Solanum Alkaloids and Their Pharmaceutical Roles: a Review

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Journal of Analytical & Pharmaceutical Research

Solanum Alkaloids and their Pharmaceutical Roles: A Review

Abstract Review Article

The genus Solanum is treated to be one of the hypergenus among the flowering

epithets. The genus is well represented in the tropical and warmer temperate Volume 3 Issue 6 - 2016 families and is comprised of about 1500 species with at least 5000 published Solanum species are endemic to the northeastern region. 1Department of Botany, India Many Solanum species are widely used in popular medicine or as vegetables. The 2Department of Botany, Trivandrum University College, India presenceregions. About of the 20 steroidal of these alkaloid solasodine, which is potentially an important starting material for the synthesis of steroid hormones, is characteristic of *Corresponding author: Murugan K, Plant Biochemistry the genus Solanum. Soladodine, and its glocosylated forms like solamargine, and Molecular Biology Lab, Department of Botany, solosonine and other compounds of potential therapeutic values. India, Email: Keywords: Solanum; Steroidal alkaloid; Solasodine; Hypergenus; Glocosylated; Trivandrum University College, Trivandrum 695 034, Kerala, Injuries; Infections Received: | Published:

October 21, 2016 December 15, 2016

Abbreviations: TGA: Total Glycoalkaloid; SGA: Steroidal range of biological activities such as antimicrobial, antirheumatics, Glycoalkaloid; SGT: Sergeant; HMG: Hydroxy Methylglutaryl; LDL: Low Density Lipoprotein; ACAT: Assistive Context Aware Further, these alkaloids are of paramount importance in drug Toolkit; HMDM: Human Monocyte Derived Macrophage; industriesanticonvulsants, as they anti-inflammatory, serve as precursors antioxidant or lead molecules and anticancer. for the synthesis of many of the steroidal drugs which have been used CE: Cholesterol Ester; CCl4: Carbon Tetrachloride; 6-OHDA: 6-hydroxydopamine; IL: Interleukin; TNF: Tumor Necrosis Factor; DPPH: Diphenyl-2-Picryl Hydrazyl; FRAP: Fluorescence treatments. This review aims to encompass various strategies for regulating inflammation, menopause and in cardiovascular Recovery After Photobleaching; O2: Oxygen, H2O2: Hydrogen Peroxide; SCVs: Small Colony Variants; PC: Prostate Cancer; medicinal values of Solanum alkaloids. In addition, the information TNFR: Tumor Necrosis Factor Receptor; TIMP: Tissue Inhibitor of relatedemployed with for medicinal the isolation, relevance purification, of these molecules characterization leads future and Metalloproteinase; EMMPRIN: Matrix Metalloproteinase; BAECs: Bovine Aortic Endothelial Cells; HPTLC: High Performance therapeutic drugs are also discussed. Thin Layer Chromatography; HPLC: High Performance Liquid scientific exploration for the development of new and effective Chromatography; DNP: Dictionary of Natural Products; CNS: Origin of the Word Alkaloid Central Nervous System The word alkaloid was framed by Meisner et al. [2] in 1819 from alkaline refers ‘alkali-like’. Alkaloids are cyclic compounds Introduction of biological origin with nitrogen atom attached to at least two Medicinal plants usage for the treatment of diseases, injuries, carbon atoms. The nitrogen may exist as primary, secondary, tertiary or quaternary amine form. Mostly, the alkaloids are as mankind. Ethnic medicine is the sum total of knowledge and crystalline and colourless with exceptions like coniine, pilocarpine practicalinfections, application, health benefits whether and explicable disease or management not, used in isdiagnosis, age old and nicotine (liquid) and berberine, colchicines (yellow) and prevention and elimination of disorders which is handed over canadine (orange). These natural organic molecules provide from generation to generation orally or in scripts. Recently, World Health Organization imitated programmes to promote and shown in Table 1 [3]. develop this indigenous medicine in health care systems and also positive response with specific reagents in qualitative analysis as to integrate this ethnic herbal medicine with modern to revitalize and strengthen the manpower [1]. The medicinal properties of documentedNarcotine isa believed pool of to bealkaloids the first alkaloidcomprising isolated approximately in 1803 [4], herbals are attributed by their rich pool of diverse phytochemicals 27,683followed types by morphine [6]. Generally, in 1806 in [5]. plants Dictionary alkaloids of Naturalprovide Products defense distributed within them. The major class of phytochemicals against pest, pathogen and herbivory. Majority of the alkaloids are weak bases, but some like theobromine and theophylline are includes the categories such as alkaloids and polyphenols. amphoteric. Solubility of alkaloids in water is poor but dissolves identified in plants with remarkable therapeutic properties Species of Solanum are widely used in health care systems and in organic solvents like diethyl ether, chloroform or petroleum represents a source for diverse phytochemicals including alkaloids. ether. Examples of water soluble alkaloids are caffeine, cocaine, Since decades, Solanum alkaloids have been a topic of interest in pharmacological and therapeutical studies because of the wide codeine and nicotine (with a solubility of ≥1g/L), while others like morphine and yohimbine are less water soluble (0.1–1g/L).

