Solanum Nigrum: Current Perspectives on Therapeutic Properties Ramya Jain (Grad

amr Monograph

Solanum nigrum: Current Perspectives on Therapeutic Properties Ramya Jain (Grad. stud.); Anjali Sharma (Grad. stu.); Sanjay Gupta,PhD; Indira P. Sarethy, PhD; and Reema Gabrani, PhD

Introduction Active Constituents Solanum nigrum (black nightshade) is a medicinal S. nigrum possesses various compounds that are plant member of the Solanaceae family of plants. responsible for diverse activities. !e major active Ramya Jain, Graduate student – !nal year B.Tech-M. !is family comprises many genera, well known for components are glycoalkaloids, glycoproteins, and Tech dual degree in biotech- their therapeutic properties. In addition to S. polysaccharides. It also contains polyphenolic nology, Jaypee Institute of nigrum, this family includes fruits and vegetables compounds such as gallic acid, catechin, protocat- Information Technology, NOIDA, India. such as potato (Solanum tuberosum), tomato, and echuic acid (PCA), caffeic acid, epicatechin, rutin, peppers, ornamental plants such as petunia, and and naringenin.17 Anjali Sharma, Graduate other medicinal plants such as Atropa student – !nal year B.Tech-M. Tech dual degree in biotech- belladonna L. (deadly nightshade), Datura nology, Jaypee Institute of stramonium L. (Jimson weed), and Information Technology. Hyoscyamus niger L. (black henbane). Sanjay Gupta, PhD – Associ- S. nigrum commonly known as Makoi ate professor, Jaypee Institute or black nightshade, usually grows as a of Information Technology; weed in moist habitats in different kinds post-doctoral fellowship from Institute of Molecular and of soils, including dry, stony, shallow, or Cell Biology (IMCB), Singa- deep soils, and can be cultivated in pore; previously a research tropical and subtropical agro climatic scientist in Genome Institute of Singapore. regions by sowing the seeds during April-May in well-fertilized nursery beds; Indira P. Sarethy, PhD – from it can be used for reclaiming the Madurai Kamaraj University, 1 India; assistant professor, degraded land as well. Jaypee Institute of Informa- S. nigrum has been extensively used tion Technology. traditionally to treat various ailments 2,3 Reema Gabrani, PhD – from such as pain, inflammation and fever. National Institute of !e plant is also used in the Oriental Immunology, New Delhi, systems of medicine for various purposes – as an !e glycoalkaloids include solamargine, solaso- India; post-doctoral research, 4 3 University of Minnesota, U.S.; antitumorigenic, antioxidant, anti-inflammatory, nine, and solanine that belong to the tropane 5 3 3 assistant professor, Jaypee hepatoprotective, diuretic, and antipyretic agent. group of compounds. Solanine’s function and Institute of Information Various compounds have been identified which are activity has been extensively studied. It comprises Technology. Correspondence address: responsible for diverse activities. 95 percent of the total alkaloid concentration Department of Biotechnology, S. nigrum is widely used in many traditional present in the plant and is found naturally in any Jaypee Institute of Informa- systems of medicine worldwide for disparate part. It is one of the plant’s major natural defenses tion Technology, A-10, Sector 62, NOIDA, India. ailments (Table 1), but has not garnered attention as it is toxic even in small quantities. With a Email: for modern therapeutic use. molecular weight of 868.04 and formula [email protected] C45H73NO15 it consists of an aglycone, solanidine (alkaloidal portion), and three sugar moieties

Table 1. Traditional Uses of S. nigrum6-16

State, Country Part Used Preparation Conditions References

Tanzania, Africa Leaf Leaves are pounded and applied Treatment of ringworm Moshi et al (2009) topically

Leaf Leaves are pounded and baked Used for dressing of warts

Fruit Ripe fruits in edible form Given to kids to stop bed-wetting

Tunisia, Africa Sap Erysipelas (acute Streptococ- Leporatti and Ghedira (2009) cus bacterial infection)

United Republic Whole plant Maceration Snake bite/sting by a Chifundera (1998) of Congo, Africa venomous animal

Algeria, Africa Fruit Diluted infusion of berries Blindness; conjunctivitis; Boulos (1983) glaucoma; trachoma; cataract

Whole plant Decoction Burns and dermal a!ections

Tamil Nadu, India Leaf Fresh leaves cooked with onion Stomachache; stomach ulcer Sivaperumal et al (2010); bulbs and cumin seeds or leaf juice Ramya and Jayakumarara can also be taken orally (2009); Ignacimuthu et al (2006); Muthu et al (2006) Leaf paste Applied directly Rabies; wound healing

