Anti-HD activity of crude/semi-purified plant extracts/fractions
Some early literature reported the usefulness of belladonna root and its alkaloids (Tomlinson, 1947 and Lazar, 1948) and the Rauvolfia alkaloid reserpine in the treatment of HD ( Vorisek, 1958, Chhuttani and Singh, 1959 and Zmorski, 1959). Recently, increasing interest has been devoted to the use of botanicals and herb-derived products against the prevention and treatment of HD. The following section describes the crude/semi-purified plant extracts/fractions/extracts rich in certain biologically active components with anti-HD activity and their implications in other neurodegenerative disorders.
3.1. Bacopa monnieri (L.) Wettst. (Plantaginaceae)
In the Indian subcontinent, the nootropic herb Bacopa monnieri (local name: Brahmi) is traditionally used as a memory enhancer, anxiolytic and in neuropharmacological disorders such as epilepsy ( Shinomol and Muralidhara, 2011, Aguiar and Borowski, 2013 and Sharma et al., 2013). The neuroprotective effect of B. monnieri was earlier reported against dementia ( Saini et al., 2012), memory dysfunction ( Dwivedi et al., 2013 and Le et al., 2013), AD (Uabundit et al., 2010), Parkinson's disease (PD) (Jadiya et al., 2011) and schizophrenia (Piyabhan et al., 2013). Bacopasides isolated from the plant have been reported to demonstrate anti-depressant action (Rauf et al., 2014). In a human trial, the plant was found to improve cognitive function and memory by partially inhibiting acetylcholinesterase (AChE) activity (Peth-Nui et al., 2012) and to prevent anxiety and depression in the elderly (Calabrese et al., 2008). In dopaminergic (N27) cells, an ethanolic extract of B. monnieri ameliorated 3-NP-induced mitochondrial dysfunctions by modulating antioxidant mechanisms (Shinomol et al., 2012a). An alcoholic leaf extract also offered in vitro neuroprotection against 3-NP challenge by ameliorating 3-NP induced elevation of oxidative markers and cytotoxicity ( Shinomol et al., 2012b).
3.2. Centella asiatica (L.) Urb. (Apiaceae)
Centella asiatica (local name: Gotu kola) is a plant native to Southeast Asia that has been used traditionally as a brain tonic ( Orhan, 2012). It has also shown anxiolytic (Wanasuntronwong et al., 2012) and anti-AD (Soumyanath et al., 2012) activities. In a double-blind placebo-controlled clinical trial, the plant was reported as efficacious against anxiety (Bradwejn et al., 2000). C. asiatica leaf powder and aqueous extract prevented 3-NP-challenge in brain mitochondria by elevating free radical scavenging activity ( Shinomol and Muralidhara, 2008).
3.3. Calendula officinalis L. (Asteraceae)
Calendula officinalis (common marigold) is native to southern Europe and naturalized in the warm temperate regions of the globe. The plant is used traditionally to treat jaundice and varicose veins, increase wound healing and act as a blood purifier ( Mekinić et al., 2013). An alcoholic extract of the plant has reportedly shown AchE inhibitory activity (Muley et al., 2009). Monosodium glutamate (MSG) mediated neurotoxicity in rats was lessened by the flower extract of the plant (Shivasharan et al., 2013b). Pretreatment with C. officinalis flower extract [100 and 200 mg/kg for seven days] followed by administration of 3-NP [15 mg/kg, intraperitoneal (i.p.) for the next seven days] in adult female Wistar rats ameliorated the toxin challenge by preventing behavioral alterations and striatal neuronal loss due to its reported antioxidant, anti-inflammatory and estrogenic properties (Shivasharan et al., 2013a).
