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Potential protective effects of Aloe vera gel on cardiovascular diseases: A mini‐

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Article  in  Phytotherapy Research · August 2021

DOI: 10.1002/ptr.7219

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Title: Potential protective effects of Aloe vera gel on cardiovascular diseases: A mini-review

Authors
Saeideh Sabbaghzadegan 1,2, Haide Golsorkhi 1,2, Mohammad Hossein Soltani 3, Mohammad Kamalinejad
4
, Mohsen Bahrami 5, Ali Kabir 6, Majid Dadmehr 1,2*

Affiliations
1
School of Persian Medicine, Iran University of Medical Sciences, Tehran, Iran
2
Research Institute for Islamic and Complementary Medicine, Iran University of Medical Sciences,
Tehran, Iran
3
Yazd Cardiovascular Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
4
Department of Pharmacognosy, School of Pharmacy, Shahid Beheshti University of Medical Sciences,
Tehran, Iran
5
MD-PhD of Persian Medicine, Private clinic, Tehran, Iran
6
Associate Professor of Epidemiology, Minimally Invasive Surgery Research Center, Iran University of
Medical Sciences, Tehran, Iran

* Corresponding author
Majid Dadmehr, MD-PhD.
Assistant professor in Persian medicine
Iran University of Medical Sciences, Tehran, Iran
Behesht St, Vahdat Islami St. Tehran, Iran. Postal Code: 1114733311 Tel: +98‐ 21‐55639667
Email: majiddadmehr@yahoo.com
Abstract
Cardiovascular diseases (CVDs) comprise the most prevalent causes of morbidity and mortality in both
men and women worldwide. CVDs are associated with several risk factors such as hyperlipidemia,
diabetes mellitus, hypertension, obesity, tobacco smoking and an unhealthy diet. Currently, in addition to
the use of related pharmacological treatments in the management of CVDs, the investigation of other
suitable healthcare approaches for these disorders such as the identification of herbal medicines has been
considered in the scientific communities. Aloe vera (L.) Burm.f. is a perennial medicinal plant. The
innermost leaf layer of this plant contains transparent gel, which is used as food. Pre-clinical studies have
shown several biological activities of Aloe vera gel (AVG), including antidiabetic, lipid-lowering,
antioxidant, anti-inflammatory, hepatoprotective, and immunomodulatory effects. Other pharmacological
activities of AVG such as anti-fibrotic, anti-hypertensive, and anti-atherosclerotic effects have been
reported. Moreover, several clinical studies have demonstrated the ameliorating effects of AVG on some
markers of CVDs risk factors. Thus, this study was conducted to review clinical trials besides in vitro and
in vivo studies on the cardiac beneficial effects of AVG. However, further high-quality studies are needed
to firmly establish the clinical efficacy of the plant.

Keywords: Aloe vera gel, herbal medicine, cardiovascular diseases, cardioprotective

Abbreviations
CVD, Cardiovascular diseases; WHO, World Health Organization; DM, diabetes mellitus; AVG, Aloe
vera gel; MetS, metabolic syndrome; Fe, iron; Mn, manganese; K, potassium; Zn, zinc; V, vanadium; Na,
sodium; Mg, magnesium; Cu, copper; Cr, chromium; Ca, calcium; Pb, lead; Se, selenium; Lo, lophenol;
Cy, cycloartenol; ROS, reactive oxygen species; LDH, lactate dehydrogenase; CK, creatine kinase; GSH,
glutathione peroxidase; I/R, ischemia-reperfusion SOD, superoxide dismutase; CAT, catalase; MDA,
malondialdehyde; ISO, isoprenaline; CK-MB, creatine kinase-MB; MP, methylprednisolone; HA,
hyaluronic acid; TGF-β, Transforming growth factor-β; AHM, Aloe vera high molecular weight fractions;
MMP-2, Matrix metalloproteinase-2; OSMF, oral submucous fibrosis; PGE2, prostaglandin E2; IL-8,
interleukin-8; HbA1c, hemoglobin A1c; FBS, fasting blood sugar; BP, blood pressure; PPG, postprandial
glucose; TC, Total Cholesterol; TG, Triglyceride; LDL, low-density lipoprotein; HDL-C, high-density
lipoprotein cholesterol; VLDL, very low-density lipoprotein cholesterol; BP, Free fatty acid; HOMA,
homeostasis model assessment; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CNS,
central nervous system; CRP, C-reactive protein.
1. Introduction
Cardiovascular diseases (CVDs) comprise the most prevalent causes of morbidity and mortality in both
men and women worldwide (Mc Namara et al., 2019; Shaito et al., 2020). According to the report of the
World Health Organization (WHO), CVDs remain an important economic and health burden and are
responsible for about 31% of annual global deaths (Shaito et al., 2020; Wu et al., 2020). CVDs refer to
several diseases, some of which include coronary heart disease, myocardial infarction, peripheral vascular
diseases and hypertension, which are mainly caused by vascular dysfunction (S. Jain, Buttar,
Chintameneni, & Kaur, 2018; Naveed et al., 2020; Shaito et al., 2020). Several risk factors have been
proposed for these diseases such as hyperlipidemia, diabetes mellitus (DM), hypertension, obesity,
tobacco smoking, and an unhealthy diet (Mc Namara et al., 2019; Thayer, Yamamoto, & Brosschot,
2010). Administration of pharmacological treatments and modification of these risk factors are some of
the approaches used to manage CVDs. Although there are many advances in the management and
treatment of CVDs, some of these pharmacological treatments have limited efficacy and long-term use of
them may have significant adverse effects. In the scientific communities, the investigation of bioactive
phytomolecules is considered a source to provide us probable therapeutic approach for different diseases.
Based on an evaluation of the clinical data on the side effects of herbal preparations, it seems that herbal
medicines are more tolerable than synthetic medications. Therefore, the use of herbal medicines has been
considered as an alternative treatment for CVDs. However, possible serious adverse events such as herb-
drug interactions should be considered (Angelo A Izzo, Hoon‐Kim, Radhakrishnan, & Williamson, 2016;
S. Jain et al., 2018; Mc Namara et al., 2019; Shaito et al., 2020; Yousefsani et al., 2021).
Aloe vera (L.) Burm.f. is a perennial medicinal plant that belongs to the Liliaceae family. Among 360
species of aloe, this type is the most widely used medicinal product and is one of the richest natural
sources for human health. It has root parts, fleshy leaves, tubular yellow flowers, fruit and seeds (Figure
1). The leaves of this plant have three main layers; outer, middle, and inner layers. The outer layer is the
green part of the leaf and the middle layer is the intact part that must be extracted to use its constituents
(Liang et al., 2020; Shakib et al., 2019).
The middle layer contains parenchymal cells and also called pulp or latex. This layer contains pericyclic
cells and is derived from secretions extracted from mid-layer parenchymal tissue cells to form a viscous,
bitter and yellow fluid (Liang et al., 2020; Steenkamp & Stewart, 2007). Only the bitter yellow exudate of
the aloe juice or sap in the middle layer contains 1,8 dihydroxyanthraquinone derivatives and their
glycosides, which have strong laxative effects (Desalegn & Ahmed, 2020; Liang et al., 2020; Steenkamp
& Stewart, 2007; Hamman, 2008).
The innermost leaf layer contains transparent mucilaginous gel, which has 99.5% water and the remaining
0.5% of the residue containing water-soluble and fat-soluble vitamins, mineral elements, enzymes,
polysaccharides, phenolic compounds, and organic acids (Guo & Mei, 2016; Hamman, 2008; Liang et al.,
2020). The mucilaginous tissue from the leaves is the part of the plant that generally used and its key
constituent is a polysaccharide. The inner layer of the leaf, or Aloe vera gel (AVG), does not contain
anthraquinone and has no laxative effect (Sánchez-Machado et al., 2017; Steenkamp & Stewart, 2007).
Current pharmacological studies represent that AVG has several biological activities, including antiulcer,
antidiabetic, lipid-lowering, antimicrobial, antineoplastic, antioxidant, anti-inflammatory,
hepatoprotective and immunomodulatory effects (Manvitha & Bidya, 2014; Shakib et al., 2019). There is
the possibility that most of the studies discussed in the present review article have been not performed in
accordance with a recent consensus document providing a perspective in best practice in pharmacological
research on bioactive preparations from plants (Angelo A Izzo et al., 2020). Therefore, further high-
quality studies are needed to firmly establish the clinical efficacy of the plant (Andrew & Izzo, 2017; A.
A. Izzo, Hoon-Kim, Radhakrishnan, & Williamson, 2016). Shakib et al. reviewed the evidence on the
favorable effects of AVG on metabolic syndrome (MetS) risk factors (e.g., hyperglycemia,
hyperlipidemia, hypertension, and obesity) (Shakib et al., 2019). Although the risk factors for MetS and
CVDs have some similarities, other pharmacological actions of this gel on CVDs risk factors, including
anti-inflammatory, antioxidant, anti-fibrosis, anti-atherosclerotic effects were not considered properly. In
this study, we intend to provide an overview of all aspects of cardiac beneficial effects of AVG through
reviewing clinical trials besides in vitro and in vivo studies. This information makes it possible to provide
a basis for future researches and to develop new therapeutic approaches.

