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Evidence-Based Complementary and Alternative Medicine
Volume 2016 (2016), Article ID 7584952, 36 pages
http://dx.doi.org/10.1155/2016/7584952
Review Article

The Genus Phyllanthus: An Ethnopharmacological, Phytochemical, and Pharmacological Review

1School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China
2Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
3Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
4Key laboratory of Chinese Internal Medicine, Beijing University of Chinese Medicine, Beijing 100700, China

Received 22 January 2016; Revised 23 March 2016; Accepted 30 March 2016

Academic Editor: Gloria Brusotti

Copyright © 2016 Xin Mao 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.

Abstract

The plants of the genus Phyllanthus (Euphorbiaceae) have been used as traditional medicinal materials for a long time in China, India, Brazil, and the Southeast Asian countries. They can be used for the treatment of digestive disease, jaundice, and renal calculus. This review discusses the ethnopharmacological, phytochemical, and pharmacological studies of Phyllanthus over the past few decades. More than 510 compounds have been isolated, the majority of which are lignins, triterpenoids, flavonoids, and tannins. The researches of their remarkable antiviral, antioxidant, antidiabetic, and anticancer activities have become hot topics. More pharmacological screenings and phytochemical investigations are required to support the traditional uses and develop leading compounds.

1. Introduction

Phyllanthus (Euphorbiaceae) is a large genus and widely distributed in tropical and subtropical zones like tropical Africa, tropical America, Asia, and Oceania. This genus, consisting of more than 700 species, can be classified into 11 subgenuses [1, 2]. The most popular 24 species are chiefly belonging to subgenus Kirganelia, Cicca, and Phyllanthus and they are traditionally used by different nationalities.

Genus Phyllanthus has been employed as herbal drugs for a long time in China, India, Brazil, and Southeast Asian countries. The most abundant species are used in India and have a beneficial role in Ayurveda for the treatment of digestive, genitourinary, respiratory, and skin diseases [3, 4]. In China, herbs and their prescriptions are used to treat hepatitis B, hypertension, dropsy, and sore throat [2]. These herbal drugs are employed by local inhabitants of Thailand, Latin America (especially Brazil), and Africa to cure jaundice, renal calculus, and malaria, respectively [57].

By virtue of the wide uses of Phyllanthus as anti-HIV, anticancer, and anti-HBV agents, there has been considerable interest in the investigations of this genus in recent years and the researches about pharmacology and chemistry had been finished in a deep going way. This report reviews the ethnopharmacological, phytochemical, and pharmacological investigations of Phyllanthus over the past few decades. More than three hundred articles were selected from the data taken from SciFinder Scholar database by searching the keyword “Phyllanthus”.

2. Ethnopharmacological Uses

The traditional application experiences of these herbs may have reference value for the treatment of recent diseases. Botanical data, folk name, and medicinal properties of twenty-four Phyllanthus species are depicted in Table 1. In Asia, seventeen plants are considered to have bitter and astringent taste. They are regarded as stomachic, diuretic, febrifuge, deobstruent, and antiseptic agents and effective remedies for hepatopathy, hypertensive, diabetes, and jaundice. In Africa, six herbs are widely employed by many tribes for the treatment of malaria wound and tetanus. Six species are used extensively in Latin America for the treatment of urination disorder and diabetes. The distribution and the main uses of Phyllanthus are pictured in Figure 1.

Table 1: The traditional use of Phyllanthus.
Figure 1: Traditional use of genus Phyllanthus in different countries. Different color represents the number of plants traditionally used in different countries: red, orange, yellow, green, blue, and purple represent fifteen, eight, five, three, two, and one kinds of plants under use, respectively. In Asia, Phyllanthus are used to treat digestive system disease, in south America, Phyllanthus are used to treat urinary system disease, and in Africa, Phyllanthus are used to treat malaria and wound.
2.1. Asia

In Asia, the clinical use of genus Phyllanthus is very prevalent. The fruit of P. emblica has a long history of use in India and is called “amla” or “Indian gooseberry.” As a tonic in Indian Ayurveda, it is often used for liver diseases [3, 4]. This fruit is known as “yuganzi” in China. It has sweet and slightly astringent taste and is used for clearing heat from throat and moistening lung for arresting cough in Traditional Chinese Medicine (TCM). In Tibetan medicine this herb is used to treat blood and bile disease, and its preparations are clinically applicable to hypertension and anuria [2]. In Thailand, it is named “makham pom” and is employed to treat gastrointestinal chronic diseases. P. emblica is commonly used together with Terminalia chebula and T. belerica and called “Triphala.” “Triphala” is used as a clinical treatment protocol of gastropathy in India and as a remedy for pestilence and fatigue in China [62].

