Ethnomedicinal uses, phytochemistry and pharmacological properties of the genus Boerhavia

Kapil Patil

ETHNOPHARMACOLOGICAL RELEVANCE: The genus Boerhavia is widely distributed in tropical, subtropical and temperate regions of the world including Mexico, America, Africa, Asia, Indian Ocean Islands, Pacific Islands and Australia. The genus Boerhavia is extensively used by local peoples and medicinal practitioners for treatments of hepatitis, urinary disorders, gastro intestinal diseases, inflammations, skin problems, infectious diseases and asthma. Present review focused on traditional uses, phytochemistry, pharmacology and toxicology of Boerhavia genus to support potential scope for advance ethnopharmacological study. MATERIALS AND METHODS: Information on the Boerhavia species was collected from classical books on medicinal plants, pharmacopoeias and scientific databases like PubMed, Scopus, GoogleScholar, Web of Science and others. Also scientific literatures based on ethnomedicinal surveys, Ph.D. and M.Sc. dissertations, published papers from Elsevier, Taylor and Francis, Springer, ACS as well as Wiley publishers and reports by government bodies and documentations were assessed. RESULTS: A total of 180 compounds from Boerhavia genus were isolated of which B. diffusa alone shared around 131 compounds and for most of which it is currently an exclusive source. In the genus, phenolic glycosides and flavonoids contribute approximately 97 compounds. These includes eupalitin, rotenoids like boeravinones, coccineons, alkaloid i.e. betanin and punarnavine etc., showing vital pharmaceutical activities such as anticancer, anti-inflammatory, antioxidant and immunomodulatory. CONCLUSION: Boerhavia is an important genus with wide range of medicinal uses. However, most of the available scientific literatures have lacked relevant doses, duration and positive controls for examining bioefficacy of extracts and its active compounds. In some studies, taxonomic errors were encountered. Moreover, there is need for accurate methods in testing the safety and ethnomedicinal validity of Boerhavia species.

Journal of Ethnopharmacology 182 (2016) 200–220 Contents lists available at ScienceDirect Journal of Ethnopharmacology journal homepage: www.elsevier.com/locate/jep Review Ethnomedicinal uses, phytochemistry and pharmacological properties of the genus Boerhavia Kapil S. Patil, Sanjivani R. Bhalsing n Department of Biotechnology, School of Life Sciences, North Maharashtra University, Jalgaon 425001, Maharashtra, India art ic l e i nf o a b s t r a c t Article history: Received 12 August 2015 Received in revised form 27 January 2016 Accepted 31 January 2016 Available online 2 February 2016 Ethnopharmacological relevance: The genus Boerhavia is widely distributed in tropical, subtropical and temperate regions of the world including Mexico, America, Africa, Asia, Indian Ocean Islands, Paciﬁc Islands and Australia. The genus Boerhavia is extensively used by local peoples and medicinal practitioners for treatments of hepatitis, urinary disorders, gastro intestinal diseases, inﬂammations, skin problems, infectious diseases and asthma. Present review focused on traditional uses, phytochemistry, pharmacology and toxicology of Boerhavia genus to support potential scope for advance ethnopharmacological study. Materials and methods: Information on the Boerhavia species was collected from classical books on medicinal plants, pharmacopoeias and scientiﬁc databases like PubMed, Scopus, GoogleScholar, Web of Science and others. Also scientiﬁc literatures based on ethnomedicinal surveys, Ph.D. and M.Sc. dissertations, published papers from Elsevier, Taylor and Francis, Springer, ACS as well as Wiley publishers and reports by government bodies and documentations were assessed. Results: A total of 180 compounds from Boerhavia genus were isolated of which B. diffusa alone shared around 131 compounds and for most of which it is currently an exclusive source. In the genus, phenolic glycosides and ﬂavonoids contribute approximately 97 compounds. These includes eupalitin, rotenoids like boeravinones, coccineons, alkaloid i.e. betanin and punarnavine etc., showing vital pharmaceutical activities such as anticancer, anti-inﬂammatory, antioxidant and immunomodulatory. Conclusion: Boerhavia is an important genus with wide range of medicinal uses. However, most of the available scientiﬁc literatures have lacked relevant doses, duration and positive controls for examining bioefﬁcacy of extracts and its active compounds. In some studies, taxonomic errors were encountered. Moreover, there is need for accurate methods in testing the safety and ethnomedicinal validity of Boerhavia species. & 2016 Published by Elsevier Ireland Ltd. Keywords: B. diffusa Boeravinones Medicinal Pharmacology Punarnavine Chemical compounds studied in this article: Boeravinone A (PubChem CID: 14018346) Boeravinone B (PubChem CID: 14018348) Boeravinone D (PubChem CID: 15081178) Boeravinone E (PubChem CID: 11537197) Boeravinone G (PubChem CID: 11537442) Boeravinone H (PubChem CID: 16745324) Coccineone B (PubChem CID: 44420939) Quercetin (PubChem CID: 5280343) Repenone (PubChem CID: 44257427) Repenol (PubChem CID: 44257428) Contents 1. 2. 3. 4. 5. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Boerhavia genus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Geographical distribution and botanical description . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Quality assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ethnomedicinal uses of Boerhavia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Phytochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201 201 201 202 202 205 205 Abbreviations: IL-2, Interleukin-2; NK, Natural Killer; TNF, Tumour Necrosis Factor; PBMCs, Peripheral Blood Mononuclear Cells; ROS, Reactive Oxygen Species; MAP, Mitogen-Activated Protein; ESR, Electron Spin Resonance; HBV, Hepatitis-B Virus; Th1, T helper 1; IFN, Interferon; WSSV, White Spot Syndrome Virus; VEGF, Vascular Endothelial Growth Factor; RT-PCR, Reverse Transcription Polymerase Chain Reaction; ELISA, Enzyme-Linked Immunosorbent Assay; HUVECs, Human Umbilical Vein Endothelial Cells; ATO, Arsenic Trioxide; NO, Nitric Oxide; IC50, 50% Inhibition Concentration; EC50, Half Maximal Effective Concentration; ED50, Median Effective Dose; LC50, Half Maximal Lethal Concentration; HPLC-PAD, High-performance Liquid Chromatography with Pulsed Amperometric Detector; ESI-MS, Electrospray Ionisation Mass Spectrometry; MMP, Matrix Metallo Peptidase; MOA, Monoamino Oxidase. EtOH, Ethanol; MeOH, Methanol; RSC50, Radical Scavenging Capacity of 50%; TDI, Toluene Diisocyanate; CMC, Carboxymethylcellulose n Corresponding author. E-mail address: bhalsingsr@gmail.com (S.R. Bhalsing). http://dx.doi.org/10.1016/j.jep.2016.01.042 0378-8741/& 2016 Published by Elsevier Ireland Ltd. K.S. Patil, S.R. Bhalsing / Journal of Ethnopharmacology 182 (2016) 200–220 201 5.2. Phenolic compounds: Phenolic acids/glycosides, Flavonoids and Rotenoids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205 5.2.1. Rotenoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205 5.3. Terpenes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209 5.4. Lignans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211 5.5. Saponins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211 6. Pharmacological properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211 6.1. Recent pharmacological investigations in Boerhavia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211 6.1.1. Effect on metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211 6.1.2. Effect on immune system: immunomodulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212 6.1.3. Effect on renal disorders: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214 6.1.4. Antioxidant activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214 6.1.5. Hepatoprotective activity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214 6.1.6. Antiviral property . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216 6.1.7. Anticancer effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216 6.1.8. Cardiovascular effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216 6.1.9. Anti-inﬂammatory activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217 6.1.10. Anticonvulsant activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217 6.1.11. Antibacterial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217 7. Toxicity studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217 8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217 Acknowledgement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218 1. Introduction 1.1. Boerhavia genus Boerhavia (frequently spelled ‘Boerhaavia’) is highly polymorphic genus of Nyctaginaceae also known as four-o’clock family because most of the species open their ﬂowers four hours after noon i.e. in early evening or morning (Fosberg, 1978; Levin et al., 2001). Nyctaginaceae encompasses 391 species in 32 genera. Due to taxonomic conﬂict and concepts, the genus Boerhavia includes variable number (20–40) of species (synonyms and homonyms) of subtropical or panatropical herbs (Fosberg, 1978; Douglas and Manos, 2007). This has impacted scientiﬁc exploitations of some species of Boerhavia as only one species i.e. B. diffusa is predominantly studied. Most Boerhavia species possess worldwide medicinal uses and hence occupied positions in different systems of medicine including Indian Ayurveda, Siddha and Unani, Martinican medicine, African medicine, traditional Chinese medicines as well as Indian and Brazilian pharmacopoeia. Six important species viz., B. diffusa, B. repens, B. chinensis, B. erecta, B. elegans (synonym: B. rubicund) and B. reniformis (synonym: B. rependa) are found in India (Chopra, 1969; Dev, 2006). Out of 180 isolated compounds from Boerhavia genus, B. diffusa shared about 131 compounds and for most of these compounds, it is currently an exclusive source. Following this 46 compounds have been isolated from B. erecta. The compounds from Boerhavia genus include characteristic chromoalkaloids, quinonolizidine alkaloids i.e. punarnavine, ﬂavonoids, phenolic glycosides, phenolic acids, sterols and organic acids. Also many pharmacological activities in B. diffusa have been reported and there are some reviews which included information on B. diffusa. However, the present review also covers studies in other species of Boerhavia genus and recent pharmacological data of B. diffusa published in last 5–6 years. 