Aloe Vera Alimento Funcional 2011

December 31, 2009 2:5 FSN BFSN_A_354613

Critical Reviews in Food Science and Nutrition, 50:1–22 (2010)Copyright C©© Taylor and Francis Group, LLCISSN: 1040-8398DOI: 10.1080/10408390802544454

Aloe vera as a Functional Ingredientin Foods

ELENA RODRIGUEZ RODRIGUEZ,1 JACINTO DARIAS MARTIN,2 andCARLOS DIAZ ROMERO1

1Department of Analytical Chemistry, Food Science and Nutrition, University of La Laguna, La Laguna, Santa Cruz deTenerife, Spain2Department of Chemical Engineering and Pharmaceutical Technology, University of La Laguna, La Laguna, Santa Cruz deTenerife, Spain

The main scientific discoveries on Aloe vera published mainly in the last three decades are presented in this work. Afterdescribing Aloe from a botanical point of view, the papers related with the chemical composition of different parts of theleaf of Aloe, particularly those in which the gel is described and are presented in a synthetic manner. The chemical analysesreveal that Aloe gel contains mannose polymers with some glucose and other sugars, among which the most importantis Acemannan. Besides these, other components such as glycoproteins, enzymes, amino acids, vitamins, and minerals aredescribed. The different factors also affecting the chemical composition of the gel, such as species and variety, climatic andsoil conditions, cultivation methods, processing and preservation, are enumerated and discussed.

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15On the other hand, the main therapeutic applications have been revised and the possible damaging effects of Aloe are also

commented upon. A special emphasis is placed on the biologically active compounds or groups of compounds responsiblefor the therapeutic applications and which are their action mechanisms. The paper concludes that more research is neededto confirm the therapeutic and beneficial effects and to definitively clarify the myth surrounding Aloe vera. A general viewon the problem of the commercialization and establishment of the quality and safety of Aloe products in the food industryhas been offered here. The main points and European regulations that need to be considered regarding the quality control ofprepared Aloe products are presented in this paper.

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INTRODUCTION

Food has drastically changed in the last thirty years. The

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main tendency is towards the production of higher amounts of25foods of better quality and at a lower price. The design of newfoods is included within these new tendencies in the world offood. In accordance with the current legislation, new foods ornew food ingredients are the ones that had not been consumedin large amounts in the European Community before May 15th301997 (Reglamento CE 258/1997). Aloe vera is one of the manyfood products that can be considered as new food or new foodingredient.

From times immemorial Aloe has been used in an empiricway for the treatment of diverse disorders and ailments. Many35authors have considered Aloe to be a member of the Liliaceaefamily, but it comes from a family of its own called Aloaceae

Address correspondence to Carlos Dıaz Romero, Department of Analyti-cal Chemistry, Food Science and Nutrition, University of La Laguna, Avda.Astrofısico Francisco Sanchez s/n, La Laguna, Santa Cruz de Tenerife. 38201.Spain, Telephone:+34 922 318049, Fax:+34 922 318003. E-mail: [email protected]

(Reynolds, 1985). This plant is however related to the Liliaceaefamily, and therefore also related to plants such as onion, garlic,and asparagus, which are known to have medicinal properties 40(Lawless and Allen, 2000). Most of these plants originated inthe dry regions of Africa, Asia, and Southern Europe, especiallyin the Mediterranean regions (Urch, 1999). Due to the numer-ous beneficial effects attributed to Aloe gel, its production isan emerging industry for making cosmetics, functional food, 45and drugs and due to its medicinal properties it is being culti-vated in other areas with different climatic conditions. Mexico isthe main producer of Aloe, followed by Latin America, China,Thailand, and the United States (Rodriguez, 2004). Aloe plantsrange in height from a few cm to 2–3 m or more. The leaves 50of some of the species are very large and are lance shaped withjagged edges (Urch, 1999). Q3

There are at least four species of the over 360 known onesthat have medicinal properties—Aloe arborescens Miller; Aloeperryi Baker; Aloe ferox Miller o Aloe capensis; and Aloe bar- 55badensis Miller, also known as Aloe vera Linne o Aloe vulgarisLamark (Atherton, 1998; Urch, 1999). This last specie is themost popular one and is also the most widely cultivated. Aloe

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2 E. R. RODRIGUEZ ET AL.

vera and other species of Aloe are succulent and xerophyteplants that are adapted to living in areas with little water. These60plants possess extensive water storage tissue in their leaves, thepart of the plant which is used for its therapeutic properties.

The aim of this paper is to provide general and syntheticinformation regarding Aloe vera and its beneficial properties,emphasizing its use in the food industry as a new or functional65food. The main scientific papers published in the last thirty yearshave been presented here. Besides, some previously publishedpapers are also included for their relevance and interest. This re-view addresses the following aspects:1) Chemical compositionof the exudate and gel of Aloe; 2) Medical uses and applications;703) Biologically active compounds and therapeutic properties; 4)Quality control and legal aspects; and 5) Concluding remarks.

CHEMICAL COMPOSITION OF THE EXUDATEAND GEL OF ALOE

Most of the whole leaf is water and, there are more than75200 chemical substances in the dry matter constituting theleaf. Therefore, the concentration of these components is rel-atively low (Luta and McAnalley, 2005). The largest compo-nent (≈60%) in the dry matter, are the carbohydrates (solublesugars and complex polysaccharides). The composition of these80carbohydrates differs depending on the part of the leaf consid-ered (Femenia et al., 1999; Ni et al., 2004). Proteins and lipidsaccount for about 6–8% and 2–5% of the dry matter, respec-tively with larger quantities being observed in the gel than inthe exudate of the plant (Femenia et al., 1999). Other minor-85ity components that may be biologically active include phenoliccompounds, organic acids and amino acids, certain vitamins andminerals, and volatile compounds (Luta and McAnalley, 2005).

Some confusion still surrounds the exudates and gel of theleaf, both of which have largely been used for various reasons90in popular medicine. Nevertheless, many authors have clearlydistinguished the two parts (Capasso et al., 1998; Femenia etal., 1999; McKeown, 1987), and others have described the sep-aration of the gel in some detail (Agarwala, 1997; McAnalley,1988, 1990; Spoerke and Elkins, 1980). There has been great95controversy about the relative effectiveness of the colorless andcolored derivatives of the gel (Agarwala, 1997; Danof, 1987).The distinction is sometimes difficult because some chemicalcomponents of the exudate can be introduced into the gel dur-ing its separation. In some studies the extracts of the complete100leaf have also been used. This can create confusion about themedical properties attributable to certain components, since thedetermined medical synergistic effects could not be observed,if both fractions were kept separately, or on the contrary, unde-sirable effects could occur as a result of the presence of some105components of the exudate in the gel. Three structural compo-nents 1) cell walls and cell membranes; 2) microparticles ofsubcelular organelles; and 3) viscous liquid gel, have been sep-arated from the pulp of the A. vera leaf (Ni et al., 2004). Each ofthese three components has a different chemical composition,110

in particular of polysaccharides. Therefore, different productswith a different chemical composition can be obtained in thefunction of the processing technique used to obtain the gel. Thisexplains, at least in part, the differences observed by differentauthors in the chemical composition of the gel, mainly referring 115to the type of polysaccharides (Ni et al., 2004).

In view of the complexities inherent in Aloe pharmacology,it is convenient to be as rigorous as possible when separatingboth fractions, and once the biological properties of each one ofthem are established in an independent way, one can combine 120both fractions in later investigations. Therefore, the chemicalcompounds in the leaf of Aloe can be divided into two groups:

Exudate Compounds

The yellow exudate is rich in anthraquinones which arephenolic compounds which have been thoroughly revised 125(Reynolds, 1985). Figure 1 shows the main phenolic compoundsisolated from the Aloe exudates. For centuries they have beenused for their purgative effects, and as a bitter agent in the prepa-ration of alcoholic drinks (Saccu et al., 2001). Anthraquinonesare formed by oxidation of low molecular weight components 130such as aloin, which is a glycoside derivative of aloe-emodin.

Exudates of around 300 species of Aloe have been exam-ined by liquid chromatography and about 80 chemical com-pounds have been separated and identified in this study. A totalof 13 phenolic compounds have been identified and quanti- 135fied by high performance liquid chromatography (HPLC) inreverse phase with UV detection—Aloesin, 8-C-glucosyl-7-O-methyl(S)-aloesol, neoaloesin A, 8-O-methyl-7-hydroxyaloin Aand B, 10-hydroxyaloin A, isoaloeresin D, aloin A and B, alo-eresin E, and aloe-emodin from A. barbadensis; and aloenin, 140aloenin B, 10-hydroxyaloin A, aloin A and B and aloe-emodinfrom A. arborescens (Park et al., 1998). Aloe ferox produces

Figure 1 Structures of Aloin A and B, Aloe-emodin, Aloenin, Aloesin, andAloeresin A.


ALOE VERA AS A FUNCTIONAL INGREDIENT IN FOODS 3

greater quantities of bitter sap and other medicinal componentsthan the more widely known Aloe vera (Van Wyk et al., 1997).A simple and fast reversed-phase HPLC method for the deter-145mination of aloesin, aloeresin A, and antraquinone in Aloe feroxand Aloe-related products was recently developed and validated(Zahn et al., 2008). Saccu et al. (2001) have characterized sev-eral commercial exudates of Aloe by means of HPLC in reversephase with a UV detector, and gas chromatography (GC) cou-150pled to a mass spectrometry (MS) detector using the headspacein the column technique, for the determination of the phenolicconstituent and of the volatile fraction, respectively. This makesthe characterization of the commercial products possible. Thephotochemical profile of A. secundiflora has been studied us-155ing the HPLC-MS finding a mixture of phenolic compounds.Among them the anthrone contents stand out (aloenin, aloeninB, aloin B, and other aloin derivates), and so also the chromonesand phenylpyrones (Rebecca et al., 2003). The aloin contentswere examined by HPLC in six species of Aloe, and they were160related with the structure of the leaf. The largest aloin quantitywas observed in A. arborescens, and the levels were low or verylow in A. vera and A. saponaria, respectively (Li et al., 2003). Itwas also found that by applying fluorescence microscopy, aloinwas stored in the large parenchymatous cells of vascular bun-165dles, the vascular bundle sheath, and the aquiferous tissue sheath(Li et al., 2003). Aloin occurs naturally as a mixture of two di-asteroisomers, aloin A and B, which have been separated byhigh-speed countercurrent chromatography (Cao et al., 2007).An attempt was made by Viljoen et al. (2001) at a taxonomic170classification of the function of the presence of anthrone isomerssuch as aloin A and B, together with aloinoside isomers and mi-crodontin A and B. These phenolic compounds such as the aloinsA and B are very unstable in aqueous solutions, in particular inalkaline conditions (Zonta et al., 1995). This may explain why175these compounds are not detected in prepared drinks with anAloe base (Zonta et al., 1995).

