Bioactive constituents of the genus Aloe and their potential therapeutic and pharmacological applications: A review

The therapeutic and pharmacological properties of plant bioactive constituents still continue to be the subject of many researches. Species of the Aloe genus have a history in folklore medicine and they have gained more attention over the years due to their various medicinal properties. Phytochemical studies have revealed that the Aloe species contain a number of constituents, such as polyphenols, phytosterols, polysaccharides, proteins, amino acids, chromones, and mineral elements. A comprehensive evidence-based review on the different constituents of Aloe species is needed in order to understand the benefits imparted by them. This review presents an overview of the bioactive components of the Aloe genus with emphasis on their anti-diabetic potential and other pharmacological benefits. This information will be beneficial for the advancement of new strategies of Aloe formulations with therapeutic and economical value in the near future. Furthermore, the potential applications and constraints have also been discussed so as to provide a wider prospect for research in this field for the benefit of the society.


INTRODUCTION
Efforts are being undertaken over the last few decades to develop efficient therapies for diseases such as diabetes, cancer, arthritis, cardiovascular diseases, etc. The medications available for treatment are costly and are associated with some side effects. Hence, it is prudent to search for options in herbal medicine. Herbal medicine or phytomedicine has been the oldest form of healthcare known to mankind. It is based on the usage of plant products as medication and it has been associated with different traditional medicine systems spread across the geo-cultural spheres in the world (David et al., 2015). The natural products have been used to isolate active constituents and some of these active leads have also been taken up for clinical trials (David et al., 2015;Fabricant and Farnsworth, 2001). Hence, in the past decade, there has been a resurgence of interest in the investigation of natural resources as a source of potential drug substance.
The Aloe species has been used for centuries for its health, beauty, medicinal, and skin care properties. Aloe barbadensis Miller commonly called as Aloe vera belongs to the family Liliaceae and is a cactus-like plant (Ahlawat and Khatkar, 2011). Aloes are perennial succulents or xerophytes which are around 60-100 cm tall; as such, they are adaptable to habitats with low or erratic water availability and are characterized by the capacity to store large volumes of water in their tissue. Aloes have in common green fleshy leaves covered by a thick cuticle or rind and an inner clear pulp. The concentration of Aloe latex in the rind depends on the leaf part, age, position of the leaf on the plant, leaf orientation, and season of collection. The latex in the plant is used as defense strategy to deter it from being consumed. The gel consists of about 99.5% water and the remaining 0.5-1% is solid material (Eshun and He, 2004). The dry weight solid material consists of a range of compounds, including water-soluble and fatsoluble vitamins, minerals, enzymes, mono (Femenia et al., 1999) and polysaccharides, lignin, proteins, polypeptides, phenolic compounds, and organic acids (Boudreau and Beland, 2006;Hamman, 2008).
The genus Aloe contains over 400 different species, among which A. barbadensis Miller (A. vera) is widely used compared to other species, like Aloe arborescens Mill, Aloe ferox Mill, for their therapeutic properties (Radha and Laxmipriya, 2015). The Aloe preparations have been used to treat frostbite, burns, radiation dermatitis, ulcers, psoriasis, wounds, skin infections, cancer, arthritis, and diabetes (Boudreau and Beland, 2006).
The phytochemistry of A. vera gel has reported the presence of more than 200 bioactive chemicals. The main constituents are monosaccharide, polysaccharides, amino acids, enzymes, chromones, anthraquinones (aloin and emodin), lignins, minerals, vitamins, salicylic acid, saponins, and sterols. The biological activities of several Aloe species have been reviewed by Reynolds and Dweck (1999) and their relationship between the components and biological effects have been reported by Choi and Chung (2003). Since then, further pharmacological activities of the components of A. vera have been reported. This review aims to provide updated information on bioactive components, their pharmacological properties, recent advances, and side effects of species of the genus Aloe.

METHOD
This review was prepared with the help of articles collected using databases such as Google Scholar, PubMed, Science Direct, and other peer reviewed journals. The Plant List (www.theplantlist.org), The International Plant Name Index (www.ipni.org), and Tropicos ® (www.tropicos.org) were used for understanding the differences between the species from Aloe genus. ChemDraw Ultra 12 was used for drawing of the structures.

