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. 2026 Jun 23;40(7):e70973. doi: 10.1002/jbt.70973

Cardioprotective Effect of Aloin Against Ischemia/Reperfusion Injury: Experimental and Computational POM Approaches

Mounime Kadi 1, Taibi Ben Hadda 2, Faisal A Almalki 3,✉, Nermine M Mohammed 4, Mohamed I S Abdelhady 4, Reham R Ibrahim 4, Abhay Prakash Mishra 5, Ahmad O Babalghith 6, Ajmal R Bhat 7,✉, Sumeer Ahmed 8,9, Abderrahim Ziyyat 1, Abdelkhaleq Legssyer 1, Younis A Hajam 9,10
PMCID: PMC13288014  PMID: 42333729

ABSTRACT

This study investigates the antihypertensive, antioxidant, and cardioprotective effects of Aloin following Langendorff rat isolated heart technique, the main bioactive compound of Aloe vera L., using both experimental (The myocardial ischemia‐reperfusion (IR) model, the determination of endogenous myocardial antioxidant enzyme activities, and histopathological examination of myocardial tissue) and computational approaches. To contextualize its potential, Aloin's activity was compared with Verapamil, a standard cardiovascular drug that, despite its efficacy, is limited by side effects and contraindications, particularly in patients with heart failure or hypersensitivity. In vivo experiments demonstrated that Aloin exerts significant cardioprotective and antihypertensive effects in a dose‐dependent manner, in some cases matching or surpassing the efficacy of Verapamil. Aloin improved cardiac performance, as shown by increased left ventricular developed pressure (LVDP) and decreased left ventricular end‐diastolic pressure (LVEDP) and coronary perfusion pressure (CPP). It also enhanced antioxidant defenses by elevating superoxide dismutase (SOD) and catalase (CAT) activities, while reducing oxidative stress, evidenced by lower malondialdehyde (MDA) levels. Complementary POM analyses confirmed Aloin's non‐toxic profile and identified pharmacophoric features underlying its bioactivity. Collectively, these findings highlight Aloin's strong potential as a natural therapeutic agent for hypertension and cardiovascular protection, warranting further clinical evaluation.

Keywords: ADMET/POM study, Aloe vera, Aloin, cardioprotective, molecular docking, pharmacophore modeling

Aloin, a bioactive compound from Aloe vera, demonstrates significant antihypertensive, antioxidant, and cardioprotective effects in experimental models. It improves cardiac function and reduces oxidative stress, comparable to Verapamil. Computational analyses confirm its safety and pharmacophoric potential, highlighting Aloin as a promising natural therapeutic for cardiovascular disease management.

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1. Introduction

Cardiovascular diseases (CVDs), including ischemic heart disease, are the leading cause of mortality worldwide. The search for new bioactive molecules with cardioprotective effects is attracting growing attention in preventive strategies to combat these diseases. This can be explained by the multiple side effects of the synthetic cardiovascular drugs. Verapamil, while effective as a calcium channel blocker, is associated with several adverse effects. Common reactions include headache, nausea, constipation, hypotension, and fatigue [1]. Cardiovascular complications such as bradycardia and exacerbation of heart failure have been reported, and hypersensitivity reactions (e.g., rash, edema) may also occur [2]. Its use is contraindicated in patients with severe cardiac dysfunction, and caution is advised during pregnancy due to potential risks to the fetus [3]. This medication is classified as a non‐dihydropyridine calcium channel blocker, a family of drugs that works by affecting the movement of calcium in the cells of the heart and blood vessels, ultimately influencing heart rate and blood pressure [4].

Recent research has focused on the role of oxidative stress in the pathogenesis of CVDs, highlighting the potential of antioxidant compounds to reduce this risk [5]. So natural substances with antioxidant properties have emerged as promising candidates for cardioprotection due to their ability to neutralize free radicals and reduce oxidative damage [6]. Due to the limitations and side effects associated with synthetic cardiovascular drugs such as Verapamil, there has been growing interest in natural compounds with antioxidant properties that may help mitigate oxidative stress and provide a safer alternative for cardiovascular protection. Among these, Aloin, a natural compound derived from Aloe vera, has shown considerable promise due to its strong antioxidant effects and its potential to improve endothelial function and reduce inflammation [7].