Besides the phenolic compounds the exudate of the leaf con-tains small quantities of polysaccharides and free sugars, espe-cially glucose, volatile and aliphatic compounds (Rebecca et al.,Q41802003; Saccu et al., 2001). Two glyoxalases I and II have alsobeen isolated from the outer green rind of A. vera leaves, whichwere compared with reported animal and other plant glyoxalases(Norton et al., 1990).

Gel Compounds185

Most of the authors attribute the beneficial effects of the plantto the gel. The reasons justifying the effectiveness of the gel areoften uncertain perhaps because in fact there are several healingactivities intervening together (Capasso et al., 1998). On theother hand, these therapeutic properties attributed to the gel are190disproportionate in relation to the contents of the substances thatthey contain. This could be explained because the “cocktail” ofchemical substances, or constituent active principles, act syn-ergically in the prevention and cure of numerous disorders and

illnesses. It is essential to understand the chemical composition 195of Aloe gel better to be able to discover the mechanisms whichprovide it with beneficial properties for health.

Few species of Aloe have been examined to establish thecharacteristics of the gel. Although A. vera gel is the only onethat has been marketed, there is the possibility of discovering 200useful and therapeutic properties among the more than 360 well-known species (Newton, 1987). The chemical composition ofthe mucilage isolated from the raw leaf without preservationprocesses is presented in Table 1. Aloe gel contains between98.5 and 99.5% of water with a pH of between 4–5 (Femenia 205et al., 1999; Gjerstad, 1971), therefore, the caloric value of the A.vera gel is very low. So, the consumption of one serving (≈200ml) of gel contributes less than 5 kcal. The pH of the previouslyfiltrated A. vera gel had a relatively low range, between 4 and 5(Eshun and He, 2004). Approximately 80% of the solids in the 210gel are water-soluble compounds (Luta and McAnalley, 2005).

Carbohydrate Fraction

This major fraction in the Aloe gel is composed of free sug-ars, soluble polysaccharides, and fibers. A study on the rheol-ogy of the gel suggests that the glucomannans of the Aloe gel 215are uncommon in most other species of plants; however, theyare related to some human corporal fluids (Yaron, 1991). Thepolysaccharides from the species A. arborescens, A. vahombe(sic.), A. plicatilis (L.) Mill, and A. barbadensis (Grindlay andReynolds, 1986), and A. saponaria and A. vanbalenii Pillans 220(Gowda, 1980), had been extracted and characterized till 1986.Later, A. ferox was added to this list (Mabusela et al., 1990). Inthis specie, the arabinogalactans and rhamnogalacturonans wereapparent, whereas glucomannans, common in the other speciesof Aloe, were less apparent in A. ferox. 225

There has been little agreement on the composition of thesepolysaccharides in the gel which could probably be related tothe different separation, and the determination methods used.Besides, it is possible that these differences are due to the soilcomposition and climatic conditions, the cultivation method, 230and other characteristics. In the 1970s, Ovodova et al. (1975)reported that the presence of uronic acid yields galacturonicacid and oligosaccharides, upon fermentative hydrolysis withpectinase. However, Segal et al. (1968) have not found uronicacids in the analytical investigation. Gjerstad (1971) indicated 235that the carbohydrates of the A. vera gel were composed of glu-cose and a polyuronide, consisting of a high molecular weightglucose-mannose polyose (molecular weight up to about 275KDa). The hexuronic acids detected produce glucose and man-nose in its hydrolysis, as well as trace amounts of galactose, 240arabinose, and xilose. Polysaccharides present in the Aloe gelare lineal polymers with no branching with different propor-tions of single sugars, which contain β-glycosidic 1–4 link-ages which can be separated by precipitation with alcohol(Gowda et al., 1979; Gowda, 1980; Manna and McAnalley, 2451993; Paulsen et al., 1978). However, there are polymers ofother hexoses, like in the case of A. ferox, in which galactose and



Table 1 Chemical composition of Aloe vera gel

I NUTRITIVE COMPOUNDS REFERENCIAS

Water/moisture 98.5–99.5%pH = 4–5

Atherton (1998); Femenia et al. (1999); Gjerstad(1971); Waller et al. (1978)

CarbohydratesSoluble polysaccharidesFree monosaccharides

0.25% (25–50% of dry matter)Glucomannans (acetylated partially) Acemannan93% Mannose (3% Glucose, 3% Galactose) 95%Free glucose (Fructose, Galactose)

Chow et al. (2005); Femenia et al. (1999); Gowda(1979); Leung et al. (2004); Liu et al. (2007);Mandal, and Das (1980); Manna, and McAnalley(1993); McAnalley (1990); Meadows (1980); Niet al. (2004); Paez et al. (2000); Paulsen et al.(1978); Pugh et al. (2001); Talmadge et al. (2004);Waller et al. (1978)

Nitrogen fractionAminoacidsGlycoproteinsEnzymes

N2 protein (0,013%)18 (7 of the 8 essential; 20% Arg)Lectins with hemoaglutination activity (A.

arborescens)Aloctin A (12% of carbohydrates; PM=18KDa)Aloctin B (50% of carbohydrates; PM=24KDa)Bradykinase, Carboxypeptidase, Catalase, SOD,GSH-Px, Peroxidase

Akev, and Can (1999); Atherton (1998);Bautista-Perez et al. (2004); Beppu et al. (2006a);Choi et al. (2001); Esteban et al. (2000); Fujita(1976, 1979); McKeown (1983); Meadows (1980);Ni et al. (2004); Reynolds, and Dweck (1999);Sabeh (1993, 1996)

Vitamins Ascorbic acidComplex B: Thiamin, riboflavin, niacin, folic acidCarotenoids, tocopherols

Atherton (1998); Lawless, and Allan (2000)

Minerals and trace elements 24–25% of dry matterMinerals and electrolytes K, Cl (Na), Ca, Mg, PTrace elements Fe, Cu, Zn, Mn, Al, Se, Cr

Atherton (1998); Femenia et al. (1999); Li et al.(2004); Ni et al. (2004); Rajasekaran et al. (2005);Sahito et al. (2003); Wang, and Strong (1993);Yamaguchi et al. (1993); Yang et al. (2004)

II) NON-NUTRITIVE COMPOUNDS REFERENCES

Organic acids Salycilic acidMalic acidLactic, acetic, succinic acids

Atherton (1998); Loots et al. (2007); Ni et al. (2004);Paez et al. (2000)

Phenolic compounds Trace of anthraquinones Aloin A y B, Aloe-emodin,Aloenin, Aloesin, Aloeresin,. . .

Loots et al. (2007); Ni et al. (2004); Okamura et al.(1996); Park et al. (1998); Perez et al. (2007)

Phytosterols β-sitosterol, campesterol. Atherton (1998); Moon et al. (1999)Other compounds Alyphatics hydrocarbons/esters long chain; volatile

compounds (acids, aldehydes, ketones,. . . .)Atherton (1998); Loots et al. (2007)

galacturonic acid polymers are frequently found (Reynolds andDweck, 1999).

The polysaccharides of the Aloe gel can be acylated, partially250acylated, or not acylated. Meadows (1980) indicated that at leastfour different and partially acetylated glucomannans were re-sponsible for producing the thick stringy mucilage characteris-tic of the raw Aloe gel. A series of highly purified galacturonatepolysaccharides have recently been extracted from the A. vera255plant and analyzed in terms of chemical composition and molec-ular weight (McConaughy et al., 2008). This A. vera polysaccha-ride has been found to exist as a high molecular weight speciesand to possess a unique chemical composition, including a highgalacturonic acid content and low degree of methyl ester sub-260stitution. Other investigators (Esua and Rauwald, 2006) haveisolated three malic acid acylated polysaccharides— Veracyl-glucans A, B, and C from A. vera gel.

According to the observations reported by different authors,especially for the case of A. barbadensis, there are consider-265able differences in the structures of the isolated polysaccha-rides (Reynolds and Dweck, 1999). These polysaccharides aremainly composed of mannose units that are randomly substi-tuted by glucose. Minority amounts of xilose, rhamnose, galac-

tose, arabinose, mucose, or uronic acids have also been identi- 270fied (Mandal and Das, 1980; t’Hart et al., 1989). It is not wellknown, whether the presence of these sugars is an integral part ofthe structure of the hydrocarbonated fraction, or whether theseare a consequence of the presence of polluting carbohydrates.The extracted majority carbohydrate of the Aloe gel is generi- 275cally denominated Acemannan (Manna and McAnalley, 1993),whose important therapeutic properties are attributed (Zhangand Tizard, 1996). The Acemannan or CarrysinTM, availablecommercially, is an acetylated polymer of mannose that is iso-lated from the A. vera gel (McDaniel et al., 1987). After sep- 280arating the Acemannan by chromatography, it was proven thatthe polysaccharide was mainly composed of mannose 93%, glu-cose, and galactose in 3% each one and less than 1% of arabinose(McAnalley, 1990; Talmadge et al., 2004). Acemannan may berelated with the “Aloe mannan” which was isolated somewhat 285earlier from A. arborescens (Yagi et al., 1977). Femenia et al.(1999) have chemically characterized the gel, pulp, and skin ofthe leaves of A. vera. The extraction of fractions of lyophilizedAloe indicates that the carbohydrates represent more than 80%.A sequential extraction of the present polysaccharides in Aloe 290revealed that there were two polymers containinig mannose. A



storage polysaccharide was found in the protoplast of parenchy-matous cells in the pulp of the Aloe gel. Mannose and glu-cose (constituent of cellulose) are the main components of thepolysaccharides in all the derivates, and pectic polysaccharides295were also detected.

Chow et al. (2005) have recently investigated the structureof the soluble fraction of polysaccharides of A. vera isolated byprecipitation with alcohol. This soluble fraction of polysaccha-rides was hydrolyzed with acid at high temperature, producing300a mixture of oligosaccharides and an acid resistant fraction,accounting for nearly 37% of the bulk material. The acid re-sistant fraction contained arabinose (18%), galactose (18%),glucose (9%), xylose (9%), and galacturonic acid (5%). Thisacid resistant fraction had a different chemical composition to305that of the water-soluble polysaccharides, which was composedof 84%, 6%, and 4% mannose, glucose, and galactose respec-tively (Chow et al., 2005). Thus, the presence of an acid re-sistant fraction with a carbohydrate composition inconsistentwith this majority structure suggests that there are other dif-310ferent substructures in the soluble polysaccharides of Aloe.These authors (Chow et al., 2005) have carried out analysesof the structure for nuclear magnetic resonance (NMR). Thisstructure, after treatments with endo β-mannanase, has morethan enough purified oligosaccharides, confirming the presence315of βGlc1-4βMan1,4Man, and βMan1,4[αGal1,6]Man connec-tions as well as di-, tri-, and tetrasaccharides of β1,4-linkedmannose. Mannose molecules, with random substitutions of glu-cose, should form the chemical structure. There are also linkagesβ1-6 between mannose and galactose. Three purified polysac-320charide fractions were prepared from A. vera gel by membranefractionation and gel filtration HPLC. Variable contents of man-nose and variable molecular weights were found in these threefractions. It was observed that the biological response of Aloepolysaccharide fraction increases as the mannose content and325the molecular weight of the polysaccharide fraction increase(Leung et al., 2004).

