INTRODUCTION:

Nature has given us many precious treasures, including plants. Plants not only recycle the oxygen but also nurture the life on our earth. Since time immemorial humans have been utilizing plants not only as source of food but also as remedies to various diseases. Every part of plant can be useful. Owing to these properties of plants, various systems of medicine have evolved. Side effects of allopathic drugs have scared people all over the world and there is consorted effort to find out an alternative therapeutic method. Ayurveda says that all plants bear medicinal properties and show phenomenal potency to cure ailments, such plants are called medicinal plant. One such plant which we intend to review is Butea monosperma.

Butea monosperma, a beautiful and unique flowering tree is known by variety of names in different areas of India but it is popularly known as flame of the forest¹. Fabaceae is among the largest families of flowering plants, comprising of about 630 genera and 18000 species². In Ayurveda and Unani even in homeopathy it is used since long ago.

This valuable plant contains various phytochemicals like alkaloids, tannin, polyphenols, glycosides, flavonoids etc. Phytochemicals play very important role in natural and modern therapy. Along with important secondary metabolites, this plant also harbors several endophytes which may or may not be important for its medical and industrial important³.

Classification⁴:

Kingdom: Plantae (Plants)

Subkingdom: Tracheobionta (Vascular plants)

Super division: Spermatophyta (Seed plants)

Division: Magnoliophyta (Flowering plants)

Class: Magnoliopsida (Dicotyledons)

Subclass: Rosidae

Order: Fabales

Family: Fabaceae (Pea family)

Genus: Butea Roxb. Ex Willd

Table 1: Synonyms and vernacular names of Butea monosperma in different regions⁵

Synonyms	Vernacular name in different regions
Butea braamania DC	Kashtadru, Karka and Kamalasana in Sanskrit
Butea frondosa Rox	Nim and palas in Bengali
Butea frondosa Wild.	Khakhara, Khakda, khakhado in Gujrati
Plaso monosperma (Lam.) Kuntze	Palashpapra in urdu
Erythrina monosperma Lam.	Palasa in tulu
Plasomonosperma var. flava Kuntze	Muttunga in kannad
Plasomonosperma var. rubra Kuntze	Brahmavriksham in malyalam, Togarumo-duga in Telgu, Porasurin Oriya, SiraTikkuru in Tamil, Chichra in Panjabi.

Distribution:

It is distributed in the drier parts specially Indo Gangtic plain (IGP) and in Indian sub continents. Mostly it is seen in southern parts of India, Warangal district of Andhra Pradesh, Aurangabad and Nizamabad in Maharashtra. Earlier it was found only in Maharashtra and recorded for the first time from the Gujarat Worldwide it is found Indonesia, Bangladesh, Thailand, Pakistan, Srilanka, Myanmar, Nepal, Germany and Laos^2,6,7.

Features of Butea monosperma:

Characteristics of different parts of Butea monospema are described briefly including its morphology, secondary metabolites, therapeutic values and presence of endophytes.

1. Leaves:

Leaves are trifoliate with obtuse leaflets and linear stipules. Size varies from 15 cm to 20 cm, leaflets are obtuse, glaborous, silky and conspicuously reticulate veined underneath connate and deltoid base and contain glucosides kino-oil containing oleic acid and ligonocelic acid².Leaf extract are useful in treatment of irregular bleeding during menstruation, stomach disorder, diabetic sore throat and is also used as astringent. Oral administration of ethanolic extract showed anti-diabetic activity and have capacity to blood glucose. Pretreatment of aqueous extract of Butea monosperma and ethyl acetate reduces the frequencies of micronuclei and increases the mitotic index in bone marrow and peripheral blood cell. Both extracts contain active ingredients that capable of inhibiting the effect of cyclophosphanmide that increases the formation of micronuclei and decreases the mitotic index and subsequent DNA damage. Ethyl extract showed significant increased hepatic GSH whereas ethyl acetate extract show significant activity of GSH⁸.Methanolic extract of leaves possess antibacterial activity against Bacillus pumilus and Salmonella typhi. Aqueous extract of leaves showed significant anthelmintic activity against adult earthworm Pheritima phostuma compare to the standard anthelmintic agent albendazole and alcoholic and ethyl acetate extract also active against round warm Ascardiagalli and tape warm Raillietinaspiralis at concentration of 100 mg/l⁹.Methanolic, petroleum ether and chloroform extract of leaf has significant free radical scavenging activity by DPPHassay¹⁰.Total 25 isolates were isolated using 166 parts of Butea monosperma of petioles and lamina. Total 08 fungal species from petioles and 10 from lamina were found that includes Curvularia sp., Colleotricum sp., Pithomyceschartarum, Sclerotium sp., Scopulariopsiscanadensis, Morphotype 1, Morphotype 2, Morphotype¹¹.

