Diabetes is the 9th killer disease in the world, where one in every ten individuals is living with diabetes and approximately 10.5% world's population is diabetic. Several other complications arise in diabetic patients. Approximately 540 million individuals (20 to 79 years) were living with diabetes in 2022 which will increase to 783.3 million by the year 2045. However, the WHO estimate shows that overall 830 individuals lived with diabetes in the year 2022 (Diabetes). One individual died 5 every second of diabetes in 2021. China has the maximum number of individuals (140.9 million) living with diabetes. Approximately 74.2 million individuals were suffering from diabetes in India in the year 2021 and India has the second largest population of diabetic individuals. Pakistan has the third largest population of diabetic patients (33 million). The USA has 32.2 million individuals living with diabetes in the year 2021 and ranks fourth in the number of diabetic individuals. Diabetes is one of the major public health concerns in the world and 966 billion USD has been spent on healthcare costs for diabetes in the year 2021 globally [1,2].

Diabetes is a metabolic disorder caused by hormonal dysregulation and defective cellular metabolism leading to raised fasting blood glucose resulting in hyperglycemia and glucose intolerance. Any individual displaying fasting blood glucose levels of more than 110 mg/dL (6.1 mmol) and postprandial glucose levels of 200 mg/dL (11.1 mmol) is considered diabetic [3]. The glucose levels in the human blood are controlled by insulin in concert with glucagon, corticosteroids, epinephrine, and growth hormone [4]. Diabetes is caused by the cessation of insulin production and the dysregulated action of insulin owing to the malfunctioning of β-cells and/or damaged pancreas. Diabetes is classified mainly into four types depending on the etiology and clinical manifestation. Insulin-dependent Diabetes mellitus or Type I (IDDM, Type I) and Type II diabetes- a non-insulin-dependent Diabetes mellitus (NIDDM, Type II). In addition, the other types of diabetes are gestational diabetes, and other specific types [5-7]. IDDM or Type I diabetes is an autoimmune disorder, where the body’s T-lymphocytes damage β-cells of islets of Langerhans leading to local inflammation and suppression of insulin secretion. IDDM is treated by insulin replacement therapy [4,8-10]. IDDM is more common in children than in adults and occurs due to genetic predisposition and its incidence is on the rise [11,12]. The most common type of diabetes in adult humans is NIDDM or Type II which is a metabolic disorder and is caused by insufficient secretion of insulin by the β cells of the pancreas and/or the insulin-sensitive tissues fail to respond to insulin secretion. The insulin release, glucose homeostasis, and insulin synthesis mechanisms an                                                                                                  d their release are meticulously controlled, however, dysregulation of these mechanisms results in diabetic disorders [10,13]. The NIDDM exhibits intermediate stages of impaired fasting glucose and impaired glucose tolerance, therefore it is also known as prediabetes.

Obesity has emerged as one of the main factors leading to Type II diabetes as 85-95% of obese individuals are diabetic. Epidemiological studies have revealed that obesity has led to an increase in diabetic individuals [1,14,15]. The symptoms of diabetes include fatigue, acanthoses nigricans, dry mouth, blurred visions, polydipsia, polyuria, polyphagia, burning sensation, numbness of feet, hyperglycemia, erectile dysfunction, hunger, itching, excess thirst, and weight loss [1,6,16]. Diabetes causes cardiomyopathies, cerebrovascular disorders, nephrotoxicity, neuropathy, and delayed wound healing [7,17,18]. Changes in lifestyle cause Type II diabetes and leading the right lifestyle can reduce the incidence of diabetes [19,20]. Several drugs are available for the cure of both Type I and Type II diabetes in modern medicine. Ayurveda is an ancient system of healthcare that lists various herbs or their formulation to treat madhumeha or diabetes. This article delineates the effect of Bael (Aegle marmelos Corrêa) in the treatment of diabetes.

Scientific Position

Bael or Aegle marmelos classified into Kingdom: Plantae, Subkingdom: Tracheobionta, Super division: Spermatophyta, Division: Magnoliophyta: Class: Magnoliopsida, Subclass: Rosidae, Order: Sapindales, Family: Rutaceae, Genus Aegle Corrêa, Species marmelos (L.) Corrêa. Bael is scientifically known as Aegle marmelos and is also known as Belou marmelos (L.) Lyons, Bilacus marmelos (L.) Kuntze, Crateva marmelos L., Crateva religiosa Ainslie, and Feronia pellucida Roth.

Distribution

Bael widely grows in the subtropical regions of the Indian subcontinent and Southeast Asia. It grows well in India, Bangladesh, Cambodia, China, Fiji, Myanmar, Nepal, Pakistan, Philippines, Thailand, Laos, Indonesia, Malaysia, Java, Tibet, Vietnam, and Sri Lanka up to an altitude of 250-1200 m above sea level [21-23]. Bael is usually found in the premises of temples in India as it has a religious and mythological importance. It is liked by Lord Shiva and therefore it is considered very holy by the Hindus and its leaves are offered to lord Shiva during worship [24-27].

Botanical Profile

Bael is a spiny and slow-growing tree that is 12-15 m tall with a stem diameter of 90-120 cm (Figure 1). The stem bark is thick, soft, and flaking (Figure 2). The deciduous leaves of Bael are alternate, pointed, pinnate, or ternate and 4-10 cm long, 2-5 cm wide, with a long petiole (Figure 3).

Figure 1: Bael, Aegle marmelos tree in its natural habitat.

Figure 2: Bael, Aegle marmelos stem and its bark.

Figure 3: Bael, Aegle marmelos leaves. (a): mature leaves and (b): new leaves.

The Bael inflorescence contains small fragrant flowers usually 4-7 in number with 4 recurved fleshy green petals outside and yellow inside. The stalked, and erect flowers are 2 cm wide, lax, having a sweet aroma. The flowers are axillary or appear as terminal cymes. The flowers have an ovoid to oblong ovary that tapers into a thick short style. The stigma is capitate and stamens are 50 or more in number (Figure 4) [23,28,29].

Figure 4: Bael, Agele marmelos flower. (a): in native form and (b): flower closeup.

The round, ovoid, oblong, or pyriform fruits of Bael are 5-20 cm in diameter. The outer rind of the fruit is very hard and becomes stone-like after drying (hence the name wood apple). The rind is almost smooth, and light yellow, brown, or cherry red. The 12 stony carpels with one or more hairy seeds are found embedded in the brownish-red Bael fruit pulp (Figure 5). The fruit pulp is astringent and has a sweet aromatic odor. The seeds are flattened and oblong, 1 cm long, 10-50 in number, and are enveloped in a gummy or transparent mucilaginous substance and become solid after drying (Figure 5) [29].

Figure 5: Bael, Aegle marmelos fruit. (a): fruits in native form (b): fruits and (c): opened fruit and (d): seeds.

Colloquial Names

The colloquial names of Bael in different languages are listed in Table 1 [26,27,30,31].

Table 1: Colloquial names of Bael (Agele maremlos) in different languages.

Traditional Medicine

Indian system of healthcare Ayurveda has been using Bael as medicine to treat various ailments since ancient times in India and other Southeast Asian countries. For 5000 years the Bael is used in the treatment of different diseases and it is mentioned in Ramayan, Charak Samhita, Upvana Vinod, and Yajur Veda [24,26,27,32,33]. Traditionally Bael is used to treat intestinal disorders, intermittent fever, control fertility, and is administered after childbirth. Bael is also used to poison fish [34]. The abdominal discomfort, acute bronchitis, asthma, brain fever, burning sensation, constipation, febrile delirium, jaundice, high blood pressure, indigestion, leprosy, stomachache, inflammations, snakebite, myalgia, nausea, mental illnesses, swelling, smallpox sores, thirst, tumors, thyroid disorders, anemia, fractures, healing of wounds, swelling of joints, ulcers and upper respiratory tract infections [26,27].

The unripe fruit pulp of Bael mixed with boiled rice water given twice daily to pregnant women stops vomiting. A mixture of unripe Bael fruit, milk, and sugar is given to treat urinogenital disorders. Taking half-roasted unripe Bael fruit pulp and sugar cures dysentery and abscesses in humans [35]. The unripe fruits of Bael are astringent, demulcent, digestive, and stomachic, and help to assuage piles. The burn wounds are treated in Southern Chhattisgarh by application of one part of dried fruit powder mixed with 2 parts of mustard oil by the traditional healers. The ripe fruits are used as a heart and brain tonic and can cure constipation, diarrhea, chronic dysentery, gonorrhea, and ulcerated intestinal mucosa. The ripe fruits of Bael are used in the treatment of parasitic infections and epilepsy and have laxative, and antiviral properties. The root decoction of Bael is also used to treat melancholia, heart palpitation, and intermittent fever. Ayurvedic medicine ‘dashmool’ also contains Bael roots as one of the ingredients. Bael fruit sharbat helps in the treatment of frequent micturition [26,27,36].

The pain of the inflamed parts is mitigated by the topical application of Bael leaves. Application of Bael leaves ‘poultice’ gives relief in ulcers and ophthalmic disorders. The beriberi, weakness of the heart, and dropsy are treated by giving fresh leaves. Fresh Bael leaf juice is given as a laxative and treats asthmatic complaints, eye affections, and ophthalmia [26,27]. Bael leaves are given to cure diabetes, catarrh, deafness, and inflammation. The young leaves of Bael induce abortions in females and sterility in males. Application of a mixture prepared from one teaspoon of half a teaspoon of kalonji (Nigella sativa), one teaspoon of Bael leaf juice, and a few black pepper seeds extracted in hot sesame oil, on the scalp can cure cold and cough. The recurrent colds and respiratory infections can be treated by using medicated Bael leaf oil. A distillate of Bael flower cures dysentery, epilepsy, cough, and cold. It is a local anesthetic and tonic for the intestine and stomach [26,27,30,33].

