Int J Clin Exp Med 2018;11(7):6509-6520 www.ijcem.com /ISSN:1940-5901/IJCEM0070937

Review Article urinaria: a potential phytopharmacological source of natural medicine

Guankui Du1*, Man Xiao1*, Siman Yu2, Mengyi Wang2, Yiqiang Xie2, Shenggang Sang2

1Department of Biochemistry and Molecular Biology, Hainan Medical College, Haikou 571101, China; 2First Affiliated Hospital of Hainan Medical College, Haikou 571199, China. *Equal contributors. Received December 14, 2017; Accepted May 20, 2018; Epub July 15, 2018; Published July 30, 2018

Abstract: is an herb in the family Euphorbiaceae. P. urinaria, which grows mainly in tropical regions such as India, Sri Lanka, Indochina, Japan, Malaysia, Indonesia and the , has long been used in traditional oriental medicine for the treatment of liver damage, hepatitis, jaundice, renal disorders, en- teritis, diarrhea, and dropsy. Experimentally, P. urinaria displays antiviral, anti-tumor, hepatoprotective, anti-diabetic, antioxidant, anti-hypertensive, anti-inflammatory, and anti-microbial effects. Phytochemical screening revealed the presence of flavonoids, carboxylic acids, tannins, coumarins, and lignans in P. urinaria extracts (PUE). Meanwhile, PUE possess various pharmacological and biological activities. This study summarizes the ethno-medical use, chemical constituents, and pharmacological profile ofP. urinaria. As a medicinal , this herb has emerged as a good source of traditional medicines. However, the composition-activity relationship for this plant deserves further research.

Keywords: Phyllanthus urinaria, chemical constituents, antivirus, antitumor, liver protection

Introduction Very recently, the anti-tumor [9], anti-inflamma- tory [10] and anti-microbial [11] activities of P. Phyllanthus urinaria L. (P. urinaria), commonly urinaria were reported. In addition, P. urinaria called chamber bitter, is an herb species in the extracts show antiviral activities against hepati- family Euphorbiaceae [1, 2]. Numerous small tis B virus (HBV) [12-14], herpes simplex viruses green-red are found along the underside (HSV) [15-19], dengue virus [20], enteroviruses of its stems. Therefore, the plant is called [21], hepatitis B virus (HCV) [22], and human “YeXiaZhu” in the Pharmacopoeia of the P. R. of immunodeficiency virus (HIV) [23-25]. This herb China [1]. P. urinaria has the features of great is also used as traditional medicine for its pro- number of , high shade tolerance, and tective effects against liver disorders [26, 27]. extensive root system, and is therefore consid- In this review, the beneficial properties ofP. uri- ered a competitive weed. It is widely found in all naria and its active components were dis- tropical regions of the world, including India, Sri cussed, so that the potential use of this plant Lanka, Indochina, Japan, Malaysia, Indonesia, as pharmaceutics or an agricultural resource and the United States. can be readdressed.

The whole plant could be used as medicine. As Ethnopharmacology a natural product, P. urinaria has long been used in traditional oriental medicine to promote As a Chinese folk medicine, P. urinaria is used healthy elimination of gallstones and kidney for the treatment of liver damage, hepatitis, stones, as an immune system inducer, and for jaundice, renal disorders, enteritis, diarrhea, liver disease treatment [3, 4]. Evidence indi- and dropsy [28]. P. urinaria was shown to have cates that P. urinaria extracts possess numer- hypoglycemic effects in northern Thailand [29]. ous biological activities (Figure 1), including In addition, the herb has long been used for cardioprotective [5], anti-hypertensive [6], anti- liver protection, diabetes, hepatitis, jaundice, plasmodial [7], and antioxidant [5, 8] effects. and dropsy in India [3]. Furthermore, P. urinaria Natural medicine Phyllanthus urinaria