The free monosaccharides represent approximately 25% ofthe dry gel, with glucose accounting for 95% of the solublesugars (Femenia et al., 1999). Other authors (Paez et al., 2000)330indicated the presence of other free sugars like fructose andgalactose, in significant amounts, although always smaller thanthe amount of glucose.

Nitrogen Fraction

Most of the suitable preparations of polysaccharides con-335tain very little or no nitrogen, hence the protein content ofa lyophilized commercial product of the gel of Aloe, deter-mined by the method Kjeldahl, was very low, around 0.013%(McKeown, 1983). On the other hand, Waller et al. (1978) ana-lyzed extracts obtained by maceration of whole leaves in acetone340and detected 17 amino acids in a free state, among which argi-nine has the highest content representing approximately 20%of total amino acids. More recently, the polypeptide compo-sition of proteins has been determined in the gel of various

species of Aloe. This disrupts the oligomeric proteins and the 345resulting polypeptides are ordered according to their molecularweight (Winters and Yang, 1996). It was observed that A. vera,A. arborescens, and A. saponaria had a total of 12, 9, and 12major polypeptides, respectively. Five major polypeptides, withmolecular weights of 15, 46, 65–66, 71, and 76–77 KDa, was 350common for these three species.

The presence of glycoproteins with biological or enzymaticactivity has been described. A fraction of A. arborescens gelwas shown to be a glycoprotein, appearing like a single elec-trophoretic band (Yagi et al., 1986), while another two gly- 355coproteins fractions were separated by differential precipitation(Kodym, 1991). A haemagglutinating activity, typical of lectins,was found in fractions of A. vera, A. arborescens, and A. chi-nensis (sic) (Winters, 1993). Two proteins were isolated, AloctinA and Aloctin B, from A. arborescens (Akev and Can, 1999; 360Saito, 1993; Suzuki et al., 1979). Aloctin A has a molecularweight of 18 KDa and it is made up of two subunits of 7.5and 10.5 KDa with a carbohydrate content of 18%. Aloctin Bwas 24 KDa, with two subunits of 12 KDa each and a carbohy-drate content of 50%. A glycoprotein denominated as ATF191, 365was subsequently isolated from the same species (Yoshimotoet al., 1987), while later another lectin, of molecular weight of35 KDa, was obtained from the outer layers of the leaf (Koikeet al., 1995). A glycoprotein (Pg21-2b) with cell proliferation-promoting activity was isolated from the A. vera gel (Yagi et al., 3701997), which had a molecular weight of 29 KDa and consistedof two subunits. Other protein fractions showed growth inhibit-ing activity; however, this could be associated with phenoliccontaminants.

Meadows (1980) claimed that at least 6 enzymes exist in the 375Aloe gel—Bradykinase, cellulase, carboxypeptidase, catalase,amylase, and oxidase. The bradykinase activity in the Aloe ex-tract has subsequently been studied by many authors (Bautista-Perez et al., 2004; Fujita et al., 1976; Yagi et al., 1982). Extractsof Aloe have been associated with enzymatic activities of di- 380verse enzymes such as superoxide dismutase (SOD) (Sabeh etal., 1996), glutathione peroxidase (GSH-Px) (Sabeh et al., 1993),and other peroxidases (Esteban et al., 2000). The SOD activityoccurred in seven previously separated electrophoretic bands,two of which were Mn dependent and the rest Cu-Zn dependent 385(Sabeh et al., 1996). GSH-Px consists of four identical subunits;and contains one atom of Se for each subunit, in a similar wayto most GSH-Px of animal origin (Sabeh et al., 1993).

Other Components

A wide variety of more or less simple compounds have been 390described in Aloe gel (Grindlay and Reynolds, 1986). However,there is always the problem of achieving a complete separa-tion of the gel from the plant exudate components (Agarwala,1997). Phenolic compounds can be included in the group of mi-nority compounds in Aloe gel (Park et al., 1998). The phenolic 395compound concentrations in Aloe gel are 1.25–3 times lowerthan those obtained in the epidermis of the Aloe leaf (Okamura



et al., 1996). Flavonols such as kaempeferol, quercetin, andmyricetin have recently been isolated from Aloe vera leaves(Sultana and Anwar, 2008). It is not known whether these phe-400nolic compounds are in the exudate, in the gel, or in both. Theantioxidant capacity and phytochemicals have recently been ex-amined in Aloe ferox gel (Loots et al., 2007). They deduced thatpolyphenols, indoles, and alkaloids were the main agent for theantioxidant capacity.405

The presence of organic acids can also be emphasized amongwhich malic acid has the highest content (Paez et al., 2000). ThisQ5

acid is not in the exudate of the plant and it has been proposedas one of the markers for the recognition of Aloe in commercialproducts (Luta and McAnalley, 2005). Other organic acids, such410as lactic or succinic, can be present as a consequence of micro-biologic or enzymatic alteration of the product (IASC, 2004).Salicylic acid has also been detected in the Aloe gel (Ather-ton, 1998). The presence of certain vitamins such as the A, C,E, B1 (thiamine), B3 (niacin), B2 (riboflavin), and folic acid,415many of them with an antioxidant capacity, have been identified(Atherton, 1998; Lawless and Allan, 2000). Some investigatorsmaintain that there are also trace amounts of vitamin B12, whichis usually only available in foods of animal origin (Atherton,1998; Lawless and Allan, 2000; Urch, 1999). However, this420finding has not been confirmed in recent studies. Aloe gel con-tains fatty acids; sterols like lupeol, cholesterol, campesterol,and β-sitosterol and a large number of long-chain hydrocar-bons and esters which are more typical of industrial contami-nants (Reynolds and Dweck, 1999; Waller et al., 1978). Umano425et al. (1999) have isolated and identified aromatic chemical com-pounds in the leaves of Aloe arborescens Mill. var. natalensisBerger using gas chromatography coupled to mass spectrom-etry. There were 42 alcohols, 23 terpenoids, 21 aldehydes, 9esters, 8 ketones, 6 acids, 5 phenols, and 9 miscellaneous com-430pounds, with a marked presence of several isomers hexenol andhexenal.

The mineral constituents of Aloe juice have also been exam-ined (Sahito et al., 2003; Wang, 1993). The concentrations of Cland K are high, whereas the Na content is smaller than the usual435content in plants. Similar to the electrolytes, the Ca and Mg werealso dominant cations. There are other minor essential mineralssuch as Fe, Cu, Zn, Mg, Mn, P, Cr, Si, and Ni, and small amountsof toxic elements such as Al, B, Ba, Sr, Cd, and Pb (Femeniaet al., 1999; Sahito et al., 2003; Yamaguchi et al., 1993; Yang440et al., 2004). The most commonly used methods for the deter-mination of minerals include atomic absorption spectrometryand flame emission spectrometry (Yang et al., 2004), and in-ductively coupled plasma (Femenia et al., 1999; Yamaguchi etal., 1993). Several methods for the mineralization of the Aloe445samples previous analysis for atomic absorption spectrometyQ6

have been studied (Sahito et al., 2003; Yang et al., 2004). Themost effective procedure for the decomposition of the organicmatter uses concentrated nitric acid and 30% oxygenated water(Sahito et al., 2003). A spectrophotometric method (Li et al.,4502004) based on the second derivative peak area in the chro-magenic system of 1,10-phenanthroline was proposed for the

simultaneous determination of metal species, such as Fe (II),Cu (I), and Co (II). There is no remarkable difference betweenthe results obtained for this method and those of inductively 455coupled plasma.

Influential Factors in the Chemical Composition of Aloe Gel

There are many factors that can influence the chemical com-position of Aloe gel which could explain the differences in theresults observed in the literature. A first factor to consider is the 460different species/subspecies or varieties of A. vera used in theinvestigation (Femenia et al., 1999; Saccu et al., 2001; Van Wyket al., 1995). Other investigators have also pointed out that otherfactors decisively influence the composition of the Aloe gel,such as the annual seasons (Grindlay and Reynolds, 1986; Le- 465ung, 1977; Meadows, 1980; Park et al., 1998; Wang and Strong,1993; 1995), exposure to light (Paez et al., 2000), the climateand the land (Grindlay and Reynolds, 1986; Meadows,1980),and cultivation methods (Femenia et al., 1999; Park et al., 1998;Saccu et al., 2001; Van Wyk et al., 1995; Wang, 2007; Wang 470and Strong, 1993,1995).

The variation in the concentration of some compounds ofA. arborescens var. natalensis Berger extracts according to sea-sonal changes such as temperature or rainfall has been studied(Beppu et al., 2004). Aloin A (barbaloin), aloin B (isobarbaloin), 475aloenin, proteins, saccharides, polyamine concentrations, andcarboxypeptidase activity, were higher in the hotter seasons;and that protein, saccharide, polyamine, and carboxypeptidaseactivity were affected in the rainy season. Park et al. (1998) in-dicated that the phenolic compound contents change in function 480of the climatic season. This contrasts with some results obtainedin the A. ferox exudate, in which the contents of the majoritycomponents (Aloeresin A, aloesin, and aloin A and B) held arelationship of 4:3:2 respectively and these three compoundsaccounted for 70–97% of the dry weight (Van Wyk et al., 1995). 485The aloin present in the plant exudate was clearly related to itsprocedence, and the minority components presented a biggervariation (Van Wyk et al., 1995). The irrigation of the plantaffects the amount of mucopolysacharides, since the contentswere smaller in well-irrigated plants (Yaron, 1993). The Na, 490K, Ca, and Mg contents, as well as the pH and fiber content,change with the climatic season have been documented (Wangand Strong, 1993, 1995).

There are also differences in the concentrations of differentcompounds in the function of the area of the leaf being analyzed 495(Beppu et al., 2004; Gutterman and Chauser-Volfson, 2000;Wang and Strong, 1993, 1995). It has also been proven that thephenolic compounds can vary depending on the part of the leafthat is analyzed (Gutterman and Chauser-Volfson, 2000).

The age of the plant is an additional and decisive factor that 500needs to be considered. The most significant increase in thealoin concentration was observed in plants of 2 and 3 years(Waller et al., 1978). The data obtained by Hu et al. (2003)suggest that the maturity of the plant plays an important rolein the antioxidant capacity of the gel. The phenolic compound 505



contents in Aloe diminished with the age of the plant (Okamuraet al., 1996).