In India, fifteen species of genus Phyllanthus are widely used by indigenous medicine. These plants have bitter and astringent taste and are considered as stomachic, diuretic, febrifuge, deobstruent, antiseptic, and effective remedies for hepatopathy. Some herbs such as P. niruri, P. amarus, P. fraternus, P. debilis, and P. maderaspatensis share the same name “bhuiamlki” [29]. The fruits of “bhuiamlki” are employed by Ayurveda to cure jaundice. P. simplex, P. reticulatus, and P. acidus are therapy of urinary disease and have the names of “bhuiaveli,” “pancoli,” and “harfarauri,” respectively. The leaves of P. polyphyllus, called “sirunelli,” are used for liver disease. Additionally, the rest of these herbs can be employed as remedies for diabetes, jaundice, wound, fever, and inflammation.

In China, five herbs are commonly used by TCM, Tibetan medicine, Dai People, and Yi People [2]. They have bitter and sweet taste and are usually used as prescriptions. The whole plant of P. urinaria, known as “yexiazhu,” can clear heat-toxin and remove dampness and is employed to treat jaundice, enteritis, diarrhea, and dropsy. Besides, the TCM prescription, named “yexiazhu capsule,” performs a beneficial role in curing hepatitis B. Other herbs such as P. reticulatus, P. niruri, and P. simplex are beneficial to the treatment of ophthalmopathy, urinary infection, inflammation, and rheumatism.

In Thailand, eight herbs of this genus are widely used by residents. P. amarus, P. urinaria, and P. virgatus share the name “look tai bai,” all of which are used for treating gonorrhea, jaundice, diabetic, and liver disease. P. acidus has three names: “otaheiti gooseberry,” “star gooseberry,” and “mayom,” and it can be used as remedy for hypertensive, constipation, skin disease, and fever. The rest of herbal drugs including P. taxodiifolius, P. niruri, and P. reticulatus are employed for the treatment of urination disorder and malaria.

2.2. Africa

Many African tribes employ six plants of genus Phyllanthus to treat malaria, fever, and wound. P. muellerianus is the most popular herbal drugs of this genus in Africa. It is named “mbolongo” in Cameroon. In Ghana and Cameroon, the stem bark is used for the therapy of wound and tetanus. In Nigeria, Zambia, and Ivory Coast the leaves and root are applied as a fever remedy. In Kenya, the root of P. polyanthus is used to cure sexually transmitted diseases. What is more, the whole plants of P. muellerianus and P. reticulatus can be used for the treatment of malaria.

2.3. Latin America

About six herb species of this genus are used in many countries in Latin America. In Brazil, P. tenellus is popularly known as “quebra-pedras” whose leaves can be used as diuretic. P. amarus is named “chanca piedra” in Peru and the leaves are employed for diabetic and jaundice therapy or as sedative and astringent. P. sellowianus is called “sarandi blanco” in South America and used widely in folk for the treatment of urination disorder and diabetes.

In summary, P. emblica, P. reticulatus, and P. niruri are the top three species widely used around the world. P. niruri is probably the most widespread herb of Phyllanthus, which is named “chanka piedra,” “bhuiamlki,” “zhuzicao,” “dukung anak,” “quebra-pedra,” and “chanca piedra.” Its whole plant can treat inflammation, lithiasis, fever, malaria, hepatitis, and gonorrhea [7, 18, 19, 21, 22].

