research article on aloe vera

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Pharmacological Update Properties of Aloe Vera and its Major Active Constituents

Aloe vera has been traditionally used to treat skin injuries (burns, cuts, insect bites, and eczemas) and digestive problems because its anti-inflammatory, antimicrobial, and wound healing properties. Research on this medicinal plant has been aimed at validating traditional uses and deepening the mechanism of action, identifying the compounds responsible for these activities. The most investigated active compounds are aloe-emodin, aloin, aloesin, emodin, and acemannan. Likewise, new actions have been investigated for Aloe vera and its active compounds. This review provides an overview of current pharmacological studies (in vitro, in vivo, and clinical trials), written in English during the last six years (2014–2019). In particular, new pharmacological data research has shown that most studies refer to anti-cancer action, skin and digestive protective activity, and antimicrobial properties. Most recent works are in vitro and in vivo. Clinical trials have been conducted just with Aloe vera , but not with isolated compounds; therefore, it would be interesting to study the clinical effect of relevant metabolites in different human conditions and pathologies. The promising results of these studies in basic research encourage a greater number of clinical trials to test the clinical application of Aloe vera and its main compounds, particularly on bone protection, cancer, and diabetes.

1. Introduction

Aloe vera ( Aloe barbadensis Miller, family Xanthorrhoeaceae) is a perennial green herb with bright yellow tubular flowers that is extensively distributed in hot and dry areas of North Africa, the Middle East of Asia, the Southern Mediterranean, and the Canary Islands. Aloe vera derives from “Allaeh” (Arabic word that means “shining bitter substances”) and “Vera” (Latin word that means “true”). The colorless mucilaginous gel from Aloe vera leaves has been extensively used with pharmacological and cosmetic applications. Traditionally, this medicinal plant has been employed to treat skin problems (burns, wounds, and anti-inflammatory processes). Moreover, Aloe vera has shown other therapeutic properties including anticancer, antioxidant, antidiabetic, and antihyperlipidemic. Aloe vera contains more than 75 different compounds, including vitamins (vitamin A, C, E, and B12), enzymes (i.e., amylase, catalase, and peroxidase), minerals (i.e., zinc, copper, selenium, and calcium), sugars (monosaccharides such as mannose-6-phosphate and polysaccharides such as glucomannans), anthraquinones (aloin and emodin), fatty acids (i.e., lupeol and campesterol), hormones (auxins and gibberellins), and others (i.e., salicylic acid, lignin, and saponins) [ 1 , 2 , 3 ].

In this review, we summarize an update of the pharmacological activities (in vitro, in vivo, and clinical trials) of Aloe vera . Publications (original papers) were published in English in the years 2014 to 2019 in peer-reviewed scientific journals of the Pubmed database. Those articles that included Aloe vera combined with other plants or Aloe species other than Aloe vera were excluded from this review.

This review is structured into different activities, which include in vitro, in vivo, and clinical trials, published in the last six years. The order of activities is based on the interest and importance of studies for Aloe vera . The Table 1 (in vitro studies), Table 2 (in vivo studies), and Table 3 (clinical trials) summarize the main pharmacological findings for Aloe vera and its isolated compounds ( Figure 1 , Figure 2 ).

In vitro pharmacological studies for Aloe vera .

In vivo pharmacological studies for Aloe vera .

Clinical trials with Aloe vera .

Chemical structure of compounds isolated from Aloe vera with pharmacological activity.

Pharmacological effects of the main constituents of Aloe vera .

2. Digestive Diseases Protection

Aloe vera extract (50%) increased cell viability of dental pulp stem cells being useful for avulsed broken teeth [ 4 ]. This effect is attributed to polysaccharides, mainly acemannan, by inducing osteogenic-specific gene expressions, DNA synthesis, growth factor, and JAK-STAT pathway [ 5 , 6 ]. Moreover, Aloe vera (225 mg/kg) exerted a radioprotective effect against salivary gland dysfunction in a rat model as evidenced in an increase of salivary flow rate [ 7 ].

Periodontitis is a serious and common dental affliction in which gums are infected and become inflamed, causing tissue and bone destruction. Gingivitis is the initial phase of periodontitis and is caused by dental plaque. Significant clinical evidence has demonstrated that Aloe vera mouthwash and gel are effective in the prevention and treatment of gingivitis and periodontitis by reducing gingival index, plaque index, and probing depth and by increasing bone fill and regeneration [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. Aloe vera has proven to be as effective as other usual treatments such as chlorhexidine, alendronate, and chlorine dioxide [ 8 , 10 , 11 , 13 ].

In a randomized placebo double-blind study with 20 healthy adults, Fallahi et al. [ 15 ] investigated the effect of Aloe vera mouthwash on postoperative complications after impacted third molar surgery. Aloe vera gel significantly reduced swelling and postoperative pain. In another work, Kalra et al. [ 16 ] evaluated the efficacy of Aloe vera gel and mineral trioxide aggregate as pulpotomy agents in primary molar teeth. The overall success rates at 3, 6, 9, and 12 months was high for patients treated with mineral trioxide aggregate. Moreover, a cross-sectional randomized interventional study revealed that Aloe vera gel promoted wound healing and reduced pain in patients that required atraumatic tooth extractions, and its effectiveness was higher than that of traditional analgesics [ 17 ]. Furthermore, Aloe vera resulted to be a promising cavity disinfecting agent in minimally invasive dentistry in a randomized clinical trial with 10 patients [ 18 ].

Oral mucositis/stomatitis is an inflammatory and/or ulcerative condition that occurs as a debilitating complication of chemotherapy and radiotherapy treatments and affects quality of life of oncological patients. Aloe vera mouthwash alleviated radiation-induced mucositis severity in patients with head and neck cancers similarly to the reference benzydamine mouthwash [ 19 ]. Moreover, Aloe vera mouthwash has also demonstrated to be efficient in the treatment of stomatitis (mean intensity and pain) associated with radiotherapy in patients with acute myeloid leukemia and acute lymphocytic leukemia [ 20 ].

Oral submucous fibrosis is a precancerous condition of the oral cavity characterized by abnormal collagen deposition. This malignant disorder is mainly caused by chewing areca nut and it is most frequent in India and Southeast Asia. Anuradha et al. [ 21 ] evaluated the efficacy of Aloe vera (systemic as juice and topical as gel) in the treatment of oral submucous fibrosis. Clinical evidence demonstrated that Aloe vera reduced burning sensation and increased cheek flexibility, mouth opening, and tongue protrusion similar to the reference treatment hydrocortisone, hyaluronidase, and antioxidant supplements. In another study on oral submucous fibrosis, the combination of Aloe vera gel with physiotherapy was more efficient in decreasing burning sensation and increasing tongue protrusion, mouth opening, and cheek flexibility than the combination of antioxidant capsules with physiotherapy [ 22 ].

Gastroesophageal reflux disease is a common chronic digestive disease in which gastric acids move up into the esophagus. Aloe vera syrup (10 mL/day) for 4 weeks reduced the frequency of symptoms of gastroesophageal reflux diseases including heartburn, food regurgitation, dysphagia, flatulence, belching, nausea, and acid regurgitation without causing adverse effects (only one case of vertigo and another of stomach ache were reported) [ 23 ].

Gastritis is an inflammation of mucous membrane layer of the stomach. Aloe vera gel protected in a Balb/c mouse model of alcohol-induced acute gastritis by increasing matrix metalloproteinase-9 inhibitory activity [ 24 ].

The topical administration of Aloe vera 3% ointment alleviated the symptoms of diarrhea and fecal urgency in patients with acute radiation proctitis induced by radiotherapy of the pelvic area [ 25 ]. Moreover, Aloe barbadensis extract (AVH200 ® ) reduced, but not significantly, the severity of gastrointestinal symptoms in patients with irritable bowel syndrome compared to a control group [ 26 ]. Lin et al. [ 5 ] revealed that Aloe polysaccharide (15 mg/kg) protected rats from 2,4,6-three nitrobenzene sulfonic acid colitis induced by increasing JAK2, p-JAK2, STAT-3, and p-STAT3 protein expression. Furthermore, Aloe vera cream applied three times daily for 6 weeks reduced chronic anal fissure pain and hemorrhaging after defection and promoted wound healing in a prospective double blind clinical trial [ 27 ].

3. Skin Protection

Most in vitro studies on skin protection study the ability of Aloe vera and active compounds in wound healing. The immortalized human keratinocyte HaCaT cell line, the primary normal human epidermal keratinocytes HEKa cell line, and fibroblasts cell lines are the most used. These studies have revealed that Aloe vera and its major compounds (aloesin, aloin, and emodin) exert their protective action mainly through antioxidant and anti-inflammatory mechanisms. Hence, Aloe vera up-regulated TFGβ1, bFGF, and Vegf-A expression in fibroblasts and increased keratinocyte proliferation and differentiation by lysosomal membrane stability [ 28 , 29 , 30 , 31 , 32 ]. Moreover, Aloe vera solution could accelerate corneal wound closure at low concentrations (≤175 μg/mL) by increasing type IV collagen-degrading activity in a cellular model of primary cultures of corneal epithelial cells [ 33 ]. Furthermore, aloin exerted skin protection by reducing IL-8 production, DNA damage, lipid peroxidation, and ROS generation and by increasing GSH content and SOD activity [ 34 ]. The compound aloesin resulted in promoting wound healing by increasing cell migration via phosphorylation of Cdc42 and Rak1, cytokines, and growth factors [ 35 ]. In addition to this healing activity, it has been seen that Aloe polysaccharide (20, 40, and 80 µg/mL for 24 h) could be a beneficial agent in psoriasis as evidenced in the inhibition of TNF-α levels and IL-8 and IL-12 protein expression in human keratinocyte HaCaT cell line.

As for in vivo studies, the most common models are genetically modified animals (BALB/c mice, HR-1 hairless mice and SKH-1 hairless mice) and UV and X-ray skin damage in animals. Most of these in vivo studies have been done with Aloe vera extracts and gel. Application of topical Aloe vera favored wound healing in animal models with dermal incisions by reducing inflammatory cell infiltration, increasing CD4+/CD8+ ratio lymphocytes, and improving epidermal thickness and collagen deposition [ 36 , 37 , 38 , 39 ]. In another study conducted in Indonesia with several medicinal plants, the effect of Nigella sativa oil gel and Aloe vera gel to treat diabetic ulcers was investigated. Aloe vera resulted to be more efficient in improving wound healing on alloxan-induced diabetes in Wistar rats with wounds on dorsum as evidenced by a decrease of necrotic tissue and inflammation and an improvement of re-epithelialization [ 40 ]. Furthermore, a UV-induced mice model revealed that Aloe vera gel powder increased epidermal growth factor and hyaluronan synthase and reduced matrix metalloproteinases expression (types 2, 9, and 13) [ 41 , 42 ]. Aloe sterols are involved in this UV protection [ 43 ]. Likewise, it has been observed that Aloe vera protected against X-radiation through antioxidant mechanisms (increased antioxidant enzyme activity and GSH content and reduced ROS production and lipid peroxidation) [ 44 , 45 ]. Among isolated compounds, investigations with the compounds aloe-emodin and aloesin have shown that their healing activity is due to angiogenic properties [ 46 , 47 ].