On the other hand, Aloe gel is very unstable as a conse-quence of the hydrolysis of the constituent polysaccharide ob-serving losses of viscosity over time (Meadows, 1980). Thus,510the manipulation and preservation methods used can modify thechemical composition and physicochemical characteristics ofthe products (He et al., 2005; Kim et al., 1998; Mandal and Das,1980). There is a decrease of the biological activity as a result ofthese physicochemical modifications, therefore it is fundamen-515tal to use adequate preservation methods to maintain the ther-apeutic activity of the products. The addition of other naturalpolysaccharides isolated from algae was beneficial to preservethe viscosity during the preservation (Yaron et al., 1992; Yaron,1993). The chemical composition of the derivative products of520the Aloe can also be affected during the post-harvest, especiallyfor the time and temperature used in the dehydration processused in the preparation of commercial extracts (Femenia et al.,2003; Simal et al., 2000). The variation in some of the resultsdescribed in the bibliography could be explained by the treat-525ment and preservation of the gel after its collection (Agarwala,1997; Briggs, 1995; Fox, 1990; Kim et al., 1998; Mandal andDas, 1980; Marshall, 1990; Simal et al., 2000). The dehydrationtemperature increases the molecular weight of the constituentpolysaccharides because of structural changes which produce530changes in the functional properties such as a decrease of thewater and fat retention capacity (Femenia et al., 2003; Simalet al., 2000; Takeyama et al., 2002). These functional changescould be due to the decrease of the soluble fiber content ofthe Aloe gel which takes place because of the relatively high535temperature used (Takeyama et al., 2002).

MEDICAL USES AND APPLICATIONS

The use of Aloe dates from biblical times, and it has been andis still used in traditional medicine for the treatment of numerousillnesses. The beneficial effects of Aloe for health have probably540been exaggerated on many occasions. Therefore, it is necessaryto be cautious when interpreting the results, and in particular,when applying it to the treatment of illnesses. Therefore, someauthors (Vogler and Ernst, 1999) have pointed out that althoughthere are some promising results, the effectiveness of the use of545A. vera at a topical level or previous oral consumption has notbeen adequately defined as yet.

Skin and Wound Healing

The therapeutic activity of Aloe seems to work in two de-fined areas; on the one hand on the damaged epithelial tissue,550and on the other, on the immune system. Aloe is known well forits topical use as an anti-inflammatory and for curing woundsand burns, since it accelerates growth and renovation of dam-aged tissues, especially those affecting the epidermis. Therefore,its benefit has been described in illnesses such as burns, cuts,555

eczemas, haemorrhoids, wounds, varicose veins, cracked skin,etc. (Reynolds and Dweck, 1999). The treatment of burns andalterations of the skin as a result of aging or oxidative damageby UV radiation should be given special emphasis in the topicaluses of Aloe (Capasso et al., 1998; Danof, 1993). A clinical 560trial demonstrated the usefulness of A. vera for prophylaxis ofradiation-induced dermatitis (Haddad et al., 2007). When it iscompared with moisturizing creams, the topical use of A. veragel has positive effects on the alterations in the skin as a conse-quence of radiotherapy including erythema, pain, and dry and 565wet desquamation (Heggie et al., 2002). There is evidence thatsupports the view that the use of A. vera gel is effective for thetreatment of first to second degree burns (Maenthaisong et al.,2007). However, well-designed trials with sufficient details ofthe contents of A. vera products should be carried out to deter- 570mine the effectiveness of A. vera for burn wound healing. It canalso be successfully used in treatments of skin ulcers, includingmouth ulcers, leg ulcers, and simple herpes. This is due to ananti-viral effect of the Aloe gel in concentrations of 80% (Es-hun and He, 2004). Kodym et al. (2003) have proposed the use 575of eye drops containing Aloe gel and neomycin sulphate in thetreatment of inflammations and infections of the external parts ofthe eye, such as conjunctivitis, eyelids, lacrimal sac, and cornea.Aloe has a marked effect in the treatment of scars, and preventsthe formation of scars after skin lesions (Eshun and He, 2004). 580The positive effect in the treatment of the wounds could alsobe due to certain anti-microbial (Heggers et al., 1995) and anti-fungal activities (Rosca-Casian et al., 2007) usually attributed tothe Aloe gel. Thus, these authors (Heggers et al., 1995) observedthat the skin cuts in rats healed more quickly when Aloe gel was 585applied. Some studies have indicated that the A. barbadensis gelaccelerates the cure of wounds in diabetic rats due to its abilityto stimulate the synthesis and maturation of collagen in fibrob-lasts (Chithra et al., 1998b). The hypoglycemic effect observedcould probably contribute in the acceleration of this cure. 590

Diabetes

A hypoglycemic effect in diabetic rats previous oral con-sumption of the Aloe gel has been indicated by some au-thors (Ajabnoor, 1990; Beppu et al., 1993; 2003; 2006a,b; Bunyapraphatsara et al., 1995, 1996). Extracts of Aloe 595gel prevented hyperglycemia in rabbits treated with alloxan(Akinmoladun and Akinloye, 2007). These authors found thata homemade aqueous extract had a more potent effect than afactory-produced gel. While the investigators mentioned abovehave pointed out the anti-diabetic activity of Aloe, other inves- 600tigators (Koo, 1994; Mossa, 1985; Roman-Ramos et al., 1991;Wagar et al., 2008) did not find these same results. In fact, Koo(1994) found an elevation of the blood glucose levels in diabeticmice (induced with Alloxan) with a product that contained theAloe gel. Okyar et al. (2001) compared the effects of the Aloe 605gel and extract of the whole leaf on the blood glucose levelsin normoglycemic and in diabetic type I and type II rats. They



observed that the complete extract of the leaf is efficient in bothtypes of diabetes, which agrees with several authors (Ajabnoor,1990; Beppu et al., 1993; Bunyapraphatsara et al., 1995; 1996).610On the other hand, the hyperglycemic effect of the Aloe gel ob-served in rats with diabetes type II (Koo, 1994), could explainthe negative results found when an aqueous extract of the wholeleaf, rich in gel, was used (Mossa, 1985; Roman-Ramos et al.,1991). It is deduced therefore that the complete extract of Aloe615leaf, instead of the gel, maybe of interest in the treatment of dia-betes, in particular of the noninsulin-dependent strain. The effectof an extract from A. vera gel containing a high concentration ofpolyphenols on experimentally-induced insulin resistance wasexamined (Perez et al., 2007). They concluded that the A. vera620gel could be effective for the control of insulin resistance.

There are studies on the effects of A. vera in diabetic hu-mans. Oral use of A. vera gel decreased fasting blood glucose(by more than 100 mg/100 ml) and the hemoglobin A1c levelsin three studies of people with type II diabetes, although no con-625trol groups were considered in these studies (Ghannam et al.,1986). In a wide study in India, A. vera gel was administeredto diabetics via bread, and the blood glucose level decreasedin 90% of the cases (Agarwal, 1985). A decrease of the bloodglucose levels was also observed in diabetic patients from New630Zealand, orally treated with A. vera gel (Yongchaiyudha et al.,1996). Chalaprawat (1997) reported a reduction of blood glu-cose levels in patients administered with A. vera gel twice a dayfor a nine-month period compared with placebo-receiving pa-tients, but the differences were not stastistically significant. In a635study (Yeh et al., 2003) reviewing the use of grasses and dietarysupplements for glycemic control in diabetes concluded that A.vera extracts show positive results according to most of the stud-ies. It is important to clarify which compound or compounds arethe ones responsible of the hypoglycemic effect.640

Besides reducing the blood glucose levels in diabetic pa-tients, the oral administration of A. vera can be useful for re-ducing lipid levels in patients with hyperlipidemia (Vogler andErnst, 1999; Yongchaiyudha et al., 1996) and hepatic choles-terol and oxidative status in aged rats (Lim et al., 2003). The645oral consumption of A. vera gel (10–20 ml/day) for 12 weeks canreduce low density lipoprotein (LDL) cholesterol by about 18%,total cholesterol by about 15%, and tryglycerides by 25–30% inpatients with hyperlipidemia (Shapiro and Gong, 2002).

Gastrointestinal Effects650

In the 1960s it was discovered that the oral intake of Aloe gelwas of interest in the treatment of peptic ulcers and other dys-functions of the gastrointestinal tract. Thus the A. vera gel hasbeen satisfactorily used by patients for the treatment of inflam-matory bowel disease (Langsmead et al., 2004). The preventive655effect against the peptic ulcers was associated with pepsin in-hibition and hydrochloric acid secretion, as well as a generaldetoxifying effect (Blitz et al., 1963). It has been demonstratedthat the A. vera gel is effective for healing wounds (Chithra

et al., 1998a,b,c; Davis et al., 1989a,c; Heggers et al., 1993) 660and has anti-inflammatory effects (Davis et al., 1989b,c; Saitoet al., 1982), which favors the anti-ulcer effect. In a recent study(Suvitayavat et al., 2004) on the effects of a preparation of Aloein models of chronic ulcers in rats, an increase of pepsin andmucus secretion was observed and a decrease in acid secretion. 665However, no significant differences were observed with regardto the control group. These authors concluded that more re-search is needed using different doses with the aim of obtainingmore conclusive results.

Immunologic Effects 670

The action on the immunological response was postu-lated to some degree several years ago (Griggs, 1996; Rubel,1983; Schechter, 1994). On the one hand the anti-tumor, anti-inflammatory, and immunosuppressive activities of the gel fromcertain species of Aloe has been indicated (Yagi and Takeo, 6752003); and on the other hand, immunostimulative activities havealso been described (Im et al., 2005; Lawless and Allan, 2000;Leung, 1977; Merriam et al., 1996; Pugh et al., 2001; Reynolds,1985; Urch, 1999). In fact, Aloe gel has been used in nutritionalsupplements in clinical trials for the treatment of the acquired 680immune deficiency syndrome (AIDS) patients for its anti-viraland immunological properties (McDaniel, 1987; Marshall andDruck, 1993; Montaner et al., 1996).

Anti-Cancer Effect

Aloe extracts have been tested in the treatment of cancer and 685positive effects have been observed in inhibiting the growth oftumors. A wide study on lung cancer and smoking performed inJapan suggested that the oral ingestion of Aloe “juice,” presum-ably the gel, prevented pulmonary carcinogenesis and cancer inother tissues (Sakai, 1989). The activation of macrophages as 690immune stimulation mechanisms was reported (Zhang and Ti-zard, 1996). In an “in vitro” study using a rat hepatocyte model,carcinogenesis by DNA adduct formation was inhibited by anAloe gel fraction rich in polysaccharides (Kim and Lee, 1997).Aloe extracts have also reported prevention or regression of 695tumor growth (Corsi et al., 1998; Akev et al., 2007).