Phytochemistry

The medicinal activity of Bael is due to its ability to synthesize several secondary metabolites. The fresh fruit pulp of bael is rich in carotenoids, flavonoids, phenols, and ascorbic acid [37]. The phytochemical analysis of fruit pulp of Bael extracted in alcohol revealed the presence of flavonoids, steroids, alkaloids, tannins, terpenoids, inulin, lignins, amino acids, proteins, carbohydrates, reducing sugars, fat, and oils. The aqueous extract of fruit pulp contains saponins and cardiac glycosides in addition to all these phytoconstituents present in the alcoholic extract however, alkaloids were not present [38]. The ethanol fruit pulp extract showed the presence of glycosides, alkaloids, phenols, saponins, tannins, terpenoids, carbohydrates, and proteins and the aqueous extract showed sterols except saponins, and tannins [39]. The analysis of petroleum ether extract of Bael fruit pulp showed, flavonoids, sterols, and tannins, whereas alkaloids, saponins, and proteins from the benzene extract sterols. [40]. The analysis of ethanol, methanol, hexane, phosphate buffer, and water extracts of Bael fruit revealed the presence of flavonoids and phenols, and the greatest quantity was detected in the hexane extract and the least in the aqueous extract [41]. Among the components detected in Bael fruit pulp were oxalates, gallotannic acid, and two types of reducing and nonreducing sugars [42]. An ethanol extract of Bael fruit revealed the presence of phenols, flavonoids, alkaloids, glycosides, saponins, tannins, and carbohydrate compounds. The flavonoids, glycosides, polyphenols, and saponins were detected in the aqueous extract [43].

The analysis of aqueous Bael fruit extract revealed the presence of flavonoids, alkaloids, glycosides, phenolic compounds, saponins, sterols, terpenoids, proteins, amino acids, and carbohydrates [44]. The unripe Bael fruit extracted in chloroform, ethyl acetate, methanol, and water contained alkaloids, glycosides, flavonoids, terpenoids, saponins, amino acids, proteins, and carbohydrates except saponins in the aqueous extract. Furthermore, methanol extracts were found to contain triterpenoids, and petroleum ether extracts to contain steroids and triterpenoids [45]. The examination of aqueous and methanol extracts from ripe Bael fruit pulp revealed the detection of various compounds, including alkaloids, coumarins, flavonoids, phenolics, glycosides, tannins, saponins, and proteins [46]. Phytochemical examination of hydroethanolic extracts of Bael fruit and peel showed phenol, coumarin, alkaloids, glycosides, terpenoids, tannins, carbohydrates, resins, and proteins [47]. The flavonoids, alkaloids, glycosides, terpenoids, phlobatannins, and reducing sugars were detected in the aqueous extract of Bael fruit [48]. Analysis of Bael fruit powder in methanol and ethanol showed the presence of flavonoids, phenol, and tannins that were in higher concentrations in the methanolic extract when compared to the ethanolic extract [49].

The methanol Bael root, stem, and leaf extracts consisted of total phenol and flavonoid and these phytochemicals were least in the root, more in the stem, and maximum in the leaf [50]. The n-hexane extract of Bael leaves contained cardiac glycosides, steroids, triterpenoids, and pseudotannins. The anthraquinone glycosides, alkaloids, catechins, furanoids, phenolics, saponins, fixed oils, fats, and proteins have been detected in the aqueous extract [51]. The alkaloids, anthocyanins, coumarins, emodins, flavonoids, cardio glycosides, diterpenes, fatty acids, phlobatannins, glycosides, phenols, saponins, tannin, amino acids, carbohydrates, and proteins have been reported from the chloroform Bael leaf extract [52]. Phytochemical examination of aqueous and methanol Bael leaf extracts led to the detection of alkaloids, carotenoids, cardiac glycosides, flavonoids, saponins, terpenoids, tannins, and reducing sugars [53]. The flavonoids and phenols were reported from the Bael leaf extracted in ethanol, methanol, ethyl acetate, phosphate buffer, and water and the maximum quantity of these phytochemicals was found in the methanol extract followed by the ethanol extract and least in the aqueous extract [41]. Analysis of ethanol, chloroform, and aqueous extracts of Bael leaf revealed the presence of cardiac glycosides, saponins, and tannins whereas flavonoids were detected in both chloroform and water extracts, and ethanol extract showed steroids only [54]. The petroleum ether, chloroform, methanol, and aqueous extracts of Bael leaf and seeds revealed the presence of alkaloids in all fractions excluding aqueous and chloroform extracts. All leaf extracts, with the sole exception of the chloroform and petroleum ether seed extracts from the Bael, were devoid of tannins [55]. The ethanol extract of Bael leaf showed the presence of flavonoids, tannins, phenol, and carbohydrates [56].

A quantitative analysis of the aqueous extract of Bael leaves indicated that it contains flavonoids at 64.0±0.05 mg/g, alkaloids at 15.58±0.05 mg/g, and phenolic compounds at 30.34±0.01 mg/g [57]. Similarly, analysis of aqueous and methanol leaf extracts of Bael revealed the existence of alkaloids, sterols, phenolics, and tannins [58]. Likewise, flavonoids, alkaloids, phenols, saponins, tannins, steroids, and carbohydrates have been detected in the water extract of Bael leaves however, acetone and ethanol extracts did not show saponins and the ethanol extract was devoid of tannins [59]. The aqueous and ethanol extracts of the leaves and stem bark of Bael showed the presence of alkaloids, coumarins, tannins, terpenoids, steroids, saponins, leucoanthocyanins, and carbohydrates. Additionally, the Bael stem extract analysis showed the presence of proteins and reducing sugars but not the coumarins [60]. The phytochemical examination of the methanol extract from Bael leaves revealed the presence of various compounds, including alkaloids, coumarins, flavonoids, glycosides, saponins, quinones, steroids, tannins, phlobatannins, and proteins. All these phytochemicals were present in the ethanol extract but not the flavonoids and sugars. Similarly, terpenoids were present in the acetone extract in addition to all the phytochemicals detected for the methanol extract however, the steroids could not be detected. The chloroform leaf extract consisted of flavonoids, coumarins, glycosides, terpenoids, saponins, tannins, steroids, phlobatannins, quinones, sugars, and proteins [61]. The alkaloids, phenolic compounds, flavonoids, and saponins were detected in the aqueous leaf extract of Bael [62]. The aqueous extract of Bael leaf consisted of 16.36 mg rutin equivalent total flavonoids and 31.38 mg gallic acid equivalent total phenolics [63]. Bael leaves extracted in 60% ethanol consisted of alkaloids, anthocyanins, flavonoids, cardiac glycosides, saponins, tannins, and terpenoids [64]. The flavonoids, alkaloids, glycosides, phenols, and carbohydrates were detected in the aqueous leaf extract of Bael but not the phytosterols [65]. The analyses of ethanol and methanol extract of Bael leaves led to the detection of alkaloids, carotenoids, cardiac glycosides, flavonoids, tannins, saponins, terpenoids, and reducing sugars [66].

The flavonoids, alkaloids, glycosides, phenolics, tannins, steroids, carbohydrates, amino acids, proteins, volatile oils, and fats have been detected in the aqueous and methanol seed extracts of Bael [67]. The ethyl acetate, ethanol, and aqueous extracts of the stem bark of Bael contained flavonoids, alkaloids, glycosides, phenols, sterols, tannins, terpenoids, carbohydrates, amino acids, and proteins [68]. The phytochemical analysis of Bael root and small twigs extracted in ethanol and water revealed the presence of quinones, phenols, reducing sugars, saponins, tannins, sugars, and triterpenoids (except aqueous extracts). The ethanol extracts contained coumarins, whereas aqueous extracts also showed the presence of alkaloids additionally [69]. Flavonoids, alkaloids, saponins, proteins, and tannins were identified in the ethanol and aqueous extracts of Bael root [70]. The alkaloids were present in the ethyl acetate extract of the Bael stem [71].

Table 2: Different phytochemicals aextracted from Bael (Aegle marmelos).

Antidiabetic

The use of different parts of Bael in experimental models proved its usefulness as an antidiabetic pharmacophore. Bael leaf extracts have been studied widely and seem to be more effective than the other parts of Bael in treating diabetes. The alloxan-induced diabetic Wistar albino rats administered with water extract of Bael leaves for 30 days elevated glucose tolerance and alleviated blood glucose, blood urea, and serum cholesterol significantly [72]. Similarly, the streptozotocin-induced diabetic rats fed with 100 mg/kg body weight Bael aqueous leaf extract once daily for 10 days decreased plasma glucose and raised insulin levels [73]. The alloxan-induced diabetic albino rats given 100 mg of aqueous leaf extract of Bael for four weeks showed a significant depletion in the blood glucose, plasma glutathione-S-transferase (GST), and lipid peroxidation and a rise in the GSH concentration in the erythrocytes at the end of 4th week [74]. Likewise, feeding of alloxan-induced diabetic rats with 100 mg/kg body weight Bael leaf methanol extract once daily for 12 days caused significant attrition in the serum glucose, serum and liver lipid peroxidation, and hydroperoxides in diabetic rats on 12-day post-treatment. The methanol leaf extract increased superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx) in the blood and liver of diabetic rats on 12 days [75]. The intraperitoneal administration of aqueous leaf extract of Bael once daily for 30 days resulted in significant attrition in fasting and postprandial blood glucose in alloxan-induced diabetic rats [76]. The oral feeding of 1 g/kg methanol extract of leaf Bael and leaf callus once daily to streptozotocin-induced diabetic rabbits for consecutive 3 days alleviated serum glucose in streptozotocin-induced diabetes in rabbits on day 10 after administration and this decline was greater for the callus extract [77].