Figure 1. Schematic effects of Phyllanthus urinaria and its active constituents in metabolic syndrome together with some relevant mechanisms. juice is used for tongue cleaning, appetite stim- Polyphenols ulation in children, and malaria treatment in Malaysia [30]. The roots and stem of this plant Polyphenols are considered the main bioactive have been used as natural medicine for the compounds in P. urinaria, and include 9 flavo- treatment of diabetes, hepatitis B virus, and noids and 17 tannins. Flavonoids constitute the kidney and urinary bladder problems in Korea major chemical components of P. urinaria. In [31]. Moreover, P. urinaria is an important 1993, quercetin, rutin and kaempferol were medicinal plant in Indonesia, and traditionally isolated from whole plant extracts of P. urinaria used to treat diseases related to urinary prob- [34]. Then, quercetin 3-O-b-D-glucoside, kaem- lems, such as kidney stones, and urinary tract pferol 7-methyl ether, rhamnocitrin, and narin- infections and malfunction [32]. Meanwhile, P. gin were further isolated from this plant [10, urinaria is used for diabetes and diarrhea treat- 35, 36]. In addition, two new acetylated flavo- ment in Trinidad and Tobago Trinidad and noid glycosides, including quercetin 3-O-α-L- Tobago [33]. (2,4-di-O-acetyl) rhamnopyranoside-7-O-α-L-rh- Phytochemistry amnopyranoside and quercetin 3-O-α-L-(2,4-di- O-acetyl) rhamnopyranoside-7-O-α-L-rhamno- Multiple functional compounds with medicinal pyranoside, alongside quercetin 3-O-α-L-rham- effects, such as flavonoids, carboxylic acids, nopyranoside, were identified [37]. tannins, coumarins, and lignans, have been isolated from P. urinaria (Table 1). In 1993, Yao Tannins QQ et al. isolated 11 compounds from P. uri- naria [34]. So far, about 76 compounds have Tannins are also very abundant in P. urinaria. been isolated and identified in this plant. Zhang LZ et al. isolated a novel polyphenolic

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Table 1. Chemical constituents of Phyllanthus urinaria Category Type Compounds Reference Polyphenols Tannins Excoecarianin [40] Trimethyl-3,4-dehydrochebulate [10] Phyllanthusiin C [41] Epigallocatechin, epicatechin-3-gallate, epicatechin, epigallocatechin-3-gallate [42] Gallocatechin-3-gallate [36] Repandinin B, Furosin, Repandusinic acid A, Mallotinin, Geraniin, Acetonylgeraniin D, Corilagin [35] phyllanthusin F, phyllanthusiin G [43] Flavonoids Rhamnocitrin [10] Rutin, quercetin [10, 36] Naringin [36] Quercetin 3-O-α-L-(2,4-di-O-acetyl) rhamnopyranoside-7-O-α-L-rhamnopyranoside, quercetin 3-O-α-L-rhamnopyranoside [37] Quercetin 3-O-b-D-glucoside, Kaempferol 7-methyl ether [35] Kaempferol [34] Phenylpropanoid Coumarin Ellagic acid, Brevifolincarboxylic acid [41] Methyl brevifolincarboxylate [10, 34] Ethyl brevifolincarboxylate [34] Lignans Phyllanthin, hypophyllanthin, nirtetralin, niranthin, phyltetralin, [45] (+)-dihydrocubebin, (+)-lyoniresiol, (7R,7’R, 8S, 8’S)-icariol A2, evofolin B, 4-oxopinoresinol, (-)-syringaresinol, (-)-episyringaresinol [44] Virgatusin, lintetralin, 5-demethoxyniranthin, urinatetralin [45] Phenols Ferulic acid, p-hydroxybenzaldehyde, 3,5-dihydroxy-4-methoxybenzoic acid, dehydrochebulic acid trimethyl ester [44] Gallic acid,methyl gallate [10, 36] Terpenoids Sesquiterpene Cloven-2β, 9α-diol [44] Monoterpene (6R)-menthiafolic acid [44] Diterpenoids Cleistanthol, Spruceanol [44] Triterpenoids 28-norlup-20(29)-ene-3,17β-diol, Betulin, β-betulinic acid, 3-oxo-friedelan-28-oic acid, oleanolic acid, 3R-E-coumaroyltaraxerol, 3R-Z-coumaroyltaraxerol [46] Glochidiol, oleanolic acid [44] Volatile oils Jasmonate derivatives (+)-cucurbic acid, (+)-methyl cucurbate, methyl[1R,2R,2’Z]-2-(5’-hydroxy-pent-2’-enyl)-3-oxocyclopentaneacetate [44] Aldehyde derivative 5-hydroxymethyl-2-furaldehyde [44] Glycosides Glycosides β-sitosterol-3-O-β-d-glucopyranoside [10] Gentisic acid 4-O-b-d-glucopyranoside, Syringin [35] Steroids Steroids β-sitosterol, [3β, 22E]-stigmasta-5,22-diene-3,25-diol [44] daucosterol [34]