Whole plant Taken as food Cough

Himalayan region, India Leaf Liver tonic; indigestion Kala (2005)

Thar Desert, India Roots Roots are boiled with a little sugar Increase fertility in women Parveen et al (2007)

Assam, India Roots Juice of roots is extracted Asthma and whooping cough Sikdar and Dutta (2008)

(glucose, galactose, and rhamnose, collectively glycoproteins consist of carbohydrate (69.74%) and known as solatriose), which are attached to the protein (30.26%, mainly hydrophobic amino acids third position of the aglycone.18,19 It is generally containing glycine and proline).22 A 150 kDa present in the form of α-solanine, but can be phytoglycoprotein isolated from seeds by affinity Key words: solanum, s. nigrum, hepatic, liver, hydrolyzed to β- and γ-solanine with one or two chromatography and ammonium sulphate precipi- hepatoprotectant, carbohydrate molecules each.20 !ese glycoalka- tation23 has been shown to exhibit antitumor nightshade, night shade, loids demonstrate marked antitumor effects on effects on HCT-116 cells, as well as diuretic and solanaceae, cancer, seizure, 21 22 epilepsy, antiproliferative, various tumor cell lines. antipyretic effects. Polysaccharides isolated from antiseizure, !e glycoproteins are obtained from S. nigrum by aqueous extracts of S. nigrum have been shown to anti-in"ammatory precipitation with 80-percent ammonium sulphate. possess antiproliferative activity that can be SNL glycoproteins I of 150 kDa and 100 kDa and attributed to their immunomodulatory ability.24,25 SNL glycoprotein II of 210 kDa are obtained from fruits, stems, and leaves, respectively.4 !e

Mechanisms of Action/Clinical extracts and isolated polysaccharides (SNL-P) were Indications found to be identical,24,25 indicating that the Solanum nigrum demonstrates a diversity of components responsible for the antiproliferative therapeutic properties (Figure 1). activity in aqueous extracts are probably the polysaccharides. SNL-P did not have any direct Antiproliferative Activity/Cancer Preventive cytotoxic effect on U14 cell lines isolated from Both the crude extracts and isolated components cervical cancer. Its antitumor property can be of S. nigrum possess antiproliferative activity on attributed to its immunomodulatory ability, which various cancer cell lines. Crude extract is usually alters the host’s immune response.25 !is is a prepared with dried berries, but can also be crucial characteristic since, during the evolution of prepared from the whole plant. !e antiprolifera- cancer, the immune system becomes weakened and tive activities of the crude organic extract and is further undermined by chemotherapy.29 SNL-P isolated compounds were studied on tumor cell treatment arrests these cells in G2/M phase and lines of liver (HepG2),21,22 colon (HT29 and results in an increase in the percentage of CD-4+ T HCT-116),21,22 breast (MCF-7),26 and cervical cells.25 SNL-P activated CD-4+ cells are mainly (U1424,25 and HeLa27). !e antiproliferative activity T-helper 1 (!-1) cells that are activated by inter- of these extracts was examined by studying the feron-gamma (IFN-γ). !ese !-1 cells help in the cytotoxicity of the extract on cells. DNA fragmen- fight against intracellular pathogens and killing tation, a hallmark of apoptosis, was used to analyze self-altered or tumor cells.30-32 Similar immuno- the extent of apoptosis in treated cells. Apoptosis modulatory and anticancer properties of SNL-P or programmed cell death is mediated by two have been confirmed in U14 cervical cancer-bear- pathways. !e extrinsic pathway is activated by ing mice.25 death receptors; whereas, the intrinsic pathway is mitochondria dependent. Apoptosis at mitochondria is controlled by Figure 1. Therapeutic Properties of Solanum nigrum antiapoptotic (Bcl-XL, Bcl-2, and Mcl-1) and proapoptotic (Bax, Bak, Bid, Bim, and Bad) proteins. It has been observed that crude extracts Antiproliferative induce different responses in cells in vitro at high and low concentrations. !is is evidenced by the fact that when liver cancer cell lines (HepG2) are treated with high concentrations of the crude extract, c-Jun Antio e N-terminal kinase (JNK) is activated, xidant Phytoremediation which results in activation of proapoptotic Anti-seziur factors like Bax. It further results in release of cytochrome c from mitochondria that activates caspases and triggers 20,27 apoptosis. Anti-pyretic When the same cell lines are treated with tive low concentrations of extracts it leads to Hepatoprotec the induction of autophagy, in contrast to Anti-in!ammato apoptosis.17 Autophagy is a lysosomal r degradation pathway in which the cell’s Anti-poison damaged organelles or defective pathway prepares the cell to adapt to stressful ound heale conditions. !at might be why the low W ry concentration leads to autophagy.28 Aqueous plant extracts possess antiproliferative activity as demonstrated by growth inhibition of cervical carcinoma.24 !e mechanisms of actions of aqueous