ETHNOMEDICAL USES OF THE GENUS ALOE
As mentioned earlier, the Aloe species are succulent, stem less xerophytes. The leaves are succulent and are usually greenish or greyish green in color. The flowers usually bloom in the months of October and January (Manvitha and Bidya, 2014). The flower grows around 90 cm, often being pendulous and consists of yellow tubular corolla around 2-3 cm (Babu et al., 2019). The Aloe plants are mostly used as decorative plants and are widely used in cosmetic industries. However, the Aloe species have a broad range of medicinal properties. Mostly, the gel portion of the plant is used for the treatment of diseases and disorders (Reynolds and Dweck, 1999). Aloe barbadensis Miller, commonly referred to as A. vera, is the most commonly used species of Aloe, followed by Aloe arborenscens, A. ferox, and Aloe chinensis. These are the species which are present in abundance geographically and also have therapeutic potential. The Indian Ayurveda medicine system uses the epidermis part of the A. vera for its anti-helminthic property and digestive system problems (Sandeep and Yadav, 2014). The Mexicans use A. vera for the treatment of burns and skin problems. Other medicinal properties of A. vera include treatment for rheumatoid arthritis, diabetes, cancer, and as an immunomodulatory agent (Cock, 2015).
The traditional use of A. arborescens involves the use as a topical agent to treat wounds and burns (Mabona and Van Vuuren, 2013). The Japanese use this species for the treatment of intestinal ailments and also as an antiseptic agent. Apart from that, it is also used as an immunomodulatory and chemo-preventive agent and it also has anti-diabetic and anti-inflammatory properties. Aloe chinensis is used for its antioxidant and immunomodulatory potential (Wu et al., 2006).
Aloe ferox is predominantly found in the African region, and according to folklore, it was used as a laxative and antipurgative agent in the African medicine system. Scientific reports are available, which report the use of this species for treating wounds, psoriasis treatment, eczema, and melanoma. It has also been used for the treatment of infectious diseases such as syphilis and candida. The latest reports that have been published credit A. ferox for having anti-diabetic, anti-cancer, anti-microbial, and anti-inflammatory properties (Kambizi and Afolayan, 2008;Loots et al., 2011;Mwale and Masika, 2014).
Species native to the Arabian nations also have a history of therapeutic properties. Among these, Aloe perryi Baker has wider usage due to its medicinal properties. It has been used to treat skin and eye infections and intestinal disorders (Al-Fatimi et al., 2005). It is also used in treatment of malaria and has anti-bacterial property (Mothana et al., 2009). Other species belonging to this region are Aloe inermis, Aloe officinalis, and Aloe tomentosa, which have been known for their antioxidant and anti-microbial properties (Cock, 2015).
Apart from these species, other species of Aloe have narrow geographical distributions and in turn, their ethnopharmacological benefits are also less. These include Aloe africana (used as a laxative), Aloe marlothii (used to treat microbial infections and respiratory disorders), and Aloe variegata (used as a laxative). More than 400 species of Aloes have been reported and most of these species have some or other medicinal benefits. Most of the work has been carried out using A. barbadensis Miller, Aloe arborescenes, and A. ferox (Cock, 2015). Table 1 lists out some of the species of A. vera that have been studied for its beneficial properties, while Figure 1 shows some of the important species of the genus Aloe.

BIOACTIVE CONSTITUENTS PRESENT IN THE GENUS ALOE
The gel of A. vera consists of around 200 active constituents such as saccharides, polyphenols, flavonoids, glycoproteins, minerals, vitamins, anthraquinones, lipids, amino acids, and enzymes (Hamman, 2008). In this section, we discuss the components of the gel and the epidermis of A. vera with some important chemical structures (Fig. 2).

Saccharides
Saccharides form the major component of the Aloe gel. Acemannan and mannose-6-phosphate are major constituents of the carbohydrates. Acetylated mannan, also called as acemannan, is considered to be one of the important bioactive polysaccharides present in the Aloe gel, which has been known for its therapeutic properties such as anti-diabetic and immunomodulation. It is made up of mannosyl residues that have been acetylated at C-2 and C-3 positions and the C-6 position consists of a side chain, which is usually galactose (Femenia et al., 1999). Other polysaccharides such as arabinan, arabinorhamnogalactan, galactan, galactogalacturan, glucogalactomannan, galactoglucoarabinomannan, and glucuronic acid containing polysaccharides have been reported to exist in the A. vera inner leaf gel part (Ni et al., 2004). Aloeride contains glucose (37.2%), galactose (23.9%), mannose (19.5%), and arabinose (10.3%). It is reported to have a molecular weight between 4 and 7 Million Dalton (Pugh et al., 2001). The saccharides are known to

