Diabetes mellitus is a
group of metabolic disorders characterized by chronic hyperglycemia resulting
from defects in insulin secretion, insulin action, or both. Insufficient
insulin activity on target tissues leads to impaired metabolism of
carbohydrates, proteins, and lipids, which manifests in symptoms such as
polyuria, polydipsia, and polyphagia (1, 2). In type 2 diabetes mellitus
(T2DM), insulin resistance in tissues such as the liver, adipose tissue, and
muscles, combined with pancreatic β-cell dysfunction, disrupts the feedback
loop between insulin sensitivity and insulin secretion. This results in erratic
blood glucose levels, reduced glucose uptake in peripheral tissues, and
increased hepatic glucose production (3). The global prevalence of diabetes is projected to rise from
4% in 1995 to 6.4% by 2025, with type 2 diabetes accounting for 85–95% of cases
in industrialized nations and an even higher percentage in developing
countries. Approximately 80% of all diabetes patients reside in emerging
economies, with India and China experiencing the highest burden. The growing
incidence of diabetes and its associated complications has intensified the
search for effective and safer anti-hyperglycemic agents (4).
Current treatment options
for T2DM include insulin therapy and several classes of oral anti-diabetic
drugs, such as biguanides, sulfonylureas, glinides, and amylolytic enzyme
inhibitors. While these medications are effective in controlling blood glucose
levels, their use is often limited by adverse effects and insufficient
long-term efficacy. Consequently, researchers are increasingly turning to
medicinal plants as sources of novel therapeutic agents. Plants have been
utilized for centuries in traditional medicine due to their natural origins and
minimal side effects. Many medicinal plants and their extracts have
demonstrated efficacy in managing diabetes, making them attractive alternatives
to conventional treatments (5). One such plant is
Praecitrullus fistulosus, commonly known as "Tinda" in Hindi, which
belongs to the Cucurbitaceae family. This plant, native to northwest India, is
widely cultivated in India, Afghanistan, and Pakistan as a vegetable. Cucurbits
are renowned for their nutritional and medicinal properties, containing
bioactive compounds essential for human health (). Previous studies have
identified various phytochemicals in P. fistulosus, including flavonoids,
polyphenols, alkaloids, tannins, phytosterols, and cardiac glycosides ().
These compounds contribute to its reported pharmacological activities, such as
antimicrobial, anthelmintic, free radical scavenging, and anti-diabetic
effects.
Declarations
Acknowledgment
The authors greatly acknowledge and express their gratitude to the Principal United Institute of Pharmacy, Prayagraj for providing instruments and laboratory and animal house facilities to carry out this research work.
Conflict of Interest
The authors declare no conflicting interest.
Data Availability
The unpublished data is available upon request to the corresponding author.
Ethics Statement
The experimental procedure was approved by the IAEC committee with approval number (UIP/IAEC/March-2023/03).
To explore the potential
of P. fistulosus as a natural remedy for diabetes mellitus, this study
investigates its anti-diabetic properties using in silico, in vitro, and in vivo approaches. By evaluating its bioactive compounds and mechanisms of
action, this research aims to provide scientific validation for the traditional
use of P. fistulosus in managing diabetes (8, 9).
Materials and
Methods
Plant Material Collection and Authentication
Fresh,
mature fruits of P. fistulosus were collected from local areas in
Prayagraj in August 2022. The plant was taxonomically identified by experts at
the National Institute of Science Communication and Information Resources
(NISCAIR), New Delhi. A voucher specimen was prepared and submitted to the Raw
Materials Herbarium and Museum (RHMD), New Delhi, under the verification number
NISCPR/RHMD/Consult/2023/4502- 03.
Preparation of Extract
The collected fruits were
thoroughly washed, air-dried, and ground into a fine powder. The powdered
material was subjected to extraction using 50% ethanol as a solvent through the
Soxhlet extraction method. The resulting extract was concentrated by evaporating
the solvent at a controlled temperature of 40–50 °C using a rotary evaporator
under reduced pressure (10).
