key: cord-1025876-nj96wf3a
authors: Nalimu, Florence; Oloro, Joseph; Kahwa, Ivan; Ogwang, Patrick Engeu
title: Review on the phytochemistry and toxicological profiles of Aloe vera and Aloe ferox
date: 2021-07-21
journal: Futur J Pharm Sci
DOI: 10.1186/s43094-021-00296-2
sha: 62f8e4220f9239ce97d0845fc83edeb7385d3e42
doc_id: 1025876
cord_uid: nj96wf3a

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.

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.

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.

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. 

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.

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] .

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] .

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-7methoxy-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, 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] .

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 antiinflammatory 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.

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.

N/A TLC, HPLC, MS, IR, and NMR [31] Leaf exudate Homonataloin, aloesin, aloenin, barbaloin, aloinosides A&B, and aloesone

Exudation into methanol TLC [32] Chromones HPLC-DAD and LCMS-IT-TOF [33] Free and glycosylated chromones: Aloesin and aloeresin A Anthraquinones: Aloin and aloe emodin Phytochemical screening [48] Condensed tannins, flavonoids, and gallotannins Extraction by sonication (methanol) followed by successive extraction with petroleum ether, dichloromethane, and ethanol)

Phytochemical screening [49] Dried leaf latex Naphtha [2,3-c] furan derivatives; 5-hydroxy-3-methylnaphtho[2,3-c] furan-4,9-dione and 5-hydroxy-3-methylnaphtho[2,3-c] furan-4(1H)-one, anthraquinones, and 5hydroxy-3-methylnaphtho[2,3-c] furan-4(9H)-one Dissolution in water X-ray analysis and spectroscopy [50] Leaf resin hydroxyanthracene derivatives (aloin) N/A TLC [51] Leaf juice Volatile oils; 5-methyl-3-heptanol, bornylene, 1, 3cyclopentadiene, 3, 6 octatriene, and 3-cyclohexane-1hetanol 

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In vivo diabetic wound healing effect and HPLC-DAD-ESI-MS/MS profiling of the methanol extracts of eight Aloe species

Antimicrobial activity and phytochemical screening of Aloe vera (Aloe barbadensis Miller)

Analysis of 13 phenolic compounds in Aloe species by high performance liquid chromatography

Comparison of phytochemical profiles, antioxidant and cellular antioxidant activities of seven cultivars of Aloe

Morphological, phytochemical and antifungal analysis of Aloe vera L. leaf extracts

Compositional features and bioactive properties of Aloe vera leaf (fillet, mucilage, and rind) and flower

Dietary Aloe vera components' effects on cholesterol lowering and estrogenic responses in juvenile goldfish, Carassius auratus

Variation in phytochemical composition reveals distinct divergence of Aloe vera

From other aloe species: rationale behind selective preference of Aloe vera in nutritional and therapeutic use

Antimicrobial and phytochemical analysis of Aloe vera L

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Effect of climate change on phytochemical diversity, total phenolic content and in vitro antioxidant activity of Aloe vera (L.) Burm. f

Analysis of phytochemical constituents and antimicrobial activities of Aloe vera L against clinical pathogens

A comparative study on antioxidant, proximate analysis, antimicrobial activity and phytochemical analysis of Aloe vera and Cissus quadrangularis by GC-MS

Phytochemical study in ethanolic leaves extract of Aloe vera using Gas chromatography

Phytochemical constituents of some leaves extract of Aloe vera and Azadirachta indica plant species

Phenolic constituents, antioxidant and preliminary antimycoplasmic activities of leaf skin and flowers of Aloe vera (L.) Burm. f. (syn. A. barbadensis Mill.) from the Canary Islands (Spain)

Identification of phenolic constituents and antioxidant activity of Aloe barbadensis flower extracts

Phenolic constituents in dried flowers of Aloe vera (Aloe barbadensis) and their in vitro antioxidative capacity

Phytochemical standardization of Aloe vera extract by HPTLC techniques

A new triglucosylated naphthalene glycoside from Aloe vera L

Observations on the phytochemistry of the Aloe leafexudate compounds

Simultaneous qualitative and quantitative determination of phenolic compounds in Aloe barbadensis Mill by liquid chromatography-mass spectrometry-ion trap-time-of-flight and high-performance liquid chromatography-diode array detector

Profile of bioactive secondary metabolites and antioxidant capacity of leaf exudates from eighteen Aloe species

Phytochemical screening and antimicrobial activity of Aloe vera

Evaluation of bioactive potential of an Aloe vera sterol extract

Five chromones from Aloe vera leaves

Identification of five phytosterols from Aloe vera gel as anti-diabetic compounds

Novel bioactive maloyl glucans from Aloe vera gel: isolation, structure elucidation and in vitro bioassays

Isolation, purification and evaluation of antibacterial agents from Aloe vera

Antibacterial activities and antioxidant capacity of Aloe vera

Anti-inflammatory activity of extracts from Aloe vera gel

In vitro study of the PLA2 inhibition and antioxidant activities of Aloe vera leaf skin extracts

Chemical constituents of Aloe barbadensis Miller and their inhibitory effects on phosphodiesterase-4D

Secondary metabolites from the resins of Aloe vera and Commiphora mukul mitigate lipid peroxidation

Aloeverasides A and B: two bioactive C-Glucosyl chromones from Aloe vera resin

Bioactive compounds isolated from Aloe ferox: A plant traditionally used for the treatment of sexually transmitted infections in the Eastern Cape, South Africa

Phytochemical constituents and antioxidant activities of the whole leaf extract of Aloe ferox Mill

Anti-inflammatory, anticholinesterase, antioxidant and phytochemical properties of medicinal plants used for pain-related ailments in South Africa