This study aims to explore the cardioprotective effects of Aloin in an ischemia‐reperfusion model of an isolated and perfused rat heart and to explain its mechanism of action. The molecular structures of Verapamil (SD) and Aloin are illustrated, highlighting their characteristic functional groups and structural differences (Figure 1).

Figure 1.

Figure 1

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Molecular structure of Verapamil (SD) and Aloin.

2. Materials and Methods

Aloin (Barbaloin) with a purity of 98% (CAS No. 1415‐73‐2) was procured from Xi'an Herbking Biotechnology Co. Ltd. (Shaanxi, China). The compound was supplied as a light yellow powder and was characterized by high‐performance liquid chromatography (HPLC) for purity verification. All reagents used were of analytical grade unless otherwise specified.

2.1. Animals Housing

The isolated hearts were extracted from 2‐ to 3‐month‐old normotensive (assessed using tail‐cuff plethysmography)male Albino Wistar rats (250–280 g) and they were fed and watered of libitum. They were kept in a ventilated space (rotating between a light/dark cycle of 12 h/12 h and a temperature of 24 ± 2°C). We carefully chose to use rats weighing between 250 and 280 g in our ischemia‐reperfusion model to enhance the clinical value of our observations, to meet current research standards, and to ensure reliable and repeatable results. We believe that this decision enhances the validity and overall breadth of our research on human cardiovascular diseases. The research was conducted in accordance with internationally recognized standards for the care and management of laboratory animals, as outlined in the European Union regulations (EEC Directive 1986; 86/609/EEC) or the US rules (NIH Publication No. 85‐23, revised 1985).

2.2. Modified Langendorff Isolated Perfused Heart Preparation

Male Wistar Albino rats (220–250 g) were anesthetized using sodium pentobarbital (40 mg/kg i.p.). A thoracotomy was then applied to quickly extract the rat heart, which was placed in an ice‐cold perfusion buffer. The heart was cleaned well and immediately perfused via the aorta into the Langendorff set‐up at constant flow (12 mL/min) with the following composition of Krebs‐Henseleit buffer (mM): NaCl, 118; KCl, 4.7; MgSO4, 1.2; KH2PO4, 1.2; NaHCO3, 25; Glucose, 11; Na‐pyruvate, 2; CaCl2, 1.8. The perfusate was first filtered (0.5 µm) and bubbled continuously with a mixture of 95% oxygen and 5% carbon dioxide. The thermal chamber of the heart and the perfusion solution were maintained at a constant temperature (37°C) and controlled throughout the manipulation [8].

2.3. Myocardial Ischemia‐Reperfusion (IR) Model

Albino Wistar rats were divided into three groups (n = 6) to study the cardioprotective potential of Aloin against myocardial lesions induced by ischemia‐reperfusion. All hearts underwent a 30‐min stabilization phase, followed by a 30‐min global isothermal ischemia phase and a 60‐min reperfusion phase. Global isothermal ischemia was achieved by stopping the perfusion of the heart while maintaining it at physiological temperature. The control group (IR, ischemic‐reperfused hearts) was perfused with Krebs‐Henseleit Buffer (KHB) solution throughout the experiment. Verapamil (10 µg/L) and Aloin (40 µg/mL) were dissolved in KHB solution to prepare their respective concentrations. These drug solutions were infused into the perfusion system for 5 min prior to the ischemic phase and continuously during the reperfusion phase to evaluate their cardioprotective effects.