2. Literature review method

In this review, we searched different electronic databases, including PubMed, Scopus, Science Direct, and
Web of Science to find articles describing beneficial effects of AVG or its isolated phytochemicals on the
cardiovascular system. Data were collected from June 1980 up to June 2020. We considered only
published articles in the English language with a focus on clinical trials, review articles, in vivo and in
vitro studies. The search was performed with the scientific name and common name of A. vera combined
with “phytochemistry”, “pharmacological activity,” “antioxidant,” “anti-fibrotic,” “anti-inflammatory,”
“atherosclerosis,” “dyslipidemia,” “hyperlipidemia,” “hypertension,” “hyperglycemia,” “diabetes
mellitus,” “diabetes type II,” “metabolic disorder,” “obesity,” “cardiovascular,” “cardioprotective,”
“heart,” “toxicity,” and “safety”. Related articles, which illustrated the effects of AVG on the
cardiovascular system, were reviewed and included in this paper.
3. Phytochemistry
Phytochemical examinations on AVG have demonstrated the presence of more than 200 different types of
bioactive chemicals, including polysaccharides, sugars, minerals, proteins, lipids, phenolic compounds,
vitamins, enzymes, lignin and saponins (Ahlawat & Khatkar, 2011; Sharma, Kharkwal, Kharkwal, Abdin,
& Varma, 2014). There are about 20 amino acids needed by the human body (including seven essential
amino acids) present in AVG (Sharma et al., 2014).
Recent studies have shown that bradykinase, cellulase, carboxypeptidase, catalase, lipase, amylase, alkaline
phosphatase, and peroxidase are among the enzymes in AVG (Ahlawat & Khatkar, 2011; Sharma et al.,
2014).
Furthermore, an anti-allergic glycoprotein namely aloprogen, C-glycosyl chromones with anti-
inflammatory properties, and saponins with antiseptic activities were isolated from AVG (Ahlawat &
Khatkar, 2011). A. vera is a rich source of polysaccharides; about 55% of the dry weight basis of AVG
consists of polysaccharides (e.g., glucomannan, acetylated polymannan, acemannan and mannose-6-
phosphate) (Ahlawat & Khatkar, 2011; Liang et al., 2020; Sánchez-Machado et al., 2017). Lots of
therapeutic effects of A. vera are related to the presence of polysaccharides in its gel (Sánchez-Machado et
al., 2017). Acemannan, is considered one of the major active components of AVG (Figure 1). It possesses
several pharmacological and biological activities, including immunomodulation, anticancer, antioxidant,
wound healing, neuroprotective, hepatoprotective and intestinal health promotion (Guo & Mei, 2016; Liu
et al., 2019).
Various mineral elements have been reported in AVG, including iron (Fe), manganese (Mn), potassium
(K), zinc (Zn), vanadium (V), sodium (Na), magnesium (Mg), copper (Cu), chromium (Cr), calcium (Ca),
lead (Pb), and selenium (Se). These minerals participate in enzymatic and antioxidant functions (Ahlawat
& Khatkar, 2011; Subbiah Rajasekaran, Sivagnanam, & Subramanian, 2005; Sharma et al., 2014). Mineral
elements, such as Fe, Zn, Cu, and Se have an important role in cell metabolism and cardiovascular function
as well. A positive correlation has been reported between balance at the levels of serum metals and
cardiovascular events and their risk factors (Mohammadifard et al., 2019).
Moreover, AVG contains a lot of antioxidant vitamins, including vitamin C, E, A, B1, B2, B12, niacin,
choline and folic acid (Ahlawat & Khatkar, 2011; Sánchez-Machado et al., 2017). Han et al. reviewed 42
articles in a meta-analysis study to evaluate the efficacy of vitamin supplements for the prevention of major
CVDs. Vitamins B, D, and E showed varying degrees of reduction in the incidence of CVDs (Han, Zhao,
Cai, & Liang, 2020). In addition, a case-control study showed that decreased serum levels of vitamin C
were significantly associated with the risk of coronary heart disease (Torkzaban, Naeini, Hassanzadeh, &
Namdari, 2020). Also, two phytosterols called lophenol (Lo) and cycloartenol (Cy) are reported in AVG,
which play an important role in the regulation of blood glucose (Shakib et al., 2019).
4. Pharmacological effects
Previous in vivo, in vitro, and clinical studies suggested that AVG has several beneficial effects on the risk
factors of CVDs, including hyperglycemia, hyperlipidemia, hypertension, atherosclerosis, and obesity
(Figure 2). A summary of the studies regarding the effects of AVG on CVDs and their risk factors is
presented in Table 1.
4.1. Anti-oxidant effect
According to the findings of recent studies, reactive oxygen species (ROS) play a significant role in the
pathogenesis of acute and chronic heart diseases. Medicinal herbs with antioxidant properties have the
potential for therapeutic effects against CVDs through scavenging and reducing ROS activity (Wang,
Mehendale, & Yuan, 2007). AVG contains important antioxidant compounds such as antioxidant
vitamins (C, A (β carotene), choline, folic acid, α tocopherol (vitamin E), B1, B2, B6, B12), carotenoids,
flavonoids, and tannins (Ahlawat & Khatkar, 2011; Sánchez-Machado et al., 2017; Shakib et al., 2019).
Also, polysaccharides are one of the most important components of AVG that have several beneficial
pharmacological properties, including antimicrobial, antitumor, antiviral, and antioxidant activities (Liu et
al., 2019; Sumi et al., 2019). Acemannan is the main bioactive polysaccharide of AVG, which
demonstrated scavenging effects on free radicals in several in vitro and in vivo experiments (Liu et al.,
2019).
4.1.1. Animal studies regarding anti-oxidant effects
Kaithwas et al. were examined the antioxidant activity of polysaccharides of AVG in vitro and in vivo.
They found that administration of AVG for 14 days in albino Wistar rats has noticeable protective effects
against doxorubicin-induced myocardial oxidative stress. This treatment exhibited a considerable
reduction in serum lactate dehydrogenase (LDH) and creatine kinase (CK) and improved levels of blood
and tissue glutathione (GSH) as an antioxidant enzyme (Kaithwas, Singh, & Bhatia, 2014).
Another animal study evaluated the effects of polysaccharides from AVG in suppressing oxidative stress
and cell injury in the ischemia-reperfusion (I/R) model of rats. At the end of the study, an improvement in
antioxidant enzyme activity (SOD, CAT, and GSH) were seen. Moreover, malondialdehyde (MDA)
levels and infarct sizes were reduced in isolated rat hearts (Yang, Yang, Ai, & Huang, 2017). Sumi et al.
evaluated the cardioprotective effect of AVG on isoprenaline (ISO)-administered myocardial infarction in
rats. After treatment with AVG for 14 days twice a week, a reduction in lipid peroxidation, creatine
kinase-MB (CK-MB) enzyme activities, glutathione concentration and oxidative stress were reported.
They reported a significant increase in cellular antioxidant activities such as SOD, CAT, and GSH (Sumi
et al., 2019).
Rahoui et al. evaluated the antioxidant effects of AVG. They mentioned that the administration of AVG at
doses of 100 and 200 mg/kg in obese rats could correct oxidative stress (Rahoui et al., 2018). Guven et al.
investigated the antioxidant and anti-inflammatory effects of AVG on rats with experimental sciatic nerve
I/R injury compared with methylprednisolone (MP). After administration of 30 mg/kg/day of AVG for
one month, a significant decrease in MDA and increase in SOD activity were detected. The authors
concluded that AVG had strong antioxidant and anti-inflammatory properties and was as effective as MP
(Guven et al., 2016).
According to the above‐mentioned studies many antioxidant effects can be considered for AVG. Its
antioxidant properties may be related to the presence of polysaccharides, vitamins and some minerals.
Bioactive polysaccharides e.g., Acemannan, have revealed scavenging effects on free radicals. Studies in
animal heart samples have shown an improvement in the antioxidant enzyme activity (SOD, CAT, and
GSH) and a reduction in MDA. However, these experimental studies have some limitations and to
evaluate the antioxidant effectiveness of AVG in the cardiovascular system, more studies with higher
quality are required, especially clinical trials in patients with CVDs.