Streptozotocin-induced diabetic Wistar rats fed orally with 150 mg/kg body weight of Bael leaf ethanol extract for 30 days significantly reduced blood glucose, hemoglobin, and HbA1c. The extract also reduced the plasma and pancreatic lipid peroxidation accompanied by the restoration of normal levels of GSH, catalase, SOD, and GPx in the pancreas. The Bael leaf extract reduced the elevated levels of vitamin C, vitamin E, and ceruloplasmin in the plasma of diabetic rats and brought it to normal non-diabetic control levels. The extract also reversed the degenerative changes initiated by streptozotocin in the pancreas [78]. The alloxan-induced diabetic Wistar rats were administered with 100, 150, and 200 mg/kg body weight Bael leaves extracted in ethanol once daily for 14 days after diabetes induction alleviated fasting serum glucose, total cholesterol, lipid peroxidation, and the activity of lactate dehydrogenase (LDH) and creatinine kinase, in the. The raised GSH levels and activity of catalase and SOD dose dependently [79].

Oral administration of 150/300 µg/kg chloroform Bael leaf extract twice daily for 60 days in Streptozotocin-induced diabetic male Wistar rats reduced blood glucose, serum creatinine, blood urea glucose, urine albumin, and HbA1c significantly. The chloroform leaf extract also attenuated the formation of total advance glycation end products (AGEs) and pentosidine, a specific AGE significantly in tail collagen. It also reduced the bovine serum albumin and protein carbonyl formation [80]. Significant attrition in the blood glucose, total cholesterol, LDL, and triglycerides, accompanied by a rise in the HDL in alloxan-induced diabetic Wistar rats administered with 200 and 400 mg/kg body weight ethanol and methanol extracts of Bael leaves once daily for 14 days [81]. Likewise, administering Bael leaf ethanol extract orally once daily for 20 days to alloxan-induced diabetic Wistar albino rats led to a decrease in serum glucose, triglyceride, urea, protein, and plasma insulin concentrations [82]. Significant depletion in blood glucose was recorded on days 3, 6, 9, 12, 15, 18, and 21 in streptozotocin-induced diabetic Wistar rats receiving 2 g/kg Bael leaf ethanol extract once daily for 21 days [54]. Similarly, administration of 250 or 500 mg/kg body weight ethanol Bael leaf extract singly or 250 mg/kg twice daily for 28 days decreased fasting serum glucose level in streptozotocin-induced diabetes in Long Evans rats. The leaf extract also suppressed sucrose absorption in the intestine and the disaccharidase enzyme activity [83]. Attrition in fasting blood glucose has been reported in fructose-fed rats given 500 mg/kg body weight of aqueous leaf extract. The extract also lowered serum total cholesterol, VLDL, LDL, triglycerides, and insulin followed by a rise in HDL and HOMA-IR after 8 weeks in the fructose-fed rats. The hyperleptinemia was also attenuated in the fructose-fed rats by the leaf extract. The Bael leaf extract also decreased liver glycogen, glucose-6-phosphate dehydrogenase, hexokinase, and fructose 1,6 biphosphatase accompanied by a rise in Janus Kinase–signal transducer and activator of transcription-3 (JAK-STAT3) and phosphatidylinositol-3-kinase (PI3K/AKT) at 8 weeks in the liver of fructose-fed rats [84]. Similarly, streptozotocin-induced diabetic Long Evans rats treated with aqueous leaf and fruit extracts of Bael for 21 days revealed a significant reduction in insulin, blood glucose, HOMA-IR, and QUICKI. However, these extracts failed to induce alteration in the lipid profile in diabetic rats [85].

Significant attrition in phosphofructokinase, hexokinase, and phosphofructokinase was observed in the high fructose or glucose-fed HepG2 cells treated with aqueous Bael leaf extract, followed by a rise in the aldehyde dehydrogenase in the glucose-fed cells. Similarly, The leaf extract significantly raised the insulin signaling enzyme phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) in the fructose-fed HepG2 cells. The leaf extract attenuated the glucose and fructose-induced activation of hypoxia-inducing factor (HIF-1α), signal transducer and activator of transcription-3 (STAT-3), and tumor necrosis factor (TNF-α) in HepG2 cells indicating the potential of Bael in diabetes cure [86]. The administration of 200 and 400 mg/kg body weight of ethanol leaf extract for 4 weeks in alloxan-induced diabetic rats depleted serum glucose, creatinine, urea, uric acid, and albumin levels [87]. The aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), blood glucose, serum albumin, total proteins, and serum creatinine, reduced significantly in the alloxan-induced diabetic Wistar rats administered with 500 mg/kg of methanol Bael leaf extract for 15-45 days [88]. Similarly, in another study administration of 100 and 250 mg/kg body weight ethanol Bael leaf extract led to a significant attrition in mean blood glucose, HbA1c, homocysteine, bilirubin, direct bilirubin, indirect bilirubin, blood urea, blood urea nitrogen (BUN), calcium, albumin, globulin, glucose-6-phosphate, inorganic phosphate, lipase, mean blood glucose, serum uric acid, and vitamin D3 and a rise in the amylase activity in alloxan-induced diabetic rats [89]. The administration of streptozotocin-induced diabetic mice with 200 or 400 mg/kg body weight hydro alcoholic alkaloid-free extract of Bael leaf significantly declined plasma (oral glucose tolerance test) and blood glucose. The 400 mg/kg extract also decreased, total cholesterol, LDL, and triglycerides and elevated HDL. The lipid peroxidation, AST, ALT, and ALP reduced significantly with a rise in SOD, CAT, and glutathione peroxidase (GPx) in the extract treated diabetic mice. The TNF-α, IL-6, and IL-1β profile reduced significantly in methanol extract of Bael leaves in diabetic mice serum. The histological architecture of pancreatic β-cells has been restored by methanol Bael fruit extract [90]. The 70% ethanol Bael leaf extract inhibited α-Amylase (IC₅₀ 73.2 μg/mL) and α-glucosidase (IC₅₀ 43.9 μg/mL) in vitro indicating its antidiabetic potential [91].

Oral administration of aqueous fruit extract of Bael fruit twice a day for 30 days reduced blood glucose, increased glycogen and HbA1c, and improved oral glucose tolerance in streptozotocin-induced diabetic Wistar rats [92]. Similarly, the aqueous extract of fruit attenuated lipid peroxidation, hydroperoxides, cernloplasmin, and α-tocopherol and significantly increased plasma reduced glutathione (GSH) and Vitamin C [93]. Streptozotocin-induced diabetic Wistar rats fed with aqueous Bael fruit extract showed a depletion in the blood glucose levels at different post-treatment times. Likewise, Bael seed extract caused attrition in the fasting blood glucose, total cholesterol, LDL-c, triglycerides, and increased HDL-c in diabetic rats [94]. Significant attrition in serum glucose, HOMA-IR (Homeostatic Model Assessment of insulin resistance), and increase in HOMA-B (β-cell function) was observed at day21 in high-fat diet-fed streptozotocin-induced Wistar administered with 250, 500, and 1000 mg/kg body weight of aqueous extract of Bael fruit once daily for 21 days depending on the extract dose. The fruit extract caused a reduction in the total cholesterol, LDL-c, and triglycerides, followed by a rise in the HDL-c on day 21 in diabetic rats. The Bael fruit extract upregulated the expression peroxisome proliferator activated receptor (PPAR-γ) expression in the liver depending on the dose. The extract elevated pancreatic SOD activity and decreased lipid peroxidation in diabetic rats [95]. Administration of 200 and 400 mg/kg body weight methanol Bael stem bark extract for 30 days resulted in a decline in blood glucose (14, 21, and 28 days), and total proteins whereas HbA1c and plasma insulin levels increased on day 28 in streptozotocin-induced diabetic Wistar rats. The extract of Bael fruit demonstrated a reduction in the levels of AST, ALT, ALP, glucose-6-phosphatase, hexokinase, and fructose 1,6-bisphosphatase, as well as liver glycogen, after a 30-days in diabetic Wistar rats [96]. Alloxan-induced diabetic rats given 500 mg/kg body weight of Bael flower aqueous extract showed a depletion in the serum glucose at 7, 21, and 42 days [97].