3.4. Cannabis sativa L. (Cannabaceae)
Cannabis is a genus of flowering plants which includes Cannabis sativa (common names: Hemp, Ganja) and related species native to Central and South Asia. The cannabinoid (CB) system is widespread in the central nervous system (CNS) where it controls a range of neurophysiological activities such as pain, appetite and cognition. Phytocannabinoids, isolated from Cannabis, target the G-protein coupled CB receptors, CB(1) and CB(2) alongside endogenous CB molecules ( Gowran et al., 2011). Δ(9)-Tetrahydrocannabinol (Δ-9-THC) and cannabidiol (CBD) are the two main ingredients of C. sativa ( Bhattacharyya et al., 2010). Botanical extracts riched in Δ(9)-THC and/or CBD (1:1) provided neuroprotection in 3-NP-intoxicated rat models of HD by attenuating gamma-aminobutyric acid (GABA) deficiency and influencing the modulation of neuronal and biochemical markers (Sagredo et al., 2011). Due to their anti-inflammatory, neuroprotective and neuroregenerative properties, cannabinoids attenuated hyperkinetic symptoms and acted as disease-modifying agents in different preclinical HD models. Sativex®, which consists of an equimolecular combination of Δ(9)-THC and/or CBD is close to a clinical trial against HD (Sagredo et al., 2012). In one study, Δ(9)-THC and/or CBD have exhibited opposite effects on human brain function and psychopathology (Bhattacharyya et al., 2010). CBD was found to activate the limbic and paralimbic regions while Δ(9)-THC appeared to exhibit possible effects on other parts of the brain (Fusar-Poli et al., 2009).
3.5. Garcinia kola Heckel (Clusiaceae)
Garcinia kola (commonly known as bitter kola) is naturally found in the tropical rain forest region of West Africa and is used in ethnomedicine for the treatment of bronchitis, infections and liver ailments ( Nzegbule and Mbakwe, 2001 and Farombi and Owoeye, 2011). Kolaviron (a bioflavonoid from Garcinia kola) has also been reported to possess antioxidant, antidiabetic, antigenotoxic and hepatoprotective activities ( Farombi and Owoeye, 2011). Clinical efficacy of Garcinia kola in the treatment of knee osteoarthritis was attributed to its analgesic or anti-inflammatory property ( Adegbehingbe et al., 2008). Kolaviron also protected pheochromocytoma (PC) 12 cells and human dopaminergic SH-SY5Y cells exposed to atrazine ( Abarikwu et al., 2011a and Abarikwu et al., 2011b) Prior administration of Garcinia kola aqueous extract (200 mg/kg for 7 days) offered hippocampus and cerebellum neuronal protection in 3-NP-induced malnourished mice (Ajayi et al., 2011).
3.6. Gastrodia elata Blume (Orchidaceae)
Gastrodia elata (Tianma), a rare plant used in traditional Chinese medicine, was reported to demonstrate CNS effects in possessing anticonvulsant, anti-hypertensive and learning and memory enhancing activities ( Tao, 2008 and Manavalan et al., 2012b). The plant exerted neuroprotection against beta-amyloid (Aβ) induced toxicity (Ng et al., 2013), with the neuroprotective property of Tianma being attributed to its ability to inhibit stress related proteins and induce neuroprotective genes (Manavalan et al., 2012a). Moreover, two neuroprotective phenolics (gastrodin B and gastrol B) were isolated from the rhizomes and showed significant protection against H2O2-induced damage in PC12 cells (Zhang et al., 2013b). Gastrodin exhibited anti-PD activity by protecting apoptotic dopaminergic neurons in vitro ( Kumar et al., 2013). G. elata prevented the aggregation of mHtt via the activation of the adenosine A2A receptor (A(2A)-R) and proteasomal activity in PC12 cell transiently transfected with mHtt (Huang et al., 2011).
3.7. Ginkgo biloba L. (Ginkgoaceae)
Ginkgo biloba (also known as the maidenhair tree) leaf extracts have been used in the traditional Chinese medicine where they were used in the treatment of age related disorders, dementia and depression ( Gaby, 1996). G. biloba extract 761 (EGb 761) is a patented and well characterized mixture of compounds extracted from the leaves ( Rojas et al., 2012). The extract has shown anti-PD activity ( Rojas et al., 2009 and Rojas et al., 2012), prevented dementia (Rainer and Mucke, 2013) and paraquat-induced apoptosis of PC12 cells (Kang et al., 2007). Exhibiting activity as a neuroprotective compound, EGb 761 acted as antioxidant and anti-apoptotic agent in 3-NP-exposed rats and improved energy metabolism as well as down-regulating striatal glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and Bax and up-regulating striatal Bcl-xl in the experimental animal (Mahdy et al., 2011).
3.8. Olea europaea L. (Oleaceae)
Olive oil is obtained from the fruit of Olea europaea (olive of Europe) native to the Mediterranean Basin. Extra virgin olive oil (VOO) was found to reduce lipid peroxidation and GSH depletion as a brain antioxidant in order to prevent 3-NP induced neurotoxicity in HD rat models ( Tasset et al., 2011).