Quantitative Phytochemical Tests
Total Phenolic Content
The total phenolic content
(TPC) in the ethanolic extract of P. fistulosus (PFEE) was
determined using the Folin-Ciocalteu reagent, following the methods described
by Chandra et al. (2014) and Harborne (1998) (11, 12). Gallic acid was used as the
reference standard. The absorbance of the sample was measured at 765 nm using a
UV-visible spectrophotometer. The TPC was calculated in terms of milligrams of
gallic acid equivalent per gram of extract (mg GAE/g) based on a standard
calibration curve.
Total Flavonoid Content
The total flavonoid
content (TFC) of the PFEE was
estimated using the method described by Sembiring et al. (2018) (13). Quercetin
was used as the reference standard. The absorbance of the sample was measured at
510 nm using a UV-visible spectrophotometer. The TFC was calculated based on a
standard calibration curve and expressed as milligrams of quercetin equivalent
per gram of extract (mg QE/g).
Molecular Docking
The objective of this study was to investigate the binding
interactions of PFEE constituents with human pancreatic α-amylase. The target protein molecule
was retrieved from the Protein Data Bank (PDB) with the identifier 1XEW at a
resolution of 2.000 Å. Preparation of the target protein for docking involved
removing all heteroatoms, non-receptor atoms, and water molecules.
Constituents of PFEE,
including α-tocopherol, linoleic acid, myristic acid, oleanolic acid, palmitic
acid, and ursolic acid, were modeled and optimized using ChemDraw Ultra 16.0
software to generate appropriate ligand structures. These ligands were then subjected
to in silico docking simulations to estimate binding energies and determine
their optimal docked configurations. The docking studies were performed using
the Mcule platform (14).
In Vitro Antidiabetic Activity
Assay of α-Amylase Inhibition
The assay was conducted using
substrates containing 0.01 M CaCl₂ (0.2 mL), 2 mg of starch, and 1 M Tris-HCl
buffer (pH 7.2). The substrate solution was pre-incubated at 37 °C for 5 min and then boiled for 5 min. The PFEE was dissolved in DMSO at various concentrations (20, 40, 60, 80,
and 100 µg/mL) and added to the substrate solution. Subsequently, 0.1 mL of
α-amylase (diluted to 2 units/mL) was introduced, and the mixture was incubated
for 10 min at 37 °C.
The enzymatic reaction was terminated
by adding 0.5 mL of 50% acetic acid to each test tube. The solution was then
centrifuged at 3000 rpm for 5 min at 4 °C, and the absorbance of the
supernatant was measured at 595 nm using a spectrophotometer. Acarbose, a known
amylolytic enzyme inhibitor, was used as the reference standard. All tests were
performed in triplicate for each concentration, and the results were calculated
using the Equation 1 (15, 20).
%Inhibition=AsAs−At×100%
Equation 1
where, As=
Absorbance of control and At= Absorbance of test samples at 595 nm.
Assay of α-Glucosidase Inhibition
The
assay was performed using a 100 mL solution of phosphate buffer (pH 6.8)
containing 1 mg of α-glucosidase. For each test, 200 µL of α-glucosidase
solution was combined with 100 µL of PFEE at concentrations of 20, 40, 60, 80, and 100 µg/mL. To initiate the
reaction, 100 µL of 3 mM p-nitrophenyl-D-glucopyranoside (p-NPG) was added to
each test tube, and the mixtures were incubated at 37 °C for 20 min.
The
enzymatic reaction was terminated by adding 2 mL of 0.1 M Na₂CO₃ to each test
tube. The activity of α-glucosidase was determined by measuring the absorbance
of the reaction product at 405 nm using a UV-visible spectrophotometer.
Acarbose, a known amylase and glucosidase inhibitor, was used as the positive
control (16).
In Vivo Studies
Animals
Adult Wistar rats (weighing 100–250 g) were procured from an animal
supplier approved by the Committee for Control and Supervision of Experiments
on Animals (CPCSEA), M/s Chakraborty Enterprises, Kolkata (registration number
1443/PO/Bt/s/11CPCSEA). The animals were transferred to the quarantine area of
the animal house at the United Institute of Pharmacy, where they were
acclimatized for two weeks before the experiment. During this period, the rats
were provided with food and water ad libitum and maintained under a controlled
environment with a 12-hour light/dark cycle. The experimental protocol was
reviewed and approved by the Institutional Animal Ethics Committee (IAEC) under
approval number UIP/IAEC/March-2023/03.