6511 Int J Clin Exp Med 2018;11(7):6509-6520 Natural medicine Phyllanthus urinaria compound phyllanthusin F [38] and an ellagi- Other compounds tannin termed phyllanthusiin G was also report- ed [39]. Further bioassay-guided purification of A number of other compounds have been iso- P. urinaria extracts (PUE) led to the isolation of lated from P urinaria, including glycosides, vola- 7 ellagitannins, including repandinin B, furosin, tile oils, and steroids. β-sitosterol-3-O-β-D-glu- repandusinic acid A, mallotinin, geraniin, aceto- copyranoside, gentisic acid 4-O-b-d-glucopy- nylgeraniin D, and corilagin [35]. Meanwhile, ranoside and syringin are the main glycosides Tseng HH reported 4 tannins, including epicat- isolated from P. urinaria (Table 1). In 2007, gen- echin, epigallocatechin-3-gallate, epicatechin- tisic acid 4-O-b-d-glucopyranoside and syringin 3-gallate and gallocatechin-3-gallate. Recently, were obtained from whole plant extracts of P. 4 major compounds, including excoecarianin, urinaria [35]. Then, in 2008, β-sitosterol-3-O-β- phyllanthusiin C, epigallocatechin, and trimeth- d-glucopyranoside was isolated from this plant yl-3,4-dehydrochebulate were identified as a [10]. Meanwhile, 4 essential oil components, plant fingerprint by HPLC/MS [10, 40-42]. including the 3 jasmonate derivatives (+)- cucurbic acid, (+)-methyl cucurbate, methyl Phenylpropanoids (1R,2R,2’Z)-2-(5’-hydroxy-pent-2’-enyl)-3-oxocy- clopentaneacetate, and the aldehyde deriva- Phenylpropanoids are considered the major tive 5-hydroxymethyl-2-furaldehyde, were iso- bioactive class among P. urinaria compounds, lated from P. urinaria [44]. In addition, three and include coumarin, lignans, and phenols. Steroids, including β-sitosterol, (3β, 22E)-sti- Studies reported 4 coumarin compounds, inclu- gmasta-5,22-diene-3,25-diol and daucosterol ding ellagic acid, methyl brevifolincarboxylate, were recently isolated from P urinaria [34, 44]. ethyl brevifolincarboxylate, and brevifolincar- boxylic acid [34, 41, 43]. In addition, 6 phenols Pharmacological properties P. urinaria (dehydrochebulic acid trimethyl ester, ferulic acid, p-hydroxy-benzaldehyde, 3,5-dihydroxy- Antiviral effects 4-methoxybenzoic acid, gallic