3.9. Panax ginseng C.A. Mey. (Araliaceae)
Striatal degeneration in 3-NP-induced rats was inhibited by Korean Red Ginseng (P. ginseng) saponins. The compounds were also found to reduce behavioral impairment and intracellular Ca(2+) elevations and increased the survival rate in the animals following toxin administration (Kim et al., 2005).
3.10. Withania somnifera L. (Dunal) (Solanaceae)
Withania somnifera (Ashawagandha) is commonly used in the Indian Ayurveda as a nerve tonic. Various extracts of the plant were reported to be active against neurodegenerative disorders such as AD, PD and HD ( Singh et al., 2011). Aβ (1–42) induced neurotoxicity in human neuronal cells was ameliorated by a methanol:chloroform (3:1) extract of the plant which was implicated in HIV-associated neurocognitive disorders (HAND) (Kurapati et al., 2013). The root extract (100 and 200 mg/kg) prevented mitochondrial dysfunction and behavioral and biochemical changes in rats in a dose dependent manner after exposure to 3-NP (Kumar and Kumar, 2009).
4. Anti-HD activity of plant derived natural compounds
This section depicts the biologically active anti-HD compounds used in various in vitro and/or in vivo studies with a note on their source(s) and mode(s) of action.
Mangosteen (Garcinia mangostana L., Clusiaceae) is a tropical tree native to Southeast Asia whose fruit pericarp contains a family of tricyclic isoprenylated polyphenols, known as mangosteen xanthones, reported to demonstrate anti-cancer, anti-inflammatory, immunomodulatory and anti-acne activities ( Gutierrez-Orozco and Failla, 2013, Asasutjarit et al., 2014 and Kasemwattanaroj et al., 2013). α-mangostin [Fig. 1(1)] ameliorated reactive oxygen species (ROS) production in 3-NP-exposed cerebellar granule neurons (CGNs) in a concentration-dependent manner (Pedraza-Chaverrí et al., 2009).
Astragalan is an Astragalus membranaceus Moench (Fabaceae) polysaccharide reported to exhibit anti-cancer and immunomodulatory activities ( Zhao and Kong, 1993 and Wang et al., 2008). It prevented polyQ-induced proteotoxicity in C. elegans via modulation of the transcription factor abnormal dauer formation-16/forkhead box O (DAF-16/FOXO) ( Zhang et al., 2012a and Zhang et al., 2012b).
Cannabidiol (CBD) [Fig. 1(2)] is a major non-psychoactive constituent of the glandular hairs of Cannabis sativa L. (Cannabaceae) known for its sedative, hypnotic, anticonvulsive, antipsychotic, anti-oxidative, anti-inflammatory and neuroprotective properties ( Zuardi, 2008, Scuderi et al., 2009 and Schiavon et al., 2014). CBD is devoid of unwanted psychotropic properties of marijuana derivatives and thus serves as an excellent therapeutic agent (Scuderi et al., 2009). CBD, as an antioxidant, protected 3-NP-intoxicated rats by reducing the striatal atrophy in the animals. The mechanism of this action appeared independent of adenosine and transient receptor potential cation channel subfamily V member 1 (TRPV1) receptors (Sagredo et al., 2007). It was suggested as a safe and effective drug against psychosis in PD (Zuardi et al., 2009). It also reduced microglial activation in different models related to AD (Martín-Moreno et al., 2011).
Celastrol [Fig. 1(3)], a pentacyclic triterpenoid, isolated from the root extracts of Tripterygium wilfordi Hook. f. (Celastraceae), is known for its anti-oxidant, anti-inflammatory, anti-cancer and immunosuppressive properties ( Li et al., 2013a, Li et al., 2013b and Gu et al., 2013). The compound modulated the heat shock protein (hsp) gene in order to increase viability in cells expressing mutant polyQ protein (Zhang and Sarge, 2007).