Acute Oral Toxicity
The determination of the median lethal dose (LD₅₀) was conducted in
accordance with OECD Guideline 423. The extract was administered to animals at
doses of 5, 50, 300, and 2000 mg/kg, as specified in the guidelines. Following
administration, the animals were closely monitored for any signs of toxicity,
behavioral changes, or adverse effects (17, 19).
Antidiabetic Activity
All animals were fed a
high-fat diet (HFD) for the first 13 days. On the 13th day, streptozotocin
(STZ) was administered intraperitoneally (I.P.) at a dose of 40 mg/kg body
weight to all animals except those in the normal control group (18). Blood
glucose levels were measured 72 h post-STZ administration. Animals with
blood glucose levels ≥ 200 mg/dL were classified as diabetic and included in
the experiment. The animals were divided
into five groups, each comprising six animals:
Group 1 (Normal Control):
Received normal food and water.
Group 2 (Diabetic
Control): Received HFD and STZ (40 mg/kg body weight).
Group 3 (Standard
Treatment): Treated with metformin (100 mg/kg body weight).
Group 4 (Low Dose PFEE):
Treated with a low dose of PFEE at
200 mg/kg body weight.
Group 5 (High Dose PFEE):
Treated with a high dose of PFEE at 400 mg/kg body weight.
All treatments, including
the vehicle, standard drug, and plant extracts, were administered orally using
an oral gavage tube. Blood samples were collected weekly via retro-orbital
puncture, and blood glucose levels were measured using a glucometer (Morepen).
Additional blood samples collected through retro-orbital puncture were used for
lipid profile analysis. Lipid parameters, including low-density lipoprotein
(LDL), high-density lipoprotein (HDL), very low-density lipoprotein (VLDL),
triglycerides (TG), and total cholesterol (TC), were assessed using standard
commercial kits (Erba Mannheim, Mumbai, India).
Statistical Analysis
Graph pad prism 9.5.1 was applied
to conduct the statistical testing. All the information is presented as
Mean ± SD. The two-way ANOVA model with Tukey’s multiple comparisons test was
used to examine body weight, blood glucose, and lipid profile.
Results
Phytochemical
Screening
The results of the quantitative
phytochemical analysis revealed that the TPC of PFEE was 250.56 mg/g, expressed as
vanillic acid equivalents (VAE). The TFC was
determined to be 273.18 mg/g, expressed as quercetin equivalents (QE) on a dry
weight basis.
Molecular Docking
Acarbose and different constituents of PFEE like α-tocopherol, linoleic acid,
myristic acid, oleanolic acid, palmitic acid, and ursolic acid were involved in effective binding relationships with the
target molecule as shown in Table 1 and Figure 1.
In Vitro Antidiabetic Activity
α-Amylase and α-Glucosidase Inhibitory Activity
The anti-diabetic potential of PFEE was evaluated by assessing its inhibitory effects on two key amylolytic enzymes, α-amylase and α-glucosidase, in comparison with the standard drug acarbose. Acarbose demonstrated 65.28% inhibition of α-amylase (Figure 2A) and 69.38% inhibition of α-glucosidase (Figure 2B) at a concentration of 100 µg/mL. At the same concentration, PFEE exhibited 52.06% inhibition of α-amylase and 58.10% inhibition of α-glucosidase. Both α-amylase and α-glucosidase play crucial roles in the digestion of carbohydrates, making them important targets for managing postprandial hyperglycemia in type 2 diabetes.Acarbose, a widely used oral hypoglycemic agent, lowers blood sugar by inhibiting these saccharide-hydrolyzing enzymes. Similarly, PFEE demonstrated inhibitory activity against both enzymes at varying concentrations, suggesting its potential as a natural alternative to conventional enzyme inhibitors.
Table 1. Interaction of constituents of PFEE target α-amylase.
Figure 1. 3D interaction of α-amylase with (A) acarbose, (B) α-tocopherol, (C) linoleic acid, (D) myristic acid, (E) oleanolic acid, (F) palmitic acid, and (G) ursolic acid.
Figure 2. Inhibition effect of PFEE on (A) α-amylase and (B) α-glucosidase.