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Alkaloids and acids form salts of different strengths and these benzylisoquinolines, canthinones, imidazoles, indolquinazolines, derived products are usually soluble in water and alcohol and less furoquinolines and quinazolines [7]. Further, a chemotaxonomic soluble in organic solvents except scopolamine hydrobromide and the water-soluble quinine sulphate. Majority of alkaloids have a bitter taste and are poisonous. characterizedapproach in alkaloid with heterocyclic classification nitrogenic was also available bases derived [8]. Another from aminoclassification acids or of heterocyclic alkaloids was nitrogen true, pseudo base is and not proto derived alkaloids from Table 1: amino acids or they are basic amines derived from amino acids, Qualitative identification of alkaloids.Reagent Positive Colour but nitrogen is not part of aromatic system (e.g. vanillylamid). A Test Composition Change non-heterocyclic group corresponding to whether or not nitrogen Potassium bismuth Dragendorffs Reagent Reddish-brown ismore a part practical of cyclic system ring system of classification [9]. includes a heterocyclic and iodide Potassio mercuric White or pale Heterocyclic alkaloids or typical alkaloids Mayer’s Reagent iodide yellow ppt This represents the largest group in which the nitrogen Hager’s Reagent Picric acid Yellow becomes a part of the cyclic ring system. It is further subdivided into 14 groups (Table 2). Solution of iodine in Yellow or Wagner’s Reagent potassium iodide brown ppt. Non-heterocyclic alkaloids or a typical alkaloids Murexide Test (for Potassium chlorate + Purple In the case of non-heterocyclic alkaloid division nitrogen is not Caffeine and Other Purine drops of HCl. Expose colouration a part of the ring system and is relatively less common. Alkaloid Derived Alkaloids) the resultant to NH 3 of this category includes hordenine, erythromycin, ephedrine, colchicine, jurubin, pachysandrine-A, mescaline, taxol and a few Distribution of Alkaloids others. and more among dicots than monocots) followed by gymnosperms, Biological potentials of alkaloids pteridophytesAlkaloids are and reported fungi. mostlyInterestingly from angiosperms animals and (10 microbes to 20% Alkaloids can be considered as one of the best studied class are also known to produce alkaloids. The common alkaloid of phytochemicals especially in taxonomic and pharmacological bearing families were Chenopodiaceae, Lauraceae, Magnoliaceae, Berberidaceae, Menispermaceae, Ranunculaceae, Papaveraceae, confusion among and within the taxa. Meanwhile, pharmacologists Fumariaceae, Papilionaceae, Rutaceae, Apocynaceae, Loganiaceae, usefields. the Chemotaxonomistsbioactive principles apply in ameliorating this in resolving simple to taxonomic complex Rubiaceae, Boraginaceae, Convolvulaceae, Solanaceae and multifaceted diseases. Many of the known alkaloids are noxious, Campanulaceae. Based on the plant species, the highest some are addictive (morphine, cocaine) while, a few have clinical concentration is noticed in the leaves (black henbane), fruits or seeds (Strychnine tree), root (Rauwolfia serpentina) or bark their source from which they were isolated. (cinchona). However, different cells of the same taxa may possess applications [6,10]. Table 3 narrates the bioactive alkaloids and diverse alkaloids. The nitrogen containing molecules of plant origin have served as scaffold in designing of cough suppressant drugs or drugs used for more chronic disorders such as Parkinson’s and cancer Classification (Table 4). Unfortunately, the total number of alkaloids that were Alkaloids are large class of nitrogen containing compounds differ in terms of structure, synthesis and biological activity. total alkaloids in the Dictionary of Natural Products (DNP) list. marketed as prescribed drugs accounts to less than 0.002% of the introduced drugs in the global pharmaceutical armamentarium Therefore different classifications are available in alkaloids based [6].In the last 20-25 years, galanthamine and taxol were the newly ona. someBiosynthetic criteria. Generally,pathway alkaloidsbased on are the classified precursor based used on: for synthesis, Solanum as source of alkaloids b. Many studies have shown Solanum species as a rich store of diverse alkaloids [11]. In pharmacological studies, these c. Chemical classification-based on chemical entity, compounds have exhibited promising biological activities both pharmacological properties and Pharmacological classification-based on specific in vitro and in vivo. Further, drug manufacturers have made use d. of these alkaloids as lead molecules in the synthesis of novel in different plant groups. Taxonomic classification-based on distribution of alkaloids Alkaloids are grouped into six based on the nature of amino steroidalSteroidal drugs glycoalkaloids for various treatments are a class (Table of glycosidic 5). compounds acid from which it initiates its biosynthesis (namely anthranilic derived from nitrogen-containing steroids. Structurally it consists acid, ornithine, lysine, histidine, phenylalanine and tryptophan). of C27 at the 3-OH region of the aglycone. The monosaccharides comprise based on chemical structure: acridines, amides, amines, D-glucose, cholestane D-galactose, skeleton D-xyloseto which 1and to 5 L-rhamnosesugar moiety andis attached many Another system of classification includes nine categories

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Jayakumar K, Murugan K (2016) Solanum Alkaloids and their Pharmaceutical Roles: A Review. J Anal Pharm Res 3(6): 00075. DOI: 10.15406/japlr.2016.03.00075 Copyright: Solanum Alkaloids and their Pharmaceutical Roles: A Review ©2016 Jayakumar et al. 3/14

(as in solanidine). In these molecules, nitrogen can be bonded as molecules belong to a subclass of pseudo-alkaloids-isoprenoid a primary amino group (free or methylated), which forms simple others. Since, nitrogen is inserted into a non–amino acid; these steroidal bases, ring-closed to skeletal as secondary NH or in two two major groups that are based on their aglycone skeleton. The rings as a tertiary N, which often regulates the chemical character spirosolanalkaloids. The category structural is made diversity up of tetrahydrofuranof glycoalkaloids and is confined piperidine to of the molecule. Glycoalkaloids always contain double bonds and spiro-linked bicyclic system with an oxa-azaspirodecane structure (as in solasodine) and the solanidane type is derived by Solanum species [11]. an indolizidine ring where tertiary nitrogen connects the 2 rings OH groups in various positions. Nearly 90 structurally unique steroidal alkaloids were reported from 350 Table 2: Types of heterocyclic alkaloids with examples.

Sl No: Name Structure Examples H H N N

1 Pyrrole and Pyrrolidine Hygrine; Stachydrine

Pyrrole Pyrrolidine

N Senecionine; Echimidine; 2 Pyrrolizidine Symphitine; Seneciphylline

H N N Arecoline; Ricinine; Trigonelline; Anabasine; Pelletierine; 3 Pyridine and Piperidine Lobeline; Nicotine; Piperine; Coniine Pyridine Piperidine HN

Tropane (piperidine/N-methyl- Cocaine; pyrrolidine) 4 Atropine; Hyoscyamine; Hyoscine; Meteloidine

Quinoline Quinine; Quinidine; Cinchonine; Cinchonidine; Cuspareine N 5

Morphine; Emetine; Isoquinoline Papaverine; Narceine; 6 N Narcotine; Tubocurarine; Codeine; Berberine; Galanthamine; Corydaline; Hydrastine; Cephaeline; Erythraline

Aporphine (reduced isoquinoline/ 7 Boldine naphthalene)

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Lupanine; Cytisine; 8 Quinolizidine N Laburnine; Sparteine

Ergometrine; Ajmaline; Calabash; Vinblastine; Vincristine; Strychnine; 9 Indole or Benzopyrole N Brucine; Ergotamine; Serpentine; H Yohimbine; Physostigmine; Reserpine

Indolizidine Castanospermine; Swainsonine N 10 H N 11 Imidazole or glyoxaline Pilosine; Pilocarpine N H N N 12 Purine (pyrimidine/imidazole) Theobromine; Caffeine N N