!e mechanism of action of isolated glycoalka- traditional medicine have proven anticonvulsant loids on various cancer cell lines such as HepG2 has properties in animal models and may be a source of also been studied. !e antiproliferative activity of new antiepileptic drugs. solanine, a glycoalkaloid, on transformed cell lines Experimentally, seizures were induced by is mainly due to its ability to facilitate the opening picrotoxin, pentylenetetrazole, or electric shock in of the permeability transition (PT) channels of the adult albino rats. !e aqueous extract of S. mitochondria by lowering the membrane potential. nigrum leaves provided protection against induced !is results in an increase of the intrinsic calcium seizures in rats and a significant dose-dependent ion level that culminates in apoptosis. Solanine protection in chicken.44 !e mechanism of action of also inhibits Bcl-2, an antiapoptotic protein leading the extract still needs to be elucidated. to an increase in cytochrome c, which activates caspases and triggers apoptosis.20 Structure and Antioxidant Activity/Degenerative Disease; antiproliferative activity of other glycoalkaloids Anti-aging from S. nigrum have not yet been studied. !e uncontrolled production of free radicals A 150 kDa phytoglycoprotein isolated from the results in the onset of many neurodegenerative plant has been shown to possess antiproliferative diseases, can accelerate aging, and can be con- activity on HCT-116 cells,22 HeLa cells,27 HT29 trolled to some extent by exogenous antioxidants.45 cells,33 Hep3B cells,34 and MCF-7 cells.35 It activates Methanol extracts of S. nigrum have shown caspase-3 and induces apoptosis. In addition, it significant antioxidant activity in various assays, inhibits transcription factor nuclear factor-kappaB including 1, 1-diphenyl-2-picryl hydrazyl (DPPH) (NF-κB), protein kinase C alpha (PKCα), and radical scavenging activity, estimation of the total inducible nitric oxide (iNO).22 PKCα is a serine phenolic compounds in the plant extracts, and threonine kinase that plays an important role in determination of the 5-lipoxygenase activity.46 tumor progression.36 NF-κB is a known eukaryotic Methanol extracts of S. nigrum inhibited the DPPH transcription factor involved in downstream signal by 92 percent; whereas, the aqueous extracts transduction paths of phosphorylated PKCα. showed considerably less effective radical scavenger NF-κB protein is present in all cell types.37 It is activities. A quantitative correlation between the responsible for activation of transcription in antioxidant activity and the content of polyphe- mature B cells and plasma cells by binding to 10 nols was seen, signifying that the phenolic com- base pair regions of nuclear kappa enhancer.38 Its pounds present in the plant contribute to the activity in other cell types is inhibited due to the radical scavenging activity. presence of a substance such as inhibitor-kappaB Other than methanolic extracts, purified S. (IκB) in the cytoplasm.39 In the presence of the nigrum glycoproteins also possess antioxidant appropriate signal, IκB is phosphorylated, releasing activity. !eir activities are distinctively specific, NF-κB. Phosphorylated IκB undergoes protea- when demonstrated on MCF-7 cell lines using somal degradation and NF-κB is translocated to assays like DPPH radical scavenging assay, 2-deoxy- the nucleus where it activates the transcription of ribose oxidation assay, and superoxide anion genes involved in tumor progression. !e activated scavenging assay.4 S. nigrum glycoproteins effec- NF-κB results in the expression of the iNO tively inhibited hydroxyl radicals in a dose-depen- synthase promoter-dependent gene and leads to dent manner. But the mechanism of scavenging the production of inducible nitric oxide, which also action by stimulating cytokines (interleukin [IL] -2, culminates in apoptosis.36 IL-4, IL-12, IFN-γ, and tumor necrosis factor-alpha [TNF-α]) remains to be elucidated.4 Antiseizure Activity/Epilepsy Seizures are defined as alterations of behavior Anti-in"ammatory Activity/In"ammatory Conditions due to disordered, synchronous, and rhythmic Inflammation is a disorder caused by the release firing of populations of brain neurons.40 Modern of leukocytes and various other complex mediator drugs have not exhibited sufficient effectiveness in molecules such as prostaglandins, leukotrienes, their ability to cure seizures; in addition there are histamines, bradykinin, platelet activating factor, many side effects such as impairment of the central and IL-1 from tissues and migrating cells.47,48 nervous system (CNS), aplastic anemia, hepatic Various drugs and extracts derived from grapes, failure, or even death. Medicinal plants such as turmeric, mint, clove, eucalyptus, lavender, and Ficus sycomorus,41 Sclerocarya birrea,42 Annona many more have been used to alleviate diversifolia,43 S. nigrum and many more used in inflammation.49