In the last 6 years, several clinical trials have also been carried out. Some of these have been aimed at evaluating the effectiveness of Aloe vera on ulcers. Hence, the administration of Aloe vera gel twice daily for 3 months improved and accelerated wound healing as well as reduced hospitalization time [ 48 , 49 ]. Moreover, in a randomized, triple-blind clinical trial with 80 patients hospitalized in the orthopedic ward, Hekmatpou et al. [ 50 ] demonstrated that Aloe vera gel twice daily for 10 days prevented the development of pressure ulcers on the areas of hip, sacrum, and heel. Moreover, clinical trials have demonstrated that Aloe vera facilitated rapid tissue epithelialization and granulation in burns [ 51 ], promoted healing of cesarean wound [ 52 ], and accelerated wound healing of split-thickness skin graft donor sites [ 53 ]. Furthermore, Aloe vera has been investigated in randomized, double-blind, placebo-controlled studies for its benefits to maintain healthy skin. Therefore, the daily oral intake of 40 µg of Aloe sterol (cycloartenol and lophenol) for at least 12 weeks improved skin elasticity in men under 46 years exposed to the sunlight but do not use sunscreen to protect themselves [ 54 ], reduced facial wrinkles in Japanese women over 40 years old by stimulating hyaluronic acid and collagen production [ 55 ], and increased gross elasticity, net elasticity, and biological elasticity in women aged 30–59 [ 56 ]. However, despite clinical evidence on the protective role of Aloe vera in the skin, there are clinical trials that have not yet found effectiveness of this medicinal plant, particularly in decreasing radiation-induced skin injury. Two clinical trials have been published between 2014 and 2019 in relation to this effect. Both studies found that topical administration of Aloe vera as gel or cream did not reduce the prevalence and severity of radiotherapy-induced dermatitis and skin toxicity in breast cancer patients compared to control group [ 57 , 58 ].

4. Anti-Inflammatory Activity

Most recent studies on anti-inflammatory activity of Aloe vera are focused on the action mechanism of isolated compounds in murine macrophage RAW264.7 cells and mice stimulated with LPS. Hence, the potential anti-inflammatory effect of aloin is related to its ability to inhibit cytokines, ROS production, and JAK1-STAT1/3 signaling pathway [ 59 , 60 ]. Moreover, aloe-emodin sulfates/glucuronides (0.5 μM), rhein sulfates/glucuronides (1.0 μM), aloe-emodin (0.1 μM), and rhein (0.3 μM) inhibited pro-inflammatory cytokines and nitric oxide production, iNOS expression, and MAPKs phosphorylation [ 61 ].

In another study, Thunyakitpisal et al. [ 62 ] demonstrated that acemannan increased IL-6 and IL-8 expression and NF-κB/DNA binding in human gingival fibroblast via a toll-like receptor signaling pathway. Since there is a relation between high IL-1β levels and periodontal diseases, Na et al. [ 63 ] investigated the anti-inflammatory properties of aloin in human oral KB epithelial cells stimulated with saliva from healthy volunteers. This study revealed that those saliva samples with high content in IL-1β stimulated IL-8 production in KB cells, and pretreatments with aloin inhibited IL-8 production by decreasing p38 and extracellular signal-regulated kinases pathway.

In addition to isolated compounds, Ahluwalia et al. [ 64 ] evaluated the activity of AVH200 ® , a standardized Aloe vera extract which contains alin and acemannan on the activation, proliferation, and cytokine secretion of human blood T cells obtained from healthy individuals aged 18–60, and they found that it decreased CD25 and CD3 expression on CD3(+) T cells. Moreover, AVH200 ® exhibited concentration-dependent T cell proliferation suppression and IL-2, IFN-γ, and IL-17A reduction. Moreover, the anti-inflammatory effect of Aloe vera has also been investigated in an acetaminophen-induced hepatitis (inflammatory condition of the liver) mice model. The results of this study revealed that Aloe vera (150 mg/kg) reduced hepatic MDA, IL-12, and IL-18 levels and ALT and increased GSH content [ 65 ].

5. Anticancer Effects

Studies conducted in the years of the review of this work focusing on cancer are mostly in vitro and in vivo studies. In vitro studies have the main purpose of identifying potential molecules with cytotoxic activity for later evaluation in in vivo studies and clinical trials. In addition, in vitro studies allow elucidating the mechanism of action by identifying promising pharmacological targets. In vivo studies allow us to understand the pharmacological activity and behavior in living organisms prior to their study in humans. Since clinical trials are very limited, and as it is not possible to confirm the anti-cancer activity of Aloe vera and its bioactive principles, it would be interesting for future research to focus on this activity based on the promising in vitro and in vivo results.

In vitro and in vivo studies included in the present review are aimed at evaluating cytotoxic and antitumor activity against a variety of cancer types using a diversity of cell lines and animal models (breast and gynecological cancers such as cervical cancer and ovarian cancer, malignant conditions of the gastrointestinal tract (i.e., oral cavity, esophagus, colon) and accessory digestive organs (pancreas), osteosarcomas, and melanoma). One clinical trial focused on the efficacy of Aloe vera on ocular surface squamous neoplasia; this clinical trial has been included at the end of this section.

MCF-7 cells, which express estrogen receptor, are the most popular breast cancer cell line, and the immortal HeLa cell line are the oldest and most used cervical cancer cells [ 66 , 67 ]. Aloe vera crude extracts (40%, 50%, and 60% for 6, 24, and 48 h) reduced cell viability of cancer cell lines (human breast MCF-7 and cervical HeLa) through apoptosis induction (chromatin condensation and fragmentation and apoptotic bodies appearance in sub-G0/G1 phases) and modulation of effector genes expression (an increase in cyclin D1, CYP1A1, and CYP1A2 expression and a decrease in p21 and bax expression) [ 68 ]. Moreover, the isolated compound aloe-emodin has resulted to be an effective anticancer agent against both MCF-7 cells and HeLa cells by inducing mitochondrial and endoplasmic reticulum apoptosis and inhibiting metastasis oxidative stress [ 69 , 70 , 71 , 72 ]. Furthermore, a recent study demonstrated that Aloe vera extract (300 mg/kg) and training (swimming) combined exerted a protective anticancer effect in mice with breast cancer by inhibiting the COX pathway (COX-2 reduction levels) and prostaglandin E2 production [ 73 ]. Finally, aloesin reduced tumor growth in in vitro and in vivo models of ovarian cancers by inhibiting the MAPK signaling pathway [ 74 ].

For malignant conditions of gastrointestinal tract and accessory digestive organs, emodin (10, 20, 30, 40 μM for 24 and 48 h) decreased cell proliferation and Bcl-2 protein levels and increased caspase-3 protein expression and Bax protein levels in human oral mucosa carcinoma KB cells [ 75 ]. Moreover, aloe-emodin has been shown to effectively suppress esophageal TE1 cancer cells in a concentration-dependent manner (from 2.5 µM to 20 µM concentrations assayed) through inhibiting AKT and ERK phosphorylation and reducing the number of cells in the S phase [ 76 ]. Furthermore, Aloe polysaccharide induced autophagy alone and in combination with radiation in pancreatic carcinoma BxPC-3 cells as evidenced in ULK1 mRNA expression upregulation and BECN1 and BCL-2 mRNA expression downregulation [ 77 ]. Finally, several in vitro and in vivo studies were performed to evaluate the potential anticancer properties of Aloe vera and its isolated compounds in colon cancer (fourth most common cancer and the third leading death cause) [ 78 ]. Chen et al. [ 79 ] exhibited cytotoxic properties of aloe-emodin on colon cancer cells at 10, 20, and 40 μM concentrations through activating the apoptotic pathway, increasing ROS production, and cytosolic calcium levels and up-regulating ER stress-related proteins. Moreover, Aloe vera powder and extract 1% and 3% protected C57BL/6J mice from aberrant crypt foci colorectal cancer by increasing hepatic phase II enzyme glutathione S-transferase mRNA levels [ 80 ]. Furthermore, Aloe vera gel (200 or 400 mg/kg/day orally) reduced inducible NO synthase and COX2 expression, NF-kB activation, and cell cycle progression, inducing cellular factors in BALB/c female mice with induced colitis-associated colon carcinogenesis.

Osteosarcomas are uncommon bone tumors in which malignant cells produce osteoid [ 81 ]. Aloe-emodin has also resulted to be a promising photosensitive agent against the human osteosarcoma MG-63 cell line via ROS/JNK signaling pathway as evidenced in an increase of caspases, cytochrome c, CHOP, and GRP78 expression [ 82 , 83 ].

For melanoma (malignant transformation of melanocytes), aloe-emodin protected against metastatic human melanoma cells by decreasing cell proliferation, increasing cell differentiation, and transamidating activity of transglutaminase and dabrafenib antiproliferative activity [ 84 , 85 ].

Regarding clinical trials conducted in recent years on anticancer activity, Damani et al. [ 86 ] reported the efficacy of Aloe vera eye drops 3 times daily for 3 months in the regression of ocular surface squamous neoplasia in a 64-year-old Hispanic woman. On the other hand, Koo et al. [ 87 ] stated that aloe polysaccharide could reduce tobacco associated diseases such as cancer due to its ability to increase urinary excretion of benzo(a)pyrene and cotinine.

6. Antidiabetic Effect

Diabetes is a chronic disease presenting with high levels of glucose in blood because of an insulin resistance or an insulin deficiency. Studies on the effect of Aloe vera in diabetes and related complications have been investigated mainly in animal models induced by streptozotocin. Consistent evidence supports that oxidative stress is a main cause of the beginning and the progression of diabetes complications such as nephropathies and neuropathies. Hence, using this experimental model, Aloe vera showed to reduce blood glucose levels, to increase insulin levels, and to improve pancreatic islets (number, volume, area, and diameter) [ 88 ], and this medicinal plant protected from oxidative stress-induced diabetic nephropathy and anxiety/depression-like behaviors [ 89 ]. Moreover, Aloe vera topical administration (60 mg/mL, four times daily for 3 days of eye drops) favored corneal re-epithelialization in streptozotocin-induced diabetic Wistar rats with corneal alkali burn injury [ 90 ]. Furthermore, experiments with genetically modified animals have revealed that Aloe vera polysaccharides (100 µg/g for 3 weeks) are responsible for the decrease of blood glucose levels [ 91 ]. A recent in vitro study showed that the action mechanism of Aloe vera polysaccharides antidiabetic effect is related to its ability to inhibit apoptosis and endoplasmic reticulum stress signaling [ 91 ]. In another in vitro study using a high-glucose-induced toxicity cell model, the compound aloe-emodin (20 μM) protected RIN-5F cells derived from rat pancreatic β-cells from glucotoxicity through an apoptotic and anti-inflammatory effects [ 92 ]. Lastly, the intake of Aloe vera (300 mg twice day for 4 weeks) decreased fasting blood glucose in pre-diabetic subjects [ 93 ].