4.2. Anti-fibrotic effect

A variety of cardiac dysfunctions appear to be caused by a common fibrotic process. Cardiac fibrosis is
mediated by changes in growth factor-β1 and stimulation of collagen-producing cardiac fibroblasts (Khan
& Sheppard, 2006). Fibrotic scars in the heart tissue lead to myocardial matrix stiffness, which result in
the reduction in the ejection fraction. These scars can also cause death by impairing electrical conduction
(Hinderer & Schenke-Layland, 2019).
4.2.1. Animal study regarding anti-fibrotic effects
Treatment with AVG showed protective effects against cardiac fibrosis of ISO-administered rats. Cardiac
damages in ISO-induced cardiotoxicity include infiltration of mononuclear inflammatory cells,
cardiomyocyte hypertrophy, heart fibrosis, and inflammation. AVG treatment at doses of 5% gel mixed
with powder chow food, w/w for 14 days ameliorated these damages and inhibited the infiltration of
inflammatory cells and necrosis in the heart. Finally, this treatment could reduce left ventricular fibrosis
in the hearts of ISO-treated rats (Sumi et al., 2019). Administration of selenium polysaccharide from
AVG for seven consecutive days in three different doses (100, 200, and 400 mg/kg) in an animal study
on rats, increases GSH activity in the heart tissue and reduces the occurrence of I/R injury (Yang et al.,
2017). Moreover, A. vera has an angiogenic effect and causes the formation of new blood vessels.
Treatment with AVG on 18 albino rats showed an increase in capillary formation in the choroid plexus
region (Kosif, Aktas, & Oztekin, 2008).
 4.2.2. Clinical studies
In a randomized clinical trial performed in 2012, Hegazy et al. revealed that AVG has anti-fibrotic effects
on acute liver fibrosis induced by a viral infection. In this study, administration of AVG for 12 weeks
demonstrated significant ameliorating effects on liver fibrosis and inflammation. The serum levels of
fibrosis markers, including hyaluronic acid (HA), transforming growth factor-β (TGF-β) and matrix
metalloproteinase-2 (MMP-2), significantly decreased after AVG treatment. Moreover, the expression of
hepatic α-smooth muscle actin (α-SMA) was reduced in comparison to the control group (Hegazy, El-
Bedewy, & Yagi, 2012).
Several clinical trials evaluated the efficacy of AVG on the treatment of oral submucous fibrosis (OSMF).
According to their findings, administration of AVG revealed considerable amelioration in most clinical
manifestations of OSMF. AVG can be safe and useful in the management of fibrosis (Alam et al., 2013;
Anuradha, Patil, & Asha, 2017).
AVG can play a role in inhibiting the infiltration of inflammatory cells and necrosis in the heart and also
reduces left ventricular fibrosis through various mechanisms. In human studies, AVG exhibited significant
anti-fibrosis effects in liver fibrosis and OSMF. However, this impact was not evaluated in cases with
cardiac fibrosis. Therefore, considering the characteristics such as improving the levels of fibrosis markers
and angiogenesis, it may be possible to consider AVG a suitable candidate for further studies on human
cardiac fibrosis.
4.3. Anti-inflammatory effects
Regardless of the etiology of heart failure, cardiac inflammation and fibrosis are among the most
important pathophysiological mechanisms (Suthahar, Meijers, Silljé, & de Boer, 2017). Current studies
demonstrate that herbal-derived products have anti-inflammatory and immunoregulatory activities and
point out special activity on inflammatory mediators (Bahrami et al., 2020). A. vera has
immunomodulatory effects and can inhibit the inflammatory response, reduction of leukocyte adhesion
and demonstrated phagocytic activity as well (Duansak, Somboonwong, & Patumraj, 2003; Im et al.,
2005). Moreover, A. vera significantly attenuated the production of pro-inflammatory cytokines and
down-regulated inflammasome in human macrophages expression (Budai, Varga, Milesz, Tőzsér, &
Benkő, 2013).
4.3.1. Experimental studies regarding anti-inflammatory effects
Several in vitro and in vivo studies have focused on the anti-inflammatory actions of AVG. Langmead et
al. evaluated AVG effects on human colorectal mucosa. This study showed that AVG was able to inhibit
the production of reactive oxygen metabolites and prostaglandin E2 (PGE2), and reduced the release of
interleukin-8 (IL-8). (Langmead, Makins, & Rampton, 2004).
The aqueous extract of AVG demonstrated anti-inflammatory property through inhibition of PGE2
production and cyclooxygenase activity in rat paw edema modeling caused by the injection of
carrageenan (Vázquez, Avila, Segura, & Escalante, 1996).
In another study with a similar method, administration of AVG extract at doses of 100-400 mg/kg
confirmed its significant acute anti-inflammatory and immune stimulant activities. The authors suggested
that AVG shows anti-inflammatory effects by affecting kinin, prostaglandin and bradykinin release
(Bhalsinge et al., 2018).
After a 14-day treatment with AVG, the pathological examination on rat cardiac tissue demonstrated its
preventive effects on the infiltration of inflammatory cells, cardiac inflammation and oxidative stress
(Sumi et al., 2019).
According to different animal studies, AVG has anti-inflammatory action probably through the inhibition
of the cyclooxygenase pathway, production of reactive oxygen metabolites and PGE2, and reduced
releasing of IL-8. Also, AVG can influence the infiltration of inflammatory cells, inflammation, and
oxidative stress in cardiac tissue.

4.4. Metabolic pathway

Metabolic syndrome (MetS) is a global public health problem. This condition generally is followed by a
sedentary lifestyle, high levels of mental stress and an unhealthy diet. MetS is a major risk factor for
CVDs and DM, which consists of several medical conditions, including hyperglycemia, dyslipidemia,
high blood pressure (BP) and the presence of central obesity (Cramer, Langhorst, Dobos, & Lauche,
2016). The ameliorative effects of AVG on various components of the MetS have been investigated.
AVG has several pharmacological effects such as lipid‐lowering, antihypertensive, hypoglycemic, anti-
obesity, and cardioprotective properties (Shakib et al., 2019).

4.4.1. Hypoglycemic effect

There is a close relationship between DM and CVDs. Diabetes is recognized as a major risk factor for the
development and progression of CVDs (Leon & Maddox, 2015). Previously, the blood-glucose-lowering
effect of AVG has been considered in several studies (Choi, Kim, Son, Oh, & Cho, 2013; S Rajasekaran,
Sivagnanam, Ravi, & Subramanian, 2004; Tanaka et al., 2006).

