Harnessing Isosaponarin: A Multifaceted Bioactive and Therapeutic Potential Compound from Nature

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Al-Sulivany B et al.2024 256
PATHOLOGY AND MEDICINAL PLANT TREATMENT OF GASTROESOPHAGEAL
REFLUX DISEASE
Basim Al-Sulivany, Dilveen Ahmed, Rondik Naif, Payman Saleem, Evan Omer.
Department of Biology, Faculty of Science, University of Zakho, Duhok, Zakho, KRG, Iraq.
Corresponding author: Dr. Basim Al-Sulivany, Department of Biology, Faculty of Science,
University of Zakho, Duhok, Zakho, KRG, Iraq.
Tel: +9647504509701.
Email: basim.ahmed@uoz.edu.krd.
DOI: 10.21608/ajgh.2024.309358.1059.
Submission date:03 August 2024.
Revision date: 26 August 2024.
Acceptance date: 01 September 2024.
First online: 05 September 2024.
Abstract
Gastroesophageal reflux disease (GERD) is a prevalent chronic disorder characterized by the
backflow of acidic gastric contents into the esophagus due to lower esophageal sphincter (LES)
dysfunction. This condition causes esophageal mucosal damage, leading to symptoms such as
heartburn and chest pain, and is associated with increased risks of severe complications, including
esophageal adenocarcinoma.
Aims:
To review the current state of GERD management and assess the potential of photochemical plant-
based treatments as alternatives to conventional therapies.
Methods:
A comprehensive literature review was performed to describe the status of GERD in detail while
focusing on the emerging role of plant-based therapies in GERD management.
Results:
Traditional treatments for GERD are effective but often come with side effects and limitations.
Plant-based treatments, particularly those with photochemical properties, are potential

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complementary therapies. Preliminary data suggest these alternatives may improve symptom
management and patient outcomes.
Conclusions:
While standard treatments for GERD are widely used, their limitations necessitate exploring
alternative options. Photochemical plant-based therapies offer a promising, supplementary
approach, pending further validation through research and clinical trials.
Keywords: Medicinal plant, Gastroesophageal reflux disease, pathophysiology, Esophagitis.
1. Introduction
Gastroesophageal reflux disease (GERD), more commonly referred to as heartburn, is a
globally widespread condition (1). It can affect individuals from various age groups and both
sexes. The worldwide frequency of the disease is estimated to be between 8% to 33% (2), which,
according to the American Gastroenterological Association, is 1/3 of the population (3). Both
gastroenterologists and general care physicians regard it as one of the most frequently occurring
conditions (4). The digestive system in a healthy body proceeds from the mouth to the esophagus
and right away to the stomach. However, in people with GERD, there is a disruption in this path,
causing stomach acids to flow backward from the stomach into the esophagus, throat, and mouth
(3)GERD has many definitions. An updated one describes it as “a condition which develops when
the reflux of stomach contents causes troublesome symptoms (i.e., at least two heartburn episodes
per week) and/or complications.”(5). The occurrence of potentially deadly consequences can be
caused by GERD, even if the condition itself is not lethal (6). Based on the symptoms produced,
it can be classified into two major types: erosive type, which is associated with esophageal mucosal
damage, and non-erosive reflux disease, which encompasses symptoms lacking endoscopic
indications of injury to the esophageal mucosa (7).
Conditions resulting from erosive reflux disease include reflux esophagitis, reflux stricture, Barrett
esophagus, and esophageal adenocarcinoma. In contrast, non-erosive reflux disease is linked to
ailments in which the patient reports pain in their chest, heartburn, or regurgitation. Yet, there is
no sign of esophageal mucosal damage. In addition to conditions that have a suggested relationship
with disease (such as inflammation of the pharynx, sinusitis, idiopathic pulmonary fibrosis, and