H N

Steroidal (some combined as Conessine; Solanidine; Funtumine; 13 glycosides) Veratramine

Aconitine; 14 Terpenoid Atisine; Lycaconitine; Aconine

chain. It is distributed in leaves, fruits and tubers of potato and S. tuberosum and solasonine and solamargine tomato. Its synthesis is considered as an adaptive defense strategy in TheS. melongena major molecules of glycoalkaloid are α-solanine and areα-chaconine spirosolane-type in glycoalkaloids that occur in Lycopersicon to gastrointestinal issues like diarrhoea, vomiting, abdominal esculentum. S. tuberosum, whereas α-tomatine and dehydrotomatine painagainst and herbivores. neurological Intoxication like hallucinations (2-5mg/kg) and fromheadache. solanine Similarly, leads which share a common aglycone, solanidine, to which a it leads to poisonings in people with consuming berries from S. produces α-chaconine and α-solanine, nigrum or S. dulcamara, or green potatoes [12]. attachedtrisaccharide to the moiety,aglycone, eitherlike solasodine chacotriose in the (α-chaconine)egg plant, thereby or Extraction and purification of Solanum alkaloids producingsolatriose the (α-solanine), glycoalkaloids is solamargine connected. Similarand solasonine. molecules Tomato are bioactive compound from among a plethora of phytochemicals only in terms of presence or absence of a double bond in the ring areExtraction, nevertheless purification, a simple fractionationprocedure and and it identification necessitates ofthe a species produces α-tomatine and dehydrotomatine, which differ requirement of having different approaches with respect to the the two dominant glycoalkaloids, but several other glycoalkaloids nature of compound in interest. Overtime, many researchers maystructure. be found Cultivar in wild potato species. contains α-solanine and α-chaconine formulated different methodologies for the effective isolation

Solanine is a toxic bitter tasted glycoalkaloid (C H73NO ). It is derived from the alkaloid solanidine with a carbohydrate side Commonly employed alkaloid extraction processes include 45 15 of alkaloids and later pharmacologists refined the protocols.

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soxhlet, Stas otto process, Kippenberger’s process, maceration, Dicentra 14 Diuretic Chelerythrine Manske’s process, negative pressure cavitation extraction, (Papaveraceae) pressurized solvent extraction, ultrasonic assisted extraction and Analgesic Codeine Papaver Narcotic Morphine (Papaveraceae) distillation approach was used [13]. The alkaloids extracted by 15 Duboisia abovepulse electricmentioned field techniques extraction were and forlikely volatile to contain alkaloids, impurities steam 16 Parkinson disease Tigloidine and these can be removed by treating the extracted alkaloids (Solanaceae) with acid solution or precipitating alkaloids using precipitating Preoperative Duboisia 17 Hyoscyamine reagents or crystallisation of alkaloid using suitable organic or treatment (Solanaceae) mineral acid or by chromatographic technique (partition, column Cinchona 18 Antiarrhythmia Quinidine or ion-exchange) [14]. Subsequently, the alkaloid mixture was (Rubiaceae) fractionated by fractional distillation, fractional crystallization, Amoebic Cephaelis 19 Emetine derivatization or by various chromatographic techniques (HPTLC, dysentery (Rubiaceae) HPLC, column or ion-exchange chromatography) [14]. Individual Cough Papaver Narcotine suppressant (Papaveraceae) alkaloids fractionated were then identified by NMR spectroscopy 20 : Trade name of the alkaloids which are marketed as prescribed Table 3: Plant alkaloids and their biological activities. Table 4 or X-ray crystallography [15]. drugs. Biological Sl.No Alkaloids Sources Activities Diseases Alkaloid Product Name Bufotenine Amanita Vincristine 1 Hallucinogen VincrisulTM; NorcristineTM Muscarine (Agaricaceae) Vinblastine PeriblastineTM; Cancer Vinorelbine Galanthus VelbanTM Navelbine® 2 Alzheimer disease Galanthamine (semisynthetic) (Amaryllidaceae) TaxolTM Taxol Alstonia (Apocynaceae) Alstonine Theobromine AtrofedTM Picralima TM 3 Antimalarial Akuammigine Lungs related Theophylline Theochron (Apocynaceae) Berberine disorders Lobeline LobatoxTM Berberis Ephedrine PeripherinTM (Berberidaceae) Rauwolfia Turbocuranine TubarineTM 4 Tranquillizer Reserpine Muscle relaxant TM (Apocynaceae) Galanthamine Nivalina Cough Narceine PenerajTM Ellipticine Ochrosia suppressant Noscapine BequitusinTM Vinblastine (Apocynaceae) Anticancer Vincristine Hyoscyamine CystospazTM; DonnatabTM Catharanthus Anti-parkinson Vindesine (Apocynaceae) Atropine EspasmoTM;ProtecorTM 5 Pacletaxel (Taxaceae) Taxus Analgesic Codeine CodicapsTM; TussipaxTM

Yohimbe TM 6 Aphrodisiac Yohimbine Eye disorders Strychnine Dysurgal (Apocynaceae) Catha Extraction protocols of alkaloids from Solanum species have 7 CNS stimulant Cathine (Campanulaceae) been proposed by many researchers. Tomatine, solasonine and solamargine were considered to be the most common Solanum Anabasis alkaloids. Guo et al. [16] employed aqueous extraction protocol Anabasine (Chenopodiaceae) 8 Insecticidal for isolating solasonine and solamargine from S. nigrum, whereas Cevadine Schoenocaulon (Liliaceae) from the leaves of Solanum lycopersicum [17]. Bhattacharya et Calystegia al.alpha-tomatine [18] isolated crystalline was purified solasodine by infusion-extraction from the fruit of Solanum method 9 Antiviral Calystegines (Convolvulaceae) xanthocarpum. Solanaviol, relatively a rare Solanum alkaloid was Coca extracted by Laskin et al. [19]. Pressurized liquid extraction of Cocaine Local anaesthetic (Erythroxylaceae) Loliine Lolium (Graminae) 10 solanidineBiological from potentialities potato peels wasof Solanum described alkaloids by Hossain et al. [20]. Induces Colchicum 11 Colchicine polyploidy (Liliaceae) Solanum species are traditionally used for curing many disorders including antimetastasis. Over time many workers have 12 Antihypertension Rubijervine Veratrum (Liliaceae) Some worked on the crude plant extracts while others isolated the 13 Anthelmintic Arecoline Areca (Palmae) typicalattempted phytochemical to scientifically like alkaloids validate thisand traditionalpolyphenols knowledge. and some fractionated the active principle or the potent derivatives (Table