Antioxidant Effect

Long term A. vera gel intake, both the raw gel and the pro-cessed gel, in Fischer 344 rats could have beneficial effects onpathologies related with aging, such as cardiopathies or fatal 700chronic nephropathy, without causing deleterious effects (Ikenoet al., 2002). These results confirm suggestions reported in pre-vious studies (Afzal et al., 1991; McCauley et al., 1990) thatindicate that A. vera maybe of use in the prevention of thromboformation. The antioxidant activity of the Aloe vera gel (Aloe 705



barbadensis Miller) has been studied and evaluated by deter-mining the free radical-scavenging activity of the gel by meansof the extraction with supercritical carbon dioxide (Hu et al.,2005). Aloe vera extracts present in an equivalent amount havea stronger anti-oxidant effect than butyl hydroxianisol (BHA)710and the α-tocopherol, which could be of interest in the design offunctional foods, cosmetics, and medications (Hu et al., 2003).It was deduced that some compounds located in the cortex of theleaf were those responsible for most of the antioxidant capac-ity of the Aloe extracts (Hu et al., 2005). Esteban et al. (2000)715have suggested that the protection of Aloe gel against aging anddamage of the skin from UV irradiation could be due to theantioxidant efficiency of a peroxidase other than the glutathioneperoxidase. These antioxidant effects of A. vera gel, as well asits antifungal and antimicrobial effects, could be involved in the720action of the gel on maintaining the quality and safety of tablegrapes (Valverde et al., 2004).

Other Beneficial Effects

There are other beneficial effects that are attributed to diverseextracts of A. vera. In a large clinical trial, an Aloe extract com-725pared versus placebo, was used on a large number of patientswith psoriasis who were cured (Syed et al., 1996). Besides, ben-eficial effects at hormonal levels have been found after the useof Aloe gel. The intake of Aloe gel decreased the calcitonin andparathyroid hormone levels in a study on rats (Herlihy et al.,7301998). On the other hand, it was observed that a leaf extractof this plant (gel of A. vera) reduces thyroid hormone levels,although in a more moderate way than Aegle marmelos extract(Kar et al., 2002). However, the choice of Aloe gel as a natu-ral antithyroidal extract has advantages in mild hyperthyroidic735cases, as it does not only not exhibit hepatotoxic effects butit is hepatoprotective in nature (Kar et al., 2002). In the fieldof dentistry, it has been used to treat many dental affections.It alleviates pain and it accelerates the healing after periodon-tal surgery (Payne, 1970). The extract of the gel has also been740used in veterinary science for external treatments on animals,including allergies, fungal infections, inflammations, pains, anditching (Anderson, 1983; Northway, 1975).

BIOLOGICALLY ACTIVE COMPOUNDSAND THERAPEUTIC ACTIVITIES745

Although some physiological properties of Aloe have beendiscovered and demonstrated “in vitro” and “in vivo,” neverthe-less, the controversy surrounding which component or groupof Aloe components having those physiological properties isnot completely clarified at present. It is very probable that the750beneficial effects of Aloe are due to the sum of the effectsof each component, or that the total effect is greater than thesum of the effects found after individual administration of eachcompound (Femenia et al., 1999, 2003; Reynolds and Dweck,

Figure 2 Contribution of diverse components to the therapeutic action of theAloe.

1999; Talmadge et al., 2004). Consequently, the focus is moving 755towards what the active principles responsible for therapeuticeffects are and these active principles could be isolated andused in the preparation of pharmaceutical products (Reynolds,1998).

The reasons justifying the effectiveness of the gel in the 760treatment of illnesses and diverse disorders are often uncertain,perhaps due to the fact that there are several therapeutic activ-ities intervening together (Capasso et al., 1998). Davies et al.(1984) used the orchestra conductor concept to explain the re-lationships that exist among more than 200 biologically active 765compounds that Aloe contains (Fig. 2). One of these molecules,a polysaccharide, acts like a conductor conducting a symphonycomposed of all the active constituents. Therefore, this polysac-charide, like an orchestra conductor, modulates the biologicalactivities of the compounds that constitute the orchestra, to act 770synergically. However, there are many examples in the bibliog-raphy that point out that the polysaccharides can show pharma-cological and physiological activities without the help of othercomponents. Therefore, it is logical to think that the mucilagi-nous Aloe gel, which is essentially a polysaccharide, holds the 775secret of the medicinal properties of the A. vera (Eshun and He,2004).

It is practically impossible to prevent the contamination of theA. vera gel by the chemical compounds present in the exudateof the leaves during its commercial extraction. It is also believed 780that in intact leaves, the anthraquinones and their derivates candiffuse towards the interior of the gel from the sheath cell bundleof the epidermis. This possibility supports the conviction ofsome investigators who maintain that the healing agent passesfrom the rind towards the gel where it remains. In fact, in many 785cases the extract of the whole leaf is the one that possessestherapeutic activities and not only the gel (Suvitayavat et al.,2004).

Several mechanisms have been proposed to explain the heal-ing properties of Aloe. However, in accordance with Spoerke 790and Elkins (1980) and Meadows (1980), the action of Aloe issimply due to its moisturizing and emollient effects. The activ-ity of Aloe as a moisturizing agent is a popular concept whichhas been known for many years (Briggs, 1995; Danof, 1987;Fox, 1990; Marshall, 1990; McKeown, 1987; Meadows, 1980; 795



Natow, 1986; Watson, 1983). This moisturizing effect can ex-plain many of its beneficial effects. In the 1960s the apparenteffectiveness of Aloe pulp was already suggested possibly be-cause of its high water content of over 98%, which provideswater easily available for the damaged tissue without taking it800from the environment (Morton, 1961). This theory could explainthe instantaneous soothing effect that the Aloe has in burns, butit would not justify the long-term effects on health.

Some investigators affirmed, some decades ago, that the ef-fective compound for the cure of wounds is tannic acid (Freytag,8051954); however, this has not been confirmed to date. Other in-vestigators (Eshun and He, 2004) have also informed aboutthe anti-inflammatory effects of complex polysaccharides, gly-coproteins, and sulfated polysaccharides. According to someauthors (Yagi et al., 1985), the presence of lectin in the gel is810responsible for the therapeutic effect on burns. However, theexistence of diverse components in the Aloe gel might con-tribute to the healing of the burn (Robson et al., 1982). Theanaesthetic effect, the bactericidal action, and an antithrombox-ane effect could be participating in the cure of the burns. Davis815et al. (1994) demonstrated that the effectiveness of Aloe in thetreatment of wounds and the reduction of the inflammation isdue to the action of the mannose-6-phosphate, a major sugarpresent in Aloe gel, which is an activator of tissue growth. It hasbeen postulated that the β-sitosterol, present in Aloe gel, is a820potent angiogenic factor that stimulated the neovascularizationand the healing of wounds (Moon et al., 1999). A glycoproteinfraction is involved in the wound-healing effect of Aloe via cellproliferation and migration (Choi et al., 2001). A glycoprotein(Pg21-2b) isolated from a preparation of A. vera gel had pro-825moter activity of the cellular proliferation (Heggers et al., 1996;Yagi et al., 1997), and it would therefore be involved in healingwounds and burns. This is due to the fact that Aloe stimulatesthe production of cells through the activity of amino acids whichare the basis of new cell formation. It is also due to the ability830of these amino acids to stimulate the regeneration of the deepestlayers of the skin by the synthesis of enzymes (Eshun and He,2004).

The anti-inflammatory activity of Aloe gel is associated withthe inhibition of the cyclooxygenase activity, which prevents835the synthesis of prostaglandins that are fundamental chemicalmediators in inflammatory processes (Davis et al., 1984). Afzalet al. (1991) indicated the possible presence of cyclooxygenasein a homogenized A. vera leaf product. The inhibition of painproducing substances, such as thromboxane or bradykinin is840often attributed to Aloe gel. In fact, a decrease in the throm-boxane concentration has been described by topical applicationof Aloe gel (Robson et al., 1982), suggesting that a substance,not present in the gel, inhibited the arachidonic acid oxidation(Penneys, 1982). Yagi et al. (2003) have isolated a glycoprotein,845with a 58% protein content, that inhibits cyclooxygenase and re-duces thromboxane synthesis. These discoveries explain, at leastpartly, the healing effects of A. vera in wounds. Bradykinin isa chemical mediator in a variety of inflammatory disorders thatproduces pain through the stimulation of sensorial primary neu-850

rons, and it causes the secretion of diverse neuropeptides (Aver-beck and Reeh, 2001). The anti-bradykinase activity observedin fractions of A. barbadensis is caused by a termosensible pro-tein. Therefore, this sustains the hypothesis of the use of Aloeextracts in inflammatory states (Bautista-Perez et al., 2004). 855

The presence of salicylates is more speculative because oftheir involvement in aspirin type effects (Canigueral and Vila,1993; Klein and Penneys, 1988; Marshall, 1990; Robson et al.,1982; Shelton, 1991), although differences have been observedbetween natural salicylates and synthetic aspirin (Frumkin, 8601989). Lactate of magnesium, another simple substance con-stituent of the gel, inhibits histamine production by the inhibi-tion of histidin decarboxylase (Briggs, 1995; Danof, 1987; Fox,1990; Marshall, 1990; McKeown, 1987; Natow, 1986; Rubel,1983). Robson et al. (1982) found salicylate, lactate, and magne- 865sium in Aloe extracts, and suggested that, the anaesthetic activitycould be due to an aspirin type effect, the high content of theion magnesium, or possibly, to both components that act syner-gically. These authors also postulated that anthraquinone com-pounds, such as emodin and aloin could be hydrolyzed to sali- 870cylates by Kolbe’s reaction. Other authors (Hutter et al., 1996)found anti-inflammatory effects in the C-glucosyl chromonefrom Aloe barbadensis.

The elevation of blood glucose in diabetic mice intraperi-toneally given the aloe carboxypeptidase was restrained when 875compared to the control group (Beppu et al., 2006a). Therefore,the inhibitory effect on the enhancement of vascular perme-ability related to the vascular acute inflammatory response atstreptomycin-induced lesions of pancreatic islets was involvedin the action mechanism of the aloe carboxypeptidase enzyme 880(Beppu et al., 2006a). These authors (Beppu et al., 2006b) sug-gest that a fraction powder, derived from the leaf skin juice of A.arborescens Miller var. natalensis Berger, alleviates the burdenof insulin secretion as it has an inhibitory action on the glucoseabsorption in the jejunum of rats. 885

Although some anti-cancer activity has been demonstrated,it is not clear as to which compounds are responsible for them.The anti-cancer activity has been attributed to two Aloe frac-tions, glycoprotein (lectins) and polysaccharides. Besides, thehemoaglutination activity of the lectin type substances promote 890the growth of the normal cells and inhibit the growth of thetumor cells (Winters, 1991, 1993). The Aloctin A, isolated fromA. arborescens, inhibited the growth of induced fibrosarcomain rats by an immunological mechanism (Imanishi et al., 1981).The crude A. vera extract showed greater antitumor activity 895than the Aloctin I (Akev et al., 2007). Therefore, the syner-gistic effect of the phytochemicals present in A. vera may beresponsible for this cancer preventive activity. The Aloemannanisolated from A. arborescens, inhibited the growth of a sarcomaimplanted in mice (Yagi et al., 1977), and another polysaccha- 900ride fraction obtained from A. vahombe, reduced the growth ofa fibrosarcoma in mice, perhaps by the stimulation of phago-cyte activity (Ralamboranto et al., 1982). Polysaccharides of A.barbadensis Miller also have antigenotoxic properties and areinhibitors of the promotion of tumors, and therefore, they have 905



been proposed as chemopreventive agents (Kim and Lee, 1997;Kim et al., 1999). The injection of Acemannan in mice inhib-ited the growth of implanted murine sarcoma and decreased themortality by around 40% (Merriam et al., 1996). Some fractionsof polysaccharides involved with cell proliferation and cancer910have recently been isolated. So, Veracylglucans A, B, and Chave anti-inflammatory effects, whereas Veracylglucans A andB possess anti-proliferative effects, Veracylglucan C enhancescell proliferation (Esua and Rauwald, 2006).