2. Flower:

Flowers are its main attraction of this plant as they are large, densely velvety outside, three and together form terminal nodes. Calyxs are 13mm, olive green in color and Corolla is about 3-5 cm long, orange or saffron color, semicircular and uniquely beaked^12,13.Flower contains triterpene, butein, butin, isobutrin, corepsin, isocareopsin, flavonoids, plasitrin, prunetin, monospermosidebutein 3 e-D-glucoside and sterols. Myricyl alcohol steric, palmitic, arachidic and lignoceric acids. Glucose, fructose, histidine, aspartic acid alanine and phenyl alanine are also found. Flower is also used to treat enlarged spleen, to treat eye disease, menstrual problem and in burning sensations. It is traditionally used as an anticonvulsant, antioxidant, antistress, anti-inflammatory, antileprotic, memory and behavior stimulant astringent, antiulcer and hepatotoxic activity. Methanolic extract along with ethyl acetate and butanol fraction showed potent free radical scavenging activity in cell culture of human hepatoma Huh-7 cell line and immortalized AML-12 mouse, it also inhibit the erythrocyte hemolysis using AAPH (amidinopropane dihydrochloride)¹⁴. The observed activity could be due to higher phenolic content in the extract. Intra peritoneal administration of the aqueous extract shows anti-tumorogenic activity in the X-15 myconcomice by maintaining liver architecture and nuclear morphometry and down regulating the serum VEGF level. Methanolic extract of flower possesses antifungal activity against Helminthosporiumsativum and free radical activity using DPPH, nitroblue tetrazolium (NBT) and ferric reducing power(FRAP)¹⁵.

3. Stem and Bark:

Stem is medium sized, slow growing about 12-15m height, with irregular and crooked trunk of about 20-40cm girth. Its bark is of ash color, upon injury it exudes a kind of red juice known as Butea gum or Benglkino. Stem contain 3hydroxyphenyl, 25-ene,2,14dihydroxyll,12dimethyle-8-oxooctadec-11-enyl-cyclonhexane, Stigmasterol-e-Dglucopyranoside and nanocosanoic acid. Bark contain kinnotannic acid, gallic acid and pyrocatechin. Also contain palastrin, majaor glycosides as butrin, alanind, allophanic acid cyaniding, lupenone, lupeol, medicarpin, mirosterol, palasimide, shelloic acid, lignine, betacyanine and fatty acids, leucoanthrocyanine, anthraquinone and Vitamine-C^16.Stem and bark is used as blood purifier, in bleeding hemorrhoid disorder, worm infections, wound treatment in cough and cold. Ethanolic extract contain anti diarrhoeal activity. Bark extract has cutaneous wound healing property¹⁷. It also reduces gastro intestinal motility after charcoal meal administration. Anti-obesity activity was observed in Cafeteria and atherogenic diet fed rat and monosodium glutamate fed rat at the dose of 200, 400 and 800 mg/kg of ethanolic extract. Ethanolic extract showed antidiarrheal activity in castor oil induced diarrhea in albino rats. Stigmasterol from bark was evaluated for thyroid hormone and glucose regulatory efficacy in mice. It also reduced serum triiodothyronineT3, Thyroxin T4, and glucose concentrations as well as the activity of hepatic glucose 6 phosphates with increase in insulin concentration showed its thyroid inhibiting and hypoglycemic property in mice. It has antioxidative potential das it decreases hepatic lipid peroxidation and increases the activity of catalase, superoxide dismutase and glutathione. Petroliumand ethyl acetate extract show antifungal activity against Cladosporimcladosporioides and ethanolic and aqueous extract of bark and methanolic extract showed good efficacy against Staphylococcus aureus, Bacillus subtilis and gram negative bacteria Escherichia coli and Pseudomonas aeruginosa according to the concentraton. Using 86 stem parts of Butea monosperma, total 27 isolates was found that includes Aspergillus niger, Curvularialunata, Fusarium verti, Pithomycescharartum, Colleotricumsp, Scopulariopsiscanadensis, Morphotype 2, Morphotype 3. Colleotricumwas found dominant among them^9,11,16.