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6). Biological activities of Solanum alkaloids and its derivatives are S. auriculatum; carried out including their genes regulating their biosynthesis. Solasodamine S. sodomaeum; Table 5: List of Solanum alkaloids and its source. S. marginatum Solasuaveoline; Dihydrosolasuaveoline; Alkaloid Source S. suaveolens Isosolasuaveoline Solaverbascine S. verbascifolium Tomatine S. cathayanum Solanaviol S. aviculare Solalyratines A and B S. lyratum Chaconine S. tuberosum

Demissidine; Dihydrosolacongestidine S. leucocarpum Solamaladine S. hypomalacophyllum Solanidane; Solanidine S. tuberosum Khasianine S. xanthocarpum Solanocardinol S. neocardenasii

Solangustine S. angustifolium Solanoforthine S. seaforthianum

Solaradixine; Solashabanine; 23-oxo-solacongestidine; 24-oxo- S. congestiflorum S. laciniatum Solacongestidine;solacongestidine Solafloridine; solaradinine solaspiralidine S. spirale S. dulcamara S. toxicarium S. Solaverines 15-alpha-hydroxy-soladulcidine; verbascifolium 15-alpha-hydroxy-tomatidine S. palinacanthum; S. Solamargine lycocarpum Solaquidine S. pseudoquina

Solamarine S. dulcamara Anticancer activities Solanandaine S. asperum Solanigrine S. nigrum year.In Moreover, India, cancer a drastic has beenincrease identified has been as recorded one of the year leading after Solanine S. nigrum; S. tuberosum yearcauses [21]. of mortality However, with in most a frequency cases conventional rate of 0.4 million radiotherapy deaths per or chemotherapy approach was considered for the treatment. But Solanocapsine; Solacasine; the drug resistance gradually developed by the patient was found to be a major hurdle in the treatment of cancer by chemotherapy. benzenethanamine; hexatriacontane; Thus, there is an increased demand for formulating more potent Solateinemine;3-ethoxyamphetamine; 2-fluoro-2’,4,5 S. pseudocapsicum novel drugs or that complement the existing ones. In this juncture, 2,2,2-trichloroacetamide; alkaloids isolated from Solanum species were attempted as the O-methylsolanocapsine; Episolacapine; anticancer agents. Isosolacapine Alpha-chaconine, a derivative of the aglycone solanidine, Aculeamine S. aculeatum exhibited remarkable inhibition of proliferation, invasion and

Solanopubamine S. schimperianum as bovine aortic endothelial cells (BAECs). The underlying molecularmigration ofmechanism A549 cells of (lungthese adenocarcinomaantimetastatic activitiescell) as wellwas Solaparnaine S. asperum shown as inhibition of phosphorylation of JNK and Akt pathways. Solapalmitine; Solapalmitenine S. tripartitum However, the alkaloid has no effect on the phosphorylation of ERK and p38. Further, alpha-chaconine remarkably lowered Solaphyllidine; Desacetylsolaphyllidine S. oblongifolium the nuclear level of NF-kappaB factors and expression of matrix S. callium BAECs (matrix metalloproteinase-2 is involved in angiogenesis) 25-isosolafloridine;Soladunalinidine Solacallinidine; S. dunalianum [22,23].metalloproteinase-2/-9 Reddivari et al.(MMP-2/-9) [24] reported in A549 that cells a and combination MMP-2 in S. leucocarpum; S. Solasodine treatment of gallic acid and alpha-chaconine was effective against trilobatum the proliferation of prostate cancer cells lines such as LNCaP S. lycocarpum; S. Solasonine and PC-3. Interestingly the same combination triggered caspase- asperum dependent apoptosis in LNCaP cells and increased cyclin- Solasurine S. surattense dependent kinase inhibitor p27 levels in LNCaP and PC-3 cell lines. This apoptotic effect can be attributed to activation of JNK Solamine; Cuscohygrine; Anabasine S. carolinense produced by the combined effect of alpha-chaconine and gallic Tomatidine S. arboretum acid.

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Table 6: Derivatives of Solanum

Alkaloid alkaloids and its therapeutic Derivativesignificance. Activity Reference

Solanidine Teratogenicity [42] 6-dihydrosolanidine solanidine N-oxide; 5 alpha, solasodine O-(diethyl phosphate); Solasodine Cholinergic N-acetyltetrahydrosolasodine [85,86] toxicity study; neuritogenic and ngf- Tomatidine Dihydrotomatidine; Pregnane derivative [87,88] enhancing activities.

®2)- Solamargine [O-a-L-rhamnopyranosyl-(1®4)]-b-D- Anticancer [89] (25R)-3b-{O-a-L-rhamnopyranosyl-(1

glucopyranosyloxy}-22a-N-spirosol-5-ene

3-βN, 23-βO-diacetylsolanopubamine; 3, Solanopubamine 3-βN,βN-dimethyl-βO-methylsolanopubamine; Anticancer and antimicrobial [42] 3-βN-octadecanoly-solanopubamine; solanopubamine-23-βO-octadecanoate; Solanopubamine 23-βO-undec-11-enoate; Chaconine Solanopubamine-23-βO-acetate6-O-sulfated chaconine Cytotoxicity studies

Solanine 6-O-sulfated solanine Cytotoxicity studies [90]

[90] In cancer studies, solanine exhibited promising chemoprotective and chemotherapeutic effects via induction of apoptosis, evaluated in yet another study. Interestingly data revealed a inhibition of proliferation, migration, invasion and angiogenesis. similar60) by chemicallycytostatic effect synthesized for all threethe three solanidine analogs, analogues with an were IC In and value range of 1.27-2.94. Similarly, increase in condensation in vitro in vivo 50 inhibited proliferation of human pancreatic carcinoma cell lines of chromatin materials and membrane permeability was also studies of alpha-solanine significantly observed (Hoechst staining method). In continuation, delayed G1, S and G2/M phases were noticed within a span of 24h. A gradual mammary(PANC-1, SW1990,carcinoma MIA cells. PaCa-2 Solanine cells), treated human mouse melanoma exhibited cell anline increased (A2058), humanexpression prostate of proapoptotic cancer cell (PC-3)Bax protein. and mouse The Another solanidine analogue demonstrated inhibitory properties suppression in expression of antiapoptotic Bcl-2 protein and reversal in these activities also noted after 48h (flow cytometry). angiogenic parameters in solanine-treated mouse were reported. scavenging activity [28]. Study on solanidine effect on human Further, suppression of phosphorylation of Akt, mTOR, and towards ribonucleotide reductase and bear significant free radical