Administration of 125, 250 or 500 mg/kg body weight ethanol extract of Bael fruit significantly decreased body weight gain, blood glucose level, total cholesterol, LDL-c, VLDL-c, triglyceride, and lipid peroxidation depending on the dose accompanied by an increase in the serum insulin level and HDL-c, GSH, and SOD significantly in the alloxan-induced diabetic rats [98]. Administration of 200, 400 or 600 mg/kg body weight 80% methanol Bael fruit pulp extract elevated glucose tolerance depending on the dose and reduced blood glucose levels at 60, 120, and 180 min in streptozotocin-induced diabetic Wistar rats. Administration of 400 mg/kg body weight of fruit pulp extract for 42 days raised the serum insulin leading to a 10-fold rise in the insulinogenic index and elevation in the β-cell function and improved architecture of pancreatic β-cells in diabetic rats at 43 days. The fruit extract alleviated the HbA1c, triglycerides, cholesterol, LDL-c, and HDL-c significantly followed by a rise in the total antioxidant status after 42 days [99]. Similarly, methanol Bael fruit extract has decreased blood glucose, serum and plasma insulin, C-peptide, HbA1c, total cholesterol, LDL-c, VLDL-c, and triglycerides in streptozotocin-induced diabetic rats. The fruit extract reduced inflammatory cytokines- TNF-α and IL-6 accompanied by a rise in IL-1β. The GSH and SOD increased and reduced catalase and LOO extract in the diabetic rats treated with the fruit extract [100].

There was a marked elevation in blood glucose concentrations in albino rats with streptozotocin-induced diabetes when challenged with sucrose at 90 minutes and 24 hours post-treatment with Aegleine, an alkaloid extracted from Bael leaves [101]. Administration of marmelosin separated from Bael and its derivatives including 9-[(2-methylprop-1-en-1-yl)peroxy]-5-nitro-7H-furo[3,2-g]chromen-7-one, 9-[(2-methylprop-1-en-1-yl)peroxy]-5-nitro-7H-furo[3,2-g]chromen-7-one, 9-[(2-methyl prop-1-en-1-yl)peroxy]-7-oxo-7H-furo[3,2-g]chromene-5- sulfonic acid and 5-bromo-9-[(2-methylprop-1-en-1-yl)peroxy]-7H-furo[3,2-g]chromen-7-one significantly depleted blood glucose level in alloxan-induced diabetes in Wistar rats indicating their antidiabetic potential [102].

Clinical Studies

The NIDDM patients given 2 g of Bael leaves twice a day for eight weeks reduced fasting and postprandial blood glucose from the second week of treatment until 8 weeks significantly indicating its potential as an antidiabetic medicine in humans [103]. Type-II diabetic patients (50) given 2 encapsulated 50 mg of leaf extract of Bael once daily after breakfast for 90 days revealed a reduction in fasting blood glucose and HbA1c significantly on day 90 post-treatment [104]. Diabetic patients taking 2 g Bael fruit pulp powder once daily for 60 days exhibited a significant reduction in fasting blood glucose, HbA1c, total cholesterol, triglycerides, LDL-C, and VLDL-C [105]. In a randomized clinical trial of 60 (25 males/35 females) diabetic patients given Bael leaf juice (20 g/100 mL) for 8 weeks significantly reduced fasting blood glucose, postprandial blood glucose, HbA1c, total cholesterol, serum triglycerides, LDL, VLDL, AST, and ALT levels followed by an increase in serum HDL [106].

Antihyperlipidemic

The hydroethanolic (50%) extract of Bael leaves significantly reduced serum cholesterol and triglyceride levels in hyperlipidemic rats [107]. The aqueous Bael leaf extract depleted total cholesterol, triglycerides, LDL, and VLDL followed by a significant rise in the HDL dose dependently in streptozotocin-induced albino rats [108]. A significant decline in triglycerides, cholesterol, LDL, and VLDL and increased HDL was detected in hyperlipidemic Wistar rats treated with aqueous, ethanol, and chloroform extracts of Bael leaves [109]. The aqueous Bael leaf extract reduced 3-hydroxy-3 methyl glutaryl coenzyme A (HMG-CoA), reductase, acyl coenzyme-A, and cholesterol acyl transferase (ACAT) in liver microsomes and triglycerides, cholesterol, LDL, and VLDL accompanied by a significant rise in HDL in the serum of hyperlipidemic Wistar rats [110]. Bael leaf extract lowered serum total cholesterol, triglycerides, LDL, HDL, and VLDL in hyperlipidemic rats significantly [111]. The hyperlipidemic albino rats fed with 125 and 250 mg/kg in the diet for 60 days showed a significant decline in the serum cholesterol, free cholesterol, cholesterol ester, triglycerides, and LDL accompanied by a rise in the HDL at 30 and 60 days [57]. The Type 2 diabetic patients given 7 g of Bael fruit pulp powder in water for 21 days showed a reduction in free fatty acid in the serum at 28 and 49 days [112].

Antioxidant

Bael leaf extracted in 50% ethanol inhibited the generation of DPPH, hydroxyl (?OH), superoxide (O₂^-), NO, and ABTS⁺ free radicals in a concentration dependent manner [113]. The aqueous, ethyl acetate, and ethanol extracts of Bael bark, inhibited DPPH radicals, with the ethyl acetate extract exhibiting the highest level of activity. All extracts showed increasing antioxidant activity indicated by the reduction in the peroxides and formation of phosphomolybdate [68]. The aqueous extract of Bael fruit demonstrated a concentration-dependent passivation of DPPH radicals, exhibiting an IC₅₀ value of 17.37 ± 2.71 mg/mL [114]. Unripe fruit extracted in water scavenged DPPH, ^•OH, O₂^•-, NO^• and ABTS^•+ radicals in a concentration dependent manner [115]. The hydromethanol (50%) extracts of Bael fruit, leaf, and stem bark passivated nitric oxide ^•OH radicals in a concentration dependently with IC₅₀ of 550, 300, and 350 µg/mL for fruit, leaf, and stem bark, respectively. The leaf extract was the most active among all the three extracts evaluated [116]. The pulp, rind, and seeds of Bael extracted in hexane, chloroform, ethyl acetate, acetone, and methanol were tested for their ability to scavenge DPPH radicals. The hexane extract was unable to scavenge DPPH radicals whereas the chloroform extract showed the least scavenging activity. These extracts were freeze-dried or oven-dried. The highest DPPH scavenging activity was recorded for methanol extract followed by ethyl acetate and acetone in order. The freeze-dried pulp (IC₅₀ 83.82 µg/mL), rind (IC₅₀ 109.52 µg/mL), and seed (IC₅₀ of 121.32 µg/mL) extracts showed marginally better activity than the oven-dried pulp IC₅₀ 84.8 µg/mL, rind IC₅₀ 111.37 µg/mL and seed IC₅₀ 123.51 µg/mL [117]. The Bael stem bark extracted in n-hexane methanol, and ethyl acetate scavenged DPPH and NO free radicals depending on their concentration. The IC₅₀ of 37.056 µg/mL, 43.379 μg/mL, and 66.180 μg/mL for methanol, ethyl acetate, and n-hexane extracts, respectively for DPPH radicals. The IC₅₀ for NO^• was 28.377 μg/mL, 45.853 μg/mL, and 66.980 μg/mL for ethyl acetate, methanol, and n-hexane extracts, respectively [118].

The methanol, ethanol, and aqueous extracts of Bael leaf dose dependently inhibited the formation of DPPH radicals. The ethanol extract exhibited the highest ferric reducing power and demonstrated significant inhibition of linseed oil-induced lipid peroxidation in vitro [119]. Furthermore, the hydroalcoholic fruit extract of Bael inhibited DPPH and ABTS free radicals, yielding IC₅₀ values of 351±37 and 228±25 µg/mL, respectively [120]. The ethyl acetate and methanol Bael leaf extracts showed scavenging of DPPH radicals and increased ferric reducing power having an IC₅₀ of 191.4±1.5 μg/mL for ethyl acetate extract and IC₅₀ of 249.3±9.4 μg/mL for the methanol extract [121]. A concentration-dependent inhibition of DPPH radical production was observed with the dehydrated Bael fruit extracted in methanol [122]. The ethanol extract of Bael leaf at a concentration of 50% demonstrated an inhibitory effect on the formation of DPPH and ABTS free radicals, with IC₅₀ values recorded at 160.47 ± 8.51 μg/mL and 282.46 ± 44.11 μg/mL, respectively. The leaf extract increased ferric reducing power in concentration dependent manner with an IC₅₀ of 147.33 ± 23.21 mM Fe2+/g dry weight [123]. Methanol (30% water), aqueous, ethyl acetate, chloroform, and butanol extracts of Bael ripe fruit increased ferric reducing power and inhibited the DPPH radicals and activity of LOX in vitro. The ethyl acetate extract was more potent than the other extracts [124].

Methanol extracts of Bael leaf, ripe fruit, half-ripe fruit, and seed scavenged DPPH and NO^• radicals in a concentration dependent manner, and the maximum scavenging was observed for half-ripe fruit with an IC₅₀ of 251.2 μg/mL (DPPH) and 46.364 μg/mL (NO^•). The methanol extract of all parts showed a dose dependent rise in cupric reducing antioxidant capacity, where a maximum antioxidant capacity was detected for the leaf extract [125]. The aqueous and ethanol (50%) Bael flower extracts inhibited DPPH, and ^•OH radicals. Both flower extracts inhibited LDL oxidation and DNA strand scission and increased ferrous chelating activity [126]. Marmelosin, a phytochemical extracted from Bael fruit passivated DPPH free radicals with an IC₅₀ of 15.4 ± 0.32 µM [127]. The aqueous fruit extract of Bael exerted antioxidant action by scavenging DPPH and ABTS^•+ radicals and by elevating the phosphomolybdenum reduction activity and ferric reducing power concentration dependently [128]. The hexane, ethyl acetate, aqueous, methanol, and ethanol extracts of Bael leaf scavenged DPPH radicals and elevated the phosphomolybdenum reduction activity and ferric reducing power concentration dependently [129].