acid, and methyl gallate) were isolated and identified [10, 34, Anti-HBV activity: Despite the availability of 36, 41, 44]. effective vaccination programs, HBV infection remains a major world health problem, with Lignans constitute the major class of phenyl- about 400 million people affected worldwide propanoid compounds. Hu et al. identified 7 [47]. It was demonstrated that P. urinaria has lignans, including (+)-dihydrocubebin, (+)-lyoni- good effects on hepatitis B treatment. Indeed, resiol, (7R,7’R, 8S, 8’S)-icariol A2, evofolin B, studies reported that PUE markedly inhibit 4-oxopinoresinol, (-)-syringaresinol, and (-)-epi- intracellular HBsAg formation [48-50] and syringaresinol, from this plant [44]. Moreover, repress HBsAg and HBcAg secretion [50, 51]. Wang CY et al. characterized several lignans PUE also significantly reduce HBV DNA levels by from P urinaria by HPLC-SPE-NMR, including inhibiting its synthesis and secretion in HBV hypophyllanthin, phyllanthin, phyltetralin, nirte- infected cells [51, 52]. In in vivo experiments, tralin, niranthin, virgatusin, lintetralin, 5-deme- Wu Y et al. demonstrated that PUE markedly thoxyniranthin and urinatetralin [45]. repress HBV replication and expression in a Terpenoids HBV transient transfection mouse model [50]. Chen YX et al. showed that PUE significantly Hu et al. isolated 2 triterpenoids (glochidiol and reduce serum DHBV DNA in a duck model of oleanolic acid), 2 diterpenoids (cleistanthol and HBV infection [53]. In clinical trials, Wang MX et spruceanol), 1 sesquiterpene (cloven-2β, 9α- al. demonstrated that P. urinaria promotes diol), 1 monoterpene [(6R)-menthiafolic acid] HBeAg and HBeAb seroconversion from posi- from whole plant extracts of P. urinaria [44]. Wu tive to negative in a total of 35 patients with Y et al. isolated 7 triterpenoids from P. urinaria, chronic hepatitis B [54]. Tong GD et al. showed including 28-norlup-20(29)-ene-3,17β-diol, bet- that P. urinaria effectively decreases HBV-DNA ulin, β-betulinic acid, 3-oxofriedelan-28-oic levels, prevents or delays the development of acid, oleanolic acid, 3R-E-coumaroyltaraxerol, HBV-associated cirrhosis into HCC in 52 and 3R-Z-coumaroyltaraxerol [46]. patients [55].