S. nigrum has been used in the traditional Indian of liver lesions.52 In another study, the ethanol medicinal system to treat inflammation, edema, extract of the fruits of S. nigrum (at a dose of 0.25 and mastitis. !e most widely used method to g/kg) was found to be hepatoprotective in a rat 5 study anti-inflammatory effects in animal models model of CCl4-induced hepatic damage. is by inducing local edema in a rat paw by injecting !e effect of S. nigrum extract was also evaluated an irritant agent such as carrageenan.47 !e on thioacetamide (TAA)-induced liver fibrosis in methanolic extract of the plant showed good mice. Liver fibrosis generally involves accumulation dose-dependent anti-inflammatory effect on of the extracellular matrix protein, mainly collagen. induced edema in the rat model. Hydroxyproline levels are indicative of collagen and Cai et al50 isolated the compounds responsible hence are used to determine the extent of fibrosis. for the anti-inflammatory activity from the Histological examination confirmed that S. nigrum ethanolic extract of the S. nigrum. Leukotrienes whole plant extract reduced the degree of fibrosis such as LTC4 are the lipid mediators that are found caused by TAA treatment by reducing the amount in increased concentration in the inflammatory of hydroxyproline and hence collagen. Also, the reactions. Anti-leukotrienes are currently pre- treatment with the S. nigrum extract reduced the scribed to treat various inflammatory diseases such elevated levels of plasma alanine aminotransferase as asthma and atopic rhinitis. (E)-ethyl caffeate, (ALT) and total bilirubin to normal levels.53 one component isolated from S. nigrum, possesses !erefore, these results suggest that S. nigrum could maximum inhibition for leukotrienes and thus protect liver against CCl4- and TAA-induced could be considered as a potential anti-inflamma- oxidative damage in rats. tory therapeutic compound. So far no clinical trials have been conducted on S. nigrum and its purified components. However, Hepatoprotective Activity/Liver Disease there are reports on clinical trials conducted using !e protective effects of the aqueous extract of S. polyherbal formulations, such as Liv 60054 and Liv nigrum whole plant were evaluated in carbon 52,55 that contain S. nigrum as one of the compo- tetrachloride (CCl4) -induced chronic hepatotoxic- nents and have been used as hepatoprotective ity in rats. CCl4-induced experimental hepatic agents. damage leads to substantial increase in the serum activities of glutamate-oxaloacetate aminotransfer- Side E!ects and Toxicity ase (GOT), glutamate-pyruvate aminotransferase Most species in the Solanaceae family are (GPT), alkaline phosphatase (ALP), and total poisonous to humans as well as to livestock. !e bilirubin that are indicators of cellular leakage and toxic effects of the plants are mainly reported in loss of functional integrity of cell membrane in the older literature. For instance, deadly night- 51 liver. CCl4 also decreases the levels of antioxidant shade contains tropane alkaloids. !e toxin, when enzymes such as glutathione (GSH) and superoxide ingested by humans in large quantities, causes dismutase (SOD). !e utilization of S. nigrum anticholinergic effects.56 Although S. nigrum is aqueous extract at the dose of 0.2 g kg-1 body considered to be an edible plant, its toxicity is weight for six weeks restored the CCl4-caused mainly due to the presence of solanine, a glycoalka- increased levels of the hepatic enzymes (GOT, GPT, loid causing varying degrees of toxicity in a ALP); the higher dosage of S. nigrum aqueous dose-dependent manner.20 !e symptoms of extract (0.5 and 1.0 g kg-1) restored the diminished poisoning in humans due to solanine are reported levels of SOD and GSH, indicating repair of the to include nausea, vomiting, diarrhea, headache, 52 hepatic tissue damage caused by CCl4. dizziness, loss of speech, fever, sweating, tachycar- Glutathione-S-transferases (GSTs) are a family of dia, pupil dilation, blindness, mental confusion, enzymes involved in detoxification of xenobiotics. convulsions, coma, and death.57,58 !e amount of