2. Geographical distribution and botanical description Boerhavia species are widespread and the dispersal is mostly due to birds and human activity. The genus name Boerhavia was given in honour of Hermann Boerhaave, a famous Dutch physician of the 18th century. The distribution of Boerhavia species is in the warmer parts up to an altitude of 2000 m. Besides this, they are found in disturbed areas, waste places, roadsides, dry pinelands, among scrub on tropical reefs (Spellenberg, 2004). Although native to India and Brazil, B. diffusa is found in the tropical, subtropical and temperate regions of the world. This may imply that worldwide distribution of B. diffusa have helped for establishment of its broader ethnomedicinal spectrum and hence a material of interest for most industries and researchers. In India rakt punarnava (B. diffusa) is known to possess more medicinal importance than shweta punarnava (B. erecta). Alone in Kerala state of India, the demand of B. diffusa roots was 1, 150 metric tonnes in year 2000 and it is among the 46 medicinal plants sourced largely from wastelands (Tewari, 2000; Ved and Goraya, 2007; Pathak et al., 2012; Patil and Bhalsing, 2015). However, considerable information on phytochemistry and pharmacology of B. diffusa is available under the taxonomically inappropriate names such as Boerhavia diffusa Linn., Boerhavia Diffusa etc. All the names of Boerhavia species discussed in this review have been checked against www.theplantlist.org. Nevertheless, most scientiﬁc literatures provided different synonyms for Boerhavia species because of taxonomic errors or incorrectly indentiﬁed from local peoples. For example, in the literature there are many synonyms have been provided for B. diffusa such as Boerhavia glabrata, B. repens, B. erecta, B. rependa, B. procumbens etc. which are actually different species (Douglas and Manos, 2007; Selvaraj et al., 2012). Also, species name Boerhavia rependa Willd is used in literatures for which the accepted name is Boerhavia reniformis Chiov. In addition, studies are also conducted under the name Boerhavia chinensis (L.) Asch. & Schweinf. but the accepted species name is Boerhavia chinensis (L.) Rottb. The species name Boerhavia paniculata has been recently used in literature for accepted name Boerhavia paludosa (Domin) Meikle. Beside the above taxonomic errors, the sources of error also seem to be those which are described by Rivera et al. (2014) and this can lead to an errorneous future research. Though Boerhavia is well polymorphic genus, a comprehensive and reliable taxanomic approache is still needed for identiﬁcation of Boerhavia species. Few noteworthy studies using molecular tools such as ITS genes are recently carried out in this respect (Douglas and Manos, 2007; Selvaraj et al., 2012). The detailed geographical distributions of some traditionally used Boerhavia species are enlisted in Table 1. 202 K.S. Patil, S.R. Bhalsing / Journal of Ethnopharmacology 182 (2016) 200–220 Fosberg (1978); Fadeyi et al. (1989) Souza et al. (2014) Asia, Africa and Mediterranean regions South America, Australia and Venezuela 10 11 Boerhavia reniformis Chiov. (Synonym: Boerhavia India (Punarnava) rependa Willd.) Boerhavia repens L. Indo-Paciﬁc and Africa (alena) Boerhavia paludosa (Domin) Meikle (Synonym: Brazil Boerhavia paniculata Rich.) 9 Hawaii Pakistan (Sentori) Boerhavia glabrata Blume Boerhavia procumbens Banks ex Roxb. 7 8 6 Boerhavia elegans Choisy (Synonym: B. rubicund) Iran (Sorhmard) Boerhavia erecta L. Tropical America (erect spiderling) Boerhavia hualienense S.H. Chen & M.J.Wu Taiwan 2 3 Brazil (pega pinto) India (Rakt Punarnava) and Brazil (Erva tostao) 4 5 Biligiri Rangana Hill ranges, Karnataka, India Chen et al. (2007) Stemmerik (1964); Singh et al. (1988) Abbasi et al. (2012); Krishna and Shanthamma (2004a) Fosberg (1978); Sadeghi et al. (2014); Edeoga and Ikem (2002); Chou et al. (2004) Chen et al. (2007) Edeoga and Ikem (2002) Fosberg (1978); Spellenberg (2004) Stemmerik (1964) All Old World tropics, including S. Malaysia and E. Java (distinctly restricted to regions subject to a seasonal climate) Brazil, Mexico, North America, Nigeria. (Worldwide distributed) Tropical, subtropical, temperate regions of the world including Mexico, American continent, Asia, Africa, Indian Ocean Islands, Paciﬁc Islands, Australia, Egypt and Sudan. Africa, India, Pakistan, and Saudi Arabia (Widely distributed)America, Africa, Madagascar, India, Java, Malaysia, Philippines, China, Taiwan (Recently a new species) This species is endemic, occurring only in the east coast of Taiwan Java north to Micronesia, Ryukyu also to the Hawaiian Islands Pakistan, South West Asia and India Malaysia Boerhavia chinensis (L.) Rottb. (Synonym: Boerhavia chinensis (L.) Asch. & Schweinf.) Boerhavia coccinea Mill. Boerhavia diffusa L. 1 References Geographical distributions Native habitat/origin and common name Sr. no. Name of the species Table 1 List of selected plant species in Boerhavia 3. Quality assessment Among many medicinally important member of Boerhavia, there seems to be continual dependence of herbal practitioners, researchers and industries on B. diffusa. However, in context of above discussed taxonomical errors and lack proper tools for taxonomical discrimition, B. diffusa often adulterated with related species like B. erecta, B. repanda, B. coccinea B. verticillata, B. repens, B. tetranda and B. albiﬂora. To address these problems, an attempt was made by Ferreres et al. (2005) through establishment of phenolic ﬁngerprint i.e. chemical identity of B. diffusa using HPLCPAD-ESI/MS technique. They concluded that, geographical location or soil composition may vary the phenolic content of B. diffusa. However, recent approach suggested the use of DNA barcoding for quality assessment in B. diffusa due to its close morphological and phytochemical proﬁle with some species. Plant nuclear rDNA regions like ITS1 (located between 5.8S rRNA and 18S rRNA genes), ITS2 (located between 5.8S rRNA and 25S rRNA genes) and chloroplast plastid gene psbA-trnH was used for phylogenetic analysis. Use of ITS regions (non-coding DNA) in plant taxonomy is related to its small size (600–700 bp) and high rate of divergence. The study revealed that compared to ITS2 and psbA-trnH genes, ITS1 effectively distinguished B. diffusa from other 14 species of Boerhavia (Selvaraj et al., 2012). 4. Ethnomedicinal uses of Boerhavia Boerhavia encompasses very important species as evident from their broad spectrum of ethnomedicinal uses worldwide which are enlisted in Table 2. Out of these species, B. diffusa documented to possess most wide uses. Other members also have reported to possess important medicinal uses. B. diffusa has been documented in very old Indian Ayurvedic books of medicine such as the Charaka Samhita, Sushrita Samhita, Ashtaanga Hridaya and Chakradatta. These books have mentioned various beneﬁts such as the book Chakradatta for treatment of chronic alcoholism, Bhaishajya ratnaavali for treatment of oedema and haematinic, Ashtaang Hridaya for stimulation of urinogenital systems etc. (Khare, 2004). In Uttarpradesh, India the local peoples used it as blood puriﬁer, myocardial stimulant, expectorant, in jaundice, cough and snake bite (Singh et al., 2010). In Ayurveda and Unani, B. diffusa plant used to cure 22 different types of ailments. In Brazilian pharmacopeia, 23 traditional uses have been described for this plant, while in Africa and Middle East, the plant is prescribed for 14 ailments (Apu et al., 2012). In Martinican medicine, B. diffusa is a pain reducing agent and decoction or juice of leaves is used for its analgesic and anti-inﬂammatory properties (Robineau and Soejarto, 1996; Hiruma et al., 2000). The drug ‘punarnava’ include whole plant of B. diffusa which is documented in Indian Pharmacopoeia as a diuretic (Chopra, 1969). It is also used in the treatment of anasarca, anaemia, scanty urine and ascites. The ﬂowers and seeds are used as contraceptive (Chopra et al., 1956). Many commercial herbal formulations make use of B. diffusa plant for which the role or indications suggest its ethnomedicinal practises are valued (Table 3). B. chinesis roots are antihelmintic, cure leucorrhoea, use to ripen ulcers (Pullaiah, 2006). In Southern Sudan, B. erecta root is used in treatment of remnant of newly detached umbilical cord in baby (Muzila, 2008). According to Baluch people, the plant of B. elegans is known to be a regenerator of heart and kidney and also, effectively used in urinary disorders, intestinal infections and diabetes (Ramazani et al., 2010). We have highlighted below important traditional uses reported for Boerhavia species which would be of potential interest for scientiﬁc study (Table 2). Table 2 Worldwide ethnomedicinal uses of important species of Boerhavia genus Name of the species Country/province Boerhavia chinensis (L.) Rottb. (Synonym Boerhavia chinensis (L.) Asch. & Schweinf.) Boerhavia coccinea Mill. Northeast of Brazil (Local people) West Africa Nigeria Boerhavia diffusa L. Angola (regions of Cuanza Norte, Golungo Alto) Brazil (Local people) Ghana India (Sahariya people) Nigeria West Africa (Ivory Coast) Iran Boerhavia elegans Choisy Namibia (Bergdamara people) (Damara people) Congo Martinique Iran Bamposht (East of Saravan) (Baluch peoples) Pakistan Boerhavia erecta L. India (Malayali peoples) India (Local communities) a) Antihelmintic Type of recipe Reference Oral administration of powdered root Pullaiah (2006) a) Treatment of venereal disease, removing kidney/liver and urinary infusion of the roots system obstructions a) Toothach Inhalation of smoke from leaf pulp mixed with peanut oil a) Vermifuge (to expel worms or other animal parasites from the Roots ground with other herbs and intestine taken in water a) Pneumonia leafy twig a) Measles Drinking tea made by boiling roots in water (sometimes interchanging with B. erecta) a) Used for arthritis, cramp, joint pain, rheumatism, kidney pain and as Infusion of stems with leaves. an anti-inﬂammatory b) For cirrhosis, jaundice, hepatitis. Spongy roots decoction a) Used as a diuretic, for urinary disorders like