The cardioprotective effect of Aloin was evaluated at a fixed concentration of 40 µg/mL, which was selected based on the results of a preliminary concentration screening study. This screening identified 40 µg/mL as the concentration providing the most significant therapeutic effect against ischemia‐reperfusion injuries. The decision to focus on this single concentration was made to demonstrate the cardioprotective potential of Aloin while adhering to ethical considerations aimed at minimizing the number of animals used in the study. By reducing unnecessary replicates across multiple concentrations, this approach aligned with the principles of the 3Rs (Replacement, Reduction, and Refinement) in animal research. Future studies could expand on these findings by exploring the full dose‐response profile of Aloin to optimize its therapeutic application further.

2.4. Measurements of Hemodynamic Parameters

A latex balloon filled with degassed water was introduced into the left ventricle for the processing of hemodynamic data. The latex balloon was connected to a pressure transducer, and then inflated to a Left Ventricular End‐Diastolic Pressure (LVEDP) around 4–10 mmHg. A wire catheter connected to the aortic perfusion cannula served for Coronary Perfusion Pressure (CPP) recording. Recovery of cardiac performance in reperfusion was by evaluation of hemodynamic parameters including the following: Left Ventricular End‐Diastolic Pressure (LVEDP), Left Ventricular Developed Pressure (LVDP), and Heart Rate (HR).

2.5. Determination of Endogenous Myocardial Antioxidant Enzyme

2.5.1. Preparation of Tissue Homogenate

The heart homogenate was prepared according to the following procedure: the grinding of the heart tissue was carried out using a phosphate buffer solution (pH 7.4), followed by centrifugation at 8000 g (4°C for 15 min). The supernatant was recovered and stored for later analyses.

2.5.2. Myocardial Superoxide Dismutase Activity (SOD)

The superoxide scavenging activity of superoxide dismutase (SOD) was carried out by measuring the inhibitory power of the reduction of nitro blue tetrazolium to formazon having a blue color by the superoxide anions produced following the photo‐oxidation of hydroxylamine hydrochloride. Superoxide dismutase activity was expressed in IU/m of protein [9].

2.5.3. Myocardial Catalase Activity (CAT)

Catalase activity in cardiac tissue was measured by following the rate of hydrogen peroxide (H2O2) disappearance spectrophotometrically at 240 nm. Optical density changes were recorded and Catalase activity was expressed in U/mg protein [10].

2.5.4. Myocardial Hydrogen Peroxide Activity (H2O2)

The determination of hydrogen peroxide content in myocardial tissue was done accordingly to the protocol of Slezak, with some modifications [11].

2.5.5. Myocardial Lipid Peroxidation (MDA)

Lipid peroxidation in cardiac tissue was determined by measuring malondialdehyde (MDA) activity through a spectrophotometric method of Buege [12].

3. Myocardialprotein Estimation

Protein content in cardiac homogenate was determined by the Bradford method, where Bovine Serum Albumin (BSA) was used as the standard [13].

3.1. Histopathological Examination of Myocardial Tissue

After the experiment, the hearts were quickly retrieved and the Nitro Blue tetrazolium (NBT) staining technique was implemented to determine infarct size [14]. The hearts were cut into slices with a thickness of 2 mm, and were then incubated with NBT 0.25 w/v (0.1 M phosphate buffer). The necrotic zone size (in cm2) was determined for each transverse slice, through planimetry using the ImageJ software. Infarcted size was expressed as follows: [infarct area]/[total area of heart slices].

ImageJ uses specific color thresholds to distinguish between infarcted myocardial tissue (paler) and viable tissue (darker red). This segmentation allows areas of interest, such as the infarcted region, to be distinguished by color variations. After segmentation, ImageJ determines the area of infarcted myocardium (highlighted in yellow), based on the number of pixels. ImageJ then uses the ratio of infarcted area to total myocardial area to determine the percentage of infarction, providing an accurate assessment of the affected area.

3.2. In Silico Molecular Docking Studies

The molecular docking studies of the Aloin and the bench mark standard drug Verapamil were carried out to explore the binding modes and affinities of the compounds withthenuclear factor kappaB (NF‐kappaB; PDB ID: 3GUT), using the software AutoDock (ADT) version 1.5.7. The docked compounds were visualized using the DISCOVERY studio visualize program suite.