1547 osteosarcoma cells, revealed significance of conformation Stat3, strengthened phosphorylation of β-catenin and decreased arrestat C-5 [29]. and C-25Despite carbon of having atoms, desirable hetero-sugar antiproliferative moiety and effect the expression profile for β-catenin and TCF-1 were documented for against5,6-double cancer bonds cells, in inducingthis compound apoptosis was and reported favouring to have cell cyclehigh PANC-1 cells following solanine treatment. α-solanine inhibited retention period in human body. Study on the absorption and PC-3NF-κB cells. activity Alpha-solanine in PANC-1 and elevated A2058 the cell expression lines and alsoof E-cadherin inhibited retention of solanidine in the human body revealed an increase inJNK PANC-1 in A2058 and cells human and prostatePI3K/Akt cancer signaling cell pathways(PC-3), correlated in A2058 with and in solaniine level in RBC compared to that of plasma, with poor reduced mRNA level of matrix metalloproteinase (MMP-2/9) and excretion rate through urine and stool. Further, spectroscopic extracellular inducer of matrix metalloproteinase (EMMPRIN) in studies of solanidine from human liver, proposed prolonged PANC-1 and PC-3 cell lines. Suppression of ERK, down regulation storage of solanidine may lead to undesired effects and metabolic of oncogenic microRNA-21 (miR-21) and up regulation of tumor suppressor miR-138 expression was noted in solanine stressSeveral [30]. studies examined the effect of tomatidine on the migration and invasion of cancer cells. Anticancer effect of alpha- treated PC-3 cells. These research findings proves significant therapeutic potentiality of α-solanine in inhibiting proliferation tumour in mice. In vitro analysis of human lung adenocarcinoma tomatine was confirmed by Tomsik et al. [31] against solid Ehrlich andSolanidine suppressing another the invasion alkaloid, of various exhibited carcinoma suppression cells [25,26]. of proliferation of MCF-7 cancer cell lines under in vivo conditions of cell invasion (Boyden chamber invasion assay) but does not [27]. Inhibition of proliferation of human leukemia cells (HL- A549 cells with tomatidine resulted in significant suppression

exhibited effective inhibition of migration and viability of A549

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cells. Furthermore, tomatidine reduced MMP-2 and MMP-9 studies evaluated cytotoxicity of O-methyl solanocapsine against (matrix metalloproteinase-2/-9) mRNA level, extracellular signal regulating kinase (immunoblotting assays), phosphorylation of cell by SRB and MTT methods. HeLa cell culture found to be more susceptiblevarious malignant to O-methyl cell lines solanocapsine such as Vero, [39]. HeLa, HEp-2 and A-549 Steroidal alkaloid soladulcidine isolated from theAkt, possible nuclear utilizationlevel of NF-κB of tomatidine and increased as a potentthe expression therapeutic of tissue drug Solanum inhibitor of metalloproteinase-1 (TIMP-1). These findings suggest dulcamara and ten of its derivatives were shown to have with paclitaxel (standard drug for cancer), exhibited enhanced cells. Further, compound designated 19 in the series showed the apoptosisin anti-metastatic of PC-3 therapycells (by [32]. PI3K/Akt α-tomatine inhibition, when elevated administered BAD highestsignificant suppression antiproliferative of PC-3 effect cell proliferation against prostate with cancer an IC (PC-3) value and lowered Bcl-2 and Bcl-xL expression) and reduced cell Solanum dulcamara viability. However, this combination produced no inhibition 50 has been hypothesised to bear tumor-inhibitory activity against of RWPE-1 (non-neoplastic prostate), but very effectively of 4.8±0.9μmol/L [40]. Beta-solamarine from controlled subcutaneous tumor development in mouse. These toxicity of solanopubamine and its derivatives against various cancerSarcoma cell 180 lines. in mice Solanopubamine [41]. Al-Rehaily alone et al.exhibited [42] evaluated remarkable cell combination with paclitaxel against prostate cancer [33]. findings propose that alpha-tomatine can be an effective drug in inhibitory action against many tumor cell lines. Solasonine from Solanum lycocarpum fruit was evaluated for the inhibition on induced apoptosis in SMMC-7721, HepG2 cells, multi drug resistant various tumor cell proliferations. Among the various cell lines Further, solamargine significantly lowered cell viability and