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recurrent otitis media), extra-esophageal disorders connected to heartburn include disorders that
are known to be associated with GERD (such as dental damage, inflammation of the larynx,
coughing, and asthma) (8). It has been demonstrated to have a significant detrimental effect on a
person's quality of life concerning their health and a significant negative economic and societal
cost (1).
2. Symptoms
Damage to the mucosa resulting from aberrant stomach acid reflux into the esophagus,
mouth, lungs, or larynx is one of the symptoms of GERD. Heartburn and/or regurgitation of acid
occur at least a single time per week as symptoms. It should be noted that GERD diagnosis has
limitations based solely on patient symptoms because some individuals have endoscopic signs of
the disease (e.g., Barrett's esophagus or esophagitis) but do not show symptoms. In contrast, other
patients show symptoms but no objective signs of the disease. The significant financial burden
associated with GERD is a result of both the illness's high prevalence and the expensive cost of
medications that lower acid levels. GERD symptoms can be classified into three primary
categories: extraesophageal, atypical, and usual. Symptoms tend to be more severe after eating a
meal, are usually exacerbated by lying down, and are often alleviated by taking acid-lowering
medications. Common GERD symptoms include acid reflux and heartburn, which have a poor
sensitivity but a high specificity (4). Achalasia, gastritis, dyspepsia, gastroparesis, and peptic ulcer
disease are among the disorders in the differential diagnosis that may be signs of GERD. Still, they
may also coexist with unusual symptoms such as nausea, bloating, belching, and dyspepsia.
Finally, a few extraesophageal symptoms persist, such as laryngitis, asthma, teeth erosions, and
coughing (9). Currently accepted theories suggest that these symptoms may be caused by refluxate
microaspiration or a vagally mediated reaction triggered by exposure to distal esophageal acid.
The esophagobronchial reflex, the process via which distal esophageal acid exposure may cause
coughing, is thought to be mediated by the common vagal innervation of the esophagus and cough
reflex. In the context of GERD, extraesophageal symptoms should not be automatically attributed
solely to GERD, particularly in the absence of typical symptoms. Symptoms of GERD have a
significant influence on quality of life and health. According to a study, a lower quality of life in
terms of physical and mental health is associated with reflux symptoms that persist even after

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receiving proton pump inhibitor (PPI) therapy. When deciding on managing a patient's disease, it
is advised to consider behavioral and psychological aspects, notably when the patient has
decreased well-being and persistent reflux symptoms even after receiving PPI treatment (10).
Therefore, to prevent adverse impacts on quality of life and a host of consequences, it is crucial to
identify, diagnose, and treat individuals with GERD appropriately (4).
3. Risk Factors
GERD risk factors are many and have been hypothesized. The most well-established links
are those involving alcohol consumption, GERD in the family, and body mass index (8).
Pregnancy, scleroderma and neuropathies-related delayed and disturbed esophageal motility, and
surgical vagotomy are additional potential risk factors. Numerous foods and medications have
been linked to promote mucosal irritation or reduce the pressure of the lower esophageal sphincter
(LES). Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), nitroglycerin, blockers
of calcium channels, anticholinergics, antidepressants, sildenafil, albuterol, and glucagon are a few
medications that may be linked to the onset of GERD symptoms. Foods like chocolate, caffeine,
and heavy meals may worsen acid reflux symptoms. Research on these contributions, however, is
inconsistent. There exists a contradiction in the studies concerning the association between GERD
and tobacco smoking. There is little to no evidence linking carbonated soft drinks, overindulging,
and eating quickly (11).
4. Pathophysiology
The etiology of gastric reflux disease is complex. Acid secretion, inflammation, and
oxidative stress are the pathophysiologic elements of GERD (12). GERD is predisposed by several
variables, such as defective mucosal resistance, delayed stomach emptying, aberrant peristalsis,
inadequate esophageal acid clearance, and increased intraabdominal pressure. When the lower
esophageal sphincter (LES) relaxes, the esophagus becomes more vulnerable to stomach contents
such as bile, pepsin, small intestinal fluid, and pancreatic secretions in addition to gastric acid.
These compounds can potentially damage the esophagus's mucosa (11). After meals, an area of
unbuffered gastric acid builds up in the proximal stomach, just next to the gastroesophageal
connection, called an "acid pocket," where acid reflux into the esophagus may be prevented. The
upper esophageal sphincter relaxes in response to activation of the stomach's stretch receptors,