Naphtho [2, 3-c] furan-4, 9-dione and its derivatives from Aloe ferox

Acute toxicity and laxative activity of Aloe ferox resin

Chemical composition of volatile constituents from the leaves of Aloe ferox

Chemical constituents of cape aloe and their synergistic growth-inhibiting effect on Ehrlich ascites tumor cells

Phytochemical constituents and allelopathic effect of Aloe ferox Mill. root extract on tomato

Aloe ferox leaf gel phytochemical content, antioxidant capacity, and possible health benefits

Toxicological evaluation of methanol extract of Aloe vera in rats

Safety evaluation of supercritical carbon dioxide extract of Aloe vera gel

Toxicologic assessment of a commercial decolorized whole leaf Aloe vera juice, lily of the desert filtered whole leaf juice with aloesorb

Toxicological studies on the leaf extract of Aloe ferox Mill. (Aloaceae)

Evaluation of anti-inflammatory activity and analgesic effect of Aloe vera leaf extract in rats

Aphrodisiac potentials of the ethanol extract of Aloe barbadensis Mill. root in male Wistar rats

Toxicological investigations of Aloe ferox Mill extracts using Brine shrimp (Artemia salina L.) assay

Toxicоlogical evaluation of the plant products using Brine Shrimp (Artemia salina L.) model

Acute and sub-chronic toxicity studies of three plants used in Cameroonian ethnoveterinary medicine: Aloe vera (L.) Burm. f. (Xanthorrhoeaceae) leaves, Carica papaya L. (Caricaceae) seeds or leaves, and Mimosa pudica L. (Fabaceae) leaves in Kabir chicks

Toxicity studies on six plants used in the traditional Arab system of medicine

A study on analgesic efficacy and adverse effects of Aloe vera in Wistar rats

In vivo safety evaluation of UP780, a standardized composition of aloe chromone aloesin formulated with an Aloe vera inner leaf fillet

Toxicological evaluation of aqueous extract of Aloe ferox Mill in loperamide-induced constipated rats

The No-Observed-Adverse-Effect Level (NOAEL) of Baby Aloe Powder (BAP) for nutraceutical application based upon toxicological evaluation

Effects of oral administration of Aloe vera plus on the heart and kidney: a subacute toxicity study in rat models

Histopathological changes of male mice kidneys treated with fresh Aloe vera whole leaf extract

Preclinical toxicological evaluation of Aloe vera health drinks in Wistar rats

Treatment-related changes after short-term exposure of SD rats to Aloe vera whole-leaf freeze-dried powder

Biochemical and histological alterations in reproductive tract tissues of male swiss albino mice exposed commercially prepared Aloe vera gel product

Safety evaluation of Aloe vera pulp aqueous extract based on histoarchitectural and biochemical alterations in mice

Safety of purified decolorized (low anthraquinone) whole leaf Aloe vera (L) Burm. whole leaf juice in a 3-month drinking water toxicity study in F344 rats

Safety studies conducted on a proprietary high-purity Aloe vera inner leaf fillet preparation

Toxicology and carcinogenesis studies of a non-decolorized whole leaf extract of Aloe barbadensis Miller (Aloe vera) in F344/N rats and B6C3F1 mice (drinking water study)

A purgative action of barbaloin is induced by Eubacterium sp. strain BAR, a human intestinal anaerobe, capable of transforming barbaloin to aloe-emodinanthrone

From the cover: aloin, a component of the Aloe vera plant leaf, induces pathological changes and modulates the composition of microbiota in the large intestines of F344/N male rats

Aloe emodin induces hepatotoxicity by activating NF-κB inflammatory pathway and P53 apoptosis pathway in zebrafish

Aloe-emodin induces apoptosis in human liver HL-7702 cells through Fas death pathway and the mitochondrial pathway by generating reactive oxygen species

Activity-guided chemo toxic profiling of Cassia occidentalis (CO) seeds: Detection of toxic compounds in body fluids of CO-exposed patients and experimental rats

Aloe-emodininduced DNA fragmentation in the mouse in vivo comet assay

Photochemistry and phototoxicity of aloe emodin

Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods

SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor

Ethnomedicinal herbs in African traditional medicine with potential activity for the prevention, treatment, and management of coronavirus disease 2019

COVID-19: Pathophysiology, diagnosis, complications and Investigational therapeutics

Pathophysiology and treatment strategies for COVID-19

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Could the COVID-19 pandemic aggravate antimicrobial resistance

Identification of potential inhibitors of SARS-CoV-2 main protease from Aloe vera compounds: a molecular docking study

In vitro anti-inflammatory activity of Aloe vera by down regulation of MMP-9 in peripheral blood mononuclear cells

Anti-inflammatory and analgesic effects of aqueous extract of Aloe vera (Aloe barbadensis) in rats

Anti-inflammatory effects of Aloe vera gel in human colorectal mucosa in vitro

Anti-inflammatory and wound healing activity of a growth substance in Aloe vera

Anti-inflammatory and wound healing properties of Aloe vera

Anti-inflammatory activity of Aloe vera against a spectrum of irritants

In vitro immunomodulatory effect of food supplement from Aloe vera

Immunomodulatory effects of Aloe vera and its fractions on response of macrophages against Candida albicans

Studies on immunomodulatory activity of Aloe vera (Linn)

Immunomodulatory properties of Aloe vera gel in mice

Beta-Sitosterol: As Immunostimulant, Antioxidant and Inhibitor of SARS-CoV-2 Spike Glycoprotein

Zn2+ inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture

Identification of potential SARS-CoV-2 main protease and spike protein inhibitors from the Genus Aloe: an in silico study for drug development

Anti-Propionibacterium acnes and the antiinflammatory effect of Aloe ferox miller components

Analgesic and anti-inflammatory activities of Aloe ferox Mill. aqueous extract