3.3. Data Analysis

The different results shown were presented as mean ± S.E.M. The comparisons were made by an analysis of variance or using the student test where appropriate. Significance was accepted at p < 0.05.

4. Results and Discussion

4.1. Changes in Hemodynamics Parameters Following IR Injury

To analyze whether Aloin is capable of preserving cardiac performance, hemodynamic parameters were recorded such as Left Ventricular End‐Diastolic Pressure (LVEDP), Left Ventricular Developed Pressure (LVDP), and Coronary Perfusion Pressure (CPP). There was a significant decrease in LVEDP (21.02 ± 7.47 mmHg, p = 0,0008), CPP (89.94 ± 1.40 mmHg) in Verapamil pre‐treated groups compared to IR (9.98 ± 3.2 mmHg and 9.67 ± 4.54, respectively). There was a significant increase (83.07 ± 2.73, corresponding to a 78.83% increse p = 0,0007) for cardiac LVDP compared to IR (25.59 ± 1.95). For those groups pre‐treated with Aloin, there was a significant increase (91.43 ± 2.69, corresponding to an increase of 86.77% p = 0,0006) of LVDP compared to IR (25.59 ± 1.95 mmHg), and a significant decrease in both LVEDP (17.37 ± 3.36, p = 0,0002) and CPP (85.19 ± 2.10, p = 0,043) as compared to IR groups (79.98 ± 3.2), (96.7 ± 4.54), (Figure 2).

Figure 2.

Figure 2

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Effect of Aloin and Verapamil on cardiac LVDP, CPP and LVDP (mm Hg) post IR respectively. Repeated measurements using Student's test were performed (n = 6); *p < 0.05, **p < 0.01, ***p < 0.001, ns: not significant compared to the IR group.

4.2. Changes in Myocardial Lipid Peroxidation and Endogenous Antioxidants Following IR Injury

4.2.1. Myocardial SOD Levels

There was a significant (p = 0.0009) increase in myocardial SOD activity (8.07 ± 0.76 U/mg of proteins) in the IR groups that were pretreated with Aloin in comparison to that of the control group (3.82 ± 1.5 U/mg of proteins) as illustred below (Figure 3).

Figure 3.

Figure 3

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Effects of Aloin and Verapamil on cardiac SOD activity (U/mg of proteins), cardiac CAT activity (U/min/g of proteins), cardiac H2O2 activity (U/g of fresh weight), cardiac MDA activity (U/g of fresh weight) and myocardial Infarct size (%) post IR. Repeated measurements using Student's test were performed (n = 6); *p < 0.05, **p < 0.01, ***p < 0.001, ns: not significant compared to the IR group.

4.2.2. Myocardial CAT Levels

There was a significant (p = 0.0005) increase in myocardial CAT activity (64 ± 7.69 U/min/g of proteins) in IR groups pre‐treated with Aloin in comparison to that of the control group (19 ± 3.6 U/min/g of proteins) as given below (Figure 3).

4.2.3. Myocardial H2O2 Levels

There was a significant (p = 0.0001) decrease in myocardial H2O2 level in Verapamil IR groups (1.1 ± 0.04 U/g of fresh weight) in comparison with IR groups (1.95 ± 0.009 U/g of fresh weight) as shown below (Figure 3).

4.2.4. Myocardial MDA Levels

There was a significant decrease (p = 0.0008) in myocardial MDA level in IR groups (1.02 ± 0.07 nmol/g wet wt.) pre‐treated with Aloin as compared to that of IR group (2.96 ± 0.12 U/g of fresh weight) (Figure 3).

4.3. Histopathological Examination of Myocardial Tissue

Based on the examination of NBT staining, a typical myocardial ischemic zone was observed in IR groups, pale for ischemic myocardium and dark red for non‐ischemic myocardium. The infarct size presented in the IR rat hearts being at 56.26 ± 1.7%. Pretreatment with Aloin (40 µg/mL) resulted in a reduction in the infarct size (37.49 ± 1.33%, p = 0.0007) whereas the infarcted area in Verapamil pre‐treated groups was (47.17 ± 0.74%, p = 0,003) as it is shown in (Figure 4).