3. Chemical Constituents

More than 510 compounds have been isolated from Phyllanthus, the majority of which are lignins, triterpenoids, flavonoids, and tannins. The compositions isolated from each species and their biological activities are partially summarized in Table 2. Lignins and tannins exhibit various activities and are considered to be the biological active compounds of this genus. Corilagin, geraniin, and gallic acid are three most prevalent compounds in this genus, and the pharmacological researches mainly focus on phyllanthin, niranthin, and geraniin.

Table 2: The compounds isolated from the genus Phyllanthus and part of pharmacological effects.
3.1. Terpenoids

Terpenoids are the most prevalent chemical class of the genus. About 125 compounds including 69 triterpenoids (1–69), 40 sesquiterpenes (70–109), 11 diterpenoids (110–120), and 5 monoterpenes (121–125) are mainly identified from P. flexuosus, P. reticulatus, P. watsonii, P. emblica, P. acuminatus, and P. veuminatus. Compounds 1–14 are tetracyclic triterpenoids, and compounds 15–69 are pentacyclic triterpenoids. In pentacyclic triterpenoids, compounds 15–36, compounds 37–49, and compounds 50–65 are oleanane type, friedelane type, and lupine type, respectively. Glochidone and lupeol are representatives of lupine type triterpenoids, which were suggested to have antitumor activities and mainly isolated from Phyllanthus species [68, 80, 96].

3.2. Phenylpropanoids

Phenylpropanoids (126–227) have typical C6–C3 constituents, which chiefly involve three groups including lignins, simple phenylpropanoids, and coumarins. 90 lignins (126–215) have been isolated from genus Phyllanthus since 1944. Compounds 126–176 are arylnaphthalene type lignins with a ring caused by the link of C-6 and C-7′. Compounds 177–190 are dibenzylbutane type lignins with two simple phenylpropanoids bounded by C-8 and C-8′. Phyllanthin, which had been studied to the most extent, was considered to be correlated with anti-inflammatory, immunomodulatory, antitumor, and hypotensive activities [127, 144, 163]. Pharmacokinetic studies of retrojusticidin B, a potential anti-HIV compound, had been done. The oral bioavailabilities dissolved in Tween 80 and in corn oil were found to be 22.1 and 33.1%, respectively [152].

3.3. Tannins

Tannins were progressively reported from the genus Phyllanthus since 1992. Hydrolyzable tannins (228–270) are characterized by the presence of one or more galloyl, hexahydroxydiphenoyl (HHDP), and HHDP metabolites attached to a glucopyranose core, which are mainly isolated from P. emblica, P. amarus, P. niruri, and P. urinaria. Compounds 271–279 are condensed tannins, which are the condensation of flavan-3-ols and linked by C-C. A great many condensed tannins were proved to have antiviral activity [53]. Ellagitannins (232–270) are the largest group of hydrolyzable tannins. Corilagin and geraniin are most extensively obtained from this genus and are characteristic compounds of ellagitannins, which exhibited multiple activities such as antioxidant, anti-HIV, antitumor, and antihyperalgesic activities [6, 111, 188, 195, 196, 199, 201, 202].

3.4. Flavonoids

Compounds 281–334 are flavonoids, which mainly contain flavonols (280–309), flavones (310–317), flavonones (318–324), flavan-3-ols (325–330), flavanonols (331), and isoflavone (332-333). Flavan-3-ols are the basic constitution of condensed tannins. Flavonols such as quercetin, quercitrin, and rutin demonstrated anti-inflammatory and antioxidant activities [151, 171, 178, 195, 203, 224].

3.5. Sterols

Until now, thirty sterols (334–363) from Phyllanthus have been reported. All the sterols are phytosterols with a side chain (C8–C10) substitution at C-17, and half of which were isolated from P. emblica.

3.6. Alkaloids

Thirty-two alkaloids (364–395) have been found in genus Phyllanthus, most of which are securinine and securinine-related compounds and mainly distributed in P. niruri. Compounds 390-391 isolated from P. fraternus are amide type alkaloids and exhibited antimalarial potential [250].

3.7. Phenols and Others

Compounds 396–468 belong to phenols, which have one and several phenolic hydroxyl groups. Thirty other constitutions (469–512) have been isolated. Mucic acid (compounds 445–455) and its derivatives (compounds 498-499) can only be found in P. emblica among this genus.