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P. urinaria compounds exhibit antiviral activi- HIV is a lentivirus that causes acquired immu- ties against hepatitis B virus infection [49, 56]. nodeficiency syndrome [64]. Zhang et al. dem- Zhong Y et al. showed that methyl ester dehy- onstrated the polyphenolic extract and gallic drochebulic acid and methyl brevifolin carboxyl- acid from P. urinaria have anti-HIV-1 activities ate possess antiviral activities against HBV [65]. In addition, the polyphenolic extract and [49]. Shin MS et al. identified the flavonoid gallic acid interact with HIV-1 RT, gp120, and ellagic acid, which effectively inhibits HBeAg P24 [65]. These properties and the anti-HIV-1 secretion in HepG2 2.2.15 cells (IC50 = 70 µg/ activities render the plant interesting for fur- ml) [56]. ther studies.

Anti-HSV properties: HSV is one of the most Human enterovirus 71 (EV71) and coxsackievi- common sexually transmitted diseases world- rus A16 (CA16) are major causative agents of wide [57, 58]. HSV is a single large double- hand, foot, and mouth disease (HFMD), espe- stranded DNA enveloped virus [58, 59]. In cially in infants and children under 5 years of 2005, Yang CM et al. assessed the anti-HSV-1 age. Yeo et al. showed that corilagin reduces and HSV-2 activities of different solvent EV71 or CA16 induced cytotoxicity in Vero cells, extracts from P. urinaria in vitro by plaque with significant antiviral activities against EV71 reduction assay [16]. The results showed that and CA16 [21]. acetone, ethanolic, and methanolic extracts of Epstein-Barr virus (EBV) is a gamma herpes P. urinaria inhibit HSV-2 but not HSV-1 infec- virus that modulates the expression of viral tion. All 3 extracts likely inhibit HSV-2 infection genes. Liu KCSC et al. showed that gallotannin, by altering the early stage of viral infection, corilagin, ellagic acid, and 7 ellagitannins iso- diminishing virus infectivity [16]. lated from P. urinaria could inhibit Epstein-Barr Further studies demonstrated that Hippomanin virus DNA polymerase [66]. A and excoecarianin from the acetone extract Anti-tumor effects of P. urinaria of P. urinaria effectively repress HSV-2 but not HSV-1 infection in vitro [19, 40]. Excoecarianin In recent years, advances in the anti-tumor could inactivate HSV-2 virus particles [40]. effects of P. urinaria have been reported. Meanwhile, geraniin and 1,3,4,6-tetra-O-gallo- Studies showed that PUE significantly reduce yl-b-D-glucose, isolated from the acetone viability in various cancer cell lines [67-70], extract of fresh whole , inhibit HSV-1 and inducing apoptosis in human cancer cells [71]. HSV-2 infection [18]. Corilagin markedly re- The methanolic extract of P. urinaria shows presses HSV induced brain pathological altera- higher cytotoxicity in A549 and MCF-7 cells tions in an animal model [60]. Corilagin mark- compared with the water PUE [72, 73]. P. uri- edly suppresses HSV induced inflammatory naria extracts, which contain polyphenols such cytokines, including TNF-α and IL-1β [60]. as gallic acid, methyl gallate, epicatechin, Furthermore, findings demonstrated that cori- epigallocatechin-3-gallate, gallocatechin-3-gal- lagin protects from HSV-1 encephalitis by inhib- late, rutin, epicatechin-3-gallate, and naringin, iting the TLR2 pathway [61]. Moreover, pro- markedly inhibit cell invasion and migration teomics showed that P. urinaria might affect [36]. P. urinaria also plays a role in angiogene- cytoskeletal protein expression at the early sis in vivo [74, 75]. infection and replication stages [62]. Therefore, P. urinaria represents a plant that can poten- Lung cancer: Lung cancer constitutes one of tially be used as an alternative anti-herpetic the malignancies with the greatest incidence drug. and mortality rates, with 1.6 million new cases and 1.4 million deaths recorded yearly [76]. P. Other antiviral effects: HCV is associated with urinaria exhibits anti-tumor and anti-angiogenic several hepatic and extra hepatic disorders, effects in mice with Lewis lung carcinoma. including malignancies [63]. Chung et al. found Treatment with PUE significantly inhibits tumor that the acetone extract of P. urinaria alters development, with lower occurrence rate and specific steps of the viral life cycle [22]. They markedly reduced tumor size in mice [69]. further found its bioactive component loliolide Furthermore, tumor neovascularization is re- potently inhibits HCV entry [22]. pressed by P. urinaria-treatment [69]. PUE trig-