Polyphenols
The polyphenols are known to exert their effect through their antioxidant properties. Apart from that, polyphenols from Aloe species have been reported to possess anti-diabetic potential, anti-inflammatory properties, and wound healing properties (Babu et al., 2019).
Coumarins, a class of polyphenols, are mostly found in the leaf of Aloe species and these are known to contribute to the bitter taste of Aloes. Feralolide is a coumarin which has been reported to be present in A. ferox (Speranza et al., 1993), while dihydroisocumarin is present in Aloe hildebrandtii (Veitch et al., 1994), which is known to stimulate the macrophages for fluid reabsorption in edema patients (Casley-Smith et al., 1993).

Flavonoids
The flavonoids that are present in the Aloe gel with antioxidant properties include naringenin, apigenin, myrcetin, quercitine, and cinnamic acid (Dagne et al., 2000), and are known to have inhibitory activity on platelets (Fuhrman and Aviram, 2001).

Sterols
Sterols are present in the leaf as well as the gel portion of the plant. Some of the important sterols which are known to be present in Aloe species are campesterol, β-sitosterol, lophenol, cycloaretonol, and lupeol (Dagne et al., 2000). These are said to have cell proliferative activities of endothelial cells. They are also reported to have a role in angiogenesis and hence are used in would healing process (Awad et al., 2007;Reynolds and Dweck, 1999).

Anthraquinones
Anthraquinones are usually present in the epidermis of the plant. Some of the anthraquinones present in the lead part are Aloin, Aloe emodin, aloesaponarin, chrysophanol, and isoxanthorin (Reynolds and Dweck, 1999). The concentration of aloin and Aloe emodin determines the antioxidant property. It is interesting to note that emodin acts as an antioxidant at high concentrations and at lower concentrations it acts as a prooxidant (Cock, 2015). Whereas aloin not only acts as a prooxidant at higher and lower levels, but it also acts as an antioxidant agent (Tian and Hua, 2005).

Anthrones
Anthrones are another set of compounds which are usually found in the leaf epidermis of the plant. These are the compounds which usually have purgative effects and are hence used as laxatives. Barbaloin is one of the first anthrones to be isolated from A. vera. Aloe ferox leaves are also reported to have higher amounts of anthrone (around 30%) (van Wyk et al., 1995). From Aloe marlotthi, anthrones such as homonataloin and nataloin have been extracted (Dagne et al., 2000). The anthrones are also known to have strong antioxidant properties. Yen et al. (2000) have suggested that the structures of anthrones determine their electrophilic nature and this enables them to have antioxidant potential. As mentioned earlier, the concentration of anthraquinones determines whether they can act as an antioxidant or a prooxidant.

Chromones
Chromones are mostly present in the leaf of the plant. Aloesin and Aloesinol are said to have anti-diabetic properties (Lee et al., 1997;Yimam et al., 2014). There are a number of isomeric forms of chromones present in the plant. These include aloeresin E, Aloerosin A, and Aloeresin F. Some of the chromones are present in a methylated form or are glycosylated at different positions (Dagne et al., 2000). These are usually said to possess antioxidant properties (Gomes et al., 2009); however, the levels of chromones would determine whether they would act as prooxidant or antioxidant agents (Maurya and Devasagayam, 2010).

Proteins/glycoproteins
In comparison to other constituents present in A. vera, not much has been reported on proteins or glycoproteins, although there have been literature reports which indicate the presence of amino acids in A. vera gel (Cock, 2015). Some lectins have also been isolated from A. vera. Most of the glycoproteins from A. vera are said to possess wound healing properties. Glycoproteins of different masses, such as 29KD, 5.5KD, 10KD, and 14KD, have been isolated from A. vera and their therapeutic potential, including anti-inflammatory, anti-diabetic, and immunomodulation, has been studied (Das et al., 2011;Siritapetawee et al., 2013;Yagi et al., 2009).