Anthraquinones, present in the leaves of Aloe and other veg-915etable products, are perhaps involved in carcinogenesis; how-ever, the scientific information is still not conclusive (Lee andPark, 2003). While there are investigators (Kim and Lee, 1997;Pecere et al., 2000; Sakai, 1989; Tsuda et al., 1993) that indicateantigenotoxic effects and apoptosis on diverse knitted organs or920tissues such as the stomach, colon, or liver, other authors (Leeet al., 1998; Mueller and Stopper, 1999; Schorkhuber et al.,1998; Strickland et al., 2000; Wolfle et al., 1990) pointed outthe promoter effects of tumors and the genotoxicity and angio-genic activity on the skin, colon, and liver. The application of925aloe-emodin, vehiculized in ethanol, on the skin of mice in com-bination with exposure to UV B (280–320 nm) radiation pro-duced a skin tumor containing melanin (Strickland et al., 2000).However, the aloe-emodin showed antileucemic activity in mice(Kupchan and Karim, 1976), and it had a selective anti-cancer930activity against neuroectodermal tumors (Pecere et al., 2000).Moreover, in agreement with some preclinical studies (Chenet al., 2007), the aloe-emodin is a suitable and novel chemother-apeutic drug candidate for the treatment of human gastric carci-noma. Besides, Aloin, due to its less undesirable side effects and935antimetastatic potential compared to other currently used ther-apeutic treatments, has been proposed as the agent of choicefor the treatment of human cervical carcinoma (Niciforovicet al., 2007). In contrast, the hydroxyanthraquinones with hy-droxyl groups in positions 1 and 8 may present tumor promoter940activities (Wolfle et al., 1990). The emodin acts by blockingand reducing the mutagenicity and DNA adducts induced by1-nitropyrene (Su et al., 1995). In mutagenecity assays withSalmonella typhimurium, a variety of compounds structurallyrelated with hydroxyanthraquinones presented mutagenic ef-945fects (Westendorf et al., 1990). It has been suggested that theinhibition of the enzymatic activity of an enzyme, denomi-nated topopisomerase II, contributes to the genotoxicity andmutagenecity induced by anthraquinones (Mueller and Stop-per, 1999). The cytochrome P450 responsible for the biotrans-950formation of anthraquinones, like the aloe-emodin, could beinvolved in the activation of these compounds (Mueller et al.,1998).

With respect to the action on the immune system, it ap-pears that the constituent polysaccharides have immunomodu-955lator properties, with an emphasis on the Acemannan in them(Agarwala, 1997; McAnalley, 1988; Schechter, 1994). On theone hand, the neutral polysaccharides, Aloemannan and Ace-mannan, have anti-tumor, anti-inflammatory, and inmunosu-pressive properties, while glycoprotein fractions with bradyki-960

nase activity and stimulants of the cellular proliferation, wereidentified in the nondialyzed fraction of the Aloe gel from sev-eral species (Yagi and Takeo, 2003). A wide variety of phar-macological properties are attributed to the Acemannan such asits antiviral effects (Leung, 1977), activation of macrophages, 965monocytes and antibodies (Marshall et al., 1993; Reynolds,1985; Zhang and Tizard, 1996), stimulation of the cells T(Urch, 1999) and tumor necrosis factor (Marshall et al., 1993),and induction in the production of nitric oxide (Lawless andAllan, 2000). The Acemannan acts as an external bridge be- 970tween unknown proteins, such as viruses or microorganisms,and macrophage particles, facilitating phagocytosis (Marshalland Druck, 1993). However, high concentrations of Aceman-nan are needed to get modest effects in the macrophage activa-tion. This suggests that Acemannan is not very potent or that 975there are other more potent components, in trace amounts ascontaminants, whose presence is high enough to produce theobserved effects. Aloeride, a high molecular weight polysac-charide, has shown a very potent immunostimulatory activityand it is present in trace amounts as a contaminant. Although 980Aloeride is comprised of only 0.015% of dry weight Aloe juice,its potency for macrophage activation fully explains the activityof the raw juice (Pugh et al., 2001). Im et al. (2005) have re-ported the immunomodulatory activity and the molecular size ofpolysaccharides isolated from Aloe. They deduced that the frac- 985tion of polysaccharides with molecular weights of between 400and 5 KDa, exhibited the most potent macrophage-activatingactivity as determined by the increase in cytokine productionrelease, nitric oxide production expression of surface moleculesand phagocytic activity. Besides, in agreement with “in vivo” 990and “in vitro” studies, these polysaccharides showed the highestanti-tumor activity.

Some chemical compounds have also been isolated fromthe extract of A. barbadensis with a similar immunomodula-tory activity to that of lectin (Qiu et al., 2000). The presence 995of two dihydrocoumarins with immunomodulatory and antiox-idant properties has also been reported (Zhang et al., 2006).Acemannan is a key compound that stimulates the immunitymediated by the cells, which is deficient in HIV infection (Mar-shall and Druck, 1993). A similar effect was observed with the 1000lectin (Imanishi and Suzuki, 1984). In a trial with advanced HIVpatients treated with Acemannan, no increase of the CD4 cellsor viral burden was found (Montaner et al., 1996).

Recently there has been a lot of interest in the biologi-cal effects of polysaccharides, which are bigger and more di- 1005verse than was originally thought. Some of these substancespresent in plants with variable chemical composition are wellknown entities, and on occasion the chemical structures are notwell-established (Franz, 1989; McAuliffe and Hindsgaul, 1997;Tizard et al., 1989). Antibacterial, antifungal, and antiviral activ- 1010ities of the gel have often been mentioned (Klein and Penneys,1988; Marshall, 1990; Shahnaz et al., 1993), while their an-tioxidant effects are of increasing interest (Ikeno et al., 1998,2002; Lee et al., 2000). Lee et al. (2000) have isolated andidentified a derivative chromone compound from methanolic 1015



extract of A. barbadensis Miller gel with a potent antioxidantactivity similar to the α-tocopherol. This compound was foundto be a chromone. Aloe vera antioxidant compounds have beenexamined against lipid peroxidation using mitochondrial andmicrosomal enzymes of rat livers. The relationship between1020the anti-inflammatory and antioxidant activities and the chem-ical structures of derivative compounds of the aloesin isolatedfrom Aloe species, such as the cinamil, p-coumaroyl, feruloyl,and caffeoyl aloesin has been studied. The isorabaichromoneshowed a potent antioxidant efficiency among the derivates of1025studied Aloesin (Yagi et al., 2002). These authors deduced thatthese activities could be associated with acyl groups. A gly-coprotein fraction with 14 KDa of molecular weight from A.vera gel was shown to have radical scavenger activity and in-hibited cyclooxygenase 2 and thromboxane A2 synthase (Yagi1030et al., 2003). Both glycoprotein fractions and aloesin-relatedcompounds play an important role in the anti-inflammatory ac-tivity of A. vera leaf gel (Yagi et al., 2002; Yagi and Takeo,2003).

It is a well-known fact that the consumption of constituent1035polysaccharides of the fraction of soluble fiber modulates the in-testinal absorption of glucose, besides reducing cholesterolemia.Therefore, the indicated antidiabetic effects of Aloe maybe dueto the components of soluble polysaccharides present in thegel. The role of certain minerals present in the A. vera gel has1040also been studied in biochemical alterations related to diabetesin rats. The results clearly indicate that the presence of sev-eral trace elements in the gel contribute to their hypoglycemicactivity (Rajasekaran et al., 2005).

TOXICOLOGICAL ACTIVITIES1045

The wide and extensive use of the plants as medicines hasbeen growing, mainly due to a certain dissatisfaction of the gen-eral population with the results of traditional medicine. How-ever, on many occasions this use of medicinal plants is not as safeas commonly thought (Rodrıguez-Fragoso et al., 2008). Most1050Aloes are not toxic but a few are extremely poisonous (Atherton,1998). Therefore, it can be dangerous to use medicinal plantswithout evaluating their possible adverse effects (Capasso et al.,2000).

A controlled toxicological evaluation of the administration1055of Acemannan administered by injection to mice, rats, and dogswas carried out without finding adverse effects. Hematologyand serum chemistry determinations and urinalyses conductedat 1, 3, and 6 months all showed values within the normalrange. After necropsy examinations, organ weights and gross1060and microscopic pathology from the treated rats were similar tocorresponding controls. However, an increase in the number ofleukocytes in the circulation was found which is probably due tothe stimulation of the immune system. There was also infiltra-tion of macrophages in the liver, lungs, and spleen (Fogleman et1065al., 1992), which is in agreement with that indicated by Zhangand Tizard (1996), who reported that Acemannan stimulates

the production of macrophages. A study of the ingestion of adiet containing 1% Aloe gel in rats did not adversely affectgrowth or have any pathological effects (Herlihy et al., 1998). 1070It was also observed that the Aloe gel did not have hepatotoxiceffects, but rather it was hepatoprotective (Kar et al., 2002).Other authors (Yeh et al., 2003) have pointed out that the prod-ucts prepared from Aloe gel seem quite safe. Life-long A. veraingestion did not cause any obvious harmful and deleterious 1075side effects in male Fisher 344 rats (Ikeno et al., 2002). Severalpolysaccharides isolated from A. vera gel were nontoxic and ex-hibited an anti-tumor activity in a murine model (Leung et al.,2004).