4. Biological Activity

The remarkable traditional uses of genus Phyllanthus lead to the various researches of biological activities, such as antiviral, antioxidant, antidiabetic, anticancer, and immunomodulatory activities. In this section, biological activity researches of the extracts of the plants are highlighted.

4.1. Antiviral Activity

Various Phyllanthus plants were reported to have strong antiviral potential such as anti-HIV, anti-HCV, anti-HSV, and anti-HCMV. The aqueous extract of P. emblica reduced viral load of HIV significantly at the dose of 400 μg/mL [282]. DNA-polymerase and ribonuclease H (RNase H) activities of HIV-1 reverse transcriptase were inhibited by aqueous extract of P. sellowianus with IC50 values of μg/mL and μg/mL, respectively [283]. Moreover, methanol extract of P. reticulatus strongly inhibited the activity of RNase H by 99% at the dose of 50 μg/mL [284].

HCV-infected HuH7 cells were used to test the anti-HCV activities of methanolic fraction of P. amarus. The fraction was proved to suppress the replication of HCV monocistronic replicon RNA and HCV H77S viral RNA without toxic effect in host cells. Inhibiting HCV-NS3 protease enzyme and NS5B enzyme may be the main mechanism [285]. Aqueous extract of P. orbicularis revealed inhibition activity against the replication of HCMV, HSV-1, and HSV-2 as well as BHV-1 with EC50 values of 57.7, 28.8, 25.7, and 21.27 μg/mL, respectively. The selectivity indexes (SI) were ranged from 8.7 to 37.6 [286, 287].

Friend murine leukemia virus (FMuLv) induced erythroleukemia in BALB/c mice was relieved by metabolic extract of P. amarus. The extract inhibited leukemic cells from infiltrating into the sinusoidal space, decreased the morbidity of anemia, and improved survival rate of leukemia animals. Besides, the extract induced the upregulation of p53 and p45NFE2 and downregulation of Bcl-2 in the spleen [288].

4.2. Antioxidant Activity

Methanolic and aqueous parts of this genus have remarkable antioxidant activity, which may be correlated with the hydroxyl rich compositions. P. acidus, P. polyphyllus, and P. fraternus showed remarkable hepatoprotective activity against liver toxicity which was induced by acetaminophen, carbon tetrachloride, bromobenzene, and thioacetamide [42, 289291]. The biochemical parameters as well as antioxidants levels were restored by these parts at the dose of 300 mg/kg. What is more, mitochondrial dysfunction in liver, induced by bromobenzene, was relieved by prior oral administration of aqueous part of P. fraternus at the dose of 100 mg/kg [51, 291].

Antimycin A governed mitochondrial protein degeneration, lipid peroxidation and mitochondrial DNA damage, and H2O2 induced membrane damage of Hep3B cells were considerably mitigated by aqueous fraction of P. amarus [164]. Mutagenesis induced by PhIP and 4-ABP and DNA damage induced by γ-ray and UVB were protected by aqueous fraction of P. orbicularis [292294].

Methanol extract of P. debilis showed strong antioxidant activity when tested by various antioxidant assays including total antioxidant, free radical scavenging, superoxide anion radical scavenging, hydrogen peroxide scavenging, and nitric oxide scavenging assays. Besides, further study demonstrated that total phenolic was correlated with antioxidant activity [52]. In addition, hydromethanolic extract of P. virgatus exhibited substantially antioxidant capacity in both DPPH scavenging (IC50 = 30.4 μg/mL) and linoleic acid oxidation inhibiting (84%) method [5].

4.3. Antidiabetic Activity

Twelve herb drugs such as P. emblica, P. reticulatus, P. niruri, P. amarus, P. urinaria, P. acidus, P. debilis, P. virgatus, P. sellowianus, P. rheedii, P. orbicularis, and P. hookeri are traditionally employed for diabetes in many countries. Recent researches about the hypoglycemic effect of Phyllanthus plants were abundant. Streptozotocin- and alloxan-induced diabetic rats were employed for the evaluation of antidiabetic potential of P. emblica, P. niruri, P. reticulatus, P. sellowianus, P. virgatus, and P. simplex [4, 295299]. After oral administration of these (aqueous, methanol, and ethanol) extracts for 21–45 days, the concentration of blood glucose was significantly reduced, and the effects of P. sellowianus and P. simplex were similar to the glibenclamide group (10 mg/kg). In addition, methanol fraction of P. virgatus considerably inhibited the activity of α-amylase in the noncompetitive pattern with IC50 of μg/mL [300].