7. Antioxidant Properties

Antioxidants are compounds that prevent or slow down biomolecule oxidative damage caused by ROS through free radical scavenging, metal chelation, and enzyme regulation [ 94 ]. Kumar et al. 2017 [ 95 ] investigated the potential antioxidant activity of crude methanolic extracts of Aloe vera from six agro-climatic zones of India using different in vitro methods (i.e., DPPH, metal chelating, and reducing power assay). Antioxidant activity was higher in those species collected in Northern India than in Southern India, which is related to a high content in alkaloids, glycosides, phenolic compounds, flavonoids, and saponin glycosides. Moreover, Aloe vera ethanol extract protected, particularly human microvascular endothelial cells, against hydrogen peroxide and 4-hydroxynonenal-induced toxicity by reducing ROS production and HNE-protein adducts formation [ 96 ]. The antioxidant activity of Aloe vera is, at least in part, due to anthraquinones and related compounds (10 µM) which possess peroxyl radical scavenging activity and reducing capacity [ 97 ].

Apart from these in vitro assays, in a clinical trial with 53 healthy volunteers, the intake of Aloe vera gel extract (14 days) increased total antioxidant capacity of plasma of subjects [ 98 ].

8. Bone Protection

In vitro studies with isolated Aloe vera compounds have been aimed at studying the potential protective effect on bone pathogenesis. Aloe-emodin induced chondrogenic differentiation on clonal mouse chondrogenic ATDC5 cells which is related to bone formation through BMP-2 and MAPK-signaling pathway activation [ 99 ]. Moreover, aloin has resulted to be beneficial in osteoporosis and osteopenia disorders by suppressing receptor activator of NFĸB ligand (RankL) induced through NF-κB inhibition in mouse macrophage RAW 264.7 cells [ 100 , 101 ].

9. Cardioprotective Effect

In vivo models of ischemia-reperfusion injury are commonly employed to evaluate the cardioprotective activity of Aloe vera . Aloe vera administered with gastric gavage previous to abdominal aorta and spinal cord ischemia increased antioxidant enzymes activity (SOD, CAT, and GPx) and reduced lipid peroxidation level (MDA content), edema, hemorrhage, and inflammatory cell migration in Wistar albino rats [ 102 , 103 ]. Moreover, barbaloin, also known as aloin, (20 mg/kg/day, 5 days) administered intragastrically reduced myocardial oxidative stress and inflammatory response and increased AMPK signaling in Sprague-Dawley rats in a myocardial ischemia/reperfusion injury [ 104 ]. Esmat et al. [ 105 ] demonstrated that this compound (50 mg/kg body weight, twice weekly over 2 weeks), administered intramuscularly, had non-atherogenic activity and iron chelating properties. Another compound isolated from Aloe vera and investigated for its cardioprotective properties is aloe-emodin. In an in vitro model of heme protein (hemoglobin), it was demonstrated that aloe-emodin (100 μM) had its maximum activity as an anti-aggregatory agent as evidenced in structural alterations of β sheet and the appearance of α helices [ 106 ]. On the other hand, an in vivo study revealed that aloe-emodin could alleviate hyperlipidemia by reducing total cholesterol and low-density lipoprotein-cholesterol levels at doses of 50 and 100 mg/kg for 6 weeks in male Wistar rats [ 107 ]. Regarding clinical studies, a double-blind randomized controlled trial showed that Aloe vera 300 mg and 500 mg/twice day for 4 and 8 weeks reduced HbA1C, total cholesterol, LDL, and triglyceride levels in pre-diabetic patients [ 92 ]. Furthermore, the oral gavage administration of Aloe vera (30 mg/kg/day for 1 month) resulted to decrease ischemic fiber degeneration by preventing the formation of lipid peroxides, increasing antioxidant enzymes, and up-regulating the transcription factor NRF1 in Wistar albino rats [ 108 ].

10. Antimicrobial and Prebiotic Activity

Different studies have been carried out to evaluate the antimicrobial activity of Aloe vera and its main constituents. Most of these studies are in vitro and focus on the antibacterial activity. One of the most studied bacteria are Staphlococcus aureus and Pseudomonas aeruginosa . Hence, Aloe vera aqueous extract reduced growth and biofilm formation against methicillin resistant Staphylococcus aureus [ 109 ]. Moreover, this bacteria has also been inhibited by Aloe vera gel (50% and 100% concentrations), along with other oral pathogens obtained from patients with periapical and periodontal abscess including Actinobacillus actinomycetemcomitans , Clostridium bacilli , and Streptococcus mutans using disc diffusion, micro-dilution, and agar dilution methods [ 110 ]. One of the compounds attributed to antibacterial activity against Staphylococcus aureus is aloe-emodin which acts by inhibiting biofilm development and extracellular protein production [ 111 ]. In the case of Pseudomonas aeruginosa , Aloe vera extracts have shown to inhibit the growth of multidrug-resistant Pseudomonas aeruginosa isolated from burned patients with wounds infections at MIC 50 and MIC 90 values of 200 µg/mL [ 112 ]. Pseudomonas aeruginosa growth and biofilm formation inhibition has been also demonstrated for Aloe vera inner gel. This Aloe vera inner gel also inhibited other Gram-negative bacteria ( Helicobacter pylori and Escherichia coli ) as well as the fungus Candida albicans [ 113 ]. Moreover, in another study, Aloe vera hydroalcoholic extract showed antibacterial activity against Enterococcus faecalis , an infecting microorganism of the root canals of teeth, with inhibition zones of 13 mm (saturated) and 9.6 mm (diluted) [ 114 ]. Furthermore, concentrations up to 1 mg/mL of Aloe vera aqueous extracts could inhibit Mycobacterium tuberculosis growth, which is the pathogen responsible for causing tuberculosis, one of the most lethal infectious diseases worldwide [ 115 ]. Finally, in a clinical trial with 53 healthy volunteers, the daily drinking of Aloe vera gel extract for 14 days exerted an antimicrobial activity as shown in a reduction of Lactobacillus spp. number [ 98 ].

Antiviral activity of Aloe vera has been investigated for herpes simplex virus type 1 and H1N1 subtype influenza virus. Aloe vera extract gel (concentrations from 0.2% to 5%) showed antiviral activity against herpes simplex virus type 1 on Vero cells by inhibiting its growth [ 116 ]. On the other hand, in vitro studies have demonstrated that Aloe polysaccharides decreased H1N1 subtype influenza virus replication and viral adsorption period by interacting with influenza virus particles. Moreover, in vivo studies with SPF BALB/c mice infected with PR8(H1N1) improved clinical symptoms and lung damage [ 117 ].

The parasite Plasmodium falciparum is the main causative agent of malaria, in its most aggressive and lethal form. Kumar et al. [ 118 ] investigated the activity of Aloe vera crude aqueous extracts collected in six different climatic regions of India (highland, semi-arid, arid, humid subtropical, tropical wet and dry, and humid subtropical climate) against a chloroquine-sensitive strain of Plasmodium falciparum . This study showed that those Aloe vera from colder climatic regions possessed the highest antiplasmodial activity which was related to the highest aloin and aloe-emodin content (EC50 value of 0.289 µg/mL).

Finally, there are other studies which support the prebiotic potential of Aloe vera defined as “a substrate that is selectively utilized by host microorganisms conferring a health benefit”. Aloe vera mucilage (rich in acemannan) could improve gastrointestinal health by increasing short chain fatty acids and modifying bacterial composition [ 119 ]. Moreover, acemannan and fructans from Aloe vera increased bacterial growth, especially Bifidobacterium spp. population [ 120 ].

11. Other Effects

Aloe vera has also been investigated for treating reproductive health care problems. The results of these works carried out with experimental animals are contradictory. While Asgharzade et al. [ 121 ] demonstrated that Aloe vera ethanol extract (150 and 300 mg/kg) had negative effects on spermatogenesis and sperm quality in Wistar rats, Erhabor and Idu [ 122 ] observed that Aloe vera ethanol extract (400 mg/kg) improved male sexual behavior (mount frequency and latency, intromission frequency and latency, and testosterone levels) and Behmanesh et al. [ 123 ] that Aloe vera extract increased body and testis weights, spermatocyte and spermatids quantity, and seminiferous tubule diameter and height.

Aloe vera processed gel prevented of ovoalbumin-induced food allergy by exerting an anti-inflammatory action (histamine, mast cell protease-1, and IgE reduction) [ 124 ].

At the blood level, the oral administration of Aloe vera gel prevented and restored lymphopenia and erythropenia as well as IgA secretion on cyclophosphamide-induced genetically modified mice [ 125 ]. Moreover, Aloe vera ethanol extract (200 mg/kg, 400 mg/kg, and 600 mg/kg) normalized levels of white blood cells, red blood cells, and platelet count through antioxidant mechanisms [ 126 ].

Regarding diseases of the musculoskeletal system, aloe-emodin showed to reduce viable cell numbers (concentrations ≥10 µM) and to induce apoptosis by arresting G2/M phase (concentrations ≥20 µM) in MH7A human synovial fibroblast-like cells, aloe-emodin being a promising agent to treat rheumatoid arthritis and a complementary treatment to methotrexate [ 127 ]. Moreover, Aloe vera lyophilized extract ointment reduced tendon lesions and increased non-collagenous proteins in Wistar rats with partial transection of the calcaneal tendon [ 128 ].

The dose of 10 mg/kg of Aloe vera aqueous extract (3 times daily for a week) resulted to be the most effective in morphine withdrawal syndrome in morphine-dependent female rats as shown in agitation, disparity, and floppy eyelids reduction [ 129 ].

Finally, highlighting the protective effect of Aloe vera gel extract (seven weeks, 500 mg/kg b.w. daily) on pulmonary tissue of cigarette smoke induced in Balb/c mice by reducing mucin production, citrulline and NO levels, and peroxidative damage [ 130 ].

12. Conclusions

Aloe vera has been traditionally used to treat skin injuries (burns, cuts, insect bites, and eczemas) and digestive problems because of its anti-inflammatory, antimicrobial, and wound healing properties. Research on this medicinal plant has been aimed at validating traditional uses and deepening the mechanism of action, identifying the compounds responsible for these activities. Likewise, new actions have been investigated for Aloe vera and its active compounds, especially highlighting its promising role as a cytotoxic, antitumoral, anticancer, and antidiabetic agent. In the last 6 years, most pharmacological studies have been in vitro and in vivo works. Among in vitro studies, antimicrobial, anti-inflammatory, cytotoxic, antitumor, anticancer, and skin protection activities are the most studied in number. It should be especially noted that among in vitro studies there are several works that evaluate the protective action of Aloe vera in bone diseases such as osteoporosis. The results on bone protection are promising; however, it is necessary to perform them with experimental animals and humans. Regarding in vivo studies, these are aimed at evaluating cardioprotective effect, cytotoxic, antitumor and anticancer activities, and skin protection activities. Compared to in vitro and in vivo assays, clinical trials are limited and focus on digestive and skin protective effects. In addition, these clinical trials have been conducted just with Aloe vera , but not with its isolated compounds; therefore, it would be of interest to study the clinical effect of relevant metabolites in different human conditions and pathologies. Among the major active compounds, research in the last six years focused on aloe-emodin, aloin, aloesin, amodin, and acemannan. Of these, aloe-emodin and aloin have been the most studied ones. Particularly, aloe–emodin has resulted to be a promising agent as an antimicrobial, antidiabetic, cytotoxic, cardiprotective, and bone protective (in in vitro studies) as well as anti-inflammatory and skin protective compound (in in vivo studies). Aloin was effective in inflammatory process and bone diseases (in vitro studies) and in cancer and cardiovascular diseases (in vivo studies). The promising results of basic research encourage a greater number of clinical trials to test the clinical application of Aloe vera and its main compounds, particularly on bone protection, cancer, and diabetes.