6513 Int J Clin Exp Med 2018;11(7):6509-6520 Natural medicine Phyllanthus urinaria ger apoptosis through Bcl-2 downregulation all malignancy cases in females [87]. Lee et al. and increased caspase-3 activity in Lewis lung found that Phyllanthus spp. can induce apopto- carcinoma cells [67, 68]. Moreover, PUE inhibit sis, in association with caspase-3 and -7 acti- A549 metastasis by suppressing ERK1/2 and vation, as well as DNA fragmentation, in A549 hypoxia pathways [72, 73]. Tseng HH et al. and MCF-7 cancer cell lines [73]. Moreover, P. demonstrated that PUE inhibit metastasis by urinaria induced apoptosis is mediated by ROS- suppressing MMP-2, MMP-9, and urokinase mediated stimulation of p38 MAPK signaling in plasminogen activator, as well as their endoge- the human breast cancer MCF-7 cell line [88]. nous inhibitors, i.e. tissue inhibitor of metallo- proteinase-2 and plasminogen activator inhibi- Prostate Cancer: Prostate cancer is the second tor-1 [36]. P. urinaria also exhibits anti-angio- most common malignancy and the fifth leading genic activity by suppressing MMP-2 secretion cause of cancer-related death in men [89]. P. and inhibiting MMP-2 activity [67]. Therefore, P. urinaria induces selective growth inhibition of urinaria could be used as alternative anti-lung human cancer PC-3 and MeWo cells through tumor drug. cell cycle modulation and apoptosis induction [90]. Further studies showed that P. urinaria Human osteosarcoma: Human osteosarcoma suppresses prostate cancer cell proliferation is one of the toughest malignancies, with few and induces apoptosis through multiple signal- therapeutic modalities [77]. P. urinaria inhibits ling pathways, including MAPK, PI3K/Akt, human osteosarcoma cell growth through the NF-kappaB, and Hypoxia pathways [90]. extrinsic apoptotic pathway, activating Fas receptor/ligand expression [78]. Meanwhile, Nasopharyngeal carcinoma (NPC): NPC is a PUE repressed Saos-2 cell invasion and migra- common cancer in Taiwan, Hong Kong and tion by inhibiting u-PA via ERK and Akt signaling southern China [91]. Huang ST et al. (2009) pathways [79]. Huang ST et al. demonstrated demonstrated that P. urinaria reduces NPC- that PUE modulate the mitochondrial dynamics BM1 cell growth in vitro through induction of via fusion and fission machineries [70, 80]. Bax/Bcl-2-mediated apoptosis and reduction in telomerase activity via c-myc signaling [41]. Melanoma: Melanoma is the most dangerous type of skin cancer [81]. P. urinaria represses Hepatoprotective effects melanin formation in melanoma B16 cells [82]. Further studies showed that P. urinaria pre- Phyllanthus species are well known for their vents tumor proliferation, metastasis, and hepatoprotective activities [92, 93]. In an ani- angiogenesis by inhibiting MAPKs, Myc/Max, mal model of CCl4-induced acute liver damage, NF-kappaB, and hypoxia pathways in human P urinaria significantly reduces ALT, inhibits oxi- melanoma cells [83]. Bharali R et al. suggest a dative stress, increases membrane mobility, possible chemopreventive property of P. uri- and decreases liver infiltration and focal necro- naria in skin papillomagenesis in mice [84]. sis [94, 95]. Further, metabolomics studies identified 17 biomarkers, including L-carnitine, Hepatocellular carcinoma (HCC): HCC is a high- taurocholic acid, and amino acids, in CCl4- ly prevalent health risk, and the third leading induced rats treated with PUE [28]. Moreover, it cause of cancer related deaths worldwide [85]. was shown that P. urinaria possesses a dose- Blumberg et al. found that PUE can significantly dependent hepatoprotective activity in acet- reduce the liver cancer rate in woodchucks, aminophen/tert-butyl hydroxide/methionine- indicating the overt anti-hepatoma effects of P. and-choline-deficiency induced hepatotoxicity, urinaria [12]. Chudapongse N found that the possibly through inhibition of cytochrome water-methanolic extract of P. urinaria induces P450, oxidative stress, inflammation, and lipid cell death in HepG2 cells, in a dose-dependent accumulation [96-98]. fashion. This extract profoundly reduces state 3 respirations and the respiratory control ratio The hepatoprotective effects of P. urinaria [86]. The authors concluded that P. urinaria could be attributed to corilagin, phyllanthin, impairs energy metabolism to fight hepatocel- and hypophyllanthin, or the combination of vari- lular carcinoma [86]. ous compounds that constitute this extract. Syamasundar KV et al. showed that phyllanthin Breast cancer: Breast cancer is the leading and hypophyllanthin protect against carbon tet- type of cancer in women, accounting for 25% of rachloride- and galactosamine-induced cyto-