After oral aqueous extract of P. niruri for 28 days, the levels of LPO and MDA were decreased while the concentrations of SOD, CAT, and GPx were increased. After being pretreated with the aqueous fraction of P. sellowianus, hemorheological parameters were ameliorated and red blood cells (RBCs) showed large globular aggregates and agglutination [301].

4.4. Anticancer Activity

Different extracts of the plants have been assessed for anticancer effects and the related mechanisms. Cancer cell lines such as NCI-H1703, MDA-MB-231, HeLa, 143B, PC-3, MCF-7, HepG2, A549, SKOV3, and HT-29 were considerably inhibited by P. emblica, P. urinaria, P. polyphyllus, P. watsonii, and P. pulcher [57, 68, 302309]. In addition, P. emblica showed no toxicity to normal cells (MRC5). The extracts inhibited growth of cells through fragmentation of DNA and dysfunction of mitochondrial including upregulated mitochondrial fission 1 protein and downregulated optic atrophy type 1 and mitofusin 1 [304]. Moreover, the extracts suppressed the ability of cell invasion, migration, and adhesion. Further researches demonstrated that the fractions induced apoptosis, invasion, and migration through increasing the expression of caspase-3, caspase-7, caspase-8, and p-JNK and decreasing the expression of ERK, p-ERK1/2, JNK, MMP-2, MMP-9, Wnt, NF-κB, Myc/Max, and hypoxia [302, 303, 307].

Ehrlich ascites carcinoma tumor model was used to evaluate the antitumor activity of P. polyphyllus. Oral administration of methanol fraction at the dose of 200 mg/kg could significantly reduce the solid tumor volume. Hematological parameters, protein, packed cellular volume (PCV), and antioxidant enzymes such as LPO, GPx, GST, SOD, and CAT were greatly regulated [57].

4.5. Immunomodulatory Activity

Ethanol extracts of P. urinaria and P. amarus were demonstrated to have inhibitory effects on the chemotaxis of neutrophils and monocytes with IC50 lower than 2.92 μg/mL. In addition, phagocytic activity and CD18 expression of neutrophils and monocytes were downregulated [163].

Oral administration of P. reticulatus extract at the dose of 100 mg/kg demonstrated a significant increase in phagocytic activity, the percentage of neutrophil adhesion, and white blood cell in albino mice [310].

4.6. Analgesic Activity

The extracts of P. corcovadensis, P. niruri, and P. tenellus showed significant reduction in writhing response induced by acetic acid, with ID50 values of 30, 19, and >30 mg/kg, respectively. The late phase of formalin-induced pain could be relieved by P. tenellus with ID50 of 100 mg/kg and both phases of formalin-induced pain could be reduced by P. corcovadensis and P. niruri with ID50 values of 100 and 52 mg/kg, respectively. The analgesic effects could not be antagonized by naloxone [311]. In addition, intraperitoneally given hydroalcoholic extracts of P. amarus, P. orbicularis, and P. fraternus produced a marked analgesic activity by inhibiting acetic acid-induced abdominal constriction, capsaicin-induced neurogenic pain, and late phase of formalin-induced paw licking [312]. The ethanol and aqueous extracts of P. emblica succeeded in inhibiting acetic acid-induced writhing response but failed in the tail-immersion test [313].

4.7. Anti-Inflammatory Activity

In recent years, different inflammatory models such as Freund’s complete adjuvant induced arthritis, carrageenin induced paw edema, and cotton pellet induced granuloma were employed to evaluate the anti-inflammatory effect of Phyllanthus. After receiving the aqueous extract of P. amarus, indexes of arthritis, joint diameter, and paw volume were decreased and thresholds of mechanical hyperalgesia and nociceptive were increased [314]. The ethanol fraction of P. simplex ameliorated the parameters of paw edema and granuloma and substantially inhibited nitric oxide (NO) production [315].