4.4.1.1. Animal studies regarding hypoglycemic effects

Several phytosterol compounds isolated from AVG, including lophenol, 24-methyl-lophenol, 24-ethyl-
lophenol, cycloartanol, and 24-methylene-cycloartanol showed a long-term anti-diabetic effect in type 2
diabetic mice. Administration of these phytosterols for 28 days significantly decreased hemoglobin A1c
(HbA1c) and fasting blood sugar (FBS) levels in comparison to vehicle-treated mice (Tanaka et al.,
2006).
Rajasekaran et al. evaluated the hypoglycemic activity of AVG. They reported that oral administration of
the alcoholic extracts of AVG on diabetic rats at doses of 200 and 300 mg/kg for 21 days exhibited a
significant reduction in the blood glucose levels in the experimental group. The results showed that the
glucose-lowering effect of AVG may be through enhancement of glucose metabolism (S Rajasekaran et
al., 2004). In another study, the effect of two phytosterols of AVG namely Lo and Cy are examined on the
obese animal model of type II diabetes. The findings of this study demonstrated that these phytosterols
could reduce random blood sugar levels, hyperglycemia and HbA1c (Misawa et al., 2008).
AVG represented significant anti-diabetic and cardioprotective properties. Administration of AVG at a
dose of 200 mg/kg for 20 days in streptozocin diabetic rats displayed a significant reduction in blood
sugar, glycosylated hemoglobin, serum LDH and serum CK levels, and also normalized the levels of
SOD and CAT activity with an increase in the blood reduced glutathione level (N. Jain, Vijayaraghavan,
Pant, Lomash, & Ali, 2010)
4.4.1.2. Clinical studies
Several clinical trials have investigated the beneficial effects of AVG in the treatment of diabetic patients
(Agarwal, 1985; Ngo, Nguyen, & Shah, 2010; Yagi, Hegazy, Kabbash, & Abd-El Wahab, 2009). A 12-
week clinical study was conducted to evaluate the hypoglycemic effect of Aloe vera high molecular
weight fractions (AHM) fractions on uncontrolled type II diabetic patients. In this study, nine males and
six females received two tablespoonsful (0.05 g) of AHM three times a day for three months, concurrently
with their oral anti-diabetic drugs. At the end of the study, a significant decrease was reported in the FBS
and HbA1C levels (Yagi et al., 2009).
Devaraj et al. in a double-blind, placebo-controlled trial examined the effect of AVG on a total of 45
subjects with prediabetes over 8-weeks. According to the findings of this study, there were significant
reductions in parameters of glycemic control (FBS, HbA1c, insulin, fructosamine). The hypoglycemic
effects of AVG have been linked to its acemannan component (Devaraj et al., 2013). Agarwal has
performed a large observational study in 5000 patients with atheromatous heart disease and DM. Over a
five-year period, he added Plantago ovata seed and AVG to their diets. At the end of the study, he found
that this herbal formula produces a specific reduction in FBS and post-prandial glucose (PPG) in diabetic
patients (Agarwal, 1985).
Ngo et al. conducted a review study in 2010. They evaluated the available literature on the efficacy of oral
A. vera in patients with DM and dyslipidemia. They included eight trials with a total of 5285 participants.
Finally, they concluded that oral consumption of A. vera is desirable for the treatment of high blood
glucose and reduction of lipid parameters in human subjects. However, evidence regarding the efficacy of
oral AVG in these patients was conflicting. Variations in the findings of these studies may be due to
different formulations and doses of AVG as well as variations in its preparation and the part of the plant
used (Ngo et al., 2010).
A meta-analysis of eight controlled studies was conducted by Suksomboon et al. for evaluation of anti-
diabetic effects of AVG. This systematic review involved 470 patients. The findings showed that AVG
treatment significantly ameliorated FBS with no effect on HbA1c in pre-diabetic patients. The results of
glycemic control in diabetic patients were as follows an improvement in FBS was marginal and a significant
improvement in HbA1c was seen (Suksomboon, Poolsup, & Punthanitisarn, 2016).
Based on different animal and clinical studies AVG is effective in reducing blood glucose. Various
mechanisms have been proposed for its hypoglycemic effects. AVG contains several phytosterol
compounds, especially Lo and Cy, which showed a long-term anti-diabetic effect. Moreover, the
Acemannan component plays an important role in the regulation of blood glucose. Other mechanisms are
related to its antioxidant activity and regulatory role in glucose metabolism.

4.4.2. Hypolipidemic effect

Dyslipidemia considerably correlates with the development of atherosclerosis and subsequent CVDs
(Rahoui et al., 2018). Several studies demonstrated that AVG has hypolipidemic properties and can reduce
serum levels of total cholesterol (TC), triglyceride (TG) and low-density lipoprotein (LDL) (Agarwal, 1985;
Kumar, Goyal, & Tewari, 2007; Manvitha & Bidya, 2014).

4.4.2.1. Animal studies regarding hypolipidemic effects

In an experimental study on streptozotocin-induced diabetic rats, the hypolipidemic effects of AVG were
evaluated. The findings of this study demonstrated that consumption of AVG for six weeks significantly
decreased levels of TG, TC, LDL and very-low-density lipoprotein cholesterol (VLDL) (Hosseini et al.,
2020). Furthermore, AVG treatment at doses of 100 and 200 mg/kg/day showed beneficial effects against
dyslipidemia and oxidative stress; also, prevented the accumulation of adipose tissue in obese rats (Rahoui
et al., 2018). The phytosterols in A. vera bind to the cholesterol and inhibit its intestinal absorption (Shakib
et al., 2019).
4.4.2.2. Clinical studies
The lipid-lowering effects of AVG have been investigated in several clinical trials. Choudhary et al.
examined the hypolipidemic effects of AVG on patients with DM. After three months of treatment, the
findings revealed a significant reduction in the levels of TC, TG, LDL and VLDL-C, and an increase in
high-density lipoprotein cholesterol (HDL-C) (Choudhary, Kochhar, & Sangha, 2014).
In another clinical study, the beneficial effects of AVG were evaluated on the lipid profile of 45 subjects
with prediabetes/metabolic syndrome. Over 8 weeks of AVG treatment, there were significant reductions
in TC and LDL-C levels (Devaraj et al., 2013).
Yagi et al. investigated the efficacy of A. vera in 15 patients with type 2 DM for 6 weeks. According to
their findings, administration of AVG could not change the serum TC whereas TG level was reduced
significantly compared to pre-treatment. No side effects were observed on kidney and liver functions (Yagi
et al., 2009).
In a meta-analysis, Zhang et al. evaluated controlled studies for the efficacy of A. vera supplementation on
patients with prediabetes and early non-treated diabetic. They included five controlled studies involving
415 participants. This systematic review indicated that A. vera supplementation was superior to placebo in
a significant reduction of TG, TC and LDL-C. Also, it increased the serum level of HDL-C in these patients
(Zhang, Liu, Liu, Zhao, & Tian, 2016).
According to animal and experimental studies, AVG has shown significant effects against hyperlipidemia.
AVG can affect dyslipidemia by inhibiting the accumulation of adipose tissue. Meanwhile, it prevents the
intestinal absorption of cholesterol by binding its phytosterols to cholesterol.
4.4.3. Antihypertensive effect
Elevated BP is a common medical condition that can be the main risk factor for CVDs. Several
pharmacological antihypertensive drugs have been used; however, in some cases inability to achieve BP
control and drug adverse reactions to these medications were reported in some cases. Accordingly, natural
plant products have been considered new BP-lowering medications (Sultana & Muhammad Asif, 2017).
The Mg in the plant may play a role in decreasing BP by maintaining a balance of Ca and K (Karimi et al.,
2020).

4.4.3.1. Animal studies regarding antihypertensive effects

The hypotensive effect of this plant has been reported by Saleem et al. in an experimental rat study
(Saleem et al., 2001). Moreover, the BP-lowering effect of AVG was evaluated in cadmium sulfate-
induced hypertensive rats. The results of this study showed that AVG pre-treatment (300 and 600 mg/kg)
had preventive effects on cadmium-induced hypertension. In another study, administration of AVG at
doses of 300 and 600 mg/kg once a day for two weeks significantly reduced BP in cadmium-induced
hypertensive rats. After 28 days of treatment with 600 mg/kg of AVG, BP was restored to normal levels
(Isirima & Siminialayi, 2012). Kumar et al. examined the positive inotropic and chronotropic effects of
AVG on isolated rat hearts. The results obtained in this study displayed that treatment with an aqueous
solution of AVG at doses of 200 and 300 mg/l increased the heart rate, myocardial contractility and
coronary blood flow in the hearts of the experimental rats. Finally, the authors concluded that the active
ingredients of AVG could be responsible for stimulation of β-adrenergic receptors and sympathetic
discharge of noradrenalin, which lead to coronary vasodilation as well as an increase in heart rate and its
contractility (Kumar et al., 2007).
4.4.3.2. Clinical studies
The antihypertensive effect of AVG was investigated in a double‐blind clinical study on 90 patients with
DM. The study participants were divided into three groups. The first group was not treated. Groups II and
III were treated with 100 and 200 mg of AVG, respectively. After three months of treatment, there is a
significant reduction in systolic and diastolic BP of the subjects of group II and III (Choudhary et al., 2014).
Few studies have examined the BP-lowering effects of AVG. Therefore, its possible path for hypotensive
effect is not clear. Owing to the phytochemical properties of the plant and its pharmacological effects in
various studies, it may be possible to raise some issues. It has the potential to improve BP due to the
presence of phenolic compounds, antioxidant vitamins and some minerals (e.g., Ca) in AVG.

4.4.4. Anti-obesity effect

Obesity and increased adipose tissue are the leading causes of CVDs. It is well known that obesity leads
to dyslipidemia, insulin resistance, hypertension, endothelial dysfunction and atheroma formation
(Cercato & Fonseca, 2019).
Several studies confirmed the beneficial effects of AVG on hyperlipidemia and obesity. AVG is involved
in lipid metabolism and reducing the accumulation of visceral fat (Shakib et al., 2019; Sumi et al., 2019)

4.4.4.1. Animal studies regarding anti-obesity effects

Misawa et al. in their studies showed that administration of Lo and Cy, two kinds of AVG phytosterols in
diabetic rats significantly affected lipid metabolism and reduced the accumulation of visceral fat. A. vera
sterols have beneficial effects on the prevention and improvement of obesity-associated metabolic disorders
by altering the expression of genes involved in lipid metabolism (Misawa et al., 2012; Misawa et al., 2008).
4.4.4.2. Clinical study
Choi et al. investigated the effect of AVG on 136 obese prediabetes and early non-treated diabetic patients
in a randomized controlled trial. After eight weeks of AVG treatment, their body weight and body fat mass
were significantly reduced compared with the control group (Choi et al., 2013).
AVG reduces obesity by affecting the expression of those genes associated with lipid metabolism,
reduction of visceral fat accumulation, and improved liver steatosis.