Figure 4.

Figure 4

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Comparative protective effect of Aloin and Verapamil (SD) on heart muscle (n = 6). Low red zone: Dead cardiomyocytes. High red zone: Living Cardiomyocyte.

Ischemia‐reperfusion applied to hearts isolated from Wistar rats is most often accompanied by a loss of contractile function of the heart, generally expressed by an elevation in LVEDP which leads to a reduction in endocardial perfusion, which results in the worsening of myocardial damage [15]. Alteration of cardiac inotropism is also one of the aspects when contractile function ofthe heart is lost [16]. Our results show a significant reduction in LVEDP in the Aloin pre‐treated group, equivalent to an increase in blood flow through the ventricular subendocardial region. We can deduce that Aloin is capable of correcting LVEDP elevation by restoring adequate blood flow (Figures 5, 6, 7).

Figure 5.

Figure 5

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Original graph of ischemia‐reperfusion (IR) group LVDP (mmHg/min).

Figure 6.

Figure 6

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Original graph of Aloin pre‐treated group: LVDP (mmHg/min).

Figure 7.

Figure 7

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Original graph of Verapamil pre‐treated group: LVDP (mmHg/min).

It is well documented that the alteration of cardiac function is generally explained by ventricular dysfunction reflected by an overload of ROS [17], whereby similar results were recorded in our study when an ischemic alteration (30 min) followed by reperfusion (120 min) were applied. Hence, Aloin showed significant preservation of hemodynamic parameters by maintaining cardiac function close to normal, which is absolutely determined by a normalization of LVEDP‐CPP and LVDP restoration.

Under normal physiological conditions, ROS production is always in balance with the quantity of antioxidants expressed. Ischemic cardiac events followed by reperfusion are considered to be physiopathological conditions whereby the alteration of the balance between ROS and antioxidants has been well documented, and essentially reflected by significant production of free oxygen radicals in parallel with a drop in expressed antioxidants. Namely, ROS are involved in lipid peroxidation, which leads to the loss of membrane integrity. It should also be noted that several antioxidants are involved in the scavenging of free oxygen radicals, and therefore protect against myocardial damage induced by the ischemia‐reperfusion sequence [18].

A range of pathological scenarios are highlighted during the cardiac ischemia phase, which leads to the majority of cases exhibiting a loss of cardiomyocytes. Myocardial reperfusion, though life‐saving, profoundly aggravates myocardial lesions in various pathological forms.

Antioxidant enzymes such as CAT and SOD constitute the ultimate defense against myocardial damage induced by ischemia‐reperfusion, through the trapping of oxygen radicals, thus improving cardiac function. In parallel, MDA is a reliable agent for the evaluation of the cardiac lipid peroxidation rate, of which the reduction of the MDA rate and the improvement of the expression of the antioxidant enzymes CAT and ROS represent an effective means of cardioprotection [19].

Several mechanisms were highlighted in our study, which aim to explain cardioprotection following the deleterious sequence of ischemia‐reperfusion. The power of trapping oxygen radicals with Aloin may be a good explanation, thus making it possible to preserve cardiomyocytes and keep their contractile function intact. It should be noted that an overproduction of ROS reflects the loss of cardiomyocytes during reperfusion. Our results are in line with this, given that the necrotic myocardial area of the hearts of rats pre‐treated with Aloin was significantly lower than that of hearts of rats having undergone only the ischemia‐reperfusion sequence. Additional confirmation of the cardiac tissue is essentially reflected by the drop in the lipid peroxidation rate represented by MDA decrease in the groups of rats pre‐treated with Aloin as compared to the IR group. In addition, pre‐treatment with Aloin significantly improved the expression of antioxidant enzymes such as CAT and SOD involved in ROS scavenging. It can be noted that Aloin is endowed witha bis‐bidentate structure which is able to coordinate Ca2+ ions [20]. So, it presents a considerable cardioprotective activity which prevents the disruption of the balance of endogenous antioxidants by normalizing and stabilizing the levels of CAT and SOD.