4. Root:

Well developed tap root is found which is thick and long, numerous lateral roots. Roots contain glucose, Glycine, Aglycon a glycosides, and aromatic hydroxyl compound. Root is used in night blindness, elephantiasis, impotency and snake bites. Used to treat piles, ulcer, tumor, sprue and also responsible for the temporary sterility in women. There are some isolates are exclusively grow in roots Aspergillus fumigatus, Pseudomonasimmersa, Cladosporium sp., Colletotricumsp., Fusariumsolani, Morphotype 1, Papulasporaimmerse. Fusarium sterilihyphosum^11,18.

5. Seed:

They are flat, 25 to 40 mm long, 15- 25 mm wide and 1.5 mm thick. The seed coat is reddish brown in color, glossy, wrinkled and encloses two large, leafy yellowish cotyledons, hilum is conspicuous. Seeds contain palasonin, isomonospermosides, monospermosides, and allophonic acid, flavones glycosides, fixed oil, mixed fatty acid. Active ingredients of seeds are enzymes like polypeptidase, lipolytic enzymes, proteinase and proteolytic enzymes^18,19. It is also used in inflammation, skin infection and eye disease. Anti-hyperglycemic and anti hyperlipaemic activity is found ethanolic extract of seeds in NIDDM rats²⁰. Seed oil of Butea monosperma shows antibacterial and antifungal activity.5,7-dihydroxy-3,6,4-trimethoxy flavone- 7-o-alpha- L xylopyranosyl(1—3)-o-alpha –L arabinopyranosy-(1—4)-o-beta –D galactopyranoside found to be active ingredient for antimicrobial activity. Seed extracts show specificity toward the human erythrocytes. Only the lectine (agglutinine) isolated from seeds of Butea monosperma show heme-agglunating property. Human blood group-A specific agglutinins demonstrated in some of the N acetylegalactosamine/galactose binding lectine. Hemaagglutinine test showed N acetylegalactosamine is the strongest inhibitor of agglutination. Seed are active against Ascarislumbricoids (human), Toxicaracanis (in dog), earthwarm^{21, 22.}.^.

6. Gum:

Gum contains mucilaginous material, pyrocatechin and tannins and is used in treating stomatitis ring warm, septic sore throat. It is used for the treatment of leucorrhoea, excessive perspiration and diarrhea. Petrolium ether and alcoholic extract of the gum of Butea monosperma were shown to have antimicrobial activity against Staphylococcus aureus, Saccharomyces cerevisiae, Candida albicans, E.coli, Pseudomonas aeuriogenosa using disc diffusion method. Both the extract was found active against Gram positive bacteria and MIC value was found 300ug/ml. None of the extract was active against Gram negative bacteria^{19, 23}.

Flavonoids of Butea monosperma and its medicinal values:

Flavonoids are polyphenol and natural occurring substances distributed among the plant kingdom. A chalcone 1, 3 diphenyl 2 propane-1-ones act as a precursor for the flavonoids formation in plants²⁴. All these flavonoids are used in various areas used in many ways tremendously. We are focusing in only four of them that are butrin, isobutrin, butin and butein²⁵.