A concentration dependent inhibition of DPPH radical was detected by both the hexane and 70% methanol extracts of Bael stem bark with an IC₅₀ of 961.53 μg/mL for the methanol extract. The hexane extract was not as effective as the methanol extract [130]. The aqueous, acetone, and ethanol extracts of Bael leaf were shown to inhibit DPPH radicals and enhance antioxidant activity, as assessed through cyclic voltammetry. The water extract was particularly effective, surpassing the efficacy of both the acetone and ethanol extracts [59]. Bael leaves extracted in ethanol passivated DPPH free radicals and elevated ferric reducing power depending on the concentration. It also inhibited 2,7-dichlorofluorescein diacetate (DCF-DA)-induced ROS formation in a similar manner in HepG2 cells [63]. The Bael seed extracted in petroleum ether, chloroform, ethyl acetate, methanol, and distilled water scavenged DPPH, hydrogen peroxide, and NO^• radicals in a concertation dependent fashion, and ethyl acetate extract was more powerful than the other extracts [131]. Ethanol extract of Bael leaves inhibited DPPH free radicals depending on concentration in vitro with an IC₅₀ of 48.99 ±1.96 µg/mL [132]. The 10, 20, 40, 60, 80, and 100 µg/mL methanol extract of Bael passivated DPPH free radicals and raised ferric reducing power depending on the concentration in vitro [133].

Mechanism

The actual mechanism of antidiabetic action of Bael is not clearly understood. It is plausible that Bael may have used several cellular pathways to control diabetes (Figure 6,7). The dysregulation of the (Nuclear factor E2-related factor 2) Nrf2/Keap1/ARE (Antioxidant Response Element) signaling pathway is reported in diabetes [134,135] and Bael seems to operate this pathway by segregation of Nrf2/Keap1 that causes translocation of Nrf2 into the nucleus where Nrf2 activates ARE leading to the stimulation of heme oxygenase-1 (HO1) and NAD[P]H: quinone oxidoreductase-1 (NQO1) as a result antioxidants like GSH, GPx, glutathione reductase (GR), catalase, SOD, glutathione-s-transferase (GST) are raised by Bael in diabetic condition and also reduce lipid peroxidation [75,98]. Bael is known to activate PPAR-γ that leads to suppression of TNF-α, NF-κB, Hsp70, PI3K/AKT, HIF-1α, IFN-γ and IL-8, IL-1β, IL-6, IL-10, IL-17, MIP-1α, COX-I, COX-II, STAT-3, AKT, tyrosinase, and galectin-3 by and consequently increase of PI3K, AKT, IL-2, JAK-STAT3, and DT-diaphorase by Bael and its active components seem to arrest the inflammatory pathways [86,90,96,100,136,137]. In addition to this Bael may also activate mechanisms that are still unknown to exert its antidiabetic action.

Figure 6: The scavenging of free radicals (reactive oxygen species ROS) by Bael causes dissociation (nuclear factor E2-related factor 2) of Nrf2/Keap1 leading to the translocation of Nrf2 into the nucleus. Once Nrf2 is in the nucleus it activates antioxidant response element (ARE), heme oxygenase-1 (HO1) and NAD[P]H: quinone oxidoreductase-1 (NQO1) which increases glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-s-transferase (GST), super oxide dismutase (SOD) and catalase (CAT) and reduces lipid peroxidation (LOO).

Figure 7: The activation of PPAR by Bael causes downmodulation of TNF-α, NF-κB, COX-I, COX-II, LOX-5, iNOS and various interleukins that leads to antidiabetic action as well as protection of various tissues.

Bael is a native of the Indian subcontinent and Southeast Asia. Its fruits are edible, eaten fresh, or in the form of sharbat and Jams. Bael possesses alkaloids, anthocyanins, flavonoids, glycosides, phenols, tannins, sterols, terpenoids, carbohydrates, proteins, quinones, reducing sugars, saponins, and phenols. The antidiabetic effect of Bael is due to the reduction in HOMA-IR, and elevating HbA1c and HOMA-B. The antidiabetic activity of Bael is due to its ability to scavenge free radicals, reduce LOO, LDH, ODC, AST, ALT, ALP, creatinine kinase, creatinine, urea, blood glucose, BUN, triglycerides, cholesterol, LDL, VLDL, HOMA-IR, hexokinase, glucose-6-phosphatase, fructose 1,6 bi phosphatase and glycogen. Bael increases insulin, catalase, SOD, GPx, GST, GR, GSH, and HDL, Bael inhibits inflammatory pathways by downregulating TNF-α, NF-κB, Hsp 70, HIF-1α IFN-γ and IL-8, IL-1β, IL-6, IL-10, IL-17, MIP-1α, COX-I, COX-II, STAT-3, and simultaneously activating at PI3K, AKT, IL-2, JAK-STAT3, PPAR-γ, DT-diaphorase molecular level. Research must be conducted in the future in order to uncover the molecular mechanisms that underlie Bael's effectiveness in controlling diabetes.

Acknowledgments

The author is grateful to his wife Mrs. Mangla Jagetia for her unstinted support and patience during the writing of this manuscript. The financial assistance from the University Grant’s Commission, New Delhi, India vide grant No. F4-10/2010(BSR) is thankfully acknowledged.