Author Contributions

All authors contributed to the conceptualization, investigation, supervision, and writing of the manuscript. All authors have read and agreed to the published version of the manuscript.

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

• Open access
• Published: 21 July 2021

Review on the phytochemistry and toxicological profiles of Aloe vera and Aloe ferox

• Florence Nalimu   ORCID: orcid.org/0000-0003-0964-1050 1 , 2 ,
• Joseph Oloro 1 , 3 ,
• Ivan Kahwa 1 , 4 &
• Patrick Engeu Ogwang 1 , 4  

Future Journal of Pharmaceutical Sciences volume  7 , Article number:  145 ( 2021 ) Cite this article

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Aloe vera and Aloe ferox have over the years been among the most sought-after Aloe species in the treatment of ailments worldwide. This review provides categorized literature on the phytochemical and scientifically proven toxicological profiles of A. vera and A. ferox to facilitate their exploitation in therapy.

Main body of the abstract

Original full-text research articles were searched in PubMed, ScienceDirect, Research gate, Google Scholar, and Wiley Online Library using specific phrases. Phenolic acids, flavonoids, tannins, and anthraquinones were the main phytochemical classes present in all the two Aloe species. Most of the phytochemical investigations and toxicity studies have been done on the leaves. Aloe vera and Aloe ferox contain unique phytoconstituents including anthraquinones, flavonoids, tannins, sterols, alkaloids, and volatile oils. Aloe vera hydroalcoholic leaf extract showed a toxic effect on Kabir chicks at the highest doses. The methanolic, aqueous, and supercritical carbon dioxide extracts of A. vera leaf gel were associated with no toxic effects. The aqueous leaf extract of A. ferox is well tolerated for short-term management of ailments but long-term administration may be associated with organ toxicity. Long-term administration of the preparations from A. vera leaves and roots was associated with toxic effects.

Short conclusion

This review provides beneficial information about the phytochemistry and toxicity of A. vera and A. ferox and their potential in the treatment of COVID-19 which up to date has no definite cure. Clinical trials need to be carried out to clearly understand the toxic effects of these species.

Aloe species (family Asphodelaceae) are among the most widely used plants over centuries for treating various ailments, for esthetic, and skincare [ 1 ]. The Aloe genus comprises over 430 species including A. vera and A. ferox among others [ 2 ]. These species have been reported to have pharmacological activities including anti-inflammatory, immunomodulatory, antibacterial, antifungal, antiviral, antiproliferative, antidiabetic, laxative, wound healing, moisturizing, anti-aging, and skin protection [ 3 , 4 , 5 ].

Aloe species are increasingly being incorporated into different cosmetic products, health drinks, foods, and beverages due to the abovementioned beneficial biological activities of the phytochemicals found mainly in the leaves.

These phytochemicals include polysaccharides, flavonoids, carbohydrates, coumarins, tannins, chromones, alkaloids, anthraquinones, organic compounds, pyrones, phytosterols, anthrones, sterols, vitamins, proteins, and mineral constituents [ 2 , 5 , 6 ]. The variation in concentration of these chemical constituents is based on the plant part used, extraction process, solvent, stage of growth, and plant source.

Though beneficial, some of these phytochemicals may be associated with toxic effects [ 7 ]. Many researchers have established potential toxicities as well as risks associated with some plants and vegetables particularly hepatotoxicity, nephrotoxicity, and cancer [ 8 , 9 ]. Due to these risks, toxicological evaluation of medicinal plants has become one of the main concerns to assure their safe use [ 10 , 11 ].

This review focuses on the phytochemistry and toxicology of A. vera and A. ferox , the two commercially popular species of Aloe . The present study will help in the standardization and quantification of the phytochemicals present in the Aloe species. It will also create awareness to the locals of the toxic effects that may be associated with the use of these species as medicine and future studies in humans.

The search was made in the databases of PubMed, ScienceDirect, Research gate, Google Scholar, and Wiley Online Library using the phrases “Genus Aloe ,” “ A. vera ,” “toxicology of Aloe species,” “acute and subacute toxicity of Aloe species,” safety, “ A. ferox ,” and “phytochemistry of Aloe species.” Published original full-text articles in English language on phytochemistry and toxicity of the Aloe species were retrieved.

Phytochemistry of the Aloe species

Aloe vera and Aloe ferox contain vast phytochemical classes including anthraquinones, chromones, anthrones, phenolic compounds, flavonoids, tannins, steroids, and alkaloids which contribute to their different pharmacological activities. The structures of the individual compounds are included (Figs. 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , and 20 ). More information on phytochemistry is summarized in Tables 1 , 2 , and 3 .

Chemical structures of chromones isolated from A. vera and A. ferox

Chemical structures of phenyl pyrones isolated from A. vera and A. ferox

Chemical structures of anthrones isolated from A. vera and A. ferox

Chemical structures of flavonoids isolated from A. vera and A. ferox

Chemical structures of sterols isolated from A. vera and A. ferox

Chemical structures of the naphthalene derivatives isolated from A. vera and A. ferox

Chemical structures of the maloyl glucans isolated from A. vera

Chemical structures of volatile oils isolated from A. ferox

Chemical structure of an ester isolated from A. vera

Chemical structures of fatty acids isolated from A. vera and A. ferox

Chemical structures of phenolic acids isolated from A. vera and A. ferox

Chemical structure of a dicarboxylic acid isolated from A. vera

Chemical structures of phenolic compounds isolated from A. vera and A. ferox

Chemical structures of naphtho [2, 3-c] furan-4, 9-dione derivatives isolated from A. ferox

Chemical structures of some terpenoids isolated from A. vera and A. ferox

Chemical structures of some alcohols isolated from A. vera and A. ferox

Chemical structures of some aldehydes isolated from A. vera and A. ferox

Chemical structures of some alkanes isolated from A. vera and A. ferox

Chemical structures of some alkynes isolated from A. vera and A. ferox

Chemical structures of some vitamins isolated from A. vera and A. ferox

Acute toxicity

According to Celestino et al. [ 51 ], A. ferox resin at a dose of 5000 mg/kg caused moderate diarrhea and reduced motor activity after 1 h post administration in Wistar rats.

Studies on both the methanolic and supercritical carbon dioxide extracts of A. vera leaf gel showed no treatment-related mortalities or changes in all the investigated parameters in rats [ 56 , 57 ].

Aqueous leaf extracts of A. vera at doses of 200, 400, and 600 mg/kg and A. ferox at doses 500, 100, 200, and 400 mg/kg did not cause any toxic effects or mortality in all the treated animals [ 58 , 59 , 60 ]. Likewise, no toxic effects were observed when male Wistar rats were treated with an ethanolic extract of A. vera roots at doses of 100, 200, and 400 mg/kg [ 61 ].

Ethanolic, acetone, and aqueous extracts of A. ferox roots and leaves caused death of nauplii of the brine shrimps at concentrations above 0.5 mg/ml [ 62 ]. Similarly, a herbal extract of A. vera at concentrations of 0.01, 0.1, and 1 mg/ml was toxic to the nauplii of the brine shrimps [ 63 ]. A hydroalcoholic extract of A. vera leaves caused mortality at 2560–5120 mg/kg within 36–48 h in Kabir chicks [ 64 ]. A study by Shah et al. [ 65 ] revealed that an ethanolic extract of A. vera leaves caused reduced motor activity at doses of 1000 and 3000 mg/kg in male Swiss albino mice.

Subacute toxicity

Administration of Aloe vera product (UP780), A. vera leaf juice, and gel for 14 days caused no harmful effects in rats and mice [ 58 , 66 , 67 ]. Wintola et al. [ 68 ] and Kwack et al. [ 69 ] reported similar results when A. vera leaf powder and A. ferox aqueous leaf extract were separately administered to rats.

A study by Koroye et al. [ 70 ] showed that administration of Aloe vera plus (GNLD) twice daily at volumes of 0.2, 0.4, and 0.8 cm 3 for 14 and 28 days caused histological variations in the kidney tissues of the treated Wistar rats. A study by Sodani [ 71 ] displayed that the administration of 0.02 cm 3 of A. vera leaf juice to male Swiss Webster mice over 21 days caused pathological effects on the kidneys.

In other studies, Aloe vera health drinks A and B administered over 28 days caused slight weight reduction and increase in white blood cell, red blood cell count, liver enzymes, serum urea, and creatinine levels in the rats given a volume of 1.0 cm 3 [ 72 ]. A. vera leaf powder at a dose of 400, 1200, and 2000 mg/kg caused a significant reduction in white blood cell count and pigmentation of the kidneys in Sprague-Dawley rats [ 73 ].

Elevation in red blood cells, platelet count, hypertrophy of lungs, heart, and kidney and necrosis of spermatogenic cells was observed when an aqueous leaf extract of A. ferox at doses of 50, 100, 200, and 400 mg/kg was administered to Wistar rats for 14 days [ 59 ]. A decrease in the size of tubules, germ cell debris, and picnotic cells in the testes and testosterone was seen when A. vera gel product was administered for 28 days to male Swiss albino mice at the highest dose [ 74 ].

A study by Bala et al. [ 75 ] displayed that an aqueous gel extract of A. vera caused histopathological alterations in male Balb/c mice at 100 and 250 mg/kg.

Sub-chronic and chronic toxicity

A study by Saritha and Anilakumar, [ 56 ] showed that administration of a methanolic gel extract of A. vera at doses of 1000, 2000, 4000, 8000, and 16000 mg/kg caused no mortalities or any changes in any of the investigated parameters at all the administered doses in the animals. Likewise, an aqueous leaf extract and supercritical carbon dioxide gel extract of A. vera caused no mortality or changes in the investigated parameters throughout the treatment period [ 57 , 58 , 76 ].

A study by Mwale and Masika [ 59 ] showed that an aqueous leaf extract of A. ferox at doses of 50, 100, 200, and 400 mg/kg caused a rise in the red blood cells, monocytes, and platelets counts and also hypertrophy of lungs, heart, and kidney and necrosis of spermatogenic cells in rats at all doses.

An ethanolic gel extract of A. vera at a dose of 100 mg/kg lowered the red blood cell count in addition to necrosis of the sex organs and hair loss around the genital area in male Swiss albino rats [ 65 ].

According to Koroye et al. [ 70 ], Aloe vera plus (GNLD) at doses of 0.2, 0.4, and 0.8 cm 3 caused chronic inflammation, cell infiltration, necrosis, and fibrosis of the renal interstitium in all treated Wistar rats after 42 days of dosing.

Qmatrix® a product from A. vera leaves also caused an increase in absolute and relative kidney weight of males at 500 and 2000 mg/kg [ 77 ].

A 2-year study showed that an aqueous non-decolorized leaf extract of A. vera was found to increase the rates of hyperplasia of the stomach, small intestines, large intestines, and mesenteric lymph nodes in both rats and mice [ 78 ].