One limitation of the present study is the absence of a sham (non‐ischemic) control group for the assessment of oxidative stress and antioxidant enzyme parameters. Although this decision was guided by ethical considerations to minimize animal use, the lack of baseline values from normal hearts restricts comparison with physiological conditions. Consequently, while our results clearly demonstrate the modulatory effect of aloin under ischemia–reperfusion injury, the extent to which these parameters are restored toward normal baseline levels cannot be fully determined.

In the study, Aloin was evaluated for its safety profile, particularly for its potential cardiotoxic effects. Aloin was administered by infusion in the perfusion solution for 5 min before ischemia, and no adverse alterations in cardiac performance were observed during this time. This absence of cardiotoxicity indicates that Aloin is well tolerated under the conditions used in this experimental design. Furthermore, the absence of adverse effects on fundamental hemodynamic parameters emphasizes its potential as a safe cardioprotector drug. However, despite the encouraging results, further studies are needed to examine the systemic toxicity and long‐term safety of Aloin in vivo, particularly when administered by various means and at higher doses.

The following analyses represent computational predictions intended to identify putative molecular targets and possible mechanisms underlying the experimentally observed cardioprotective effects of Aloin. These in silico approaches, including POM analysis, Molinspiration prediction, and molecular docking, are hypothesis‐generating tools and do not constitute direct experimental validation of molecular targets or mechanisms of action.

4.4. POM Analyses

POM Theory is a bioinformatic platform that we have developed in collaboration with NCI and TAACF of United states. It is able to predict, with high precision, various types of pharmacophore sites (Figure 8).

Figure 8.

Figure 8

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Organigram of POM theory showing antibacterial, antifungal, antitumor, antiparasitic, and antiviral pharmacophore sites [21, 22, 23, 24, 25, 26, 27].

A comparative analysis of Molecular properties of Aloin and Verapamil (SD) indicates that both compounds are save; no side effect is given as mutagenic, tumorogenic, irritant, and reproductive effect (Table 1).

Table 1.

Osiris prediction of side effects and drug‐score of studied Aloin and Verapamil.

Compd Molecular structure Side effects and drug‐score
Aloin graphic file with name JBT-40-e70973-g016.jpg graphic file with name JBT-40-e70973-g017.jpg
SD graphic file with name JBT-40-e70973-g010.jpg graphic file with name JBT-40-e70973-g009.jpg
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SD: Verapamil.

Molinspiration prediction (Table 2) of the potential biotargets of Aloin and Verapamil show clearly that both Aloin and SD are active as GPCR ligand (18%–24%) but the Aloin is more interesting than SD, as Nuclear receptor ligand (33% and 0%, respectively for Aloin and SD). More surprisingly, Table 2 shows that Aloin has no comparative potential with SD, as Enzyme inhibitor (34% and 9%, respectively for Aloin and SD).

Table 2.

Molinspiration prediction of potential biotargets of Aloin and Verapamil (SD).

Compd 3D Molecular structure hysicochemical properties Drug‐scores
Aloin graphic file with name JBT-40-e70973-g003.jpg miLogP 0.18 GPCR ligand 0.18
TPSA 167.90 Ion channel modulator 0.08
MW 418.40 Kinase inhibitor 0.14
nON 9 Nuclear receptor ligand 0.33
nOHNH 7 Proteaseinhibitor 0.08
nviolations 1 Enzyme inhibitor 0.34
volume 352.43
SD graphic file with name JBT-40-e70973-g004.jpg miLogP 4.55 GPCR ligand 0.24
TPSA 63.97 Ion channel modulator 0.23
MW 454.61 Kinase inhibitor 0.01
nON 6 Nuclear receptor ligand −0.01
nOHNH 0 Proteaseinhibitor 0.06
nviolations 0 Enzyme inhibitor 0.09
volume 454.30
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SD: Verapamil.