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which is mediated by the vago-vagal reflex system (13). When the lower esophageal sphincter
briefly relaxes, stomach contents escape into the esophagus. Although small quantities of acid
reflux are acceptable, gastroesophageal reflux is deemed abnormal if it persists over an extended
period at pH<4. Long-term exposure of the esophagus to digestive enzymes and acid from gastric
fluid or duodenal contents regurgitated into the stomach (such as bile salts) can cause and
encourage irritation of the esophageal mucosa, leading to symptoms and morphological
abnormalities. Because the mucosal tissues of the esophagus have limited inherent resistance to
reflux, the integrity of the anti-reflux barrier, which is made up of the crural diaphragm and the
lower esophageal sphincter is essential for preventing reflux-related symptoms and injury (14). A
hiatus hernia is a substantial risk factor for GERD because it may reduce the lower esophageal
sphincter's ability to prevent stomach contents from entering the esophagus (13).
5. Complications
5.1. Esophagitis
Esophagitis, or inflammation of the distal esophageal mucosa resulting in erosions, affects
around 18% to 25% of individuals with GERD symptoms (15). Erosive esophagitis, a significant
GERD side effect marked by ulcers and damage to the esophageal mucosa, is one of the main
symptoms. Patients with erosive esophagitis typically exhibit the classic signs of GERD, even
though they may not have any symptoms at all. The most widely used method for grading
esophagitis severity is the Los Angeles Esophagitis Classification System. Mucosal breaks'
circumferential severity, height, location, and quantity determine the Los Angeles system's A, B,
C, and D grading system (8).
Although erosive reflux esophagitis may present with symptoms like GERD, it may also
present with none. Once endoscopy reveals esophagitis, the degree of mucosal erosive areas is
graded from A to D according to the Los Angeles classification system. Less than five-millimetre
erosions are classified as grade A, five-millimetre erosions as grade B, erosions between the tops
of two or more mucosal folds that involve less than seventy-five percent of the circumference as
grade C, and erosions involving seventy-five percent or more of the circumference as grade D.
Long-term care is necessary for individuals with esophagitis because quitting PPI medication

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usually causes recurrence. However, after the drug is proven to work therapeutically, The
recommended daily dosage must be lowered to the lowest amount the patient can handle (15).
5.2. Structure
Fibrotic scarring brought on by acidic exposure to the esophagus can result in the
development of peptic esophageal strictures. In untreated patients with erosive esophagitis, the
incidence of peptic strictures ranges from 7% to 23% (16). The cause of esophageal strictures is a
disturbed healing mechanism and continuous acid irritation that scars the esophagus. Most GERD-
related strictures happen at the squamocolumnar junction. Dysphagia and food impaction are
common complaints from patients. Taking extra care when swallowing food is necessary to
manage esophageal strictures, and esophageal dilatation may be required. When a patient is
refusing treatment, injecting corticosteroids into the stricture may be an option. Although stent
migration, chest discomfort, bleeding, and esophageal perforation are risks, stricture stenting may
be an alternative. Using a PPI to reduce acid production might be beneficial, especially in
preventing stricture recurrence (8). Dysphagia is frequently observed in patients with esophageal
stricture. Continuous long-term PPI medication is part of the treatment, along with endoscopic
balloon dilatation, which may need to be repeated but effectively treats esophageal strictures in
over 80% of cases. If scarring returns after many dilatations, dilatation plus corticosteroid injection
may be an option; however, the studies supporting this strategy are tiny, have little follow-up, and
are inconclusive (17).
5.3. Barrett Esophagus
One GERD consequence that may turn cancerous is Barrett's esophagus. Barrett's
esophagus predisposes esophageal adenocarcinoma. Typically, the stratified squamous epithelium
lining the distal esophagus is replaced by meta-plastic columnar epithelium in Barrett's esophagus.
Histologically, mucus-secreting goblet cells are present in metaplastic columnar epithelium—the
development of the metaplastic epithelium results from long-term exposure to stomach acid and
other refluxed materials. Male sex, age above 50, obesity, smoking, hiatal hernia, and Caucasian
racial background are additional risk factors. A diet rich in fruits and vegetables, NSAID use, and
H pylori infection in the stomach may, for unknown reasons, protect against Barrett's esophagus.