nephritis, abundant Decoction of Root urine, albuminuria, gallstones, urinary retention, for hepatitis, jaundice, cystitis, ascites, Beriberi and blenorrhagia. a) Anaemia and applied externally to yaws, Root decoction a) Abdominal tumours Powdered root with butter or oil. a) To treat heart troubles, palpitations and jaundice. Decoction of root a) Asthma, scanty urine, and internal inﬂammation disorders, piles Root decoction leucorrhoea, rheumatism, and stomach ache elephantiasis, to treat seminal weakness and blood pressure a) Anticonvulsant, antiasthmatic, expectorant, and emetic. Decoction of leaves a) Sprain, blennorrage, rheumatism, diffuse pains, maux of reins Decoction of roots b) a) a) a) a) a) a) a) a) a) b) a) a) Asthma, Cholera, Paludism Gonorrhoea, nephritis and oedema. Appetiser and to treat joint pain Gastro-enteritic problems, Prolapsed uterus Mumps, laryngitis and burns Analgesic and anti-inﬂammatory To treat dysmenorrhoea, urinary tract disorders, intestinal infections, inﬂammation, jaundice, and body weakness in traditional medicine. Moreover, this species has expectorant, anti-diabetic, motive and diuretic properties and is used as the regenerator of heart and kidney They use its decoction for removing fatigue and as an aphrodisiac and used for inﬂammation Used in opthalmia, eye wounds and pain of the joints. Carminative and useful in muscular pain, lumbago scabies and hasten delivery. Asthma A diuretic to treat jaundice, enlarged spleen, gonorrhoea and other internal inﬂammations. It is also used as stomachic, cardio tonic, hepatoprotective, laxative, antihelmintic (expels parasitic worms), febrifuge (reduces fever), and an expectorant. Decoction of leaves Whole plant decoction Infusion of leaves Chewing or boiled roots Tea made from boiled root Root sap is rubbed on neck and throat Fresh juice or decoction of leaves Leaves Fruits Smoke of plant powder Root Braga (1960) Muzila (2008) Jiofack et al. (2009) Austin (2010) Bossard (1996) Bossard (1996) Cruz (1995) Muzila (2006) Mitra and Gupta (1997) Andesina (1982) Bouquet and Debray (1974) Guessan N’ et al. (2009) Zagari (1992) Muzila (2008) Muzila (2008) Muzila (2008) Hiruma et al. (2000) Ramazani et al. (2010) K.S. Patil, S.R. Bhalsing / Journal of Ethnopharmacology 182 (2016) 200–220 Cameroon (Local people) Mexico (Seri, Gurijiyo, Mayo peoples) Ethnomedicinal uses Sadeghi et al. (2014); Zargari (1987). Najam et al. (2008) Sandhu et al. (2011) Anjalam et al. (2014) Rameshkumar and Ramakritinan (2013); Donald (2012) 203 204 Table 2 (continued ) Name of the species Country/province Soligas Peoples (Biligiri Rangana Hill ranges, Karnataka, India) Mali Niger Benin Kenya Tanzania Burkina Faso India (Gond and Bhill peoples) Pakistan Boerhavia reniformis Chiov. (Synonym: India Traditional practitioners (YaBoerhavia rependa Willd.) landur, Chamarajanagar, Karnataka, India) Boerhavia repens L. India (medicine practitioners) West Africa Central Africa Nigeria (Yoruba people) Type of recipe Reference a) Infective hepatitis Roots with goat’s milk b) To ripen abscesses and ulcers. Root paste is rubbed on the skin a) To treat liver problems, gastrointestinal diseases and infertility problems a) Against fungal infections a) To treat convulsions in children a) To treat diarrhoea a) To treat rheumatism and scabies a) Conjunctivitis a) Antimalarial, antibacterial, antiviral a) Jaundice b) Against oedema, dropsy, and in dysmenorrhoea. c) Used in the treatment of respiratory and pulmonary diseases, in disorders of liver, eyes, stomach, urinary, and throat. cleansing the bowel, reducing fevers, and for the killing of intestine helminthes d) To treat, anaemia, dropsy and gonorrhoea and also used as Eye tonic e) Against swelling and Scorpion sting a) Jaundice and Hepatitis a) To cure jaundice Leaves decoction Krishna and Shanthamma (2004a) Rameshkumar and Ramakritinan (2013) Muzila (2008 Ash of the whole plant Whole plant decoction Aqueous extract of leaves Ash of the whole plant mixed with oil Sap of leaves Decoction of plant Decoction of fresh plant Leaves dried roots Muzila (2008) Muzila (2008) Muzila (2008) Muzila (2008) Muzila (2008) Hilou et al. (2013) Lone et al. (2015) Shah and Khan (2006) Qureshi et al. (2010) Root decoction Root paste Whole plant Roots with butter milk Katewa et al. (2004) Katewa et al. (2004) Abbasi et al. (2009) Krishna and Shanthamma (2004a) a) Jaundice Wabale and Petkar (2005) a) a) b) c) Wabale and Petkar (2005) Muzila (2008) Muzila (2008) Muzila (2008) a) b) a) b) Crushed roots as well as a necklace of small pieces of roots are worn by patient Bronchial asthma Root juice mixed with chilli Asthma, Leprosy and Syphilis Decoction of leaves Ulcers, yaws Roots Chickenpox Ground roots with seeds powder of Blighia sapida Aphrodisiac or curing of Stomach ache Root decoction To treat ﬁlarial infection Root sap (Ethnomedicinally considered effective and hence preferred over B. Decoction of leaves and whole plant pulp diffusa and B. erecta), Ecbolic, to cure jaundice, and poulticing sprains Albuminuria, asthma, depurative, diarrhoea, dropsy, epilepsy, erysipelas, hysteria, jaundice, measles, nerves and spasm Muzila (2008) Muzila (2008) Muzila (2008) Muzila (2008) K.S. Patil, S.R. Bhalsing / Journal of Ethnopharmacology 182 (2016) 200–220 Boerhavia procumbens Banks ex Roxb. Ethnomedicinal uses 205 K.S. Patil, S.R. Bhalsing / Journal of Ethnopharmacology 182 (2016) 200–220 Table 3 Important commercially available herbal formulations in which B. diffusa is used Sr. No. Name of herbal/polyherbal formulation Name of company Role/indications 1 2 3 4 5 6 7 8 9 10 11 Himalaya punarnava capsules Diabecon Livgood capsules Punarnava capsules, organic Dabur chyawanprash junior 500G Immunowin Pain nivaran churna Femon C Hepatonej syrup Hridya (Heart Tonic) Herbal Tea Medohar (Anti-Obesity) Tea Himalaya Himalaya LivgoodTM Fushi Dabur Rajasthan aushadhalaya Pvt. Ltd. Rajasthan aushadhalaya Private Limited Ocean herbal pvt. ltd. Nej biotech, Nadiad, Gujarat Ayushkar Nirogam India Private Limited Controls swelling/oedema, diuretic Used for diabetes Used in Liver diseases and as diuretic renewing and rejuvenating Supplement General debility and immune-deﬁciency Rheumatoid/osteo Arthritis treatments Antiﬁbrinolytic, Haemostatic Jaundice, Hepatitis, Liver cirrhosis Cardioprotective tonic Prevents obesity 5. Phytochemistry In view of ethnopharmacological uses and with the advancement of technologies like MS, LCMS, ESI-MS etc., many studies in Boerhavia species revealed number of important phytochemicals in different parts (Table 4). A general approach to isolate compounds includes extraction, partitioning in different solvents and bioactivity guided fractionation using silica gel chromatography. 5.1. Alkaloids The phytochemical studies in Boerhavia genus seems to be carried out because of its immense use in traditional medicines across the world. Therefore, it is obvious to search for alkaloids (1– 4) in this genus as alkaloids are well known to possess important biological activities. The characteristic chromoalkaloids known as betacyanins are located in the cellular vacuoles of subepidermal tissues hence the stem barks of Boerhavia species appear red (Stemmerik, 1964) (Fig. 1). Evaluation of antioxidant potential in B. erecta showed that these betacyanins i.e. betanins (2–4) were most potent antioxidants (Stintzing et al., 2004; Hilou et al., 2013). This illustrates why traditionally the redder species are more preferable in disease treatments. Total quantity of betacyanin alkaloids reported from B. erecta was 186 mg/100 g (Stintzing et al., 2004). However, the most promising bioactive alkaloid found in Boerhavia genus is a type of quinolizidine alkaloid known as punarnavine (1) having chemical formula C17H22N2O and M.P. of 236–237°C (Agarwal and Dutt, 1936; Manu and Kuttan, 2009a; Manu and Kuttan, 2009b; Saraswati et al., 2013; Dhingra and Valecha, 2014). Punarnavine has been crystallised but its molecular structure is yet to be elucidated because most studies rely on old protocol (Agarwal and Dutt, 1936) and require advanced techniques. Maximum punarnavine accumulation was found in different parts of the B. repens as the plant gets older (Nandi and Chaterjee, 1974). In another study total alkaloid content (estimated as punarnavine content) in the root of three year old mature plant of B. diffusa was higher (2%) than in vitro regenerated roots (0.15%) (Shrivastava and Padhya, 1995). Many factors such as stress, endogenous cytokinins are known to promote alkaloids which come into play as the plant ages and suggested to have physiological or regulatory role in metabolism of plants. Recently, ethanolic extract of whole plant of B. diffusa provided total alkaloid content 0.232 g per 100 g (0.2%) (Beegum et al., 2014) while same extract contain punarnavine as 0.01% (Manu and Kuttan, 2009a). 5.2. Phenolic compounds: Phenolic acids/glycosides, Flavonoids and Rotenoids Although alkaloids were early detected in an approach to assess ethnomedicinal values of Boerhavia species recent studies indicate that ﬂavonoids (including rotenoids) are responsible for most of these traditional uses. The total ﬂavonoid content in B. diffusa was found to be 5.651 g/100 g (5.6%) which is many folds higher than alkaloids (0.2%) (Beegam et al., 2014). Approximately 97 (5–101) phenolic compounds which includes ﬂavonoids, rotenoids, phenolic acids and phenol glycosides (Table 4) attributing many different biological activities are isolated from Boerhavia species. Traditional use of Boerhavia species as a laxative is related to its high content of phenolic compounds (Fadeyi et al., 1989). Phenolic content can also be correlated with antioxidant property of plant species and presence of tannins contributes to astringency (Ma et al., 2014). B. diffusa contains moderate tannins (16 mg/gm) and high phenols (2.471 g/100 g) (Beegam et al., 2014). Punarnavoside, a phenolic glycoside isolated from B. diffusa act as an antiﬁbrolytic agent. Phenolic compounds such as ferulic acid and vanillin have been reported with important biological activities in B. diffusa (Tacchini et al., 2015). Biactivity guided fractionation led to the isolation of eupalitin-3-O-β-D-galactopyranoside from B. repens (14.4 mg/1.2 kg) (Li et al., 1996). Another study claimed that for large scale isolation of eupalitin-3-O-β-D-galactopyranoside, B. diffusa sample from Jammu region, India (yield ¼3 g/1 kg) can be more promising than that of B. repens (Mundkinajeddu et al., 2003). From this study, it can be inferred that geographical location of B. diffusa may affect its phytochemical productivity. A partition technique using different solvents was carried out for enrichment of ﬂavonoids from methanolic extract of B. diffusa roots (Mahesh et al., 2011). Recently, spectroscopic analysis of Boerhavia erecta stem bark has proven to be a potential source for bioactive molecules (54–58). (Nugraha et al., 2015) (Fig. 2). 