K562/A02 cells and osteosarcoma U2OS cells. Solamargine susceptibleevaluated such with as IC B16F10, HT29, MCF-7, HeLa, HepG2, MO59J, aincreased suppression the mRNA, in phosphorylation protein expression of Akt, of mRNA p53, Bax expression and Bcl-2 and in U343 and U251 by MTT assay, HepG2 was found to be most 50 promoterU2OS and K562/A02activity of cellsEP4, (real protein time-PCR, expression western of blot),SP1 andwhereas NF- Neurotoxicity and 6.01μg/mL neuroprotective [43]. activity cell lines. A down Neurotoxicity refers to structural or functional damage regulation of MDR1 mRNA, P-glycoprotein and actin were noted occurred to nervous system caused by agents which usually result κB subunit p65 were noted in lung cancer into impaired or altered functioning. Impairment in function enhanced cytochrome c release and up regulation of caspase-9 may occur via interactions of toxic agents with the normal andin solamargine capsase-3 in treated U2OS, SMMC-7721 K562/A02 cells.and HepG2 Further, cells solamargine (western neurotransmission mechanisms with or without causing structural blot, colorimetric assay). In SMMC-7721 and HepG2 cells, damage. Expression of these effects is sometimes spontaneous or transient and still others are much more insidious. The search for of the researchers also correlated the role of carbohydrate moiety novel molecules that can interact with central nervous system ofsolamargine solamargine caused in inducing cell cycle apoptosis. arrest at phase G2/M [34,35]. Most (CNS) and can be used for treatment purposes was initiated in Anticancer properties of solasodine in mice model was the nineteenth century. However, investigations targeting plant attempted and found that under in vivo solasodine glycosides sources with this sort of biological activity was limited. Many of treatments the Solanum alkaloids are shown to have regulatory activity on nervous system at low dosage regimens, but exert its neurotoxicity investigation, exerted the probable significant role inhibition of rhamnose of murine in solasodine sarcoma above optimal doses. 180 cell lines (S180) [36]. Based on further molecular Neuroprotective activity of solasodine was evaluated against ischemia in rats. The suppression of LPO and NO and wasglycosides demonstrated binding toon be tumour an effective cells anddose itson specificityhuman beings. was enhancement of GSH, CAT and thiols was observed in ischemic proposed. 0.005% mixture of solasodine glycosides (Zycure) rats after solasodine administration. Also solasodine exhibited follow-up, respectively [37]. In another study, the importance of neuron protection in brain coronal region as revealed by 0.005% exhibited 66% and 78% curability at 56 days and 1 year protective activity of neuron exhibited by solasodine could cellcarbohydrate toxicity, cellmoiety proliferation (C3 side chain) inhibition, and conformation cell cycle arrest at C-5 and behistopathology ascribed by studies.its free radical Based scavenging on these findings,properties a [44]. part In of C-25 of solasodine in apoptosis induction was evaluated. Further, addition to neuroprotection, solasodine was experimentally also evaluated by many workers [38]. induction of apoptosis (human 1547 osteosarcoma, MCF-7) was Khasianine is a steroidal alkaloid. Khasianine C3 side chain model. Solasodine induced differentiation of mouse embryonic showed to possess significant neurogenesis properties in mice possess 4’Rha-Glc. The cytotoxic studies on human hepatoma cells teratocarcinoma P19 cells into cholinergic neurons with axonal formation. Also, solasodine treated left brain ventricle exhibited cancer cells. Carbohydrate moiety in khasianine has a regulatory remarkable hike in bromodeoxyuridine utilization by ependymal effectshowed on that expression this alkaloid of TNFR has Ian and insignificant II. These results toxic effectpropose against that cells. Moreover, differentiated and matured ependymal cells the carbohydrate moieties seen in steroidal alkaloids may have regained their division and differentiation properties. Solasodine stimulated GAP-43/HuD signal pathway and regeneration of which ultimately result in gene expression regulation in varied mannera role in [38]. altering Akter et the al. binding[38] worked specificity on cell tocycle steroid arrest receptorsand anti- neuroblastsNeuroprotective and GABAergic effects ofprogenitors tamatidine in has GAD65-GFP been demonstrated mice [45]. apoptotic properties of khasianine on MCF-7 cell lines. Several by Taveira et al. [46]. Tamatidine exhibited protective effect

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on neuron against glutamate-induced cell toxicity in SH- et al neuroblastoma cells. Further, tomatidine was shown to isolated from the fruits of S. palinacanthum and S. lycocarpum by nicotinic receptors, MTT .,colorimetric [55] investigated assay. In trypanocidal in vitro studies, activity solamarine of solamargine exhibited thereSY5Y being nullifying its effect on muscarinic receptors. Thus, the strong molluscicidal properties against snail, Galba truncatula selectivehave interacted cholinesterases specifically inhibition with alpha of tomatidine 7 type eventually may against Candida albicans and C. tenuis [42]. Solaphyllidine and desacetylsolaphyllidine[56]. Solanopubamine exhibitedfrom Solanum remarkable oblongifolium fungicidal, were studied activity Rozengart et al. [47] conducted a comparative study on the find its way in the development of novel neuroprotective drugs. S. effect of 18 different anabasine derivatives, on the activity of leucocarpum showed inhibitory action against Staphylococcus brain cholinesterase and visual ganglia of Rana temporaria aureusfor their effects on pathogenic microbes. Some [57]. other Solasodine works studiedfrom (frog) and squids (Todarodes pacificus and Berryte uthis). Its the antifungal properties of solasonine against Rhizoctonia effect on butyrylcholinesterase (serum) and acetylcholinesterase solani and in agar Phoma well medicaginis diffusion assay over [52] a wide range of pH. However, (erythrocyte) was also determined. solasonine showed no action against Rhizoctonia solani, but O-alkyl-O-(anabasinoisopropyl)- and O-alkyl- P. medicaginis in a pH O-(anabasinobutin-2-yl)-phenylphosphonates and dependent manner. Inhibitory activity increased with an increase diphenylphosphynates has been evaluated for its anti- insignificantly pH (as indicated inhibited by mycelia dose-response growth of curves). Interestingly, monooxygenase and anti-cholinesterase potentialities. a combination of solasonine and solamargine in the ratio 1:1 Anticholinesterase property of these compounds were found to be dependent upon the structure of phosphoryl part and alkyl effective against R. solani radical of the investigated molecule. Further, antimonooxygenase produced more potential inhibition (50 µM each) and found to be Tomatidine, an aglycone of tomatine, possess strong test, showed that these compounds were better inhibitors than , but not influenced by pH [58]. antimicrobial effects. Staphylococcus aureus, is considered to be the standard inhibitor SKF [48]. one of the noxious infectious agent due to its resistances to many of the available synthetic antibiotic drugs. S. aureus has the ability to produce small-colony variants (SCVs) with reduced susceptibility Roddick et al. [49] showed that up to a range of 100 µM, to aminoglycoside antibiotics. Studies has shown that tamatidine theβ-solamarine possibility has of no the influence synthesis against of acetylcholinesteraseideal acetylcholinesterase but at inhibitorhigher doses from it causesolanocapsine membrane and damage. its synthetic Garcia etderivatives, al. [50] proved as a growth. The underlying mechanism of bactericidal activity was probable cure for Alzheimer’s disease. attributedpossess significant by the impaired inhibitory or effect dysfunctional against small-colony electron transport variants system caused by tomatidine treatment in S. aureus cells. Further, Similarly, direct excitation of cholinergic receptors may be tomatidine blocks the intracellular replication of a clinical SCV in another possible way for neutralizing scopolamine related polarized CF-like epithelial cells. These results indicate that the amnesia when compared with indirect excitation of cholinergic alkaloid tomatidine may be used as microbicidal either alone or receptors by inhibitors of cholinesterase. Further, scopolamine in combination therapy with traditional antibiotics to eliminate is playing variable roles in ambulation, grooming and rearing resistant strains of S. aureus responses. For example at higher dose of scopolamine leads to an increase in rearing and U shaped response curve for ambulation, [59].in vitro conditions exhibited there being producing nil effect on grooming. Pine needle extract schistosomicidal properties against Schistosoma mansoni. counteract the effect of scopolamine induced memory impairment SchistosomicidalSolasonine (50μM) properties in include tegument damage (amnesia) in mice. Experimentation of mice pre-treated with and suppressed egg development. When supplemented in pine extract followed by scopolamine injection intraperitoneally combination with solamargine, an augmentation in these results to evaluate the memory function test by Morris water maze task was noted. In another study solasonine exhibited leishmanicidal method exhibited a rise in cumulative path-length, escapes latency activity against Leishmania amazonensis (protozoa). Here also and lessened time spent in target quadrant. Further, pre-exposure an equimolar mixture of solasonine and solamargine, exhibited induced impaired acetylcholinesterase and neurogenesis function unripe S. asperum fruits was validated for its molluscicidal activity to pine needle extract significantly counteracted the scopolamine againstbetter activityBiomphalaria [60]. Further, glabrata solasonine [61]. and solanandaine from Anabasine, an alkaloid showing close proximity to nicotine and andAntimicrobial, also improved aphicidal,multiplication trypanocidal, and maturation molluscicidal, of neurons [51]. schistosomicidal, leishmanicidal potentialities was validated for its antimicrobial (antibacterial and antifungal) anabasine and evaluated its antifungal and antibacterial properties. tomatidine, dihydrosolacongestidine and solasodine from Solanum Parallely,efficacy. KulakovBakbardina et al. et [62]al. [63] synthesised chemically thiourea synthesised derivatives alkaloid of leucocarpumThe purified alkaloid demissidine along with the alkaloids anabasine and cytisine derivatives of monothiooxamides antibacterial properties of solacasine from S. pseudocapsicum and determined its biological activity in terms of aphicidal were showed bactericidal activities [52]. Similarly, and fungicidal properties. Anabasine showed strong insecticidal alkaloid solacongestidine against selected fungal strains such as properties against Lepidopterous larvae (Pieris rapae larval Candidahave already albicans been, Cryptococcus reported [53]. albidus Fungicidal and Trichophyton potentiality rubrum of the bioassay). Use of anabasine even in trace amounts in insect traps proved to be effective in killing insects [64]. Solaverbascine, a new revealed significant MIC values and time kill analysis [54]. Moreira