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While dysplasia may be evident in Barrett's esophageal reflux disease, not all patients with
Barrett's esophagus have dysplastic alterations. Every year, approximately 0.25% of people with
Barrett's esophagus go on to develop esophageal cancer. Patients with high-grade dysplasia and
extended segments of the afflicted esophagus are more likely to progress to esophageal cancer (8).
The precursor lesion to esophageal adenocarcinoma, Barrett's esophagus, can be brought
on by GERD. Barrette's esophagus, which is not dysplastic, has a modest absolute risk of
esophageal cancer, but dysplasia increases that risk significantly. According to a second meta-
analysis involving 20 papers and 74943 Barrett esophageal patients, male sex, older age, tobacco
use, longer Barrett mucosal segment, and central obesity were the primary risk variables for tumor
advancement (15).
5.4. Esophageal Adenocarcinoma
Barrett's esophageal development is linked to esophageal cancer in cases of GERD (15). Over the
past forty years, there has been a significant rise in esophageal adenocarcinoma, especially in
Western nations. The global incidence rate of this disease is 1.1 cases per 100,000 person-years
for men and 0.3 cases per 100,000 person-years for women (18). The 5-year survival rate is less
than 20%. Nonetheless, due to the tumor's rarity in the general population, even while GERD
patients have a higher relative chance of developing esophageal adenocarcinoma, the absolute risk
is minimal. It is debatable if GERD medication lowers the risk of esophageal adenocarcinoma
(15).
6. Treatment
Treatment for gastric reflux disease (GERD) consists of medication, lifestyle changes, and
long-term surgical alternatives. Reducing weight and elevating the head of the bed are two
effective lifestyle modifications. Patients are also recommended to avoid lying down for three
hours after eating and to avoid trigger foods like chocolate, coffee, and alcohol (19). It is especially
advised for those who have gained weight recently to lose weight. Proton-pump inhibitors (PPIs),
which are more effective than histamine-receptor antagonists (H2RAs), are the mainstay of
medical therapy for acid control. Since most patients with erosive reflux disease (ERD) return after
stopping PPI therapy, maintenance therapy at the lowest effective dose is advised. In treating non-
erosive reflux disease (NERD), H2RA therapy or on-demand PPI medication may be helpful.

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Compliance and appropriate dosage should be addressed first in PPI-refractory GERD. If
symptoms don't go away, a different PPI can be used, or the dosage can be. Using baclofen or
adding H2RAs at night may also be beneficial. For individuals who refuse to take their medicine,
are intolerant of it, or have symptoms that are not improving medically, surgical options such as
laparoscopic fundoplication or bariatric surgery are taken into consideration (20).
GERD symptoms can be well alleviated with a laparoscopic fundoplication, while some
patients may still need medication after the procedure. Gas bloat syndrome and dysphagia are
possible side effects. An alternative with encouraging outcomes is the LINX Reflux Management
System, which entails putting a magnetic wristband over the lower esophageal sphincter (LES).
There has been little progress with endoscopic treatments, and several methods have been taken
off the market because they don't work. There have been conflicting outcomes with transoral
incisionless fundoplication; nonetheless, research is still being conducted to enhance endoscopic
GERD therapy choices. It is advised that individuals with GERD who are morbidly obese (BMI >
35 kg/m2) undergo gastric bypass surgery, preferably Roux-en-Y gastric bypass. This technique
lowers the risk of long-term mortality and comorbidities associated with obesity in addition to
more effectively addressing GERD causes. In this population, sleeve gastrectomy and adjustable
gastric banding are less effective than Roux-en-Y gastric bypass in improving GERD results (20).
About 20–40% of GERD patients do not respond to PPI medications (20). Even with PPI
drugs, specific GERD therapeutic needs remain unfulfilled. Furthermore, because of PPI
refractoriness, up to 40%–55% of daily PPI users experience persistent symptoms (11). Potassium-
competitive acid blockers (P-CABs) competitively inhibit the potassium-binding site of H+, K+-
adenosine triphosphate ATPase. While this class of medications has a long history, two P-CABs,
Vonoprazan and Revaprazan, have only recently been licensed for clinical usage in Japan and
Korea, respectively (11). P-CABs overcome several PPI's disadvantages and restrictions. A
growing amount of evidence indicates that they offer a significant additional benefit when taken
as main or adjunctive medications (to standard treatment), especially in treating symptoms that do
not improve with PPI therapy (11). Furthermore, studies have demonstrated that vonoprazan's
acid-inhibitory impact is more substantial than PPIs' (20).
7. Medicinal Plants