5.2.1. Rotenoids Rotenoids are a group of isoﬂavonoid type of compounds less acutely toxic in mammals and can be act as bioinsecticide (Wagner et al., 2012). Rotenoids seem to be of interest for elaborative research in this genus as they accounted for most of the pharmacology or ethnomedicinal claims of Boerhavia species (Borelli et al., 2006; Belkacem et al., 2007; Aviello et al., 2011; Bairwa et al., 2013a, 2013b; Do et al. 2013a, 2013b). Using Kupchan partitioning and bioactivity guided fractionation technique 30 rotenoids (66– 96) and 5 coumaronochromonoids (96–100) have been isolated from three different plants viz. B. diffusa, B. erecta and B. repens (Borelli et al., 2006; Belkacem et al., 2007; Bairwa et al., 2013a, 2013b; Do et al. 2013a, 2013b ) (Table 4 Fig. 5). Rotenoids can be linked to isoﬂavonoids as biosynthesis of isoﬂavones involves a characteristic step of migration of phenyl from the 6a carbon atom in rotenone to 12a carbon atom. So, C-6 is not inherent but an additional carbon in rotenoids possibly supplied by methionine (Crombie, 1984). All rotenoids possess rotoxen skeleton (Fig. 3. i.) and the best known naturally occurring rotenoid is rotenone. Rotenone is mostly used as insecticide and ﬁsh poison but can act as anticancer agents possibly by inhibiting mitochondrial oxidation of NADH (Crombie, 1984; Crombie et al., 1992; Belkacem et al., 206 K.S. Patil, S.R. Bhalsing / Journal of Ethnopharmacology 182 (2016) 200–220 Table 4 List of phytochemicals isolated from Boerhavia species Chemical category/class/subclass Sr. no. Chemical compound 1. Alkaloids: 1 Punarnavine 2 3 4 5 Betanin Isobetanin Neobetanin Eupalitin 6 Eupalitin-3-O-β-D-galactopyranoside 2. Phenolics a) Flavonoids /Phenolic acids/glycosides 7 8 9 10 11 12 13 14 15 16 17 Eupatilin-7-O-β-D-galactopyranoside Eupatilin 7-O-α-L-rhamnopyranosyl (1-2) α-Lrhamnopyranosyl (1-6)- β-D-galactopyranoside. Eupalitin 3-O-β-D-galactopyranosyl-(1-2)-β-Dglucopyranoside Quercetin-3-O- β-D-glucopyranoside- 7-O- β-Dglucopyranoside Quercetin- 3-O-α-L-rhamnopyranosyl (1-6) - β-Dgalactopyranoside. 3,3ʹ,5-Trihydroxy-7-methoxyﬂavone 3,4-dimethoxyphenyl-1-O-β-D-glucopyranoside 4ʹ,7-dihydroxy-3ʹ-methylﬂavone 3′,4′,5,7-tetrahydroxyﬂavone-3-O-α-D-rhamnopyranosyl (1-6)O-β-D-glucopyranoside 4′,5,7-tetrahydroxy-3′-methoxy ﬂavones-3-O-α-Drhamnopyranosyl(1-6)O-β-D-glucopyranoside Kaempferol Name of the species Source Reference B. B. B. B. B. B. B. Root Root Root Stem bark Stem bark Stem bark Whole plant Manu and Kuttan (2009a) Nandi and Chatterjee (1974) Abbasi et al. (2012) Hilou et al. (2013) Stintzing et al. (2004) Stintzing et al. (2004) Maurya et al. (2007) Li et al. (1996) Maurya et al. (2007) Mundkinajeddu et al. (2003) B. repens Whole plant Whole plant Leaves, Stem, Flowers Whole plant B. diffusa B. diffusa Whole plant Maurya et al. (2007) Whole plant Maurya et al. (2007) B. repens Whole plant Li et al. (1996) B. diffusa Whole plant Maurya et al. (2007) B. diffusa Whole plant Maurya et al. (2007) B. B. B. B. Whole Whole Whole Whole diffusa repens procumbens erecta erecta erecta diffusa B. repens B. diffusa B. diffusa diffusa diffusa diffusa erecta B. erecta erecta diffusa Aerial parts Do et al. (2013a) Whole plant Maurya et al. (2007) diffusa diffusa Roots Gupta and Ahmed (1984) Whole plant Maurya et al. (2007) diffusa Leaves, roots Leaves, roots Leaves, roots Leaves, roots Leaves, roots Leaves, roots Leaves, roots Leaves, 36 3,4-dihydroxy-5-methoxycinnamoylrhamnoside B. diffusa 37 Quercetin 3-O-(2″- rhamnosyl)-robinobioside B. diffusa 38 Kaempferol 3-O-(2″-rhamnosyl)-robinobioside B. diffusa 39 3,5,4′-trihydroxy-6,7-dimethoxyﬂavone B. diffusa 40 B. diffusa 41 3-O-galactosyl(1-2)glucoside [eupalitin 3-O-galactosyl(1-2)glucoside] Kaempferol 3-O-robinobioside 42 Eupalitin 3-O-galactoside B. diffusa 21 22 23 24 25 26 27 28 29 30 31 32 33 34 Whole plant Nugraha (2010) Root , leaves Aerial parts Whole plant Whole plant Root , leaves Whole plant Leaves Whole plant Leaves Leaves Leaves Whole plant Whole plant Leaves Leaves Leaves Leaves Leaves Aerial parts 35 20 Maurya et al. 2007) Maurya et al. 2007) Maurya et al. (2007 Nugraha (2010) diffusa erecta procumbens repens diffusa procumbens erecta procumbens erecta erecta erecta procumbens procumbens erecta erecta erecta erecta erecta erecta B. B. B. 6-methoxykaempferol 3-O-β-D-(1-6)-robinoside B. Quercetin B. B. Catechin B. B. [(-)-epicatechin] B. Isorhamnetin B. Rutin B. B. Myricetin B. Narcissin B. Procyanidins B. Isoquercitrin B. isorhamnetin B. Isorhamnetin-3-O-β-D-glucopyranoside B. Isorhamnetin 3-O-α-L-rhamnopyranosyl-(1- 6)-β-D- B. glucopyranoside Isovitexin B. Eupalitin 3-O-β-D- galactopyranosyl-(1 ʹ- 2 )-O-β- B. D-galactopyranoside 5,7-dihydroxy-6-8-dimethoxy ﬂavones (Borhavone) B. 3,4-Dimethoxyphenyl-1-O-β-D-apiofuranosyl-(1 ʹ- B. 3 )-O-β-D-galactopyranoside hexaacetate Quercetin 3-O-robinobioside B. 18 19 plant plant plant plant Li et al. (1996) B. diffusa Ferreres et al. (2005) Do et al. (2013a) Bokhari et al. (2015b) Li et al. (1996) Ferreres et al. (2005) Bokhari et al. (2015b) Petrus et al. 2012) Bokhari et al. 2015b) Petrus et al. 2012) Petrus et al. (2012) Petrus et al. (2012) Bokhari et al. (2015b) Bokhari et al. (2015b) Petrus et al. (2012) Petrus et al. (2012) Petrus et al. (2012) Petrus et al. (2012) Petrus et al. (2012) Do et al. (2013a) Ferreres et al. (2005) Ferreres et al. (2005) Ferreres et al. (2005) Ferreres et al. (2005) Ferreres et al. (2005) Ferreres et al. (2005) Ferreres et al. (2005) Ferreres et al. (2005) 207 K.S. Patil, S.R. Bhalsing / Journal of Ethnopharmacology 182 (2016) 200–220 Table 4 (continued ) Chemical category/class/subclass b) Rotenoids d)Coumaronochromonoids 3.Terpenes Sr. no. Chemical compound Name of the species 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. diffusa diffusa diffusa diffusa erecta erecta erecta erecta erecta erecta erecta erecta erecta erecta erecta erecta 59 60 61 62 63 64 Punarnavoside Phenol, 4, 6-di (1, 1-dimethylethyl)-2-methylAlkamide N-trans-feruloyltyramine Epicatechin Quercetin diglycoside Quercetin 3-O-rutinoside Kaempferol diglycoside Isorhamnetin diglycoside Isorhamnetin 3-O-rutinoside Isorhamnetin 3-O-glucoside 3-methoxybenzoic acid 4-O-β-glucoside 3-methoxyacetophenone 4-O-β-glucopyranoside Isorhamnetin-3-O-rutinoside-7-O-β-glucopyranoside Isorhamnetin-3-O-rutinoside 2,3-dihydroxypropyl-benzoate 3-O-β-[4 -methoxy] Glucuronide 5,7,3'-trihydroxycoumaronochromone Ferulic acid Syringic acid Gentisic acid O-coumaric acids Caffeoyltartaric acid B. B. B. B. B. B. repens diffusa diffusa diffusa diffusa diffusa 65 66 Boerhaavic acid Boeravinone A 67 Boeravinone B 68 Boeravinone C 69 70 71 Boeravinone D Boeravinone E Boeravinone F 72 Boeravinone G 73 74 75 76 Boeravinone Boeravinone Boeravinone Boeravinone 77 78 Boeravinone N Boeravinone P 79 80 81 82 83 Boeravinone Q Boeravinone R Boeravinone S 9-O-methyl-10-hydroxycoccineone B 10-demethylboeravinone C 84 85 86 87 88 89 90 2ʹ-O-methylabroisoﬂavone 6-O-demethylberavinone H 9-O-methyl-10 hydroxycoccineone B Cucumegastigmane Kaempferol 3-O-rutinoside Quercetin 3-O-β-D-glucopyranoside Coccineon B 91 92 93 94 95 96 97 98 Coccineon C Coccineon D Coccineon E Repenone Repenol Boerharotenoid B Boeravinone O Boeravinone J 99 100 101 102 103 Boeravinone L Coccineon A Boerharotenoid A Boerhavisterol Camphor B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. B. diffusa diffusa coccinea diffusa coccinea diffusa coccinea erecta diffusa diffusa diffusa repens diffusa erecta diffusa diffusa erecta diffusa erecta erecta diffusa diffusa diffusa diffusa diffusa diffusa diffusa erecta diffusa diffusa diffusa erecta erecta erecta diffusa coccinea coccinea coccinea diffusa repens repens repens erecta diffusa erecta erecta coccinea repens diffusa diffusa H I K M Source Reference roots Root Leaves Root Root Stem Stem Stem Stem Stem Stem Stem Stem bark Stem bark Stem bark Stem bark Stem bark Jain and Khanna (1989) Umamenaka et al. (2012) Do et al. (2013b) Do et al. (2013b) Stintzing et al. (2004) Stintzing et al. (2004) Stintzing et al. (2004) Stintzing et al. (2004) Stintzing et al. (2004) Stintzing et al. (2004) Stintzing et al. (2004) Nugraha et al. (2015) Nugraha et al. (2015) Nugraha et al. (2015) Nugraha et al. (2015) Nugraha et al. (2015) Whole plant Leaves Leaves Leaves Leaves Leaves, roots Aerial parts Root Root Root Root Root Root Aerial parts Root Root Root Whole plant Root Aerial parts Root Root Aerial parts Root Aerial parts Aerial parts Root Aerial parts Root Root Root Root Root Aerial parts Root Root Aerial parts Aerial parts Aerial parts Root Root Root Root Root Whole plant Whole plant Whole plant Aerial parts Root Aerial parts Aerial parts Root Whole plant Roots Roots, Nazir et al. (2011) Tacchini et al. (2015) Daniel (2006) Daniel (2006) Daniel (2006) Ferreres et al. (2005) Do et al. (2013b) Kadota et al. (1988a) Santos et al. (1998) Kadota et al. (1988a) Santos et al. (1998) Kadota et al. (1988b) Santos et al. (1998) Do et al. (2013a) Borelli et al. (2006) Borelli et al. (2006) Borelli et al. (2006) Nazir et al. (2011) Borelli et al. (2006) Do et al. (2013a) Borelli et al. (2006) Belkacem et al. (2007) Do et al. 2013a) Bairwa et al. (2013a, 2013b) Do et al. (2013a) Do et al. 2013a) Bairwa et al. (2013a, 2013b) Do et al. (2013b) Bairwa et al. (2013a, 2013b) Bairwa et al. (2013a, 2013b) Bairwa et al. (2013a, 2013b) Borelli et al. (2006) Borelli et al. (2006) Do et al. (2013a) Borelli et al. (2006) Borelli et al. (2006) Borelli et al. (2006) Do et al. (2013a) Do et al. (2013a) Do et al. (2013a) Borelli et al. (2006) Messana et al. (1986) Ferrari et al. (1991) Ferrari et al. (1991) Santos et al. (1998) Ahmed et al. (1990) Ahmed et al. (1990) Nazir et al. (2011) Do et al. (2013a) Belkacem et