1. Antihepatotoxic effect:

Butrin 7, 3, 4-trihydroxyflavanone-7, 3-diglucoside is the active ingredient of flower which shows antihepatotoxic effect in rat. The methanolic extract of Butea monosperma possess hepato-protective effect and also suppress the oxidative stress and polyamine biosynthetic pathway by significant reduction in Aspartate transaminase (AST), Alanine transaminase (ALT), Lactate dehydrogenase (LDH) and gamma glutamyltranspeptidase activity (GGT)²⁶.

2. As sensitizer:

Isobutrin, a yellow color pigment belonging to chalcone class is ecofriendly sensitizer for optoelectronic applications. Chelation of this dye with Ti ions results strong Tiisobutrin chelate is stable, irreversible and it is thermal stable above 100 ̊C²⁷.

3. Enhancement of gene expression and immunomodulatory activity:

Isobutrin enhanced the rate of RNA synthesis in vitro by as much as 78% compared to a control (Dose 20ug per ml) and corresponding to a stimulatory effect on protein biosynthesis in liver cells. The activity of butrin was 63% above control level. In another study, it was found that four polyphenol butrin, isobutrin, isocoreopsin and butein from Butea monosperma has ability to enhance gene expression related with inflammations. It reduces the phorbol 12-myristate 13-acetate and calcium ionophore and suppresses the NF-κB p65 activation by increasing the production of TNF-α, IL-6, and IL-8 in HMC-1cell line. Most potent activity was found in isobutrin as compare with butrin and butein. In vitro kinase activity assay revealed that isobutrin was a potent inhibitor of IκB kinase complex activity ^{26, 28}.

4. Antiestrogenic and antifertility activity:

Butin is an important ingredient of Butea monosperma. It is active ingredients of flower, seed stem. When it given to female rats orally at the dose of 5, 10, 20 mg /kg. Anti-implantation activity 40%, 70% and 90% of the treated animal from day 1 to 10 days was recorded respectively. Dose dependent termination of pregnancy and reduction in implantation site was found at lower doses. Butin also exhibit the estrogenic activity in ovary ectomized young female rats at comparable anticonceptive doses but was devoid of antiestrogenic activity. It is a weak estrogenic uterotrophic effect was discerned even at 1/20 anti-conceptive doses and antifertility activity²⁹.

5. Anticancerous property:

Butein has been reported to demonstrate substantial antitumor activities in various cancers. However, the effect of butein on tumor glycolysis remains unclear. In this study, the effect of butein on tumor glycolysis and the underlying mechanism were investigated in hepatocellular carcinoma (HCC). After butein treatment, HCC cell proliferation was significantly inhibited. Moreover, the number of colonies formed in the agar was substantially decreased, with the suppression of HK-2 expression, glucose consumption in Hep3B and Huh-7 cells decreased by 48.4% and 56.3%, respectively and lactate production also was reduced accordingly. Mechanism investigations demonstrated that butein dose-dependently blocked the activation of the EGFR signaling pathway in HCC cells. In EGFR exogenous overexpression cells, the glycolysis suppression exerted by butein was substantially attenuated. Butein has a substantial inhibitory effect on tumor glycolysis in HCC cells, and the glycolysis suppression exerted by butein is closely related to its effect on the EGFR signaling pathway³⁰.

Butein has property to inhibit epidermal growth factor which stimulate the auto phosphotyrosine level of EPGF receptor in HePG2 cell and also inhibit tyrosine specific protein kinase at the level of competitive and noncompetitive to ATP and phosphate receptor respectively³¹.

Butein was found to have the potential to activate group enzymes, known as the sirutrin, which make use of oxidized nicotinamide adenine dinucleotide to remove acetyle group from protein. The compound is a potent inhibitor of aromatase, a key enzyme in biosynthesis of estrogen in the human, so it is used in treatment of breast cancer by reducing 90% aromatase activity³².