Toxic compounds in the Aloe vera and Aloe ferox

Aloin, an anthraquinone present in both A. vera and A. ferox , has been associated with increased gastric motility causing diarrhea [ 79 ]. This explains why the Aloe species have been explored in relieving constipation. A study by Boudreau et al. [ 80 ] established that aloin caused pathological changes on the mucosa that were compared to those caused by Aloe vera whole leaf extract.

Aloe emodin, an anthraquinone present in A. vera , has been associated with hepatoxicity, genotoxicity, nephrotoxicity, phototoxicity, and reproductive toxicity [ 81 , 82 , 83 , 84 , 85 ].

Potential for treatment of COVID 19

COVID 19 is caused by the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). It belongs to RNA viruses and has four structural proteins (M (membrane), E (envelope), N (nucleocapsid), and S (spike)) [ 86 ]. The virus through its spike protein binds to the angiotensin-converting enzyme 2 (ACE2) receptors on the surface of the respiratory tract to facilitate its attachment and fusion with the host cell [ 86 ]. This is followed by entry into the host cell after priming of the S protein by the host cellular serine proteases TMPRSS2 [ 87 ]. The virus then releases its particles into the host cell, replicates, and invades the upper respiratory tract causing inflammation which later leads to acute respiratory distress. Treatment strategies involve use of antiviral drugs, immunomodulators, antibiotics, antioxidants, anti-inflammatory drugs, corticosteroids, and antipyretics [ 88 , 89 , 90 , 91 , 92 , 93 ]. Various medicinal plants including Aloe vera and Aloe ferox are being explored as potential drugs in the management of COVID 19 due to the various compounds they contain.

In silico studies have shown that anthraquinones including chrysophanol, aloe emodin, aloeresin, aloin A & B, 7-O-methylaloeresin, 9-dihydroxyl-2-O-(z)-cinnamoyl-7-methoxy-aloesin, and isoaloeresin are potential SARS-CoV-2 3CLpro protease inhibitors [ 94 ].

In addition, Aloe vera possesses anti-inflammatory activity [ 42 , 60 , 95 , 96 , 97 , 98 , 99 , 100 ] which helps in preventing the release of pro-inflammatory markers that cause inflammation which induces acute respiratory distress, the leading cause of mortality in COVID patients. Aloe vera also possesses immunomodulatory property [ 101 , 102 , 103 , 104 ], which strengthens the immune system of the host hence curbing the spread of the infection.

In addition, A. vera contains a phytosterol, β-sitosterol, with immunostimulatory activity helping to reinforce the host’s immune system. Molecular docking studies have shown that β-sitosterol strongly binds with the receptor-binding domain of the SARS-CoV-2 spike protein preventing the entry of the virus into the host cell [ 105 ].

Furthermore, Aloe vera contains mineral elements like zinc. Zinc has been found to inhibit the activity of corona RNA polymerase and SARS-coronavirus (SARS-CoV-2) replication in cell culture studies [ 106 ].

In silico studies showed that anthraquinones (aloe emodin, aloinoside A, aloeresin D, Isoaloeresin A, etc.), phenolic compounds (pyrocatechol, p-Hydroxyacetophenone), and fatty acid derivatives (10-Hydroxyoctadecanoic acid, 10-Oxooctadecanoic acid) are potential SARS-CoV-2 main protease inhibitors [ 107 ].

Similar to A. vera , A. ferox is well endowed with anti-inflammatory compounds [ 108 , 109 ]. These prevent the release of pro-inflammatory markers and cytokines that cause severe inflammation leading to acute respiratory distress in the patients.

Conclusions

A. vera and A. ferox contain vast phytochemicals including anthraquinones, flavonoids, and phytosterols, which can be further studied for activity against SARS-CoV-2. Since herbal preparations made from A. vera and A. ferox are currently sold, this information will be used by the regulatory authorities before they issue marketing approval to the manufacturers of these products. More toxicity studies need to be carried out on the aqueous extracts of A. vera and A. ferox since decoctions are the most commonly used preparations by the local population. Also, more studies need to be done on the isolated compounds from these species so that they can be excluded from the preparations in case they are found to be toxic.

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Acknowledgements

We would like to thank Mr Emanuel L Peter for the help rendered in the preparation of the manuscript.

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Pharm-Bio Technology and Traditional Medicine Centre of Excellence, Mbarara University of Science and Technology, Mbarara, Uganda

Florence Nalimu, Joseph Oloro, Ivan Kahwa & Patrick Engeu Ogwang

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Florence Nalimu

Department of Pharmacology and Therapeutics, Faculty of Medicine, Mbarara University of Science and Technology, Mbarara, Uganda

Joseph Oloro

Department of Pharmacy, Faculty of Medicine, Mbarara University of Science and Technology, Mbarara, Uganda

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FN conceived the research idea, collected the data and prepared the first draft of the manuscript. JO and POE screened for duplication and also carried out data analysis. IK drew all the structures in the manuscript. All the authors read and approved the final manuscript.

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Nalimu, F., Oloro, J., Kahwa, I. et al. Review on the phytochemistry and toxicological profiles of Aloe vera and Aloe ferox . Futur J Pharm Sci 7 , 145 (2021). https://doi.org/10.1186/s43094-021-00296-2

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• Phytochemistry

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• Published: 26 February 2015

Evolutionary history and leaf succulence as explanations for medicinal use in aloes and the global popularity of Aloe vera

• Olwen M Grace 1 , 2 ,
• Sven Buerki 3 ,
• Matthew RE Symonds 4 ,
• Félix Forest 1 ,
• Abraham E van Wyk 5 ,
• Gideon F Smith 6 , 7 , 8 ,
• Ronell R Klopper 5 , 6 ,
• Charlotte S Bjorå 9 ,
• Sophie Neale 10 ,
• Sebsebe Demissew 11 ,
• Monique SJ Simmonds 1 &
• Nina Rønsted 2  

BMC Evolutionary Biology volume  15 , Article number:  29 ( 2015 ) Cite this article

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Aloe vera supports a substantial global trade yet its wild origins, and explanations for its popularity over 500 related Aloe species in one of the world’s largest succulent groups, have remained uncertain. We developed an explicit phylogenetic framework to explore links between the rich traditions of medicinal use and leaf succulence in aloes.

The phylogenetic hypothesis clarifies the origins of Aloe vera to the Arabian Peninsula at the northernmost limits of the range for aloes. The genus Aloe originated in southern Africa ~16 million years ago and underwent two major radiations driven by different speciation processes, giving rise to the extraordinary diversity known today. Large, succulent leaves typical of medicinal aloes arose during the most recent diversification ~10 million years ago and are strongly correlated to the phylogeny and to the likelihood of a species being used for medicine. A significant, albeit weak, phylogenetic signal is evident in the medicinal uses of aloes, suggesting that the properties for which they are valued do not occur randomly across the branches of the phylogenetic tree.

Conclusions

Phylogenetic investigation of plant use and leaf succulence among aloes has yielded new explanations for the extraordinary market dominance of Aloe vera . The industry preference for Aloe vera appears to be due to its proximity to important historic trade routes, and early introduction to trade and cultivation. Well-developed succulent leaf mesophyll tissue, an adaptive feature that likely contributed to the ecological success of the genus Aloe , is the main predictor for medicinal use among Aloe species, whereas evolutionary loss of succulence tends to be associated with losses of medicinal use. Phylogenetic analyses of plant use offer potential to understand patterns in the value of global plant diversity.

The succulent leaf tissue of Aloe vera is a globally important commodity, with an estimated annual market of $13 billion [ 1 ]. The ‘gel’ tissue—polysaccharide-rich inner leaf mesophyll—provides a reservoir of water to sustain photosynthesis during droughts, and has been ascribed multiple bioactive properties associated with its use for skincare and digestive health [ 2 ]. Aloe vera has supported a thriving trade for thousands of years [ 3 ] and is arguably one of the most popular plants known in cultivation today, yet its origins in the wild have long been speculated. We have established that at least 25% of aloes (~120 species) are used for medicine yet fewer than 10 Aloe species are traded commercially, and these are used primarily for the purgative leaf exudate and on much lesser scales than Aloe vera (e.g. Aloe ferox in South Africa and Aloe arborescens in Asia) [ 4 ]. The immense market dominance of Aloe vera over other species of Aloe is not fully explained by available phytochemical evidence [ 5 , 6 ]. The extent to which the value of Aloe vera may be a consequence of evolutionary processes of selection and speciation, resulting in apparently unique properties and phylogenetic isolation, has not previously been considered.

Aloe (>500 species) is by far the most speciose of the six genera known collectively as aloes, which include Aloiampelos (7 species), Aloidendron (6 species), Aristaloe (1 species), Gonialoe (3 species) and Kumara (2 species). They are iconic in the African flora, and occur predominantly in eastern sub-Saharan Africa, and on the Arabian Peninsula, Madagascar and western Indian Ocean islands. Succulent plants are usually associated with arid environments; although numerous aloes occur in the drylands of Africa, they are also abundantly represented in tropical and subtropical vegetation infrequently impacted by drought. All aloes possess some degree of leaf succulence, as well as crassulacean acid metabolism (CAM) and a thick, waxy cuticle common in plants exhibiting a succulent syndrome [ 7 ]. Most are habitat specialists with narrow ranges and extraordinary rates of endemism, from an estimated 70% in southern Africa, 90% in Ethiopia, to 100% on Madagascar [ 8 ]. These centres of diversity coincide alarmingly with Africa’s biodiversity Hotspots, where a highly endemic biota is under substantial threat of extinction [ 9 ]. Risks posed by extensive habitat destruction and other threats to their survival are reflected by the inclusion of all aloes, except Aloe vera , in the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES). The species-level diversity, ecological importance and threats to aloes place them among the world’s most important succulent plant lineages, other examples of which are ice plants (Aizoaceae), cacti (Cactaceae) and Agave (Agavaceae) [ 10 ]. Phylogenetic studies of related groups have focussed on the South African endemic Haworthia (e.g. [ 11 , 12 ]), whereas aloes have received little attention (but see [ 13 ]), and the origins and diversification of Aloe have remained unclear. It has therefore not been possible to determine whether Aloe vera is phylogenetically distinct from its many relatives, nor whether such phylogenetic distance may account for any potentially unique properties underpinning the value of the succulent leaf tissue.

Phylogenetic prediction is emerging as a promising tool for exploring correlations between the phylogenetic diversity and useful attributes of medicinal plants [ 14 - 17 ]. Rich biocultural traditions surround the use of aloe leaves for medicine, cosmetics, digestive health and general wellbeing [ 4 ]. Two natural products are derived from the leaves: carbohydrate-rich succulent leaf mesophyll tissue, applied topically to the skin or taken internally for digestion; and exudate, a liquid matrix high in phenolic compounds and most often used as a potent purgative, or in veterinary medicine (see [ 18 ]). The literature describing these uses is an untapped resource for understanding plant use in an evolutionary context, and in particular the extraordinary case of Aloe vera , which is used almost exclusively for its succulent leaf tissue. One point of interest is whether leaf succulence in aloes, which ranges from barely succulent in some species to very fleshy in others, could influence their use.