1. International Diabetes Federation, IDF Diabetes Atlas | Tenth Edition, 2021.
2. Ong LK, Stafford LK, McLaughlin SA, Boyko EJ, Vollset SE, Smith AE, et al. Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the global burden of disease study 2021. Lancet. 2023; 402: 203-234.
3. Definition and Diagnosis of Diabetes Mellitus and Intermediate Hyperglycemia: report of a WHO/IDF consultation, World Heal. Organ. 2006; 50.
4. Thomassian BD. Diabetes mellitus and metabolic syndrome. Card Nurs Sixth Ed. 2011; 876-888.
5. Definition, diagnosis and classification of diabetes mellitus and its complications. Report of a WHO consultation. part 1: Diagnosis and classification of Diabetes mellitus., Publ. No. WHO/NCD/NCS99.2. 1999.
6. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2014; S81-S90.
7. Antar SA, Ashour NA, Sharaky M, Khattab M, Ashour NA, Zaid RT, et al. Diabetes mellitus: Classification, mediators, and complications; A gate to identify potential targets for the development of new effective treatments, Biomed Pharmacother. 2023; 168: 115734.
8. McGill DE, Levitsky LL. Management of hypoglycemia in children and adolescents with Type 1 Diabetes Mellitus. Curr Diab Rep. 2016; 16: 88.
9. Roep BO, Thomaidou S, van Tienhoven R, Zaldumbide A. Type 1 diabetes mellitus as a disease of the β-cell (do not blame the immune system?). Nat Rev Endocrinol. 2021; 17: 150-161.
10. Ojo OA, Ibrahim HS, Rotimi DE, Ogunlakin AD, Ojo AB. Diabetes mellitus: From molecular mechanism to pathophysiology and pharmacology. Med Nov Technol Devices. 2023; 19: 100247.
11. You WP, Henneberg M. Type 1 diabetes prevalence increasing globally and regionally: The role of natural selection and life expectancy at birth. BMJ Open Diabetes Res Care. 2016; 4: e000161.
12. Shah AS, Nadeau KJ. The changing face of paediatric diabetes, Diabetologia. 2020; 63: 683-691.
13. Galicia-Garcia U, Benito-Vicente A, Jebari S, Larrea-Sebal A, Siddiqi H, Uribe KB, et al. Pathophysiology of Type 2 Diabetes Mellitus. Int J Mol Sci. 2020; 21: 6275.
14. Herman WH, Zimmet P. Type 2 diabetes: An epidemic requiring global attention and urgent action, Diabetes Care. 2012; 35: 943-944.
15. Ruze R, Liu T, Zou X, Song J, Chen Y, Xu R, et al. Obesity and type 2 diabetes mellitus: connections in epidemiology, pathogenesis, and treatments. Front Endocrinol. 2023; 14: 1161521.
16. Ramachandran A. Know the signs and symptoms of diabetes. Indian J Med Res. 2014; 140: 579-581.
17. Dunlay SM, Givertz MM, Aguilar D, Allen LA, Chan M, Desai AS, et al. Type 2 diabetes mellitus and heart failure a scientific statement from the American Heart Association and the Heart Failure Society of America. Circulation. 2019; 140: E294-E324.
18. Wetmore JB, Li S, Ton TGN, Peng Y, Hansen MK, Neslusan C, et al. Association of diabetes-related kidney disease with cardiovascular and non-cardiovascular outcomes: A retrospective cohort study. BMC Endocr Disord. 2019; 19: 1-11.
19. Kolb H, Martin S. Environmental/lifestyle factors in the pathogenesis and prevention of type 2 diabetes. BMC Med. 2017; 15: 131.
20. Uusitupa M, Khan TA, Viguiliouk E, Kahleova H, Rivellese AA, Hermansen K, et al. Prevention of type 2 diabetes by lifestyle changes: A systematic review and meta-analysis. Nutrients. 2019; 11: 2611.
21. Sharma PC, Bhatia V, Bansal N, Sharma A. A review on Bael tree. Nat Prod Radiance. 2007; 6: 171-178.
22. Singh AK, Singh S, Saroj PL, Krishna H, Singh RS, Singh RK. Research status of bael (Aegle marmelos) in India: A review. Indian J Agric Sci. 2019; 89: 1563-1571.
23. Akbar S. Agele marmelos(L.) Correa (Rutaceae) Handbook of 200 Medicinal Plants: A Comprehensive Review of Their Traditional Medical Uses and Scientific Justifications, in: Handb 200 Med Plants. Springer Int Publ. 2020; 109-122.
24. Roy SK, Singh RN. Bael fruit (Aegle marmelos)—A potential fruit for processing. Econ Bot. 1979; 33: 203-212.
25. Mali SS, Dhumal RL, Havaldar VD, Shinde SS, Jadhav NY, Gaikwad BS. A systematic review on Aegle marmelos (Bael). Res J Pharmacogn Phytochem. 2020; 12: 31-36.
26. Jagetia GC. Ethnomedicinal properties of Bael Aegle marmelos Correa family Rutaceae: A review, Trends Hortic. 2023; 6: 2941.
27. Jagetia GC. Medicinal and phytopharmacological properties of Bael Aegle marmelos correa family Rutaceae. Pharm Sci Anal Res J. 2024; 6: 180055.
28. Sharma N, Dubey W. History and taxonomy of Aegle marmelos: A review. Int J Pure App Biosci. 2013; 1:7-13.
29. Pathirana CK, Madhujith T, Eeswara J. Bael (Aegle marmelos Correa), a medicinal tree with immense economic potentials. Adv Agric. 2020; 2020: 8814018.
30. Dhankhar S, Ruhil S, Balhara M, Dhankhar S, Chhillar AK. Aegle marmelos (Linn.) Correa: A potential source of Phytomedicine. J Med Plants Res. 2011; 5: 1497-1507.
31. Vasava D, Kher MM, Nataraj M, Teixeira da SJA. Bael tree (Aegle marmelos (L.) Correa): importance, biology, propagation, and future perspectives. Trees. 2018; 32: 1165-1198.
32. Chopra RN, Nayar SL, Chopra IC. Glossary of Indian Medicinal Plants. National Institute of Science Communication and Information Resources, New Delhi. 2002.
33. Jagetia GC, Venkatesh P, Baliga MS. Aegle marmelos (L.) Correa inhibits the proliferation of transplanted Ehrlich ascites carcinoma in mice. Biol Pharm Bull. 2005; 28: 58-64.
34. Basu D, Sen R. Alkaloids and coumarins from root-bark of Aegle marmelos. Phytochemistry. 1974; 13: 2329-2330.
35. Bhar K, Mondal S, Suresh P. An eye-catching review of Aegle marmelos (Golden Apple). Pharmacogn J. 2019; 11: 207-224.
36. Dutta A, Lal N, Naaz M, Ghosh A, Verma R. Ethnological and Ethno-medicinal importance of Aegle marmelos (L.) Corr (Bael) among indigenous people of India. Am J Ethnomedicine. 2014; 1: 290-312.
37. Charoensiddhi S, Anprung P. Bioactive compounds and volatile compounds of Thai bael fruit (Aegle marmelos (L.) Correa) as a valuable source for functional food ingredients. Int Food Res J. 2008; 15: 287-295.
38. Rajan S, Gokila M, Jency P, Brindha P, Sujatha RK. Antioxidant and phytochemical properties of Aegle marmelos fruit pulp. Int J Curr Pharm Res. 2011; 3: 65-70.
39. Rafiqkhan M, Radhakrishnan D, Mohamed M, Shamseer M, Johnson S. Phytochemical screening of Aegle marmelos (L.) correa fruit pulp: A potential source of ethnomedicine. World J Pharm Res. 2013; 2: 2919-2927.
40. Laddha CS, Kunjalwar SG, Itankar PR, Tauqeer M. Nutritional and phytochemical assesment of wild edible fruit of Aegle marmelos (Linn.) used by the tribes of Bhiwapur Tahsil Nagpur district, India. Asian J Pharm Clin Res. 2015; 8: 76-78.
41. Kejariwal M. Evaluation of antioxidant potential and phytochemical investigations on Aegle marmelos (L.) Corr. Bull Environ Pharmacol Life Sci. 2016; 5: 42-52.
42. Kaur A, Kalia M. Physico chemical analysis of Bael (Aegle Marmelos) fruit pulp, seed and pericarp, Chem Sci Rev Lett. 2017; 6: 1213-1218.
43. Gupta A, Thomas T, Khan S. Physicochemical, phytochemical screening and antimicrobial activity of Aegle marmelos. Pharm Biosci J. 2018; 6: 17-24.
44. Chaubey A, Dubey A. Phytochemical profiling and antioxidant activity of aqueous extract of Aegle marmelos fruit shell. 2019; 5432.
45. Sivakumar G, Gopalasatheeskumar K, Gowtham K, Sindhu E, Raj KA, Rajaguru B, et al. Phytochemical analysis, antioxidant and antiarthritic activities of different solvent extract of Aegle marmelos Unripe fruit. Res J Pharm Technol. 2020; 13: 2759-2763.
46. Thaware P, Karale P, Karale M, Chavan P. Phytochemical screening and pharmacological evaluation of Aegle marmelos fruit. Indian Drugs. 2020; 57: 59-64.
47. Ganpat SP, Jagdish SD, Onkarappa GR. Quantitative phytochemical analysis and in vitro study of antioxidant and anti-inflammatory activities of Aegle marmelos fruit with peel and without peel: A comparative evaluation. Int J Pharm Investig. 2022; 12: 15-19.
48. Kudlur DS, Meghashree AM, Vinutha SA, Kumar KCS, Karthik G, Venkatesh PA, et al. One pot synthesis of CuO-NiO nanoparticles using Aegle marmelos fruit extract and their antimicrobial activity. Mater Today Proc. 2023; 89: 1-7.
49. Rahman MT, Halim MA, Mozumder NHMR, Ove TA, Khatun AA. Phytochemicals and antioxidant properties of bael (Aegle marmelos) pulp powder and its products. J Agric Food Res. 2024; 15: 100971.
50. Siddique NA, Mujeeb M, Najmi AK, Akram M. Evaluation of antioxidant activity, quantitative estimation of phenols and flavonoids in different parts of Aegle marmelos. African J Plant Sci. 2010; 4: 1 005.
51. Hameed MA, Faheem A, Koay YC, Fathima S. Phytochemical screening, anti-pyretic and antidiarrhoeal activities of the n-hexane and aqueous extracts of the leaves of Aegle marmelos, Arch. Pharm Pract. 2011; 2: 90-94.
52. Ariharan VN, Prasad PN. Quantitative phytochemical analysis on leaf extract of Aegle marmelos. J Chem Pharm Res. 2014; 6: 1100-1104.