MINERAL ELEMENTS AND OTHER CONSTITUENTS
Trace mineral elements, such as magnesium, zinc, copper, manganese, potassium, sodium, and iron, have been reported and have been studied for their therapeutic properties (Rajasekaran et al., 2005). Aloe vera also contains alkaloids, benzene derivatives, and furan derivatives (Cock, 2015).
These are some of the bioactive components which are present in the A. vera plants. It can be inferred that bioactive components such as saccharides, glycoproteins, polyphenols, sterols, and mineral elements are present in the gel. The leaf or the epidermis part usually consists of a large amount of anthraquinones, anthrones, and chromones. The therapeutic potential of A. vera depends not only on the amount of constituents present in the plant but also on the ratio of these chemicals and their nature. The interaction of these constituents with one others may also affect the medicinal benefit imparted by this plant. It is observed that even though more than 400 species are present in Aloe genus, most of the constituents (sterols, polyphenols, saccharides, proteins, glycoproteins, and minerals) have been reported either from A. vera, A. ferox, or A. arborescens. The therapeutic potential of these bioactive constituents, such as antidiabetic, anti-oxidant, anti-inflammatory, anti-cancer, wound healing, and immunomodulation, have been discussed in the following sections with their pre-clinical/clinical studies and their possible mechanism of action.

Role of Aloe gel and its constituents in the alleviation of diabetes
Most of the studies have focused on the effect of the Aloe gel for their pharmacological actions. According to the reports, A. vera extract has shown not only to reduce blood sugar levels (Noor et al., 2008;Rajasekaran et al., 2004), but has also shown a protective effect on organs like pancreas, liver, and small intestine in streptozotocin-induced diabetic rats (Noor et al., 2008;Noor et al., 2017). Clinical trials have been reported wherein the patients were administered 100 g of A. vera gel with 20 g of Psyllium seed husks (Agarwal, 1985) and another clinical trial reported on the anti-hyperglycemic and anti-hypercholesterolemia effects on type 2 diabetic patients (Huseini et al., 2012) and lowering of blood glucose levels in diabetic patients when administered A. vera juice (Choudhary et al., 2014;Radha and Laxmipriya, 2015). The literature available on the active constituents of A. vera for its antidiabetic property has been summarized in Table 2.

Anti-hyperglycemic effect of Aloe polyphenols
The polyphenols are known to exert their effect through their antioxidant properties (Pandey and Rizvi, 2009). A polyphenol-rich A. vera extract (350 mg/kg) containing 181.7mg/g aloin and 3.6mg/g Aloe emodin when administered for a period of 4 weeks to insulin-resistant mice showed a decrease in blood glucose levels (Pérez et al., 2007). Aloesin and Aloesinol of A. ferox have shown to decrease blood sugar levels in mice with an increase in adiponectin levels in vitro and a decrease in plasma insulin levels in vivo (Yimam et al., 2014). Phytosterols (lophenol, 24-methyl lophenol, 24-ethyl lophenol, cycloartanol, and 24-methlyene cycloartanol) have shown to reduce blood sugar levels as well as triglyceride levels (Tanaka et al., 2006).

Anti-hyperlipidemia effect of Aloe polyphenols
Phytosterols (lophenol and cycloartanol) have shown to reduce the serum-free fatty acid and triglyceride levels in Zucker diabetic fatty rats. Reduction in levels of PPARɣ/Liver X receptor α by A. vera gel can lead to proper functioning of insulin and these phytosterols may be one of the compounds acting via their inhibiting activity on PPARɣ/Liver X receptor α, pro-inflammatory cytokines (Misawa et al., 2008) Acemannan, a mucopolysaccharide enriched A. vera extract, when given to diabetic patients showed anti-hyperglycemic and anti-hypercholesterolemic activities (Huseini et al., 2012).

Hypoglycemic effect by Aloe Proteins/polypeptides
A glycoprotein named verectin (29KD), along with polysaccharide fraction of 1,000KD, has shown hypoglycemic effect in patients with type 2 diabetes (Yagi et al., 2009). Verectin indicated anti-oxidative, anti-thromboxane A2 synthase inhibition, and cyclooxygenase-2 inhibiting activities in vitro and these may be correlated with vasodilatation in diabetic patients (Yagi et al., 2003). The mechanism of action of these constituents in alleviating diabetes is shown in Figure 3. Narayanan et al. (2007) reported that these minerals may play a direct or indirect role in insulin secretion in a synergistic way (Narayanan et al., 2007). Rajasekaran et al. (2005) reported that the presence of these minerals in A. vera extract plays a role in antidiabetic activity (Rajasekaran et al., 2005). Magnesium is one of the important compounds which usually takes part in the metabolism of carbohydrates and fats by improving glucose and insulin homeostasis (Rumawas et al., 2006). Zinc enhances the effectiveness of insulin acting as a cofactor. Narayanan et al. (2007) reported that the presence of zinc in A. vera can modulate the targets for insulin activity (Narayanan et al., 2007). Potassium takes part in releasing insulin from beta cells, calcium in stimulation of insulin in pancreatic islets, vanadium elicits glucose levels, copper is involved in insulin binding, and chromium is essential for normal carbohydrate metabolism (Rajasekaran et al., 2005).

