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

Background 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.

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.

Main text
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.

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 nondecolorized 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.

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 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, βsitosterol, 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].

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.     Ethanol herbal extract 6-phenyl-2-pyrone derivatives (p-coumaroyl aloenin and aloenin A), naphthalene derivatives (aloveroside A), and anthraquinones.