4.8. Antispasmodic Activity

Isolated rabbit jejunum and guinea-pig ileum were employed for the in vitro tests for the antispasmodic effects of P. emblica. Carbachol and K+ induced contractions of rabbit jejunum were released by the extract with IC50 values of 0.09 mg/mL and 1.38 mg/mL. The pretreatment of guinea-pig ileum with the extract at 0.3 mg/mL caused a rightward parallel shift in the concentration-response curves of acetylcholine without suppression of the maximum contractile response. Dual blockade of muscarinic receptors and Ca2+ channels can explain its antispasmodic activity [316].

4.9. Hypotensive and Hypolipidemic Activity

Aqueous extract of the leaves of P. amarus was found to restrain both force and rate of myocardial contraction and to inhibit the intrinsic myogenic contraction of isolated rat portal vein [317]. Aqueous part of P. reticulatus was effective in releasing total cholesterol, lipid profile, and oxidative stress in hypercholesterolemic albino rats after oral administrated for 45 days at 250 mg/kg [14].

4.10. Wound Healing

Extracts of P. emblica and P. niruri were demonstrated to have wound healing effect. Topical application with P. emblica could promote the proliferation of cells and cross-link of collagen in the full thickness excision wound [318]. Oral administration of P. emblica at the dose of 60 mg/kg showed healing effect against NSAID-induced gastric ulcer through upregulating the concentration of IL-10 and downregulating the levels of TNF-α and IL-1β [319]. After treatment with P. niruri at the dose of 200 mg/kg, 98.8% of wound could be recovered in the excision and incision wound models on the 16th day [320].

4.11. Antimalarial Activity

Malaria is a prevalent disease in many tropical and subtropical countries and folks of these places especially African people employed Phyllanthus as antimalarial agency. Plasmodium falciparum was suppressed by ethyl acetate fraction of P. acidus with IC50 of 9.37 μg/mL, and the SI equals 4.88 for HEp-2 cells and 11.75 for Vero cells [321]. What is more, chloroquine-resistant P. falciparum could be exhibited by P. amarus and P. muellerianus with IC50 values of 11.7 and 9.4 μg/mL, respectively. P. amarus presented protection effect on human RBCs damage caused by the virus [322]. The SI of P. muellerianus was higher than 5.3 for L-6 and MRC-5 cell lines [25, 202].

4.12. Antidepressant Activity

The aqueous extract of P. emblica (200 mg/kg) significantly decreased immobility period in both tail suspension test and forced swim test by decreasing the levels of MAO-A and GABA [323]. In the plus-maze, Hebb-Williams maze, and passive avoidance apparatus test, preparation of P. emblica produced a dose-dependent upgrade in scores. The preparation was also proved to reverse the amnesia induced by diazepam and scopolamine and to reduce the cholinesterase activity and total cholesterol level in brain [324, 325].

4.13. Others

The essential oil fraction of P. muellerianus exhibited strong antibacterial activity against Clostridium sporogenes, Streptococcus mutans, and S. pyogenes with MIC values ranging from 13.5 to 126 μg/mL [326]. Methanol extract of P. acuminatus (100 mg/mL) showed stronger antifungal than Dithane M-45 (10 000-ppm solution) against Pythium ultimum [327].

Aqueous extract of P. acidus was proved to regulate electrolyte transport in cystic fibrosis airways by increasing the intracellular levels of cAMP and Ca2+, stimulating basolateral K+ channels, and activating and redistributing cellular localization of cystic fibrosis transmembrane conductance regulator [328].

Eight hours after being treated with the aqueous extract of P. sellowianus at a dose of 400 mg/kg, urine output of test animals was decreased from 2.59 to 3.69 mL/100 g [329].

5. Clinical Studies

The extracts of P. niruri were proved to have immunomodulatory effect and played a crucial role in treating pulmonary tuberculosis and vaginal candidiasis as well as varicella. In patients with pulmonary tuberculosis, after oral administration of P. niruri 50 mg/mL for 2–6 months, the level of IL-10 was decreased and the levels of plasma IFN-γ and TNF-α were significantly increased. After 1-month treatment, the increase of the ratio of CD4+/CD8+ was observed. In the vaginal candidiasis patients, after receiving P. niruri 100 mg/mL for 1–3 months, the levels of IFN-γ and IL-12 were elevated. As for varicella patients, the number of papules and the number crusts were decreased after treatment with the extract at the dose of 5 mg/mL [330].

