Screening of antidiabetic and antioxidant potential along with phytochemicals of Annona genus: a review

Annona species can be found in the subtropical and tropical parts of the world. Because of their medicinal capabilities and highly exotic edible fruits, they are one of the most important members of the Annonaceae family. Isoquinolines, pyrimidine-β-carboline alkaloids, lectins, acetogenins, and volatile oils are among the active metabolites found in this genus, all of which have been shown to have anti-diabetic and antioxidant activities. The fundamental objective of this review was to summarize the antidiabetic and antioxidant activity based on reported secondary data from different plants of the genus Annona. These species include Annona cherimola, Annona squamosa, Annona macroprophyllata, Annona muricate, Annona reticulata, Annona carcans, Annona coriacea, Annona cornifolia, and Annona senegalensis. The Annona species investigated had significant antihyperglycemic and antioxidant properties. The available evidence, both in vitro and in vivo, confirms the ability of Annona species to treat diabetes in addition to producing oxidative damage.

species that have anti-diabetic and anti-oxidant capabilities.

Botanical distribution
Nine species of the Annona genus were characterized in this study, whose botanical representation is summarized in Table 1.

Annona cherimola
Annona cherimola Miller belongs to the genus Annona in the Annonaceae family in magnolias order, which is also provides edible fruit species. It is a steep, semi momentary but low bunched tree. The plant, highly prevalent in Ecuador and Peru is widely distributed throughout the tropics and subtropics of America, Africa, Asia, and even South Europe [8,9]. Alone or in combination with others, it has been used in Mexican Traditional medicine to treat several diseases like fever, cough, worms, headache, and inflammation. Currently, this is utilized in the treatment of diabetes [10][11][12].

Annona squamosa
Annona squamosa L., known as custard apple, generally is an endemic of the West Indies, and throughout India, it is well grown. Annona squamosa is renowned for its anti-diabetic properties among tribal men in and around Aligarh district's village in Uttar Pradesh [13].. There, native people make a mixture of 4-5 newly emerged leaves with five grains of black pepper early in the morning to treat diabetes. Continuing the therapy ensured up to 80% positive results [13].

Annona macroprophyllata
Annona macroprophyllata Donn. Sm. is yet another species that is known to be classified under the genus Annona. It is referred to as "ilama," a common tree in central Mexico. It is familiar by "papauce" or "anona blanca" in the Southeast [14,15]. Its fruits are consumed as food, but its leaves are used as anticonvulsants [16].
In traditional medicine, it is also prescribed as an analgesic and anti-inflammatory agent [17].

Annona reticulata
Annona reticulata in India is typically known as "custard apple" or "heart bullock." It is locally useful in the treatment of epilepsy, dysentery, cardiac problem, parasite and worm infection, constipation, and bacterial infection [19].

Annona carcans
Annona carcans is a member of the Annonaceae family, which comprises woody, arbustive, or arborist plants and many fruits [21,31] and also known as Annona amambayensis Hassl. It is commonly known as "araticum-caga -reso" or "cortic -a reso." It is used as purgative in folk medicine, and found in the Brazil [21].

Annona coriacea
Annona coriacea is a fruit tree native to Brazil. The ecoregions of Cerrado, Caatinga, and Pantanal are part of their original habitat. Buildings and toys are made from the wood. Synonyms of this plant are Annona coriacea var. cuneata R.E. Fr and Annona geraensis Barb. Rodr [32].

Annona cornifolia
Annona cornifolia is part of the family of Annonaceae and Annona walkeri S.Moore is used as a synonym of this plant. It is commonly referred to as "aratian-mirim." The fruit pulp is mature, orange, and sweet and aromatic. The green fruit is well-known for its ability to treat ulcers [24].

Annona senegalensis
Annona senegalensis, referred to as sour soup (English), abo (Yoruba, Western Nigeria), and uburuocha (Igbo, Eastern Nigeria), is commonly found in Nigeria [25]. The bark of the stem is silvery gray or gray-brown. The leaves are simple, alternate, and oblong, and they're hairless on top with brownish hair on the underside. Leaves are used to treat diarrhea, joint disease, respiratory disease, conjunctivitis, burns, snakebite sores, trypanosomiasis, jaundice, bleeding, female barrenness, seizures, asthenia, and fever [25].

Phytochemicals
Nine species of the Annona genus were characterized in this study, whose phytochemical study is summarized in Table 2.