We aimed to explore the Aloe vera ‘phenomenon’ [ 5 ] by combining the largest ever phylogenetic hypothesis for the aloes with predictive methods. We used this to infer a scenario for their evolution, addressing a persistent gap in the understanding of global succulent plant diversity and biogeography. Links between the medicinal usefulness of aloes, their phylogenetic history, and extent of leaf succulence were evaluated by identifying evolutionary correlations and phylogenetic signal in uses and habit. Our comprehensive sampling represents the full morphological and geographical diversity of the aloes, and enabled the origins, geographical range evolution and divergence times of Aloe and relatives to be inferred. We synthesized our findings to determine whether the global value of Aloe vera can be better explained by evolutionary distinctiveness or by historical anthropogenic factors.

Phylogenetic hypothesis

A dataset was assembled representing seven plastid and nuclear DNA regions in 239 taxa in Xanthorrhoeaceae, including 197 species in the genera Aloe , Aloidendron , Aloiampelos , Aristaloe , Gonialoe and Kumara . We generated 480 new sequences from leaf or floral specimens collected from natural populations or from curated living collections and DNA banks held primarily at the Royal Botanic Gardens, Kew. A further 279 sequences were obtained from GenBank (ncbi.nlm.nih.gov/genbank/), including 93 rbcL and 64 psbA sequences. Agapanthus africanus (Amaryllidaceae) was used as the outgroup taxon in all analyses.

Total genomic DNA was isolated from fresh plant material (ca. 1 g) or specimens dried in silica gel (ca. 0.3 g) using a modified CTAB protocol [ 19 ] or the Qiagen DNeasy kit (Qiagen, Copenhagen). Sequences of ITS, matK and trnL-F were amplified using methodology previously described by [ 6 ]. The trnQ-rps16 region was amplified with the primers trnQ(UUG)Aloe (5′-ATCTTRATACAATGTGATCCAC-3′; this study) and rps16x1 [ 20 ]. Sequences from the complementary strands were obtained for all taxa whenever possible, using the BigDye Terminator v3.1 on a 3730 DNA Analyzer (Applied Biosystems/Hitachi). Sequences were assembled in Sequencher 4.8 (Gene Codes, Ann Arbor) and submitted to GenBank (Additional file 1 ). Sequences were aligned automatically using MUSCLE [ 21 ] implemented with default settings in SeaView v4.2.12 [ 22 ], and adjusted manually in BioEdit v7.1.11 [ 23 ]. The DNA regions were aligned separately before the data were concatenated using an R [ 24 ] script to produce a final dataset comprising 240 taxa and 6732 nucleotides in seven DNA regions.

We used Bayesian inference, maximum likelihood and parsimony to produce a phylogenetic hypothesis for Aloe and allied genera , using single-partition ( ITS , matK , rps16 , psbA , rbcL , trnL-F intron and spacer) and combined datasets. We ran all analyses on the Cyber Infrastructure for Phylogenetic Research (CIPRES) portal [ 25 ]. Separate parsimony analyses of the ITS (175 taxa, 799 nucleotides) and plastid (231 taxa, 5933 nucleotides) datasets were undertaken with the parsimony ratchet implemented in PAUPRat [ 26 ], to check for strongly supported phylogenetic conflicts (bootstrap percentages >75), before proceeding with analyses based on a total evidence approach using all characters. A maximum likelihood analysis, comprising 1000 bootstrap replicates followed by a heuristic tree search, was executed in RAxML [ 27 ] with each partition assigned specific parameters under the recommended GTRCAT model. An additional 530 gaps and indels in the combined dataset of all DNA regions were coded using the algorithm described by [ 28 ] in the FastGap v1.2 interface [ 29 ]. Finally, we ran a Bayesian analysis of the combined dataset with gaps coded in MrBayes v3.1.2 [ 30 ]. Best-fitting models for each data partition for Bayesian inference were identified using the Akaike Information Criterion calculated in Modeltest v3.8 [ 31 ]. The Hasegawa, Kishino and Yano (HKY) model with gamma-shaped distribution of rate heterogeneity among sites (HKY + G) was selected for the ITS, matK , trn Q- rps16 and trnL-F data partitions, while the General Time Reversible (GTR) model with gamma distribution of rate heterogeneity among sites was selected for psbA (GTR + G), and with a proportion of invariable sites (GTR + I + G) for rbcL . For the Bayesian analysis, the parameters were unlinked between loci and four Metropolis Coupled Markov Chains with heating increments of 0.2 were run for 50 million generations and sampled every 1000th generation. The resulting parameters were summarised in Tracer 1.5.0 [ 32 ]. A quarter of the least likely trees were discarded, and a majority rule consensus tree with branch supports expressed as posterior probabilities (PP) was produced from the remaining trees.

Divergence time estimates and biogeographic scenario

Divergence times were estimated using a penalised likelihood (PL) approach previously applied in Hyacinthaceae, a related family in Asparagales, as described by [ 33 ]. In the absence of fossil data for aloes and related genera, analyses were constrained to the mean age of 34.2 Ma inferred for the crown node of Asphodeloideae in a recent study of all Asparagales families [ 34 ]. Due to the computational demands of analyses on the full Xanthorrhoeaceae dataset and our focus on the aloes ( Aloe , Aloiampelos , Aloidendron , Aristaloe , Gonialoe and Kumara ), we excluded subfamilies Xanthorrhoeoideae and Hemerocallidoideae from subsequent analyses and pruned the Bayesian consensus tree to 228 species in Asphodeloideae. The penalised likelihood method [ 35 ] was run on 1000 randomly selected trees from the Bayesian stationary distribution and summarised on the consensus tree [ 33 ]. The optimal rate smoothing value for this dataset was determined by cross validation on the pruned Bayesian consensus tree, using the Truncated Newton algorithm (S = 5) implemented in r8s v 1.8 [ 36 ]. The outgroup taxon was pruned prior to the estimation of divergence times, as required by r8s. Mean age values and 95% confidence intervals for the nodes on the Bayesian consensus tree were computed in TreeAnnotator [ 37 ].

A biogeographic scenario for the aloes was inferred using the dispersal-extinction-cladogenesis (DEC) likelihood model implemented in Lagrange v2.0.1 [ 38 ]. Species distribution data were compiled from authoritative checklists for Asphodeloideae [ 39 , 40 ] and standardised according to the Taxonomic Data Working Group (TDWG) guidelines [ 41 ]. We defined eight areas based on the statistically-delimited biogeographical regions of Africa, incorporating the faunal and floral diversity of the continent, described recently by [ 42 ]. For subfamily Asphodeloideae, Arabia, Madagascar and Eurasia were added to the Southern African, Zambezian and Congolian regions, together with expanded Ethiopian-Somalian and Saharan-Sudanian regions. Assigning species to areas was straightforward due to the typically narrow distribution of most Aloe species, and because neighbouring areas are separated by physical barriers or marked differences in climatic conditions. Ancestral area reconstructions in Lagrange [ 38 ] were performed on the dated consensus (allcompat) tree obtained from the penalised likelihood analysis. In brief, ancestral areas were computed at each node of the tree under the DEC likelihood model, following a method described in detail by [ 33 ]. Ancestral areas with a relative probability >1 were combined with the node age and lengths of the descendent branches on the tree to infer the frequency and nature of transition events between ancestral and descendant nodes [ 33 ]. The resulting biogeographic scenario was visualised on the dated Bayesian consensus tree using pie charts showing the likelihoods of all possible ancestral areas per node for subfamily Asphodeloideae.

Phylogenetic signal in utility and habit

We interrogated a dataset of over 1400 use records from the literature [ 18 ] to investigate phylogenetic signal in the uses of aloes. Data were coded according to the Economic Botany Data Standard [ 43 ] from which two categories of use were considered. In the first category, we combined all TDWG Level 1 data to yield a discrete binary character describing any documented use, while the second comprised data in the TDWG Level 2 Medicines category. General use (e.g. for food, materials, social purposes, etc.) and medicinal use specifically were scored as present (=1) or absent (=0) in each of the terminal taxa. Records describing a plant as not used are unusual in the ethnobotanical literature, and hence in all cases 0 indicated a lack of reported use, rather than definitive knowledge of no use. The consensus (allcompat) tree inferred by Bayesian analysis with gaps coded was pruned to 197 species representing Aloe , Aloiampelos , Aloidendron , Aristaloe , Gonialoe and Kumara.

We calculated phylogenetic signal using the D metric [ 44 ], a measure specifically developed for quantifying phylogenetic signal in binary characters, implemented in the R package caper [ 45 ]. D compares the number of observed changes in a trait over a phylogeny with the number that would be expected under two alternative simulated scenarios: one where there is strong phylogenetic dependence and the trait has evolved via a gradual Brownian motion model of evolution, and the second where there is no phylogenetic dependence and the trait is randomly scattered across the species, regardless of phylogeny. The D metric generates a value that usually lies between 0 and 1, where a value of 1 indicates that the trait has evolved in essentially a random manner (i.e. no phylogenetic signal), and 0 indicates that the trait is highly correlated with phylogeny, in a manner predicted by Brownian motion. Tests for significant differences from D = 1 (no phylogenetic signal) are derived by simulating the random distribution of the trait among species 1000 times to generate a null distribution for the D statistic. We conducted the analysis in two ways, one using just the consensus phylogeny, and the second using 1000 trees selected at random from the Bayesian posterior distribution calculating median values for D and associated P values.

The putative contribution of leaf succulence to the ‘usefulness’ of aloes was explored using a phylogenetic comparative approach. A character set describing the extent of water-storing mesophyll tissue in the leaves was assembled from species descriptions [ 46 - 48 ] and observations of leaf morphology in aloes . Species were broadly scored as ‘succulent’ or ‘barely succulent’ and additionally classified as barely succulent shrubs (the grass aloes, Aloe section Leptaloe ), succulent shrubs ( Aristaloe , Gonialoe and most of Aloe ), branching trees ( Aloidendron , Kumara ) and scrambling shrubs with variably succulent leaves ( Aloiampelos ). These were visualised on the Bayesian consensus tree by reconstructing the ancestral states of three characters (succulence, habit and medicinal use), scored as binary traits, under the parsimony optimisation in Mesquite [ 49 ].

For calculation of phylogenetic signal using the D metric in these traits, they were coded as four separate dummy binary variables (e.g. succulence: 0 = no, 1 = yes). Pairwise comparison tests [ 50 ] were used to assess possible evolutionary correlations between habit and documented uses generally and medicinal uses specifically (dependent variables). This method takes phylogenetically independent pairs of species and observes any correlated differences in the states of two binary characters. For every gain or loss in one character (in this case, the measure of leaf succulence), it assesses whether there is an associated loss, gain or no change in the other (medicinal or general use), and compares any patterns with those expected if the second character were randomly distributed on the phylogeny. Pairwise comparison calculations were carried out using Mesquite [ 49 ]. As with our D metric calculations, to account for uncertainty in the phylogenetic topology and weak branch supports, we ran all the analyses on the Bayesian consensus (allcompat) topology (using 100 randomly selected sets of pairwise comparisons) and on a random sample of 1000 trees from the Bayesian posterior distribution, calculating median probability values associated with the correlation.