4.5. Effect on atherosclerosis

Atherosclerosis is a chronic vascular disease that occurs following inflammation and accumulation of
cholesterol in the arterial wall. It is the main risk factor of CVD (Dana et al., 2012; Shaito et al., 2020).
Owing to the limited efficacy of its pharmacological treatments as well as their side effects, plant-derived
products have been considered natural and non-toxic substances in the prevention and treatment of
atherosclerosis (Moradi, Sewell, Lorigooini, & Rafieian-Kopaei, 2018). Medicinal plants can potentially
show anti-atherosclerotic activity mainly through their anti-inflammatory, antioxidant, anti-atherogenic,
hypotensive, lipid-lowering, and anti-thrombotic effects (Kirichenko et al., 2020). Molecular mechanisms
of the effectiveness of medicinal plants against atherosclerosis are as follows inhibitory effect on 3-
hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase), modulation of inflammatory
factors expression, activation of peroxisome proliferator-activated receptors (PPARs), regulation of ATP-
binding cassette transporter A1 (ABCA1), promotion of ATP-binding cassette transporter G (ABCG) and
antioxidant activity (Gholipour, Sewell, Lorigooini, & Rafieian-Kopaei, 2018). Several bioactive
compounds in medicinal plants, including phenols, flavonoids, flavones, anthocyanins, and tannins have
beneficial effects on the prevention and management of atherosclerosis. It seems that AVG can help to
treat atherosclerosis by reducing inflammation and dyslipidemia due to the presence of these components
(Asadi-Samani & Bahmani, 2016).

4.5.1. Animal study regarding the anti-atherosclerotic effect

The direct anti-atherosclerotic effect of AVG was confirmed in an experimental study. Dana et al.
examined the effects of AVG on some risk factors for atherosclerosis and fatty streak formation in 32
white male hypercholesterolemic rabbits. After 30 days of AVG treatment, TC and C-reactive protein
(CRP) levels were significantly reduced. Also, an investigation of atherosclerosis plaque formation in
aorta showed a significant reduction in the formation of fatty streaks in these animals. The authors
concluded that AVG has favorable effects on the prevention of fatty streak development through
modification of atherosclerosis risk factors (Dana et al., 2012).
It is believed that the consumption of vitamins such as vitamin C, D, and E is effective in preventing
atherogenesis as well as inhibiting the progression of atherosclerotic plaque (Rashidi, Hoseini, Sahebkar,
& Mirzaei, 2017). Furthermore, AVG can exhibit anti-atherosclerotic activity through its pharmacological
actions, such as anti-inflammatory, antioxidant, lipid-lowering, and anti-thrombotic effects, which can be
evaluated in animal and clinical studies.
5. Toxicity and safety of AVG
In the pre-clinical studies, determining the safety of natural compounds is as necessary as proving their
efficacy to be able to use safe compounds in the clinic (Angelo A Izzo et al., 2020). Although medicinal
plants are considered a good candidate for the treatment of some diseases, they are not completely safe
and their long-term use can have side effects. In very limited case reports aloe-induced toxicity has been
reported; however, numerous in vitro and in vivo studies have rejected AVG side effects (Akaberi,
Sobhani, Javadi, Sahebkar, & Emami, 2016).
5.1. Animal studies regarding toxicity and safety
In several animal studies, AVG treatment showed clear safety without genotoxicity (Bolkent et al., 2004;
Kishore, 2015; Sehgal, Winters, Scott, & Kousoulas, 2013). Serum liver enzymes such as alanine
aminotransferase (AST), aspartate aminotransferase (AST), alkaline phosphatase (ALP) were
significantly elevated in ISO-treated rats. Administration of AVG showed a significant hepatoprotective
effect and attenuated those serum biomarkers (Sumi et al., 2019).
Kosif et al. evaluated the effects of AVG on the central nervous system (CNS) of rats. The results of this
study demonstrate that AVG has not shown any toxic effects on neurons and glial cells in different areas of
CNS (Kosif et al., 2008).
5.2. Clinical studies
The first clinical use of AVG dates back to the 1930s for the treatment of radiation burns. Subsequently,
other clinical trials of AVG have been performed in the treatment of burn wounds, oral lichen planus,
hyperlipidemia in patients with DM, and recurrent aphthous stomatitis. Only some negligible adverse
effects have been reported. Moreover, no carcinogenic effects are available from using AVG (Guo & Mei,
2016).
Pothuraju et al. reported long-term administration of different preparations of A. vera had medicinal
properties in several human diseases. According to available reports, AVG preparations are considered
safe (Pothuraju, Sharma, Onteru, Singh, & Hussain, 2016).
In a human study, Yagi et al. investigated the effect of oral administration of AHM on diabetic patients for
12 weeks. The results showed no adverse effects on kidney and liver functions. At the end of the study,
serum creatinine (Cr), ALT, and AST levels did not change (Yagi et al., 2009).
Several clinical trials evaluated the efficacy of AVG supplementation in various diseases. According to
their findings, AVG is considered a safe remedy with no significant side effects (Bunyapraphatsara,
Yongchaiyudha, Rungpitarangsi, & Chokechaijaroenporn, 1996; Hegazy et al., 2012; L Langmead et al.,
2004; Shakib et al., 2019; Yagi et al., 2009).
6. Conclusion
Cardiovascular diseases and their associated mortality are on the rise worldwide. They are caused by
several correctable risk factors, including hyperlipidemia, DM, hypertension, obesity, tobacco smoking,
and an unhealthy diet. Their chemical drugs, in addition to limited therapeutic effects, may also have
adverse reactions in long-term use. Therefore, the use of herbal medicines as a complementary treatment
has been the focus of researchers. A. vera from the Liliaceae family has shown such potential effects. Its
innermost leaf layer is a clear gel or mucilage (AVG), which contains water-soluble and fat-soluble
vitamins, minerals, enzymes, polysaccharides, phenolic compounds, and organic acids. AVG does not
contain anthraquinone compounds and has no laxative effect. AVG has several beneficial properties, such
as antiulcer, antidiabetic, lipid-lowering, antimicrobial, antineoplastic, antioxidant, anti-inflammatory,
hepatoprotective, and immunomodulatory effects. Previous preclinical and clinical evidence demonstrated
the cardioprotective impacts of AVG and also its beneficial effects on cardiovascular risk factors,
including hyperglycemia, hyperlipidemia, hypertension, and obesity.
Phytochemical investigation indicated that AVG is a potent antioxidant agent and contains a lot of
antioxidant vitamins. Its bioactive polysaccharide, such as Acemannan, demonstrated scavenging effects
on free radicals. Moreover, AVG treatment in the I/R model of rats showed a significant increase in
cellular antioxidant activities (SOD, CAT, GSH).
The fibrotic process is a common part of several cardiac dysfunctions. AVG treatment showed
ameliorative effects against ISO-induced cardiac fibrosis in rats and inhibited the infiltration of
inflammatory cells and necrosis in the heart. This treatment could reduce left ventricular fibrosis.
Administration of AVG showed several pharmacological effects such as lipid‐lowering, antihypertensive,
hypoglycemic, and anti-obesity effects. Furthermore, AVG has a direct anti-atherosclerotic effect by
reducing inflammation and dyslipidemia due to the presence of phenols, flavonoids, flavones, anthocyanins,
and tannins. According to available reports, long-term administration of AVG preparations is considered
safe in several human diseases.
Based on the available evidence on the anti-inflammatory, antioxidant, anti-hyperglycemic,
antihypertensive, anti-dyslipidemic, anti-obesity, anti-fibrotic and anti-atherosclerotic effects of AVG,
further high-quality clinical studies with a focus on cardiovascular patients are needed to firmly establish
the clinical efficacy of the plant for the treatment of CVDs.
CONFLICT OF INTEREST
We have no conflict of interest to declare.
Funding information
The authors received no financial support for the research, authorship, and/or publication of this article.
References

Agarwal, O. (1985). Prevention of atheromatous heart disease. Angiology, 36(8), 485-492.