In Vivo Studies
Oral Acute Toxicity
In the oral acute toxicity study,
the PFEE was administered at
doses of 5, 50, 300, and 2000 mg/kg body weight to assess its safety profile.
Throughout the study, no mortality or significant adverse effects were observed
at any of the tested doses, indicating that the extract is safe for use within
the evaluated dosage range.
Effect of PFEE on Blood Glucose Level
Oral administration of PFEE at doses of 200 mg/kg and 400 mg/kg resulted in a significant
reduction in blood glucose levels over 39 days, as shown in Figure 3A. After
the treatment period, PFEE at a dose of 200 mg/kg reduced glucose levels from
222.16 mg/dL to 115 mg/dL. A higher dose of 400 mg/kg resulted in a more
pronounced reduction, from 222.16 mg/dL to 105.5 mg/dL. For comparison, the
standard drug metformin, administered at 100 mg/kg, reduced glucose levels from
222.16 mg/dL to 98.16 mg/dL.
In comparison to the diabetic control group, all treated
groups exhibited a significant (p < 0.0001) dose-dependent decrease in blood
glucose levels. These results demonstrate the potential of PFEE as an effective
agent for lowering blood glucose levels in diabetic rats.
Effect of PFEE on Lipid Profile
During the experimental study,
various lipid parameters, including high-density lipoprotein (HDL), very
low-density lipoprotein (VLDL), low-density lipoprotein (LDL), total
cholesterol (TC), and triglycerides (TG), were evaluated to assess the efficacy
of PFEE. As shown in Figure 3B,
PFEE at a dose of 400 mg/kg had a significant impact on the lipid profile of
diabetic rats.
PFEE treatment led to a marked
reduction in TC levels from 148 ± 12.26 mg/dL to 78.33 ± 4.71 mg/dL (p <
0.0001), TG levels from 108.5 ± 6.47 mg/dL to 81.33 ± 4.81 mg/dL, LDL levels
from 54.16 ± 8.91 mg/dL to 32.5 ± 6.21 mg/dL, and VLDL levels from 37.16 ± 5.59
mg/dL to 25.33 ± 2.74 mg/dL. Additionally, HDL levels were significantly
increased from 17.83 ± 6.71 mg/dL to 23.5 ± 4.92 mg/dL compared to the diabetic
control group.
Discussion
This study investigated the antidiabetic effect of PFEE using a rodent model combining a high-fat diet (HFD) and low-dose streptozotocin (STZ). HFD induces insulin resistance through mechanisms like the glucose-fatty acid cycle (Randle cycle) (21, 22), while low-dose STZ impairs insulin secretion, mimicking late-stage type 2 diabetes mellitus (23). Diabetic rats exhibited elevated fasting glucose levels, indicating insulin resistance. This model effectively simulates human metabolic conditions, including hyperglycemia, insulin resistance, and hyperlipidemia, making it highly relevant for studying diabetes-related pathophysiology (24).
Figure 3. Effect of PFEE on (A) glucose level and (B) lipid profile. (c, p < 0.0001) compared to the diabetic control group and (z, p < 0.0001) compared to the normal control group.
The
fruits of P. fistulosus are rich in phytochemicals such as
flavonoids, terpenoids, phenols, and other secondary metabolites, which
contribute to its potential as an anti-hyperglycemic agent (25, 26). In this
research, the total phenolic and flavonoid contents of PFEE were quantified,
and the observed anti-diabetic effects were attributed to the presence of
polyphenols and flavonoids. These compounds act as free radical scavengers,
reducing glucose absorption, enhancing glucose uptake in peripheral tissues,
and regulating key metabolic pathways such as glycolysis and glycogen synthesis
(27).
Molecular
Docking
In
the molecular docking analysis, α-tocopherol exhibited the most favorable
binding interaction with α-amylase (PDB ID: 1XEW), forming hydrogen bonds with
residues GLY304, GLN302, ARG303, THR163, ASP300, ASN301, HIS201, LEU165, GLY74,
and LEU32. The docking energy for this interaction was -8.2 kcal/mol. Ursolic
acid also demonstrated strong binding, interacting with residues LEU26, ARG303,
GLY304, GLY308, ALA33, HIS305, THR84, and ASP300, with a docking energy of -5.6
kcal/mol. These phytoconstituents are known for their roles in managing type 2
diabetes and oxidative stress in metabolic disorders (25, 26).