Clinical studies of P. niruri in Brazil had been finished, from which the P. niruri showed beneficial effects on the treatment of urolithiasis. After 3-month treatment, calculi elimination was increased. Furthermore, urinary calcium excretion and residual stone fragments after lithotripsy were decreased. Toxic effects on kidney, cardiovascular, and nervous systems were not found [331].

In China, the clinical study of P. urinaria in treating chronic hepatitis B with 140 patients was well established. The results indicated that, after treatment with P. urinaria capsule for 3 months or 2 years, especially in the long term, the recovery rate in the index of HBV-DNA and HBeAg was 88.2% and 52.5%, respectively. Once the treatment stopped, the recurrence rate was 10.4% to 13.4% [332].

6. Toxicity Studies

After given aqueous leaf extract of P. niruri at the dose of 2000 mg/mL, no acute toxicity was observed at the levels of bilirubin, ALT, AST, total protein, albumin, globulin, ALP, GGT, urea, creatinine, full blood count, and hemoglobin [333]. After being treated with ethanol extract of P. niruri over a period of 90 days at doses of 30 and 300 mg/kg, the rats showed no genotoxic effect at the test of PCE/NCE ratio [334]. Reproductive toxicity of P. niruri was tested using estrogen values, progesterone values, and testosterone levels. The estrogen and progesterone levels increased more than 1.5-fold above the control group after receiving 50 and 500 mg/kg aqueous leaf extract for 90 days, which reminded us of the cytotoxic of male antifertility properties [335].

Nephrotoxicity including interstitial oedema and tubular necrosis were detected after receiving 400 and 800 mg/kg of aqueous extract from P. amarus for 30 days [336]. The test animals were given 800 and 1600 mg/kg of the aqueous extract of P. amarus for 10 days, and significant pathological changes were found in the liver, kidney, and testis. The frequency of MNPCE, sperm abnormalities, total white blood cell, and lymphocyte counts were significantly increased, which suggested the genetic and systemic toxicity of P. amarus [337]. In addition, aqueous, methanolic, and hydromethanolic extracts of P. amarus (400 mg/kg) reduced locomotor activity and showed CNS depressant effect [338].

The LD50 of ethanolic extract from P. fraternus was 1125 mg/kg in the toxicity test. When the rats received the extract at doses of 400 mg/kg for 7 days, no toxicity was detected in liver and kidney [339]. Hydroethanolic extract P. fraternus showed the quick onset and long duration of reduction of locomotor activity at the dose of 400 mg/kg [338].

7. Conclusion

514 compounds have been isolated from different species of Phyllanthus, including 126 terpenoids, 102 phenylpropanoids, 73 phenols, 54 flavonoids, 53 tannins, 33 sterols, 31 alkaloids, and a number of other compositions. Their wide range of biological activities such as antiviral, antioxidant, antidiabetic, anticancer, anti-inflammatory, hypolipidemic, immunomodulatory, and antidepressant activities are tested using polar solvents (water, methanol, and ethanol) extracts. These extracts are considered rich in phenols, flavonoids, and tannins, which may exhibit antioxidant activity in different degree due to their hydroxyl [340]. Consequently, most bioactivities of Phyllanthus may be correlated with the hydroxyl rich compounds.

In recent years, the traditional uses of Phyllanthus had been partly confirmed, and more evidences such as pharmacological researches and clinical studies are urgently needed to be taken. Further studies of phytochemical discovery and subsequent screenings are necessary to be taken to extend the use of Phyllanthus and to develop leading compound.

Competing Interests

The authors declare that they have no competing interests.

Acknowledgments

This project was supported by the National Natural Science Foundation of China (81274187 and 81274006) and Transformation and industrialization of Science and Technology Achievements, “New Drug AIKEXIN Development Research for the Treatment of AIDS.”

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