al. (2007) Do et al. (2013a) Do et al. (2013a) Messana et al. (1986) Nazir et al. (2011) Gupta and Ali (1998) Pereira et al. (2009) 208 K.S. Patil, S.R. Bhalsing / Journal of Ethnopharmacology 182 (2016) 200–220 Table 4 (continued ) Chemical category/class/subclass 4. Saponin 5. Lignans 6. Others Sr. no. Chemical compound Name of the species 104 Isomenthone B. diffusa 105 Limonene B. diffusa 106 Menthol B. diffusa 107 Phellandrene B. diffusa 108 Safranal B. diffusa 109 α-Pinene B. diffusa 110 Geranylacetone B. diffusa 111 cis 4-Hexen-1-ol B. diffusa 112 trans 2-Octanalc B. diffusa 113 2-Nonen-1-olc B. diffusa 114 2-Decen-1-ol B. diffusa 115 Methylpyrrole B. diffusa 116 3-Phenyl-2-(20-pyridyl)-indole B. diffusa 117 Indole B. diffusa 118 Eugenol B. diffusa 119 β-Cyclocitral B. diffusa 120 β-Ionone B. diffusa 121 Dihydroactinidiolide B. diffusa 122 123 124 Stigmasterol Campesterol β-sitosterol 125 126 127 128 129 130 131 132 133 134 135 136 α-2-sitosterols Ursolic acid β-amyrin β-amyrin acetate 3-acetoxy-α-amyrin 4, 10-dihydroxy-8-methoxyguai-7(11)-en-8,12-olide Oleanolic acid heteroside Liriodendrin Syringaresinol mono-β-D-glucose Myo-lnositol,4-C-methyl-1,14-Tetradecanediol 1-pentadecyne Phytol 137 138 139 3,5-Bis(trimethylsilyl)-2,4,6-cycloheptatrien-1-one Androstane-11, 17-dione, 3-[(trimethylisilyl)oxy]-17[O-(phenylmethyl)oxime], (3a,5a) hypoxanthine 9-L-arabinose B. diffusa B. diffusa B. diffusa B. erecta B. repens B. diffusa B. diffusa B. diffusa B. diffusa B. diffusa B. diffusa B. diffusa B. diffusa B. diffusa B. diffusa B. diffusa B. diffusa B.repens B. diffusa B. diffusa leaves Roots, leaves Roots, leaves Roots, leaves Roots, leaves Roots, leaves Roots, leaves Roots, leaves Roots, leaves Roots, leaves Roots, leaves Roots, leaves Roots, leaves Roots, leaves Roots, leaves Roots, leaves Roots, leaves Roots, leaves Roots, leaves Root Root Root Whole plant Whole plant Root Root Whole plant Whole plant Aerial parts Aerial parts Roots Roots Roots Leaves Leaves Leaves Whole plant Leaves Leaves B. diffusa Roots 140 myricyl alcohol B. diffusa 141 myristic acid B. diffusa 142 143 144 145 146 147 148 149 150 151 152 β-ecdysone Anthocyanins Squalene Procyanidin B1 Procyanidin B2 Dimeric procyanidin Boerhadiffusene Diffusarotenoid boerhavilanastenyl benzoate Boerhavine Borhavone B. B. B. B. B. B. B. B. B. B. B. diffusa erecta repens erecta erecta erecta diffusa diffusa diffusa diffusa diffusa Source Reference Pereira et al. (2009) Pereira et al. (2009) Pereira et al. (2009) Pereira et al. (2009) Pereira et al. (2009) Pereira et al. (2009) Pereira et al. (2009) Pereira et al. (2009) Pereira et al. (2009) Pereira et al. (2009) Pereira et al. (2009) Pereira et al. (2009) Pereira et al. (2009) Pereira et al. (2009) Pereira et al. (2009) Pereira et al. (2009) Pereira et al. (2009) Pereira et al. (2009) Kadota et al. (1989) Kadota et al. (1989) Misra and Tiwari (1971) Nugraha (2010) Ahmed et al. (1990) Ranjini et al. (2013) Misra and Tiwari (1971) Maurya et al. (2007) Maurya et al. (2007) Do et al. (2013b) Do et al. (2013b) Bep Oliver-Bever (1986) Lami et al. (1992) Lami et al. (1992) Umamenaka et al. (2012) Umamenaka et al. (2012) Umamenaka et al. (2012) Ahmed et al. (1990) Umamenaka et al. (2012) Umamenaka et al. (2012) Ojewole and Andesina (1985) Roots Ojewole and Andesina (1985) Roots Ojewole and Andesina (1985) Root Suri et al. (1982) Stem bark Marulkar et al. (2012) Whole plant Ahmed et al. (1990) Stem Stintzing et al. (2004) Stem Stintzing et al. (2004) Stem Stintzing et al. (2004) Roots Gupta and Ali (1998) Roots Gupta and Ali (1998) Roots Gupta and Ali (1998) Roots Ahmed and Yu (1992) Roots Gupta and Ahmed (1984); 209 K.S. Patil, S.R. Bhalsing / Journal of Ethnopharmacology 182 (2016) 200–220 Table 4 (continued ) Chemical category/class/subclass Sr. no. Chemical compound Name of the species Source Reference 153 154 155 156 157 158 159 B. B. B. B. B. B. B. diffusa diffusa diffusa diffusa diffusa diffusa diffusa Roots Aerial Aerial Aerial Aerial Aerial Aerial parts parts parts parts parts parts Ahmed and Yu (1992) Tacchini et al. (2015) Do et al. (2013b) Do et al. (2013b) Do et al. (2013b) Do et al. (2013b) Do et al. (2013b) Do et al. (2013b) parts parts parts parts Do Do Do Do B. B. B. B. diffusa diffusa diffusa diffusa Aerial Aerial Aerial Aerial 164 165 166 167 168 169 170 171 172 173 174 Vanillin Allantoin Sophorophenolone N-trans-feruloyl-3-Methyldopamine (þ )-zedoalactone A Ciwujiatone 1-β-D-glucopyranosyloxy-3,5-dimethoxy-4hydroxybenzene 1-β-D-glucopyranosyloxy-3,4-dimethoxybenzene 1-β-D-glucopyranosyloxy-1-phenylmethane 1-β-D-glucopyranosyloxy-2-pheny-lethane 1- β-D-glucopyranosyloxy-2-methoxy-4ethanoylbenzene Palmitic acid Heptadecyclic acid Oleic acid Strearic acid Arachidic acid Behenic acids Sterol esters Caefﬁc acid Hentriacontane Triacontanol Quinic acid B. B. B. B. B. B. B. B. B. B. B. diffusa diffusa diffusa diffusa diffusa diffusa diffusa procumbens diffusa diffusa diffusa 175 Fumaric acid B. diffusa 176 Ketoglutaric acid B. diffusa 177 Pyruvic acid B. diffusa 178 Oxalic acid B. diffusa 179 180 Vitamin E acetate Potassium nitrate B. diffusa B. diffusa Roots Kadota et al. (1989) Roots Kadota et al. (1989) Roots Kadota et al. (1989) Roots Kadota et al. 1989) Roots Kadota et al. (1989) Roots Kadota et al. (1989) Roots Kadota et al. (1989) Whole plant Bokhari et al. (2015b) Roots Misra and Tiwari (1971) Roots Suri et al. (1982) Roots, Pereira et al. (2009) leaves Roots, Pereira et al. (2009) leaves Roots, Pereira et al. 2009) leaves Roots, Pereira et al. (2009) leaves Roots, Pereira et al. (2009) leaves Leaves Umamenaka et al. (2012) Leaves Kokate et al. (2005) 160 161 162 163 et et et et al. al. al. al. (2013b) (2013b) (2013b) (2013b) Note: the serial number given in the table corresponds to the number given (bold) in brackets in the discussion part. Betanin PubChem CID: 54600918 hand, boeravinone G (72) which is methoxy substituted at C-9 rather than C-10 showed most potent anticancer and antioxidant activities (Belkacem et al., 2007; Aviello et al., 2011). Among ﬁve new rotenoids (boeravinone M, P, Q, R, S) from B. diffusa, boeravinone S (81) was observed to be most potent in vitro COX-1 and COX-2 inhbitory agent while signiﬁcant in vivo anti-inﬂammatory potential observed for boeravinone B (67) (Bairwa et al., 2013a, 2013b). Microwave-assisted extraction (MAE) technique (a rapid method over conventional soxhlet and maceration) has estimated yields of boeravinone B (0.15%) and boeravinone E (70) (0.32%) in B. diffusa (Bhope et al., 2011). However, advanced study in B. diffusa using RP-HPLC has estimated 0.22% and 0.05% yields of boeravinone B and boeravinone E respectively (Bhope et al., 2013). Later study was supported by Bairwa et al. (2014) in which boeravinone B was detected as a major compound when quantiﬁed by UPLC/PDA technique in three different geographically located samples of B. diffusa. Fig. 1. Alkaloid from Boerhavia diffusa. 5.3. Terpenes 2007; Figs. 4 and 5). However, rotenoids in Nyctaginaceae differes from that occur in Leguminosae in which former lack isoprenoid residue on ring D, possess either mono- or no substitution on ring A and sometimes methoxy substituted at C-10. Loss of C-6 in rotenoids because of bioenegetically direct cyclization of isoﬂavonoids leads to coumaronochromonoids such as boeravinone J, boeravinone L, boeravinone O and coccineone A. All these structural features in rotenoids from Nyctaginaceae are unfavourable for their cytotoxic activity (Fig. 4) (Belkacem et al., 2007; Kadota et al., 2007; Do et al., 2013a and Do et al., 2013b). On the other A ‘ﬂavour ﬁngerprint’ of plant species generally recognised by animals and humans can be derived from a modiﬁed form of terpens so called ‘terpenoids’ (Pereira et al., 2009). The term ‘terpenes’ and ‘terpenoids’ are derived from ‘turpentine’. The ﬁve carbon units in terpenoids are called isoprene units (give off the gas isoprene at high temperatures) or hemiterpenes as C-10 terpenoids (Monoterpenes) were initially thought to be smallest group of this class (Buchanan et al., 2015). Terpenes are components of essential oil and possess important biological activities. In 210 K.S. Patil, S.R. Bhalsing / Journal of Ethnopharmacology 182 (2016) 200–220 Name R1 R2 R3 R4 R5 R6 Eupalitin H OH H OH OCH3 CH3 Eupalitin-3-O-β-D-galactopyranoside H OH H a OCH3 CH3 Quercetin (PubChem CID: 5280343) H OH H H H H Isorhamnetin (PubChem CID: 5281654) CH3 OH H H H H Isoquercetin (PubChem CID: 5280804) H OH H b H H Punarnavoside Fig. 2. Chemical structures of ﬂavonoids from Boerhavia genus. K.S. Patil, S.R. Bhalsing / Journal of Ethnopharmacology 182 (2016) 200–220 i. 211 ii. Fig. 3. i. Rotexon skeleton ii. General rotenoid structure of Boerhavia spp. Fig. 4. General structural features of i. Rotenone from Leguminosae and Fabaceae ii. Rotenoid from Boerhavia spp. (Nyctaginaceae) iii. Coumaronochromonoid from Boerhavia spp. shown positivity (pink) and negativity (green) in cytotoxic activity. (For interpretation of the references to color in this ﬁgure legend, the reader is referred to the web version of this article.) view of this, approximately 28 terpenes (102–130) have been reported from leaves and roots of B. diffusa (Pereira et al., 2009). Structures of some important terpenes have been shown in Fig. 6. 5.4. Lignans Liriodendrin (132) and Syringaresinol mono-β-D-glucose (133) were the two major lignans detected from B. diffusa (Lami et al., 1992). Recent approach has evaluated the bioactive potential of liriodendrin isolated from B. diffusa using PASS (Prediction of Activity Spectra for Substances) assessment technique. It was found that out of total 22 reported activities of B. diffusa, 10 activities including smooth muscle relaxant, reproductive dysfunction, vasoprotector and emetic properties were predicted by PASS for liriodendrin with prediction coefﬁcient of 0.45. The remaining activities were predicted by PASS for other compounds of this plant gaining the overall coefﬁcient of 0.77 (Goel et al., 2011). Fig. 7 5.5. Saponins Although different saponins were detected in other Nyctaginaceae members there are meagre studies in saponins from Boerhavia. One current study estimated moderate amount of saponins (1.59%) in the chloroform extract of whole plant of B. diffusa (Beegam et al., 2014). Only one triterpenoid saponin i.e. oleanolic acid heteroside was reported from B. diffusa which showed antiinﬂammatory activities (Bep Oliver-Bever, 1986). 