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Asiatica Artemisia: in a study exploring the effect of Artemisia asiatica extract (DA-9601),
the findings showed that DA-9601 was significantly more effective than ranitidine in treating
reflux esophagitis. DA-9601 reduced the number of ulcers, decreased esophageal wall thickness,
and improved inflammation and mucosal recovery, showing superior healing effects. In contrast,
ranitidine did not significantly reduce ulceration and inflammation or promote mucosal
regeneration. The findings suggested that DA-9601 offers a more comprehensive approach by
addressing both acid-induced and oxidative damage, making it a superior treatment option (21).
Myrtus communis: Administration of an aqueous extract of Myrtus communis fruit
significantly reduced dyspeptic and reflux ratings in a randomized controlled experiment (22).
Rats with stomach ulcers were demonstrated to benefit from the preventive effects of several fruit
extracts. Additionally, the extracts decreased the overall acidity and amount of gastric juice.
Olea Europea: Giving olive oil for two to six months to post-gastrectomy patients with
highly symptomatic duodeno-gastric reflux who did not respond to traditional treatments either
eliminated the patients' symptoms or significantly reduced them (23).
Cydonia oblonga (quince): When a syrup made from the fruit of this plant was given to kids with
GERD, their symptoms significantly improved over time. Still, the decline was not statistically
significant compared to the control group. Quince syrup continued to work even after stopping the
use of omeprazole for two weeks (22).
Morus alba: In rats treated with leaf extract from the plant before GERD was induced, the amount
of mucus on the stomach wall increased. H+-K+-ATPase and plasma histamine levels both sharply
dropped. By reducing lipid peroxidation and raising the concentration of antioxidant enzymes,
morus alba extract showed antioxidant activity (12).
Panax quinquefolium: Rats receiving Panax quinquefolium first showed a dose-dependent
reduction in lipid peroxidation, increased antioxidant status, and a notable decrease in the extent
of tissue damage caused by RE. However, whereas omeprazole effectively reduced mucosal
damage, it did not show any antioxidant activity. The expression of genes encoding proteins
associated with acute inflammation, such as cytokine-induced neutrophil chemoattractant 2
(CINC-2) and intercellular adhesion molecule 1 (ICAM-1), was also considerably reduced by

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Panax quinquefolium. It did not affect monocyte chemotactic protein 1 (MCP-1), a marker of
ongoing inflammation (12).
Rubus spp. (black raspberry): Black raspberry dietary supplementation did not alter
cellular antioxidant or lipid peroxidation levels in a brief experiment, including the production of
GERD in an animal model of esophagoduodenal anastomosis compared to the control diet.
Furthermore, it did not influence the onset of Barrett's esophagus or the degree of esophagitis (12).
Salvia miltiorrhiza: By causing rats' lower esophageal sphincters (LES) to contract tonic,
Salvia miltiorrhiza appears to help treat gastroesophageal reflux disease. It was discovered that the
underlying mechanism of this contractile action is the extracellular Ca (2+) influx pathway (12).
Atropa belladonna, sometimes referred to as a deadly nightshade, has an alkaloid in its
leaves and roots that blocks muscarinic receptors. In human trials, this anticholinergic herb has
been demonstrated to reduce relaxation of the lower esophageal sphincter and reflux episodes.
Rather than having a local effect on the LES, atropine influences the brain stem. People with
GERD are advised to use only whole-plant extracts as purified atropine has more negative effects.
8–10 drops of a 1:5 tincture of belladonna leaf is usually taken with each meal. Although possible,
mild dry mouth does not warrant changing the dosage. On the other hand, symptoms such as
confusion or impaired vision that appear after consuming the plant may indicate an overdose. The
herbal intake should be stopped if these symptoms occur and should not return till they do. After
that, it can be given again at half the original dose (24).
Brassica oleracea (cabbage): The outcomes of an experimental study establish that giving
chronic and severe GERD patients plant-based fresh raw cabbage juice extract resulted in a 100%
cure. In its natural state, the composition of cabbage may help prevent or treat acid reflux. Varied
factors, such as a person's work environment, lifestyle, and level of anxiety, may contribute to
varied compositions of acid reflux disease (GERD). However, all of the patients in the experiment
experienced a cure from fresh, raw cabbage juice extract, which went beyond these differences in
composition and reduced GERD (3).
Euphorbia hirta: this plant is widely known for its hypoglycemic, antiasthmatic,
antifungal, antibacterial, anti-inflammatory, galactogenic, antidiarrheal, antioxidant, and
antimalarial properties. The effects of a whole plant extract and flavonoids from E. hirta on gastric