Curcumin [Fig. 1(4)], a dietary polyphenol with an excellent safety profile derived from the rhizome of Curcuma longa L. (Zingiberaceae), possesses great potential as an anti-oxidant, anti-inflammatory and anti-cancer agent ( Basnet and Skalko-Basnet, 2011 and Noorafshan and Ashkani-Esfahani, 2013). Curcumin encapsulated solid lipid nanoparticles (C-SLNs) increased neuromotor coordination and decreased mitochondrial dysfunction in the same in vivo HD model ( Sandhir et al., 2014). The neuroprotective effect of curcumin was also demonstrated in the treatment of spinal cord injury (Kim et al., 2014), traumatic brain injury (Samini et al., 2013), bipolar disorder (BD) (Gazal et al., 2014), PD (Qualls et al., 2014), etc.
Epigallocatechin gallate (EGCG) [Fig. 1(5)], a major non-toxic and safe constituent of green tea [Camellia sinensis (L.) Kuntze (Theaceae)], is a potent anti-oxidant, anti-angiogenic and antitumor agent ( Singh et al., 2011). EGCG dose-dependently prevented the aggregation of mutant htt exon 1 (Httex1) protein, decreased polyQ-mediated htt protein aggregation and improved motor functions in various HD models (Ehrnhoefer et al., 2006). EGCG also inhibited Alzheimer Aβ (1–42) dimer, one of the major causative agents in AD (Zhang et al., 2013a).
Fisetin (3,3′,4′,7-tetrahydroxyflavone) [Fig. 1(6)], a flavonol found in various plants, is a known antioxidant and a potent health promoting agent with anti-cancer, anti-inflammatory and neurotrophic properties (Khan et al., 2013). In studies it reduced the damage caused by mHtt, possibly via extracellular signal-regulated kinases (ERK) activation in PC12 cells and Drosophila expressing mutant Httex1 and in an R6/2 mouse model of HD ( Maher et al., 2011).
Galantamine [Fig. 1(7)], an alkaloid extracted from Galanthus sp. (Amaryllidaceae) and related genera, is an AchE inhibitor with therapeutic potential against AD and vascular and mixed dementia ( Corey-Bloom, 2003 and Erkinjuntti et al., 2003). It was reported to modulate the nicotinic acetylcholine receptor (nAChR) in order to prevent apoptosis and neurodegeneration in a 3-NP-induced rat HD model (Park et al., 2008). Galantamine was declared as safe and well tolerated in community-dwelling persons with mild AD (Richarz et al., 2014). In an open controlled trial, galantamine was found to reduce dementia in PD patients with minimal side effects (Litvinenko et al., 2008).
Ginsenosides, a diverse group of steroidal saponins, are the active components of Panax ginseng C.A. Meyer (Araliaceae) and exhibit a wide therapeutic potential as angiomodulatory, neurological, anti-cancer and cardioprotective agents ( Attele et al., 1999, Leung et al., 2007, Leung and Wong, 2010, An et al., 2013 and Lim et al., 2013). Korean ginseng contains 38 ginsenosides whereas American ginseng (P. quinquefolius L., Araliaceae) possesses 19 ( Choi, 2008). Ginsenosides Rb1 [Fig. 1(8)], Rc, and Rg5 isolated from the root of ginseng inhibited glutamate-induced Ca(2+) responses in cultured medium spiny neurons (MSNs) from the yeast artificial chromosome (YAC) 128 HD mouse (Wu et al., 2009). Ginseng and ginsenosides have been reported active against a number of CNS disorders such as AD, PD, cerebral ischemia, depression and others (Kim et al., 2013).
Hesperidin [Fig. 1(9)], a flavanone glycoside found mainly in citrus fruits, has anti-inflammatory, anti-hyperlipidaemic, calcium channel blocker, antihypertensive, diuretic, anti-fertility and anti-cancer activities (Garg et al., 2001). It improved locomotor activity, increased malondialdehyde (MDA) levels and acted as an antioxidant, anti-inflammatory and anti-apoptotic agent increasing resistance against 3-NP-induced neurotoxicity in rats (Menze et al., 2012). The compound modulated neuronal survival via inducing mitogen-activated protein kinase (MAPK) and phosphatidylinositide 3-kinases (PI3K) pathways, which makes it a possible candidate for the treatment of various neurodegenerative diseases ( Nones, 2011).
Kaempferol (3,4′,5,7-tetrahydroxyflavone) [Fig. 1(10)], is a natural plant flavonol and health promoting dietary constituent found in many edible plants reported for their antioxidant, anti-inflammatory, anti-cancer, cardioprotective, neuroprotective and antidiabetic activities (Calderón-Montaño et al., 2011). It prevented motor deficit, mortality and striatal lesions in 3-NP-treated rats (Lagoa et al., 2009).