CCl4 treatment decreases the expression of hepatic toxic compound in a plant depends on the climate, GST isoforms, GST Mu and GST Al; whereas, the soil type, season, and maturity.58 !e green unripe GST Pi expression is up-regulated. S. nigrum extract berries are generally considered more toxic than restored expression levels of the GST subunits to the ripe berries.59 It is probable that by boiling the control levels. Whether the mechanism of action of plant, the toxic components are destroyed as the S. nigrum is attributed to its direct action on the plant is reported to be edible after cooking.

GST subunits or its neutralization of CCl4 remains Traditionally, consumption of nightshade to be elucidated. Liver histopathological analysis vegetables like tomato, potato, and eggplant has also conﬁrms that S. nigrum reduced the incidence been considered to be problematic for arthritic

patients, leading to aggravation of joint pain. It has Kaushik and co-workers also documented anti- been reported that solanine present in the green inflammatory activity using higher doses of an parts of these vegetables is probably responsible ethanolic extract of S. nigrum fruits (500 mg/kg for joint pain. However, scientific documentation p.o.).62 on a correlation between S. nigrum consumption !e above studies show that the aqueous and and inflammation of joints is lacking. organic extracts were prepared from different parts of S. nigrum using different protocols to study its Therapeutic Dosage therapeutic effects. !ough the scattered studies S. nigrum crude extracts as well as its purified have indicated S. nigrum as a promising therapeutic compounds have been used to study antitumor, agent, further studies need to be carried out using antiseizure, anti-inflammatory, and hepatoprotec- standardized preparation methods from specific tive activities in various animal models such as rat, plant parts. mice, and chick. In most of the studies the extract has been either orally fed (p.o.) or administered Conclusion intra-peritoneal (i.p.). S. nigrum, a widely used plant in oriental S. nigrum aqueous extract of the whole plant was medicine, has been shown to possess various prepared by hot extraction at 100°C for 40 minutes activities such as antitumorigenic,17,20-27 antioxi- and fed to mice at a dose of 2 mg/kg daily for 15 dant,4 anti-inflammatory,48 hepatoprotective,51-55,63 days to study its effect on melanoma cells metasta- diuretic, and antipyretic.44 Major compounds have sized to the lung. !is dosage resulted in more than been isolated and characterized. !e in vivo activity 50-percent reduction in tumor weight and lung of these compounds has also been studied. metastatic nodules. !e metastasis was probably Although it is mentioned as a component in several suppressed due to decreased expression of signal- popular polyherbal formulations in the form of ing molecules PKCα, RAS, NF-κB and AKT alcoholic or hydroalcoholic extracts, it is an phosphorylation.60 attractive candidate plant for formulating targeted In another study, polysaccharides isolated from drugs. A combined approach of parallel preclinical dried whole plant powder were further purified on studies involving in vitro and in vivo models could DEAE-cellulose and Sephadex G-100 columns into provide necessary data to assess its suitability in three subfractions (SNL-P-1a, 1b and 1c). !ese this regard. While the exact mechanism of action purified subfractions were given i.p. to mice at a remains to be elucidated in many cases, this plant dose of 25 or 50 mg/kg daily for 12 days and with wide-ranging therapeutic properties needs to SNL-P1a was found to be more effective in inhibit- be investigated in well-designed clinical studies. ing cervical cancer than SNL-P1b and SNL-P1c. SNL-Ps protected the T-cells from tumor-induced References apoptosis, resulting in host immune counter surge 1. Kiran, Kudesia R, Rani M, Pal A. Reclaiming to fight the tumors.61 degraded land in India through the cultivation of Antiseizure activity of S. nigrum aqueous extract medicinal plants. Bot Res Int 2009;2:174-181. from leaves was evaluated in rats, mice, and chicks. 2. Acharya E, Pokhrel B. Ethno-medicinal plants used !e extract was prepared using the soxhlet appara- by Bantar of Bhaudaha, Morang, Nepal. Our Nature tus for 72 hours at 60°C. Seizures were induced by 2006;4:96-103. picrotoxin, pentylenetetrazole, or electric shock. 3. Zakaria ZA, Gopalan HK, Zainal H, et al. !e therapeutic dose for anticonvulsant activity Antinociceptive, anti-inflammatory and antipyretic was found to be 30-60 mg/kg in rats and mice, effects of Solanum nigrum chloroform extract in while the dose of 10-40 mg/kg was effective in animal models. Yakugaku Zasshi electroshock-induced seizures in chicks. !e study 2006;126:1171-1178. concluded that, although S. nigrum exhibited 4. Lee SJ, Lim KT. Antioxidative effects of glycoprotein anticonvulsant activity, it did not have antiepileptic isolated from Solanum nigrum Linne on oxygen activity.44 radicals and its cytotoxic effects on the MCF-7 cell. Dose-dependent anti-inflammatory, antipyretic J Food Sci 2003;68:466-470. and antinociceptive activities were observed using 5. Raju K, Anbuganapathi G, Gokulakrishnan V, et al. the chloroform extract of S. nigrum leaves. !e Effect of dried fruits of Solanum nigrum LINN extract was administered subcutaneously (s.c.) in against CCl4-induced hepatic damage in rats. Biol rat and mice models at a dose of 20-200 mg/kg.3 Pharm Bull 2003;26:1618-1619.