4.5. Mechanism of Interaction of Aloin as Cardiovascular Delator Agent

Verapamil is a drug which acts as a calcium antagonist or calcium channel blocker, that is to say which modifies the ionic movements of calcium inside the smooth muscle cells of the vessel wall and the cells of the myocardium. A comparative analysis of the atomic charges (Figure 9); and the 3D molecular structures of the Verapamil and Aloin confirms the ability of Aloin to transfer/coordinate two Ca2+ ions instead of one Ca2+ ion coordinated by Verapamil as standard drug (Table 2 and Figure 10).

Figure 9.

Figure 9

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Atomic charge calculations of Aloin and Verapamil.

Figure 10.

Figure 10

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Plausible mechanism of interaction of Aloin with Ca2+ ions.

A preliminary test of coordination of Aloin, in the presence of various metals (M2+ = Cu2+, Ni2+, Fe2+, Ru2+) leads us to the obtention of colored new complexes that are still under spectroscopic and electrochemical analyses. The structural and computational analyses suggest that Aloin may possess the ability to coordinate Ca2+ ions; however, this proposed mechanism requires direct biochemical and biophysical confirmation. The topology of Aloin is specific as bis‐coordinator ligand. So, it deserves to be used as a catalyst in various fields (Figure 10).

It is well established that the solubility of calcium oxalate monohydrate is great in the presence of various natural coordinative products such as carboxylic acids, amino acids, and polyphenols. This complexation with calcium ions plays a vital role and is influenced by material and charge balance. Moreover, the observed increase in induction time with all the compounds studied suggests a strong potential for these substances to bind effectively with calcium [28]. This finding opens up opportunities for further exploration of these interactions and their applications in various fields.

Many times, the POM theory is described as a bioinformatic solution that able to identify various pharmacophore sites of drugs but lacks external validation. So we have to support its predictive reliability with additional data via the history of its success in various fields [29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64].

4.6. Molecular Docking

Molecular docking is a valuable tool in drug discovery, enabling the prediction of interactions between small molecules and biological targets. Recent advancements have markedly improved its precision and efficacy, facilitating the comprehension of receptor‐ligand interactions, the design of inhibitors for various ailments and the examination of enzyme‐substrate dynamics in industrial applications.

Molecular docking studies were performed to predict potential interactions of Aloin with NF‐κB (PDB ID: 3GUT), a target implicated in inflammatory signaling associated with ischemia–reperfusion injury. and it was observed that the selected Aloin compound showed strong binding interactions in comparison with that of the standard reference drug, Verapamil, with the binding sites of the receptor via hydrogen bonding, hydrophobic and π‐bonding interaction (Figures 11, 12, 13; Table 3).

Figure 11.

Figure 11

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3D‐Docking poses of Aloin (a) and Verapamil (b) with NF‐κB (3GUT).

Figure 12.

Figure 12

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Docking poses showing hydrogen bond pattern of Aloin (a) and Verapamil (b) with NF‐κB (3GUT).

Figure 13.

Figure 13

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Docking poses showing charge distribution of Aloin (a) and Verapamil (b) with NF‐κB (3GUT).

Table 3.

Molecular docking parameters of the Aloin and Verapamil with NF‐κB (PDB ID: 3GUT).