53. Mujeeb F, Bajpai P, Pathak N. Phytochemical evaluation, antimicrobial activity, and determination of bioactive components from leaves of Aegle marmelos. Biomed Res Int. 2014; 2014; 497606.
54. Asaduzzaman M, Nahar L, FazleyRabbi M, Hasan M, Khatun A, Tamannaa Z, et al. Phytochemicals, nutritonal constituents, anti-bacterial and hypoglycemic activity of Aegle marmelos leaf extract in alloxan induced diabetic rats. J Nutr Food Sci. 2016; 6: 533.
55. Shantaram BP, Ramachandra BS, Eknath GA. Preliminary phytochemical analysis of seeds and leaves of Aegle marmelos extracts and in-vitro assessment of their antibacterial activity. Int J Pharma Res Heal Sci. 2016; 4: 1315-1319.
56. Raja WW, Khan DSH. Estimation of some phytoconstituents and evaluation of antioxidant activity in Aegle marmelos leaves extract. J Pharmacogn Phytochem. 2017; 6: 37-40.
57. Asghar N, Mushtaq Z, Arshad MU, Imran M, Ahmad RS, Hussain SM. Phytochemical composition, antilipidemic and antihypercholestrolemic perspectives of Bael leaf extracts, Lipids Health Dis. 2018; 17: 68.
58. Gade R, Deshmukh A, Patil M, Pensalwar S, Virshette S, Gade CR. Comparative study of phytochemical analysis and extractive value of Aegle marmelos, Bauhinia racemosa and Psidium guajava. J Pharmacogn Phytochem. 2018; 7: 2904-2907.
59. Veer B, Singh R. Phytochemical screening and antioxidant activities of Aegle marmelos Anal Chem Lett. 2019; 9: 478-485.
60. Sahu A, Kar B, Deepthi K, Pallath K, Dakni S, Niharika SPN, et al. Gas chromatography and mass spectroscopy analysis and phytochemical characterization of Aegle marmelos (Bael) leaf, Stem and its screening of antimicrobial activity. GSC Biol Pharm Sci. 2019; 8: 122-130.
61. Seemaisamy R, Faruck L, Gattu S, Neelamegam R, Bakshi H, Rashan L, et al. Anti-microbial and anti-cancer activity of Aegle marmelos and gas chromatography coupled spectrometry analysis of their chemical constituents. Int J Pharm Sci Res. 2019; 10: 373-380.
62. Anandhu KS, Jose M, Kuriakose S, Jayalakshmi PM. Phytochemical analysis and in vitro antidiabetic activity of aqueous extract of Lagerstroemia speciosa and Aegle marmelos. Res J Pharm Technol. 2021; 14: 4697-4701.
63. Ahmad W, Amir M, Ahmad M, Ali A, Ali A, Wahab S, et al. Aegle marmelos leaf extract phytochemical analysis, cytotoxicity, in vitro antioxidant and antidiabetic activities, Plants (Basel, Switzerland). 2021; 10: 2573.
64. Sharma A, Singh T, Pathak D, Virmani T, Kumar G, Alhalmi A. Antidepressive-like effect of Aegle marmelos leaf extract in chronic unpredictable mild stress-induced depression-like behaviour in rats. Biomed Res Int. 2022; 2022: 6479953.
65. Kumar DR, Awasthi K. Phytochemical analysis of Aegle marmelos leaves: A comparative study. Eur Chem Bull. 2023; 12: 3576-3582.
66. Antram KM, Ashokrao MR. Phytochemical evaluation and antimicrobial activity of leaves of Aegle marmelos (Bael). Int J Res Anal Rev. 2024; 11: 137-142.
67. Sharma GN, Dubey SK, Sati N, Sanadya J. Phytochemical screening and estimation of total phenolic content in Aegle marmelos Int J Pharm Clin Res. 2011; 3: 27-29.
68. Dheeba B, Sampathkumar P, Priya RRS, Kannan M. Phytochemical studies and evaluation of antioxidant potential of various extracts of Aegle marmelos Pharmacologyonline. 2010; 3: 831-839.
69. Meena AK, Ilavarasan R, Singh R, Parashar D, Motiwale M, Perumal A, et al. Evolution of pharmacological activity with molecular docking of active constituents present in roots and small branches of Aegle marmelos: A comparative study using HPLC, GC-MS, LC-MS. Phytomedicine Plus. 2022; 2: 100210.
70. Tripathi M, Kumar SP, SIkarwar R, Tiwari A, Dwivedi N, Tripathi S. Pharmacognostic evaluation of Bilva [Aegle marmelos (L.) Correa] root bark. Indian J Tradit Knowl. 2019; 18: 670-676.
71. Syahrir M, Kadola E, Salempa P. Isolation and identification of secondary metabolites in ethyl acetate extract from the Maja bark (Aegle marmelos). Pharmaciana. 2021; 11: 15-24.
72. Ponnachan P, Paulose CS, Panikkar K. Effect of leaf extract of Aegle marmelose in diabetic rats. Indian J Exp Biol. 1993; 31: 347-347.
73. Sharma S, Dwivedi SK, Varshney VP, Swarup D. Antihyperglycaemic and insulin release effects of Aegle marmelos leaves in streptozotocin–diabetic rats. Phyther Res. 1996; 10: 426-428.
74. Upadhya S, Shanbhag K, Suneetha G, Naidu MB. A study of hypoglycemic and antioxidant activity of Aegle marmelos in alloxan induced diabetic rats. Indian J Physiol Pharmacol. 2004; 48: 476-480.
75. Sabu M, Kuttan R. Antidiabetic activity of Aegle marmelos and its relationship with its antioxidant properties. Indian J Physiol Pharmacol. 2004; 48: 81-88.
76. Muralidharan L, Krishna K. Beneficial effects of Aegle marmelos leaves on blood glucose levels and body weight changes in alloxan-induced diabetic rats. J Med Plants Stud. 2014; 2: 46-49.
77. Arumugam S, Kavimani S, Kadalmani B, Ahmed ABA, Akbarsha MA, Rao MV. Antidiabetic activity of leaf and callus extracts of Aegle marmelos in rabbit. ScienceAsia. 2008; 34: 317-321.
78. Narendhirakannan RT, Subramanian S. Biochemical evaluation of the protective effect of Aegle marmelos (L.), Corr. leaf extract on tissue antioxidant defense system and histological changes of pancreatic beta-cells in streptozotocin-induced diabetic rats. Drug Chem Toxicol. 2010; 33: 120-130.
79. Bhatti R, Sharma S, Singh J, Ishar MPS. Ameliorative effect of Aegle marmelos leaf extract on early stage alloxan-induced diabetic cardiomyopathy in rats. Pharm Biol. 2011; 49: 1137-1143.
80. Panaskar SN, Joglekar MM, Taklikar SS, Haldavnekar VS, Arvindekar AU. Aegle marmelos Correa leaf extract prevents secondary complications in streptozotocin-induced diabetic rats and demonstration of limonene as a potent antiglycating agent. J Pharm Pharmacol. 2013; 65: 884-894.
81. Ferdous N, Karim MR, Khatun S. Antihyperglycemic and antihyperlipidemic effects of the alcoholic extracts of Aegle marmelos leaves. Int J Biosci. 2014; 4: 353-360.
82. Bhavani R, Rajeshkumar S. Anti-hyperglycemic activity of alcoholic leaf extract of Aegle marmelos (Linn.) on alloxan induced diabetic rats. Int J Pharma Sci Res. 2014; 5: 56-62.
83. Ansari P, Afroz N, Jalil S, Azad SB, Mustakim MG, Anwar S, et al. Anti-hyperglycemic activity of Aegle marmelos (L.) corr. is partly mediated by increased insulin secretion, α-amylase inhibition, and retardation of glucose absorption. J Pediatr Endocrinol Metab. 2017; 30: 37-47.
84. Mathur R, Sehgal R, Rajora P, Sharma S, Kumar R, Mathur S. Aegle marmelos impedes onset of insulin resistance syndrome in rats provided with drinking fructose from weaning to adulthood stages of development-a mechanistic study. Can J Physiol Pharmacol. 2017; 95: 572-579.
85. Mudi SR, Akhter M, Biswas SK, Muttalib MA, Choudhury S, Rokeya B, et al. Effect of aqueous extract of Aegle marmelos fruit and leaf on glycemic, insulinemic and lipidemic status of type 2 diabetic model rats. J Complement Integr Med. 2017; 14: 20160111.
86. Aggarwal H, Nair J, Sharma P, Sehgal R, Naeem U, Rajora P, et al. Aegle marmelos differentially affects hepatic markers of glycolysis, insulin signalling pathway, hypoxia, and inflammation in HepG2 cells grown in fructose versus glucose-rich environment. Mol Cell Biochem. 2018; 438: 1-16.
87. Siddiqui MS, Sharma G, Sharma A. Anti-diabetic and nephrotoxicity effect of Aegle marmelos leaf on alloxan-induced diabetic rat. Int J Res Pharm Sci. 2020; 11: 3966-3971.
88. Birudu R, Pamulapati P, Manoharan S, Manoharan S. Evaluation of biochemical changes in diabetic rats treated with Aegle marmelos (L.) methanolic leaf extract. Pharmacognosy Res. 2020; 12: 127-130.
89. Birudu RB, Pamulapati P, Manoharan SK. Effects of Aegle marmelos (L.) methanolic leaf extracts on biochemical parameters in diabetic rats. J Reports Pharm Sci. 2021; 10: 209-215.
90. Ibrahim M, Parveen B, Zahiruddin S, Gautam G, Parveen R, Khan MA, et al. Analysis of polyphenols in Aegle marmelos leaf and ameliorative efficacy against diabetic mice through restoration of antioxidant and anti-inflammatory status. J Food Biochem. 2022; 46: e13852.
91. Venkatesan S, Rajagopal A, Muthuswamy B, Mohan V, Manickam N. Phytochemical analysis and evaluation of antioxidant, antidiabetic, and anti-inflammatory properties of Aegle marmelos and its validation in an in-vitro cell model. Cureus. 2024; 16: e70491.
92. Kamalakkanan N, Rajadurai M, Prince PSM. Effect of Aegle marmelos fruits on normal and streptozotocin-diabetic Wistar rats. J Med Food. 2003; 6: 93-98.
93. Kamalakkannan N, Prince PSM. Hypoglycaemic effect of water extracts of Aegle marmelos fruits in streptozotocin diabetic rats. J Ethnopharmacol. 2003; 87: 207-210.
94. Kesari AN, Gupta RK, Singh SK, Diwakar S, Watal G. Hypoglycemic and antihyperglycemic activity of Aegle marmelos seed extract in normal and diabetic rats. J Ethnopharmacol. 2006; 107; 374-379.