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reflux disease (GERD) in rats were studied. According to the findings, the groups who received
both the plant extract and the flavonoids also had higher amounts of stomach wall mucus and
significantly lower levels of plasma histamine and H+ K+ ATPase. Plant extract and flavonoids
increased catalase, reduced glutathione levels, and decreased superoxide dismutase and lipid
peroxidation. The potential of E. hirta to treat GERD is associated with its antisecretory,
gastroprotective, and antioxidant qualities. It also has this property in common with kaempferol,
quercetin, rutin, and omeprazole, among other proton pump inhibitors. Standardized E. hirta plant
extract, which contains kaempferol, rutin, and quercetin, significantly impacted the production of
stomach mucus and prevented the discharge of stomach acid. The study results show that treating
rats' GERD with an extract from the E. hirta plant is beneficial. This demonstrates that the
antisecretory and antioxidant qualities of E. hirta plants may be responsible for their positive
effects, supporting the use of these seeds to treat GERD (25, 26).
8. Mechanism of Medicinal Plants
The antioxidant and anti-inflammatory properties of medicinal herbs are the main
underlying processes responsible for their impact on GERD. The following herbal medicines and
therapeutic herbs function along these pathways: Panax quinquefolium, Artemisia asiatica,
Lonicera japonica, STW 5, Curcuma longa, and Lonicera asiatica. Additional mechanisms include
decreasing gastric acid (Curcuma longa, Morus alba, acidinol syrup), upregulating the genes
encoding proteins involved in acute inflammation, such as ICAM-1 and CINC-2 (Panax
quinquefolium), and suppressing the pro-inflammatory cytokines TNF-a and IL-1b (STW 5). Anti-
secretory medication has not been demonstrated to diminish inflammation or the severity of RE;
therefore, it is insufficient to provide comprehensive recovery. An anti-secretory medication that
enhances mucosal aging is omeprazole, for instance. Thus, it could not considerably lessen the
oxidative stress and inflammatory parameter alterations linked with RE. Anti-inflammatory and
antioxidant activity are what most medicinal herbs studied for GERD exhibit, not anti-secretory
qualities. The potential benefit of medicinal plants over traditional anti-secretory medicines lies in
their ability to treat NERD, an area where PPIs do not exhibit any possible impact. In addition, the
therapeutic effects of medicinal plants seem to continue longer than those of traditional anti-
secretory drugs. To illustrate, two weeks after stopping, Cydonia oblonga remained effective (12).

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9. Conclusion
GERD is a chronic condition that carries significant risks if not effectively managed,
including serious complications such as Barrett's esophagus, esophageal strictures, and esophageal
cancer. Conventional treatment approaches, including pharmacotherapy and lifestyle
modifications, effectively control symptoms and prevent disease progression. However, there is a
growing interest in complementary therapies, particularly the implication of medicinal plants,
which may offer additional therapeutic options.
An integrated approach that combines traditional medical interventions with rigorously
validated alternative therapies could provide a more comprehensive treatment strategy for GERD,
thereby enhancing patient outcomes and quality of life. Additional research is essential to
substantiate the efficacy of these alternative treatments.
Footnotes.
Ahmed Gad (lecturer of internal medicine) and Ayman Sadek (assistant professor of
internal medicine) were the peer reviewers.
E- Editor: Salem Youssef Mohamed, Osama Ahmed Khalil, Amany Mohammed.
Copyright ©. This open-access article is distributed under the Creative Commons Attribution
License (CC BY). It may be used, distributed, or reproduced in other forums, provided the original
author(s) and the copyright owner(s) are credited. The original publication in this journal must be
cited according to accepted academic practice.
Disclaimer: The authors' claims in this article are solely their own and do not necessarily represent
their affiliated organizations or those of the publisher, the editors, and the reviewers. Any product
evaluated in this article or its manufacturer's claim is not guaranteed or endorsed by the publisher.
Ethical approval: All procedures involving human participants followed the institutional and
national research committee's moral standards, the 1964 Helsinki Declaration, and its later
amendments or comparable ethical standards. All authors declare that consent was obtained from
the patient (or other approved parties) to publish this study.
Data and materials availability: The datasets used or analyzed during the current study are
available from the corresponding author upon reasonable request.
Competing interests: The authors declare that they have no competing interests.

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Funding: This study had no funding from any resource.
This work was done according to the STROBE guidelines.
Authors’ contributions
All authors thoroughly reviewed and approved the final version of the manuscript.
Acknowledgment: I sincerely thank Assistant Professor Dr. Khalid Ibrahim for his valuable
comments on this manuscript.
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