6. Moshi MJ, Otieno DF, Mbabazi PK, 17. Sikdar M, Dutta U. Traditional 27. Son YO, Kim J, Lim JC, et al. Ripe fruit Weisheit A. !e ethnomedicine of the phytotherapy among the Nath people of Solanum nigrum L. inhibits cell growth Haya people of Bugabo ward, Kagera of Assam. Ethno-Med 2008;2:39-45. and induces apoptosis in MCF-7 cells. Region, north western Tanzania. J 18. Lin HM, Tseng HC, Wang CJ, et al. Food Chem Toxicol 2003;41:1421-1428. Ethnobiol Ethnomed 2009;5:24. Induction of autophagy and apoptosis 28. Oh PS, Lim KT. HeLa cells treated with 7. Leporatti ML, Ghedira K. Comparative by the extract of Solanum nigrum Linn phytoglycoprotein (150 kDa) were analysis of medicinal plants used in in HepG2 cells. J Agric Food Chem killed by activation of caspase 3 via traditional medicine in Italy and 2007;55:3620-3628. inhibitory activities of NF-kappaB and Tunisia. J Ethnobiol Ethnomed 19. Glossman-Mitnik D. CHIH-DFT AP-1. J Biomed Sci 2007;14:223-232. 2009;5:31. determination of the molecular 29. Tournier C, Hess P, Yang DD, et al. 8. Chifundera K. Livestock diseases and structure and IR and UV spectra of Requirement of JNK for stress-induced the traditional medicine in the Bushi solanidine. J Mol Model 2007;13:43-46. activation of the cytochrome c-medi- area, Kivu province, Democratic 20. Glossman-Mitnik D. CHIH-DFT ated death pathway. Science Republic of Congo. Afr Study Monogr determination of the molecular 2000;288:870-874. 1998;19:13-33. structure and infrared and ultraviolet 30. Salgaller ML, Lodge PA. Use of cellular 9. Boulos L. Medicinal Plants of North spectra of gamma-solanine. Spectrochim and cytokine adjuvants in the immuno- Africa. Algonac, Michigan: Reference Acta A Mol Biomol Spectrosc therapy of cancer. J Surg Oncol Publications, Inc.; 1983. 2007;66:208-211. 1998;68:122-138. 10. http://www.metafro.be/prelude/ 21. Ji YB, Gao SY, Ji CF, Zou X. Induction of 31. Fujiwara H, Fukuzawa M, Yoshioka T, et view_plant?pi=11710 [Accessed Jan. 20, apoptosis in HepG2 cells by solanine al. !e role of tumor-specific Lyt-1+2- T 2011] and Bcl-2 protein. J Ethnopharmacol cells in eradicating tumor cells in vivo. I. 11. Sivaperumal R, Ramya S, Ravi AV, et al. 2008;115:194-202. Lyt-1+2- T cells do not necessarily Ethnopharmacological studies on the 22. Lee KR, Kozukue N, Han JS, et al. require recruitment of host’s cytotoxic medicinal plants used by tribal Glycoalkaloids and metabolites inhibit T cell precursors for implementation of inhabitants of Kottur Hills, the growth of human colon (HT29) and in vivo immunity. J Immunol Dharmapuri, Tamilnadu, India. Environ liver (HepG2) cancer cells. J Agric Food 1984;133:1671-1676. We Int J Sci Technol 2010;5:57-64. Chem 2004;52:2832-2839. 