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alkaloid from S. verbascifolium encephalocele) on oral administration in Syrian hamsters. These toxic effects of solanine were attributed by the ionic imbalance , displayed significant germicidal in the cells. Several studies investigated the effects of solanine propertiesAnti inflammatory [65]. effects on intracellular concentration of Ca2+ on mouse neuroblastoma x rat glioma aggravated with the chronic diseases such as cancer, autoimmune L-929 cells and mouse Balb/3T3 cells lines. The results revealed disorders,Chronic arthritisinflammation and isvascular an undesirable disorders. phenomenon Numerous and studies gets that the solanine-evoked hybrid NG 108-15 Ca2+ cells, mouse-skin fibroblastoma have proved that natural compounds or extracts as human health of the cell membrane. Further, all the solanine treated cell lines rejuvenators with safety and non-toxic effects. Eventhough many showed a marked increase in influxintracellular due to Ca the2+ concentrations destabilization of the phytochemicals isolated from herbs have exhibited anti- with the concentration of solanine [71]. In one investigation, solasodine produced sterility in male rats and dogs. The effect was reversed on cessation of solasodine inflammatory effects, only a few studies have investigated the phytochemicals. supplement. Further testing showed inhibition of spermatogenesis underlying molecular events in anti-inflammatory actions of and testosterone production and reduced movement of sperm in solasodine treated groups, without any remarkable change in size Solanidine, α-chaconine and α-solanine were reported as of sex organs [72]. Above optimal doses anabasine is believed to anti-inflammatory compounds. Kenny et al. [66] revealed that be teratogenic in swine [73]. asα-chaconine interleukin-2/8 and in solanidine Con A-induced exhibited Jurkat significant cells. Further, inhibitory nitric action on the production of key inflammatory compounds such smokeless tobacco and 99 were cigarette smokers) showed that presenceJacob etof al. anabasine [74] studied in urine 304 individuals samples and (205 can individuals be used as used an oxide production was significantly reduced in LPS-stimulated effective marker to validate tobacco abstinence or to measure raw macrophages following α-solanine and solanidine treatment. solasodine from S. trilobatum in animal models. Solasodine the extent of use of tobacco in individuals who undergo nicotine Pandurangan et al. [67] evaluated anti-inflamatory activity of manner in carrageenan-induced rat paw oedema. Interestingly, a 96 well plate-based capillary LC-tandem mass spectrometry exerted antiinflammatory effect in a concentration dependent methodreplacement which therapy was regarded [74]. von to Weymarnbe accurate et and al. [75]precise developed for the analysis of anabasine and two more compounds nornicotine and solasodine on topical application significantly reduced Further, reduction in exudates volume, leucocyte count as well anatabine in urine. Study was carried out on 827 smokers with a tetradecanoyl-phorbol 13-acetate induced inflammation in ear. as neutrophil migration was recorded following solasodine vast range of tobacco exposures. Traces of anabasine were found administration. Zhao et al. [68] demonstrated that α-tomatine also in almost all the sample of urines (97.7%). The average amount of inducedshowed similarmacrophages. effects. Expression Chiu et ofal. pro-inflammatory [69] compared cytokinesSolanum anabasine in urine was detected as 5.53ng/mL. The median ratio alkaloidswas greatly specially suppressed tomatidine by α-tomatine and insolasodine LPS (lipopolysaccharide) against LPS- of the glucuronidated to free anatabine was 0.74 (range, 0.1 to 10.9), and the median ratio of glucuronidated to free anabasine wasLocomotor 0.3 (range, activity 0.1 to 2.9) [75]. stimulated inflammation in macrophage. Tomatidine found to be more effective in suppressing inflammation than solasodine by Locomotor activity in scopolamine treated mice strains, namely attenuatingAntioxidant the expressionpotential/degenerative of NF-κB and JNK signallingdisorders molecules. and anti-aging revealed behavioural suppression [76]. Another study in rats, demonstratedA, DBA/2 and the C57BL/6, effects of inscopolamine association on with pre and shock post-synaptic treatment Uncontrolled synthesis of free radicals or ROSs results into events related with dopaminergic function. Scopolamine showed many neurodegenerative disorders can trigger aging and can be antagonist effects against inhibition produced by spiperone on regulated by exogenous antioxidants. Extracts of Solanum species apomorphine associated behavioural action. In animals, exposed have shown potential antioxidant power in 1, 1-diphenyl-2-picryl to 6-hydroxydopamine (6-OHDA), an increase in scopolamine- .- hydrazyl (DPPH) radical scavenging, ABTS, FRAP, O2 , H2O2 etc. Positive correlation was noticed between the antioxidant activity inhibited this stimulation. However, the enzyme dopamine-beta- and the content of alkaloids, signifying that the compounds to the hydroxylaseinduced locomotor remains activityunaffected was in noted, these buttreatments α-methyltyrosine supports radical scavenging potentiality. But the mechanism of scavenging the hypothesis that scopolamine association with presynaptic action by stimulating cytokines (interleukin [IL] -2, IL-4, IL-12, administered to rats with 6-OHDA, recorded a suppression of spiperonedopaminergic inhibition fibers. of Also, locomotion when alpha-methyltyrosineinduced by apomorphine. was IFN-γ and tumor necrosis factor-alpha [TNF-γ]) remains to be In addition, the level of 3H-spiperone in brain and dopamine Toxicity studies elucidated [70]. associated activity of adenylate cyclase remains unchanged Administration of solanine body weight) on a Solaphyllidine and desacetylsolaphyllidine from S. oblongifolium, treated animals wereα- also suffered (75-100 from mg/kg other undesired effects wereconfirming studied the for post-synaptic their effects associationon locomotor of activity scopolamine (mice) [77]. i.e., daily basis found to be lethal in hamsters within 4-5solanine days. Solanine induced both the alkaloids reduced duration of sleep, while, solaphyllidine craniofacial malformations (exencephaly, anophthalmia and such as fluid-filled and dilated small intestines. α- enhanced locomotor activity [57].