Ahlawat, K. S., & Khatkar, B. S. (2011). Processing, food applications and safety of aloe vera products: a review. Journal of Food
Science Technology, 48(5), 525-533.
Akaberi, M., Sobhani, Z., Javadi, B., Sahebkar, A., & Emami, S. A. (2016). Therapeutic effects of Aloe spp. in traditional and
modern medicine: A review. Biomedicine & Pharmacotherapy, 84, 759-772.
Alam, S., Ali, I., Giri, K., Gokkulakrishnan, S., Natu, S. S., Faisal, M., . . . Sharma, H. (2013). Efficacy of aloe vera gel as an adjuvant
treatment of oral submucous fibrosis. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, 116(6), 717-724.
Andrew, R., & Izzo, A. A. (2017). Principles of pharmacological research of nutraceuticals. British Journal of Pharmacolgy,
174(11), 1177-1194. doi:10.1111/bph.13779
Anuradha, A., Patil, B., & Asha, V. R. (2017). Evaluation of efficacy of Aloe vera in the treatment of oral submucous fibrosis–a
clinical study. Journal of Oral Pathology Medicine, 46(1), 50-55.
Asadi-Samani, M., & Bahmani, M. (2016). Trends on the treatment of atherosclerosis; new improvements. Angiologica Persica
Acta, 1(1).
Bahrami, M., Kamalinejad, M., Latifi, S. A., Seif, F., & Dadmehr, M. (2020). Cytokine storm in COVID‐19 and parthenolide:
Preclinical evidence. Phytotherapy Research, 34(10), 2429-2430.
Bhalsinge, R., Rajbhoj, S., Limaye, M., Vaidya, M., Rane, P., & Tilak, A. (2018). Anti-inflammatory and immunomodulatory
activity of ethanol extract of Aloe vera gel. International Journal of Pharmaceutical Sciences Research, 9(2), 832-835.
Bolkent, S., Akev, N., Ozsoy, N., Sengezer-Inceli, M., Can, A., Okyar, A., & Yanardag, R. (2004). Effect of Aloe vera (L.) Burm. fil.
leaf gel and pulp extracts on kidney in type-II diabetic rat models. Indian Journal of Experimental Biology, 42(1), 48-52.
Budai, M. M., Varga, A., Milesz, S., Tőzsér, J., & Benkő, S. (2013). Aloe vera downregulates LPS-induced inflammatory cytokine
production and expression of NLRP3 inflammasome in human macrophages. Molecular Immunology, 56(4), 471-479.
Bunyapraphatsara, N., Yongchaiyudha, S., Rungpitarangsi, V., & Chokechaijaroenporn, O. (1996). Antidiabetic activity of Aloe
vera L. juice II. Clinical trial in diabetes mellitus patients in combination with glibenclamide. Phytomedicine, 3(3), 245-
248.
Cercato, C., & Fonseca, F. (2019). Cardiovascular risk and obesity. Diabetology Metabolic Syndrome, 11(1), 74.
Choi, H.-C., Kim, S.-J., Son, K.-Y., Oh, B.-J., & Cho, B.-L. (2013). Metabolic effects of aloe vera gel complex in obese prediabetes
and early non-treated diabetic patients: Randomized controlled trial. Nutrition, 29(9), 1110-1114.
Choudhary, M., Kochhar, A., & Sangha, J. (2014). Hypoglycemic and hypolipidemic effect of Aloe vera L. in non-insulin
dependent diabetics. Journal of Food Science Technology, 51(1), 90-96.
Cramer, H., Langhorst, J., Dobos, G., & Lauche, R. (2016). Yoga for metabolic syndrome: A systematic review and meta-analysis.
European Journal of Preventive Cardiology, 23(18), 1982-1993.
Dana, N., Javanmard, S. H., Asgary, S., Asnaashari, H., & Abdian, N. (2012). The effect of Aloe vera leaf gel on fatty streak
formation in hypercholesterolemic rabbits. Journal of Research in Medical Sciences, 17(5), 439.
Desalegn, A. Y., & Ahmed, M. R. (2020). Anticoccidial Activity of Aloe debrana and Aloe pulcherrima Leaf Gel against Eimeria
Oocysts. Journal of Parasitology Research, 2020, 8524973. doi:10.1155/2020/8524973
Devaraj, S., Yimam, M., Brownell, L. A., Jialal, I., Singh, S., & Jia, Q. (2013). Effects of Aloe vera supplementation in subjects with
prediabetes/metabolic syndrome. Metabolic Syndrome Related Disorders, 11(1), 35-40.
Duansak, D., Somboonwong, J., & Patumraj, S. (2003). Effects of Aloe vera on leukocyte adhesion and TNF‐α and IL‐6 levels in
burn wounded rats. Clinical Hemorheology Microcirculation, 29(3, 4), 239-246.
Gholipour, S., Sewell, R. D., Lorigooini, Z., & Rafieian-Kopaei, M. (2018). Medicinal plants and atherosclerosis: A review on
molecular aspects. Current Pharmaceutical Design, 24(26), 3123-3131.
Guo, X., & Mei, N. (2016). Aloe vera: A review of toxicity and adverse clinical effects. Journal of Environmental Science and
Health. Part C, Environmental Carcinogenesis & Ecotoxicology Reviews, 34(2), 77-96.
doi:10.1080/10590501.2016.1166826
Guven, M., Gölge, U. H., Aslan, E., Sehitoglu, M. H., Aras, A. B., Akman, T., . . . & Cosar, M. (2016). The effect of Aloe vera on
ischemia—Reperfusion injury of sciatic nerve in rats. Biomedicine & Pharmacotherapy, 79, 201-207.
Hamman, J. H. (2008). Composition and applications of Aloe vera leaf gel. Molecules, 13(8), 1599-1616.
doi:10.3390/molecules13081599
Han, J., Zhao, C., Cai, J., & Liang, Y. (2020). Comparative efficacy of vitamin supplements on prevention of major cardiovascular
disease: Systematic review with network meta-analysis. Complementary Therapies in Clinical Practice, 39, 101142.
doi:10.1016/j.ctcp.2020.101142
Hegazy, S. K., El-Bedewy, M., & Yagi, A. (2012). Antifibrotic effect of aloe vera in viral infection-induced hepatic periportal
fibrosis. World Journal of Gastroenterology, 18(17), 2026.
Hinderer, S., & Schenke-Layland, K. (2019). Cardiac fibrosis–A short review of causes and therapeutic strategies. Advanced Drug
Delivery Reviews, 146, 77-82.
Hosseini, A., Khoshsovt, F., Ahmadi, M., Azarbayjani, M. A., Salehi, O., & Farkhaie, F. (2020). Effects of Aloe Vera and Swimming
Training on Lipid Profile of Streptozotocin Induced Diabetic Rats. Nutrition Food Sciences Research, 7(1), 9-16.
Huseini, H. F., Kianbakht, S., Hajiaghaee, R., & Dabaghian, F. H. (2012). Anti-hyperglycemic and anti-hypercholesterolemic
effects of Aloe vera leaf gel in hyperlipidemic type 2 diabetic patients: a randomized double-blind placebo-controlled
clinical trial. Planta Medica, 78(04), 311-316.
IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. (2016). Some Drugs and Herbal Products. IARC
monographs on the evaluation of carcinogenic risks to humans, 108, 37-71.
https://www.ncbi.nlm.nih.gov/books/NBK350406/.
Im, S.-A., Oh, S.-T., Song, S., Kim, M.-R., Kim, D.-S., Woo, S.-S., . . . Lee, C.-K. (2005). Identification of optimal molecular size of
modified Aloe polysaccharides with maximum immunomodulatory activity. International Immunopharmacology, 5(2),
271-279.
Isirima, J., & Siminialayi, I. (2012). Effect of Aloe Vera Gel Extract on Cadmium-Induced High Blood Pressure. West African
Journal of Pharmacology Drug Research, 28, 22-27.
Izzo, A. A., Hoon-Kim, S., Radhakrishnan, R., & Williamson, E. M. (2016). A Critical Approach to Evaluating Clinical Efficacy,
Adverse Events and Drug Interactions of Herbal Remedies. Phytotherapy Research, 30(5), 691-700.
doi:10.1002/ptr.5591
Izzo, A. A., Teixeira, M., Alexander, S. P., Cirino, G., Docherty, J. R., George, C. H., . . . Panattieri, R. A. J. B. J. o. P. (2020). A
practical guide for transparent reporting of research on natural products in the British Journal of Pharmacology:
Reproducibility of natural product research. British Journal of Pharmacology, 177(10), 2169-2178.
Jain, N., Vijayaraghavan, R., Pant, S. C., Lomash, V., & Ali, M. (2010). Aloe vera gel alleviates cardiotoxicity in streptozocin‐
induced diabetes in rats. Journal of Pharmacy Pharmacology, 62(1), 115-123.
Jain, S., Buttar, H. S., Chintameneni, M., & Kaur, G. (2018). Prevention of cardiovascular diseases with anti-inflammatory and
anti-oxidant nutraceuticals and herbal products: an overview of pre-clinical and clinical studies. Recent Patents on
Inflammation Allergy Drug Discovery, 12(2), 145-157.
Kaithwas, G., Singh, P., & Bhatia, D. (2014). Evaluation of in vitro and in vivo antioxidant potential of polysaccharides from Aloe
vera (Aloe barbadensis Miller) gel. Drug Chemical Toxicology, 37(2), 135-143.
Karimi, Z., Firouzi, M., Dadmehr, M., Javad‐Mousavi, S. A., Bagheriani, N., & Sadeghpour, O. (2020). Almond as a nutraceutical
and therapeutic agent in Persian medicine and modern phytotherapy: A narrative review. Phytotherapy Research,
10.1002/ptr.7006. Advance online publication. https://doi.org/10.1002/ptr.7006
Khan, R., & Sheppard, R. (2006). Fibrosis in heart disease: understanding the role of transforming growth factor-beta in
cardiomyopathy, valvular disease and arrhythmia. Immunology, 118(1), 10-24. doi:10.1111/j.1365-2567.2006.02336.x
Kirichenko, T. V., Sukhorukov, V. N., Markin, A. M., Nikiforov, N. G., Liu, P.-Y., Sobenin, I. A., . . . Aliev, G. (2020). Medicinal Plants
as a Potential and Successful Treatment Option in the Context of Atherosclerosis. Frontiers in Pharmacology, 11, 403.
Kishore, K. (2015). Effect of aloe vera (Aloe barbadensis) on thrombosis in mice. Pharmacologia, 6(6), 347-354.
Kosif, R., Aktas, R. G., & Oztekin, A. (2008). The effects of oral administration of Aloe vera [barbadensis] on rat central nervous
system: An experimental preliminary study. Neuroanatomy, 7, 22-27.