Some authors (Briggs, 1995; Ernst, 2000; Klein and Penneys, 10801988) have warned about possible allergic side effects. Someisolated cases have been observed. A single case of the ap-pearance of an eczema after topical and internal applicationof A. vera gel was followed by another in a hypertensive pa-tient treated with A. arborescens gel (Shoji, 1982). On the other 1085hand, a study on 20 human subjects treated with Aloe gel andexposed to UV radiation showed a persistent pigmentation ofthe skin (Dominguez-Soto, 1992). The effect of allergic der-matitis was described again in patients that used Aloe gel forthe treatment of chronic leg ulcers (Hogan, 1988). Other au- 1090thors (Zawahry et al., 1973) confirmed that Aloe gel was ofinterest for the treatment of this chronic lesion, although localpain was observed in the beginning, which was attributed tothe improvement in circulation. In a study on burns, Aloe gelcould also worsen to some extent the cure of the wound by not 1095fulfilling all the healing requirements (Kaufman et al., 1988).In clinical studies (Fulton, 1990), the multiple factors involvedin the healing of wounds were studied. The zones tried withAloe healed more rapidly and completely than the untreatedzones, although burning sensations were perceived at times. A 1100severe burning sensation was also observed followed by long-term erythema in a case of local application of Aloe (Hunter andFrumkin, 1991).

The Food and Drug Administration (FDA) Special Nutri-tional Adverse Event Monitoring System listed 30 matches for 1105Aloe in 27 adverse event reports. In 7 matches of 30 events,the only ingredient listed was A. vera. Adverse events reportedincluded stomach problems—nausea, dizziness, and tiredness;buzzing and tingling in ears, pressure in head, dizziness, in-creased blood pressure, panic attacks, teeth chattering, insom- 1110nia, inability to concentrate, and memory problems; parox-ysmal atrial fibrillation with rapid ventricular response withsymptomatic light-headedness and palpitations; red, itchy rash;shakiness, no strength, dizzy spells, aseptic meningitis, andstroke. 1115

There are several single-case reports on toxicity in hu-mans, but there are no published controlled toxicology studies(Steemkamp and Stewart, 2007). Two cases of possible oralA. vera induced hepatitis have recently been reported (Rabe etal., 2005; Bottenberg et al., 2007). One patient experienced mas- 1120sive intraoperative bleeding after consumption of A. vera tablets,which could have been due to a herb-drug interaction between



Aloe and sevoflurane (Lee et al., 2004). Luyckx (2002) reporteda patient with acute renal failure following Aloe ingestion whereno other cause was found. A case of severe vomiting after Aloe1125ingestion was reported by Wang et al. (2003). On the other handthe additional decrease of the blood glucose levels caused by theA. vera gel apart from that due to the antidiabetic drugs (Bushet al., 2007), could increase the risk of hypoglycemia. Overuseof Aloe, along with cardiac glycoside drugs, can increase the1130risk of toxicity and might potentiate diuretic-induced potassiumdepletion, increasing the risk of hypokalemia (De Smet, 2002;Shaw et al., 1997). Besides, there is some concern based onanecdotal reports that Aloe exudates might induce abortion andstimulate menstruation (Federici et al., 2005; Bush et al., 2007).1135

A factor that could be decisive regarding the toxicity of theseproducts is the presence of phenolic substances of the exudate,particularly the anthrone C-glycosides, in the gel-like contam-inants. This contamination by anthraquinone derivatives mayhave played a role in the adverse events such as laxative effects1140reported in A.vera gel (Ishii et al., 1990; De Smet, 2004). Aloe-emodin has been extensively studied for apoptosis-inducing ef-fects. Treatment with aloin induces apoptosis in Jurkat cells,which are an established model for apoptosis inducing effects(Buenz, 2008). It has been demonstrated that aloin, besides its1145purgative effects, can have carcinogenic properties due to itsdeleterious action on the cellular DNA when certain intake lev-els are reached (Lee et al., 1998; Mueller and Stopper, 1999;Schorkhuber et al., 1998; Strickland et al., 2000; Wolfle et al.,1990). Aloe supplements not containing aloin may be safer than1150Aloe supplements containing aloin, and the aloin should be con-sidered in addition to concentrations of Aloe-emodin (Buenz,2008). It has been demonstrated that the yellow leaf exudateskilled fibroblasts in cell cultures, while the clear gel stimulatedcell growth (Danof, 1987). Again the duality arises between1155the colorized and decolorized gels (Davis et al., 1986), the for-mer having a much lower healing capacity. The decolorized gelreduced the wound swelling caused by infiltration of polymor-phonuclear leukocytes to a greater extent than the colorized gel(Davis et al., 1986). This colorized gel also reduced the diameter1160of the wound more quickly (Davis et al., 1987).

Studies comparing a “commercial stabilized” gel with freshgel of the plant previously dialysed to separate the componentsof low molecular weight were carried out. Cytotoxic effectswere observed in the sample of commercial gel, which is asso-1165ciated with substances introduced during processing (Winterset al., 1981). Some commercial samples that contained yellowsaponins had cytotoxic effects in fibroblast cell cultures (Danofand McAnalley, 1983). Later studies carried out on fractions oflow molecular weight (<10 KDa) of whole leaves of A. vera,1170have shown that these have a disruptive effect on monolayercell cultures and they inhibit neutrophils from the liberation ofreactive species of oxygen (Avila et al., 1997). Aloe-emodinand aloin had similar effects. For these reasons aloin has beenincluded in a list of twelve compounds that, due to its pharmaco-1175logical activity, the European Union has set a maximum allowedconcentration in alimentary products (European Council, 1988).

QUALITY CONTROL AND LEGAL ASPECTS

The legal status and the practical use of traditional herbalmedicines vary significantly from one country to another, 1180thereby complicating the free circulation of such products withinthe European Union. Adequate information is needed by theconsumers, including a clear distinction between the medic-inal and the non-medicinal use of some herbal products andpreparations (Silano et al., 2004). By July 2007, the European 1185Commission presented a report on the advisability of incorpo-rating additional categories of substances into the existing legalprovisions allowing the use of herbal substances and prepara-tions in medicines as well as in food supplements (Committeeof Herbal Medicinal Products, 2007). In this report the concen- 1190trated and dried juice of the leaves were evaluated. It was con-cluded that in view of existing possible risks, such traditionaluse cannot be recommended and referred to in the “Commu-nity list of herbal substances, preparations, and combinationsthereof for use of traditional herbal medicinal products.” This is 1195in accordance with the German pharmacovigilance actions foranthranoid-containing laxatives (Committee of Herbal Medici-nal Products, 2007). Aloe vera is one of the natural commercialproduct derivates of plants that has grown most in popularityand interest in the last few years. In 2003 alone, it was one of 1200the ingredients most frequently used (1557 new products) inthe preparation of new foods, cosmetics, and pharmacologicalproducts (Hale, 2003).

The Aloe gel is expensive, therefore it is not surprising thatsome producers try to increase their business profits by adding 1205water to the Aloe components (Cordella et al., 2002; Diehl andTeichmuller, 1998). A lot of confusion exists about the effec-tiveness of the large variety of Aloe products on the market.Consumers often wonder “what is the best Aloe vera?” Un-fortunately, there is no easy way to distinguish an adulterated 1210product from an unadulterated one. Although price can be aguide, the most expensive Aloe is not always the best. In con-clusion, the way the consumer judges the Aloe is usually basedon its empirical results. If there is no improvement in the pathol-ogy for which it is used, the consumer changes brand and tries 1215again.

Several factors including the harvest of the leaves, theirpreservation and distribution, can cause Aloe to be of a lowerquality thereby reducing its beneficial effects. Many of the in-consistencies of the clinical results in the evaluation of its ther- 1220apeutic effectiveness are because of how the gel was treatedfrom when the leaf was cut to the final product, or even the con-ditions of growth of the plant (Yaron, 1993). After collectingthe fresh leaves which must then be used immediately in theproduction process, or they should be appropriately frozen to 1225prevent the loss of their biological properties which can occuras a result of the oxidation and hydrolysis of the gel (Coats,1979). It is important to separate the gel from the outer cortexperfectly. The addition of celullase can facilitate the mechanicalseparation. After the aloe liquid obtained is treated with acti- 1230vated carbon to remove aloin and anthraquinones, which have



laxative effects (Cobble, 1975). The therapeutic value of AloeQ7

diminishes a lot if the sterilization procedure is based on theapplication of a high temperature for long periods of time. If theheating of the product is increased, the elimination of bacteria1235is favored, but the mucopolysaccharides and other active com-pounds of the Aloe are partially destroyed, and consequently,decreases its effectiveness (Lawless and Allan, 2000). In thecold-processing technique, the use of enzymes such as glucoseoxidase or catalase has been proposed to inhibit the growth of1240aerobic microorganisms (Coats, 1994). Besides, exposing gelto UV irradiation followed by ultra-filtration was reported as away of sterilizing Aloe gel (Coats, 1994). The stabilization ofthe gel can be achieved using preservatives and other additiveslike sodium benzoate, potassium sorbate, citric acid, vitamins C1245or E (Cerqueira et al., 1999).

Management quality (ISO9000:2000) and safety (systemsHACCP; hazardous analysis and critic control points) systemshave been developed by the food industry to ensure biologicalintegrity, sensorial stability, and the quality of the final product1250prepared from the Aloe gel (He et al., 2005). It was revealedthat the safety control points were the addition of vitamin C andcitric acid, and pasteurization; while the quality control pointswere the reception of raw materials, filleting operation, grind-ing or homogenization, pectolytic enzymes addition, filtration,1255addition of vitamin C and citric acid, deaeration, pasteurization,flash cooling, and storage (He et al., 2005).

Therefore, with a market of dietary supplements saturated bya large variety of Aloe products, methods to distinguish qualityproducts from altered or fraudulent products are needed as much1260by consumers as by industry. However, it is difficult to establishreference methods to determine the different compounds dueto the complexity and variability of the derivative componentsof the plants (Blumenthal and Milot, 2004; Reif et al., 2004).At present, simple, reproducible, and economic techniques to1265determine the content of A. vera in commercial products are notsuitable (Eberendu, 2004). To carry out an exhaustive qualitycontrol of commercial food products containing A. vera, thefollowing analyses should be carried out (Lachenmeier et al.,2005):1) Investigation of the authenticity; 2) Test for identifica-1270tion of inadmissible preservatives; and 3) Determination of thealoin content.

Investigation of the Authenticity

According to some investigations, there is a high number ofcommercial products stating a certain quantity of A. vera gel1275on the label that was found to be lower in the actual product(De Smet, 2004; Diehl and Teichmuller, 1998; Pelley et al.,1998). Of the many Aloe-based products on the market, fewcontain more Aloe than is claimed on the labels; others havelesser amounts of Aloe than claimed on the labels; and some1280contain no Aloe at all. To make sure that one is buying a productcontaining Aloe and paying a reasonable price, it is importantto identify and quantify the Aloe gel used in the preparation

of the commercial product, as well as to recognize possibleadulterations or dilutions. Therefore, on the label it is advisable 1285to see the logotype of the International Aloe Science Council(IASC), a nonprofit making international organization, whoseaim is to improve and to standardize the Aloe industry.