Free radical damage causes glutathione s transferase level reduced caused by hydrogen peroxide stress in human caucasian neuroblastoma IMR 32 cell. Butein increases the level of glutathione s transferase about 86% at the concentration of 10um^33.

Flower extract of Butea monosperma having butein and isobutrin has preventive role in hepatatic carcinogenesis and oxidative stress in male wistar rat in significant dose dependent manner caused by 2 AAF (2 acetyle amino fluorine) at a concentration of 100 and 200 mg/kg body weight. Pretreatment of Butea monosperma flower extract in 2-AAF administrated rat increases glutathione reductase, glutathione peroxidase, quinone reductase and glutathione transferase level to 9-48%, 26-38%, 5-23%and 9-21% respectively. It also suppress the formation of MDA (26-42%) and H₂O₂ (33-35%) in dose dependent manner. It also reduces the hepatic toxic marker and decreases the incident of tumor³⁴.

Sodium salts of butrin are also found in flower extract of Butea monosperma along with butrin and isobutrin. Over expression of SIRT-1 and AURK-B are related with colorectal cancer. Overexpression of SIRT-1 is one the causative factor of uncontrolled replication of DNA and is also crush the p53 expression and induces cell proliferation. Butea monosperma floral compound treatment in SW 480 CRC cell suppress the SIRT- 1 gene, cyclin D1, PAkt, TGF 3B and also suppresses procaspase 3. It down regulates the AURk-B expression and regulates cell signaling related to Wnt pathway³⁵.

6. Free radical scavenging activity:

Butrin and butein are active ingredients of flower of Butea monosperma and they show free radical scavenging activity, oxidative activity and proapoptotic activity in human heploma Hub 7 cell line and in immortalized AML-12 mouse hepatocyte. Cellular glutathione level, lipid peroxidation and glutathione s transferase are marker of defective liver than are inhibited by both butrin and butein. Butein was found to be more effective than butrin almost 87% activity at 1mg/ml and 22% activity for butein and butrin respectively¹⁴.

7. Antiapoptotic effect:

The antioxidant property of butin was investigated for cytoprotective effect against H₂O₂ induced cell damage. This compound showed intracellular reactive oxygen species (ROS) scavenging, 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging, inhibition of lipid peroxidation, and DNA damage. This radical scavenging activity of butin protected cell damage exposed to H₂O₂. Also, butin reduced the apoptotic cells induced by H₂O₂, as demonstrated by the decreased DNA fragmentation, apoptotic body formation, and caspase 3 activities³⁶.

Butin has property to reduced risk of cardiovascular disease caused by diabetes mellitus in ischemia/ reperfusion injured myocardial injury in diabetic mice. Myocardial function improved by treatment with butin by improving caspase activity and box/bcl-2 gene and Nrf 2, AMPK, AKT-3b signaling pathway³⁷.

Butin has property to reduced or inhibit H₂O₂ induced cell damage. When butin was exposed to cell pretreated with H₂O₂. It has free radical scavenging activity, By DNA fragmentation, caspase 3 activation. Butin restores the activity and expression of superoxide dismutase (SOD) and catalase (CAT) enzyme dismutase (SOD) and catalase (CAT) enzymes in v79-4 cells. 39U/mg at 10 ug/ml of butin and in case of CAT it was 51 Umg/protein at 10 ug/ml butin in respect of control 29U/mg protein and 30 U/mg protein for SOD and CAT respectively³⁸.

Butein could induce apoptosis in human leukaemic HL-60 cells. The treatment of HL-60 cells with butein induced apoptotic cell death as determined by morphological and biochemical changes. Apoptotic DNA fragments in the butein-treated HL-60 cells were increased gradually as determined by flow cytometric analysis. The caspase-3 activity was increased during butein-induced apoptosis. However, caspase-3 inhibitor abrogated the butein-induced DNA fragmentation. Furthermore, the treatment of HL-60 cells with butein decreased the expression of Bcl-2 protein, but increased the expression of Bax protein. These results suggest that butein-induced apoptosis is mediated through the activation of caspase-3 and it is associated with changed expression of Bcl-2 and Bax³⁹.