Kumar, P., Goyal, M., & Tewari, S. (2007). Positive inotropic and chronotropic effect of aloe gel on isolated rat heart. Indian
Journal of Pharmacology, 39(5), 249.
Langmead, L., Feakins, R., Goldthorpe, S., Holt, H., Tsironi, E., De Silva, A., . . . Rampton, D. (2004). Randomized, double‐blind,
placebo‐controlled trial of oral aloe vera gel for active ulcerative colitis. Alimentary Pharmacology Therapeutics, 19(7),
739-747.
Langmead, L., Makins, R. J., & Rampton, D. S. (2004). Anti‐inflammatory effects of aloe vera gel in human colorectal mucosa in
vitro. Alimentary Pharmacology Therapeutics, 19(5), 521-527.
Leon, B. M., & Maddox, T. M. (2015). Diabetes and cardiovascular disease: Epidemiology, biological mechanisms, treatment
recommendations and future research. World Journal of Diabetes, 6(13), 1246.
Liang, J., Cui, L., Li, J., Guan, S., Zhang, K., & Li, J. (2020). Aloe vera: A Medicinal Plant Used in Skin Wound Healing. Tissue
Engineering. Part B, Reviews, 10.1089/ten.TEB.2020.0236. Advance online publication.
https://doi.org/10.1089/ten.TEB.2020.0236
Liu, C., Cui, Y., Pi, F., Cheng, Y., Guo, Y., & Qian, H. (2019). Extraction, purification, structural characteristics, biological activities
and pharmacological applications of acemannan, a polysaccharide from aloe vera: A review. Molecules, 24(8), 1554.
Manvitha, K., & Bidya, B. (2014). Aloe vera: a wonder plant its history, cultivation and medicinal uses. Journal of Pharmacognosy
and Phytochemistry, 2(5), 85-88.
Mc Namara, K., Alzubaidi, H., Jackson, J. K., & practice. (2019). Cardiovascular disease as a leading cause of death: how are
pharmacists getting involved? Integrated Pharmacy Research, 8, 1.
Misawa, E., Tanaka, M., Nomaguchi, K., Nabeshima, K., Yamada, M., Toida, T., & Iwatsuki, K. (2012). Oral ingestion of Aloe vera
phytosterols alters hepatic gene expression profiles and ameliorates obesity-associated metabolic disorders in Zucker
diabetic fatty rats. Journal of Agricultural Food Chemistry, 60(11), 2799-2806.
Misawa, E., Tanaka, M., Nomaguchi, K., Yamada, M., Toida, T., Takase, M., . . . Kawada, T. (2008). Administration of phytosterols
isolated from Aloe vera gel reduce visceral fat mass and improve hyperglycemia in Zucker diabetic fatty (ZDF) rats.
Obesity Research Clinical Practice, 2(4), 239-245.
Mohammadifard, N., Humphries, K. H., Gotay, C., Mena-Sánchez, G., Salas-Salvadó, J., Esmaillzadeh, A., . . . & Sarrafzadegan, N.
(2019). Trace minerals intake: risks and benefits for cardiovascular health. Critical Reviews in Food Science and
Nutrition, 59(8), 1334-1346.
Moradi, F., Sewell, R. D., Lorigooini, Z., & Rafieian-Kopaei, M. (2018). Immunosuppression-lipid metabolism interplay and
medicinal plants in atherosclerosis: A review. Current Pharmaceutical Design, 24(24), 2789-2793.
Naveed, M., Majeed, F., Taleb, A., Zubair, H. M., Shumzaid, M., Farooq, M. A., . . . Changxing, L. (2020). A Review of Medicinal
Plants in Cardiovascular Disorders: Benefits and Risks. The American Journal of Chinese Medicine, 48(02), 259-286.
Ngo, M. Q., Nguyen, N. N., & Shah, S. A. (2010). Oral aloe vera for treatment of diabetes mellitus and dyslipidemia. American
Journal of Health-System Pharmacy 67(21), 1804-1811.
Pothuraju, R., Sharma, R. K., Onteru, S. K., Singh, S., & Hussain, S. A. (2016). Hypoglycemic and hypolipidemic effects of Aloe
vera extract preparations: A review. Phytotherapy Research, 30(2), 200-207.
Rahoui, W., Merzouk, H., El Haci, I. A., Bettioui, R., Azzi, R., & Benali, M. (2018). Beneficial effects of Aloe vera gel on lipid
profile, lipase activities and oxidant/antioxidant status in obese rats. Journal of Functional Foods, 48, 525-532.
Rajasekaran, S., Sivagnanam, K., Ravi, K., & Subramanian, S. (2004). Hypoglycemic effect of Aloe vera gel on streptozotocin-
induced diabetes in experimental rats. Journal of Medicinal food 7(1), 61-66.
Rajasekaran, S., Sivagnanam, K., & Subramanian, S. (2005). Antioxidant effect of Aloe vera gel extract in streptozotocin-induced
diabetes in rats. Pharmacological Reports, 57(1), 90-96.
Rashidi, B., Hoseini, Z., Sahebkar, A., & Mirzaei, H. (2017). Anti‐atherosclerotic effects of vitamins D and E in suppression of
atherogenesis. Journal of Cellular Physiology, 232(11), 2968-2976.
Saleem, R., Faizi, S., Siddiqui, B. S., Ahmed, M., Hussain, S. A., Qazi, A., . . . Akhtar, S. (2001). Hypotensive effect of chemical
constituents from Aloe barbadensis. Planta Medica, 67(08), 757-760.
Sánchez-Machado, D. I., López-Cervantes, J., Sendón, R., & Sanches-Silva, A. (2017). Aloe vera: Ancient knowledge with new
frontiers. Trends in Food Science Technology, 61, 94-102.
Sehgal, I., Winters, W. D., Scott, M., & Kousoulas, K. (2013). An in vitro and in vivo toxicologic evaluation of a stabilized aloe vera
gel supplement drink in mice. Food and Chemical Toxicology, 55, 363-370.
Shaito, A., Thuan, D. T. B., Phu, H. T., Nguyen, T. H. D., Hasan, H., Halabi, S., . . . Pintus, G. (2020). Herbal Medicine for
Cardiovascular Diseases: Efficacy, Mechanisms, and Safety. Frontiers in Pharmacology, 11.
Shakib, Z., Shahraki, N., Razavi, B. M., & Hosseinzadeh, H. (2019). Aloe vera as an herbal medicine in the treatment of metabolic
syndrome: A review. Phytotherapy Research, 33(10), 2649-2660.
Sharma, P., Kharkwal, A. C., Kharkwal, H., Abdin, M., & Varma, A. (2014). A review on pharmacological properties of Aloe vera.
International Journal of Pharmaceutical Sciences Review and Research, 29(2), 31-37.
Steenkamp, V., & Stewart, M. J. (2007). Medicinal Applications and Toxicological Activities of Aloe. Products. Pharmaceutical
Biology, 45(5), 411-420. doi:10.1080/13880200701215307
Suksomboon, N., Poolsup, N., & Punthanitisarn, S. (2016). Effect of Aloe vera on glycaemic control in prediabetes and type 2
diabetes: a systematic review and meta‐analysis. Journal of Clinical Pharmacy Therapeutics, 41(2), 180-188.
Sultana, S., & Muhammad Asif, H. (2017). Medicinal plants combating against hypertension: A green antihypertensive
approach. Pakistan Journal of Pharmaceutical Sciences, 30(6).
Sumi, F. A., Sikder, B., Rahman, M. M., Lubna, S. R., Ulla, A., Hossain, M. H., . . . & Subhan, N. (2019). Phenolic Content Analysis
of Aloe vera Gel and Evaluation of the Effect of Aloe Gel Supplementation on Oxidative Stress and Fibrosis in
Isoprenaline-Administered Cardiac Damage in Rats. Preventive Nutrition and Food Science, 24(3), 254.
Suthahar, N., Meijers, W. C., Silljé, H. H., & de Boer, R. A. (2017). From inflammation to fibrosis—molecular and cellular
mechanisms of myocardial tissue remodelling and perspectives on differential treatment opportunities. Current Heart
Failure Reports, 14(4), 235-250.
Tanaka, M., Misawa, E., Ito, Y., Habara, N., Nomaguchi, K., Yamada, M., . . . Inagaki, M. (2006). Identification of five phytosterols
from Aloe vera gel as anti-diabetic compounds. Biological Pharmaceutical Bulletin, 29(7), 1418-1422.
Thayer, J. F., Yamamoto, S. S., & Brosschot, J. F. (2010). The relationship of autonomic imbalance, heart rate variability and
cardiovascular disease risk factors. International Journal of Cardiology, 141(2), 122-131.
Torkzaban, A., Naeini, A. A., Hassanzadeh, A., & Namdari, M. (2020). The Relationship between Serum Vitamin C and Uric Acid
Levels, Antioxidant Status and Coronary Artery Disease: a Case-Control Study. Clinical Nutrition Research, 9(4), 307.
Vázquez, B., Avila, G., Segura, D., & Escalante, B. (1996). Antiinflammatory activity of extracts from Aloe vera gel. Journal of
Ethnopharmacology, 55(1), 69-75.
Wang, C.-Z., Mehendale, S. R., & Yuan, C.-S. (2007). Commonly used antioxidant botanicals: active constituents and their
potential role in cardiovascular illness. The American Journal of Chinese Medicine, 35(04), 543-558.
Wu, M., Liu, L., Xing, Y., Yang, S., Li, H., & Cao, Y. (2020). Roles and mechanisms of hawthorn and its extracts on atherosclerosis:
A review. Frontiers in Pharmacology, 11, 118.
Yagi, A., Hegazy, S., Kabbash, A., & Abd-El Wahab, E. (2009). Possible hypoglycemic effect of Aloe vera L. high molecular weight
fractions on type 2 diabetic patients. Saudi Pharmaceutical Journal, 17(3), 209-215.
Yang, Y., Yang, M., Ai, F., & Huang, C. (2017). Cardioprotective effect of Aloe vera biomacromolecules conjugated with selenium
trace element on myocardial ischemia-Reperfusion Injury in rats. Biological Trace Element Research, 177(2), 345-352.
Yousefsani, B. S., Boozari, M., Shirani, K., Jamshidi, A., & Dadmehr, M. (2021). A review on phytochemical and therapeutic
potential of Iris germanica. Journal of Pharmacy and Pharmacology, 73(5), 611-625.
Zhang, Y., Liu, W., Liu, D., Zhao, T., & Tian, H. (2016). Efficacy of Aloe vera supplementation on prediabetes and early non-
treated diabetic patients: a systematic review and meta-analysis of randomized controlled trials. Nutrients, 8(7), 388.
Table 1. Pre-clinical and clinical studies regarding cardiobeneficial effects of AVG

