safest remedy for allergy and
sinus treatment is nettle. Indeed, it has been reported used in
various ailments ranging from allergic rhinitis to hypertension. Lyophilized leaves of nettle have been clinically
proven to relieve allergy symptoms [89, 113]. For example, a
double-blind, randomized study was conducted with 98
individuals to try the effect of freeze-dried U. dioica herb (2
times 300 mg) on allergic rhinitis. After one week of therapy,
daily symptom diaries and global response documented after
follow-up were considered for assessment [131, 132]. In the
overall evaluations, U. dioica was ranked higher than placebo, and when the diary data were compared, U. dioica was
just marginally higher [132]. Thus, even if the U. dioica trial
appears to be effective, more research with a bigger and
better-matched sample size and possibly a longer treatment
period might be beneficial. Research into the mechanism of
action of U. dioica and its potential for application in other
allergy disorders is also recommended.
5.4. Antidiabetic Effect. The health benefit of the hydroalcoholic extract of U. dioica on blood lipids, hepatic enzymes, and nitric oxide levels was investigated in a
randomized control trial, including 50 women with type 2
diabetes. U. dioica significantly decreased FPG and TG and
increased SGPT levels and HDL, NO, and SOD levels
compared to the control group after 8 weeks of treatment.
This result supports using the hydroalcoholic extract of
U. dioica as an antioxidant agent for additional therapy of
diabetes to minimize complications, such as cardiovascular
risk factors in diabetic patients [133]. However, the relatively
small sample size and the lack of exact diet and exercise
management of patients who participated in the study make
the findings suggestive rather than conclusive. Therefore,
trials with a larger number of patients and a longer intervention period are recommended to better understand
U. dioica’s benefits in diabetic patients.
Overall, these clinical studies are not appropriate for traditional use in indications, like the acute attack of chronic joint
disease, myocardial or chronic venous insufficiency, and allergic rhinitis. Indeed, only the well-established use can be
relevant in these indications; however, they are hardly good
enough and the results of these trials cannot be used [134].
Since a small number of participants were included in
the studies and were not double-blind (except Mittman’s
study) and that data are not detailed enough, the
Evidence-Based Complementary and Alternative Medicine
consequences are not influential. These studies may only
support the authenticity of diuretic and anti-inflammatory
effects; in this way, the traditional indications may be
supported by them.
6. Safety, Drug-Drug Interaction, and Adverse
Effect of the Genus Urtica
Though sweating and gastric discomfort are reported in
some cases, the Urtica plant usually causes skin irritation
upon touching it [135].
Hypersensitivity cases have been reported in patients
with renal ailments [33, 130]. When the hairs or spines on
the stems and leaves of the stinging nettle come into contact
with the skin, various physiologically active chemicals are
released within seconds and in turn induce irritation, dermatitis, and urticaria [136]. These findings imply that histamine, which is released by the nettle, has a role in the rapid
reaction to nettle stings. Moreover, the endurance of the
stinging sensation, on the other hand, could indicate that
there are chemicals in nettle fluid that are directly harmful to
nerves or that can cause the subsequent release of other
mediators [137]. Furthermore, urine flow is enhanced by the
aerial parts of Urtica; hence, it is advised to inform the
healthcare provider of whether the patient suffers from
diabetes or kidney problems [33, 130]. Urtica aerial parts at
1.25 g/kg decline blood sugar following intake [135] and may
potentiate concurrent antidiabetics’ effect, high or low blood
pressure [138–140].
Furthermore, the key underlying processes of this food
plant and its phytonutrients in the management of urolithiasis include a diuretic effect, which can exacerbate the
diuretic therapy in patients with renal disorders. Though
nettle is reputed to be an abortifacient and to affect the
menstrual cycle in traditional medicine, oral administration
of 250 mg/kg of nettle to mice is devoid of antifertility activity. In the absence of clear evidence of antifertility potency, Urtica spp. should be completely avoided during
pregnancy or in breastfeeding women and children [127].
For sure, Urtica dioica and Urtica urens preparations have
been used orally as a postpartum “tonic” for treating anemia
in nursing mothers and is a purported galactagogue. Still, no
scientifically valid clinical trials support the safety and efficacy in nursing mothers or infants for any use [141].
Urtica dioica is used as an anti-inflammatory in rheumatoid arthritis. The anti-inflammatory effect of Urtica
extract is due to its inhibitory effect on NF-kappaB activation and the genetic transcription factor that activates
TNF-α and IL-1B in synovial tissue that lines the joint,
lowering TNF-α and other inflammatory cytokines levels
[123, 142]. Therefore, Urtica spp. should be avoided in the
case of acute arthritis due to the risk of drug-drug interaction
[138].
Urtica spp. has also been reported to enhance the impact
of CNS depressant medications [138]. The concomitant use
of Urtica aerial parts with sedatives, including lorazepam
(Ativan), phenobarbital (Donnatal), clonazepam (Klonopin), zolpidem (Ambien), and others may lead to sleepiness
and drowsiness [127].
25
7. Conclusions and Future Perspectives
In short, while summarizing the ethnopharmacological reports on the use of Urtica species, U. dioica emerged as the
most reported species, providing a rich source of active
principles for developing novel treatment strategies. Despite its
ancient use by people from different cultures and in different
regions for the treatment of various ailments, the current
achievements have stated that Urtica spp. have renowned
pharmacological potentialities, including anti-inflammatory,
anticancer, antioxidant, antidiabetic, antimicrobial, and antiviral effects that correlate, by one hand, with some traditional
uses and, on the other hand, with the bioactive phytochemicals
present, including phenolic compounds and terpenoids that
may be effectively applied for preventive or therapeutic
purposes in communicable and noncommunicable diseases.
However, there is still a large gap in in vivo experiments and
clinical trials using plant-based preparations or isolated
phytochemicals from Urtica spp. that need to be filled in a
short time so that new windows for preventive, therapeutic,
and agroindustrial purposes can be open.
Data Availability
The data supporting this review were taken from previously
reported studies and datasets, which have been cited. The
processed data are available from the corresponding author
upon request.
Conflicts of Interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial
interest in or financial conflict with the subject matter or
materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or
options, expert testimony, grants or patents received or
pending, or royalties.
Authors’ Contributions
All the authors made a significant contribution to the work
reported, whether that is in the conception, study design,
execution, acquisition of data, analysis, and interpretation,
or in all these areas: that is, revising or critically reviewing
the article; giving final approval of the version to be published; agreeing on the journal to which the article has been
submitted; and confirming to be accountable for all aspects
of the work. All the authors have read and agreed to the
published version of the manuscript.
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