32. Mumberg D, Monach PA, Wanderling S, 12. Ramya S, Jayakumararaj R. Antifeedant 23. Lee SJ, Oh PS, Ko JH, et al. A 150-kDa et al. CD4(+) T cells eliminate MHC activity of selected ethno-botanicals glycoprotein isolated from Solanum class II-negative cancer cells in vivo by used by tribals of Vattal Hills on nigrum L. has cytotoxic and apoptotic indirect effects of IFN-gamma. Proc Natl Helicoverpa armigera (Hübner). J Pharm effects by inhibiting the effects of Acad Sci U S A 1999;96:8633-8638. Res 2009;2:1414-1418. protein kinase C alpha, nuclear 33. Schüler T, Qin Z, Ibe S, et al. T helper 13. Ignacimuthu S, Ayyanar M, Sivaraman factor-kappa B and inducible nitric cell type 1-associated and cytotoxic T KS. Ethnobotanical investigations oxide in HCT-116 cells. Cancer lymphocyte-mediated tumor immunity among tribes in Madurai District of Chemother Pharmacol 2004;54:562-572. is impaired in interleukin 4-deficient Tamil Nadu (India). J Ethnobiol 24. Joo HY, Lim K, Lim KT. mice. J Exp Med 1999;189:803-810. Ethnomed 2006;2:25. Phytoglycoprotein (150 kDa) isolated 34. Lim KT. Glycoprotein isolated from 14. Muthu C, Ayyanar M, Raja N, from Solanum nigrum Linne has a Solanum nigrum L. kills HT-29 cells Ignacimuthu S. Medicinal plants used preventive effect on dextran sodium through apoptosis. J Med Food by traditional healers in Kancheepuram sulfate-induced colitis in A/J mouse. J 2005;8:215-226. district of Tamil Nadu, India. J Appl Toxicol 2009;29:207-213. 35. Lee SJ, Lim KT. Cell death signal by Ethnobiol Ethnomed 2006;2:43. 25. Li J, Li Q, Feng T, Li K. Aqueous extract glycine- and proline-rich plant glycopro- 15. Kala CP. Ethnomedicinal botany of the of Solanum nigrum inhibit growth of tein is transferred from cytochrome c Apatani in the Eastern Himalayan cervical carcinoma (U14) via modulat- and nuclear factor kappa B to caspase 3 region of India. J Ethnobiol Ethnomed ing immune response of tumor bearing in Hep3B cells. J Nutr Biochem 2005;1:11. mice and inducing apoptosis of tumor 2008;19:166-174. 16. Parveen, Upadhyay B, Roy S, Kumar A. cells. Fitoterapia 2008;79:548-556. 36. Heo KS, Lee SJ, Ko JH, et al. Traditional uses of medicinal plants 26. Li J, Li QW, Gao DW, et al. Antitumor Glycoprotein isolated from Solanum among the rural communities of Churu and immunomodulating effects of nigrum L. inhibits the DNA-binding district in the !ar Desert, India. J polysaccharides isolated from Solanum activities of NF-kappaB and AP-1, and Ethnopharmacol 2007;113:387-399. nigrum Linne. Phytother Res increases the production of nitric oxide 2009;23:1524-1530. in TPA-stimulated MCF-7 cells. Toxicol In Vitro 2004;18:755-763.