Our phylogenetic analyses of >7 kb plastid and nuclear characters (6732 nucleotides and 550 gaps) in ca. 40% of Aloe species substantiate current understanding of taxonomic relationships in Xanthorrhoeaceae subfamily Asphodeloideae [ 11 , 12 , 51 ] and divergence times within Asparagales [ 33 ] (Figure  1 , Additional files 2 and 3 ). We sampled 26 genera and 240 species in Xanthorrhoeaceae, using a total evidence approach despite sequence data for some taxa being incomplete (Additional files 1 and 4 ). The effects of missing data on phylogenetic analyses have been widely debated, but there is convincing evidence for the accurate phylogenetic placement of taxa with considerable missing data (summarised by [ 52 ]). Model-based methods of phylogenetic inference perform better than parsimony in estimating trees from datasets with missing data [ 53 , 54 ], and we therefore based subsequent analyses on the Bayesian phylogenetic inference (Additional file 3 ). Low levels of genetic polymorphisms, taxonomic complexities, and the number of inaccessible, narrowly distributed species challenge the study of aloes; this is the first phylogeny to include >10% of Aloe species . Parsimony and maximum likelihood topologies (trees not shown) compared well to the Bayesian tree used in downstream analyses. Branching tree aloes ( Aloidendron ) are basal to the remainder of the alooids. A clade comprising the Cape endemic genus Kumara and Haworthia s.s. is sister to Aloiampelos , which is in turn sister to Aloe . Within the large Aloe clade (184 species), well-supported terminal branches highlight species-level relationships but the clades, which will ultimately underpin a taxonomic revision, are incompletely resolved. The placement of Aloiampelos juddii at the base of the alooid topology, on a branch sister to Kumara-Haworthia , warrants further investigation of reciprocal monophyly in Aloiampelos . We included four members of Astroloba , two Tulista , three Haworthiopsis and four Haworthia in our study and recovered these as paraphyletic with varying support. The haworthioid taxa were, until recently [ 12 ], phylogenetically problematic (e.g. [ 11 ]).

Subfamilies and genera of Xanthorrhoeaceae. Summary phylogram with Bayesian posterior probabilities (>0.5) above branches; red branches represent the six genera known collectively as aloes: Aloe , Aristaloe , Gonialoe , Kumara , Aloiampelos and Aloidendron .

Biogeographic scenario for Aloe. Distribution and biogeographic scenario for Aloe inferred from nucleotide and plastid data for 228 taxa in Xanthorrhoeaceae subfamily Asphodeloideae. Enlarged map shows the natural distribution of Aloe , with northernmost limits indicated by dashed line. Direction and timing of diversification events inferred from ancestral state reconstruction and penalised likelihood dating are shown by arrows. Histograms show branch-based (dispersal and extinction) and node-based (vicariance and peripheral isolations) events in speciation processes since the divergence of the Aloe crown group ~16 Ma.

Bayesian consensus tree for Aloe. Core Aloe clade from a Bayesian analysis of Xanthorrhoeaceae highlighting relationships of interest in the biogeographical scenario . Inset shows representative variation in the extent of leaf succulence among aloes: a, Aloiampelos ciliaris ; b, Aloidendron eminens ; c, Kumara plicatilis ; d, Aloe vera ; e, Aloe marlothii.

Bayesian consensus tree for Aloe (continued from Figure 3 ).

Divergence times estimated using a penalised likelihood approach and ancestral area reconstructions revealed that aloes originated in southern Africa in the early Miocene, ~19 million years ago (Ma) (Additional file 3 ). Aloe vera was recovered in a strongly supported clade with eight other Arabian species, allowing us to infer its origins on the Arabian Peninsula within the last five million years. Two southern African species supporting commercial natural products industries, Aloe arborescens and A. ferox , were recovered together in a southern African clade. We estimate that the diversification of the genus Aloe began ~16 Ma in South Africa with a period of range expansion of ancestral taxa north-eastwards into the Zambezian and Ethiopian-Somalian regions ~10 Ma. Peripheral isolation and, to a lesser extent, vicariance were inferred to be the major speciation processes for the early diversification of aloes until around ~5 Ma, when a sharp increase in dispersal events occurred in several near-simultaneous radiations of the aloes at the extremities of their range, particularly in Madagascar. During this period, aloes reached West Africa, the Saharan-Sudanian region and the Arabian Peninsula via the Ethiopian-Somalian region, and arrived on Madagascar from the Zambezian region (Figure  2 ). This scenario identifies the Ethiopian-Somalian region as a cross-road for speciation processes in Aloe , as the majority of dispersal events (16 events) in our dataset were from here into each of the four adjacent regions. We identified multiple introductions to Madagascar (three dispersals). Similarly, diversification of aloes on the Arabian Peninsula resulted from one or more dispersals, as well as vicariance and peripheral isolation, with no evidence of dispersal back to continental Africa. A single southerly dispersal event was detected from the Zambezian to the Southern African regions.

Leaf succulence increased steadily with the emergence of aloes in southern Africa, from the barely succulent tree aloes ( Aloidendron and Kumara ) and rambling aloes (Aloiampelos ), to Aloe and neighbouring genera (Figures  1 , 3 and 4 ). Though difficult to quantify, pronounced succulence is restricted to Aloe , and has been almost completely lost in several members of this genus, notably in the clade comprising southern African grass aloes, Aloe section Leptaloe , during the last ~10 Ma (Figure  3 ; Additional file 5 a-c). The habit of relatively large, succulent leaves borne in basal rosettes on an unbranched stem, typical of Aloe vera and other commercially valuable species, exhibits a strong phylogenetic signal. Using Fritz & Purvis’s D-metric [ 44 ] as our measure of phylogenetic signal, where D = 1 indicates no phylogenetic structure to the trait data and D = 0 indicates strong correlation between trait distribution and phylogeny (see methods for full description), we found the degree of phylogenetic signal in succulence per se was highly significant (D = 0.132, p < 0.001).

Uses are documented for 48% of the aloes sampled in this study . Of the 81 Aloe species in our analysis that have documented medicinal use, 98% have succulent leaves. By contrast, in 87% of the 15 species in which succulent leaf mesophyll has been almost entirely lost, there is negligible documented tradition of medicinal use, even in regions with thoroughly documented ethnoflora, such as South Africa. Whilst many succulent-leaved aloes do not have known medicinal uses, the likelihood of use is significantly higher in the succulent aloes (Fisher’s exact test comparing proportions of succulent vs. non-succulent species with medicinal utility, prior to considering phylogenetic effects: p = 0.014). Our pairwise comparison analyses indicated that there most likely have been six evolutionary losses of leaf succulence in aloes, as predicted from the Bayesian consensus phylogeny and 884 of the 1000 Bayesian posterior distribution trees. With the consensus tree, we tested the hypothesis that the use of an aloe for medicine diminishes or is lost entirely with a reduction in leaf succulence. Four of the six evolutionary transitions in aloes where succulence is severely reduced are associated with loss of medicinal use, providing weakly significant support for the hypothesis (pairwise comparison test: p = 0.065). The same analysis using 1000 trees sampled randomly from the Bayesian posterior distribution, was unable to resolve clearly whether four or three transitions in aloe leaf succulence were associated with loss of medicinal use (p = 0.125). We detected a weak phylogenetic signal in the general use of these genera (D = 0.828, p = 0.063). Focussing on the use of aloes for medicine, we also identified a weak, but significant, phylogenetic signal (D = 0.794, p = 0.029).

Species with documented medicinal use are not randomly distributed across the phylogeny. In a large clade comprising 29 species of maculate aloes, characterised by large, succulent leaves and a short stem, 55% are used for medicine. A clade of 18 closely related species native to East Africa, Ethiopia and the Horn of Africa (the Zambezian and Ethiopian-Somalian biogeographic regions) included 27% species with known medicinal uses. Aloe vera was among three medicinal species in a clade of eight species native to the Arabian Peninsula.

The phylogenetic hypothesis for the aloes reveals a distinctive geographical pattern of major clades of Aloe with four biogeographical centres of diversity: Southern Africa (~170 species), Madagascar (~120 species), East Africa/Zambezian region (~100 species), and the Horn of Africa/Ethiopian-Somalian region (~90 species). Based on strongly supported close relationships with morphologically similar Arabian species, we clarify that Aloe vera is native to the Arabian Peninsula. Previous suggestions have included Sudan or the Arabian Peninsula, based on morphological affinities with Arabian species [ 55 ] and even further afield in the Canary Islands, Cape Verde Islands, Madeira or Spain [ 3 ], which could be explained by naturalised populations, introduced via ancient trade routes, being mistaken for indigenous elements of the flora. Our explicitly phylogenetic context places Aloe vera for the first time among related Arabian species at the northernmost natural range limit of aloes, in habitats at the extremes for aloes in terms of aridity and diurnal temperature fluctuations. Here, at the hot and dry edge of their natural range, aloes are characterised by leathery, glaucous leaves that likely protect the water-storing leaf mesophyll from diurnal temperature and radiation extremes. The evolutionary distinctiveness of aloes on the Arabian Peninsula which could account for atypical properties in Aloe vera , is thrown into question by their affinities with species in the Ethiopian-Somalian region [ 13 , 56 ]. We found evidence for at least one dispersal from the Ethiopian-Somalian region to the Arabian Peninsula within the last 5 Ma. The biogeographic scenario inferred here (Figure  2 ) elucidates the diversification of Aloe prior to its arrival in north-east Africa and the Arabian Peninsula, and reveals a southern African cradle for the genus ~16 Ma, in the early Miocene. Consequently, the longstanding hypothesis that aloes first appeared in southeast Africa considerably earlier, in the late Mesozoic-early Cenozoic [ 56 ] is contradicted by the molecular evidence in the present study.

The establishment of the Mediterranean climate in south-western Africa and the expansion of southern African deserts in the Miocene caused large-scale extinctions in the prevailing subtropical flora [ 57 ] and appear to have had a profound impact on the evolution of aloes. Habitat expansion has been proposed as the main driver for the simultaneous global diversification of plants with a succulent habit [ 10 ]. But on a local scale, loss of suitable habitat forced southern African aloes to migrate north-eastwards as these species struggled to adapt to bioclimatic changes at the southernmost tip of Africa. The establishment of the winter-rainfall region, in particular, appears to have largely excluded aloes from the semi-arid Succulent Karoo region, a celebrated global centre of succulent plant diversity with ~5,000 species and 40% endemism. The Succulent Karoo flora is characterised by short-lived, drought-sensitive dwarf and leaf-succulent shrubs [ 58 ] such as the ~1500 members of Aizoaceae subfamily Ruschioideae [ 59 ] and ~1000 species of Crassulaceae [ 60 ]. Aloes, in contrast, tend to be long-lived and drought tolerant, and are relatively poorly represented in the Succulent Karoo and winter-rainfall regions of southern Africa. Water-use efficiencies may have placed even the earliest, barely-succulent aloes at an ecological advantage over non-succulent lineages in the relictual subtropical vegetation.