Insulinotropic effect by Aloe minerals
In addition to antidiabetic potential, the Aloe constituents also exhibit other therapeutic properties, such as antiinflammatory, anti-allergic, anti-bacterial, anti-cancer, angiogenic, antioxidant, immunomodulation, and wound healing. The details of the findings are discussed in the following sections and are summarized in Table 3.

Antioxidant and anti-cancer properties of Aloe constituents
APS-1, a polysaccharide from A. vera, was shown to have both anti-oxidant property and protective effect on heart tissue (Wu et al., 2006), which may be due to a higher content of rhaminose and arabinose in polysaccharide fraction (Kang et al., 2014). Aloe vera polyphenols have exhibited antioxidant and anti-cancer properties (Jeon et al., 2011;Naqvi et al., 2010) with Aloe emodin exhibiting anti-cancer potential against hepatoma cells. Aloin has shown to exhibit anti-cancer activity by inhibiting the tumor angiogenesis by inactivating the signal transduction and activators of transcription 3 pathway (Pan et al., 2013). Aloe polysaccharides were reported for antitumor activity against sarcoma 180 cells (Liu et al., 2006). Another polysaccharide G2E1DS2 was shown to activate macrophages and exhibit potent anti-tumor activity when injected into mice implanted with sarcoma cells. Polysaccharides also inhibit the activity of PMA-induced tyrosine kinase activity in human leukemic cells, leading to apoptosis of leukemic cells (Kim et al., 1999). A glycoprotein fraction and Aloesin was found to promote cell proliferation activity in human hepatoma SK-HEP1 cell lines, while a 53KD lectin was observed to have anti-proliferative activity against colon and lung cancer cell lines (Kaur et al., 2011). Figure 4a shows the mechanism of action of these constituents in cancer therapy.

Aloe constituents with anti-microbial properties
The polysaccharides have shown antibacterial activity by destroying the bacteria through generation of leukocytes (Pugh et al., 2001). Yates et al. (1992) demonstrated the anti-viral activity of acemannan in a pilot study of clinically symptomatic immunodeficiency virus-infected cat (Yates et al., 1992). Aloe emodin, purified from barbaloin, was also reported to inactivate a variety of viruses, including herpes simplex virus type I and type II, varicella-zoster, and the influenza virus (Jeon et al., 2011). The mechanism proposed for the anti-bacterial and anti-viral effects of Aloe emodin is the inhibition of nucleic acid biosynthesis, thereby inhibiting protein synthesis.

Aloe constituents with angiogenic property
β-Sitosterol possesses angiogenic activity and shows an increase in the formation of new blood vessels in a dose-dependent fashion (≥500 mg/kg) in gerbil brain cells by increasing the levels of vascular endothelial growth factor, the vascular endothelial growth factor receptor fetal liver kinase-1, and blood vessel matrix laminin, which has been damaged due to ischemia (Choi et al., 2002) .

Aloe constituents with immunomodulation and wound healing properties
Aloe polysaccharides between 400KD and 5KD molecules were shown to have immunomodulatory activity. Acemannan acts by activating and improving the macrophage action through an increased expression of cytokines IL-6 and TNF-α and the release of nitric oxide (Im et al., 2005;Kang et al., 2014). Lu et al. (2012) observed that A. vera polysaccharides mitigate ischemia and reperfusion injury in hemorrhagic rats (Lu et al., 2012).
The growth of endothelial, epithelial, and fibroblast cells plays a critical role in wound healing processes. Aloe polysaccharides increased the expression of matrix metalloprotease-3 and tissue inhibitor of metalloproteinases genes, thereby accelerating the process of wound healing (Tabandeh et al., 2014). A 5.5KD glycoprotein of A. vera was reported by Choi et al. (2001) for wound healing property by increasing the cell proliferation with elevated levels of epidermal growth factor receptor, fibronectin receptor, fibronectin, keratin 5/14, and keratin 1/10 (Choi et al., 2001). Figure 4c and d shows the immunomodulation action and wound healing action of these bioactive constituents, respectively.