37. O’Brian CA, Ward NE, Gravitt KR, 46. Akula US, Odhav B. In vitro 5-lipoxygen- 57. Caksen H, Odabas D, Akbayram S, et al. Gupta KP. !e tumor promoter receptor ase inhibition of polyphenolic antioxi- Deadly nightshade (Atropa belladonna) protein kinase C: a novel target for dants from undomesticated plants of intoxication: an analysis of 49 children. chemoprevention and therapy of South Africa. J Med Plants Res Hum Exp Toxicol 2003;22:665-668. human colon cancer. Prog Clin Biol Res 2008;2:207-212. 58. Watt JM, Breyer-Brandwijk MG. 1995;391:117-120. 47. Prakash V, Mishra PK, Mishra M. Medicinal and Poisonous Plants of 38. Ghosh S, May MJ, Kopp EB. NF-kappa Screening of medicinal plant extracts Southern and Eastern Africa. 2nd ed. B and Rel proteins: evolutionarily for antioxidant activity. J Med Plants Edinburgh and London: E. and S. conserved mediators of immune Res 2009;3:608-612. Livingstone Ltd.; 1962:996-1000. responses. Annu Rev Immunol 48. Ravi V, Saleem TSM, Patel SS, et al. 59. Cooper MR, Johnson AW. Poisonous 1998;16:225-260. Anti-inflammatory effect of methanolic Plants in Britain and their Effects on 39. Baeuerle PA, Baltimore D. Activation of extract of Solanum nigrum Linn berries. Animals and Man. London: H.M.S.O.; DNA-binding activity in an apparently Int J Appl Res Nat Prod 2009;2:33-36. 1984:219-220. cytoplasmic precursor of the NF-kappa 49. Vane J, Botting R. Inflammation and 60. Schilling EE, Ma QS, Andersen RN. B transcription factor. Cell the mechanism of action of anti-inflam- Common names and species identifica- 1988;53:211-217. matory drugs. FASEB J 1987;1:89-96. tion in black nightshades, Solanum sect. 40. Baeuerle PA, Baltimore D. I kappa B: a 50. Darshan S, Doreswamy R. Patented Solanum (Solanaceae). Econ Bot specific inhibitor of the NF-kappa B antiinflammatory plant drug develop- 1992;46:223-225. transcription factor. Science ment from traditional medicine. 61. Wang HC, Wu DH, Chang YC, et al. 1988;242:540-546. Phytother Res 2004;18:343-357. Solanum nigrum Linn. water extract 41. James OM. Drugs effective in the 51. Cai XF, Chin YW, Oh SR, et al. Anti- inhibits metastasis in mouse melanoma therapy of epilepsy. In: Joel GH, Lee EL, inflammatory constituents from cells in vitro and in vivo. J Agric Food Alfred GG, eds. !e Pharmacological Solanum nigrum. Bull Korean Chem Soc Chem 2010;58:11913-11923. Basis of !erapeutics. 10th ed. New York, 2010;31:199-201. 62. Li J, Li Q, Peng Y, et al. Protective NY: McGraw-Hill; 2001:521-547. 52. Drotman RB, Lawhorn GT. Serum effects of fraction 1a of polysaccharides 42. Sandabe UK, Onyeyili PA, Chibuzo GA. enzymes as indicators of chemically isolated from Solanum nigrum Linne on Sedative and anticonvulsant effects of induced liver damage. Drug Chem Toxicol thymus in tumor-bearing mice. J aqueous extract of Ficus sycomorus L. 1978;1:163-171. Ethnopharmacol 2010;129:350-356. (Moraceae) stembark in rats. Vet Arhiv 53. Lin HM, Tseng HC, Wang CJ, et al. 63. Kaushik D, Jogpal V, Kaushik P, et 2003;73:103-110. Hepatoprotective effects of Solanum al. Evaluation of activities of Solanum 43. Ojewole JAO. Anticonvulsant effect of nigrum Linn extract against CCl(4)- nigrum fruit extract. Arch Appl Sci Sclerocarya birrea (A. Rich.) Hochst. induced oxidative damage in rats. Chem Res 2009;1:43-50. subsp. caffra (Sond.) Kokwaro Biol Interact 2008;171:283-293. 64. Sultana S, Perwaiz S, Iqbal M, Athar M. (Anacardiaceae) stem-bark aqueous 54. Hsieh CC, Fang HL, Lina WC. Inhibitory Crude extracts of hepatoprotective extract in mice. J Nat Med effect of Solanum nigrum on thioacet- plants, Solanum nigrum and Cichorium 2007;61:67-72. amide-induced liver fibrosis in mice. J intybus inhibit free radical-mediated 44. Eva González-Trujano M, Tapia E, Ethnopharmacol 2008;119:117-121. DNA damage. J Ethnopharmacol López-Meraz L, et al. Anticonvulsant 55. Sharma YK, Singh H, Mehra BL. 1995;45:189-192. effect of Annona diversifolia Saff. and Hepatoprotective effect of few palmitone on penicillin-induced Ayurvedic herbs in patients receiving convulsive activity. A behavioral and antituberculus treatment. Indian J EEG study in rats. Epilepsia Traditional Knowledge 2004;3:391-396. 2006;47:1810-1817. 56. Das JKL, Prasad SR, Mitra SK. 45. Wannang NN, Anuka JA, Kwanashie Evaluation of Liv.52 DS tablet as a HO, et al. Anti-seizure activity of the hepatoprotective agent in prophylaxis aqueous leaf extract of Solanum nigrum with statin therapy. Med Update linn (solanaceae) in experimental 2007;15:31-36. animals. Afr Health Sci 2008;8:74-79.