Lutein [Fig. 1(11)], a xanthophyllous carotenoid found in dark-green leafy vegetables, is known for its anti-cancer and cardioprotective properties, together with activity against age-related macular degeneration (Krinsky et al., 2003 and Ribaya-Mercado and Blumberg, 2004). It increased body weight, neurobehavior and mitochondrial enzymes complex activities in 3-NP-treated rats, possibly by way of an antioxidant mechanism (Binawade and Jagtap, 2013). The neuroprotective ability of lutein was attributed to its anti-apoptotic, anti-oxidative and anti-inflammatory properties (Li et al., 2012b).
Lycopene [Fig. 1(12)], a dietary antioxidant carotenoid from tomato (Solanum lycopersicum L.), is known for its cardioprotective, anti-inflammatory, anti-mutagenic and anti-cancer activities ( Heber and Lu, 2002 and Bhuvaneswari and Nagini, 2005). Lycopene (2.5, 5 and 10 mg/kg) improved behavioral, biochemical and mitochondrial functions in 3-NP-intoxicated rats via NO modulation ( Kumar et al., 2009). Lycopene protected rat CGNs against methylmercury-induced neurotoxicity by preventing mitochondrial dysfunction (Qu et al., 2013).
Melatonin [Fig. 1(13)], a hormone found in many animals, plants, and microbes, is reported to possess anti-cancer, anti-insomniac and neuroprotective efficacies (Olde Rikkert and Rigaud, 2001, Mills et al., 2005 and Macleod et al., 2005). Melatonin (1 mg/kg body weight i.p./day), protected against oxidative damage in synaptosomes of 3-NP treated rats (Túnez et al., 2004). It was further reported to possess beneficial effects against spinal cord injury (Lee et al., 2014), Cockayne syndrome (CS) (Okoshi et al., 2014), PD (Zaitone et al., 2013) and hypobaric hypoxia (Vornicescu et al., 2013).
Naringin [Fig. 1(14)], a flavanone glycoside from citrus fruit extracts, is reported for its radioprotective, anti-apoptotic, antioxidant and cardioprotective activities (Jagetia et al., 2003, Chen et al., 2014a and Chen et al., 2014b). It protected 3-NP-exposed rats by preventing behavioral alterations and mitochondrial dysfunction via modulation of nitric oxide (NO) ( Kumar and Kumar, 2010). Moreover, via antioxidation and anti-apoptosis, Naringin inhibited diabetic neuropathic pain in rats ( Kandhare et al., 2012).
Nicotine [Fig. 1(15)] is a potent parasympathomimetic alkaloid and a stimulant drug with psychoactive effects present in the solanaceae plant family members including Nicotiana tabacum L. ( Lyon, 1999). Nicotine (0, 0.25, 0.50 and 1.00 mg/kg daily for 7 days) attenuated 3-NP induced depletion of striatal dopamine (DA) and glutathione (GSH) in HD rat models (Tariq et al., 2005). Nicotine promoted the survival of cells accumulating Aβ protein which is associated with AD pathology (Brown et al., 2013).
4.17. Onjisaponin B
Onjisaponin B, isolated from the ethanol extracts of Radix Polygalae (Yuan Zhi) (Polygalaceae), induced autophagy via the 5′-adenosine monophosphate-activated protein kinase-mammalian target of rapamycin (AMPK-mTOR) signaling in PC12 cell expressing mHtt. The compound was also implicated in modulating neurodegenerative disorders including HD by reducing intracytosolic aggregation of toxic mutant proteins ( Wu et al., 2013). Onjisaponins of Polygala tenuifolia, which are ingredients of the Japanese herbal medicine Ninjin-yoei-to, induced nerve growth factor (NGF) synthesis in astrocytes; this suggests possible use in the treatment of AD ( Yabe et al., 2003).
Quercetin [Fig. 1(16)], a plant flavonol found in various fruits and vegetables, is known to possess diverse pharmacologic properties including anti-inflammatory, antioxidant, anti-cancer, anti-anaphylaxis, anti-obesity, anti-aging, anti-infectious and immunomodulatory activities (Bischoff, 2008 and Cai et al., 2013). Quercetin (25 mg/kg body weight orally for 21days) prevented 3-NP induced oxidative stress, mitochondrial dysfunction and neurobehavioral deficits in HD rats (Sandhir and Mehrotra, 2013).