In Vitro
Enzyme Inhibition
The in vitro anti-diabetic potential of PFEE was evaluated using α-amylase and
α-glucosidase inhibition assays, with acarbose as the standard. Both enzymes
play key roles in carbohydrate digestion and postprandial glucose elevation.
Inhibiting these enzymes can reduce postprandial hyperglycemia and lower the
risk of developing diabetes (23). Phenolic acids and flavonoids, the dominant
polyphenolic constituents in PFEE, have demonstrated significant inhibitory
effects on amylolytic enzymes (28). The presence of these compounds in PFEE
supports its ability to inhibit these enzymes at different concentrations,
thereby reducing blood glucose levels in diabetic rats, as observed in
comparison with acarbose.
Acute
Toxicity and Safety Profile
In
the oral acute toxicity study, PFEE was administered at doses up to 2000 mg/kg
body weight. No signs of toxicity or mortality were observed during the
observation period, indicating an LD₅₀ greater than 2000 mg/kg. These findings
confirm the extract's safety at the tested doses.
Dose-Dependent
Effects on Glycemic and Lipid Profiles
The
study also observed that PFEE exhibited dose-dependent effects, with higher
doses producing greater reductions in fasting blood glucose levels. This effect
is likely due to the higher concentration of active constituents in the extract
at increased doses. PFEE also ameliorated lipid abnormalities, including
reductions in cholesterol and triglyceride levels, along with an increase in
HDL levels. These improvements in lipid metabolism suggest enhanced insulin
activity.
The
flavonoids present in PFEE may play a key role in these effects. Flavonoids are
known to inhibit cholesterol absorption, enhance triglyceride-laden lipoprotein
catabolism, and promote bile acid excretion. Additionally, they can inhibit
enzymes such as HMG-CoA reductase, reducing cholesterol synthesis, and
cholesterol acyltransferase, decreasing cholesterol esterification in the liver
and intestines. These mechanisms collectively contribute to reduced cholesterol
absorption and incorporation into lipoproteins (29).
Conclusion
In the Cucurbitaceae
family, P. fistulosus is one of the potent plants containing
essential phytoconstituents that promote human health. The entire plant and its
fruit are considered natural antioxidant storehouses with significant
therapeutic potential for combating various diseases. The present study
demonstrated the antidiabetic potential of P. fistulosus in STZ and
high-fat diet-induced diabetic animal models, with no observed side effects or
toxicity. Blood glucose levels decreased from 222.16 mg/dL to 115 mg/dL at a
dose of 200 mg/kg bw (p < 0.0001). Additionally, molecular docking research
supports the development of this plant as a potential diabetic medication,
showing positive interactions with constituents responsible for the antiglycation
activity. In vitro results also confirmed that the extract's inhibition of
amylolytic enzymes in the intestine could contribute to its antidiabetic and
antihyperlipidemic effects. Our findings suggest that P. fistulosus
could be considered a promising natural remedy for the treatment of diabetes
and its related complications.
This study explored the safety and antidiabetic potential of a hydroalcoholic extract of Praecitrullus fistulosus fruits, along with qualitative and quantitative phytochemical analyses. The antidiabetic effect was evaluated using in vitro methods, including α-amylase and α-glucosidase inhibition assays, as well as an in vivo high-fat diet and low-dose streptozotocin-induced diabetic model. Molecular docking studies were conducted to identify phytochemicals responsible for the antidiabetic effects. The fruit extract exhibited maximum inhibition of 52.06% and 58.10% for α-amylase and α-glucosidase enzymes, respectively, at a concentration of 100 µg/mL. The extract also demonstrated a significant (p < 0.001) and dose-dependent antidiabetic effect at oral doses of 200 mg/kg and 400 mg/kg in the tested animals. In silico analysis revealed that α-tocopherol exhibited the best docking pose, with a docking energy of -8.2 kcal/mol. Based on the results, it can be concluded that the hydroalcoholic extract of Praecitrullus fistulosus contains phytochemicals effective in controlling glucose levels. This study also validates the traditional use of Praecitrullus fistulosus fruits in managing diabetes.
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