Urtica dioica-Derived Phytochemicals for Pharmacological and Therapeutic Applications

Yasaman Taheri; Cristina Quispe; Jesús Herrera-Bravo; Javad Sharifi-Rad; Shahira M. Ezzat; Rana M. Merghany; Shabnum Shaheen; Lubna Azmi; Abhay Prakash Mishra; Bilge Sener; Mehtap Kılıç; Surjit Sen; Krishnendu Acharya; Azadeh Nasiri; Natália Cruz-Martins; Patrick Valere Tsouh Fokou; Alibek Ydyrys; Zhandos Bassygarayev; Sevgi Durna Daştan; Mohammed M. Alshehri; Daniela Calina; William C. Cho

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.

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. 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