Resveratrol [Fig. 1(17)] is a natural polyphenol found in many plants including grapes, berries and peanuts. It is a potent anti-aging compound providing improved metabolism and promoting cardioprotection, together with cancer and diabetes prevention (Saldanha et al., 2013 and Carter et al., 2014). In Htt challenged Drosophila, resveratrol prevented neuronal degeneration by modulating SIRT1 ( Pallos et al., 2008). In PC12 cells and Drosophila expressing mutant Httex1, resveratrol provided neuroprotection by reducing the damage caused by mHtt, a phenomenom attributed to ERK activation by the compound ( Maher et al., 2011). Moreover, resveratrol exerted neuroprotection against other neuropsychiatric disorders via antioxidation ( Quincozes-Santos et al., 2014) and anti-apoptosis (Renaud et al., 2014).
S-allylcysteine [Fig. 1(18)], a natural major organosulfur derivative from garlic (Allium sativum L., Amaryllidaceae), is reported to exhibit anti-cancer, anti-atherogenic, antioxidant, cardioprotective and neuroprotective properties ( Ho et al., 2001, Ng et al., 2012, Avula et al., 2014 and Imai et al., 2014). It prevented mitochondrial dysfunction, lipid peroxidation and oxidative stress in 3-NP-affected rat brain synaptosomes (Pérez-De La Cruz et al., 2006).
4.21. (−)schisandrin B
(−)schisandrin B [Fig. 1(19)] is a potent enantiomer of schisandrin B present in Schisandra chinensis (Turcz.) Baill. (Schisandraceae). S. chinensis fruit extract is reportedly used in traditional oriental medicine to treat vascular diseases ( Chun et al., 2014). Schisandrin B has been reported to exhibit anti-vascular fibrosis, hepatoprotective, nephroprotective and anti-inflammatory effects ( Park et al., 2012 and Checker et al., 2012; Lee et al., 2013; Bunel et al., 2013). In rat differentiated neuronal PC12 cells exposed to 3-NP, the compound exhibited anti-apoptotic and anti-necrotic abilities possibly via blocking activated C-jun N-terminal kinase (JNK)-mediated pyruvate dehydrogenase (PDH) inhibition ( Lam and Ko, 2012). Schisandrin B prevented Aβ 1–42-induced neurotoxicity in rat cortical neurons via anti-apoptosis and anti-apoptotic activities ( Wang and Wang, 2009) and exhibited anti-neuroinflammatory activity via suppressing the toll-like receptor 4 (TLR4)-dependent myeloid differentiation primary response gene 88 (MyD88)/IκB kinase (IKK)/NF-κB signaling pathway ( Zeng et al., 2012).
Lignans of sesame, such as sesamin, sesamolin, sesaminol and sesamol [Fig. 1(20)] isolated from Sesamum indicum, L. (Pedaliaceae), exhibit a diverse array of bioactivity including antihypertensive, anti-cancerous and hypocholesterolemic activities ( Dar and Arumugam, 2013). Sesamol (5, 10 and 20 mg/kg) pre-treatment exhibited free radical scavenging activity to provide neuroprotection against 3-NP-induced-toxicity (Kumar et al., 2010).
Trehalose [Fig. 1(21)] is a natural alpha-linked disaccharide. Due to its physiochemical properties, it is considered, unlike other sugars, to be a popular candidate in food, health, beauty and pharmaceuticals (Richards et al., 2002). In COS-7 and PC12 cells expressing mHtt (EGFP-HDQ74), the disaccharide enhanced autophagy against mHtt aggregation and also acted as chemical chaperone (Sarkar et al., 2007).
4.24. Zeatin riboside
Zeatin riboside is a cytokinin and plant hormone found to reverse mHtt-induced protein aggregations and to modulate A(2A)-R signaling in PC12 cells transfected with mHtt (Lee et al., 2012). Earlier studies have shown cytokinins, cytokinin ribosides and their analogs to possess cytotoxic and anti-carcinogenic activities against a number of cancer cell lines (Voller et al., 2010 and Casati et al., 2011).
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