Adulteration is a major concern for the A. vera market, mainlybecause of the high cost of the raw materials. Aloe can also be 1290found in some of the most adulterated new products. Its dilutionwith cheaper substitutes is the most common form of adulter-ation (Cordella et al., 2002). Historically, the most commonsubstance used to adulterate Aloe gel powder is maltodextrin(Kim et al., 1998). Glucose, glycerine, and malic acid have 1295also been reported (Pelley, 1992; Pelley et al., 1993). Therehave been several attempts at establishing methods to determineadulteration in A. vera commercial products. Many methodshave been developed to detect adulteration and establish the au-thenticity of Aloe gel powders. L-malic acid and some phenolic 1300compounds (aloesin, aloin A, and aloe-emodin) have been pro-posed as markers (Kim et al., 1998; Pelley, 1992; and Pelleyet al., 1993), although their concentrations in Aloe gel powderscan vary significantly (due to normal biological variability) anddepend on the manufacturing process. Carbohydrate analysis 1305has also been considered. However, in this case only adulter-ation with sugars (i.e. glucose, sucrose) or polysaccharides (i.e.maltodextrin) could be revealed (Kim et al., 1998).

The identity, purity, and the quality of Aloe vera can bedetermined using a proton nuclear magnetic resonance spec- 1310troscopy method, HPLC or other traditional wet chemistry meth-ods (IASC, 2004). Identification is based upon polysaccharideswhich possess the 2,3,6 acetylation pattern that is unique toAloe. Quality is measured by the profile of organic acids someof which are native (malic acid) to Aloe, while others (lac- 1315tate, succinate, fumarate, formate, and acetate acids) indicatepossible microbial contamination. Purity is determined by theabsence of foreign materials.

Marker compounds, biologically active or not, must defini-tively be proposed for establishing the amount of Aloe gel that 1320a determined product contains (Blumenthal and Milot, 2004).Diverse markers have also been proposed for the quality recog-nition of different botanical materials or for the recognition ofpossible adulterants. One of the main problems in the devel-opment of valid methods for Aloe products is the absence of 1325standardized and safe reference material, as well as methods forevaluating bioactivity to perform a quality analysis (Luta andMcAnalley, 2005; Reif et al., 2004). The IASC is in the processof formulating a reference standard for Aloe gel to be used forthe emission of certifications concerning whether certain prod- 1330uct contains Aloe in the quantities stated on the label, and alsowhether this product is well preserved. These standards musthave contents of parameters such as total solids, Ca, Mg, malicacid, and polysaccharides to be able to evaluate the presence ofAloe gel (IASC, 2004; Luta and McAnalley, 2005). The produc- 1335tion, validation, preservation, and distribution of these chemicalcompounds of reference or botanical reference standards forquality control in herbal preparations is, on many occasions,



very laborious and expensive (Flaster and Lassiter, 2004; Reifet al., 2004).1340

Ross et al. (1997) determined the mucilage content of A.vera in commercial products by means of exclusion chromatog-raphy. These authors applied it to 18 commercial samples ofAloe, observing very variable contents. In half of the sam-ples, the contents ranged between 0.22 and 1.30 mg/ml, and1345the mucilage was not detected in two of them. Another methodof discovering whether an Aloe commercial product is of ap-propriate Aloe quality and quantity, is to know the number ofmucopolysacharides. This is sometimes included on the label.The highest therapeutic value is in the products containing be-1350tween 10,000 and 20,000 mucopolysacharides per litre (Lawlessand Allan, 2000). Nine powdered concentrates of A. vera gel,obtained from leading international suppliers, were examinedand compared with fresh A. vera gel (Bozzi et al., 2007). Thequality of commercial A. vera gel powder samples analyzed by1355NMR was found to be very inconsistent, and in some cases verypoor. Only three products out of the nine analyzed containedsatisfactory amounts of Acemannan.

Several methods have been developed and they could be con-sidered as a part of a certification process. A quick and simple1360colorimetric method based on proving the absence of Aceman-nan (Garifallidi et al., 2004) was proposed. Acemannan is theonly polysaccharide in A. vera gel that causes a displacementof the absorbance of the Congo red due to the formation of acomplex. Kim et al. (1998) also developed a simple and accu-1365rate method to detect the adulteration of commercial Aloe gelpowder. This method is based on the determination of ash con-tents and constituent sugars of polysaccharide fractions usinggas chromatography. The maltodextrin content in adulteratedproducts was determined by HPLC and thin layer chromatog-1370raphy (Kim et al., 1998). The determination of the total ioncontents in a commercial Aloe product could be an indicator ofthe purity (Pelley et al., 1998). However, these authors empha-sized that the most practical form of differentiating authenticAloe from the adulterated or the fraudulent ones is based on the1375use of many more parameters than in the determination of onlyone marker substance. Therefore, Saccu et al. (2001) have pro-posed the determination of volatile compounds for GC-MS andphenolic compounds for HPLC as a useful analytical tool foridentifying the origin and type of Aloe used in the elaboration1380of the commercial product.

Test for Identification of Inadmissible Preservatives

Commercial products available worldwide often contain sta-bilizers and preservatives since some components are subject tooxidation. It is important to demonstrate the presence of inad-1385missible preservatives in commercial products containing Aloe.Many Aloe products are preserved by sorbic acid addition orbenzoic acid over 1000 mg/l. As the preservation of Aloe juiceis prohibited in the European Union (European Parliament andEuropean Council Directive, 1995), some producers add ascor-1390bic acid to their products and they describe their juices of Aloe

as “dietary supplements.” This is done to avoid the applicationof the previous European directives, since dietary supplementscan contain preservatives. It is necessary to point out that Aloejuices do not contain concentrated nutrients or other ingredi- 1395ents of dietary value and with the addition of ascorbic acid thejuices of Aloe do not qualify as dietary supplements. In thisway, all the vegetable juices could have added vitamins, andthen be described as dietary liquid supplements. Therefore theaddition of preservatives above 2000 mg/l to vegetable juices 1400would evade the current law on preservatives. The qualificationof A. vera juices or gels enriched with vitamin C as dietarysupplements is therefore inadmissible. In a study performed oncommercial drinks containing A. vera, it was proven that therewas a considerable number of samples containing inadmissible 1405preservatives, which suggests that the controls in relation to thepreservatives used should be intensified to assure the quality ofthe products (Lachenmeier et al., 2005).

Determination of the Aloin Content

Aloe vera gel should not contain aloin or other hydroxyan- 1410thracene derivatives, as they are exclusively concentrated in theleaf skin. However, the mechanical separation process is notalways complete, so some Aloe exudate can be found in the gel.The LOAEL (lower observed adverse effect level) for aloin isestimated at 11.8 g/Kg body weight (Zhou et al., 2003). Aloe 1415supplements not containing aloin may be safer than Aloe sup-plements containing aloin, and the aloin should be considered inaddition to concentrations of aloe-emodin (Buenz, 2008). There-fore, A. vera food products for human consumption must be freeof aloin, with an existing maximum threshold of 0.1 mg/l (Euro- 1420pean Council, 1988). There are standardized methods availablefor the detection and determination of aloin in samples con-taining Aloe (Lachenmeier et al., 2005; Yamamoto et al., 1985;Zonta et al., 1995). A capillary zone electrophoresis method forthe determination of the active Aloin and Aloe-emodin compo- 1425nents in A. vera has been developed to find a simple and low-costmethod to control the quality of the herb (Wang et al., 2000).Lachenmeier et al. (2005) concluded that only one of the 24 an-alyzed samples contained aloin in an amount above the admittedmaximum value, concluding that the producers have improved 1430not only their production methods, but also their quality andsafety. In another paper (Bozzi et al., 2007), the Aloin A andB was determined in commercial A. vera powders and variableconcentrations were found from trace levels to 16 mg/Kg. How-ever, these concentrates are generally added to food products or 1435beverages at the maximum level of 0.1%. Therefore, the aloinconcentration is far below the regulatory limit for all the samplesanalysed.

CONCLUDING REMARKS

Only four species of the over 360 known species have been 1440studied in relation to their therapeutic properties. There are two



products extracted from the Aloe leaf—yellow exudate, richin anthraquinones—which is used as a laxative, and gel thathas traditionally been used as a remedy for a great number ofdisorders and ailments. The heterogeneous nature of the Aloe1445products as well as their variable chemical composition, oftencause confusion on their therapeutic and toxicologic activities.

Most of the Aloe vera gel is water, representing ≈99%, so thecontribution to the macronutrient intake is low. The dry extractof the gel is mainly composed of carbohydrates, emphasizing1450the lineal polymers of mannose with random substitutions ofglucose, other monosaccharides, and uronic acids. These solu-ble polysaccharides have ß-1,4 linkages and a variable degreeacylation. Although, the content of nitrogen is low, the presenceof glycoproteins, enzymes, free aminoacids, and peptides can1455contribute to the functional properties. There is a wide varietyof nutrient and no nutrient compounds in low concentrationssuch as vitamins, minerals, phenolics, and orgacic acids. Manyfactors influence the chemical composition, and therefore theefficacy of Aloe gel, such as species/subspecies or varieties,1460climate and exposure to light, land, irrigation, and cultivationmethods.

Current scientific investigation is producing evidence aboutits multiple beneficial effects at a topical level, but apart fromthis, in vitro and in vivo tests have demonstrated diverse ther-1465apeutic effects after oral consumption. Hypoglycemic effect,treatment of peptic ulcers, and gastrointestinal dysfunctions,immunologic, antioxidant, and anti-cancer effects have been at-tributed to the oral use of Aloe vera gel repeatedly. There area number of discrepancies about its therapeutic properties, and1470clinical studies have not always found it to be effective. Thus,it is important to conduct wider, more rigorous, and conclusiveclinical studies to confirm or discover some of its biologicaland therapeutic properties; and to clarify which component orcomponents, acting alone or together, are responsible for the1475different therapeutic effects. Although, some single-case stud-ies have warned about some possible toxicologic and allergicside effects, in agreement with existing data, Aloe gel is rea-sonably safe, without serious toxicological risks. However, it isnecessary to control the content of phenolic compounds.1480

The control of the biologically active principles of Aloe geland their preservation is complex and is still not resolved. Manycommercial products may have partially lost these active prin-ciples, and as a consequence, their biological effects. Thus, itis essential to have suitable, simple, and sufficiently contrasted1485methods as well as adequate reference material, to issue thecorresponding quality certificates. The quality control shouldbe guided towards three fundamental objectives—the establish-ment of the authenticity, recognition of fraudulent management,and aloin content control.1490

ACKNOWLEDGEMENTS

This work was carried out within the programs researchdeveloped by the Food Quality Canary Institute. The authors

gratefully acknowledge the help of Dr. Rodolfo Rios Rull forthe assistance in the preparation of the manuscript. Besides, the 1495authors acknowledge the help of Patrick Dennis for improvingthe English in this paper.

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Aloe Vera Alimento Funcional 2011