6514 Int J Clin Exp Med 2018;11(7):6509-6520 Natural medicine Phyllanthus urinaria toxicity in primary cultured rat hepatocytes Thrombolytic effects: Shen ZQ et al. showed [99]. Liu et al. showed that corilagin treatment that corilagin has a dose-dependent thrombo- effectively ameliorates neutrophil accumula- lytic effect in rats. Meanwhile, corilagin signifi- tion, pro-inflammatory mediator production, cantly inhibits PAI-1 activity in rat plasma, while and increased enzyme release following hepat- increasing plasma tPA activity [4]. ic injury. Interestingly, blocking Akt activation abolishes the hepatoprotective effects of cori- Bladder contraction: Dias MA et al. showed that lagin [100]. However, in a clinical trial, P. urinar- contraction induced by water-ethanolic PUE in ia showed no superiority to placebo in improv- the guinea pig urinary bladder involves direct ing histological non-alcoholic fatty liver disease effects on smooth muscle and relies on the (NAFLD) activity scores in 60 patients (40 and mobilization of extracellular calcium influx 20 treated with PUE and placebo, respectively [109]. [101]. The mechanism underlying the hepato- Antimicrobial activities: Helicobacter pylori is protective effects of P. urinaria is not fully associated with the majority of peptic ulcers understood, and requires further studies. and some types of gastric cancer, and shows antibiotic resistance worldwide. Lai CH et al. Anti-diabetic effects demonstrated that treatment with PUE mark- Diabetes mellitus (DM) is one of the most com- edly inhibits bacterial adhesion and invasion to mon diseases in humans. The ethno-medicinal AGS cells in vitro, in a model of H. pylori infec- plant P. urinaria has been used as herbal anti- tion. Furthermore, PUE remarkably inhibits H. diabetic remedies in Vietnam, and Trinidad and pylori-induced NF-κB activation and IL-8 release Tobago [33, 102]. PUE may exert hypoglycemic [11]. effects by enhancing glucose metabolism and/ Materials and methods or suppressing glucose absorption in the gut [103]. In addition, it was found that PUE signifi- Relevant literature was retrieved by searching cantly affect amylase [32], and inhibit glucose major scientific databases, including PubMed, diffusion across the plasma membrane into Google scholar, and CNKI, for phytochemical, blood vessels [104]. Furthermore, compounds phytopharmacological, and medicinal signifi- isolated from this herb, including gallic acid, cance of P. urinaria. Additional articles were corilagin and macatannin B, significantly obtained by tracking citations from the select- inhibitα-glucosidase [32, 102]. ed publications or directly accessing the jour- nals’ websites. Articles were considered based Anti-oxidative activities on geographical regions of origin. The literature search included all available reports covering Studies have shown that P. urinaria has poten- the period from 1988 to 2017. tial antioxidant agents [5, 10, 35]. Further stud- ies demonstrated that compounds isolated In summary, through comprehensive assess- from P. urinaria have strong antioxidant activi- ments in recent studies, the effects of P. uri- ties, e.g. phenolic compounds [35], trimethyl- naria (e.g. antiviral, anti-tumor, and liver protec- 3,4-dehydrochebulate [10], methyl-gallate [10], tive activities) have been demonstrated. Con- methyl brevifolincarboxylate [10], and geraniin sequently, tablets, granules, capsules, and [6]. By dampening oxidative stress, this plant other formulations based on P. urinaria have may serve as an alternative source of medicine surfaced, with good curative effects in liver dis- for steatohepatitis alleviation [98], skin disor- eases such as hepatitis B. Therefore, exploita- der treatment [105], skin aging amelioration tion and further evaluation of P. urinaria is [106], protection against DOX cardiotoxicity [5, urgent thanks to its clinical significance and 107], and modulation of phagocyte associated great potential for application. It is believed innate immune response [108]. that broad application of P. urinaria with improved treatment effects can be achieved in Other activities the future.

Antihypertensive activity: Geraniin from P. uri- Disclosure of conflict of interest naria displays anti-hypertensive effects, lower- ing systolic and diastolic blood pressures [6]. None.

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