Compound vdW + H bond + Electrostatic + dissolvingenergy (1) (kcal/mol) Final total internal energy (2) (kcal/mol) Torsional free energy (3) (kcal/mol) Unboundsystem's energy (4) (kcal/mol) Estimated free energy of binding [1 + 2 + 3–4] (kcal/mol)
Aloin –5.7 –4.83 2.98 –4.83 –2.85
Verapamil –5.92 –3.01 3,88 –3.01 –10.73
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The Aloin compound shows three hydrogen bond interactions with the selected receptor. It exhibits one hydrogen bond between the oxygen atom of the Aloin and the hydrogen atom of ARG 41 (O·HN = 1.90 Å, dihedral angle = 157.17°), and two hydrogen bonds between the hydrogen atom of the Aloin compound and CYS 38 residues of NF‐κB (PDB ID: 3GUT) receptor molecule. Whereas Verapamil shows two hydrogen bond interactions with the selected receptor. The Verapamil drug compound exhibits one hydrogenbond between the oxygenatom of the drug compound with the hydrogenatom of the ARG 41 (O⋯HN = 2.48 Å, dihedral angle = 129.91°), and one hydrogen bond betweenthe oxygen atom of the drug compound with the hydrogenatom of the SER 42 (O⋯HN = 2.19 Å, dihedral angle = 119.12°). These docking results suggest that NF‐κB may represent a potential molecular target of Aloin; however, this interaction remains to be experimentally validated.

5. Conclusion

Our study clearly demonstrates the cardioprotective effects of Aloin against myocardial lesions induced by ischemia‐reperfusion in the Wistar rat heart using the Langendorff model. These protective effects are primarily attributed to Aloin's potent antioxidant activity, as evidenced by the enhancement of SOD and CAT activity and reducing H2O2 and MDA activity. Additionally, Aloin ameliorated the heart's hemodynamic profile and significantly reduced infarct size, mitigating the deleterious sequence of ischemia‐reperfusion injury. Given its hydro‐solubility and potential for oral bioavailability, Aloin may be more suitable for oral administration, which could enhance patient compliance and practicality for therapeutic use. However, further pharmacokinetic studies are needed to confirm its absorption and distribution profile when administered orally. Further investigations into the coordination of Aloin with transition and alkaline metals would provide valuable insights into its coordinative behavior and potential applications for other diseases, such as Alzheimer's and HIV. While the findings from POM Theory underscore Aloin's potential in treating cardiovascular diseases, additional preclinical and clinical studies are essential to evaluate its efficacy and safety compared to standard drugs. Overall, the study corroborates experimental evidence of the profound cardioprotective effects of Aloin against ischemia–reperfusion injury in the isolated Wistar rat heart model as indicated by improved haemodynamic parameters, reduced infarct size, decreased lipid peroxidation, and increased antioxidant enzyme activity. Furthermore, bioinformatic prediction tools and molecular docking analyses suggest potential interactions with targets such as NF‐κB and possible calcium‐coordination properties. However, these molecular targets and mechanistic hypotheses are still preliminary and need to be validated by additional experimental data, such as biochemical, molecular and in vivo studies.

Author Contributions

Mounime Kadi: writing – original draft. Taibi Ben Hadda: software, methodology. Faisal A. Almalki: writing – review and editing. Nermine M. Mohammed: validation, writing – review and editing. Mohamed I. S. Abdelhady: data curation, formal analysis. Reham R. Ibrahim: writing – review and editing, validation. Abhay Prakash Mishra: investigation, conceptualization. Ahmad O. Babalghith: formal analysis, writing – review and editing. Ajmal R. Bhat: writing – review and editing, software, supervision. Sumeer Ahmed: software, resources. Abderrahim Ziyyat: validation, methodology. Abdelkhaleq Legssyer: visualization, investigation. Younis A. Hajam: investigation, writing – review and editing.

Conflicts of Interest

The authors declare no conflicts of interest.

Acknowledgments

The authors extend their appreciation to Euromed University of Fes, Morocco for offering facilities. This research work was funded by Umm Al‐Qura University, Saudi Arabia under grant number: 26UQU4290462GSSR03.

Contributor Information

Faisal A. Almalki, Email: famalki@uqu.edu.sa.

Ajmal R. Bhat, Email: bhatajmal@gmail.com.

Data Availability Statement

The data that support the findings of this study are available from the corresponding authors upon reasonable request.

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Data Availability Statement

The data that support the findings of this study are available from the corresponding authors upon reasonable request.

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