Aloe constituents with anti-fibrinolytic and hemagglutination properties
A protease inhibitor protein of 11.8KD was reported to have anti-fibrinolytic potential (Siritapetawee et al., 2013). Aloctin I and Aloctin II have been reported with hemagglutination activity (Akev and Can, 1999), while 53KD lectin Mucin was shown to have hemeagglutinating activity and anti-proliferative activity against lung and colon cancer cell lines (Kaur et al., 2011).

RECENT ADVANCES ON EFFECTIVE UTILIZATION OF GENUS ALOE
Different formulations have been used to process A. vera as a commercial product. Depending on the requirement in product quality, various processing steps are followed by the industries. It is important to make sure that the constituents in A. vera do not lose their activity (Maan et al., 2018).
Research has been focused on controlled release of Aloe bioactive constituents. In case of wound healing, hydrogels and functional films have been developed for release of these constituents. The gel has been combined with biomaterials such as cellulose, alginate, and gelatin (Saibuatong and Phisalaphong, 2010;Silva et al., 2014). These formulations have prolonged drug release, better mechanical support, and prevention of body fluid loss. Attention has also been focused on tissue engineering, wherein growth factors and biomaterials have been employed for regeneration (Ikada, 2006). A nanofibrous scaffold comprising of gel and silk fibroin showed better synergistic effect in skin tissue regeneration (Suganya et al., 2014).
Micro and nanoparticles have also been used as a drug delivery system due to great stability of encapsulated drug. The microparticles consisting of A. vera, chitosan, and Vitamin E have been used for treating skin burns with better adhesive  ,10,13-trimethyl-2,3,4,5,6,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a] 3,4,7,8,9,11,12,14,15,16,17- (Kaur et al., 2011) properties and prolonged release of the constituents (Pereira et al., 2014). Nanoparticles along with A. vera gel led to improved antiviral property along with high loading efficiency (Joshy et al., 2016). Co-encapsulation of A. vera along with curcumin has enhanced the antioxidant property of the phytoconstituents (Kitture et al., 2015). Liposomes of 200 nm with Mannose-6-phosphate have shown anti-inflammatory potential and are used for collagen synthesis and growth of skin cells (Conte et al., 2017;Takahashi et al., 2009). The use of liposomes, biomaterials, and micro and nano encapsulation studies on these constituents for their other therapeutic potential needs to be explored further.

SIDE EFFECTS/TOXICOLOGICAL STUDIES OF THE GENUS ALOE
Most of the studies on A. vera and their constituents have been reported to be safe. But some side effects have also been mentioned. Application of A. vera to skin may cause redness, burning, or stinging sensations due to the presence of anthraquinones like aloin and barbaloin (Ferreira et al., 2007;Reider et al., 2005). It is also reported that prolonged use of Aloe latex or the Aloe epidermis region can increase the risk of arrhythmia (Ulbricht et al., 2008) due to its laxative property, leading to depletion of potassium. Based on our literature survey, most of the side effects reported are mainly because of the latex which has been poorly described (Kato et al., 2004).
Most of the works reported have used the Aloe plant or the gel portion alone. It can be inferred that the use of the entire plant or only the gel portion of Aloe can prevent these side effects. The presence of constituents, such as saccharides, proteins, and polyphenol minerals, in the gel may mask the effects of the Aloe latex which is usually rich in antharquinones such as aloin and barbaloin.

CONCLUSION
The genus Aloe consists of many species and the most prominent is the A. barbadensis Miller plant, commonly known as A. vera. There is no wonder in considering A. vera as the 'Miracle plant' as there is untapped potential in it for the management of therapeutic uses, and this review seeks to create more interest in screening of as many constituents as possible. Potential biological activity of constituents may be affected by the climate, season, harvesting, processing, storage conditions, and geographical origin which may bring about change in constituents, which may result in variations. Therefore, careful assessment of these constituents, their ecological and seasonal variation, metal contents, and toxicology studies need to be carried out to keep the toxic components, if any, at very low or permissible levels. The pharmacokinetic parameters, such as dose, its absorption and release and its metabolism also need to be studied. The action and the desired activity of these constituents, the time duration, and the therapeutic window need to be analyzed and validated through proper clinical trials. In addition to this, the route of delivery of the constituents needs to be studied. Studies regarding the usage, efficacy, safety of liposomes, polymers, bioadhesives, and nanoparticles to deliver these phytoconstituents need to be carried out. The bioactive constituent's role in the clinical applications may help in development of new formulations, wherein these constituents may be used as an alternate source for treating various ailments. Therefore, it is considered that studies on the genus Aloe