6. Pharmacological properties Although substantial pharmacological data in the literatures is available for Boerhavia genus, many pharmaceuticals activities essentially lack appropriate comparisons with positive controls. Also, the studies carried out were inappropriate with relevant pharmacological doses of active extracts as well as positive controls and their time duration, source of materials used and minimum effective dose. Due to its wide medicinal uses in traditional systems the B. diffusa has been executed from long for its ethnopharmacological potential and many reviews included this information. However, here (Table 5) we have enlisted available information on Boerhavia species and only discussed below (Section 6.1) the recent data published in last 5-6 years. 6.1. Recent pharmacological investigations in Boerhavia 6.1.1. Effect on metabolism 6.1.1.1. Antidiabetic activity. The global prevalence of diabetes is increasing and can lead to secondary complications such as blindness, increased risk for cardiovascular diseases and also kidney failure. Moreover, 80% deaths occur in middle- and low-income countries due to diabetes (WHO 2015). Most of the peoples in these countries mainly rely on traditional or indigenous medicines, especially in ailments such as diabetes for which Western medicines are associated with severe side effects (Zuang et al., 2013). In such circumstances, it is utmost important to evaluate the scientiﬁc validity and effectiveness of these traditional medicines. Oral admistration of Boerhavia diffusa (at high dose of 400 mg/kg b.w.) reduced the blood glucose concentration when observed on 7th, 14th and 21st day compared to negative control (received 0.5 ml of 5% Tween 80) diabetic rats. To explain a high dose of Boerhavia extract for antidiabetic assay, they also carried out the toxicity studies at this high dose and said that at a dose of 400 mg/kg b.w. B. diffusa is safer to use. The positive control rats in this study received glibenclamide (0.5 mg/kg b.w.). According to one study, methanolic extract of B. diffusa is more effective than 212 K.S. Patil, S.R. Bhalsing / Journal of Ethnopharmacology 182 (2016) 200–220 ethanolic extract (each at a dose of 200 mg/kg b.w.) in regenerating damaged β-cells of pancreas in streptozotocin as well as alloxan treated male diabetic rats. This study used glibenclamide (10 mg/kg b.w.) as positive control (Bhatia et al., 2011). A study of aqueous extract of B. diffusa in alloxan-induced diabetic rats observed 38.07%, 51.95% and 21.56% reduction of glucose level respectively at the doses of 100, 200 and 400 mg/kg in 6 h (Chude et al., 2001). They postulated that this hypoglycaemic activity was due to pheripheral utilisation of glucose. However, the study requires the positive controls for comparative efﬁcacy. 6.1.2. Effect on immune system: immunomodulation 6.1.2.1. Immunosuppressive activity. Immunomodulation is the regulation of immune responses by stimulating them to prevent infectious diseases or by suppressing them in the undesired conditions. Boerhavia genus has long been used traditionally in treatment of ulcers and asthmic conditions but require scientiﬁc validation. In recent study, 95% ethanol extract of B. diffusa has Name R1 R2 R3 R4 R5 R6 Boeravinone A H H CH3 H CH3 OCH3 H H H H CH3 CH3 OH H CH3 H H CH3 OH H H H H CH3 H OH CH3 H CH3 H H OH CH3 H CH3 CH3 H H H OH H CH3 Boeravinone M H OH H H CH3 H Boeravinone P H H CH3 H H H Boeravinone Q H H CH3 OCH3 H CH3 Boeravinone R H H H OCH3 H CH3 Boeravinone S OH H H H H H Coccineone B (PubChem CID: H H H H OH H 6-O-demethylboeravinone H H OH H H CH3 CH3 Repenone (PubChem CID: 44257427) H H e H H OH Repenol (PubChem CID: 44257428) OH H e H H OH Boerharotenoid B H OH H H H H 5,7,3'-trihydroxycoumaronochromone H H H H OH CH3 (PubChem CID: 14018346) Boeravinone B (PubChem CID: 14018348) Boeravinone D (PubChem CID: 15081178 ) Boeravinone E (PubChem CID: 11537197) Boeravinone G (PubChem CID: 11537442) Boeravinone H (PubChem CID: 16745324) Boeravinone I (PubChem CID: 16203334) 44420939) Fig. 5. Chemical structure of rotenoids from Boerhavia genus. , K.S. Patil, S.R. Bhalsing / Journal of Ethnopharmacology 182 (2016) 200–220 213 Fig. 5. (continued) R = H (β-sitosterol) R = Glucose (β-sitosterol-β-D-glucoside) 4,10-dihydroxy-8-methoxyguai-7(11)-en-8,12-olide Ursolic acid Fig. 6. Chemical structure of Terpenes from Boerhavia genus. shown to suppress inﬂammatory response both in vivo (mouse gastritis ulcer model) and in vitro (LPS-treated RAW264.7 cells) in a dose dependent manner (20 to 200mg/kg b.w.) which is comparable to standard drug ranitidine (40 mg/kg b.w.). The study further evaluated molecular inhibitory mechanisms lying behind this immunosuppressive activity and it was found that B. diffusa extract and its active ingredient luteolin markedly suppressed the activation of NF-κB by blocking a series of signalling cascades ranging from Syk/Src to IκBα. The AP-1 signalling pathway, which is controlled by TRAF6/TAK1, was also inhibited by the extract (Thai et al., 2015). Also, methanolic extract of B. procumbens at a dose of 200 mg/kg b.w. showed anti-asthmatic activity in TDI 214 K.S. Patil, S.R. Bhalsing / Journal of Ethnopharmacology 182 (2016) 200–220 crystallisation. In this study, cycstone as a standard drug (at high dose of 750 mg/kg b.w.) was used for comparative efﬁcacy (Chitra et al., 2012). Fig. 7. Chemical structure of lignans from Boerhavia genus. provoked rats by inhibiting inﬁltration of eosinophils and lymphocytes in lungs. Dexamethasone (2.5 mg/kg b.w.), a steroid medication was used as positive control in this study (Bokhari and Khan, 2015). These results support the ethnomedicinal practises of Boerhavia genus in immune reactions such as allergies, asthma, inﬂammation and ulcers. 6.1.2.2. Immunostimulatory activity. Interestingly, the alkaloidal fraction of B. diffusa showed immunostimulatory activity in Balb/c mice. This alkaloid fraction possessed ‘punarnavine’ which acquired its name from punarnava (a Hindi name for Boerhavia diffusa) plant. Punarnavine dose (40 mg/kg b.w.) in Balb/c mice for 5 days inhibited the production of proinﬂammatory cytokines such as TNF-α, IL-1β and IL-6. It has shown to stimulate immune system with enhanced stem cell proliferation, stem cell differentiation and antibody formation. In this study, the results were compared with untreated control mice (Manu and Kuttan, 2009b). 6.1.3. Effect on renal disorders: 6.1.3.1. Nephroprotective effect. The studies in mercury chloride toxicity rats demonstrated that 200 mg/kg b.w. aqueous leaf extract of B. diffusa was given orally for 5 days effectively protect kidneys from damage (Indhumathi et al., 2011). In eupalitin-3-O-βD-galactopyranoside treated Koi carp (Cyprinus carpio) ﬁsh, the levels of urea, creatinine and marker enzymes were normal and no pathological changes in renal tissue were observed (Fathima, 2012). Although these studies lack of positive controls, their results suggested the traditional signiﬁcane of Boerhavia diffusa in urinary disorders. A recent study in gentamicin-induced nephrotoxicity rats was carried out in two parts for different parameters. Among ﬁve different groups of rats in each part, a positive control group received α-lipoic acid in 0.5% CMC while test groups received 200 mg/kg and 400 mg/kg of aqueous extract of B. diffusa orally for 10 days. Assessment of parameters such as blood urea nitrogen (BUN), serum creatinine level, kidney malondialdehyde (MDA), and glutathione (GSH) levels, kidney injury on histopathology. However, their results demonstrated that B. diffusa did not show signiﬁcant improvement in PAH clearance, which was reduced due to gentamicin damage (Sawardekar and Patel, 2015). The results of the study showed that, aqueous extract of B. diffusa showed comparable results with positive control. 6.1.3.2. Antilithiatic activity. The growth-inhibition behaviour of struvite crystals by using in vitro single diffusion gel growth technique was studied. With increasing concentrations of herbal extract of B. diffusa, the number, dimensions, total mass, total volume, growth rate and depth of growth of struvite crystals were decreased (Chauhan et al., 2012). In ethylene glycol (0.75%) induced lithiatic rats, signiﬁcant reduction in the elevated levels of calcium, phosphate, uric acid and oxalate ions in urine was observed on oral administration of alcoholic extract of roots (250 mg/ kg b.w. and 500 mg/kg b.w.) of B. diffusa. The extract elevated the levels of magnesium in urine which acts as an inhibitor of 6.1.4. Antioxidant activity Since B. diffusa can contains high tannins and phenols as well as ﬂavonoids, many studies on antioxidant potential of B. diffusa have been reported (Gopal et al., 2010; Olaleye et al., 2010; Vaghasiya et al., 2011). Antioxidant activity guided chromatographic fractionation led to the isolation of eupatilin-7-O-α-rhamnosyl(1-2)αrhamnosyl(1-6)-β-D-galactopyranoside, a non-catechol group ﬂavone and two catechol group ﬂavonol glycosides viz., quercetin3-O-α-L-rhamnosyl(1-6)-β-galactopyranoside and quercetin-3,7di-O-glucoside (Fig. 2) (Joshi and Verma, 2012). Ethanolic extract of B. diffusa scavenged 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals with reduction potential of 0.657 0.02 mg/g ascorbic acid (Olaleye et al., 2010). An electron spin resonance (ESR)-guided fractionation of the methanolic extract of B. diffusa led to the isolation of boeravinone D, boeravinone G and boeravinone H which showed remarkable radical-scavenging activity (Aviello et al., 2011). When they compared chemical structure of these three compounds, boeravinone G showed higher antioxidant activity remarkably at nanomolar range due to the absence of methyl group at position 10 (Fig. 2). This study further demonstrated that MAP kinase and NF-kB pathways seem to be involved in the antioxidant effect of boeravinone G and it might be useful in reactive oxygen species (ROS)-mediated injuries (Aviello et al., 2011). In African tranditional medicine, the redder stems of B. erecta are preferred over less red. Led by this, a study evaluated the antioxidant potential of redder stem bark of B. erecta and proved that betacyanins (which gives a characteristic red colour to stems) are more antioxidant than phenolic compounds of the stem (Hilou et al., 2013). In another study, different extracts of B. elegans have scavenged the DPPH and reduced the ferric ion. This study concluded that the phenolic content of the extracts and antioxidant activity has positive correlation (Sadeghi et al., 2014). Similarly, polyphenolic concentration in B. procumbens found to be responsible for its marked antioxidant potential when assayed through various antioxidant parameters (Bokhari and Khan, 2015a). Very recently, Boerhavia diffusa, at a dose of 100 mg/ml, protected oxidative damage against quinolinic acid (QA), 3-nitropropionic acid (NPA), sodium nitroprusside (SNP), and Fe (II)/ EDTA complex induced oxidative stress in rat brain homogenates. The study also demonstrated that B. diffusa can protect hydroxyl radical induced DNA damage in the tissues (IC50 ¼ 38.91 70.12 μg/ ml) (Ayyappan et al., 2015). 