Biological activity Antidiabetic activity
Annona cherimola Ethanol extract of Annona cherimola was tested in alloxan-induced type-2 diabetic rats to study the antidiabetic effect of the leaves of Annona cherimola. Plant extract administered at dose 300 mg/kg on alloxan-induced anti-hyperglycemic rats decreased blood glucose level 331.5 mg/dl to 149.2 mg/dl 4 h after the administration (P < 0.05) compared to the acarbose (151.3 mg/dl), an alpha glucosidase inhibitor. The above study proved that rutin, a flavonal glucoside present at the ethanol extract, acts as an alpha glucosidase inhibitor like acarbose, which contributes significantly to the decrease of blood glucose level [59] (Table 3).
Annona squamosa A research study was conducted using the aqueous extract of Annona squamosa in streptozotocin-nicotinamide type 2 diabetic rats where symptomatic decrease in plasma glucose level was seen for oral glucose tolerance test from 30 min onwards compared to 250 mg/kg and 500 mg/kg doses administered in normal rats. The result ensured that, aqueous extract of A. squamosa has significant potential of antihypoglycemic effect. In that study, the antihyperglycemic effect of that aqueous extract was independent of the dose since no significant difference in results were observed between 250 and 500 mg/kg extract [61].
Annona macroprophyllata A study in Mexico stated that Annona muricata, Annona glabra, and Annona cherimola are used as antidiabetic plants. Based on their research, another study is carried out on Annona macroprophyllata as it is a similar species of the Annona genus. Kamalakkannan, N., & Prince, P. S. M. (2006) isolated a flavonol compound rutin from Annona microprophyllata extract which was tested on hyperglycemic rats, and was found to inhibit fasting plasma glucose level, while the insulin and the antioxidant levels were increased [70,71]. Rutin also reduced the alpha-glucosidase activity in both in vivo and in vitro studies [72]. They demonstrated the same yeast alpha-glucosidase behavior as -Antioxidant activity not reported. --

Peel, Seeds, Pulp
Ethanol and aqueous extract express in vitro antioxidant potential.

Annona coriacea Seeds, Pulp
• DPPH and beta carotene bleaching test showed free radical scavenging activity of 31.53%, 51.59% respectively in in vitro model.
DPPH, Beta-carotene bleaching and ABTS radical cation. [68] Annona carcans Pulp, Seeds, Leaves Potent in vitro antioxidant activity was shown by pulp, leaves and seeds extract and fractions.
Annona muricata Research has shown that a single dose of 100 mg/kg and 200 mg/kg of an aqueous extract of Annona muricata did not significantly affect blood glucose levels in regular rats. The extract administration of single dosing effectively lowered the blood glucose levels in hyperglycemic rats after 2 h of dosing. Plant extracts at 100 mg/kg and 200 mg/kg reduced blood glucose levels by 31.77% and 45.77% after injection of streptozotocin for 14 days, respectively. Repetitive administering of Annona muricata aqueous extract at all doses led to a substantial decline of near-normal blood glucose levels on day 7. Also, 76.56% and 58.3% reductions were shown at doses 100 mg/kg and 200 mg/kg, respectively, compared to the initial value. The result also showed that before streptozotocin injection, plant extract's daily administration did not inhibit streptozotocin-induced hyperglycemia during 3 days. However, a significant drop in blood glucose levels during 14 days without treatment has shown that plant extract can work long. The findings also indicate decreased bodyweight loss, fluid and water intake in streptozotocin-induced rats, and blood glucose levels decreased during the four weeks of daily extract administration within one week. The presence of tannins and flavonoids in the phytochemistry of Annona muricata confirmed their hypoglycemic activity [64].
Annona reticulata Various fractions of 100 mg/kg of ethyl acetate, methanol, and residual fractions were obtained from Annona reticulata leaves hydro-alcoholic extract and was examined to determine its reduction of blood glucose level potential in streptozotocin-induced diabetic rats. After 14 days of treatment, fasting blood glucose levels decreased in hyperglycemic rats. Fasting blood glucose level decreased by 3.67%, 14.03%, 47.69%, and 50.93% for treatment with residual fraction, methanol fraction, ethyl acetate fraction, and standard drug. The study exhibited a significant (P < 0.001) decreased blood glucose level in comparison to the diabetic control group. The blood glucose levels decreased by a residual fraction and methanol fraction from 417.83 to 402.50 mg/dl and 432.33 to 371.67 mg/dl. Compared to diabetic control groups, these levels were not substantial and the fraction of ethyl acetate was capable of controlling the increase in blood glucose and also attenuating secondary variables with hyperglycemia due to streptozotocin [73].