Type of study Duration Dosage Key Effects References

Animal study; obese rat 8 weeks 100 and Reduced adipose tissue accumulation (Rahoui et al.,
model 200 mg/kg/day Correction of hyperlipidemia and 2018)
oxidative stress
Body-weight and weight gain
.
Animal study; male rats 14 days 5% gel mixed  Inflammation, fibrosis, and oxidative (Sumi et al.,
with powder stress. 2019)
chow food twice CK-MB enzyme and glutathione
a week Antioxidant activities
Infiltration of inflammatory cells Left
ventricular fibrosis.
 AST and ALP
Animal study; diabetic 3 weeks 200 and 300 Blood glucose and urea (S
albinos male rat mg/kg Body-weight Rajasekaran
Serum protein et al., 2004)
Animal study; diabetic 44 days 1 mL of aloe FBS and random glucose level (Misawa et
Zucker fatty rats sterols (Lo and Insulin resistance al., 2012)
Cy) solution Visceral fat weights
(25 μg/kg/day) TC, TG, improved liver steatosis
once a day
Animal study; white male 30 days 3.2% AVG per TC and CRP (Dana et al.,
rabbits day Prevention in the formation and 2012)
development of fatty streaks in the
aorta.
Animal study; rats 14 days 300 and 600  Blood pressure (Isirima &
mg/kg AVG more than 600 mg/kg/day was Siminialayi,
more effective 2012)
Animal study; albino rats 10 min 200 and 300 Heart rate, myocardial contractility (Kumar et al.,
mg/lit aqueous and coronary blood flow 2007)
solution
Animal study; diabetic rats 20 days 200 mg/kg FBS and HbA1c (N. Jain et al.,
 SOD, CAT and GSH 2010)
LDH and CK
Animal study; rats 7days 100, 200, and Infarct sizes (Yang et al.,
400 mg/kg MDA, CK-MB and LDH 2017)
Serum and myocardial endogenous
antioxidants (SOD, GSH and CAT)
Animal study; female albino 3 weeks 25 mg/ kg and Creates new vessels after I/R injury. (Kosif et al.,
rats 100 mg/kg Analgesic effect 2008)
Animal study; Wistar albino 1 month 30 mg/kg/day Antioxidant enzymes activity (SOD, (Guven et al.,
rats CAT and GSH) 2016)
Lipid peroxidation level (MDA
content)
 Hemorrhage, edema and
inflammatory cell migration
Clinical trial on 12 weeks Two tablespoon FBS, HbA1c and TG (Yagi et al.,
15 patients with DM of AHM three No change in Cr, ALT and AST 2009)
times daily
RCT on 45 8 weeks 500 mg twice a TC, LDL, glucose, fructosamine, (Devaraj et
prediabetic/metabolic day HbA1c, FBS, insulin, and HOMA al., 2013)
syndrome patients
Clinical trial on 90 DM 12 weeks 100 mg and 200 FBS, PPG, TC, TG, LDL, VLDL and (Choudhary et
patients with dyslipidemia mg BP al., 2014)
HDL-C
RCT on 30 DM patients with 8 weeks One 300 mg cap FBS, HbA1c, TC and LDL (Huseini,
dyslipidemia every 12 hours No effects on liver/kidney function tests Kianbakht,
Hajiaghaee, &
Dabaghian,
2012)
RCT on 136 obese 8 weeks 147 mg of Body fat mass, body weight, insulin (Choi et al.,
prediabetes/early DM AVG/cap; 2 caps level, HOMA and insulin resistance 2013)
patients after breakfast
and dinner
RCT on 74 patients with oral 3 months Drink 30 ml of A. Both groups with P < 0.001 showed (Anuradha et
sub mucosal fibrosis vera juice twice improvements in the study parameters. al., 2017)
daily before food The clinical response to A. vera was
and to apply 5 mg comparable to hyaluronidase with
of AVG over the antioxidant supplementation and
lesion 3 times per intralesional injections of
day for 3 months hydrocortisone
RCT on 90 cases (50 healthy 12 weeks 0.15 gm/d AHM The serum levels of the fibrosis markers (Hegazy et
volunteers and 40 patients (HA, TGF-β and MMP-2) were al., 2012)
with liver fibrosis) decreased

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