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Action on cell membrane exhibited haemolytic properties against RBC. Roddick et al. [49] studied membrane damage and enzyme activity inhibition of The effects tomatine on membrane damage was assessed by solasonine. As the study reveals that a combined application 2+ measuring intracellular free Ca of solasonine and N-nitrososolamargine failed to produce any cells and Balb/3T3 cells in rat model. Positive correlation was level in NG 108-15 cells, L-9292+ seen with the concentration of tomatine with intracellular Ca and solatriosides, solasonine produced disruption of liposome level i.e., remarkable ED andliposomes also exhibited disintegration. disruption But of with erythrocytes. 75µM solamarine, solanine 50 combination with other alkaloids in NG 108-15 associated cells was poisoning noticed. [78]. These A Genes regulating alkaloid synthesis in Solanum findings suggest the role of tomatine in membrane damage2+ or in evoked by chaconine could not be prevented by metal ions or Most of the Solanum members are toxic because of certain bysimilar inhibitors trend was of alsoCa2+ noticed transport with across α- chaconine. membranes The Ca suchinflux as metabolites like glycoalkaloids. Many workers attempted voltage-operatedα- channel antagonists, muscarinic and nicotinic to elucidate gene regulated biosynthetic pathway related to antagonists or Na(+) and K(+) channel blockers. The optimal glycoalkaloid synthesis particularly in potato. Nurun [82] reported concentrations of alpha-chaconine that yield half-maximal six genes in association with steroidal glycoalkaloids (SGA) and response (ED sterol biosynthesis in potato. Down regulation of StDWF1 (gene

50 the assumption) thatin NG the 108-15 alkaloid-evoked cells, L-929 Ca and2+ Balb/3T3 were 12.0 steroidal glycoalkaloid content (SGA), suggesting some crosstalk encoding a sterol Δ 24-reductase) reduced both cholesterol and themum, cell 10.2 membrane mum and destabilization. 9.5 mum respectively. Chaconine The was resultalso assayed supports by between sterol and SGA synthesis. Carpintero et al. [83] studied Roddick et al. [49] in order to assess its effect influxon disruption may be dueof cell to expression of genes related to steroidal glycoalkaloid (SGA) membrane and enzyme-inhibition. metabolic pathway, namely HMG1 (3-hydroxy-3-methylglutaryl coenzyme-A reductase), HMG2, SQE (squalene epoxidase), Hepatoprotective activity SGT1 (solanidine galactosyltransferase) and SGT2 (solanidine glucosyltransferase) [83]. Similarly, Mariot et al., [84] based on Hepatomegalyic (liver weight increase) effect of tomatidine genetic analysis in S. tuberosum proposed existence of relationship was evaluated by Friedman et al. [79]. Pregnant and non-pregnant between content of total glycoalkaloid (TGA) and the expression mice were fed with 2.4 =mmol/kg of tomatidine for 14 days. The ratios of liver weight to body weight were found to be markedly higher than those of the control values Conclusionprofile of SGT1, SGT3 and GAME genes in S. tuberosum [85-90]. with a propotional increase in pregnant % inmice. non-pregnant Further, in mice, this Solanum species are unique source of several pharmacologically foetuses in pregnant mice and also no abortion of foetuses were important lead molecules, especially steroidal alkaloids such as reported.study tomatidine In another exerted study, insignificant khasianine effects remarkably on the weight suppressed of the solasodine, solasonine, solamargine and various other medicinally useful alkaloids. This review has attempted to bring almost all sort CCl4 induced liver damage under in vitro

Effect on cholesterol condition [80]. conducted on Solanum alkaloids. As most of the studies are basic andof scientific are not informationup to the quality in relation for the to synthesis pharmacological of compounds studies Fujiwara et al. [81] examined the inhibitory effects of with prescription grade, this comprehensive review is expected tomatidine on the accumulation of cholesterol ester (CE) in human monocyte-derived macrophages (HMDM) and also atherogenesis to help the investigators to explore deep into this field that may dependent suppression of cholesterol ester accumulation induced benefit the development and emergence of new molecules with in mice with apoE-deficiency. Tomatidine showed a concentration by acetylated LDL in HMDM. In Chinese hamster ovary cells, Referencessignificant therapeutic activities. CE formation found to be greatly suppressed after tomatidine treatment. Further, tomatidine suppressed the ACAT-1 and ACAT- 1. 2 activities (cholesterol acyl-transferase-1/-2) in hamster ovary Review on the elemental contents of Pakistani medicinal plants: ImplicationsAziz MA, Adnan for folk M, Begummedicines. S, Azizullah J Ethnopharmacol A, Nazir R,188: et 177-192. al. (2016)

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Jayakumar K, Murugan K (2016) Solanum Alkaloids and their Pharmaceutical Roles: A Review. J Anal Pharm Res 3(6): 00075. DOI: 10.15406/japlr.2016.03.00075