6.1.5. Hepatoprotective activity Brazilian folk medicines as well as Indian medicinal practitioners have been using B. diffusa and B. erecta for various hepatic disorders. So, it is much of interest for researchers to investigate their hepatoprotective potential. Pre-treatment of the ethanolic extract of B. diffusa (100, 200, 300 and 400 mg/kg) once daily for 7 consecutive days in acetaminophen-induced liver damage rats decreased activity of serum enzymes which was elevated by acetaminophen. Also, acetaminophen induced oxidative stress which was counteracted by B. diffusa extract. The negative control in this study received physiological saline but a positive control seems to be lacking (Olaleye et al., 2010). Very recent study suggested that the aqueous extracts of B. diffusa when orally administered at the doses of 250 mg/kg b.w./day and 500 mg/kg b. w./day for 4 days decreased the elevated levels of alanine transferases (ALT), serum asparate transferases (AST), alkaline phosphatase (ALP) and serum albumin against CCl4 induced liver toxicity in albino rats. The positive control in the study was silymarin (50 mg/kg/b.w.) (Beedimani and Jeevangi, 2015). Table 5 Pharmacological activities reported for Boerhavia species Species Assaying parameters Boerhavia elegans Antimalarial In vitro and in vivo Antioxidant In vitro Cytotoxicity In vitro Antimalarial In vivo Heptoprotective In vivo Antioxidant In vitro In vitro anti-plasmodial activity observed with IC50 values 15.337 0.07 mg/ml and 11.97 70.05 against two strains of Plasmodium falciparum K1 (chloroquineresistant strain) and CY27 (chloroquine-sensitive strain) using pLDH assay and also in vivo assay in mice inoculated with Plasmodium berghei (ANKA strain) showed anti-plasmodial activity with IC50 values of o 20 μg/ml. DPPH, FRAP Leaves Signiﬁcant antioxidant activity with IC50 ¼ 6.85 μg/ml. 96-Well cell cytotoxicity assay Leaves 50 μg/ml Very low cytotoxicity against MCF-7 at 50 μg/ ml of extract compared to standard drug Doxorubicin (10 μg/ml) Blood schizonticidal activity Stem 50–1000 mg/ Red stem bark of B. erecta against Plasmodium bark kg/day berghei berghei in mice showed low acute toxicity (ED50 value of 564.95 76.23 mg/kg and LD50 value of 2148 mg/kg) compared to standard drug chloroquine (ED50 value of 14.59 7 3.2 mg/kg) when observed on 4th day. Serum enzyme such as ALT, AST Roots 100 mg/100 g Levels of serum bilirubin, total protein, albuand ASP b.w. for 25 days min and also serum enzymes were restored in CCl4 hepatotoxic male Wistar rats (175–200 gm weight). SOD, catalase and peroxidase Leaves B. erecta exhibited enzymic antioxidant activactivity ities such as superoxide dismutase (SOD) catalase (CAT) and peroxidase (POD) 0.086 7 0.009, 0.4407 0.350, 40.95 712.60 units/mg protein respectively ABTS stem bark 70% MeOH extract showed higher antioxidant activity of betacyanin fractions than phenolic compounds (RSC50 ¼171.2 7 8.4) Paralysis time and death time Root At 20 mg/g extract showed in vitro antihelmintic activity against Pheretima posthuma with paralysis time of 3.25 7 0.21 min and death time of 19.03 70.25 min antiproliferative SulforhodaAerial Rotenoids puriﬁed from ethyl acetate extract mine B (SRB) assay part were found to exhibit signiﬁcant cytotoxicity against HeLa (human epithelial carcinoma) and MCF-7 (human breast cancer) cell lines at the concentration of 100 μg/ml with camptothecin as the positive control. In vitro Antihelmintic In vitro Anticancer In vitro parasite lactate dehydrogenase (pLDH) assay and 4-day suppressive test in mice Parts used Dose range Aerial part 4.68–50 μg/ml Results/outcomes Bioactive metabolite and/type of References extract Dichloromethane extract partitioned from ethanol extract Ramazani et al., 2010 Phenolics in MeOH extract Sadeghi et al., 2014. Phenolics in MeOH extract Sadeghi et al., 2014. Decoction Hilou et al., 2006 50% EtOH extract Krishna and Shanthamma, 2004a Phenolics and or ﬂavonoids in MeOH extract Rajeswari et al., 2010 Betanin Hilou et al., 2013 Tannins in MeOH extract Marulkar et al., 2011 Boeravinone C, K, (HeLa cells) Boeravinone M (MCF-7 cell line) 10-methylboeravinone C (both) Do et al., 2013a K.S. Patil, S.R. Bhalsing / Journal of Ethnopharmacology 182 (2016) 200–220 Type Boerhavia erecta Pharmacological activity 215 216 Krishna and Shanthamma, 2004b Krishna and Shanthamma, 2004a Bokhari et al., 2015b Serum enzymes In vivo Leaves and callus Serum enzyme such as ALT, AST Roots and ASP Hepatoprotective Boerhavia rependa Anti-inﬂammatory In vivo Whole plant In vivo Anti-edemous effect was observed at all stages MeOH extract of oedema development which led to the conclusion that both early and delayed phases of carrageenan-induced inﬂammation were attenuated may because of histamine or NO release Levels of serum bilirubin, total protein, albu50% EtOH extract min and also serum enzymes were restored in CCl4 hepatotoxic male Wistar rats although B. erecta roots extract was found to be more effective than B. rependa Levels of serum enzymes, serum albumin etc., EtOH extract were restored in Wistar rats and evaluated that leaf calli can be efﬁciently used as alternative to in vivo leaves for hepatoprotective purpose Polyphenols in n-butanol fraction Bokhari et al., 2015b Various assays showed antioxidant potential 300, 250, 200, 150, 100, 50, and 25 mg/ml Whole plant DPPH, ABTS, superoxide, OH, H2O2 and phosphomolybdate radical scavenging activity carrageenan induced Paw oedema. Antioxidant Boerhavia procumbens In vitro Bioactive metabolite and/type of References extract Results/outcomes Dose range Parts used Assaying parameters Type Pharmacological activity Species Table 5 (continued ) K.S. Patil, S.R. Bhalsing / Journal of Ethnopharmacology 182 (2016) 200–220 6.1.6. Antiviral property From above hepatoprotective activities it might be suggested that B. diffusa has curative role in the liver damage. According to modern studies, B. diffusa showed a potential to cure infectitious hepatitis by antiviral mechanism. In a study, 90% EtOH root extract (5 mg/ml) of B. diffusa showed antiviral potency by inhibiting surface antigen as well as inhibition of HBV (hepatitis B virus) DNA polymerase (Kannan et al., 2011). Additionally, 200 mg/ml of B. diffusa induced a proinﬂammatory Th1 antiviral cytokine i.e. IFN-γ in peripheral blood mononuclear cells (PMBC). For this cytokinin induction activity, PHA (5 mg/ml) was used as positive control. All these results further concluded that B. diffusa contains anti-HBV substance(s) but exact mechanism of action need to be elucidated (Kannan et al., 2011). Recently, a supportive study to antiviral principles in Boerhavia genus came from moderate anti-HIV integrase activity of quercetin-3-O-rutinoside (IC50 ¼ 10 mg/ml) and isorhamnetin-3-O-rutinoside (IC50 ¼22 mg/ml) isolated from stem bark of B. erecta (Nugraha et al., 2015). Effectiveness of Boerhavia species have been already reported against plant viruses (Awasthi and Verma, 2006) but the above studies indicated their potential against human viruses which would be of certain interest for evaluation of molecular mechanism and production of antiviral compounds from Boerhavia. 6.1.7. Anticancer effect Indian Ayurveda has mentioned the use of B. diffusa in the treatment of tumours which may have driven the researchers to explain its anticancer potential through different mechanisms. Treatment of punarnavine, an active component from B. diffusa resulted in the presence of apoptotic bodies and DNA fragmentation in B16F-10 melanoma cells in a dose dependent manner. The study demonstrated that punarnavine induces apoptosis via activation of p53 induced caspase-3 mediated pro-apoptotic signalling and suppression of NF-κB induced Bcl-2 mediated survival signalling (Manu and Kuttan, 2009a). Also, extracts from B. diffusa root showed that a methanol: chloroform fraction at a concentration of 200 μg L 1 signiﬁcantly reduced cell proliferation with visible morphological changes in HeLa cells after 48 hrs of exposure. Cell cycle analysis suggested that antiproliferative effect of B. diffusa could be due to inhibition of DNA synthesis in HeLa cells (Chopra et al., 2011). In another study, higher doses of phytoproteins from B. diffusa have shown anticarcinogenic potential in MCF-7 cell line possessing the membrane receptor for estrogens and androgen (Singh et al., 2012). Latest ﬁndings suggest that, punarnavine at 50 mM inhibited in vitro MMP-2 and MMP-9 expression in HUVECs and neovascularisation in sponge implant assay. It also showed in vivo anticancer potential by decreasing ascitic ﬂuid volume by 60.94% and tumour volume by 86.40% in Ehrlich ascites model (Saraswati et al 2013). The study also demonstrated its role in anti-angiogenesis by inhibiting VEGF expression as evident from RT-PCR, ELISA and Western blotting assay (Saraswati et al., 2013). 