Antioxidant activity
Annona cherimola The cherimoya skin, flesh, and juice were isolated from Annona cherimola and analyzed for antioxidant content using the oxygen radical absorbance capacity (ORAC) assay. The juice showed the highest antioxidant activity, while the flesh exhibited the lowest [60]. Gupta-Elera et al. stated that the cherimoya juice extract enhanced the antioxidant uptake against the burkitt's lymphoma and colon cancer cell lines [60].
Annona crassiflora Ethanol and aqueous extract of Annona crassiflora peel, seed, and pulp were screened for in vitro antioxidant activity, whereas antioxidants were measured using DPPH and lipid peroxidation assay. The ethanol extract exhibited substantial and concentration-based scavenging activity in DPPH, together with lipid peroxidation activity inhibition in mice's model. Furthermore, the in-vitro antioxidant activity of peel, seed, and pulp exposed noticeable total phenolic content (TPC), whereas the ethanol peel extract contains the maximum TPC [67].
Annona muricate, A. squamosa, A. reticulata Using different in vitro models (DPPH, ABTS, nitric oxide, superoxide, hydroxyl radical, and lipid peroxidation), the antioxidant potential of leaves of three other species of Annona (Annona muricata, Annona. squamosa, Annona reticulata) were studied. Annona muricata ethanol extract displayed a maximum scavenging activity (90.05%) at 500 μg/ml for ABTS, followed by hydroxyl radical scavenging (85.88%) and nitric oxide scavenging (72.60%), whereas a moderate action observed for lipid peroxidation assay. Annona squamosa extract showed the least inhibition in all in vitro antioxidant models. The ethanol extract of Annona reticulata showed maximum inhibition of 89.37% in DPPH, 89.05% in ABTS, 71.10% in nitric oxide, 77.72% in hydroxyl radical, 80.88% in superoxide radical, and 35.54% in lipid peroxidation at 500 μg/ml. The ethanol extract of Annona squamosa showed maximum inhibition of 88.77% in DPPH, 88.06% in ABTS, 68.03% in nitric oxide, 79.79% in hydroxyl radical, 77.21% in superoxide radical, and 50.83% in lipid peroxidation at 500 μg/ml. These findings indicate that Annona muricata extracts have strong in-vitro antioxidants efficacy compared to Annona squamosa and Annona reticulata leaves, which show the function as an effective, free radical scavenger, increasing its therapeutic value [62,65].
Annona coriacea Seeds and pulp extracts of fruit Annona coriacea and Annona sylvatica were tested for antioxidant potential. DPPH, Beta-carotene bleaching, and ABTS methods were applied to determine the antioxidant activity. The pulp and seeds of the fruits were extracted by using methanol/water (8:2) for maceration. An excellent extraction yield was shown in the seeds and pulp extracts of fruit Annona coriacea (14.5 and  [21].
Annona cornifolia Annona cornifolia has been tested for its antioxidant potential against DPPH using seed ethanol extract fractions containing acetogenins, and these compounds exhibited a robust antioxidant activity at 10-100 μg/ml in DPPH assay with a lower IC 50 [41].

Conclusion
This review involves nine of the Annonaceae species and highlights the antidiabetic and antioxidant ability of Annona plants. Annona species are widely distributed worldwide, while many species are used for both medicinal and food use. As the global scenario is now heading toward non-toxic herbal products with therapeutic applications, comprehensive research into this gold mine of centuries-old expertise should be emphasized. The majority of the plants in this study demonstrated that their antidiabetic and antioxidant activity was potent. Five species were reviewed as having antidiabetic activity, and they demonstrated potent antihyperglycemic effect. Furthermore, antioxidant activity was reviewed from ten species, and they showed potent antioxidant activity with different in vitro models. Though several in vitro studies have confirmed the antioxidant and antidiabetic potential of the species of the Annona genus, still only a few in vivo and clinical trials were performed to date to validate the in vitro outcomes. So their potential in animal and human models should be assessed in the future. Furthermore, the mechanism of action by which they confer antidiabetic and antioxidant activities is still not developed elaborately. This should also be developed in further studies. Moreover, it can be concluded that, since natural medicines have the least side effects and are considered safe for human health, they can substantially substitute synthetic drugs in the future.