key: cord-0816949-5m9nfm0b
authors: Taheri, Yasaman; Quispe, Cristina; Herrera-Bravo, Jesús; Sharifi-Rad, Javad; Ezzat, Shahira M.; Merghany, Rana M.; Shaheen, Shabnum; Azmi, Lubna; Prakash Mishra, Abhay; Sener, Bilge; Kılıç, Mehtap; Sen, Surjit; Acharya, Krishnendu; Nasiri, Azadeh; Cruz-Martins, Natália; Tsouh Fokou, Patrick Valere; Ydyrys, Alibek; Bassygarayev, Zhandos; Daştan, Sevgi Durna; Alshehri, Mohammed M.; Calina, Daniela; Cho, William C.
title: Urtica dioica-Derived Phytochemicals for Pharmacological and Therapeutic Applications
date: 2022-02-24
journal: Evid Based Complement Alternat Med
DOI: 10.1155/2022/4024331
sha: e88fe0112f1b584e85777fd10b80dcc0fad23bd1
doc_id: 816949
cord_uid: 5m9nfm0b

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.

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] [3] [4] [5] [6] [7] [8] [9] [10] [11] .

ese 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] [3] [4] [5] [6] [7] [8] [9] [10] [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] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [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.

Urtica species is a nitrophilous plant that can grow up to 1-2 m in height depending on edaphic conditions. Despite growing well in areas with high water availability [29] [30] [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] . e plant is commonly found as a weed, mainly in moist and shady places and often in anthropogenic habitats. e 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] . e 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] [39] [40] [41] [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 

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] . e 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] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] . e 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. e 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-ethyl-1, 1, 4, 4-tetramethyltetralin (Table 12 ) [61, 62] . Overall, considerably less attention has been paid to the phytochemistry of bioactive compounds in these plants. [73] . U. dioica extract (0.5-1 g/ml) and derived N-acetyl glucosamine-specific lectin (the 50% effective concentration (EC 50 ) 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). Evidence-Based Complementary and Alternative Medicine Evidence-Based Complementary and Alternative Medicine 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 EC 50 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 

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- Oxime-methoxy-phenyl [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] .

HO 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-

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 IC 50 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] . e aqueous extract of U. dioica leaves significantly decreased the cell proliferation of AML U937 cell line (acute myeloid leukemia), with IC 50 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] .

Antioxidants are synthetic or natural compounds that can help to prevent or delay cell damage [90, 91] . e aqueous extract of U. dioica leaves presented antioxidant activity, assessed through the DPPH radical scavenging (IC 50 � 16.93 ug/mL), reducing power (EC 50 � 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. e resulting response surface plots approved a positive association between the antioxidant actions and the phenolic acids content [92] . (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. e 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] [94] [95] [96] . 

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 (IC 50 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] .

ose 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. e more potent batches were batch 1 that inhibited collagenase enzyme by 16.23% and batch 26 that inhibited elastase enzyme by 24.51%.

is potency was linked to the high content of quercetin and ursolic acid, respectively (Table 1 ) [92] .

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 ).

e 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].

e 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.). is efficacy was linked to increased cell apoptosis and suppression of cell proliferation through BCL2 downregulation and increased caspase-3 activity [72] .

e kidney is a key organ of the metabolism of any xenobiotic; thus, preventing its alteration is crucial [101] . e 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.). e extract has a potent antioxidant activity through enhancing glutathione level and 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] .

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] .

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] [107] [108] .

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] .

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 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] [111] [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] .

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. e 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] .

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 (ED 50 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. is combination also significantly inhibited reductase and aromatase enzymes with ED 50 of 14.15 mg/ml and 0.24 mg/ml, respectively (Table 13 ) [116] .

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] .

e discovery of new anti-inflammatory agents has long been a source of concern. e 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] . e 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] .

e 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). e 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

Evidence-Based Complementary and Alternative Medicine 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] .

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] .

e 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] .

Trial Findings [127, 128] . Results of this study indicated that both treatments were equally effective in mitigating clinical symptoms occurring due to acute arthritis. ese 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] .

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. e daily volume of urine was increased significantly throughout the treatment. e patients with myocardial insufficiency in the 2 nd 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.

e 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] . us, 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.

e 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.

is 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. erefore, 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 24 Evidence-Based Complementary and Alternative Medicine consequences are not influential.

ese studies may only support the authenticity of diuretic and anti-inflammatory effects; in this way, the traditional indications may be supported by them.

Effect of the Genus Urtica ough 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] . ese 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] [139] [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. ough 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. e 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] . erefore, 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] . e 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] .

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.

e data supporting this review were taken from previously reported studies and datasets, which have been cited. e processed data are available from the corresponding author upon request.

e 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.

is includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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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