6.1.8. Cardiovascular effects Ethanolic extract of B. diffusa (20 μg/mL) found to protect 5 mM arsenic trioxide (ATO) -induced cardiotoxicity in H9c2 Myoblasts. A decreased activity of lactate dehydrogenase (6.61 71.97 μU/mL, respective control group: 16.157 1.92 μU/mL), reduced oxidative stress, reduced calcium inﬂux and organelle damage marked the protective effect (Vineetha et al., 2013). In one more study, ethanolic extract of B. diffusa was shown to have protective effect against mitochondrial dysfunction in angiotensin II induced hypertrophy in H9c2 cardiomyoblast cells. The study demonstrated that activities of aconitase and thioredoxin reductase lowered due to hypertrophy and were increased by ethanolic extract of B. diffusa. Further, the extract signiﬁcantly prevented the generation of K.S. Patil, S.R. Bhalsing / Journal of Ethnopharmacology 182 (2016) 200–220 intracellular ROS and mitochondrial superoxide radicals. It has protected the mitochondria by preventing dissipation of mitochondrial transmembrane potential (ΔΨm), opening of mitochondrial permeability transition pore (mPTP) and mitochondrial swelling. The extract also enhanced the activities of respiratory chain complexes and oxygen consumption rate in embryonic rat heart-derived H9c2 cell line (Prathapan et al., 2014). 6.1.9. Anti-inﬂammatory activity As described earlier, traditional use of Boerhavia in asthma and inﬂammatory disorders led to investigate its potential in these ailments. 95% EtOH extract of B. diffusa roots at the doses of 100 mg/kg, 200 mg/kg and 400 mg/kg showed protection against preconvulsive dyspnoea in histamine aerosol exposed experimental animals suggesting anti-histaminic activity. They further concluded that the activity may be due to H1-receptor blocking or bronchodilation (Suralkar et al., 2012). Boeravinone B, a rotenoid isolated from roots of B. diffusa showed signiﬁcant in vivo antiinﬂammatory activity (56.6% at 50 mg/ kg), better than the positive control ibuprofen (43.52% and 50.40% at 50 and 100 mg/kg po, respectively) in female Sprague–Dawley rats (Bairwa et al., 2013a). ‘Punarnavasava’ is an Ayurvedic formulation mainly contains B. diffusa which inhibited carrageenan-induced paw oedema in rats (Gharate and Kasture, 2013). Nitric oxide (NO) is a potent pleiotropic inhibitor of physiological processes such as smooth muscle relaxation, neuronal signalling and platelet aggregation. Ethanolic extract showed nitric oxide inhibition (IC50 ¼370.47 77.33) and scavenged the nitric oxide free radicals in vitro which led to conclusion that B. diffusa may have role in free radical mediated chain reactions in inﬂammation (Muthu et al., 2014). The same extract inhibited protein denaturation (IC50 ¼356.2971.46) and proteinase activity (IC50 ¼348.84 71.40) (Muthu et al., 2014). Furthermore, the study demonstrated that ethanolic extract reduced the thickness of paw volume in both carrageenan induced inﬂammation and cotton pellet induced granuloma, showing in vivo antiinﬂammatory effect (Muthu et al., 2014). Very recent study has isolated ﬁve new rotenoids viz., boeravinones P, boeravinones Q, boeravinones R, boeravinones S, boeravinones M and four known viz., boeravinone A, 10-O-demethylboeravinone C, boeravinone B and boeravinone E as anti-inﬂammatory agents from 70% ethanolic extract of B. diffusa (Bairwa et al., 2013a; Bairwa et al., 2013b). Among these, boeravinone S (40 μM) showed highest in vitro COX1 (IC50 ¼21.1 μM) and COX-2 (IC50 ¼ 26.7 μM) inhibitory activities. 6.1.10. Anticonvulsant activity In Nigerian folk medicine, the B. diffusa has been known in treatment of epilepsy and hence study has been carried to elucidate its usefulness in convulsions. Anti-convulsant activity of methanolic extract of B. diffusa roots (1000, 1500 and 2000 mg kg 1, intraperitoneally (i.p.)) and liriodendrin-rich fraction (10, 20 and 40 mg kg 1, i.p.), chloroform fraction (20 mg kg 1, i.p.) and phenolic compound fraction (1 mg kg 1, i. p.) were studied in pentylenetetrazol (PTZ) (75 mg kg 1, i.p.)-induced seizures. The crude methanolic extract of B. diffusa and only its liriodendrin-rich fraction showed a dose-dependent protection against PTZ-induced convulsions. The observed anticonvulsant activity was due to calcium channel antagonistic action of the liriodendrin-rich fraction (Kaur and Goel, 2011). 6.1.11. Antibacterial activity Nowadays, researchers are focusing on plant extracts and their metabolites as antimicrobials because of prevalence of multi-drug resistant bacteria and their low susceptibility to antibiotics. Apu et al. (2012) have noticed that the methanolic extract of Boerhavia diffusa was possessed antimicrobial activity against three pathogenic organisms namely, Staphylococcus aureus (Gram positive), 217 Shigella dysenteriae (Gram negative) at 1000 mg/disc of extract. The study used ciproﬂoxacin (5 mg/disc) as positive control. The ethanolic extract of whole plant of Boerhavia diffusa showed antimicrobial activity against bacterial strains Bacillus subtilis UC564, Staphylococcus aureus 15 ML296, Staphylococcus aureus ML329 and Salmonella typhi DI at 2000 mg/ml. Oﬂoxacin was used as positive control (Das, 2012). 7. Toxicity studies While the Boerhavia species offer cures for variety of ailments, its use in traditional medicine as emetic endorses toxicity. Boerhavia diffusa L., as of 2007, has been enlisted in US govt. FDA poisonous plant database (www.accessdata.fda.gov/scripts) which seems to be primarily sourced from different books (Bessey, 1902; Dastur, 1962; McGufﬁn et al., 2000; Merrill, 1943). According to one such book, roots of B. diffusa affects kidney if used as food (Merrill, 1943). However, scientiﬁc study suggest no any observable adverse effect on foetal development after daily administration of 250 mg/kg b.w. of ethanolic root extract in rats throughout pregnancy (Singh et al., 1991). A range from 500, 1000, 2000 mg/kg b.w. of aqueous extract of B. diffusa leaves given orally to albino mice and rats did not affect both the absolute and relative organ weights between the control and the test group. The liver enzymes and haematological parameters were statistically equal in all the groups and suggested LD50 value more than 2000 mg/kg b.w. (Orisakwe et al., 2003). Nevertheless, decoction of stem bark of B. erecta was observed to have low acute toxicity with LD50 value of 2148 mg/kg b.w. in male mice (Hilou et al., 2006). This can be correlated with the traditional use of Boerhavia species as emetic when taken in large dose. Also, 80% ethanol extract of aerial parts of B. elegans have shown very low toxicity with LD50 value of 1020 mg/ml when screened with brine shrimp (Artemia salina) toxicity test (Ramazani et al., 2010). Conversely, Boerhavia chinensis has shown potential neurotoxicity at LD50 value of 41000 mg/kg b.w. in mice of either sex weighing 15–20 g (Dhawan et al., 1980). In short-term toxicity test, the aqueous leaf extract of Boerhavia erecta at the dose of 1000 mg/kg/day for 28 days affected glucose level in male and female Wistar rats. At the same time, the sub chronic toxicity of the same extract at three doses of 100 mg/kg/day, 300 mg/kg/day and 1000 mg/kg/day, orally administered for 90 days, did not result in any mortality (Lagarto et al., 2011). A study claimed that crude methanolic extract of B. repens found to be potentially toxic when tested at different concentrations (0.78125, 1.5625, 3.125, 6.25, 12.50, 25, 50, 100, 200 and 400 μg/ml) against Artemia salina (brine shrimp lethality assay). The LC50 value (based on Log C) for B. repens observed in this study was 4.19 mg/ml compared to vincristine sulphate as the positive control (LC50 ¼0.840 μg/ml based on Log C) (Rahman et al., 2014). 8. Conclusion From above studies, it is concluded that the genus Boerhavia has long been used as traditional medicine worldwide most notably in liver disorders, inﬂammation, urinary disorders, gastrointestinal problems, malaria, asthma and microbial infections. Many studies reported ﬂavonoids as major bioactive compounds from this genus and their number seems to be increased with advent of research. Various rotenoids are isolated and primarily well investigated for anticancer, anti-inﬂammatory and antioxidant potential. Several studies are repeatedly published on antidiabetic, hepatoprotective and nephroprotective effects of Boerhavia species. Latest ﬁndings have shown interest in obtaining 218 K.S. Patil, S.R. Bhalsing / Journal of Ethnopharmacology 182 (2016) 200–220 antiviral and anti-inﬂammatory principles from genus Boerhavia. However, there are some problems which need to be addressed (i) Although most studies have focused on evaluating the bioactive potential of B. diffusa but other species of Boerhavia still need attention. For this to achieve, research also need to be directed in setting up proper tools for effective discrimination of Boerhavia species. (ii) Many studies claimed the bioactive potential of phytochemicals from genus Boerhavia. However, further research is needed on the mechanism of action or pharmacodynamics of phytochemical compounds to clarify their bioefﬁcacy as well as feasibility for commercial drug formulation. (iii) Because of inadequately characterized data, various pharmaceutical activities reported for quinolizidine alkaloid i.e. punarnavine are erratic. (iv) Clinical studies should have priority for compounds with well established pharmaceutical activities. (v) Leaves and roots are mainly exploited for phytochemical and pharmaceutical investigation. Study of other parts such as seeds, ﬂowers and stems are necessary for effective utilisation of these species. (vi) Though few reports disprove the toxicity of B. diffusa through various assays, toxicity studies must be carried out in all the members of Boerhavia as there are few reports of potential toxicity in B. repens and B. chinensis. Acknowledgement One of the authors, Mr. Kapil Suresh Patil is thankful to UGC, New Delhi for ﬁnancial support to this work under the Research Fellowship in Science for Meritorious Students (RFSMS) (sanctioned vide letter No F. 4-1/2006 (BSR)/7-137/2007 (BSR) dated June 26, 2012). Authors gratefully acknowledge ﬁnancial assistance towards research facility at School of Life Sciences, NMU, Jalgaon from UGC, New Delhi under SAP-DRS programme and DST, New Delhi under FIST programme. References Abbasi, A.M., et al., 2009. Medicinal plants used for the treatment of jaundice and hepatitis based on socio-economic documentation. Afr. J. Biotechnol. 8 (8), 1643–1650. Abbasi, A.M., Rubab, K., Rehman, A., et al., 2012. In vitro assessment of relief to oxidative stress by different fractions of Boerhavia procumbens. Pak. J. Pharm. Sci. 25 (2), 357–364. Agarwal, R.R., Dutt, S.S., 1936. Chemical examination of Punarnava or Boerhavia diffusa Linn.II. Isolation of an alkaloid Punarnavine. 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