Butin is reported to protective property in mitochondria, it upregulates Mn SOD (manganese superoxide dismutase) expression via activation of p13k, Akt, Nrf 2 pathway. Exposure to H₂O₂ decreases the expression of MnSOD in hamster lung fibroblast V79-4 cell line which is important in preventing oxidative stress. Butin activates the expression of MnSOD gene, p13k and Akt gene which are major signaling enzymes involved in protection against cellular oxidative stress⁴⁰.

8. Inhibition of inflammatory effect:

Butein shows anti-inflammatory effect in vitro. Butein has anti-inflammatory effect as it reduces the expression of IL-6 and STAT 3 signal transduction. STAT 3 signal transduction is the principle mechanism of inflammatory reaction’s and malignant tumor formation. Butein inhibit the expression of STAT 3 in epithelial cell⁴¹.

9. Anti angiogenesis activity:

Butein exhibit the anti-angiogenesis activity effect both in vivo and in vitro by targeting the translational machinery. Bone marrow derived endothelial progenitor cells can contribute to tumor angiogenesis. Butein inhibits serum and vascular endothelial growth factor induced cell proliferation. It repressed the phosphorylation of Akt, mToR involved in signaling pathway of angiogenesis⁴¹.

10. Anti mycobacterial activity:

Antimicrobial activity was assessed against Mycobacterium tuberculosis H₃₇Ra using the microplate alamar blue assay. Butein was found more effective for Mycobacterium with a MIC value 12.5 ug/ml against Mycobacterimbovis, a causative agent of tuberculosis in cattle. Butin has antimycobacterial property, it inhibit pVV16, a putatative dehydrogenase enzyme involved in fatty acid synthesis 11 and it over expression strain pVV16-Rv636 with MIC value 43 and 59 ug/ml respectively⁴².

11. Cell cycle arrest:

Liver cirrhosis, inflammation in liver induces hepato-cellular carcinoma (HCC). Butein induces cell cycle arrest at G2/M phase and inhibit cell growth in two cell line HepG2 and Hep3B. Butein has tendency to decreases the cyclin cdc25 and cdc2 in both cell line and activates JNK pathway which induces reactive oxygen species (ROS). Butein induced G2/Mphase arrest was associated with increased ATM, Chk1 and Chk2 phosphorylation⁴³.

12. Melaninebooster:

Absence of melanine and abnormal level of MDA, CHE and TYR are main clinical manifestation of vitiligo. In hydroquinone induced vitiligo model mice, sodium salt of butrin showed positive effect. It increases melanine containing hair follicle, basal layer melanocyte and melanine containing epidermal cell by increasing the expression of Typ and TPR-1 and decreases the concentration of MDA and CHE activity in dose dependent manner at 4.25 mg/kg and 42.5mg/kg⁴⁴.

CONCLUSION:

Vast varieties of plants harbor extraordinary potential in treatment of various ailments and infectious diseases. Butea monsperma is one such example. Butin, butein, butrin and isobutrin are the four major secondary metabolites, which impart this plant with its valuable medicinal property. Though these flavonoids have shown their activity in manifesting various immunomodulatory effects, anti-tumorogenic activity and modulation of cell signaling, still their full potential stands to be assessed. For instance, their activity for or against various lentivirus and protozoans has not been reported till date. Association of endophytes with Butea monosperma has been established since long time but no study had been reported whether they play any role in secretion and accumulation of these bioactive compounds in the plant? These are few questions which need to be answered to address the lacunae in the existing knowledge about the flavonoids of B. monosperma.

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Received on 10.12.2019 Modified on 14.03.2020

Research J. Pharm. and Tech. 2020; 13(11):5647-5653.

DOI: 10.5958/0974-360X.2020.00984.1