95. Sharma AK, Bharti S, Goyal S, Arora S, Nepal S, Kishore K, et al. Upregulation of PPARγ by Aegle marmelos ameliorates insulin resistance and β-cell dysfunction in high fat diet fed-streptozotocin induced type 2 diabetic rats. Phytother Res. 2011; 25: 1457-1465.
96. Gandhi GR, Ignacimuthu S, Paulraj MG. Hypoglycemic and β-cells regenerative effects of Aegle marmelos (L.) Corr. bark extract in streptozotocin-induced diabetic rats. Food Chem Toxicol. 2012; 50: 1667-1674.
97. Kumari K, Samarasinghe K, Suresh TS. Hypoglycaemic effect of the traditional drink, the water extract of dried flowers of Aegle marmelos (L.) Correa (bael fruit) in Wistar rats. Indian J Tradit Knowl. 2013; 12: 384-389.
98. Abdallah IZA, Salem IS, Abd El-Salam NAS. Evaluation of antidiabetic and antioxidant activity of Aegle marmelos Correa fruit extract in diabetic rats. Egypt J Hosp Med. 2017; 67: 731-741.
99. Hafizur RM, Momin S, Fatima N. Prevention of advanced glycation end-products formation in diabetic rats through beta-cell modulation by Aegle marmelos. BMC Complement Altern Med. 2017; 17: 227.
100. Haimed AYS, Sharma K, Kumar Jha D. Anti-type I diabetic activity of the methanolic extract of Aegle marmelos on streptozotocin induced rat model. J Pharm Res Int. 2022; 34: 83761.
101. Narender T, Shweta S, Tiwari P, Papi Reddy K, Khaliq T, Prathipati P, et al. Antihyperglycemic and antidyslipidemic agent from Aegle marmelos. Bioorg Med Chem Lett. 2007; 17: 1808-1811.
102. Prajapat R, Gupta V, Soni B, Choudhary D, Ram V, Bhhandari A. Extraction and isolation of marmelosin from Aegle Marmelos, synthesis and evaluation of their derivative as antidiabetic agent. Der Pharm Lett. 2012; 4: 1085-1092.
103. Sankhla A, Sharma S, Sharma N. Hypoglycemic effect of bael patra (Aegle marmelos) in NIDDM patients. J Dairying Foods Home Sci. 2009; 28: 233-236.
104. Sharma P, Sharma S. A randomised, double-blind, placebo-controlled trial of “Aegle marmelos” supplementation on glycaemic control and blood pressure level in type 2 Diabetes mellitus. Aust J Med Herbal. 2013; 25: 141-145.
105. Sharma K, Shukla S, Chauhan ES. Evaluation of Aegle marmelos (Bael) as hyperglycemic and hyperlipidemic diminuting agent in type II Diabetes mellitus Pharma Innov J. 2016; 5: 43-46.
106. Nigam V, Nambiar VS. Aegle marmelos leaf juice as a complementary therapy to control type 2 diabetes – Randomised controlled trial in Gujarat, India. Adv Integr Med. 2019; 6: 11-22.
107. Vijaya C, Ramanathan M, Suresh B. Lipid lowering activity of ethanolic extract of leaves of Aegle marmelos (Linn.) in hyperlipidaemic models of Wistar albino rats. Indian J Exp Biol. 2009; 47: 182-185.
108. Devi K, Sivaraj A, Kumar P, Ahmed K, Sathiyaraj K, Kumar BS, et al. Hypolipidemic effect of Aegle marmelos leaf extract in streptozotocin (STZ) induced diabetic male albino rats. Int J PharmTech Res. 2010; 2: 259-265.
109. Bhuvaneswari R, Sasikumar K. Antihyperlipidemic activity of Aegle marmelos (L) Corr., leaf extract in triton WR- 1339 induced hyperlipidemic rats. Pharm Glob Int J Compr Pharm. 2013; 4: 1-3.
110. Suriyamoorthy P, Rosaland M, Mary F, Subrhamanian H, Kanagasapabathy D. Anti hyperlipidemic effect of aqueous extract of Aegle marmelos and Camellia sinensis in oil fed hyperlipidemic rats. Int J Pharm Pharm Sci. 2014; 6: 338-341.
111. Krupanidhi AM, Kalleshappa CM, Chanchi AR, Dabadi P, Akshara A. Antihyperlipidemic activities of isolated bio compounds of Aegle marmelos. IOSR J Pharm Biol Sci. 2016; 11: 42-45.
112. Aziz M, Ayub TE, Chowdhury S, Debnath R, Islam F, Ahmed F. Assessment of Aegle marmelos fruit pulp as lipid lowering agent in Type 2 diabetic adults. J Army Med Coll Jashore. 2024; 5: 3-6.
113. Jagetia GC, Venkatesh P, Baliga MS. Evaluation of the radioprotective effect of Aegle marmelos (L.) Correa in cultured human peripheral blood lymphocytes exposed to different doses of γ-radiation: A micronucleus study. Mutagenesis. 2003; 18: 387-393.
114. Gheisari HR, Amiri F, Zolghadri Y. Antioxidant and antimicrobial activity of Iranian bael (Aegle marmelos) fruit against some food pathogens. Int J Curr Pharm Res. 2011; 3: 85-88.
115. Krushna GSS, Kareem MA, Reddy VD, Padmavathi P, Hussain SA, Kodidhela LD. Aegle marmelos fruit extract attenuates isoproterenol-induced oxidative stress in rats. J Clin Biochem Nutr. 2011; 50: 199-204.
116. Gupta N, Agrawal RC, Shrivastava V, Roy A, Prasad P. In vitro Antioxidant activity and phytochemical screening of Aegle marmelos Res J Pharmacogn Phytochem. 2012; 4: 80-83.
117. Prashanth SJ, Suresh D, Potty VH, Maiya PS. Antioxidant and reducing activities of bael (Aegle marmelos) extracts. Int J Process Post Harvest Technol. 2012; 3: 121-128.
118. Hamid K, Diba F, Urmi F, Uddin ME, Zohera FT, Habib MR. In vitro antioxidant and cytotoxicity screening of different bark extracts of Aegle marmelos J Appl Pharm Sci. 2012; 2: 92-95.
119. Reddy VP, Urooj A. Antioxidant properties and stability of aegle marmelos leaves extracts. J Food Sci Technol. 2013; 50: 135-140.
120. Nallamuthu I, Tamatam A, Khanum F. Effect of hydroalcoholic extract of Aegle marmelos fruit on radical scavenging activity and exercise-endurance capacity in mice. Pharm Biol. 2014; 52: 551-559.
121. Wali A, Gupta M, Mallick SA, Guleria S, Sharma M. Antioxidant potential and phenol profile of bael leaf (Aegle marmelos). Indian J Agric Biochem. 2015; 28: 138-142.
122. Wijewardana RMNA, Nawarathne SB, Wickramasinghe I, Gunawardane CR, Wasala WMCB, Thilakarathne BMKS. Retention of physicochemical and antioxidant properties of dehydrated bael (Aegle marmelos) and palmyra (Borassus flabellifer) fruit powders. Procedia Food Sci. 2016; 6: 170-175.
123. Kumar S, Bodla RB, Bansal H. Antioxidant activity of leaf extract of Aegle marmelos Correa ex Roxb. Pharmacogn J. 2016; 8: 447-450.
124. Rahman A, Imran H, Iqbal L, Taqvi SIH, Fatima N, Yaqeen Z. Dry and ripe fruit of Aegle marmelos. L: A potent source of antioxidant, lipoxygenase inhibitors and free radical scavenger. Pak J Pharm Sci. 2016; 29: 1127-1131.
125. Bristy NJ, Hasan AHM, Alam MN, Wahed TB, Roy P, Alam KMK. Characterization of antioxidant and cytotoxic potential of methanolic extracts of different parts of Aegle marmelos (L.). Int J Pharm Sci Res. 2017; 8: 1476-1484.
126. Chandrasekara A, Daugelaite J, Shahidi F. DNA scission and LDL cholesterol oxidation inhibition and antioxidant activities of Bael (Aegle marmelos) flower extracts. J Tradit Complement Med. 2018; 8: 428-435.
127. Pynam H, Dharmesh SM. Antioxidant and anti-inflammatory properties of marmelosin from Bael (Aegle marmelos); Inhibition of TNF-α mediated inflammatory/tumor markers. Biomed Pharmacother. 2018; 106: 98-108.
128. Vardhini S, Sivaraj C, Arumugam P, Himanshu R, Kumaran T, Baskar M. Antioxidant, anticancer, antibacterial activities and GCMS analysis of aqueous extract of pulps of Aegle marmelos (L.) Correa. J Pharmacol. 2018; 7: 72-78.
129. Perumal A, Krishna S, Biotek A. GC-MS analysis, antioxidant and antibacterial activities of ethanol extract of leaves of Aegle marmelos (L.) correa. J Drug Deliv Ther. 2018; 8: 247-255.
130. Nemkul CM, Bajracharya GB, Shrestha I. Phytochemical, antibacterial and DPPH free radical scavenging evaluations of the barks of Aegle marmelos (L.) Correa. J Pharmacogn Phytochem. 2018; 7: 1637-1641.
131. Parmar D, Apte M. Evaluation of seeds of an Indian sacred plant Aegle marmelos, for their antioxidant and cytotoxic potential. Int J Pharm Sci Res. 2022; 13: 3261-3274.
132. Pandey AK, Pande P. Evaluation of phytochemicals, anti-inflammatory and antioxidant potential of Aegle marmelos leaves. Adv Pharmacol Pharm. 2023; 11: 66-77.
133. Sahu K, Tiwari SP, Shrivastava P, Sharma S. Formulation and assessment of herbal formulation containing extracts of Aegle marmelos for antioxidant activity. Acta Biomed. 2024; 95: 808-822.
134. David JA, Rifkin WJ, Rabbani PS, Ceradini DJ. The Nrf2/Keap1/ARE pathway and oxidative stress as a therapeutic target in Type II Diabetes mellitus. J Diabetes Res. 2017; 2017: 4826724.
135. Behl T, Kaur I, Sehgal A, Sharma E, Kumar A, Grover M, et al. Unfolding Nrf2 in diabetes mellitus. Mol Biol Rep. 2021; 48: 927-939.
136. Raja SB, Murali MR, Devaraj SN. Differential expression of ompC and ompF in multidrug-resistant Shigella dysenteriae and Shigella flexneri by aqueous extract of Aegle marmelos, altering its susceptibility toward β-lactam antibiotics. Diagn Microbiol Infect Dis. 2008; 61: 321-328.
137. Rajaram A, Vanaja GR, Vyakaranam P, Rachamallu A, Reddy GV, Anilkumar A, et al. Anti-inflammatory profile of Aegle marmelos (L) Correa (Bilva) with special reference to young roots grown in different parts of India. J Ayurveda Integr Med. 2018; 9: 90-98.