The timing of two periods of diversification detected in aloes, in the late Miocene and more recently in the Pliocene, coincide remarkably with the simultaneous ‘burst’ of evolution in major succulent plant lineages globally, attributed to a rapid decline in atmospheric CO 2 and increased aridity during the mid- to late Miocene [ 10 ]. Consistently low rates of extinction in our data agree with previous findings [ 56 ], suggesting continuous but irregular diversification of aloes. We identified a distinct shift from node-based speciation processes (namely, vicariance and peripheral isolations) to branch-based events (dispersals and extinctions) coincident with each of the radiations of the aloes . We interpret this as a period of range expansion and diversification of relatively widespread species until the Miocene-Pliocene boundary. The second rapid diversification was likely the result of species fragmentation and increased niche availability, when isolated taxa dispersed short distances into the rich habitat mosaics formed by geological processes during the Pliocene, giving rise to the present-day distribution of Aloe . This is evident in a five-fold increase in dispersal events in our dataset, while node-based processes and extinctions are low to negligible during the same period. The tempo of these pulsed radiations in Aloe is strikingly similar to that of Agave (Agavaceae), a New World group of ~200 species of leaf succulent rosette plants [ 61 ], adding new depth to this celebrated example of convergent evolution among succulents.

The evolution of leaf succulence followed the pattern of divergence in aloe and relatives, in tandem with the expansion of semi-arid habitats in Africa between ~ 10 and 5 Ma. Like the earliest cacti [ 62 ], ancestral aloes were barely succulent and tree-like. Large and markedly succulent leaves are restricted to the genus Aloe and, unlike other lineages in which succulence has arisen multiple times (e.g. Portulacineae [ 63 ] and Aizoaceae [ 59 ]), variation in the extent of leaf succulence among species of Aloe is due to loss of water-storing tissues (e.g. in the barely succulent grass aloes) (Figure  3 ). The idea that rich traditions of use in the aloes may be linked to the extent of leaf succulence has not been previously investigated, and our analyses suggest that a decrease in the proportion of water-storing leaf mesophyll reduces the possibility that a species is used for medicine, irrespective of whether the leaf mesophyll tissue and/or liquid exudate are used. Documented medicinal uses for barely succulent members of Aloidendron , Kumara and Aloiampelos focus on the roots or leaf exudate, and never the leaf mesophyll. Additionally, our phylogenetic reconstruction suggests that medicinal utility appears less likely in lineages where reduced succulence has evolved. For instance, we found very few documented medicinal uses for the barely-succulent grass aloes despite their relative abundance in regions with thoroughly documented ethnoflora, such as the fire-adapted grasslands of KwaZulu-Natal in South Africa. We detected weak, but significant, phylogenetic signals in the use of aloes generally, and for medicinal purposes specifically. A comparable study of the Amaryllidaceae, a family with well-characterised bioactive alkaloids, recovered a similar overall phylogenetic signal for medicinal use [ 15 ].

A link between leaf succulence and medicinal use suggests a traditionally pragmatic approach to the selection of aloes with large, succulent leaves for use in medicine [ 4 ]. Features such as firm leaf mesophyll, a short stem, small teeth on the leaf margins, and ease of propagation, are shared by Aloe vera and numerous other Aloe species used medicinally, including closely related species from the Arabian Peninsula and the Ethiopian-Somalian region. Our evolutionary hypothesis for Aloe locates Aloe vera in close phylogenetic proximity to seven other species native to the Arabian Peninsula, discounting a distinctive evolutionary history for Aloe vera which could imply unique leaf properties. Mounting anecdotal evidence for the beneficial properties of Aloe vera continues to stimulate research into the bioactivity of the succulent leaf mesophyll [ 2 ]. Recent studies of Aloe vera and a phylogenetically-representative sampling of nearly 30 Aloe species have shown very low levels of variation in the monosaccharide composition of leaf mesophyll carbohydrates [ 6 , 64 ], although differences in carbohydrate structure may yet be discovered pending systematic evaluation of these highly complex carbohydrates which are assumed to be responsible for the medicinal value of the leaf mesophyll [ 5 ]. On the other hand, documented traditions of use indicate that few of the closest relatives of Aloe vera are used medicinally. Records of the therapeutic uses of Aloe vera leaf mesophyll and exudate date to classical times [ 3 , 5 , 65 ]. Trade routes for Aloe vera were well established in the Red Sea and Mediterranean by the 4th century BCE [ 3 ] and, assuming the species occupied a narrow range typical of Arabian aloes, it may have been rapidly harvested to near-extinction to meet market demands. The remarkable contemporary market dominance of Aloe vera over other aloes therefore appears to be the consequence of its origins near important early trade routes, ancient selection for medicine and cultural history, which introduced the species into trade and cultivation thousands of years ago.

Phylogenetic investigation of plant use and leaf succulence among aloes has yielded new explanations for the extraordinary market dominance of Aloe vera . The evolutionary history inferred from our analyses of Aloe and related genera shows for the first time that Aloe vera is native to the Arabian Peninsula, and discounts phylogenetic distance as an explanation for its popularity over many other species of Aloe . The industry preference for Aloe vera appears to be due to its proximity to important historic trade routes, and early introduction to trade and cultivation. Well-developed succulent leaf mesophyll tissue, an adaptive feature that likely contributed to the ecological success of the genus Aloe , is the main predictor for medicinal use among Aloe species, whereas evolutionary losses of succulence tend to be associated with losses of medicinal use. Phylogenetic analyses of plant use offer potential to understand patterns in the value of global plant diversity.

Data accessibility

DNA sequences are deposited in GenBank and accession numbers are listed in Additional file 1 .

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Acknowledgements

The authors thank Martin Årseth Hansen, Eshetu Fentaw, Amra Dzajic, Halima Amir, Livhuwani Nkuna, Erich van Wyk, Walter Mabatha, Neil Crouch, Arrie Klopper, Anthony Miller and Abdul Wali al Khulaidi for help with plant collecting, maintaining living collections, and laboratory work. This study was supported by grants awarded to OMG and NR in the Marie Curie Actions of the 7th European Community Framework Programme (grant ALOEDIVERSITY PIEF-GA-2009-251766) and Brødrene Hartmanns Fond, Denmark.

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Olwen M Grace, Félix Forest & Monique SJ Simmonds

Natural History Museum of Denmark, University of Copenhagen, Sølvgade 83 Entrance S, DK1307, Copenhagen K, Denmark

Olwen M Grace & Nina Rønsted

Department of Life Sciences, Natural History Museum, Cromwell Road, London, SW7 5BD, UK

Sven Buerki

Centre for Integrative Ecology, School of Life & Environmental Sciences, Deakin University, 221 Burwood Highway, Burwood, Victoria, 3125, Australia

Matthew RE Symonds

Department of Plant Science, H.G.W.J. Schweickerdt Herbarium, University of Pretoria, Pretoria, 0002, South Africa

Abraham E van Wyk & Ronell R Klopper

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Natural History Museum, University of Oslo, PO Box 1172, Blindern, NO-0318, Oslo, Norway

Charlotte S Bjorå

Centre for Middle Eastern Plants, Royal Botanic Garden Edinburgh, 20A Inverleith Row, Edinburgh, EH3 5LR, UK

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Sebsebe Demissew

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Authors’ contributions

OMG and NRØN conceived and designed the study. OMG assembled sequence data, conducted the phylogenetic analyses and interpreted the results. SB conducted the node age estimate and ancestral area reconstructions, and interpreted these with OMG and FF. MRES conducted the phylogenetic signal analyses, and interpreted the results with OMG and NRØN. AEvW and GFS helped to interpret the results of phylogenetic and biogeographical analyses. RRK, CSB, SN and SD participated in obtaining essential plant material and/ or sequences for phylogenetic analysis. MSJS facilitated the utility analysis. OMG, SB, MRES and NRØN prepared the manuscript. All authors read and approved the final manuscript.

Additional files

Additional file 1:.

GenBank sequence data for taxa studied. Accession/collectors’ numbers and international codes for herbaria where vouchers are deposited are given for sequences from this study: C, Copenhagen; E, Edinburgh; ETH, Addis Ababa; K, Kew; O, Oslo; NBG, Compton; PRE, Pretoria; DNA signifies DNA bank accession; — signifies no sequence.

Additional file 2:

Phylogenetic hypothesis for Xanthorrhoeaceae. Bayesian consensus tree for 240 species of Xanthorrhoeaceae subfamilies Xanthorrhoeoideae, Hemerocallidoideae and Asphodeloideae, with posterior probabilities >0.5 displayed above branches.

Additional file 3:

Ancestral area reconstructions for Xanthorrhoeaceae subfamily Asphodeloideae. a) Ancestral areas displayed on the penalised likelihood-dated Bayesian consensus tree; b) detail of the clade containing Aloe vera . Legend refers to regions modified from [ 57 ] for this analysis: A, Southern Africa; B, Zambezi; C, Congolian; D, Ethiopian-Somalian; E, Saharan-Sudanian; F, Arabian; G, Madagascan; H, Eurasian; Trash, sum of ancestral area probabilities <0.1.

Additional file 4:

Summary statistics for phylogenetic dataset. Taxon sampling, sequence length and model selection for data partitions.

Additional file 5:

Phylogenetic distribution of leaf succulence, habit and medicinal use in alooid taxa. Most parsimonious reconstructions of character states mapped to Bayesian consensus tree in a) leaf succulence, b) habit and c) medicinal uses.

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Grace, O.M., Buerki, S., Symonds, M.R. et al. Evolutionary history and leaf succulence as explanations for medicinal use in aloes and the global popularity of Aloe vera . BMC Evol Biol 15 , 29 (2015). https://doi.org/10.1186/s12862-015-0291-7

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Published : 26 February 2015

DOI : https://doi.org/10.1186/s12862-015-0291-7

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Preparation and Characterization of Gelatin Based Antimicrobial Edible Films Incorporated with Aloe Vera Gel and Garlic Peel Extract

• Research Article
• Published: 08 May 2024

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• Drisya Raj MP 1 ,
• Kanimozhi NV 1 &
• Sukumar M   ORCID: orcid.org/0000-0003-0614-5473 1  

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Edible films based on the addition of Garlic peel extract (GPE) and Aloe Vera gel (AV) into gelatin with antimicrobial properties for food packaging applications were proposed in this work. Both extracts, GPE and AV showed high total phenolic content (TPC), total flavonoids and antioxidant activity. Nine different formulations were obtained by the addition of GPE:AV in the ratios 1:1, 2:1 and 1:2 with concentrations of 1, 2 and 3 wt% to gelatin, showing films with 3 wt% of extracts with the ratio of 1:1 the best performance. Gelatin films enriched with GPE and AV retarded the growth of S. aureus and E. coli counts during the well diffusion plating technique. The addition of extracts did not significantly affect mechanical and barrier properties like water vapor transmission ratio and oxygen transmission ratio. The incorporation of these extracts into gelatin could be proposed as a potential effective packaging material for meat and poultry products by retarding the microbial growth and extending the shelf-life of these food products.

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MP, D.R., NV, K. & M, S. Preparation and Characterization of Gelatin Based Antimicrobial Edible Films Incorporated with Aloe Vera Gel and Garlic Peel Extract. J Package Technol Res (2024). https://doi.org/10.1007/s41783-024-00166-1

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DOI : https://doi.org/10.1007/s41783-024-00166-1

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